Do dietary interventions exert clinically important effects on the bioavailability of β-lactam antibiotics? A systematic review with meta-analyses

Agnieszka Wiesner; Paweł Zagrodzki; Paweł Paśko

doi:10.1093/jac/dkae028

. 2024 Feb 9;79(4):722–757. doi: 10.1093/jac/dkae028

Do dietary interventions exert clinically important effects on the bioavailability of β-lactam antibiotics? A systematic review with meta-analyses

Agnieszka Wiesner ^1,², Paweł Zagrodzki ³, Paweł Paśko ^4,^✉

PMCID: PMC11528546 PMID: 38334389

Abstract

Background

Managing drug–food interactions may help to achieve the optimal action and safety profile of β-lactam antibiotics.

Methods

We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 β-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices.

Results

Eighteen of 25 β-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or C_max decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or C_max increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed β-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor).

Conclusions

Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient’s health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Introduction

Background

Due to the broad spectrum of activity, against both Gram-positive and Gram-negative bacteria, the possibility of oral administration, availability in outpatient treatment, high tolerability and relatively good safety profile, β-lactams remain the most commonly prescribed antibiotic class worldwide, with numerous clinical indications.¹ The main groups of orally administered β-lactam antibiotics are penicillins and cephalosporins, whereas carbapenems (except tebipenem) and monobactams (except tigemonam) are used intravenously. All β-lactam antibiotics inhibit the last step in synthesizing peptidoglycan—a vital component of the bacterial cell wall that maintains its mechanical stability.²

The growing development of resistant bacteria and the rapid spreading of resistance mechanisms threaten the use of β-lactams. The basis of resistance to β-lactams is multifactorial. Bacteria may produce β-lactamases—enzymes that degrade β-lactam antibiotics, modify target-site penicillin-binding proteins (PBPs) to lower their affinity to antibiotics or pump the antibiotic out of the periplasmic space.^1,2 Additionally, Gram-negative bacteria can reduce the permeability of their outer membranes (OMs) by, for example, changing the number, type, or conformation of OM proteins—porins.³

One of the proposed ways to fight antimicrobial resistance is to optimize the use of antibiotics.⁴ Specific indices have been identified that link pharmacokinetic (PK) antibiotic exposure and pharmacodynamic (PD) efficacy. As the bactericidal action of β-lactams is time-dependent—the duration of exposure to the antibiotic is crucial for bacterial eradication—the most relevant PK/PD index for this group is T_>MIC (time above the MIC).⁵ It was demonstrated for β-lactams that T_>MIC was a vital index, with magnitudes of 50%–100% for preventing the emergence of resistance.⁶

To achieve optimal antibiotic efficacy, following a dosing schedule that ensures the drug’s appropriate PK and PD parameters and avoiding underdosing is essential.⁷ The way of taking medications with food is one of the factors that may either negatively or positively impact drug bioavailability, the effectiveness of therapy, and patient safety. Drug–food interactions can, for example, improve or alter drug absorption, reduce or potentiate the effect of pharmacotherapy, and contribute to an increase or decrease in the frequency and severity of adverse drug reactions.⁸ Therefore, the appropriate use of antibiotics in relation to food may help optimize the treatment’s effectiveness and safety profile.

Existing evidence

We found two systematic reviews addressing the topic of interactions between antibiotics and food, beverages, antacids or mineral supplements. In the first one, from 2018, Pino-Marin et al.⁹ covered drug–food and drug–drug interactions. However, the authors included only 42 studies and used very general keywords (‘antimicrobial agents’ and ‘food–drug interactions’). Moreover, only one included study referred to β-lactam antibiotics, describing the interaction between amoxicillin and antacids.¹⁰ In the second systematic review from 2020, Mergenhagen et al.¹¹ investigated interactions between antibiotics and alcohol. The authors provided detailed and current evidence on this topic; hence, we decided not to include studies evaluating the impact of alcohol in our analysis.

In light of the existing evidence, there is a need for an up-to-date, comprehensive, systematic review that considers the effect of food, beverages, antacids and mineral supplements on particular β-lactam antibiotics.

Objectives

This systematic review was the first of a series of studies evaluating interactions between antibiotics and food. The main objectives were to investigate the impact of food, beverages, antacids, and mineral supplements on the PK parameters or PK/PD indices of orally taken β-lactam antibiotics, to identify the clinically significant drug–food interactions, and to propose practical guidelines on how to take β-lactam antibiotics with food, beverages, antacids and mineral supplements.

Methods

When conducting and reporting the review, we adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. In November 2022, we registered the systematic review protocol in the OSF Registries (https://doi.org/10.17605/OSF.IO/V2EBJ). In Supplementary Material 1 (available as Supplementary data at JAC Online), we have provided the full text of the protocol.

Eligibility criteria

Types of studies

All studies describing or investigating the impact of food, beverages, antacids or mineral supplements on PK parameters or PK/PD indices of orally taken β-lactam antibiotics were considered for inclusion. We made no limitations regarding study type, language, year or number of participants. We excluded reviews, in vitro and in silico studies, and studies performed on animals.

Types of participants

We applied no restrictions regarding study participants’ characteristics (e.g. race, gender, age, health state).

Types of interventions

As an experimental intervention, we considered the intake of oral β-lactam antibiotic in a fed state—with or after a meal (e.g. high-fat, low-fat, high-protein etc.), beverage (e.g. juice, milk, coffee), antacid or mineral supplement.

The control intervention for meals, antacids and mineral supplements was the intake of oral β-lactam antibiotics in a fasting state (before a meal, antacid or mineral supplement), whereas for beverages, it was the administration of oral β-lactam antibiotics on an empty stomach (before a liquid) or with water.

We made no restrictions concerning the formulation and dose of an orally taken drug or type of meal/antacid/mineral supplement. For beverages, we excluded studies involving alcohol.

Types of outcomes

For PK parameters, the primary outcomes of interest were pre- and postprandial values of AUC (area under the plasma drug concentration–time curve), which reflects the extent of exposure to a drug, and C_max (the maximum or peak serum drug concentration) and T_max (the time to reach C_max) that both refer to the rate of drug absorption. To link antibiotic PK exposure and antibacterial PD response, we also searched for studies reporting the postprandial changes in PK/PD indices. As the bactericidal action of β-lactams is time-dependent, the most relevant indices were the time above the MIC₅₀, MIC₉₀ or MIC (T_>MIC50, T_>MIC90 or T_>MIC) and the time to reach the MIC₅₀, MIC₉₀ or MIC.

The secondary outcomes were pre- and postprandial values of other PK parameters (if given), e.g. t_½ (half-life), V_d (volume of distribution), CL (clearance), % of the urinary recovery, % of the urinary excretion etc.

Information sources and search strategy

We performed the search in three databases: MEDLINE (via PubMed), Embase and Cochrane Library, covering reports from the date of database inception to the date of the search (November and December 2022). Further reports were found by checking the product characteristics of β-lactam antibiotics registered on the global market and the reference lists of previously identified studies. We identified additional records classified as grey literature via a Google Scholar search.

During the searching process, we applied the following keywords and phrases: β-lactam antibiotics names combined with ‘food’, ‘food–drug interaction’, ‘drug–food interaction’, ‘fed’, ‘fasted’, ‘fasting’, ‘postprandial’, ‘meal’, ‘breakfast’, ‘dietary supplement’, ‘antacids’, ‘milk’, ‘coffee’ and ‘juice’. When possible, MeSH terms and Emtree terms were used. In PubMed, Embase and Cochrane Library, we restricted the keyword search to titles and abstracts, whereas in Google Scholar to titles only. The search strategy is described in detail in Supplementary Material 2.

Selection process

The database search results were exported and uploaded to the Rayyan software, where the selection process occurred. In the first step, two review authors (A.W. and P.P.) independently screened the titles and abstracts of each search record and selected those eligible for inclusion in the systematic review. In the second step, the authors uploaded and thoroughly read the full texts of the chosen articles (if available) and decided on their inclusion. After each step, disagreements were resolved by discussion and consensus or, if necessary, by consulting a third review author (P.Z.).

Data collection process

Two authors (A.W. and P.P.) individually extracted data from included studies into an Excel spreadsheet. We collected the following data items: (i) regarding study characteristics—the first author, study year, study design and study language; (ii) regarding study participants—the number of participants, participants’ health state, age, gender and race; (iii) regarding study intervention—β-lactam antibiotic name, dose, formulation, type of meal, beverage, antacid or mineral supplement, the time between the intake of a drug and a meal, beverage, antacid or mineral supplement, quantitative food composition (caloric load, percentage or weight amount of fat, carbohydrates and protein) and qualitative meal composition; and (iv) regarding study outcomes—pre- and postprandial values of PK parameters or PK/PD indices (listed in the ‘Types of outcomes’ section), % postprandial change of PK parameters or PK/PD indices.

The data collection process was supervised by P.Z., who resolved any discrepancies.

Assessment of risk of bias in individual studies

Two authors (A.W. and P.P.) individually evaluated the quality of each study included in the systematic review. Depending on the study type, we used different tools to assess the risk of bias, such as Version 2 of the Cochrane risk-of-bias tool for parallel trials (RoB 2),¹² the Cochrane risk-of-bias tool for crossover studies,¹³ and the NIH quality assessment tool for before–after (pre–post) studies.¹⁴ We discussed any differences in the assessment and reached a consensus.

Data synthesis

We performed quantitative analyses for each β-lactam antibiotic if two or more food-effect studies with specified and comparable study designs were available, e.g. parallel and crossover studies were not synthesized in the same meta-analysis, and neither were randomized and non-randomized studies.

Meta-analyses were conducted in Review Manager (RevMan) Version 5.4.1, The Cochrane Collaboration, 2020. As the heterogeneity of studies was predicted to be high, we used the random-effects model with the inverse variance method to calculate study weights. The results of meta-analyses were visualized as forest plots.

For drugs for which meta-analyses could not be performed due to missing PK data or the unknown/variable study designs, we summarized and discussed the results of available studies.

The effect measures

The effect measures were the ratio of means (fed versus fasted) for AUC and C_max and mean difference (fed versus fasted) for T_max. We assumed a 90% CI, as indicated by the FDA for bioequivalence studies. For AUC, the adopted unit was µg·h/mL, for C_max it was µg/mL, and for T_max it was h. If values were reported in other units, we transformed them accordingly.

If effect measures were expressed as geometric means (with CIs or the coefficient of variation), we converted them to arithmetic means and standard deviations using the method designed by Higgins et al.¹⁵ When median values and range or IQR were reported, we used the approach proposed by Wan et al.¹⁶ to estimate the arithmetic mean and standard deviation.

Assessment of heterogeneity

To identify and measure the heterogeneity of studies included in the meta-analyses, we calculated I² statistics and the chi-squared test. I² < 25%, together with a P value from the chi-squared test of >0.1, indicated low heterogeneity; 25% < I² < 75% indicated moderate heterogeneity; and I² > 75% and P < 0.1 indicated high heterogeneity.¹⁷

Additional analyses

In cases of moderate or high heterogeneity, we performed subgroup analyses. Grouping variables were, for example, drug formulation, type of meal, participants’ health state, or risk of bias in individual studies. The grouping variables differed between the meta-analyses, depending on the characteristics of the included studies. According to the instructions in the Cochrane Handbook for Systematic Reviews of Interventions, subgroup analyses are justified when at least 10 studies are in a meta-analysis. However, due to few studies being available, we conducted a subgroup analysis if at least two studies were included in each subgroup.

To assess the robustness of the synthesized results, we conducted sensitivity analyses (by changing the analysis model from random to fixed).

For meta-analyses including 10 or more studies, we investigated publication bias (by generating and interpreting funnel plots).

Judgement of clinical relevance

For AUC and C_max, we adopted the FDA criteria for bioequivalence to predict whether the interaction with food is relevant to clinical practice. We judged interaction as follows: clinically important—if we obtained statistically significant results and the ratio of means (fed versus fasted) did not fall within the range of 0.8–1.25; possibly clinically important—when the ratio of means was within the range, but the lower or upper limit of the CI fell outside the range; probably not clinically important—if both the ratio of means and CI limits were within the bioequivalence range; and not clinically important—when the meta-analysis produced statistically non-significant results.

For T_max, if the results of meta-analyses were statistically significant, we assumed that interaction with food could be clinically important when the mean difference between fed versus fasted was higher than 1 h.

Additionally, for clinically important interactions, we defined the interaction as having: a high impact—when the average AUC or C_max after the dietary intervention was lower by more than 40% or higher by more than 45%, and the results of studies were consistent; a moderate impact—when the average AUC or C_max after the dietary intervention decreased by 30%–40% or increased by 35%–45%, and/or the results of studies were conflicting; and a low impact—when the average AUC or C_max after the dietary intervention decreased by 20%–30% or increased by 25%–35%, and/or the results of studies were conflicting.

Results

Eligible studies

During the comprehensive databases search, we identified 14 225 records: 6771 in MEDLINE (via PubMed), 6036 in Embase and 1418 in Cochrane Library. Automation tools (Mendeley and Rayyan) were used to remove 8065 duplicates, and we deleted the other 924 duplicate records manually. In the next step, we thoroughly screened the titles and abstracts of the remaining 5236 papers. Of the remaining studies, 5024 did not address the research question or meet the exclusion criteria. Of the remaining 212 studies, we did not retrieve three^18–20 as full texts were unavailable, and abstracts did not contain sufficient information. Of the 209 reports assessed for eligibility, we excluded 68. Inter-rater reliability was almost perfect (% of agreement: 99.54%, Cohen’s kappa: 0913). The list of excluded studies, with reasons, is provided in Supplementary Material 3.

Additionally, we identified 466 records during a search in other information sources such as Google Scholar (428), summaries of product characteristics (SmPCs) (29), conference reports (1) and citation searching (8). Twenty-three records were sought for retrieval, and we did not retrieve three reports^21–23 as we could not find either the full text or comprehensive abstract. Of 20 reports assessed for eligibility, four studies from SmPCs were found to be duplicates of already retrieved papers, and 16 remaining reports were included.

Finally, our systematic review included 166 studies from 156 reports. In Figure 1, we present the flowchart of the search strategy.

Study characteristics

The open-label, crossover study is a study design recommended by the FDA for assessing the effect of food.²⁴ Such studies comprised only 52% of all those included in our systematic review. The remaining studies were longitudinal or parallel (19% for each design). For 15 (9%) included studies, the information provided did not define the exact design. Table 1 presents the list of studies included in the systematic review, whereas detailed study characteristics are provided in Supplementary Material 4. In separate tables, we have presented studies investigating the impact of food, antacids or mineral supplements, and beverages. We pooled studies for each drug and organized them by the type of intervention and drug formulation. Hence, some studies may appear in the table more than once if the impact of food on several drugs’ PK parameters or PK/PD indices was assessed or if different formulations or interventions were tested.

Table 1.

List of studies included in the systematic review

Study ID	Reference	Investigated drugs	Type of intervention	Randomized?	Study design	Source	Participants’ health state	Number of participants
Akimoto1994	²⁵	cefalexin	food	non-randomized clinical trial	open-label, parallel	article	with infection	56
Ali1980	²⁶	ampicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	4
Ali1981	²⁷	bacampicillin	food	non-randomized clinical trial	open-label, crossover	article	healthy	5
Barbhaiya1990	²⁸	cefaclor, cefprozil	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Barr1991	²⁹	ceftibuten	food	randomized clinical trial	open-label, crossover	article	healthy	18
Barr1995	³⁰	ceftibuten	food	randomized clinical trial	open-label, crossover	article	healthy	18
Bauer1976	³¹	ampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	11
Bergdahl1986	³²	flucloxacillin	food	non-randomized clinical trial	open-label, not specified	article	with infection	31
Blouin1989	³³	cefetamet pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	24
Blouin1990	³⁴	cefetamet pivoxil	antacid	randomized clinical trial	open-label, crossover	article	healthy	18
Bolme1995	³⁵	penicillin V	food	non-randomized clinical trial	open-label, parallel	article	healthy, with infection	47
Borin1995	³⁶	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	healthy	20
Borin1995_2	³⁷	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	healthy	11
Borin1995_3	³⁸	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	healthy	20
Chen1992	³⁹	cefuroxime axetil	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Cronk1960	⁴⁰	penicillin V	food	non-randomized clinical trial	open-label, parallel	article	healthy	45
Deppermann1989	¹⁰	amoxicillin, cefalexin	antacid	randomized clinical trial	open-label, crossover	article	healthy	10
Digenis2000	⁴¹	amoxicillin	food	non-randomized clinical trial	open-label, crossover	article	healthy	10
Ding2012	⁴²	cefalexin	mineral supplement	randomized clinical trial	open-label, crossover	article	healthy	12
diStefano1981	⁴³	cefadroxil	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	13
Ducharme1993	⁴⁴	cefetamet pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	18
Eckburg2019	⁴⁵	tebipenem pivoxil	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	83
Eden1997	⁴⁶	penicillin V	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	19
Eshelman1978	⁴⁷	ampicillin	food	randomized clinical trial	open-label, parallel	article	healthy	16
Everts2019	⁴⁸	flucloxacillin	food	non-randomized clinical trial	open-label, crossover	article	healthy	11
Faulkner1988	⁴⁹	cefixime	food	randomized clinical trial	open-label, crossover	article	healthy	20
Fernandez1973	⁵⁰	pivampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	15
Finkel1981	⁵¹	penicillin V	food	non-randomized clinical trial	open-label, parallel	article	with infection	47
Finn1987	⁵²	cefuroxime axetil	food	randomized clinical trial	open-label, crossover	article	healthy	12
Fujii1991	⁵³	cefdinir	food	no data	no data	article	no data	163
Fujii1991_2	⁵⁴	cefpodoxime proxetil	food	no data	no data	article	no data	60
Fujii1992	⁵⁵	cefprozil	food	non-randomized clinical trial	open-label, parallel	article	with infection	60
Fujimoto1985	⁵⁶	cefaclor	food	non-randomized clinical trial	open-label, crossover	article	healthy	3
Gardiner2018	⁵⁷	flucloxacillin	food	randomized clinical trial	open-label, crossover	article	healthy	12
Ginsburg1978	⁵⁸	cefadroxil	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	30
Ginsburg1979-1	⁵⁹	amoxicillin, ampicillin	beverage	non-randomized clinical trial	open-label, crossover	article	with infection	11
Ginsburg1979-2	⁵⁹	amoxicillin	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	13
Ginsburg1979_2	⁶⁰	cefradine	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	16
Ginsburg1981	⁶¹	cyclacillin	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	27
Ginsburg1982	⁶²	cefadroxil	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	15
Ginsburg1985	⁶³	cefuroxime axetil	beverage, food	non-randomized clinical trial	open-label, longitudinal	article	healthy, with infection	43
Ginsburg1985_2	⁶⁴	sultamicillin	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	20
Glynne1978	⁶⁵	cefaclor	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Gottfries1996	⁶⁶	amoxicillin	food	randomized clinical trial	open-label, crossover	article	healthy	6
Gower1969	⁶⁷	cefalexin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Guggenbichler1978	⁶⁸	cefalexin	food	non-randomized clinical trial	open-label, parallel	article	with infection	14
Guggenbichler1979	⁶⁹	amoxicillin, ampicillin, cefalexin, penicillin V, pivampicillin	food	non-randomized clinical trial	open-label, parallel	article	with infection	15
Gupta2022	⁷⁰	tebipenem pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	36
Haginaka1979	⁷¹	cefalexin	food	non-randomized clinical trial	open-label, crossover	article	healthy	4
Hamid1987	⁷²	ampicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Harding1984	⁷³	cefuroxime axetil	food	randomized clinical trial	open-label, crossover	article	healthy	16
Harvengt1973	⁷⁴	cefalexin, cefradine	food	randomized clinical trial	open-label, parallel	article	healthy	12
Hayashi1980	⁷⁵	cefradine	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	9
Healy1989	⁷⁶	cefixime	antacid	randomized clinical trial	open-label, crossover	article	healthy	12
Hughes1989	⁷⁷	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	healthy	16
Iwai1989	⁷⁸	cefpodoxime proxetil	food	non-randomized clinical trial	open-label, crossover	article	with infection	4
James1991	⁷⁹	cefaclor, cefuroxime axetil	food	randomized clinical trial	open-label, crossover	article	healthy	6
Jones1978-1	⁸⁰	ampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	32
Jones1978-2	⁸⁰	ampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	16
Kamme1974	⁸¹	flucloxacillin	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	12
Karim2003	⁸²	cefaclor	food	randomized clinical trial	open-label, crossover	article	healthy	18
Kassem2004	⁸³	cefradine	food	randomized clinical trial	open-label, crossover	article	healthy	8
Kato2002	⁸⁴	cefdinir	mineral supplement	randomized clinical trial	open-label, crossover	article	healthy	9
Kearns1998	⁸⁵	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	with infection	17
Khan2004	⁸⁶	cefaclor	food	randomized clinical trial	open-label, crossover	article	healthy	23
Khuroo2008	⁸⁷	amoxicillin	beverage, food	randomized clinical trial	open-label, cross-over	article	healthy	9
Kibayashi1990	⁸⁸	cefdinir	food	non-randomized clinical trial	open-label, parallel	article	with infection	10
Kimura1989	⁸⁹	cefpodoxime proxetil	food	non-randomized clinical trial	open-label, parallel	article	with infection	3
Koup1988	⁹⁰	cefetamet pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	6
Koyama1986	⁹¹	cefteram pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	6
Lai2021	⁹²	cefradine	food	non-randomized clinical trial	open-label, parallel	article	healthy	50
Lecaillon1980	⁹³	cefroxadine, cefalexin	food	non-randomized clinical trial	open-label, crossover	article	healthy	6
Leigh1976	⁹⁴	ampicillin	food	non-randomized clinical trial	open-label, crossover	article	no data	4
Li1997	⁹⁵	cefditoren pivoxil	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	8
Li2009-1	⁹⁶	amoxicillin	beverage	non-randomized clinical trial	open-label, crossover	article	healthy	28
Li2009-2	⁹⁶	cefaclor	beverage	randomized clinical trial	open-label, crossover	article	healthy	28
Li2013	⁹⁷	cefprozil	food	randomized clinical trial	open-label, parallel	article	healthy	10
Lin2020	⁹⁸	cefprozil	food	non-randomized clinical trial	open-label, parallel	article	healthy	60
Lode1979	⁹⁹	cefadroxil, cefalexin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Lode1979_2	¹⁰⁰	cefaclor	food	non-randomized clinical trial	open-label, not specified	article	healthy	6
Lv2021	¹⁰¹	cefalexin	food	randomized clinical trial	open-label, parallel	article	healthy	56
Magni1975	¹⁰²	bacampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	12
Marzec2005	¹⁰³	cefaclor	food	non-randomized clinical trial	open-label, parallel	article	healthy	no data
Matsumoto1975	¹⁰⁴	cefradine	food	non-randomized clinical trial	open-label, parallel	article	healthy	4
McCarthy1960	¹⁰⁵	penicillin G, penicillin V	food	non-randomized clinical trial	open-label, crossover	article	healthy	16
McCracken1978	¹⁰⁶	ampicillin, cefalexin, penicillin G, penicillin V	beverage	non-randomized clinical trial	open-label, longitudinal	article	with infection	56
McCracken1978_2	¹⁰⁷	cefaclor	beverage	non-randomized clinical trial	open-label, not specified	article	with infection	28
Meyers1969	¹⁰⁸	cefalexin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	10
Michel1974	¹⁰⁹	amoxicillin, pivampicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	9
Mischler1974	¹¹⁰	cefradine	food	randomized clinical trial	open-label, crossover	article	healthy	14
Motohiro1992	¹¹¹	cefdinir	food	non-randomized clinical trial	open-label, parallel	article	with infection	8
Munkholm1993-1	¹¹²	pivampicillin	antacid	non-randomized clinical trial	open-label, crossover	article	healthy	8
Munkholm1993-2	¹¹²	pivampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	14
Nakamura1988	¹¹³	sultamicillin	food	non-randomized clinical trial	open-label, crossover	article	with infection	11
Nakamura1989	¹¹⁴	cefteram pivoxil	food	non-randomized clinical trial	open-label, crossover	article	no data	12
Nakamura1991	¹¹⁵	cefixime	food	non-randomized clinical trial	open-label, crossover	article	with infection	6
Nakamura1992-1	¹¹⁶	cefdinir	food	non-randomized clinical trial	open-label, cross-over	article	with infection	20
Nakamura1992-2	¹¹⁶	cefdinir	food	non-randomized clinical trial	open-label, parallel	article	with infection	60
Nakashima1987	¹¹⁷	cefixime	food	non-randomized clinical trial	open-label, crossover	article	healthy	6
Nakashima1988	¹¹⁸	ceftibuten	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Nakashima2009	¹¹⁹	tebipenem pivoxil	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Nakashima2009_2	¹²⁰	tebipenem pivoxil	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Nakashima2009_3	¹²¹	tebipenem pivoxil	food	non-randomized clinical trial	open-label, parallel	article	healthy	16
Nakashima2009_4	¹²²	tebipenem pivoxil	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Neu1974	¹²³	amoxicillin, ampicillin	food	non-randomized clinical trial	open-label, crossover	article	healthy	12
Neu1981	¹²⁴	bacampicillin	food	non-randomized clinical trial	open-label, crossover	unpublished data	healthy	24
Neuvonen1977	¹²⁵	ampicillin, pivampicillin	food	randomized clinical trial	open-label, crossover	article	healthy	8
Nishimura1981	¹²⁶	cefroxadine	food	non-randomized clinical trial	open-label, crossover	article	with infection	3
None	¹²⁷	cefixime	food	no data	no data	SmPC	healthy	12
None	¹²⁸	cefdinir	food	no data	no data	SmPC	healthy	12
None	¹²⁸	cefdinir	food	no data	no data	SmPC	healthy	12
None	¹²⁸	cefdinir	mineral supplement	no data	no data	SmPC	healthy	12
None	¹²⁹	cefditoren pivoxil	food	no data	no data	SmPC	healthy	12
None	¹²⁹	cefditoren pivoxil	food	no data	no data	SmPC	healthy	12
None	¹²⁹	cefditoren pivoxil	antacid	no data	no data	SmPC	healthy	12
None	¹³⁰	ceftibuten	food	no data	no data	SmPC	healthy	26
None	¹³¹	cefpodoxime proxetil	antacid	no data	no data	SmPC	healthy	12
Oguma1991	¹³²	cefaclor	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	8
Olaganathan2017	¹³³	amoxicillin	antacid	randomized clinical trial	open-label, crossover	article	healthy	6
Parsons1977	¹³⁴	amoxicillin, ampicillin, cefalexin	food	non-randomized clinical trial	open-label, longitudinal	conference	healthy	13
Patel2023	¹³⁵	tebipenem pivoxil	antacid	non-randomized clinical trial	open-label, longitudinal	article	healthy	20
Petitjean1989	¹³⁶	cefixime	antacid	randomized clinical trial	open-label, crossover	article	healthy	8
Pfeffer1977	¹³⁷	cefadroxil, cefalexin	food	randomized clinical trial	open-label, crossover	article	healthy	16
Qu2022	¹³⁸	cefaclor	food	non-randomized clinical trial	open-label, parallel	article	healthy	48
Radwanski1998	¹³⁹	ceftibuten	antacid	randomized clinical trial	open-label, crossover	article	healthy	18
Roholt1974	¹⁴⁰	pivampicillin	food	non-randomized clinical trial	open-label, parallel	article	healthy	17
Saathoff1992	¹⁴¹	cefpodoxime proxetil	antacid	non-randomized clinical trial	open-label, longitudinal	article	healthy	10
Sabto1973	¹⁴²	amoxicillin	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	4
Saito1975-1	¹⁴³	ampicillin	food	non-randomized clinical trial	open-label, crossover	article	no data	13
Saito1975-2	¹⁴³	ampicillin	food	non-randomized clinical trial	open-label, crossover	article	no data	8
Sakai1985	¹⁴⁴	sultamicillin	food	non-randomized clinical trial	open-label, parallel	article	healthy	5
Santoro1978	¹⁴⁵	cefaclor	food	non-randomized clinical trial	open-label, crossover	article	healthy	5
Sarel1989	¹⁴⁶	penicillin V	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	12
Satterwhite1992	¹⁴⁷	cefaclor	antacid	randomized clinical trial	open-label, crossover	article	healthy	15
Shiba1992	¹⁴⁸	cefditoren pivoxil	antacid	non-randomized clinical trial	open-label, crossover	article	healthy	6
Shiiki1990	¹⁴⁹	cefetamet pivoxil	food	non-randomized clinical trial	open-label, crossover	article	healthy	5
Shimada1989	¹⁵⁰	cefdinir	food	non-randomized clinical trial	open-label, crossover	article	healthy	6
Shimada1990	¹⁵¹	cefteram pivoxil	antacid	non-randomized clinical trial	open-label, crossover	article	healthy	7
Shukla1992	¹⁵²	cefprozil	food	randomized clinical trial	open-label, crossover	article	healthy	15
Sutherland1967	¹⁵³	ampicillin	food	non-randomized clinical trial	open-label, parallel	article	healthy	24
Shyu1992	¹⁵⁴	cefprozil	antacid	randomized clinical trial	open-label, crossover	article	healthy	8
Sidell1964	¹⁵⁵	cloxacillin, oxacillin	food	non-randomized clinical trial	open-label, parallel	article	healthy	23
Sommers1984	¹⁵⁶	bacampicillin, cefuroxime axetil	food	non-randomized clinical trial	open-label, crossover	article	healthy	6
Staniforth1982	¹⁵⁷	amoxicillin	food	non-randomized clinical trial	open-label, crossover	article	healthy	18
Staniforth1985	¹⁵⁸	amoxicillin	beverage, antacid	non-randomized clinical trial	open-label, crossover	article	healthy	16
Tam1990	¹⁵⁹	cefetamet pivoxil	food	randomized clinical trial	open-label, crossover	article	healthy	16
Tateno1985	¹⁶⁰	cefaclor	food	non-randomized clinical trial	open-label, crossover	article	healthy	9
Tetzlaff1978	¹⁶¹	cefalexin	food	non-randomized clinical trial	open-label, longitudinal	article	with infection	15
Thambavita2021	¹⁶²	amoxicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	12
Totsuka2001	¹⁶³	cefpodoxime proxetil	food	randomized clinical trial	open-label, crossover	article	healthy	8
Toyonaga1985	¹⁶⁴	amoxicillin	food	non-randomized clinical trial	open-label, parallel	article	with infection	46
Toyonaga1989	¹⁶⁵	cefteram pivoxil	food	non-randomized clinical trial	open-label, parallel	article	with infection	8
Ueno1993	¹⁶⁶	cefdinir	mineral supplement	randomized clinical trial	open-label, crossover	article	healthy	6
Wagatsuma1989	¹⁶⁷	cefteram pivoxil	food	non-randomized clinical trial	open-label, parallel	article	with infection	3
Wagatsuma1989_2	¹⁶⁸	cefpodoxime proxetil	food	non-randomized clinical trial	open-label, parallel	article	with infection	2
Wang2005	¹⁶⁹	cefradine	food	randomized clinical trial	open-label, crossover	article	no data	12
Wang2019	¹⁷⁰	cefuroxime axetil	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	23
Weitschies2008	¹⁷¹	amoxicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	9
Welling1977	¹⁷²	amoxicillin, ampicillin	food	non-randomized clinical trial	open-label, longitudinal	article	healthy	6
Williams1984	¹⁷³	cefuroxime axetil	food	randomized clinical trial	open-label, crossover	article	healthy	23
Xu2022	¹⁷⁴	amoxicillin	food	non-randomized clinical trial	open-label, parallel	article	healthy	24
Yamaguchi1992	¹⁷⁵	cefaclor, cefuroxime axetil	food	non-randomized clinical trial	open-label, crossover	article	healthy	7
Yang2017	¹⁷⁶	cefuroxime axetil	food	randomized clinical trial	open-label, crossover	article	healthy	12
Yaoguo1994	¹⁷⁷	cefixime	food	no data	no data	article	healthy	8
Yazdani2012	¹⁷⁸	amoxicillin	beverage	randomized clinical trial	open-label, crossover	article	healthy	16
Zhang2020	¹⁷⁹	cefdinir	food	randomized clinical trial	open-label, parallel	article	healthy	62

Open in a new tab

Risk-of-bias assessment

One hundred and fifty-one studies with a defined study design were eligible for quality evaluation. The risk-of-bias assessments carried out by A.W. and P.P. provided generally consistent results. The assessment differed in one domain for 18 studies, but the final decisions were the same for all studies. We judged 61% of studies as having poor quality (or a high risk of bias) and only 8% as having a good quality (or low risk of bias). The remaining studies were of fair quality (or moderate risk of bias). In Supplementary Material 5, we present detailed results of the risk-of-bias assessment.

Quantitative synthesis

Eighteen of 32 analysed β-lactam antibiotics qualified for the quantitative synthesis. Drugs and studies excluded from meta-analyses (with reasons) are listed in Supplementary Material 6. We conducted 105 meta-analyses: 6 for beverages, 12 for antacids and mineral supplements, and 87 for food. Table 2 combines the results of meta-analyses for individual β-lactam antibiotics, whereas in Supplementary Material 7, forest plots of each synthesis are available.

Table 2.

Results of meta-analyses for individual β-lactam antibiotics

Drug	Intervention	Outcome	Study designs	Number of studies	Number of participants	Effect measure^a	Test for overall effect (Z)	Interpretation of results	Clinically important interaction?	I² (%)	P value for the chi-squared test	Judgment of heterogeneity	Subgroup analysis?
Amoxicillin	antacid	AUC	randomized, crossover	2	20	0.91 (0.75–1.10)	0.81 (P = 0.42)	no statistically significant difference between AUC with and without antacid	no	0	0.62	low	no
		C _max	randomized, crossover	2	20	1.15 (0.93–1.42)	1.06 (P = 0.29)	no statistically significant difference between C_max with and without antacid	no	0	0.67	low	no
		T _max	randomized, crossover	2	20	−0.45 (−0.63 to −0.26)	4.01 (P < 0.0001)	T _max with antacid shorter by on average 30 min (from 15 to 40 min)	probably no	0	0.57	low	no
	beverage	AUC	non-randomized, crossover	3	52	1.00 (0.93–1.09)	0.11 (P = 0.91)	no statistically significant difference between AUC with water and beverage	no	0	0.47	low	no
		C _max	non-randomized, crossover	4	63	0.99 (0.91–1.07)	0.24 (P = 0.81)	no statistically significant difference between C_max with water and beverage	no	0	0.61	low	no
		T _max	non-randomized, crossover	2	36	0.70 (0.45–0.96)	4.52 (P < 0.00001)	T _max with beverages longer by on average 40 min (from 25 min to 1 h)	probably no	0	0.42	low	no
	food	AUC	non-randomized, crossover	2	28	1.00 (0.91–1.10)	0.00 (P = 1.00)	no statistically significant difference between AUC in fasted and fed states	no	0	0.45	low	no
			non-randomized, longitudinal	6	63	0.78 (0.62–0.98)	1.79 (P = 0.07)	AUC in fed lower by on average 22% (from 2% to 38%)	possibly yes	88	<0.00001	high	yes
			non-randomized, parallel	2	48	0.96 (0.90–1.01)	1.27 (P = 0.20)	no statistically significant difference between AUC in fasted and fed states	no	0	0.67	low	no
			randomized, crossover	6	48	0.91 (0.85–0.99)	1.94 (P = 0.05)	AUC in fed lower by on average 9% (from 1% to 15%)	probably no	0	0.95	low	no
			randomized, longitudinal^b	2	18	1.36 (1.25–1.48)	5.81 (P < 0.00001)	AUC in fed higher by on average 36% (from 25% to 48%)	yes	0	0.57	low	no
		C _max	non-randomized, crossover	2	28	1.02 (0.91–1.14)	0.26 (P = 0.80)	no statistically significant difference between C_max in fasted and fed states	no	0	0.89	low	no
			non-randomized, longitudinal	6	63	0.66 (0.50–0.88)	2.37 (P = 0.02)	C _max in fed lower by on average 34% (from 12% to 50%)	yes	91	<0.00001	high	yes
			non-randomized, parallel	7	109	0.68 (0.60–0.76)	5.33 (P < 0.00001)	C _max in fed lower by on average 32% (from 24% to 40%)	yes	50	0.06	moderate	yes
			randomized, crossover	6	48	0.81 (0.75–0.88)	4.33 (P < 0.0001)	C _max in fed lower by on average 19% (from 12% to 25%)	possibly yes	0	0.57	low	no
			randomized, longitudinal^b	2	18	0.99 (0.91–1.09)	0.16 (P = 0.87)	no statistically significant difference between C_max in fasted and fed states	no	0	0.66	low	no
		T _max	non-randomized, longitudinal	6	63	0.93 (0.47–1.39)	3.30 (P = 0.0009)	T _max in fed longer by on average 1 h (from 30 min to 1 h 25 min)	possibly yes	40	0.14	moderate	NA^c
			after excluding Parsons1977—the only liquid formulation:	5	50	1.25 (0.89–1.61)	5.72 (P < 0.00001)	T_max in fed longer by on average 1 h 15 min (from 55 min to 1 h 35 min)	possibly yes	0	0.86	low	no
			non-randomized, parallel	6	94	0.57 (0.27–0.86)	3.19 (P = 0.001)	T _max in fed longer by on average 35 min (from 15 min to 50 h)	probably no	80	0.0001	high	no
			randomized, crossover	6	48	0.58 (0.22–0.94)	2.67 (P = 0.008)	T _max in fed longer by on average 35 min (from 15 min to 55 min)	probably no	47	0.09	moderate	yes
			randomized, longitudinal^b	2	18	0.23 (−0.49 to 0.95)	0.52 (P = 0.60)	no statistically significant difference between T_max in fasted and fed states	no	64	0.1	moderate	NA
Ampicillin	food	AUC	non-randomized, longitudinal	7	49	0.64 (0.50–0.82)	2.94 (P = 0.003)	AUC in fed lower by on average 36% (from 18% to 50%)	yes	73	0.001	moderate	NA
			after excluding Parsons1977—the only liquid formulation:	6	36	0.57 (0.49–0.66)	6.18 (P < 0.00001)	AUC in fed lower by on average 43% (from 34% to 51%)	yes	0	0.91	low	no
		C _max	non-randomized, crossover	6	30	0.59 (0.54–0.65)	9.07 (P < 0.00001)	C _max in fed lower by on average 41% (from 35% to 46%)	yes	46	0.1	moderate	NA
			non-randomized, longitudinal	7	49	0.52 (0.47–0.58)	10.51 (P < 0.00001)	C _max in fed lower by on average 48% (from 42% to 53%)	yes	91	<0.00001	high	NA
			after excluding Parsons1977—the only liquid formulation:	6	36	0.45 (0.4– 0.46)	64.56 (P < 0.00001)	C_max in fed lower by on average 55% (from 54% to 56%)	yes	9	0.36	low	no
		T _max	non-randomized, longitudinal	7	49	0.50 (0.23–0.77)	3.04 (P = 0.002)	T _max in fed longer by 0.5 h (from 15 min to 45 min)	probably no	18	0.29	low	no
			after excluding Parsons1977—the only liquid formulation:	6	36	0.70 (0.36–1.03)	3.43 (P = 0.0006)	T_max in fed longer by 40 min (from 20 min to 1 h)	probably no	0	0.53	low	no
Bacampicillin	food	C _max	non-randomized, crossover	3	54	0.90 (0.75–1.08)	0.97 (P = 0.33)	no statistically significant difference between C_max in fasted and fed states	no	96	<0.00001	high	NA
			randomized, crossover	2	24	1.09 (1.05–1.12)	4.58 (P < 0.00001)	C _max in fed higher by on average 9% (from 5% to 12%)	probably no	0	0.37	low	no
Cefaclor	food	AUC	non-randomized, crossover	3	30	0.93 (0.85–1.01)	1.45 (P = 0.15)	no statistically significant difference between AUC in fasted and fed states	no	0	0.41	low	no
			non-randomized, longitudinal	5	38	0.96 (0.89–1.04)	0.87 (P = 0.38)	no statistically significant difference between AUC in fasted and fed states	no	15	0.32	low	no
			non-randomized, parallel	2	92	0.97 (0.92–1.03)	0.85 (P = 0.40)	no statistically significant difference between AUC in fasted and fed states	no	0	1	low	no
			randomized, crossover	11	199	1.02 (0.97–1.07)	0.73 (P = 0.47)	no statistically significant difference between AUC in fasted and fed states	no	17	0.28	low	yes^d
		C _max	non-randomized, crossover	5	42	0.56 (0.50–0.63)	8.70 (P < 0.00001)	C _max in fed lower by on average 44% (from 37% to 50%)	yes	0	0.63	low	no
			non-randomized, longitudinal	5	38	0.55 (0.44–0.68)	4.54 (P < 0.00001)	C _max in fed lower by on average 45% (from 32% to 56%)	yes	78	0.001	high	yes
			non-randomized, parallel	2	93	0.31 (0.28–0.35)	18.51 (P < 0.00001)	C _max in fed lower by on average 69% (from 65% to 72%)	yes	0	0.64	low	no
			randomized, crossover	11	199	0.86 (0.71–1.05)	1.22 (P = 0.22)	no statistically significant difference between C_max in fasted and fed states	no	94	<0.00001	high	yes
		T _max	non-randomized, crossover	4	37	0.99 (0.56–1.43)	3.80 (P = 0.0001)	T _max in fed longer by on average 1 h (from 35 min to 1 h 25 min)	possibly yes	90	<0.00001	high	NA
			after excluding Tateno1985—the only light meal:	3	28	0.70 (0.52–0.89)	6.14 (P < 0.00001)	T_max in fed longer by on average 40 min (from 30 min to 55 min)	probably no	39	0.2	moderate	NA
			non-randomized, parallel	2	93	1.31 (1.02–1.60)	7.41 (P < 0.00001)	T _max in fed longer by on average 1 h 20 min (from 1 h to 1 h 35 min)	possibly yes	0	1	low	no
			randomized, crossover	2	12	0.63 (0.30–0.96)	3.13 (P = 0.002)	T _max in fed longer by on average 40 min (from 20 min to 1 h)	probably no	58	0.12	moderate	NA
Cefadroxil	beverage	C _max	non-randomized, longitudinal	2	28	0.77 (0.66–0.90)	2.83 (P = 0.005)	C _max with beverage lower by on average 23% (from 10% to 34%)	possibly yes	0	0.63	low	no
	food	C _max	non-randomized, longitudinal	3	25	1.07 (0.98–1.17)	1.32 (P = 0.19)	no statistically significant difference between C_max in fasted and fed states	no	0	0.47	low	no
Cefdinir	food	AUC	non-randomized, crossover	2	12	0.75 (0.60–0.93)	2.15 (P = 0.03)	AUC in fed lower by on average 25% (from 7% to 40%)	possibly yes	50	0.16	moderate	NA
			non-randomized, parallel	4	68	0.86 (0.73–1.01)	1.53 (P = 0.13)	no statistically significant difference between AUC in fasted and fed states	no	0	0.52	low	no
			randomized, parallel	2	60	0.83 (0.77–0.90)	3.74 (P = 0.0002)	AUC in fed lower by on average 17% (from 10% to 23%)	possibly yes	0	0.61	low	no
		C _max	non-randomized, cross-over	2	12	0.57 (0.49–0.65)	6.86 (P < 0.00001)	C _max in fed lower by on average 43% (from 35% to 51%)	yes	0	0.37	low	no
			non-randomized, parallel	5	78	0.78 (0.67–0.90)	2.78 (P = 0.006)	C _max in fed lower by on average 22% (from 10% to 33%)	possibly yes	86	<0.0001	high	yes
			randomized, parallel	2	61	0.70 (0.65–0.76)	7.07 (P < 0.00001)	C _max in fed lower by on average 30% (from 24% to 35%)	yes	0	0.84	low	no
		T _max	non-randomized, crossover	2	12	1.22 (0.50–1.94)	2.81 (P = 0.005)	T _max in fed longer by on average 1 h 15 min (from 30 min to 1 h 55 min)	possibly yes	75	0.05	high	NA
			non-randomized, parallel	4	70	0.77 (0.02–1.51)	1.69 (P = 0.09)	T _max in fed longer by on average 45 min (from 2 min to 1 h 30 min)	probably no	76	0.006	high	NA
			randomized, parallel	2	61	1.09 (0.79–1.39)	5.95 (P < 0.00001)	T _max in fed longer by on average 1 h 10 min (from 45 min to 1 h 25 min)	possibly yes	10	0.29	low	no
	mineral supplement	AUC	randomized, crossover	2	15	0.29 (0.03–2.71)	0.91 (P = 0.36)	no statistically significant difference between AUC with and without supplement	no	99	<0.00001	high	NA
		C _max	randomized, crossover	2	15	0.33 (0.04–2.50)	0.90 (P = 0.37)	no statistically significant difference between C_max with and without supplement	no	97	<0.00001	high	NA
		T _max	randomized, crossover	2	15	−1.03 (−2.99 to 0.92)	0.87 (P = 0.38)	no statistically significant difference between T_max with and without a supplement	no	83	0.02	high	NA
Cefetamet pivoxil	food	AUC	randomized, crossover	5	62	1.21 (1.09–1.34)	2.95 (P = 0.003)	AUC in fed higher by on average 21% (from 9% to 34%)	possibly yes	60	0.04	moderate	NA
		C _max	randomized, crossover	8	104	1.15 (1.06–1.24)	2.86 (P = 0.004)	C _max in fed higher by on average 15% (from 6% to 24%)	probably no	65	0.009	moderate	yes
			after excluding Ducharme1993—the only liquid formulation:	7	86	1.19 (1.11–1.27)	4.27 (P < 0.0001)	C_max in fed higher by on average 19% (from 11% to 27%)	possibly yes	38	0.14	moderate	yes
		T _max	randomized, crossover	8	104	1.47 (1.09–1.84)	6.44 (P < 0.00001)	T _max in fed longer by on average 1.5 h (from 1 h 10 min to 1 h 55 min)	possibly yes	73	0.001	moderate	yes
Cefixime	antacid	AUC	randomized, crossover	3	28	1.11 (0.93–1.32)	1.00 (P = 0.32)	no statistically significant difference between AUC with and without antacid	no	0	0.99	low	no
		C _max	randomized, crossover	3	28	1.22 (1.06–1.42)	2.25 (P = 0.02)	no statistically significant difference between C_max with and without antacid	no	0	0.72	low	no
		T _max	randomized, crossover	3	28	−0.16 (−0.52 to 0.21)	0.71 (P = 0.48)	no statistically significant difference between T_max with and without antacid	no	0	0.87	low	no
	food	AUC	non-randomized, crossover	2	6	0.96 (0.69–1.34)	0.21 (P = 0.83)	no statistically significant difference between AUC in fasted and fed states	no	39	0.20	moderate	NA
		C _max	non-randomized, crossover	2	6	1.11 (0.77–1.60)	0.46 (P = 0.65)	no statistically significant difference between C_max in fasted and fed states	no	68	0.08	high	NA
		T _max	non-randomized, crossover	2	6	0.15 (−0.39 to 0.69)	0.45 (P = 0.65)	no statistically significant difference between T_max in fasted and fed states	no	0	0.37	low	NA
Cefpodoxime proxetil	food	AUC	randomized, crossover	10	156	1.20 (1.14–1.27)	5.82 (P < 0.00001)	AUC in fed higher by on average 20% (from 14% to 27%)	possibly yes	31	0.16	moderate	yes
		C _max	randomized, crossover	10	156	1.12 (1.02–1.24)	1.94 (P = 0.05)	C _max in fed higher by on average 12% (from 2% to 24%)	probably no	79	<0.00001	high	yes
		T _max	randomized, crossover	10	156	0.65 (0.49–0.81)	6.53 (P < 0.00001)	T _max in fed longer by on average 40 min (from 30 min to 50 min)	probably no	34	0.13	moderate	yes
Cefprozil	food	AUC	non-randomized, parallel	3	178	0.98 (0.94–1.02)	0.81 (P = 0.42)	no statistically significant difference between AUC in fasted and fed states	no	0	0.43	low	no
		C _max	non-randomized, parallel	3	178	0.71 (0.62–0.80)	4.51 (P < 0.00001)	C _max in fed lower by on average 29% (from 20% to 38%)	yes	81	0.005	high	NA
		T _max	non-randomized, parallel	3	178	0.72 (0.37–1.07)	3.42 (P = 0.0006)	T _max in fed longer by on average 40 min (from 20 min to 1 h 5 min)	probably no	82	0.004	high	NA
Cefroxadine	food	C _max	non-randomized, crossover	2	9	0.50 (0.34–0.74)	2.90 (P = 0.004)	C _max in fed lower by on average 50% (from 26% to 66%)	yes	50	0.16	moderate	NA
Cefteram pivoxil	food	C _max	non-randomized, parallel	2	11	1.36 (0.96–1.92)	1.44 (P = 0.15)	no statistically significant difference between C_max in fasted and fed states	no	0	0.97	low	no
		C _max	randomized, crossover	2	12	1.14 (0.88–1.47)	0.85 (P = 0.39)	no statistically significant difference between C_max in fasted and fed states	no	81	0.02	high	NA
Ceftibuten	food	AUC	randomized, crossover	2	36	0.86 (0.80–0.91)	4.02 (P < 0.0001)	AUC in fed lower by on average 14% (from 9% to 20%)	probably no	0	0.44	low	no
		C _max	randomized, crossover	2	36	0.78 (0.72–0.84)	5.11 (P < 0.00001)	C _max in fed lower by on average 22% (from 16% to 28%)	possibly yes	15	0.28	low	no
		T _max	randomized, crossover	2	36	0.62 (0.21–1.03)	2.50 (P = 0.01)	T _max in fed longer by on average 40 min (from 10 min to 1 h)	probably no	45	0.18	moderate	NA
Cefuroxime	beverage	AUC	non-randomized, longitudinal	4	65	1.42 (1.23–1.64)	4.06 (P < 0.0001)	AUC with beverage higher by on average 42% (from 23% to 64%)	yes	58	0.07	moderate	yes
		C _max	non-randomized, longitudinal	4	65	1.36 (1.25–1.48)	5.88 (P < 0.00001)	C _max with beverage higher by on average 36% (from 25% to 48%)	yes	0	0.63	low	no
	food	AUC	non-randomized, crossover	2	18	1.55 (1.37–1.76)	5.79 (P < 0.00001)	AUC in fed higher by on average 55% (from 37% to 76%)	yes	0	0.43	low	no
			non-randomized, longitudinal	3	44	1.29 (1.11–1.50)	2.72 (P = 0.007)	AUC in fed higher by on average 29% (from 11% to 50%)	yes	56	0.10	moderate	NA
			randomized, crossover	3	30	1.46 (1.33–1.61)	6.47 (P < 0.00001)	AUC in fed higher by on average 46% (from 33% to 61%)	yes	10	0.33	low	no
		C _max	non-randomized, crossover	3	25	1.76 (1.57–1.97)	8.28 (P < 0.00001)	C _max in fed higher by on average 76% (from 57% to 97%)	yes	0	0.82	low	no
			non-randomized, longitudinal	3	44	1.20 (1.04–1.38)	2.11 (P = 0.03)	C _max in fed higher by on average 20% (from 4% to 38%)	possibly yes	32	0.23	moderate	NA
			after excluding Wang2019—the only high-fat study:	2	21	1.31 (1.11–1.55)	2.67 (P = 0.008)	C_max in fed higher by on average 31% (from 11% to 55%)	yes	0	0.33	low	no
			randomized, crossover	3	30	1.35 (1.12–1.62)	2.66 (P = 0.008)	C _max in fed higher by on average 35% (from 12% to 62%)	yes	76	0.02	high	NA
		T _max	non-randomized, crossover	3	25	0.20 (−0.13 to 0.54)	0.99 (P = 0.32)	no statistically significant difference between T_max in fasted and fed states	no	59	0.09	moderate	NA
			randomized, crossover	3	30	0.57 (0.09–1.06)	1.93 (P = 0.05)	T _max in fed longer by on average 35 min (from 5 min to 1 h 5 min)	probably no	62	0.07	moderate	NA
			after excluding Yang2017—the only high-fat study:	2	18	0.89 (0.53–1.24)	4.1 (P < 0.0001)	T_max in fed longer by on average 50 min (from 30 min to 1 h 15 min)	probably no	0	0.62	low	NA
Cefalexin	antacid and mineral supplement	AUC	randomized, crossover	2	22	0.85 (0.64–1.13)	0.95 (P = 0.34)	no statistically significant difference between AUC with and without supplement	no	89	0.002	high	NA
		C _max	randomized, crossover	2	22	0.82 (0.61–1.11)	1.07 (P = 0.29)	no statistically significant difference between C_max with and without supplement	no	82	0.02	high	NA
		T _max	randomized, crossover	2	22	−0.25 (−0.47 to −0.03)	1.86 (P = 0.06)	T _max in with supplement shorter by on average 15 min (from 2 min to 30 min)	probably no	0	0.77	low	no
	food	AUC	non-randomized, longitudinal	2	25	0.98 (0.61–1.57)	0.07 (P = 0.94)	no statistically significant difference between AUC in fasted and fed states	no	87	0.006	high	NA
			randomized, parallel	2	56	0.84 (0.80–0.88)	6.19 (P < 0.00001)	AUC in fed lower by on average 16% (from 12% to 20%)	probably no	0	0.86	low	no
		C _max	non-randomized, longitudinal	4	40	0.77 (0.63–0.94)	2.17 (P = 0.03)	C _max in fed lower by on average 23% (from 6% to 37%)	possibly yes	46	0.13	moderate	yes
			after excluding Lode1979:	3	28	0.87 (0.72–1.05)	1.24 (P = 0.22)	no statistically significant difference between C_max in fasted and fed states	no	0	0.68	low	no
			non-randomized, parallel	2	70	0.99 (0.76–1.29)	0.05 (P = 0.96)	no statistically significant difference between C_max in fasted and fed states	no	61	0.11	moderate	NA
			randomized, parallel	3	68	0.55 (0.41–0.75)	3.22 (P = 0.001)	C _max in fed lower by on average 45% (from 25% to 59%)	yes	97	<0.00001	high	NA
			after excluding Harvengt1973:	2	56	0.41 (0.39–0.44)	28.24 (P < 0.00001)	C_max in fed lower by on average 59% (from 56% to 61%)	yes	0	0.75	low	no
		T _max	non-randomized, longitudinal	2	25	0.73 (0.41–1.05)	3.77 (P = 0.0002)	T _max in fed longer by on average 45 min (from 25 min to 1 h 5 min)	probably no	75	0.05	high	NA
Cefradine	food	AUC	non-randomized, parallel	2	49	0.94 (0.87–1.01)	1.38 (P = 0.17)	no statistically significant difference between AUC in fasted and fed states	no	0	0.74	low	no
		C _max	non-randomized, parallel	2	49	0.53 (0.42–0.66)	4.62 (P < 0.00001)	C _max in fed lower by on average 47% (from 34% to 58%)	yes	49	0.16	moderate	NA
		T _max	non-randomized, parallel	2	49	1.38 (0.61–2.14)	2.96 (P = 0.003)	T _max in fed longer by on average 1 h 20 min (from 35 min to 2 h 10 min)	possibly yes	68	0.08	moderate	NA
Pivampicillin	food	AUC	randomized, crossover	2	22	0.99 (0.90–1.08)	0.25 (P = 0.80)	no statistically significant difference between AUC in fasted and fed states	no	0	0.45	low	no
		C _max	non-randomized, parallel	2	32	0.84 (0.70–1.01)	1.55 (P = 0.12)	no statistically significant difference between C_max in fasted and fed states	no	0	0.42	low	no
Tebipenem pivoxil	food	AUC	non-randomized, crossover	5	60	0.90 (0.85–0.95)	3.55 (P = 0.0008)	AUC in fed lower by on average 10% (from 5% to 15%)	probably no	0	0.76	low	no
			non-randomized, longitudinal	9	59	1.16 (0.92–1.48)	1.04 (P = 0.3)	no statistically significant difference between AUC in fasted and fed states	no	88	<0.00001	high	yes
			non-randomized, parallel	4	64	0.94 (0.87–1.02)	1.22 (P = 0.22)	no statistically significant difference between C_max in fasted and fed states	no	0	0.52	low	no
		C _max	non-randomized, crossover	5	60	0.57 (0.47–0.68)	5.27 (P < 0.00001)	C _max in fed lower by on average 43% (from 32% to 53%)	yes	78	0.0009	high	yes
			after excluding Nakashima2009_4 (the only tablet formulation):	4	48	0.52 (0.45–0.60)	7.86 (P < 0.00001)	C_max in fed lower by on average 48% (from 40% to 55%)	yes	54	0.09	moderate	no
			non-randomized, longitudinal	9	59	0.83 (0.62–1.12)	1.03 (P = 0.31)	no statistically significant difference between C_max in fasted and fed states	no	85	<0.00001	high	yes
			non-randomized, parallel	4	64	0.85 (0.75–0.96)	2.23 (P = 0.03)	C _max in fed lower by on average 15% (from 4% to 25%)	probably no	0	0.61	low	no
		T _max	non-randomized, crossover	5	60	0.18 (0.06–0.29)	2.54 (P = 0.01)	T _max in fed longer by on average 10 min (from 4 min to 17 min)	probably no	0	0.65	low	no
			non-randomized, longitudinal	9	59	2.04 (1.19–2.89)	3.94 (P < 0.0001)	T _max in fed longer by on average 2 h (from 1 h 10 min to 2 h 55 min)	yes	93	<0.00001	high	yes
			non-randomized, parallel	4	64	0.20 (−0.07 to 0.47)	1.21 (P = 0.23)	no statistically significant difference between T_max in fasted and fed states	no	78	0.003	high	NA

Open in a new tab

NA, not applicable.

^aFor AUC and C_max: ratio of means (RoB) with 90% CI; for T_max: mean difference (MD) with 90% CI.

^bStudies for extended-release (ER) formulation.

^cNA due to fewer than two studies in each subgroup.

^dSubgroup analysis was done due to the expected difference between formulations.

Subgroup analyses

In 55 (52%) meta-analyses, we revealed moderate or high heterogeneity; for these, we conducted subgroup analyses (when possible). Drug formulation was the only grouping variable that potentially explained the heterogeneity of some studies. In Table 3, we present only the statistically significant results of subgroup analyses, whereas in Supplementary Material 7, forest plots of all performed analyses are available.

Table 3.

Results of subgroup analyses for meta-analyses with moderate or high heterogeneity

Drug	Intervention	Outcome	Overall	Subgroup analysis	Test for subgroup differences	Interpretation
Amoxicillin	food	T _max	n = 48, MD (90% CI) = 0.58 (0.22–0.94), I² = 47%, P = 0.09	Grouping variable—drug formulation MR tablets: n = 12, MD (90% CI) = 0.01 (−0.47 to 0.50), I² = 0%, P = 0.33 Capsules: n = 36, MD (90% CI) = 0.83 (0.52–1.14), I² = 0%, P = 0.4	I² = 81.8%, P = 0.02	Different drug formulations can explain the heterogeneity. For MR tablets—no significant differences in T_max between fasted and fed states. For capsules—T_max in a fed state longer by on average 50 min (from 30 min to 1 h 10 min), probably not clinically important.
Cefaclor	food	AUC	n = 199, RoM (90% CI)= −1.02 (0.97–1.07), I² = 17%, P = 0.28	Grouping variable—drug formulation ER tablets: n = 115, RoM (90% CI) = 1.09 (1.03–1.16), I² = 0%, P = 0.97 Other: n = 84, RoM (90% CI) = 0.93 (0.86–0.99), I² = 0%, P = 0.81	I² = 89.2%, P = 0.002	Different drug formulations can explain the heterogeneity. For ER tablets—AUC in a fed state higher by on average 9% (from 3% to 16%), probably not clinically important. For other formulations—AUC in a fed state lower by on average 7% (from 1% to 14%), probably not clinically important.
		C _max	n = 199, RoM (90% CI) = −0.86 (0.71–1.05), I² = 94%, P < 0.00001	Grouping variable—drug formulation ER tablets: n = 115, RoM (90% CI) = 1.26 (1.14–1.39), I² = 57%, P = 0.05 Other: n = 84, RoM (90% CI) = 0.61 (0.56–0.67), I² = 21%, P = 0.28	I² = 98.9%, P < 0.00001	Different drug formulations can partially explain the heterogeneity. For ER tablets—C_max in a fed state higher by on average 26% (from 14% to 39%), possibly clinically important. For other formulations—C_max in a fed state lower by on average 39% (from 33% to 44%), clinically Important.
Cefpodoxime proxetil	food	AUC	n = 156, RoM (90% CI) = 1.20 (1.14–1.27), I² = 31%, P = 0.83	Grouping variable—drug formulation Suspension: n = 48, RoM (90% CI) = 1.10 (1.04–1.17), I² = 0%, P = 0.79 Tablets: n = 108, RoM (90% CI) = 1.28 (1.21–1.36), I² = 0%, P = 0.83	I² = 89.8%, P = 0.002	Different drug formulations can partially explain the heterogeneity. For suspension—AUC in a fed state higher by on average 10% (from 4% to 17%), probably not clinically important. For tablets—AUC in a fed state higher by on average 28% (from 21% to 36%), possibly clinically important.
		C _max	n = 156, RoM (90% CI) = 1.12 (1.02–1.24), I² = 79%, P < 0.00001	Grouping variable—drug formulation Suspension: n = 48, RoM (90% CI) = 0.95 (0.88–1.01), I² = 18%, P = 0.29 Tablets: n = 108, RoM (90% CI) = 1.27 (1.19–1.36), I² = 11%, P = 0.35	I² = 96.3%, P < 0.00001	Different drug formulations can partially explain the heterogeneity. For suspension—no significant differences in C_max between fasted and fed states. For tablets—C_max in a fed state higher by on average 27% (from 19% to 36%), possibly clinically important.
Tebipenem pivoxil	food	AUC	n = 59, RoM (90% CI) = 1.16 (0.92–1.48), I² = 88%, P < 0.00001	Grouping variable—drug formulation ER tablets (6–12 h): n = 21, RoM (90% CI)= 1.93 (1.45–2.57), I² = 72%, P = 0.03 Other formulations: n = 38, RoM (90% CI) = 0.87 (0.78–0.98), I² = 26%, P = 0.24	I² = 94.4%, P < 0.0001	Different drug formulations can partially explain the heterogeneity. For ER tablets (6–12 h)—AUC in a fed state higher by on average 93% (from 45% to 157%), clinically important. For other formulations [ER tablets (2–4 h) and immediate release tablets]—AUC in a fed state lower by on average 13% (from 2% to 22%), probably not clinically important.
		C _max	n = 59, RoM (90% CI) = 0.83 (0.62–1.12), I² = 85%, P < 0.00001	Grouping variable—drug formulation ER tablets (6–12 h): n = 21, RoM (90% CI) = 1.43 (1.19–1.71), I² = 0%, P = 0.67 Other formulations: n = 38, RoM (90% CI) = 0.59 (0.49–0.72), I² = 45%, P = 0.11	I² = 96.6%, P < 0.00001	Different drug formulations can explain the heterogeneity. For ER tablets (6–12 h)—C_max in a fed state higher by on average 43% (from 19% to 71%), clinically important. For other formulations (ER tablets (2–4 h) and immediate release tablets]—C_max in a fed state lower by on average 41% (from 28% to 51%), clinically important.
		T _max	n = 59, MD (90% CI) = 2.04 (1.19–2.89), I² = 93%, P < 0.00001	Grouping variable—drug formulation ER formulations: n = 39, MD (90% CI) = 2.77 (2.21–3.34), I² = 56%, P = 0.05 IR formulations: n = 20, MD (90% CI) = 0.40 (−0.08 to 0.87), I² = 54%, P = 0.12	I² = 96.4%, P < 0.00001	Different drug formulations can partially explain the heterogeneity. For ER formulations—T_max in a fed state longer by on average 2 h 45 min (from 2 h 15 min to 3 h 20 min), clinically important. For IR formulations—no significant differences in T_max between fasted and fed states.

Open in a new tab

ER, extended-release; MD, mean difference; MR, modified-release; RoM, ratio of means.

Sensitivity analyses

For 98 meta-analyses, the change of the statistical model from the random-effects model to the fixed-effects model did not produce significant qualitative differences in overall effect. For the fixed-effects models, CIs of mean differences were generally narrower. However, the change in magnitude of the overall effect (expressed as Z value) was variable; we did not observe the consistent increase or decrease of Z value for fixed-effects models compared with random-effects models.

For seven remaining meta-analyses, we observed significant differences between random- and fixed-effects models (see Table 4). Forest plots of these meta-analyses are provided in Supplementary Material 7. In all cases, using the random-effects model produced the result of no statistically significant differences after the intervention. In contrast, changing to a fixed-effects model resulted in statistically significant differences (indicating both negative and positive impacts of the intervention, depending on the drug).

Table 4.

Significant qualitative differences in the results of meta-analyses after changing the statistical model from random- to fixed-effects model

Drug	Intervention	Outcome	Random-effects model	Interpretation of results	Fixed-effects model	Interpretation of results
Cefdinir	food	C _max	RoM (90% CI) = 0.86 (0.56–1.33), Z = 0.56 (P = 0.58)	no statistically significant difference between C_max in fasted and fed states	RoM (90% CI) = 0.78 (0.67–0.90), Z = 2.78 (P = 0.006)	C _max in fed lower by on average 22% (from 10% to 33%), possibly clinically important.
	mineral supplement	AUC	RoM (90% CI) = 0.29 (0.03–2.71), Z = 0.91 (P = 0.36)	no statistically significant difference in AUC with and without supplement	RoM (90% CI) = 0.17 (0.14–0.20), Z = 15.23 (P < 0.00001)	AUC with supplement lower by on average 83% (from 80% to 86%), clinically important.
		C _max	RoM (90% CI)= 0.33 (0.04–2.50), Z = 0.90 (P= 0.37)	no statistically significant difference in C_max with and without supplement	RoM (90% CI) = 0.61 (0.45–0.82), Z = 2.75 (P = 0.006)	C _max with supplement lower by on average 39% (from 18% to 55%), clinically important.
Cefuroxime	food	T _max	MD (90% CI) = 0.20 (−0.13 to 0.54), Z = 0.99 (P = 0.32)	no statistically significant difference between T_max in fasted and fed states	MD (90% CI) = 0.27 (0.08–0.46), Z = 2.35 (P = 0.02)	T _max in fed higher by on average 15 min (from 5 min to 30 min), probably not clinically important.
Cefalexin	antacid and mineral supplement	AUC	RoM (90% CI) = 0.85 (0.64–1.13), Z = 0.95 (P = 0.34)	no statistically significant difference between AUC in fasted and fed states	RoM (90% CI) = 0.78 (0.72–0.84), Z = 5.63 (P < 0.00001)	AUC with antacid and mineral supplement lower by on average 22% (from 16% to 28%), possibly clinically important.
		C _max	RoM (90% CI) = 0.82 (0.61–1.11), Z = 1.07 (P = 0.29)	no statistically significant difference between C_max in fasted and fed states	RoM (90% CI) = 0.78 (0.69–0.88), Z = 3.38 (P = 0.0007)	C _max with antacid and mineral supplement lower by on average 22% (from 12% to 31%), possibly clinically important.
	food	AUC	RoM (90% CI) = 0.98 (0.61–1.57), Z = 0.07 (P = 0.94)	no statistically significant difference between AUC in fasted and fed states	RoM (90% CI) = 0.81 (0.72–0.90), Z = 3.28 (P = 0.001)	AUC in fed lower by on average 19% (from 10% to 28%), possibly clinically important.

Open in a new tab

RoM, ratio of means; MD, mean difference; Z, test for overall effect.

Additionally, for 11 meta-analyses, we observed a significantly higher overall effect and reduced heterogeneity after excluding one of the studies. We describe all the exclusions in Table 2.

Publication bias

We reached the minimum level of 11 studies only in two meta-analyses of cefaclor. The same studies were included in both syntheses but for different outcomes—AUC and C_max. In Figure 2, we present funnel plots of these syntheses. For AUC, the funnel plot is asymmetrical to the right, which suggests possible publication bias, whereas for C_max, the symmetry seems to be maintained.

Figure 2. — Funnel plots of meta-analyses for postprandial changes of (a) AUC and (b) C_max of cefaclor.

Qualitative synthesis

For 19 β-lactam antibiotics, we could not conduct meta-analyses for at least one of the interventions. The most common reason was an insufficient number of studies with similar designs. The complete list of drugs excluded from quantitative synthesis is available in Supplementary Material 6. For these drugs, we summarize the existing evidence in Table 5, whereas a comprehensive description of studies is provided in Supplementary Material 4.

Table 5.

The qualitative synthesis of evidence regarding the impact of food, dietary supplements and beverages on β-lactam antibiotics

Drug	Intervention	Outcome	Number of studies	Number of participants	Overall effect	Clinically important interaction?
Ampicillin	beverage	AUC	2	26	no statistically significant difference between AUC with milk and with water	no
		C _max	2	26	no statistically significant difference between C_max with milk and with water	no
		T _max	2	26	T _max ↑ 1 h with milk	possibly yes
Cefaclor	beverage	AUC	2	56	no statistically significant difference between AUC with milk or cranberry juice and with water	no
		C _max	2	56	C _max ↓ 17%–35% with milk, no significant difference between C_max with and without cranberry juice	possibly yes
		T _max	2	56	T _max ↑ 0.5 h with milk, no significant difference between T_max with cranberry juice and with water	probably no
	antacid	AUC	1	15	AUC ↓ 18% with aluminium magnesium hydroxide	probably no
		C _max	1	15	no statistically significant difference between C_max with and without aluminium magnesium hydroxide	no
		T _max	1	15	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefditoren pivoxil	food	AUC	3	32	AUC ↑ 35%–70% with standard and high-fat meals	yes
		C _max	3	32	C _max ↑ 50% with standard and high-fat meals	yes
		T _max	1	8	no statistically significant difference between T_max in the fed and fasted state	no
	antacid	AUC	2	18	no statistically significant difference between AUC with and without aluminium magnesium hydroxide	no
		C _max	2	18	no statistically significant difference between C_max with and without aluminium magnesium hydroxide	no
		T _max	1	6	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefetamet	antacid	AUC	1	18	no statistically significant difference between AUC with and without aluminium magnesium hydroxide	no
		C _max	1	18	no statistically significant difference between C_max with and without aluminium magnesium hydroxide	no
		T _max	1	18	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefpodoxime proxetil	antacid	AUC	2	22	AUC ↓ 27%–40% with supplements (aluminium magnesium hydroxide, sodium bicarbonate)	yes
		C _max	2	22	C _max ↓ 24%–42% with supplements (aluminium magnesium hydroxide, sodium bicarbonate)	yes
		T _max	1	10	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefprozil	antacid	AUC	1	8	no statistically significant difference between AUC with and without aluminium magnesium hydroxide	no
		C _max	1	8	no statistically significant difference between C_max with and without aluminium magnesium hydroxide	no
		T _max	1	8	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefteram pivoxil	antacid	AUC	1	7	no statistically significant difference between AUC with and without aluminium hydroxide	no
		C _max	1	7	no statistically significant difference between C_max with and without aluminium hydroxide	no
		T _max	1	7	no statistically significant difference between T_max with and without aluminium hydroxide	no
Ceftibuten	antacid	AUC	1	18	no statistically significant difference between AUC with and without aluminium magnesium hydroxide	no
		C _max	1	18	no statistically significant difference between C_max with and without aluminium magnesium hydroxide	no
		T _max	1	18	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no
Cefalexin	beverage	AUC	1	20	AUC ↓ 43% with milk	yes
		C _max	1	20	C _max ↓ 62% with milk	yes
		T _max	1	20	T _max ↑ 0.5 h with milk	probably no
Cefradine	beverage	AUC	1	16	AUC ↓ 21% with milk	possibly yes
		C _max	1	16	C _max ↓ 54% with milk	yes
		T _max	1	16	no statistically significant difference between T_max with milk and with water	no
Cloxacillin	food	C _max	1	23	C _max ↓ 59% with a standard meal	yes
		T _max	1	23	T _max ↑ 1 h with a standard meal	possibly yes
Cyclacillin	beverage	AUC	1	27	no statistically significant difference between AUC with milk and with water	no
		C _max	1	27	no statistically significant difference between C_max with milk and with water	no
		T _max	1	27	no statistically significant difference between T_max with milk and with water	no
Flucloxacillin	food	AUC	3	54	conflicting results—AUC from ↓16% to ↑ 52% in a fed state	yes
		C _max	4	66	with a high-fat meal: C_max ↓ 54% with a standard meal: C_max ↓ 10%–29%	yes
		T _max	3	35	T _max ↑ 1–1.2 h in a fed state	possibly yes
Oxacillin	food	C _max	1	23	C _max ↓ 60% with a standard meal	yes
		T _max	1	23	T _max ↑ 1 h with a standard meal	possibly yes
Penicillin G	beverage	AUC	1	14	AUC ↓ 41% with milk	yes
		C _max	1	14	C _max ↓ 37% with milk	yes
		T _max	1	14	no statistically significant difference between T_max with milk and with water	no
	food	C _max	1	16	no statistically significant difference between C_max in the fed and fasted state	no
		T _max	1	16	T _max ↑ 4 h with a standard meal	yes
Penicillin V	beverage	AUC	1	16	AUC ↓ 37% with milk	yes
		C _max	1	16	C _max ↓ 48% with milk	yes
		T _max	1	16	no statistically significant difference between T_max with milk and with water	no
	food	AUC	2	62	for liquid formulations (drops, solutions, suspensions): AUC ↓ 14%–67% in a fed state no data for other formulations	yes
		C _max	6	154	for liquid formulations (drops, solutions, suspensions): C_max ↓ 29%–78% in a fed state for tablets: C_max ↓ 31%–69% in a fed state for capsules: C_max ↑ 23% in a fed state	yes
		T _max	5	142	for tablets: T_max ↑ 0.5–1.5 h in a fed state for other formulations: no statistically significant difference between T_max in the fed and fasted state	possibly yes
Pivampicillin	antacid	AUC	1	8	AUC ↓ 28% with magnesium aluminium silicate	possibly yes
		C _max	1	8	no statistically significant difference between C_max with magnesium aluminium silicate and with water	no
		T _max	1	8	no statistically significant difference between T_max with magnesium aluminium silicate and with water	no
Sultamicillin	beverage	AUC	1	20	no statistically significant difference between AUC with milk and with water	no
		C _max	1	20	no statistically significant difference between C_max with milk and with water	no
		T _max	1	20	no statistically significant difference between T_max with milk and with water	no
	food	C _max	2	16	C _max ↓ 38%–54% in a fed state	yes
		T _max	2	16	T _max ↑ 1.5 h in a fed state	yes
Tebipenem pivoxil	antacid	AUC	1	20	no statistically significant difference between AUC with and without aluminium magnesium hydroxide	no
		C _max	1	20	C _max ↓ 23% with aluminium magnesium hydroxide	possibly yes
		T _max	1	20	no statistically significant difference between T_max with and without aluminium magnesium hydroxide	no

Open in a new tab

Summary of results

Clinically important interactions

In Figures 3 and 4, we present the summaries of results based on quantitative and qualitative analyses. Of 25 β-lactams for which data on food impact were available, we found clinically important interactions with food for 19 antibiotics (76%). The majority of these interactions resulted in a decrease in drug absorption. We observed the highest negative impact of food (AUC or C_max decreased by more than 40%) for ampicillin, cefaclor [immediate-release (IR) formulations], cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive impact (AUC or C_max increased by more than 45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil [extended-release (ER) tablets].

Figure 3. — Summary of results regarding the impact of dietary interventions on the bioavailability of β-lactam antibiotics and their comparison with the recommendations given in SmPCs.

Figure 4. — The magnitude of the impact of dietary interventions on β-lactam antibiotic bioavailability.

The influence of antacids and mineral supplements was tested for 13 drugs, and clinically significant lower bioavailability was noted for 4 (31%), with the highest negative impact for cefdinir (after intake with iron salts) and moderate for cefpodoxime proxetil (after coadministration with antacids).

Data for beverage impact were limited to 11 compounds; in the presence of milk, the extent of absorption was substantially decreased (by more than 40%) for 4 β-lactams (cefalexin, cefradine, penicillin G and penicillin V) and moderately decreased for cefaclor, whereas it was moderately increased for cefuroxime.

Differences from recommendations in SmPCs

As seen in Figure 3, there are several discrepancies between the recommendations given in the SmPCs of β-lactam antibiotics and the results of our study. The most prominent differences concern cefaclor (IR formulations), cefradine and sultamicillin, for which we established a high negative food impact, and cefuroxime (tablets), with an observed high positive food impact. In contrast, according to SmPCs, all these drugs can be taken regardless of meals.

Additionally, we observed moderate food influence for amoxicillin (IR formulations), cefdinir and cefalexin, suggesting that intake on an empty stomach should be preferable. However, in SmPCs, taking these antibiotics with or without food is recommended.

For cefprozil and ceftibuten (tablets), the impact of food on absorption was low but potentially clinically important. Hence, the intake while fasting could be optimal. With reference to SmPCs, both antibiotics can be administered without regard to meals. Given the low amplitude of the food effect, the patient’s comfort and personal preferences regarding the administration regimen may be of primary importance.

According to the SmPC, penicillin V capsules should be taken on an empty stomach (similar to the other formulations: tablets and liquids). In our study, we did not confirm the negative influence of food on capsules; on the contrary, it is the only penicillin V formulation potentially unaffected by simultaneous intake with meals.

Regarding the influence of antacids and mineral supplements, in the SmPCs of cefaclor and cefditoren pivoxil, avoiding concomitant intake of these antibiotics with di- and trivalent metals preparations is recommended. However, our analyses did not reveal the clinically important negative impact of antacids/mineral supplements, suggesting that the interval between their administration and cefaclor/cefditoren pivoxil intake is unnecessary.

We found no information in SmPCs about the optimal administration of β-lactam antibiotics concerning beverages. Our study partially covered the existing gaps in knowledge in this field. However, for most β-lactams, we still do not possess any data on the potential impact of beverages on absorption.

Discussion

Factors potentially affecting the interactions

Results of our review suggest that the impact of food, antacids, mineral supplements and beverages on the PK parameters and PK/PD indices of β-lactam antibiotics is significant and diverse. The overall heterogeneity of analysed studies was high, which suggests a multifactorial basis of interactions. Based on quantitative and qualitative analyses, we discuss several factors that may potentially contribute to the variable effects of tested interventions.

Physicochemical properties of drugs

In Figure 5, we present the physicochemical properties of β-lactam antibiotics concerning the food effect. Individual β-lactam antibiotics differ in terms of solubility in water; however, it is a group of generally hydrophilic compounds with logarithm of partition coefficient (log P) values indicating low (log P < 0) or moderate lipophilicity (0 < log P < 3). Regarding the Biopharmaceutical Classification System (BCS), the members of all four classes are present, but the BCS class was not specified for a substantial number of drugs.

We observed a positive impact of food (increased drug absorption) for cefetamet pivoxil, which belongs to the II BCS class, and for cefuroxime axetil, cefditoren pivoxil and cefpodoxime proxetil, which are classified either as II or IV BCS class antibiotics. It is consistent with the fact that members of the II BCS class have low solubility in water and high intestinal permeability—food usually positively impacts their absorption, e.g. by improving the dissolution of lipophilic drugs.¹⁸⁰

For IV BCS class drugs, on the contrary, the solubility and permeability are low, so their bioavailability is often poor, and the impact of food may vary depending on an individual drug. This applied to β-lactam antibiotics, as we observed a neutral food effect for cefixime, whereas for cefdinir, ceftibuten, cloxacillin, penicillin V and sultamicillin, absorption was decreased in the presence of meal.

For β-lactams from the III BCS class, ampicillin, cefaclor, cefprozil, cefroxadine, cefradine and oxacillin, we noted the lower bioavailability in the fed state, as these drugs have a low permeability rate but dissolve fast, so that food may adversely alter their dissolution process.¹⁸⁰

Drug formulation

It is well established that appropriately designed drug formulation may help optimize the treatment and overcome food effects on drug bioavailability.¹⁸¹

Modified-release (MR) formulations offer controlled and sustained drug release. Specifically for β-lactam antibiotics with time-dependent action and short half-lives, these formulations could help to maintain consistent drug levels over a prolonged period, potentially reducing dosing frequency while ensuring sustained efficacy against bacterial infections. Mitigating the need for frequent dosing may improve patient compliance and convenience.^182,183 During quantitative synthesis, we used drug formulation as a grouping variable in subgroup analyses, and for three drugs, amoxicillin, cefaclor and tebipenem pivoxil, different drug formulations (MR versus IR) explained the heterogeneity of studies.

For the majority of amoxicillin formulations, food generally decreased drug bioavailability. However, Weitschies et al.¹⁷¹ observed higher values of AUC for ER tablets under fed conditions. The authors suggested that the reduced bioavailability of the ER amoxicillin formulation in the fasting state could be due to early gastric emptying and, in consequence, antibiotic release in the distal parts of the small intestine (jejunum and ileum), where the absorption is lower than in the proximal part (duodenum).¹⁷¹

Similarly, significantly higher values of both AUC and C_max occurred in the presence of food for ER and MR cefaclor tablets.^86,103 Interestingly, Khan et al.⁸⁶ observed increased drug bioavailability for high-fat non-vegetarian and low-fat vegetarian meals. Food affects the rate of drug absorption for the remaining cefaclor formulations, causing a significant decrease in C_max and prolongation of T_max.

Eckburg et al.⁴⁵ tested several different experimental formulations of tebipenem pivoxil and compared their postprandial bioavailability with marketed formulations (granules). Interestingly, for 6 and 12 h ER tablets, the researchers observed significantly improved AUC (by an average of 93%) and C_max (by an average of 43%). In contrast, the impact of food varied from neutral to negative for the remaining formulations (2 and 4 h ER tablets, IR tablets and granules). Based on the results of other studies included in this review, the tebipenem pivoxil formulation that can be negatively affected by the interaction with food is granules—although no significant changes in AUC were reported, substantial decreases in C_max occurred, by on average 48%.^45,119,120 For IR tablets, postprandial changes in C_max are probably not clinically important.^{45,70,121,122}

These results align with the hypothesis that the impact of food on ER products primarily arises from intestinal region-dependent absorption.¹⁸⁴ According to Zou et al.,¹⁸⁴ consuming food tends to increase rather than decrease the exposure to ER formulations because it prolongs the transit time, leading to enhanced absorption in the small intestine.

β-Lactam antibiotics often serve as a first-line antimicrobial treatment in paediatric and elderly patients. In both populations, liquid formulations are frequently used for precise dosing adjustments based on weight, ensuring accurate antibiotic administration and for easier ingestion in case of swallowing difficulties. While liquids offer more rapid absorption due to their pre-dissolved state, solid formulations might provide sustained-release characteristics and better stability in the gastrointestinal tract.¹⁸⁵ We found diverse impacts of food for solid versus liquid formulations of cefetamet pivoxil, cefpodoxime proxetil and penicillin V.

Our meta-analyses of the Koup et al.⁹⁰ and Tam et al.¹⁵⁹ studies indicated a slight but possibly clinically significant postprandial increase in AUC and C_max of cefetamet pivoxil tablets. Additionally, Blouin et al.³³ observed statistically significant higher absolute bioavailability (up to 25%) of tablets in a fed versus fasted state. In contrast, Ducharme et al.⁴⁴ tested the syrup formulation of cefetamet pivoxil and did not observe any postprandial changes in the absolute bioavailability and C_max, but T_max after the meal was longer by 2 h.

Similarly, for cefpodoxime proxetil, several authors observed that taking tablets with meals may result in significantly increased AUC and C_max,^38,77 whereas, for oral suspension, the food effect on these parameters seemed neutral.^36,37,54 For syrup formulation, data were conflicting (from neutral⁷⁸ to the positive impact^89,168 of food). However, only for liquid formulations (oral suspension and syrup) was the postprandial rate of cefpodoxime proxetil absorption slower (T_max increased by 1–3 h), and no such changes occurred for tablets.

Regarding penicillin V, capsules were the most resistant to interactions with food—their intake with standard meals slightly increased C_max by 22%.¹⁰⁵ Food negatively affected AUC and C_max for all the remaining penicillin V formulations, such as oral solution,⁵¹ oral suspension^35,46,69,146 or tablets.⁴⁰

The possible explanation for the observed disparity in food effects between liquid and solid β-lactam formulations could be their different state upon ingestion. Solid tablets require disintegration and dissolution before absorption, and these processes may be enhanced by food.¹⁸⁵ Conversely, liquid formulations are already in a pre-dissolved or suspended state, experiencing less influence from food on dissolution or solubility in the stomach. Additionally, their transit time in a fasted state is substantially more rapid than that of solid formulations.¹⁸⁵ Thus, the effect of food on the extent of absorption tends to be less significant for liquid forms, whereas the rate of absorption can be significantly slower.

Drug dose

In several studies included in our review, different doses of β-lactams were examined to establish whether antibiotic–food interactions can be dose-dependent.

Toyonaga et al.¹⁶⁴ investigated the impact of varying doses of amoxicillin—7.5, 10, 15 and 20 mg/kg under fed and fasted conditions. The research revealed a significant decrease in C_max (by 46%–52%) and an increase in T_max by 0.5–1.5 h for the lowest (7.5 mg/kg) and highest (20 mg/kg) doses. Conversely, the intermediate doses exhibited no significant effect on C_max and T_max. The authors did not provide a possible explanation for these differences. Moreover, their results should be cautiously interpreted, as different children were analysed for each dose and condition, potentially introducing intrasubject variability in PK profiles.

Additionally, Ginsburg et al.⁵⁹ examined amoxicillin doses of 15 and 25 mg/kg with and without milk. While there were no significant changes in the AUC and T_max for both doses, only the 15 mg/kg dose showed a marked reduction of 41% in C_max when administered with milk. However, limitations arose from using separate groups of children for each dose and different study designs, potentially impacting the study’s findings.

Across trials investigating the impact of food or milk on varied doses of bacampicillin (400 and 800 mg)^102,124 and cefadroxil (250 mg, 500 mg, 10 mg/kg, 15 mg/kg),^43,62 a consistent pattern emerged: there were no significant changes in drug absorption after dietary interventions regardless of the antibiotic dose.

Studies examining different doses of cefaclor (10 and 15 mg/kg),¹⁰⁷ cefpodoxime (3 and 6 mg/kg)⁵⁴ and flucloxacillin (500 and 1000 mg)⁸¹ consistently indicated that food intake decreased C_max of these antibiotics by 17%–35% for cefaclor, 21%–26% for cefpodoxime and 26%–29% for flucloxacillin. The impact of food on drug absorption was dose-independent.

In contrast, in a Fujii et al.⁵³ study on cefdinir, two groups of children received 3 or 6 mg/kg doses in fed and fasted conditions.⁵³ A significant 32% decrease in C_max in the fed state occurred for the lower dose, while no significant postprandial changes in PK parameters were observed for the higher one. Fujii et al. suggested that dose-dependent variations in the impact of food on cefdinir absorption may exist.

Studies on cefuroxime axetil indicated a persistent positive impact of food on drug absorption, regardless of the dosage used. Harding et al.⁷³ demonstrated significantly higher postprandial urinary recovery for both 500 and 1000 mg doses. Similarly, Ginsburg et al.⁶³ observed substantial increases in drug exposure (AUC by 26%–41% and C_max by 35%–45%) for doses of 15 and 20 mg/kg.

Eckburg et al.⁴⁵ investigated different doses (300 and 600 mg) and formulations (ER tablets with varying release times, IR tablets, and granules) of tebipenem pivoxil in the fed versus fasted state. The authors suggested that drug formulation rather than dose may influence the impact of food on tebipenem bioavailability (and our meta-analyses confirmed these conclusions). Additionally, Nakashima et al.¹²¹ tested ascending doses of tebipenem pivoxil tablets (100, 200, 300 and 500 mg) in fed and fasted conditions, with a similar neutral food effect regardless of the dose.

To conclude, we found evidence for the possible impact of dosage on the interaction with food only for amoxicillin and cefdinir. However, properly designed studies (with the same group of participants for different doses and interventions) are needed to confirm the dose dependence.

Type of dietary intervention

For many of the previously investigated drugs, the magnitude of the food effect often depended on the type of meal (e.g. high-fat, low-fat, high-protein etc.) and quantitative meal composition (e.g. caloric load, fat content).^180,186 That is why, in our review, we collected available data regarding food, and, where applicable, we used the type of meal as a grouping variable in subgroup analyses. Interestingly, this factor did not explain heterogeneity in any analysed case. Generally, if the overall effect of food on individual β-lactam absorption was negative or positive, such an effect occurred for all types of tested meals. However, in the case of flucloxacillin, we observed substantially lower C_max after intake with the high-fat meal compared with the standard meal (a decrease of 54% and 29%, respectively).^57,81

In meta-analyses regarding the impact of antacids or mineral supplements on cefdinir and cefalexin absorption, we revealed high heterogeneity (above 76%–90%). As only two reports were combined in each synthesis, we analysed studies separately. We found that the impact of antacids or mineral supplements depended on their type for both drugs. Ueno et al.¹⁶⁶ observed that concomitant administration of cefdinir and ferrous sulphate (as a multivitamin preparation or single compound) decreased antibiotic absorption by 31% and 80%, respectively. Authors suggested that this effect could be due to forming of a chelate complex between a 7-hydroxyimino radical of cefdinir and iron ions. Such a complex restricts the gastrointestinal absorption of antibiotic. In contrast, in a study by Kato et al.,⁸⁴ the intake of calcium polycarbophil did not produce significant changes in cefdinir absorption, although sufficient numbers of calcium ions were present to cause formation of cefdinir-calcium chelate complexes in the gastrointestinal tract. Additionally, in an in vitro study, authors observed that the release of cefdinir from the cellulose membrane was slower in the presence of iron but not calcium ions.⁸⁴ These results suggest that chelate complexes do not form between cefdinir and calcium ions.

For cefalexin, Deppermann et al. ¹⁰ did not observe significant impairment of absorption after co-intake with an antacid containing aluminium magnesium hydroxide. On the contrary, in a study by Ding et al.,⁴² when cefalexin was ingested with zinc sulphate preparation, AUC, C_max and T_>MIC decreased significantly (by 27%, 31% and 24%, respectively). Possibly, zinc acts as a competitive inhibitor of the peptide transporter 1 (PEPT1) that is engaged in the uptake of β-lactams from the gastrointestinal tract.⁴² Another explanation could be the chelation of cefalexin with zinc; however, the lack of interaction with aluminium magnesium hydroxide does not support this hypothesis.⁴²

Regarding the impact of beverages, we found evidence only for two types of interventions: cranberry juice and milk. The effect of cranberry juice was tested for amoxicillin and cefaclor; in both cases, no significant changes in drug absorption occurred.⁹⁶ The impact of milk consumption was investigated solely in the paediatric population, with results varying for individual drugs (see Figure 3 for more details). Ginsburg et al.⁶³ observed enhanced absorption of cefuroxime axetil with milk. Non-specific esterases hydrolyse this ester pro-drug in the intestinal wall to the active drug (cefuroxime). The most probable mechanism for positive interaction is that prolonged intestinal transit in the fed state (after milk or food consumption) provides optimal conditions for hydrolysis and absorption.⁶³ On the contrary, the bioavailability of cefalexin, cefradine, penicillin G and penicillin V significantly decreased after co-intake with milk.^60,106 The mechanisms for the negative interaction with milk were not proposed. We hypothesize that cefalexin and cefradine may form chelate complexes with calcium from milk, but we did not find evidence in the literature to support this assumption. For cefadroxil, a meta-analysis of two studies revealed that the C_max in the presence of milk is slightly but significantly decreased. However, the studies’ authors did not consider changes in C_max to be clinically significant.⁵⁸ Additionally, in the later study, which was not included in the meta-analysis due to reporting PK values without standard deviations, no significant changes occurred in cefadroxil absorption after administration with milk.⁶² Given the available evidence, we decided to judge the impact of milk on cefadroxil bioavailability as neutral.

Patient age

Differences in the physiology of paediatric patients compared with adults can significantly influence the PK of drugs.¹⁸⁷ Regarding the impact of mineral supplements, all analysed reports involved healthy adult volunteers. In contrast, most studies testing the effects of beverages (especially milk) were performed on paediatric patients. Only two studies investigating the effect of cranberry juice consumption were conducted in the adult population. Hence, we did not obtain sufficient evidence for those interventions to discuss the possible differences due to patient age. However, for 14 β-lactam antibiotics, we found separate food-effect studies of children with infection and healthy adults. In most reports, the meal’s qualitative and quantitative impact was similar, regardless of age. In meta-analyses of amoxicillin and cefdinir, we used participants’ age as a grouping variable, but it did not explain the heterogeneity of studies.

In one study, Ginsburg et al.⁶³ compared the postprandial bioavailability of cefuroxime axetil in adults and children. In both populations, intake of light meals significantly improved cefuroxime absorption, regardless of the participants’ age.

For flucloxacillin, the food effect may be age-dependent. Bergdahl et al.³² analysed antibiotic bioavailability in three age groups: newborns (0–1 month), infants (1–5months) and young children (6 months to 4 years). In the fasting state, the highest AUC of flucloxacillin was in the infants group and the lowest in young children. Flucloxacillin is mainly excreted through the kidneys, and most of the drug is recovered unaltered. The renal excretion of unchanged drugs is generally lower in newborns and infants.¹⁸⁷ This may result in maintaining the plasma flucloxacillin concentration higher for a longer time in these age groups. Additionally, newborns and children above 6 months were tested in the fed state. Interestingly, in the youngest participants, flucloxacillin bioavailability improved after meals, whereas in the older children, food intake did not influence drug concentration. Bergdahl et al. did not explain these results; possibly prolonged gastric emptying and reduced intestinal motility in newborns may improve drug bioavailability despite the presence of meals.¹⁸⁷

Blouin et al.³³ compared the PK of cefetamet pivoxil in elderly and young participants and assessed the impact of food in both groups. The only significant age-related change, both in fed and fasted conditions, was the increase in plasma half-life in elderly patients (due to the reduced renal clearance). However, the postprandial absorption characteristics of cefetamet were similar in both populations.

Health state of patients

Seventy-three percent of the reports analysed in our review involved healthy adult volunteers, which aligns with FDA recommendations. Most studies recruiting infected individuals were conducted in the paediatric population (due to ethical considerations). We found only two reports that considered the impact of a patient’s health state while investigating the food effect.

In the first study, Sabto et al.¹⁴² compared pre- and postprandial amoxicillin PK in dialysed patients. The peak blood levels of antibiotics were similar in the absence and presence of food but significantly higher than in patients with normal renal function.

In the second study, Bolme et al.³⁵ administered penicillin V oral suspension (20 mg/kg) to children with different nutritional statuses (normal, underweight, marasmus and kwashiorkor). Although the postprandial absorption of penicillin V was lower in all groups, the most significant difference between fasting and non-fasting states occurred for children with marasmus and kwashiorkor. Substantially decreased absorption could be due to malnutrition-related villous atrophy or oedema in the intestinal wall in kwashiorkor status. In severely malnourished children, Bolme et al.³⁵ advised changing the penicillin V administration route to IV or giving the antibiotic in the fasting state.

Secondary PK outcomes

Elimination half-life (t_½)

Most β-lactams have relatively short elimination t_½s of 0.5 to 2 h, except for several cephalosporins, e.g. cefixime and cefpodoxime, with t_½ reaching up to approximately 3–4 h and 2–3 h, respectively.¹⁸⁸ Theoretically, food intake may indirectly affect t_½ by delaying/accelerating drug absorption.

For 21 β-lactams (84%), t_½ was examined in fasted and fed conditions. For the majority of drugs, no significant postprandial changes occurred. However, Welling et al.¹⁷² and Hamid et al.⁷² observed that ampicillin was eliminated significantly more slowly after the meal (t_½ longer by 30–40 min). The authors proposed that the prolonged elimination t_½ in the fed state could be due to the continued absorption of small amounts of antibiotics during the post-absorptive phase. Additionally, in single reports for cefaclor¹⁷⁵ and cefdinir,¹¹¹ prolonged t_½ occurred (by 1 h 20 min and 55 min, respectively). However, no such changes were observed in the remaining studies for either drug, so it is difficult to draw conclusions given these conflicting results. Interestingly, for tebipenem pivoxil, Eckburg et al.⁴⁵ observed significantly shorter postprandial t_½ (by 2.5 h); however, this was only for the 600 mg 12 h ER tablet. For other tebipenem pivoxil doses and experimental formulations, terminal t_½ was not affected by food. The authors did not comment on that result.

Regarding the impact of antacids/mineral supplements on t_½, we found data for nine β-lactams (69%), and no significant changes occurred in any of the studies (for details, refer to Supplementary Material 4). Similarly, beverages did not substantially influence the elimination t_½ of all 11 β-lactams for which data were available.

V_d

β-Lactams are small, hydrophilic compounds, with V_d usually below 0.6 L/kg (which is considered low, according to the classification proposed by Smith et al.).¹⁸⁹ The main factors influencing V_d value can be patient-related (e.g. age, gender, muscle and fat mass, body water volume etc.) and drug-related (e.g. molecular size, charge, lipophilicity etc.).¹⁹⁰ After single-dose administration, alterations in drug concentration due to dietary interventions, theoretically, should not impact the V_d.

However, of six β-lactams (24%) for which V_d was included as one of the investigated PK parameters, significant postprandial changes were observed for cefdinir, cefuroxime and tebipenem pivoxil. Nakamura et al.¹¹⁶ administered cefdinir in fed versus fasted conditions to different age groups of children: infants (<1 year old), young children (1–6 years old) and schoolchildren (7–10 and 7–14 years old). A substantial postprandial increase in V_d occurred for young children and schoolchildren between 7 and 10 years old—by 139% and 97%, respectively. In the remaining groups, V_d was unchanged after the meal. In contrast, Wang et al.¹⁷⁰ observed significantly reduced apparent V_d of cefuroxime (by 38%) after intake of food. Tebipenem pivoxil exhibited a substantial 84% reduction in postprandial V_d when administered as an experimental 12 h ER tablet. In contrast, the tablet with a 2 h ER formulation demonstrated a 52% increase in postprandial V_d.⁴⁵ Neither group of authors commented on these results nor provided possible explanations.

In reports investigating the impact of antacids/mineral supplements, V_d appeared among PK parameters for five β-lactams (42%). Saathoff et al.¹⁴¹ revealed significantly increased V_d (by 68%) after cefpodoxime proxetil co-intake with aluminium and magnesium-containing antacids. Of studies regarding beverages, only one report concerning amoxicillin included information about pre- and postprandial values of V_d; no significant changes were observed.⁸⁷

CL

Most β-lactams are primarily eliminated through kidneys, and their CL mainly depends on renal function, age and concomitant diseases (e.g. sepsis).¹⁹¹ Although food intake does not directly influence clearance, postprandial drug absorption and distribution changes may indirectly affect this PK parameter.¹⁹²

The comparative investigation of CL in both fed and fasted states encompassed nine β-lactams (36%). A significant reduction in CL was observed for cefuroxime axetil and the experimental 12 h ER tablet of tebipenem pivoxil (declines of 34% and 63%, respectively) following antibiotic administration with a high-fat meal.^45,170 Fat-rich meals may delay gastric emptying and prolong residence time in the intestine, resulting in a higher AUC of both drugs. Together with the decreased apparent V_d, these factors may correlate with the lower postprandial apparent CL.¹⁷⁰

Of studies assessing the impact of antacids/mineral supplements and beverages, CL was examined for 3 (25%) and 2 (18%) β-lactams, respectively. Significant changes due to dietary interventions occurred in none of the reports (see Supplementary Material 4).

PK/PD indices

The analysis of PK/PD indices rather than PK parameters alone is of greater clinical relevance, as it provides a more complete understanding of the drug’s behaviour in the presence of food. However, we found data regarding the impact of dietary interventions on the PK/PD indices only for amoxicillin, cefaclor, cefprozil, cefalexin and flucloxacillin. The effect varied depending on the antibiotic and nutritional conditions.

Amoxicillin

Khuroo et al.⁸⁷ observed that different meals (high- or low-fat, vegetarian or non-vegetarian) had no significant effect on T_>MIC compared with fasting. However, the impact of diets was notable when considering the AUC/MIC index. The most significant decreases in AUC/MIC occurred for non-vegetarian meals: 49% and 54% for high-fat and low-fat, respectively. Only for amoxicillin co-intake with milk was AUC/MIC unaffected. Amoxicillin exhibits both time-dependent and concentration-dependent bactericidal activity, emphasizing the importance of maintaining plasma concentrations to achieve effective antimicrobial activity. Our meta-analyses revealed the negative impact of food on C_max of amoxicillin (except for ER tablets). Hence, PK data and postprandial changes in the AUC/MIC index support the use of amoxicillin while fasting.

Cefaclor

As we previously discussed, the effect of interaction with food depends on cefaclor formulation. For IR capsules, Karim et al.⁸² observed no significant changes in T_>MIC50 after cefaclor intake with different meals (when compared with a fasting state). However, vegetarian diets led to a significantly greater T_>MIC50 than non-vegetarian diets. Additionally, all meals resulted in a substantially increased time to reach the MIC₅₀ compared with fasting, with the high-fat non-vegetarian diet causing the maximum delay (by 1 h) and the low-fat non-vegetarian diet causing the minimum delay (by 0.5 h). The time to reach MIC is not an established PK/PD index for β-lactams; however, Karim et al. hypothesized that the delay in achieving the minimum efficacy level may potentially compromise an antibiotic therapy’s effectiveness.

On the contrary, for ER tablets of cefaclor, Khan et al.⁸⁶ reported that all tested diets (high- or low-fat, vegetarian or non-vegetarian) increased T_>MIC90 compared with the fasting state, with the low-fat vegetarian meal showing a statistically significant increase (by 0.5 h). An increased T_>MIC allows the antibiotic to maintain adequate concentrations in the body for longer, leading to enhanced bactericidal activity, optimal therapeutic effect, and minimized development of antibiotic resistance.

Cefprozil

According to Li et al.,⁹⁷ for cefprozil, there were no significant differences in T_>MIC90 against Streptococcus pneumoniae and Staphylococcus aureus between fed and fasting conditions. Although the food intake had no notable impact on the T_>MIC of cefprozil for these bacterial strains, a significant postprandial decrease in C_max and an increase in T_max were observed in several other studies. For these reasons, we judged the overall impact of food on cefprozil absorption as negative.

Cefalexin

Ding et al.⁴² investigated the effect of zinc sulphate administered concurrently with cefalexin, finding that zinc supplements decreased the T_>MIC by 25% when used with antibiotic. This decrease in T_>MIC could potentially result in clinical failure, especially for individuals receiving doses of cefalexin lower than the standard maximal dose used in the study (500 mg) or with longer dosing intervals. Therefore, Ding et al. suggested the potential interaction with zinc supplements should be considered when prescribing cefalexin.

Flucloxacillin

In our review, we judged the overall food effect on flucloxacillin absorption as negative based on several studies reporting decreased bioavailability in the presence of food (especially rich in fat). However, two recent reports questioned the recommendation to take flucloxacillin on an empty stomach based on the PK/PD indices analysis.

In the first study, comparing flucloxacillin intake with food and while fasting, Gardiner et al.⁵⁷ investigated how a meal affects free plasma flucloxacillin concentrations exceeding specific thresholds (30%, 50% and 70%) over 6 and 8 h intervals. Only the fed/fasting ratios of free concentrations exceeding 30% of the first 6 and 8 h after the dose showed statistical inferiority of the fed state. The study also examined the PTA—achieving the desired free flucloxacillin concentrations above a certain MIC. The pre- and postprandial PTAs were generally similar, especially for a target MIC of 0.25 mg/L (corresponding to most strains of bacteria causing mild to moderate skin and soft tissue infections, including β-haemolytic streptococci). However, for an MIC of 0.5 mg/L (specific for some S. aureus strains), the fasting state was slightly beneficial in achieving the target concentration over a 30% dose interval. Gardiner et al.⁵⁷ concluded that taking flucloxacillin with food does not compromise effective plasma concentrations and may improve patient compliance in most clinical circumstances.

In the second study, Everts et al.⁴⁸ administered flucloxacillin alone or with probenecid in a fasting/fed state.⁴⁸ The concentrations of free flucloxacillin exceeding 30%, 50% and 70% of 6, 8 and 12 h dose intervals were estimated, and no significant differences occurred between probenecid fasting and fed conditions. Moreover, when considering a target MIC of 0.5 mg/L, the probability of achieving effective flucloxacillin concentrations was consistently higher when administered with probenecid, regardless of whether it was taken with or without food. Everts et al.⁴⁸ suggested that co-intake of probenecid with flucloxacillin significantly enhances antibiotic effectiveness and may help overcome the negative food effect.

Limitations of studies included in the review

Actuality of studies

Our systematic review included food-effect studies regardless of the publication year. It was done to ensure the broadest possible evidence pool, especially given that β-lactams are a relatively old group of antibiotics, and food-effect studies were performed usually upon introducing drugs to the market. Hence, the oldest analysed report was from 1960, and many studies were published in the 1970s, 1980s or 1990s. These earlier reports often provided only elementary methodological descriptions, which complicated the risk-of-bias assessment.

Methodology of studies

Just over half of analysed food-effect studies followed the study design recommended by FDA guidelines (which is open-label, crossover). A possible explanation could be that the first FDA recommendations were not published until 2002, and most included studies were performed earlier than that. Various concerns arose regarding the crossover design strategy during the risk-of-bias assessment, such as the absence of separate data from each trial period, incomplete disclosure of the participant count within study sequences, and too short durations of washout periods.

Only 57% of crossover and 33% of all investigated studies were randomized. Unfortunately, most randomized trials failed to provide comprehensive details about the randomization process (the phrase ‘randomized’ was the only mention). This leaves ambiguity about the true randomness and concealment of the allocation sequence.

Another concerning fact is that the study design remained unspecified for 15 studies. Hence, we could not assess the quality of those trials and include them in the quantitative synthesis.

Additionally, we observed differences in the bioanalytical methodology of analysed studies. In older reports, from the 1960s to early 1990s, researchers determined plasma concentrations of antibiotics using primarily microbiological assays, with different methods and assay microorganisms often used. Starting in the 1990s, with the development of more modern and precise technologies, determining antibiotic concentrations by high-performance liquid chromatography (HPLC) and liquid chromatography - tandem mass spectrometry (LC-MS/MS) has become increasingly popular. Combining the results of studies that used different bioanalytical methods may increase heterogeneity.

Concerns related to participants

The number of participants in investigated trials was generally small, with 39% of the studies recruiting fewer than 12 volunteers (the minimal sample size recommended by the FDA in 2002 guidelines). As previously mentioned, most studies involved healthy adult volunteers, which may limit the results’ applicability to the target population.

Another significant limitation is the lack of detailed participant characteristics. In 28% of studies, gender was not specified, and 55% lacked information about the participants’ race. Among the studies that did address these factors, African Americans were substantially under-represented (appeared in only 4% of studies). Given all these factors, translating the studies’ results into clinical practice could be challenging.

Significant gaps in data

Our meta-analyses suggest that drug formulation might significantly influence the extent of the food effect on specific β-lactam antibiotics. Nevertheless, a substantial number of the examined drugs lacked assessments for all available formulations in the presence of food. Moreover, several studies did not clarify which drug formulation was under investigation.

Although in our meta-analyses the type of meal did not explain the studies’ heterogeneity, the different effects of various meals on absorption of β-lactam antibiotics cannot be ruled out due to the gaps in data. In 31% of studies, the type of meal was not specified, and 78% did not mention the meals’ quantitative and/or qualitative composition. Another recurring concern was the substantial variance in qualitative and quantitative components even among identical meal types (e.g. high-fat, high-protein, low-fat etc.).

Considering all the limitations outlined above, we categorized the studies included in this review as carrying a moderate or high risk of bias (refer to Supplementary Material 5 for more detailed information).

Limitations of the review

The primary constraint within our study is the unequal distribution and quality of evidence concerning interactions between β-lactam antibiotics and dietary interventions (food, antacids, mineral supplements and beverages). We found no studies addressing the research question for 6 of 32 analysed antibiotics: azidocillin, carbenicillin, carindacillin, cefotiam, dicloxacillin and propicillin. Of the remaining 26 β-lactams, 19 were excluded from quantitative analysis for at least one of the interventions, usually because the data were limited to only one report or the study design was not sufficiently described.

Although we were able to perform meta-analyses of evidence for 18 β-lactams, many studies were ineligible for inclusion in the quantitative synthesis. The primary causes of exclusion were the absence or incomplete data on outcomes under investigation or the inappropriate or uncertain study design. In total, we were forced to exclude 52 studies, which could result in a significant loss of potentially important results regarding the impact of dietary interventions.

As combining reports with different study designs in the same meta-analysis is the wrong approach, in cases of many drugs we needed to perform several syntheses for each outcome. As a result, the average number of studies in a single meta-analysis was 3–4. Additionally, sometimes analyses of the same outcome provided different results, which makes the interpretation harder.

Following the Cochrane guidelines, a minimum of over 10 studies is recommended for conducting subgroup analysis and assessing funnel plot asymmetry. In our review, we reached the number of 11 studies for only two meta-analyses (both performed for cefaclor). At the stage of protocol preparation, we predicted the overall heterogeneity to be high, so we decided to perform subgroup analyses if potential grouping factors were present and at least two studies were in each subgroup. This approach allowed us to identify the drug formulation (and not the type of meal) as a possible factor explaining the heterogeneity in some studies; however, we advise prudent interpretation of these results due to the abovementioned limitations.

Summary

Optimizing β-lactam antibiotic use is an emerging issue due to the growing number of resistant bacterial strains. Dietary interventions may significantly impact the bioavailability and action of β-lactam antibiotics. The type and magnitude of the effect vary for individual drugs. Several factors can influence interactions, such as physicochemical features of antibiotic compounds, drug formulation, type of intervention, and the patient’s health state.

Our review provides comprehensive evidence on the impact of food, antacids, mineral supplements and beverages on the PK parameters and PK/PD indices of individual β-lactam antibiotics. However, the quality of evidence is low due to the poor actuality and diverse methodology of included studies and unproportionate evidence for individual drugs. Well-designed clinical trials assessing interactions between β-lactams and nutrients are strongly needed to fill the existing knowledge gaps and provide more reliable sources of evidence.

Supplementary Material

dkae028_Supplementary_Data

dkae028_supplementary_data.docx^{(2.5MB, docx)}

Contributor Information

Agnieszka Wiesner, Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, Krakow, Poland; Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

Paweł Zagrodzki, Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

Paweł Paśko, Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

Funding

This work was supported by a grant from the Faculty of Pharmacy under the Strategic Programme Excellence Initiative at Jagiellonian University (Research Support Module, project number: U1C/W42/NO/28.15).

Transparency declarations

None to declare.

Author contributions

Conceptualization: Paweł Paśko, Agnieszka Wiesner, Paweł Zagrodzki; systematic literature search: Agnieszka Wiesner, Paweł Paśko; data collection and extraction: Agnieszka Wiesner, Paweł Paśko; study risk-of-bias assessment: Agnieszka Wiesner, Paweł Paśko; data analysis and interpretation: Agnieszka Wiesner; writing—original draft preparation: Agnieszka Wiesner; writing—review and editing: Agnieszka Wiesner, Paweł Paśko, Paweł Zagrodzki; supervision: Paweł Paśko.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Supplementary data

Supplementary Materials 1–8 are available as Supplementary data at JAC Online.

References

1. Pandey N, Cascella M. Beta-lactam antibiotics. In: StatPearls. StatPearls Publishing, 2022. https://www.ncbi.nlm.nih.gov/books/NBK545311/. [PubMed] [Google Scholar]
2. Mora-Ochomogo M, Lohans CT. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med Chem 2021; 12: 1623–39. 10.1039/D1MD00200G [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Choi U, Lee CR. Distinct roles of outer membrane porins in antibiotic resistance and membrane integrity in Escherichia coli. Front Microbiol 2019; 10: 953. 10.3389/fmicb.2019.00953 [DOI] [PMC free article] [PubMed] [Google Scholar]
4. ECDC . Antimicrobial Resistance in the EU/EEA—a One Health Response. 2022. https://www.ecdc.europa.eu/sites/default/files/documents/antimicrobial-resistance-policy-brief-2022.pdf.
5. Veiga RP, Paiva JA. Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients. Crit Care 2018; 22: 233. 10.1186/s13054-018-2155-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Vinks AA, Mouton JW, Derendorf H. Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics. Springer, 2014. [Google Scholar]
7. Dzierżanowska D. Walka z zakażeniami [Fight against infections]. In: Antybiotykoterapia Praktyczna [Antibiotic therapy in Practice]. Alfa Medica Press, 2018; 714. [Google Scholar]
8. Zachwieja Z. Interakcje leków z pożywieniem [Interactions between drugs and food]. MedPharm Polska, 2016. https://medpharm.pl/interakcje-lekow/310-interakcje-lekow-z-pozywieniem.html. [Google Scholar]
9. Pino-Marín DE, Madrigal-Cadavid J, Amariles P. Clinical relevance of drug interactions with antibiotics related to changes in the absorption: structured review. CES Medicina 2018; 32: 235–49. 10.21615/cesmedicina.32.3.5 [DOI] [Google Scholar]
10. Deppermann KM, Lode H, Höffken G et al. Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid. Antimicrob Agents Chemother 1989; 33: 1901–7. 10.1128/AAC.33.11.1901 [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Mergenhagen KA, Wattengel BA, Skelly MK et al. Fact versus fiction: a review of the evidence behind alcohol and antibiotic interactions. Antimicrob Agents Chemother 2020; 64: e02167-19. 10.1128/AAC.02167-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
12. Sterne JAC, Savović J, Page MJ et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898. 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]
13. Higgins JPT, Li T, Sterne JAC. Revised Cochrane risk of bias tool for randomized trials (RoB 2.0): additional considerations for crossover trials. Cochrane Methods, 2021. https://www.riskofbias.info/welcome/rob-2-0-tool/rob-2-for-crossover-trials.
14. NIH . Study Quality Assessment Tools. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.
15. Higgins JPT, White IR, Anzures-Cabrera J. Meta-analysis of skewed data: combining results reported on log-transformed or raw scales. Stat Med 2008; 27: 6072–92. 10.1002/sim.3427 [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Wan X, Wang W, Liu J et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135. 10.1186/1471-2288-14-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Deeks J, Higgins J, Altman D. Chapter 10: Analysing data and undertaking meta-analyses (section 10.10.2 - Identifying and measuring heterogeneity). In: Cochrane Handbook for Systematic Reviews of Interventions Version 6.3. Cochrane Collaboration, 2022. [Google Scholar]
18. Bouter KP, Diepersloot RJA, Bourgonjen M et al. Oral pharmacokinetics of cefuroxime axetil in diabetic patients with autonomic neuropathy. Tijdschrift voor Therapie Geneesmiddel en Onderzoek 1993; 18: 73–6. [Google Scholar]
19. Chen RRL, Chung JM, Hsieh WC. Effect of food on the bioavailability of cefpodoxime proxetil in healthy Chinese subjects. Chin Pharm J 1996; 48: 103–12. [Google Scholar]
20. Henness DM, Richards D. Oral bioavailability of cefadroxil, a new semisynthetic cephalosporin. Clin Ther 1978; 1: 263–73. [Google Scholar]
21. Kislak JW, Eickhoff TC, Finland M. Cloxacillin: activity in vitro, and absorption and urinary excretion in normal young men. Am J Med Sci 1965; 249: 636–46. 10.1097/00000441-196506000-00002 [DOI] [PubMed] [Google Scholar]
22. Health Products Regulatory Authority . Pinaclor (Pinewood Laboratories). Summary of Product Characteristics. https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA0281-155-003_27052019144542.pdf.
23. FDA . Ceftin (GlaxoSmithKline). Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050605s042lbl.pdf.
24. FDA . Guidance for industry: food-effect bioavailability and fed bioequivalence studies. 2002. https://www.fda.gov/files/drugs/published/Food-Effect-Bioavailability-and-Fed-Bioequivalence-Studies.pdf.
25. Akimoto Y, Uda A, Omata H et al. Cephalexin concentrations in radicular granuloma following a single oral administration of 250 or 500 mg cephalexin. Gen Pharmacol 1994; 25: 1563–6. 10.1016/0306-3623(94)90355-7 [DOI] [PubMed] [Google Scholar]
26. Ali HM, Farouk AM. The effect of Sudanese diet on the bioavailability of ampicillin. Int J Pharm 1980; 8: 301–6. 10.1016/0378-5173(80)90113-1 [DOI] [Google Scholar]
27. Ali HM. The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets. Int J Pharm 1981; 9: 185–90. 10.1016/0378-5173(81)90043-0 [DOI] [Google Scholar]
28. Barbhaiya RH, Shukla UA, Gleason CR et al. Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor. Antimicrob Agents Chemother 1990; 34: 1210–3. 10.1128/AAC.34.6.1210 [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Barr WH, Lin CC, Radwanski E et al. The pharmacokinetics of ceftibuten in humans. Diagn Microbiol Infect Dis 1991; 14: 93–100. 10.1016/0732-8893(91)90096-X [DOI] [PubMed] [Google Scholar]
30. Barr WH, Affrime M, Lin CC et al. Pharmacokinetics of ceftibuten in children. Pediatr Infect Dis J 1995; 14: S93–101. 10.1097/00006454-199507001-00005 [DOI] [PubMed] [Google Scholar]
31. Bauer KH, Foerster D, Hoff D et al. Urinary recovery after ingestion of ampicillin tablets together with a standard breakfast as compared with administration to fasting subjects. Pharmazeutische Industrie 1976; 38: 1153–4. [Google Scholar]
32. Bergdahl S, Eriksson M, Finkel Y et al. Oral absorption of flucloxacillin in infants and young children. Acta Pharmacol Toxicol (Copenh) 1986; 58: 255–8. 10.1111/j.1600-0773.1986.tb00105.x [DOI] [PubMed] [Google Scholar]
33. Blouin RA, Kneer J, Stoeckel K. Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects. Antimicrob Agents Chemother 1989; 33: 291–6. 10.1128/AAC.33.3.291 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Blouin RA, Kneer J, Ambros RJ et al. Influence of antacid and ranitidine on the pharmacokinetics of oral cefetamet pivoxil. Antimicrob Agents Chemother 1990; 34: 1744–8. 10.1128/AAC.34.9.1744 [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Bolme P, Eriksson M, Paalzow L et al. Malnutrition and pharmacokinetics of penicillin in Ethiopian children. Pharmacol Toxicol 1995; 76: 259–62. 10.1111/j.1600-0773.1995.tb00140.x [DOI] [PubMed] [Google Scholar]
36. Borin MT, Forbes KK. Effect of food on absorption of cefpodoxime proxetil oral suspension in adults. Antimicrob Agents Chemother 1995; 39: 273–5. 10.1128/AAC.39.1.273 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Borin MT, Forbes KK, Hughes GS. The bioavailability of cefpodoxime proxetil tablets relative to an oral solution. Biopharm Drug Dispos 1995; 16: 295–302. 10.1002/bdd.2510160405 [DOI] [PubMed] [Google Scholar]
38. Borin MT, Driver MR, Forbes KK. Effect of timing of food on absorption of cefpodoxime proxetil. J Clin Pharmacol 1995; 35: 505–9. 10.1002/j.1552-4604.1995.tb04095.x [DOI] [PubMed] [Google Scholar]
39. Chen RR, Lee TY, Hsieh WC. Effect of food on pharmacokinetics of cefuroxime axetil in Chinese subjects. J Formos Med Assoc 1992; 91: 1177–81. [PubMed] [Google Scholar]
40. Cronk GA, Wheatley WB, Fellers GF et al. The relationship of food intake to the absorption of potassium alpha-phenoxyethyl penicillin and potassium phenoxymethyl penicillin from the gastrointestinal tract. Am J Med Sci 1960; 240: 219–25. [PubMed] [Google Scholar]
41. Digenis GA, Sandefer EP, Page RC et al. Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture. Pharm Res 2000; 17: 572–82. 10.1023/A:1007568900147 [DOI] [PubMed] [Google Scholar]
42. Ding Y, Jia YY, Li F et al. The effect of staggered administration of zinc sulfate on the pharmacokinetics of oral cephalexin. Br J Clin Pharmacol 2012; 73: 422–7. 10.1111/j.1365-2125.2011.04098.x [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Di Stefano A, Gemme G. A recent cephalosporin: cefadroxil. Clinical study and comparative blood levels after administration during fasting and after a meal. Minerva Pediatr 1981; 33: 871–80. [PubMed] [Google Scholar]
44. Ducharme MP, Edwards DJ, McNamara PJ et al. Bioavailability of syrup and tablet formulations of cefetamet pivoxil. Antimicrob Agents Chemother 1993; 37: 2706–9. 10.1128/AAC.37.12.2706 [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Eckburg PB, Jain A, Walpole S et al. Safety, pharmacokinetics, and food effect of tebipenem pivoxil hydrobromide after single and multiple ascending oral doses in healthy adult subjects. Antimicrob Agents Chemother 2019; 63: e00618-19. 10.1128/AAC.00618-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Eden T, Lindstrom D, Perlhagen J. Serum concentrations of penicillin V in children after peroral administration in two forms, fasting and at mealtimes. Lakartidningen 1977; 74: 2443–4. [PubMed] [Google Scholar]
47. Eshelman FN, Spyker DA. Pharmacokinetics of amoxicillin and ampicillin: crossover study of the effect of food. Antimicrob Agents Chemother 1978; 14: 539–43. 10.1128/AAC.14.4.539 [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Everts RJ, Begg R, Gardiner SJ et al. Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers. J Infect 2020; 80: 42–53. 10.1016/j.jinf.2019.09.004 [DOI] [PubMed] [Google Scholar]
49. Faulkner RD, Bohaychuk W, Haynes JD et al. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol 1988; 34: 525–8. 10.1007/BF01046715 [DOI] [PubMed] [Google Scholar]
50. Fernandez CA, Menezes JP, Ximenes J. The effect of food on the absorption of pivampicillin and a comparison with the absorption of ampicillin potassium. J Int Med Res 1973; 1: 530–3. 10.1177/030006057300100604 [DOI] [Google Scholar]
51. Finkel Y, Bolme P, Eriksson M. The effect of food on the oral absorption of penicillin V preparations in children. Acta Pharmacol Toxicol (Copenh) 1981; 49: 301–4. 10.1111/j.1600-0773.1981.tb00910.x [DOI] [PubMed] [Google Scholar]
52. Finn A, Straughn A, Meyer M et al. Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharm Drug Dispos 1987; 8: 519–26. 10.1002/bdd.2510080604 [DOI] [PubMed] [Google Scholar]
53. Fujii R, Yoshioka H, Fujita K et al. Pharmacokinetic and clinical studies of cefdinir in the pediatric field. Jpn J Antibiot 1991; 44: 1168–91. 10.11553/antibiotics1968b.44.1168 [DOI] [PubMed] [Google Scholar]
54. Fujii R. Clinical trials of cefpodoxime proxetil suspension in paediatrics. Drugs 1991; 42: 57–60. 10.2165/00003495-199100423-00011 [DOI] [PubMed] [Google Scholar]
55. Fujii R, Meguro H, Tajima T et al. Overall clinical evaluation of cefprozil against infections in pediatric fields. Jpn J Antibiot 1992; 45: 1592–608. 10.11553/antibiotics1968b.45.1592 [DOI] [PubMed] [Google Scholar]
56. Fujimoto M, Sakai K, Ueda T et al. Pharmacological and clinical studies on the long acting cefaclor (S6472). Jpn J Antibiot 1985; 38: 849–57. 10.11553/antibiotics1968b.38.849 [DOI] [PubMed] [Google Scholar]
57. Gardiner SJ, Drennan PG, Begg R et al. In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances. PLoS One 2018; 13: e0199370. 10.1371/journal.pone.0199370 [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Ginsburg CM, McCracken GH, Clahsen JC et al. Clinical pharmacology of cefadroxil in infants and children. Antimicrob Agents Chemother 1978; 13: 845–8. 10.1128/AAC.13.5.845 [DOI] [PMC free article] [PubMed] [Google Scholar]
59. Ginsburg CM, McCracken GH, Thomas ML et al. Comparative pharmacokinetics of amoxicillin and ampicillin in infants and children. Pediatrics 1979; 64: 627–31. 10.1542/peds.64.5.627 [DOI] [PubMed] [Google Scholar]
60. Ginsburg CM, McCracken GHJ. Pharmacokinetics of cephradine suspension infants and children. Antimicrob Agents Chemother 1979; 16: 74–6. 10.1128/AAC.16.1.74 [DOI] [PMC free article] [PubMed] [Google Scholar]
61. Ginsburg CM, McCracken GH, Zweighaft TC et al. Comparative pharmacokinetics of cyclacillin and amoxicillin in infants and children. Antimicrob Agents Chemother 1981; 19: 1086–8. 10.1128/AAC.19.6.1086 [DOI] [PMC free article] [PubMed] [Google Scholar]
62. Ginsburg CM. Comparative pharmacokinetics of cefadroxil, cefaclor, cephalexin and cephradine in infants and children. J Antimicrob Chemother 1982; 10: 27–31. 10.1093/jac/10.suppl_B.27 [DOI] [PubMed] [Google Scholar]
63. Ginsburg CM, McCracken GH, Petruska M et al. Pharmacokinetics and bactericidal activity of cefuroxime axetil. Antimicrob Agents Chemother 1985; 28: 504–7. 10.1128/AAC.28.4.504 [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Ginsburg CM, McCracken GHJ, Olsen K et al. Pharmacokinetics and bactericidal activity of sultamicillin in infants and children. J Antimicrob Chemother 1985; 15: 345–51. 10.1093/jac/15.3.345 [DOI] [PubMed] [Google Scholar]
65. Glynne A, Goulbourn RA, Ryden R. A human pharmacology study of cefaclor. J Antimicrob Chemother 1978; 4: 343–8. 10.1093/jac/4.4.343 [DOI] [PubMed] [Google Scholar]
66. Gottfries J, Svenheden A, Alpsten M et al. Gastrointestinal transit of amoxicillin modified-release tablets and a placebo tablet including pharmacokinetic assessments of amoxicillin. Scand J Gastroenterol 1996; 31: 49–53. 10.3109/00365529609031626 [DOI] [PubMed] [Google Scholar]
67. Gower PE, Dash CH. Cephalexin: human studies of absorption and excretion of a new cephalosporin antibiotic. Br J Pharmacol 1969; 37: 738–47. 10.1111/j.1476-5381.1969.tb08513.x [DOI] [PMC free article] [PubMed] [Google Scholar]
68. Guggenbichler JP, Kienel G. Bioavailability of new galenic preparations of cephalexin (author’s transl). Padiatr Padol 1978; 13: 315–20. [PubMed] [Google Scholar]
69. Guggenbichler JP, Kienel G. Bioavailability of orally administered antibiotics: influences of food on resorption (author’s transl). Padiatr Padol 1979; 14: 69–74. [PubMed] [Google Scholar]
70. Gupta VK, Patel G, Gasink L et al. Bioequivalence of two oral formulations of tebipenem pivoxil hydrobromide in healthy subjects. Clin Transl Sci 2022; 15: 1654–63. 10.1111/cts.13280 [DOI] [PMC free article] [PubMed] [Google Scholar]
71. Haginaka J, Yamaoka K, Nakagawa T et al. Evaluation of effect of food ingestion on bioavailability of cephalexin by moment analysis. Chem Pharm Bull (Tokyo) 1979; 27: 3156–9. 10.1248/cpb.27.3156 [DOI] [PubMed] [Google Scholar]
72. Hamid S, Beg AE. Influence of ethnic diets on ampicillin bioavailability and pharmacokinetics in healthy Pakistani subjects. Pol J Pharmacol Pharm 1987; 39: 337–42. [PubMed] [Google Scholar]
73. Harding SM, Williams PE, Ayrton J. Pharmacology of cefuroxime as the 1-acetoxyethyl ester in volunteers. Antimicrob Agents Chemother 1984; 25: 78–82. 10.1128/AAC.25.1.78 [DOI] [PMC free article] [PubMed] [Google Scholar]
74. Harvengt C, De Schepper P, Lamy F et al. Cephradine absorption and excretion in fasting and nonfasting volunteers. J Clin Pharmacol New Drugs 1973; 13: 36–40. 10.1002/j.1552-4604.1973.tb00066.x [DOI] [PubMed] [Google Scholar]
75. Hayashi Y Kojima T. Absorption and excretion of cefradine in healthy volunteers (author’s transl). Jpn J Antibiot 1980; 33: 655–63. 10.11553/antibiotics1968b.33.655 [DOI] [PubMed] [Google Scholar]
76. Healy DP, Sahai J V, Sterling LP et al. Influence of an antacid containing aluminium and magnesium on the pharmacokinetics of cefixime. Antimicrob Agents Chemother 1989; 33: 1994–7. 10.1128/AAC.33.11.1994 [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Hughes GS, Heald DL, Barker KB et al. The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther 1989; 46: 674–85. 10.1038/clpt.1989.204 [DOI] [PubMed] [Google Scholar]
78. Iwai N, Taneda Y, Nakamura H et al. Pharmacokinetic, bacteriological and clinical evaluation of cefpodoxime proxetil in pediatrics. Jpn J Antibiot 1989; 42: 1571–92. 10.11553/antibiotics1968b.42.1571 [DOI] [PubMed] [Google Scholar]
79. James NC, Donn KH, Collins JJ et al. Pharmacokinetics of cefuroxime axetil and cefaclor: relationship of concentrations in serum to MICs for common respiratory pathogens. Antimicrob Agents Chemother 1991; 35: 1860–3. 10.1128/AAC.35.9.1860 [DOI] [PMC free article] [PubMed] [Google Scholar]
80. Jones KH, Langley PF, Lees LJ. Bioavailability and metabolism of talampicillin. Chemotherapy 1978; 24: 217–26. 10.1159/000237784 [DOI] [PubMed] [Google Scholar]
81. Kamme C, Ursing B. Serum levels and clinical effect of flucloxacillin in patients with staphylococcal infections. Scand J Infect Dis 1974; 6: 273–8. 10.3109/inf.1974.6.issue-3.11 [DOI] [PubMed] [Google Scholar]
82. Karim S, Ahmed T, Monif T et al. The effect of four different types of food on the bioavailability of cefaclor. Eur J Drug Metab Pharmacokinet 2003; 28: 185–90. 10.1007/BF03190484 [DOI] [PubMed] [Google Scholar]
83. Kassem AKY. Cephradine bioequivalence and its interaction with khat and food (al-sayadeyah) in Yemen. Master's Thesis. University of Khartoum, Sudan, 2004.
84. Kato R, Ooi K, Takeda K et al. Lack of interaction between cefdinir and calcium polycarbophil: in vitro and in vivo studies. Drug Metab Pharmacokinet 2002; 17: 363–6. 10.2133/dmpk.17.363 [DOI] [PubMed] [Google Scholar]
85. Kearns GL, Abdel-Rahman SM, Jacobs RF et al. Cefpodoxime pharmacokinetics in children: effect of food. Pediatric Infect Dis J 1998; 17: 799–804. 10.1097/00006454-199809000-00010 [DOI] [PubMed] [Google Scholar]
86. Khan BAH, Ahmed T, Karim S et al. Comparative effect of different types of food on the bioavailability of cefaclor extended release tablet. Eur J Drug Metab Pharmacokinet 2004; 29: 125–32. 10.1007/BF03190587 [DOI] [PubMed] [Google Scholar]
87. Khuroo AH, Monif T, Verma PRP et al. Comparison of effect of fasting and of five different diets on the bioavailability of single oral dose of amoxicillin 500 mg capsule. Clin Res Regul Aff 2008; 25: 73–86. 10.1080/10601330802064272 [DOI] [Google Scholar]
88. Kibayashi M Watanabe A. Laboratory and clinical studies on cefdinir in pediatric field. Jpn J Antibiot 1990; 43: 1424–35. 10.11553/antibiotics1968b.43.1424 [DOI] [PubMed] [Google Scholar]
89. Kimura H, Takeuchi H, Ishikawa H et al. Bacteriological, pharmacokinetic and clinical studies on cefpodoxime proxetil in the pediatric field. Jpn J Antibiot 1989; 42: 1593–606. 10.11553/antibiotics1968b.42.1519 [DOI] [PubMed] [Google Scholar]
90. Koup JR, Dubach UC, Brandt R et al. Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob Agents Chemother 1988; 32: 573–9. 10.1128/AAC.32.4.573 [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Koyama M Nakagawa K. Clinical phase I study of T-2588. Jpn J Antibiot 1986; 40: 55–76. 10.11553/antibiotics1968b.40.55 [DOI] [PubMed] [Google Scholar]
92. Lai X, Ye S, Chen L et al. An open-label, randomized, 2-way, crossover bioequivalence study of cefradine capsules in healthy Chinese volunteers. Clin Pharmacol Drug Dev 2021; 10: 1478–84. 10.1002/cpdd.991 [DOI] [PubMed] [Google Scholar]
93. Lecaillon JB, Hirtz JL, Schoeller JP et al. Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans. Antimicrob Agents Chemother 1980; 18: 656–60. 10.1128/AAC.18.5.656 [DOI] [PMC free article] [PubMed] [Google Scholar]
94. Leigh DA, Reeves DS, Simmons K et al. Talampicillin: a new derivative of ampicillin. Br Med J 1976; 1: 1378–80. 10.1136/bmj.1.6022.1378 [DOI] [PMC free article] [PubMed] [Google Scholar]
95. Li JT, Hou F, Lu H et al. Phase I clinical trial of cefditoren pivoxil (ME1207). Tolerance in healthy volunteers. Drugs Exp Clin Res 1997; 23: 131–8. [PubMed] [Google Scholar]
96. Li M, Andrew MA, Wang J et al. Effects of cranberry juice on pharmacokinetics of β-lactam antibiotics following oral administration. Antimicrob Agents Chemother 2009; 53: 2725–32. 10.1128/AAC.00774-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Li X, Wang Z, Liu W-P et al. Chronokinetic study of cefprozil in postprandial and fasting volunteers. Biol Rhythm Res 2013; 44: 95–102. 10.1080/09291016.2011.652862 [DOI] [Google Scholar]
98. Lin PP, Wang CJ, Liu YP et al. Pharmacokinetics and bioequivalence of cefprozil for suspension and granule formulation in healthy Chinese volunteers: two single-dose crossover studies. Adv Ther 2020; 38: 1130–42. 10.1007/s12325-020-01593-7 [DOI] [PubMed] [Google Scholar]
99. Lode H, Stahlmann R, Koeppe P. Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP 9000. Antimicrob Agents Chemother 1979; 16: 1–6. 10.1128/AAC.16.1.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
100. Lode H, Köppe P, Stahlmann R. Pharmacokinetics of cefaclor and initial therapeutical experience (author’s transl). Infection 1979; 7: 600–2. 10.1007/BF01659745 [DOI] [PubMed] [Google Scholar]
101. Lv X, Zhong G, Yao H et al. Bioequivalence of cefalexin in healthy Chinese subjects. Int J Clin Pharmacol Ther 2021; 59: 725–33. 10.5414/CP203986 [DOI] [PubMed] [Google Scholar]
102. Magni L, Sjoberg B, Sjovall J et al. Clinical pharmacological studies with bacampicillin. In: Williams JD, Geddes AM eds. Penicillins and Cephalosporins. Springer, 1975; 109–14. [Google Scholar]
103. Marzec A, Kunicki P, Bogiel M et al. Comparison of cefaclor absorption characteristics from the suspension and modified-release tablets in fast and fed condition. Ther Drug Monit 2005; 27: 231. 10.1097/00007691-200504000-00096 [DOI] [Google Scholar]
104. Matsumoto K, Kimura H Noguchi Y. Laboratory and clinical studies on cephradine. Chemotherapy 1975; 23: 98–105. 10.11250/chemotherapy1953.23.98 [DOI] [Google Scholar]
105. McCarthy CG, Finland M, Wilcox C et al. Absorption and excretion of four penicillins. N Engl J Med 1960; 263: 315–26. 10.1056/NEJM196008182630701 [DOI] [Google Scholar]
106. McCracken GHJ, Ginsburg CM, Clahsen JC et al. Pharmacologic evaluation of orally administered antibiotics in infants and children: effect of feeding on bioavailability. Pediatrics 1978; 62: 738–43. 10.1542/peds.62.5.738 [DOI] [PubMed] [Google Scholar]
107. McCracken GH, Ginsburg CM, Clahsen JC et al. Pharmacokinetics of cefaclor in infants and children. J Antimicrob Chemother 1978; 4: 515–21. 10.1093/jac/4.6.515 [DOI] [PubMed] [Google Scholar]
108. Meyers BR, Kaplan K, Weinstein L. Cephalexin: microbiological effects and pharmacologic parameters in man. Clin Pharmacol Ther 1969; 10: 810–6. 10.1002/cpt1969106810 [DOI] [PubMed] [Google Scholar]
109. Michel MF, Driessen O. Comparative study of serum concentrations of amoxicillin, pivampicillin and hetacillin (Dutch). Ned Tijdschr Geneeskd 1974; 118: 1508–14. [PubMed] [Google Scholar]
110. Mischler T, Sugerman A, Willard D et al. Influence of probenecid and food on the bioavailability of cephradine in normal male subjects. J Clin Pharmacol 1974; 14: 604–11. 10.1002/j.1552-4604.1974.tb01380.x [DOI] [PubMed] [Google Scholar]
111. Motohiro T, Handa S, Yamada S et al. Pharmacokinetics and clinical effects of cefdinir 10% fine granules in pediatrics. Jpn J Antibiot 1992; 45: 74–86. 10.11553/antibiotics1968b.45.74 [DOI] [PubMed] [Google Scholar]
112. Munkholm P, Olsen J, Hovgaard C et al. Absorption of pivampicillin as related to dose, and tolerability of a 700 mg tablet. Infection 1993; 21: 30–3. 10.1007/BF01739307 [DOI] [PubMed] [Google Scholar]
113. Nakamura H, Miyazu M, Kasai K et al. Studies on sultamicillin in the field of pediatrics. Jpn J Antibiot 1988; 41: 1874–94. 10.11553/antibiotics1968b.41.1874 [DOI] [PubMed] [Google Scholar]
114. Nakamura H Iwai N. Pharmacokinetic studies on oral antibiotics in pediatrics. II. A pharmacokinetic study on cefteram pivoxil in pediatrics. Jpn J Antibiot 1989; 42: 1981–2003. 10.11553/antibiotics1968b.42.1981 [DOI] [PubMed] [Google Scholar]
115. Nakamura H Iwai N. Pharmacokinetic study on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics. Jpn J Antibiot 1991; 44: 964–78. 10.11553/antibiotics1968b.44.964 [DOI] [PubMed] [Google Scholar]
116. Nakamura H Iwai N. Pharmacokinetic study on oral antibiotics in pediatrics. V. A pharmacokinetic study on cefdinir in pediatrics. Jpn J Antibiot 1992; 45: 12–27. 10.11553/antibiotics1968b.45.12 [DOI] [PubMed] [Google Scholar]
117. Nakashima M, Uematsu T, Takiguchi Y et al. Phase I study of cefixime, a new oral cephalosporin. J Clin Pharmacol 1987; 27: 425–31. 10.1002/j.1552-4604.1987.tb03043.x [DOI] [PubMed] [Google Scholar]
118. Nakashima M, Uematsu T, Takiguchi Y et al. Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. J Clin Pharmacol 1988; 28: 246–52. 10.1002/j.1552-4604.1988.tb03140.x [DOI] [PubMed] [Google Scholar]
119. Nakashima M, Morita J, Takata T et al. Effect of diet on the pharmacokinetics of tebipenem pivoxil fine granules in healthy male volunteers. Jpn J Antibiot 2009; 62: 136–42. [PubMed] [Google Scholar]
120. Nakashima M, Morita J, Aizawa K. Effect of diet including ice cream and pudding on tebipenem pivoxil fine granules pharmacokinetics in healthy male volunteers. Jpn J Chemother 2009; 57: 95–8. [PubMed] [Google Scholar]
121. Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of oral carbapenem antibiotic tebipenem pivoxil tablets in healthy male volunteers. Jpn J Chemother 2009; 57: 82–9. [Google Scholar]
122. Nakashima M, Morita J, Aizawa K. Effect of probenecid or diet on tebipenem pivoxil tablets pharmacokinetics in healthy male volunteers. Jpn J Chemother 2009; 57: 103–8. [PubMed] [Google Scholar]
123. Neu HC. Antimicrobial activity and human pharmacology of amoxicillin. J Infect Dis 1974; 129: S123–31. 10.1093/infdis/129.Supplement_2.S123 [DOI] [PubMed] [Google Scholar]
124. Neu HC. The pharmacokinetics of bacampicillin. Rev Infect Dis 1981; 3: 110–6. 10.1093/clinids/3.1.110 [DOI] [PubMed] [Google Scholar]
125. Neuvonen PJ, Elonen E, Pentikäinen PJ. Comparative effect of food on absorption of ampicillin and pivampicillin. J Int Med Res 1977; 5: 71–6. 10.1177/030006057700500113 [DOI] [PubMed] [Google Scholar]
126. Nishimura T, Tabuki K, Hiromatsu K et al. Laboratory and clinical studies of cefroxadine. Jpn J Antibiot 1981; 34: 1634–46. 10.11553/antibiotics1968b.34.1634 [DOI] [PubMed] [Google Scholar]
127. FDA . Suprax (Lupin Pharma). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202091s005,203195s006lbl.pdf.
128. FDA . Omnicef (Abbott Laboratories). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050739s015,050749s021lbl.pdf.
129. FDA . Spectracef (Cornerstone BioPharma). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021222s012lbl.pdf.
130. FDA . Cedax (Pernix Therapeutics). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050686s016lbl.pdf.
131. FDA . Vantin (Pfizer). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050674s015,050675s018lbl.pdf.
132. Oguma T, Yamada H, Sawaki M et al. Pharmacokinetic analysis of the effects of different foods on absorption of cefaclor. Antimicrob Agents Chemother 1991; 35: 1729–35. 10.1128/AAC.35.9.1729 [DOI] [PMC free article] [PubMed] [Google Scholar]
133. Olaganathan AA, Ruckmani A, Lakshmi G et al. Pharmacokinetic interaction between antacid and commonly prescribed medications - metformin, diclofenac and amoxicillin. Eur J Mol Clin Med 2017; 3: 7–8. 10.1016/j.nhtm.2016.01.001 [DOI] [Google Scholar]
134. Parsons RL, Hossack GA, Paddock GM et al. The effect of a Lundh meal on the plasma concentration/time curve of ampicillin, amoxycillin, pivampicillin and cephalexin in normal subjects. Br J Clin Pharmacol 1977; 4: 406P–7P. 10.1111/j.1365-2125.1977.tb00752.x [DOI] [PubMed] [Google Scholar]
135. Patel G, Gupta VK, Gasink L et al. Effect of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole) on the pharmacokinetics of tebipenem pivoxil hydrobromide (TBP-PI-HBr) in healthy adult subjects. Antimicrob Agents Chemother 2023; 67: e0149522. 10.1128/aac.01495-22 [DOI] [PMC free article] [PubMed] [Google Scholar]
136. Petitjean O, Brion N, Tod M et al. Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results. Presse Med 1989; 18: 1596–8. [PubMed] [Google Scholar]
137. Pfeffer M, Jackson A, Ximenes J et al. Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob Agents Chemother 1977; 11: 331–8. 10.1128/AAC.11.2.331 [DOI] [PMC free article] [PubMed] [Google Scholar]
138. Qu X, Deng Q, Li Y et al. Pharmacokinetics and safety of the two oral cefaclor formulations in healthy Chinese subjects in the fasting and postprandial states. Front Pharmacol 2022; 13: 1012294. 10.3389/fphar.2022.1012294 [DOI] [PMC free article] [PubMed] [Google Scholar]
139. Radwanski E, Nomeir A, Cutler D et al. Pharmacokinetic drug interaction study: administration of ceftibuten concurrently with the antacid Mylanta double-strength liquid or with ranitidine. Am J Ther 1998; 5: 67–72. 10.1097/00045391-199803000-00003 [DOI] [PubMed] [Google Scholar]
140. Roholt K, Nielsen B, Kristensen E. Clinical pharmacology of pivampicillin. Antimicrob Agents Chemother 1974; 6: 563–71. 10.1128/AAC.6.5.563 [DOI] [PMC free article] [PubMed] [Google Scholar]
141. Saathoff N, Lode H, Neider K et al. Of cefpodoxime proxetil and interactions with an antacid and an H2 receptor antagonist. Antimicrob Agents Chemother 1992; 36: 796–800. 10.1128/AAC.36.4.796 [DOI] [PMC free article] [PubMed] [Google Scholar]
142. Sabto J, Carson P, Morgan T. Evaluation of amoxycillin—a new semisynthetic penicillin. Med J Aust 1973; 2: 537–41. 10.5694/j.1326-5377.1973.tb129635.x [DOI] [PubMed] [Google Scholar]
143. Saito A, Kato Y, Murakami K. Studies on talampicillin. Kansenshogaku Zasshi 1975; 49: 458–69. 10.11150/kansenshogakuzasshi1970.49.458 [DOI] [PubMed] [Google Scholar]
144. Sakai K, Fujimoto M Ueda T. Clinical trials of sultamicillin (ester of sulbactam-ampicillin) on the skin and soft tissue infections in the field of surgery. Chemotherapy 1985; 33: 446–56. 10.11250/chemotherapy1953.33.Supplement2_446 [DOI] [Google Scholar]
145. Santoro J, Agarwal BN, Martinelli R et al. Pharmacology of cefaclor in normal volunteers and patients with renal failure. Antimicrob Agents Chemother 1978; 13: 951–4. 10.1128/AAC.13.6.951 [DOI] [PMC free article] [PubMed] [Google Scholar]
146. Sarel R, Miskin A, Ashkenazi A. Penicillin VK absorption during fasting and after eating. Harefuah 1989; 117: 430–2. [PubMed] [Google Scholar]
147. Satterwhite JH, Cerimele BJ, Coleman DL et al. Pharmacokinetics of cefaclor AF: effects of age, antacids and H2-receptor antagonists. Postgrad Med J 1992; 68: S3–9. [PubMed] [Google Scholar]
148. Shiba K, Maezawa H, Yoshida M et al. Effects of antacids on pharmacokinetics of cefditoren pivoxil and its metabolism in humans. Chemotherapy 1992; 40: 1310–9. 10.11250/chemotherapy1953.40.1310 [DOI] [Google Scholar]
149. Shiiki K, Hara H Kanno K. Effect of food intake on pharmacokinetics of cefetamet pivoxil. Chemotherapy 1990; 38: 340–3. 10.11250/chemotherapy1953.38.Supplement1_340 [DOI] [Google Scholar]
150. Shimada K Oka S-I. Effect of food on bioavailability of cefdinir. Chemotherapy 1989; 37: 246–56. 10.11250/chemotherapy1953.37.Supplement2_246 [DOI] [Google Scholar]
151. Shimada J, Saito A, Shiba K et al. Effects of antacids on absorption, excretion and metabolism of cefteram pivoxil. Jpn J Antibiot 1990; 43: 1353–70. 10.11553/antibiotics1968b.43.1353 [DOI] [PubMed] [Google Scholar]
152. Shukla UA, Pittman KA, Barbhaiya RH. Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers. J Clin Pharmacol 1992; 32: 725–31. 10.1002/j.1552-4604.1992.tb03876.x [DOI] [PubMed] [Google Scholar]
153. Sutherland R, Robinson OP. Laboratory and pharmacological studies in man with hetacillin and ampicillin. Br Med J 1967; 2: 804–8. 10.1136/bmj.2.5555.804 [DOI] [PMC free article] [PubMed] [Google Scholar]
154. Shyu WC, Shah VR, Campbell DA et al. Excretion of cefprozil into human breast milk. Antimicrob Agents Chemother 1992; 36: 938–41. 10.1128/AAC.36.5.938 [DOI] [PMC free article] [PubMed] [Google Scholar]
155. Sidell S, Bulger RJ, Brodie JL et al. Cloxacillin, a new oral synthetic penicillin comparisons with oxacillin. Clin Pharmacol Ther 1964; 5: 26–34. 10.1002/cpt19645126 [DOI] [PubMed] [Google Scholar]
156. Sommers DK, van Wyk M, Moncrieff J et al. Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil. Br J Clin Pharmacol 1984; 18: 535–9. 10.1111/j.1365-2125.1984.tb02501.x [DOI] [PMC free article] [PubMed] [Google Scholar]
157. Staniforth DH, Lillystone RJ, Jackson D. Effect of food on the bioavailability and tolerance of clavulanic acid/amoxycillin combination. J Antimicrob Chemother 1982; 10: 131–9. 10.1093/jac/10.2.131 [DOI] [PubMed] [Google Scholar]
158. Staniforth DH, Clarke HL, Horton R et al. Augmentin bioavailability following cimetidine, aluminum hydroxide and milk. Int J Clin Pharmacol 1985; 23: 154–7. [PubMed] [Google Scholar]
159. Tam YK, Kneer J, Dubach UC et al. Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers. Antimicrob Agents Chemother 1990; 34: 1556–9. 10.1128/AAC.34.8.1556 [DOI] [PMC free article] [PubMed] [Google Scholar]
160. Tateno M, Ito M, Iida M et al. Absorption and excretion studies of S6472 (sustained release preparations of cefaclor). Jpn J Antibiot 1985; 38: 834–48. 10.11553/antibiotics1968b.38.834 [DOI] [PubMed] [Google Scholar]
161. Tetzlaff TR, McCracken GH, Thomas ML. Bioavailability of cephalexin in children: relationship to drug formulations and meals. J Pediatr 1978; 92: 292–4. 10.1016/S0022-3476(78)80029-8 [DOI] [PubMed] [Google Scholar]
162. Thambavita DD, Galappatthy P, Jayakody RL. Pharmacokinetics and bioequivalence of two amoxicillin 500 mg products: effect of food on absorption and supporting scientific justification for biowaiver. J Pharm Sci 2021; 110: 3735–41. 10.1016/j.xphs.2021.06.011 [DOI] [PubMed] [Google Scholar]
163. Totsuka K, Shimizu K, Mori N et al. Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil. Int J Antimicrob Agents 2001; 18: 463–9. 10.1016/S0924-8579(01)00443-5 [DOI] [PubMed] [Google Scholar]
164. Toyonaga Y, Kurosu Y Sugita M. Fundamental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field. Jpn J Antibiot 1985; 38: 373–413. 10.11553/antibiotics1968b.38.373 [DOI] [PubMed] [Google Scholar]
165. Toyonaga Y, Imai H, Sugita M et al. Bacteriological, pharmacokinetic and clinical studies on cefteram pivoxil in the pediatric field. Jpn J Antibiot 1989; 42: 1799–814. 10.11553/antibiotics1968b.42.1799 [DOI] [PubMed] [Google Scholar]
166. Ueno K, Tanaka K, Tsujimura K et al. Impairment of cefdinir absorption by iron ion. Clin Pharmacol Ther 1993; 54: 473–5. 10.1038/clpt.1993.178 [DOI] [PubMed] [Google Scholar]
167. Wagatsuma Y, Takase A, Fukushima N et al. Clinical evaluation of cefteram pivoxil fine granules in pediatric infections. Jpn J Antibiot 1989; 42: 1735–44. 10.11553/antibiotics1968b.42.1735 [DOI] [PubMed] [Google Scholar]
168. Wagatsuma Y, Takase A, Fukushima N et al. A clinical study on cefpodoxime proxetil dry syrup in pediatric infections. Jpn J Antibiot 1989; 42: 1464–70. 10.11553/antibiotics1968b.42.1464 [DOI] [PubMed] [Google Scholar]
169. Wang C, Yang J. Effect of food intake on pharmacokinetics of sustained-release cefradine capsules in healthy volunteers. J China Pharm Univ 2005; 36: 556–8. [Google Scholar]
170. Wang Y, Fan L, Cheng Y et al. Diet-induced alterations in pharmacokinetics of cefuroxime axetil in healthy Chinese subjects. Indian J Pharm Sci 2019; 81: 966–70. 10.36468/pharmaceutical-sciences.592 [DOI] [Google Scholar]
171. Weitschies W, Friedrich C, Wedemeyer RS et al. Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying. Eur J Pharm Biopharm 2008; 70: 641–8. 10.1016/j.ejpb.2008.05.011 [DOI] [PubMed] [Google Scholar]
172. Welling PG, Huang H, Koch PA et al. Bioavailability of ampicillin and amoxicillin in fasted and nonfasted subjects. J Pharm Sci 1977; 66: 549–52. 10.1002/jps.2600660423 [DOI] [PubMed] [Google Scholar]
173. Williams PEO, Harding SM. The absolute bioavailability of oral cefuroxime axetil in male and female volunteers after fasting and after food. J Antimicrob Chemother 1984; 13: 191–6. 10.1093/jac/13.2.191 [DOI] [PubMed] [Google Scholar]
174. Xu S-M, Qin F, Zhang Y-D et al. Pharmacokinetics of amoxicillin and clavulanate potassium for suspension (200 mg/28.5 mg) in healthy subjects: sample add stabilizer study and food effects. Clin Pharmacol Drug Dev 2022; 11: 1314–21. 10.1002/cpdd.1143 [DOI] [PubMed] [Google Scholar]
175. Yamaguchi M, Satoh T, Kikuchi F et al. Comparative study on human blood concentration of oral cephem antibiotics CXM-AX vs CCL - effect of food on bioavailability. Oral Ther Pharmacol 1992; 11: 99–104. 10.11263/jsotp1982.11.99 [DOI] [Google Scholar]
176. Yang TY, Huang XX, Zhou JL et al. Effects of high-fat and high-calorie diets on pharmacokinetics of cefuroxime axetil tablets. Chin Pharm J 2017; 52: 1531–5. 10.11669/cpj.2017.17.011 [DOI] [Google Scholar]
177. Yaoguo S, Qin Z, Jichen Y et al. Pharmacokinetics of cefixime in healthy volunteers. Chin J Antibiotics 1994; 19: 293–8. [Google Scholar]
178. Yazdani-Brojeni P, Garcia-Bournissen F, Fujii H et al. Bioavailability of amoxicillin dissolved in human milk. J Popul Ther Clin Pharmacol 2012; 19: e295-6. [Google Scholar]
179. Zhang Z, Zhang X, Yang S et al. Bioequivalence of cefdinir capsules in Chinese healthy population under fasting/high-fat fed condition. Chin J Clin Pharmacol Therapeutics 2020; 25: 740–5. 10.12092/j.issn.1009-2501.2020.07.004 [DOI] [Google Scholar]
180. Wiesner A, Skrońska M, Gawlik G et al. Interactions of antiretroviral drugs with food, beverages, dietary supplements, and alcohol: a systematic review and meta-analyses. AIDS Behav 2023; 27: 1441–68. 10.1007/s10461-022-03880-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
181. O’Shea JP, Holm R, O’Driscoll CM et al. Food for thought: formulating away the food effect—a PEARRL review. J Pharm Pharmacol 2019; 71: 510–35. 10.1111/jphp.12957 [DOI] [PubMed] [Google Scholar]
182. Gao P, Nie X, Zou M et al. Recent advances in materials for extended-release antibiotic delivery system. J Antibiot 2011; 64: 625–34. 10.1038/ja.2011.58 [DOI] [PubMed] [Google Scholar]
183. Gorria P, Revel J. Modified-release formulations: improving efficacy and patient compliance. Pharm Technol 2019; 2019: s6–8. [Google Scholar]
184. Zou P, Vaidyanathan J, Tran D et al. Predicting food effects on oral extended-release drug products: a retrospective evaluation. AAPS J 2023; 25: 36991196. 10.1208/s12248-023-00804-7 [DOI] [PubMed] [Google Scholar]
185. Bardal SK, Waechter JE, Martin DS. Pharmacokinetics. In: Applied Pharmacology. Elsevier, 2011; 17–34. [Google Scholar]
186. Wiesner A, Gajewska D, Paśko P. Levothyroxine interactions with food and dietary supplements—a systematic review. Pharmaceuticals 2021; 40: 206. 10.3390/ph14030206 [DOI] [PMC free article] [PubMed] [Google Scholar]
187. Batchelor HK, Marriott JF. Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol 2015; 79: 395–404. 10.1111/bcp.12267 [DOI] [PMC free article] [PubMed] [Google Scholar]
188. Smith PW, Zuccotto F, Bates RH et al. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect Dis 2018; 4: 1439–47. 10.1021/acsinfecdis.8b00160 [DOI] [PMC free article] [PubMed] [Google Scholar]
189. Smith DA, Beaumont K, Maurer TS et al. Volume of distribution in drug design. J Med Chem 2015; 58: 5691–8. 10.1021/acs.jmedchem.5b00201 [DOI] [PubMed] [Google Scholar]
190. Onetto AJ, Sharif S. Drug distribution. In: StatPearls. StatPearls Publishing, 2023; 2–5. [PubMed] [Google Scholar]
191. Boidin C, Moshiri P, Dahyot-Fizelier C et al. Pharmacokinetic variability of beta-lactams in critically ill patients: a narrative review. Anaesth Crit Care Pain Med 2020; 39: 87–109. 10.1016/j.accpm.2019.07.016 [DOI] [PubMed] [Google Scholar]
192. Williams L, Hill DP, Davis JA et al. The influence of food on the absorption and metabolism of drugs: an update. Eur J Drug Metab Pharmacokinet 1996; 21: 201–11. 10.1007/BF03189714 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

dkae028_Supplementary_Data

dkae028_supplementary_data.docx^{(2.5MB, docx)}

Data Availability Statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

[dkae028-B1] 1. Pandey N, Cascella M. Beta-lactam antibiotics. In: StatPearls. StatPearls Publishing, 2022. https://www.ncbi.nlm.nih.gov/books/NBK545311/. [PubMed] [Google Scholar]

[dkae028-B2] 2. Mora-Ochomogo M, Lohans CT. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med Chem 2021; 12: 1623–39. 10.1039/D1MD00200G [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B3] 3. Choi U, Lee CR. Distinct roles of outer membrane porins in antibiotic resistance and membrane integrity in Escherichia coli. Front Microbiol 2019; 10: 953. 10.3389/fmicb.2019.00953 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B4] 4. ECDC . Antimicrobial Resistance in the EU/EEA—a One Health Response. 2022. https://www.ecdc.europa.eu/sites/default/files/documents/antimicrobial-resistance-policy-brief-2022.pdf.

[dkae028-B5] 5. Veiga RP, Paiva JA. Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients. Crit Care 2018; 22: 233. 10.1186/s13054-018-2155-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B6] 6. Vinks AA, Mouton JW, Derendorf H. Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics. Springer, 2014. [Google Scholar]

[dkae028-B7] 7. Dzierżanowska D. Walka z zakażeniami [Fight against infections]. In: Antybiotykoterapia Praktyczna [Antibiotic therapy in Practice]. Alfa Medica Press, 2018; 714. [Google Scholar]

[dkae028-B8] 8. Zachwieja Z. Interakcje leków z pożywieniem [Interactions between drugs and food]. MedPharm Polska, 2016. https://medpharm.pl/interakcje-lekow/310-interakcje-lekow-z-pozywieniem.html. [Google Scholar]

[dkae028-B9] 9. Pino-Marín DE, Madrigal-Cadavid J, Amariles P. Clinical relevance of drug interactions with antibiotics related to changes in the absorption: structured review. CES Medicina 2018; 32: 235–49. 10.21615/cesmedicina.32.3.5 [DOI] [Google Scholar]

[dkae028-B10] 10. Deppermann KM, Lode H, Höffken G et al. Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid. Antimicrob Agents Chemother 1989; 33: 1901–7. 10.1128/AAC.33.11.1901 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B11] 11. Mergenhagen KA, Wattengel BA, Skelly MK et al. Fact versus fiction: a review of the evidence behind alcohol and antibiotic interactions. Antimicrob Agents Chemother 2020; 64: e02167-19. 10.1128/AAC.02167-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B12] 12. Sterne JAC, Savović J, Page MJ et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898. 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]

[dkae028-B13] 13. Higgins JPT, Li T, Sterne JAC. Revised Cochrane risk of bias tool for randomized trials (RoB 2.0): additional considerations for crossover trials. Cochrane Methods, 2021. https://www.riskofbias.info/welcome/rob-2-0-tool/rob-2-for-crossover-trials.

[dkae028-B14] 14. NIH . Study Quality Assessment Tools. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.

[dkae028-B15] 15. Higgins JPT, White IR, Anzures-Cabrera J. Meta-analysis of skewed data: combining results reported on log-transformed or raw scales. Stat Med 2008; 27: 6072–92. 10.1002/sim.3427 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B16] 16. Wan X, Wang W, Liu J et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135. 10.1186/1471-2288-14-135 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B17] 17. Deeks J, Higgins J, Altman D. Chapter 10: Analysing data and undertaking meta-analyses (section 10.10.2 - Identifying and measuring heterogeneity). In: Cochrane Handbook for Systematic Reviews of Interventions Version 6.3. Cochrane Collaboration, 2022. [Google Scholar]

[dkae028-B18] 18. Bouter KP, Diepersloot RJA, Bourgonjen M et al. Oral pharmacokinetics of cefuroxime axetil in diabetic patients with autonomic neuropathy. Tijdschrift voor Therapie Geneesmiddel en Onderzoek 1993; 18: 73–6. [Google Scholar]

[dkae028-B19] 19. Chen RRL, Chung JM, Hsieh WC. Effect of food on the bioavailability of cefpodoxime proxetil in healthy Chinese subjects. Chin Pharm J 1996; 48: 103–12. [Google Scholar]

[dkae028-B20] 20. Henness DM, Richards D. Oral bioavailability of cefadroxil, a new semisynthetic cephalosporin. Clin Ther 1978; 1: 263–73. [Google Scholar]

[dkae028-B21] 21. Kislak JW, Eickhoff TC, Finland M. Cloxacillin: activity in vitro, and absorption and urinary excretion in normal young men. Am J Med Sci 1965; 249: 636–46. 10.1097/00000441-196506000-00002 [DOI] [PubMed] [Google Scholar]

[dkae028-B22] 22. Health Products Regulatory Authority . Pinaclor (Pinewood Laboratories). Summary of Product Characteristics. https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA0281-155-003_27052019144542.pdf.

[dkae028-B23] 23. FDA . Ceftin (GlaxoSmithKline). Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050605s042lbl.pdf.

[dkae028-B24] 24. FDA . Guidance for industry: food-effect bioavailability and fed bioequivalence studies. 2002. https://www.fda.gov/files/drugs/published/Food-Effect-Bioavailability-and-Fed-Bioequivalence-Studies.pdf.

[dkae028-B25] 25. Akimoto Y, Uda A, Omata H et al. Cephalexin concentrations in radicular granuloma following a single oral administration of 250 or 500 mg cephalexin. Gen Pharmacol 1994; 25: 1563–6. 10.1016/0306-3623(94)90355-7 [DOI] [PubMed] [Google Scholar]

[dkae028-B26] 26. Ali HM, Farouk AM. The effect of Sudanese diet on the bioavailability of ampicillin. Int J Pharm 1980; 8: 301–6. 10.1016/0378-5173(80)90113-1 [DOI] [Google Scholar]

[dkae028-B27] 27. Ali HM. The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets. Int J Pharm 1981; 9: 185–90. 10.1016/0378-5173(81)90043-0 [DOI] [Google Scholar]

[dkae028-B28] 28. Barbhaiya RH, Shukla UA, Gleason CR et al. Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor. Antimicrob Agents Chemother 1990; 34: 1210–3. 10.1128/AAC.34.6.1210 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B29] 29. Barr WH, Lin CC, Radwanski E et al. The pharmacokinetics of ceftibuten in humans. Diagn Microbiol Infect Dis 1991; 14: 93–100. 10.1016/0732-8893(91)90096-X [DOI] [PubMed] [Google Scholar]

[dkae028-B30] 30. Barr WH, Affrime M, Lin CC et al. Pharmacokinetics of ceftibuten in children. Pediatr Infect Dis J 1995; 14: S93–101. 10.1097/00006454-199507001-00005 [DOI] [PubMed] [Google Scholar]

[dkae028-B31] 31. Bauer KH, Foerster D, Hoff D et al. Urinary recovery after ingestion of ampicillin tablets together with a standard breakfast as compared with administration to fasting subjects. Pharmazeutische Industrie 1976; 38: 1153–4. [Google Scholar]

[dkae028-B32] 32. Bergdahl S, Eriksson M, Finkel Y et al. Oral absorption of flucloxacillin in infants and young children. Acta Pharmacol Toxicol (Copenh) 1986; 58: 255–8. 10.1111/j.1600-0773.1986.tb00105.x [DOI] [PubMed] [Google Scholar]

[dkae028-B33] 33. Blouin RA, Kneer J, Stoeckel K. Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects. Antimicrob Agents Chemother 1989; 33: 291–6. 10.1128/AAC.33.3.291 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B34] 34. Blouin RA, Kneer J, Ambros RJ et al. Influence of antacid and ranitidine on the pharmacokinetics of oral cefetamet pivoxil. Antimicrob Agents Chemother 1990; 34: 1744–8. 10.1128/AAC.34.9.1744 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B35] 35. Bolme P, Eriksson M, Paalzow L et al. Malnutrition and pharmacokinetics of penicillin in Ethiopian children. Pharmacol Toxicol 1995; 76: 259–62. 10.1111/j.1600-0773.1995.tb00140.x [DOI] [PubMed] [Google Scholar]

[dkae028-B36] 36. Borin MT, Forbes KK. Effect of food on absorption of cefpodoxime proxetil oral suspension in adults. Antimicrob Agents Chemother 1995; 39: 273–5. 10.1128/AAC.39.1.273 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B37] 37. Borin MT, Forbes KK, Hughes GS. The bioavailability of cefpodoxime proxetil tablets relative to an oral solution. Biopharm Drug Dispos 1995; 16: 295–302. 10.1002/bdd.2510160405 [DOI] [PubMed] [Google Scholar]

[dkae028-B38] 38. Borin MT, Driver MR, Forbes KK. Effect of timing of food on absorption of cefpodoxime proxetil. J Clin Pharmacol 1995; 35: 505–9. 10.1002/j.1552-4604.1995.tb04095.x [DOI] [PubMed] [Google Scholar]

[dkae028-B39] 39. Chen RR, Lee TY, Hsieh WC. Effect of food on pharmacokinetics of cefuroxime axetil in Chinese subjects. J Formos Med Assoc 1992; 91: 1177–81. [PubMed] [Google Scholar]

[dkae028-B40] 40. Cronk GA, Wheatley WB, Fellers GF et al. The relationship of food intake to the absorption of potassium alpha-phenoxyethyl penicillin and potassium phenoxymethyl penicillin from the gastrointestinal tract. Am J Med Sci 1960; 240: 219–25. [PubMed] [Google Scholar]

[dkae028-B41] 41. Digenis GA, Sandefer EP, Page RC et al. Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture. Pharm Res 2000; 17: 572–82. 10.1023/A:1007568900147 [DOI] [PubMed] [Google Scholar]

[dkae028-B42] 42. Ding Y, Jia YY, Li F et al. The effect of staggered administration of zinc sulfate on the pharmacokinetics of oral cephalexin. Br J Clin Pharmacol 2012; 73: 422–7. 10.1111/j.1365-2125.2011.04098.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B43] 43. Di Stefano A, Gemme G. A recent cephalosporin: cefadroxil. Clinical study and comparative blood levels after administration during fasting and after a meal. Minerva Pediatr 1981; 33: 871–80. [PubMed] [Google Scholar]

[dkae028-B44] 44. Ducharme MP, Edwards DJ, McNamara PJ et al. Bioavailability of syrup and tablet formulations of cefetamet pivoxil. Antimicrob Agents Chemother 1993; 37: 2706–9. 10.1128/AAC.37.12.2706 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B45] 45. Eckburg PB, Jain A, Walpole S et al. Safety, pharmacokinetics, and food effect of tebipenem pivoxil hydrobromide after single and multiple ascending oral doses in healthy adult subjects. Antimicrob Agents Chemother 2019; 63: e00618-19. 10.1128/AAC.00618-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B46] 46. Eden T, Lindstrom D, Perlhagen J. Serum concentrations of penicillin V in children after peroral administration in two forms, fasting and at mealtimes. Lakartidningen 1977; 74: 2443–4. [PubMed] [Google Scholar]

[dkae028-B47] 47. Eshelman FN, Spyker DA. Pharmacokinetics of amoxicillin and ampicillin: crossover study of the effect of food. Antimicrob Agents Chemother 1978; 14: 539–43. 10.1128/AAC.14.4.539 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B48] 48. Everts RJ, Begg R, Gardiner SJ et al. Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers. J Infect 2020; 80: 42–53. 10.1016/j.jinf.2019.09.004 [DOI] [PubMed] [Google Scholar]

[dkae028-B49] 49. Faulkner RD, Bohaychuk W, Haynes JD et al. The pharmacokinetics of cefixime in the fasted and fed state. Eur J Clin Pharmacol 1988; 34: 525–8. 10.1007/BF01046715 [DOI] [PubMed] [Google Scholar]

[dkae028-B50] 50. Fernandez CA, Menezes JP, Ximenes J. The effect of food on the absorption of pivampicillin and a comparison with the absorption of ampicillin potassium. J Int Med Res 1973; 1: 530–3. 10.1177/030006057300100604 [DOI] [Google Scholar]

[dkae028-B51] 51. Finkel Y, Bolme P, Eriksson M. The effect of food on the oral absorption of penicillin V preparations in children. Acta Pharmacol Toxicol (Copenh) 1981; 49: 301–4. 10.1111/j.1600-0773.1981.tb00910.x [DOI] [PubMed] [Google Scholar]

[dkae028-B52] 52. Finn A, Straughn A, Meyer M et al. Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharm Drug Dispos 1987; 8: 519–26. 10.1002/bdd.2510080604 [DOI] [PubMed] [Google Scholar]

[dkae028-B53] 53. Fujii R, Yoshioka H, Fujita K et al. Pharmacokinetic and clinical studies of cefdinir in the pediatric field. Jpn J Antibiot 1991; 44: 1168–91. 10.11553/antibiotics1968b.44.1168 [DOI] [PubMed] [Google Scholar]

[dkae028-B54] 54. Fujii R. Clinical trials of cefpodoxime proxetil suspension in paediatrics. Drugs 1991; 42: 57–60. 10.2165/00003495-199100423-00011 [DOI] [PubMed] [Google Scholar]

[dkae028-B55] 55. Fujii R, Meguro H, Tajima T et al. Overall clinical evaluation of cefprozil against infections in pediatric fields. Jpn J Antibiot 1992; 45: 1592–608. 10.11553/antibiotics1968b.45.1592 [DOI] [PubMed] [Google Scholar]

[dkae028-B56] 56. Fujimoto M, Sakai K, Ueda T et al. Pharmacological and clinical studies on the long acting cefaclor (S6472). Jpn J Antibiot 1985; 38: 849–57. 10.11553/antibiotics1968b.38.849 [DOI] [PubMed] [Google Scholar]

[dkae028-B57] 57. Gardiner SJ, Drennan PG, Begg R et al. In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances. PLoS One 2018; 13: e0199370. 10.1371/journal.pone.0199370 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B58] 58. Ginsburg CM, McCracken GH, Clahsen JC et al. Clinical pharmacology of cefadroxil in infants and children. Antimicrob Agents Chemother 1978; 13: 845–8. 10.1128/AAC.13.5.845 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B59] 59. Ginsburg CM, McCracken GH, Thomas ML et al. Comparative pharmacokinetics of amoxicillin and ampicillin in infants and children. Pediatrics 1979; 64: 627–31. 10.1542/peds.64.5.627 [DOI] [PubMed] [Google Scholar]

[dkae028-B60] 60. Ginsburg CM, McCracken GHJ. Pharmacokinetics of cephradine suspension infants and children. Antimicrob Agents Chemother 1979; 16: 74–6. 10.1128/AAC.16.1.74 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B61] 61. Ginsburg CM, McCracken GH, Zweighaft TC et al. Comparative pharmacokinetics of cyclacillin and amoxicillin in infants and children. Antimicrob Agents Chemother 1981; 19: 1086–8. 10.1128/AAC.19.6.1086 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B62] 62. Ginsburg CM. Comparative pharmacokinetics of cefadroxil, cefaclor, cephalexin and cephradine in infants and children. J Antimicrob Chemother 1982; 10: 27–31. 10.1093/jac/10.suppl_B.27 [DOI] [PubMed] [Google Scholar]

[dkae028-B63] 63. Ginsburg CM, McCracken GH, Petruska M et al. Pharmacokinetics and bactericidal activity of cefuroxime axetil. Antimicrob Agents Chemother 1985; 28: 504–7. 10.1128/AAC.28.4.504 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B64] 64. Ginsburg CM, McCracken GHJ, Olsen K et al. Pharmacokinetics and bactericidal activity of sultamicillin in infants and children. J Antimicrob Chemother 1985; 15: 345–51. 10.1093/jac/15.3.345 [DOI] [PubMed] [Google Scholar]

[dkae028-B65] 65. Glynne A, Goulbourn RA, Ryden R. A human pharmacology study of cefaclor. J Antimicrob Chemother 1978; 4: 343–8. 10.1093/jac/4.4.343 [DOI] [PubMed] [Google Scholar]

[dkae028-B66] 66. Gottfries J, Svenheden A, Alpsten M et al. Gastrointestinal transit of amoxicillin modified-release tablets and a placebo tablet including pharmacokinetic assessments of amoxicillin. Scand J Gastroenterol 1996; 31: 49–53. 10.3109/00365529609031626 [DOI] [PubMed] [Google Scholar]

[dkae028-B67] 67. Gower PE, Dash CH. Cephalexin: human studies of absorption and excretion of a new cephalosporin antibiotic. Br J Pharmacol 1969; 37: 738–47. 10.1111/j.1476-5381.1969.tb08513.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B68] 68. Guggenbichler JP, Kienel G. Bioavailability of new galenic preparations of cephalexin (author’s transl). Padiatr Padol 1978; 13: 315–20. [PubMed] [Google Scholar]

[dkae028-B69] 69. Guggenbichler JP, Kienel G. Bioavailability of orally administered antibiotics: influences of food on resorption (author’s transl). Padiatr Padol 1979; 14: 69–74. [PubMed] [Google Scholar]

[dkae028-B70] 70. Gupta VK, Patel G, Gasink L et al. Bioequivalence of two oral formulations of tebipenem pivoxil hydrobromide in healthy subjects. Clin Transl Sci 2022; 15: 1654–63. 10.1111/cts.13280 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B71] 71. Haginaka J, Yamaoka K, Nakagawa T et al. Evaluation of effect of food ingestion on bioavailability of cephalexin by moment analysis. Chem Pharm Bull (Tokyo) 1979; 27: 3156–9. 10.1248/cpb.27.3156 [DOI] [PubMed] [Google Scholar]

[dkae028-B72] 72. Hamid S, Beg AE. Influence of ethnic diets on ampicillin bioavailability and pharmacokinetics in healthy Pakistani subjects. Pol J Pharmacol Pharm 1987; 39: 337–42. [PubMed] [Google Scholar]

[dkae028-B73] 73. Harding SM, Williams PE, Ayrton J. Pharmacology of cefuroxime as the 1-acetoxyethyl ester in volunteers. Antimicrob Agents Chemother 1984; 25: 78–82. 10.1128/AAC.25.1.78 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B74] 74. Harvengt C, De Schepper P, Lamy F et al. Cephradine absorption and excretion in fasting and nonfasting volunteers. J Clin Pharmacol New Drugs 1973; 13: 36–40. 10.1002/j.1552-4604.1973.tb00066.x [DOI] [PubMed] [Google Scholar]

[dkae028-B75] 75. Hayashi Y Kojima T. Absorption and excretion of cefradine in healthy volunteers (author’s transl). Jpn J Antibiot 1980; 33: 655–63. 10.11553/antibiotics1968b.33.655 [DOI] [PubMed] [Google Scholar]

[dkae028-B76] 76. Healy DP, Sahai J V, Sterling LP et al. Influence of an antacid containing aluminium and magnesium on the pharmacokinetics of cefixime. Antimicrob Agents Chemother 1989; 33: 1994–7. 10.1128/AAC.33.11.1994 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B77] 77. Hughes GS, Heald DL, Barker KB et al. The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin Pharmacol Ther 1989; 46: 674–85. 10.1038/clpt.1989.204 [DOI] [PubMed] [Google Scholar]

[dkae028-B78] 78. Iwai N, Taneda Y, Nakamura H et al. Pharmacokinetic, bacteriological and clinical evaluation of cefpodoxime proxetil in pediatrics. Jpn J Antibiot 1989; 42: 1571–92. 10.11553/antibiotics1968b.42.1571 [DOI] [PubMed] [Google Scholar]

[dkae028-B79] 79. James NC, Donn KH, Collins JJ et al. Pharmacokinetics of cefuroxime axetil and cefaclor: relationship of concentrations in serum to MICs for common respiratory pathogens. Antimicrob Agents Chemother 1991; 35: 1860–3. 10.1128/AAC.35.9.1860 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B80] 80. Jones KH, Langley PF, Lees LJ. Bioavailability and metabolism of talampicillin. Chemotherapy 1978; 24: 217–26. 10.1159/000237784 [DOI] [PubMed] [Google Scholar]

[dkae028-B81] 81. Kamme C, Ursing B. Serum levels and clinical effect of flucloxacillin in patients with staphylococcal infections. Scand J Infect Dis 1974; 6: 273–8. 10.3109/inf.1974.6.issue-3.11 [DOI] [PubMed] [Google Scholar]

[dkae028-B82] 82. Karim S, Ahmed T, Monif T et al. The effect of four different types of food on the bioavailability of cefaclor. Eur J Drug Metab Pharmacokinet 2003; 28: 185–90. 10.1007/BF03190484 [DOI] [PubMed] [Google Scholar]

[dkae028-B83] 83. Kassem AKY. Cephradine bioequivalence and its interaction with khat and food (al-sayadeyah) in Yemen. Master's Thesis. University of Khartoum, Sudan, 2004.

[dkae028-B84] 84. Kato R, Ooi K, Takeda K et al. Lack of interaction between cefdinir and calcium polycarbophil: in vitro and in vivo studies. Drug Metab Pharmacokinet 2002; 17: 363–6. 10.2133/dmpk.17.363 [DOI] [PubMed] [Google Scholar]

[dkae028-B85] 85. Kearns GL, Abdel-Rahman SM, Jacobs RF et al. Cefpodoxime pharmacokinetics in children: effect of food. Pediatric Infect Dis J 1998; 17: 799–804. 10.1097/00006454-199809000-00010 [DOI] [PubMed] [Google Scholar]

[dkae028-B86] 86. Khan BAH, Ahmed T, Karim S et al. Comparative effect of different types of food on the bioavailability of cefaclor extended release tablet. Eur J Drug Metab Pharmacokinet 2004; 29: 125–32. 10.1007/BF03190587 [DOI] [PubMed] [Google Scholar]

[dkae028-B87] 87. Khuroo AH, Monif T, Verma PRP et al. Comparison of effect of fasting and of five different diets on the bioavailability of single oral dose of amoxicillin 500 mg capsule. Clin Res Regul Aff 2008; 25: 73–86. 10.1080/10601330802064272 [DOI] [Google Scholar]

[dkae028-B88] 88. Kibayashi M Watanabe A. Laboratory and clinical studies on cefdinir in pediatric field. Jpn J Antibiot 1990; 43: 1424–35. 10.11553/antibiotics1968b.43.1424 [DOI] [PubMed] [Google Scholar]

[dkae028-B89] 89. Kimura H, Takeuchi H, Ishikawa H et al. Bacteriological, pharmacokinetic and clinical studies on cefpodoxime proxetil in the pediatric field. Jpn J Antibiot 1989; 42: 1593–606. 10.11553/antibiotics1968b.42.1519 [DOI] [PubMed] [Google Scholar]

[dkae028-B90] 90. Koup JR, Dubach UC, Brandt R et al. Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob Agents Chemother 1988; 32: 573–9. 10.1128/AAC.32.4.573 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B91] 91. Koyama M Nakagawa K. Clinical phase I study of T-2588. Jpn J Antibiot 1986; 40: 55–76. 10.11553/antibiotics1968b.40.55 [DOI] [PubMed] [Google Scholar]

[dkae028-B92] 92. Lai X, Ye S, Chen L et al. An open-label, randomized, 2-way, crossover bioequivalence study of cefradine capsules in healthy Chinese volunteers. Clin Pharmacol Drug Dev 2021; 10: 1478–84. 10.1002/cpdd.991 [DOI] [PubMed] [Google Scholar]

[dkae028-B93] 93. Lecaillon JB, Hirtz JL, Schoeller JP et al. Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans. Antimicrob Agents Chemother 1980; 18: 656–60. 10.1128/AAC.18.5.656 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B94] 94. Leigh DA, Reeves DS, Simmons K et al. Talampicillin: a new derivative of ampicillin. Br Med J 1976; 1: 1378–80. 10.1136/bmj.1.6022.1378 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B95] 95. Li JT, Hou F, Lu H et al. Phase I clinical trial of cefditoren pivoxil (ME1207). Tolerance in healthy volunteers. Drugs Exp Clin Res 1997; 23: 131–8. [PubMed] [Google Scholar]

[dkae028-B96] 96. Li M, Andrew MA, Wang J et al. Effects of cranberry juice on pharmacokinetics of β-lactam antibiotics following oral administration. Antimicrob Agents Chemother 2009; 53: 2725–32. 10.1128/AAC.00774-08 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B97] 97. Li X, Wang Z, Liu W-P et al. Chronokinetic study of cefprozil in postprandial and fasting volunteers. Biol Rhythm Res 2013; 44: 95–102. 10.1080/09291016.2011.652862 [DOI] [Google Scholar]

[dkae028-B98] 98. Lin PP, Wang CJ, Liu YP et al. Pharmacokinetics and bioequivalence of cefprozil for suspension and granule formulation in healthy Chinese volunteers: two single-dose crossover studies. Adv Ther 2020; 38: 1130–42. 10.1007/s12325-020-01593-7 [DOI] [PubMed] [Google Scholar]

[dkae028-B99] 99. Lode H, Stahlmann R, Koeppe P. Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP 9000. Antimicrob Agents Chemother 1979; 16: 1–6. 10.1128/AAC.16.1.1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B100] 100. Lode H, Köppe P, Stahlmann R. Pharmacokinetics of cefaclor and initial therapeutical experience (author’s transl). Infection 1979; 7: 600–2. 10.1007/BF01659745 [DOI] [PubMed] [Google Scholar]

[dkae028-B101] 101. Lv X, Zhong G, Yao H et al. Bioequivalence of cefalexin in healthy Chinese subjects. Int J Clin Pharmacol Ther 2021; 59: 725–33. 10.5414/CP203986 [DOI] [PubMed] [Google Scholar]

[dkae028-B102] 102. Magni L, Sjoberg B, Sjovall J et al. Clinical pharmacological studies with bacampicillin. In: Williams JD, Geddes AM eds. Penicillins and Cephalosporins. Springer, 1975; 109–14. [Google Scholar]

[dkae028-B103] 103. Marzec A, Kunicki P, Bogiel M et al. Comparison of cefaclor absorption characteristics from the suspension and modified-release tablets in fast and fed condition. Ther Drug Monit 2005; 27: 231. 10.1097/00007691-200504000-00096 [DOI] [Google Scholar]

[dkae028-B104] 104. Matsumoto K, Kimura H Noguchi Y. Laboratory and clinical studies on cephradine. Chemotherapy 1975; 23: 98–105. 10.11250/chemotherapy1953.23.98 [DOI] [Google Scholar]

[dkae028-B105] 105. McCarthy CG, Finland M, Wilcox C et al. Absorption and excretion of four penicillins. N Engl J Med 1960; 263: 315–26. 10.1056/NEJM196008182630701 [DOI] [Google Scholar]

[dkae028-B106] 106. McCracken GHJ, Ginsburg CM, Clahsen JC et al. Pharmacologic evaluation of orally administered antibiotics in infants and children: effect of feeding on bioavailability. Pediatrics 1978; 62: 738–43. 10.1542/peds.62.5.738 [DOI] [PubMed] [Google Scholar]

[dkae028-B107] 107. McCracken GH, Ginsburg CM, Clahsen JC et al. Pharmacokinetics of cefaclor in infants and children. J Antimicrob Chemother 1978; 4: 515–21. 10.1093/jac/4.6.515 [DOI] [PubMed] [Google Scholar]

[dkae028-B108] 108. Meyers BR, Kaplan K, Weinstein L. Cephalexin: microbiological effects and pharmacologic parameters in man. Clin Pharmacol Ther 1969; 10: 810–6. 10.1002/cpt1969106810 [DOI] [PubMed] [Google Scholar]

[dkae028-B109] 109. Michel MF, Driessen O. Comparative study of serum concentrations of amoxicillin, pivampicillin and hetacillin (Dutch). Ned Tijdschr Geneeskd 1974; 118: 1508–14. [PubMed] [Google Scholar]

[dkae028-B110] 110. Mischler T, Sugerman A, Willard D et al. Influence of probenecid and food on the bioavailability of cephradine in normal male subjects. J Clin Pharmacol 1974; 14: 604–11. 10.1002/j.1552-4604.1974.tb01380.x [DOI] [PubMed] [Google Scholar]

[dkae028-B111] 111. Motohiro T, Handa S, Yamada S et al. Pharmacokinetics and clinical effects of cefdinir 10% fine granules in pediatrics. Jpn J Antibiot 1992; 45: 74–86. 10.11553/antibiotics1968b.45.74 [DOI] [PubMed] [Google Scholar]

[dkae028-B112] 112. Munkholm P, Olsen J, Hovgaard C et al. Absorption of pivampicillin as related to dose, and tolerability of a 700 mg tablet. Infection 1993; 21: 30–3. 10.1007/BF01739307 [DOI] [PubMed] [Google Scholar]

[dkae028-B113] 113. Nakamura H, Miyazu M, Kasai K et al. Studies on sultamicillin in the field of pediatrics. Jpn J Antibiot 1988; 41: 1874–94. 10.11553/antibiotics1968b.41.1874 [DOI] [PubMed] [Google Scholar]

[dkae028-B114] 114. Nakamura H Iwai N. Pharmacokinetic studies on oral antibiotics in pediatrics. II. A pharmacokinetic study on cefteram pivoxil in pediatrics. Jpn J Antibiot 1989; 42: 1981–2003. 10.11553/antibiotics1968b.42.1981 [DOI] [PubMed] [Google Scholar]

[dkae028-B115] 115. Nakamura H Iwai N. Pharmacokinetic study on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics. Jpn J Antibiot 1991; 44: 964–78. 10.11553/antibiotics1968b.44.964 [DOI] [PubMed] [Google Scholar]

[dkae028-B116] 116. Nakamura H Iwai N. Pharmacokinetic study on oral antibiotics in pediatrics. V. A pharmacokinetic study on cefdinir in pediatrics. Jpn J Antibiot 1992; 45: 12–27. 10.11553/antibiotics1968b.45.12 [DOI] [PubMed] [Google Scholar]

[dkae028-B117] 117. Nakashima M, Uematsu T, Takiguchi Y et al. Phase I study of cefixime, a new oral cephalosporin. J Clin Pharmacol 1987; 27: 425–31. 10.1002/j.1552-4604.1987.tb03043.x [DOI] [PubMed] [Google Scholar]

[dkae028-B118] 118. Nakashima M, Uematsu T, Takiguchi Y et al. Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. J Clin Pharmacol 1988; 28: 246–52. 10.1002/j.1552-4604.1988.tb03140.x [DOI] [PubMed] [Google Scholar]

[dkae028-B119] 119. Nakashima M, Morita J, Takata T et al. Effect of diet on the pharmacokinetics of tebipenem pivoxil fine granules in healthy male volunteers. Jpn J Antibiot 2009; 62: 136–42. [PubMed] [Google Scholar]

[dkae028-B120] 120. Nakashima M, Morita J, Aizawa K. Effect of diet including ice cream and pudding on tebipenem pivoxil fine granules pharmacokinetics in healthy male volunteers. Jpn J Chemother 2009; 57: 95–8. [PubMed] [Google Scholar]

[dkae028-B121] 121. Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of oral carbapenem antibiotic tebipenem pivoxil tablets in healthy male volunteers. Jpn J Chemother 2009; 57: 82–9. [Google Scholar]

[dkae028-B122] 122. Nakashima M, Morita J, Aizawa K. Effect of probenecid or diet on tebipenem pivoxil tablets pharmacokinetics in healthy male volunteers. Jpn J Chemother 2009; 57: 103–8. [PubMed] [Google Scholar]

[dkae028-B123] 123. Neu HC. Antimicrobial activity and human pharmacology of amoxicillin. J Infect Dis 1974; 129: S123–31. 10.1093/infdis/129.Supplement_2.S123 [DOI] [PubMed] [Google Scholar]

[dkae028-B124] 124. Neu HC. The pharmacokinetics of bacampicillin. Rev Infect Dis 1981; 3: 110–6. 10.1093/clinids/3.1.110 [DOI] [PubMed] [Google Scholar]

[dkae028-B125] 125. Neuvonen PJ, Elonen E, Pentikäinen PJ. Comparative effect of food on absorption of ampicillin and pivampicillin. J Int Med Res 1977; 5: 71–6. 10.1177/030006057700500113 [DOI] [PubMed] [Google Scholar]

[dkae028-B126] 126. Nishimura T, Tabuki K, Hiromatsu K et al. Laboratory and clinical studies of cefroxadine. Jpn J Antibiot 1981; 34: 1634–46. 10.11553/antibiotics1968b.34.1634 [DOI] [PubMed] [Google Scholar]

[dkae028-B127] 127. FDA . Suprax (Lupin Pharma). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202091s005,203195s006lbl.pdf.

[dkae028-B128] 128. FDA . Omnicef (Abbott Laboratories). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050739s015,050749s021lbl.pdf.

[dkae028-B129] 129. FDA . Spectracef (Cornerstone BioPharma). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021222s012lbl.pdf.

[dkae028-B130] 130. FDA . Cedax (Pernix Therapeutics). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050686s016lbl.pdf.

[dkae028-B131] 131. FDA . Vantin (Pfizer). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050674s015,050675s018lbl.pdf.

[dkae028-B132] 132. Oguma T, Yamada H, Sawaki M et al. Pharmacokinetic analysis of the effects of different foods on absorption of cefaclor. Antimicrob Agents Chemother 1991; 35: 1729–35. 10.1128/AAC.35.9.1729 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B133] 133. Olaganathan AA, Ruckmani A, Lakshmi G et al. Pharmacokinetic interaction between antacid and commonly prescribed medications - metformin, diclofenac and amoxicillin. Eur J Mol Clin Med 2017; 3: 7–8. 10.1016/j.nhtm.2016.01.001 [DOI] [Google Scholar]

[dkae028-B134] 134. Parsons RL, Hossack GA, Paddock GM et al. The effect of a Lundh meal on the plasma concentration/time curve of ampicillin, amoxycillin, pivampicillin and cephalexin in normal subjects. Br J Clin Pharmacol 1977; 4: 406P–7P. 10.1111/j.1365-2125.1977.tb00752.x [DOI] [PubMed] [Google Scholar]

[dkae028-B135] 135. Patel G, Gupta VK, Gasink L et al. Effect of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole) on the pharmacokinetics of tebipenem pivoxil hydrobromide (TBP-PI-HBr) in healthy adult subjects. Antimicrob Agents Chemother 2023; 67: e0149522. 10.1128/aac.01495-22 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B136] 136. Petitjean O, Brion N, Tod M et al. Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results. Presse Med 1989; 18: 1596–8. [PubMed] [Google Scholar]

[dkae028-B137] 137. Pfeffer M, Jackson A, Ximenes J et al. Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob Agents Chemother 1977; 11: 331–8. 10.1128/AAC.11.2.331 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B138] 138. Qu X, Deng Q, Li Y et al. Pharmacokinetics and safety of the two oral cefaclor formulations in healthy Chinese subjects in the fasting and postprandial states. Front Pharmacol 2022; 13: 1012294. 10.3389/fphar.2022.1012294 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B139] 139. Radwanski E, Nomeir A, Cutler D et al. Pharmacokinetic drug interaction study: administration of ceftibuten concurrently with the antacid Mylanta double-strength liquid or with ranitidine. Am J Ther 1998; 5: 67–72. 10.1097/00045391-199803000-00003 [DOI] [PubMed] [Google Scholar]

[dkae028-B140] 140. Roholt K, Nielsen B, Kristensen E. Clinical pharmacology of pivampicillin. Antimicrob Agents Chemother 1974; 6: 563–71. 10.1128/AAC.6.5.563 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B141] 141. Saathoff N, Lode H, Neider K et al. Of cefpodoxime proxetil and interactions with an antacid and an H2 receptor antagonist. Antimicrob Agents Chemother 1992; 36: 796–800. 10.1128/AAC.36.4.796 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B142] 142. Sabto J, Carson P, Morgan T. Evaluation of amoxycillin—a new semisynthetic penicillin. Med J Aust 1973; 2: 537–41. 10.5694/j.1326-5377.1973.tb129635.x [DOI] [PubMed] [Google Scholar]

[dkae028-B143] 143. Saito A, Kato Y, Murakami K. Studies on talampicillin. Kansenshogaku Zasshi 1975; 49: 458–69. 10.11150/kansenshogakuzasshi1970.49.458 [DOI] [PubMed] [Google Scholar]

[dkae028-B144] 144. Sakai K, Fujimoto M Ueda T. Clinical trials of sultamicillin (ester of sulbactam-ampicillin) on the skin and soft tissue infections in the field of surgery. Chemotherapy 1985; 33: 446–56. 10.11250/chemotherapy1953.33.Supplement2_446 [DOI] [Google Scholar]

[dkae028-B145] 145. Santoro J, Agarwal BN, Martinelli R et al. Pharmacology of cefaclor in normal volunteers and patients with renal failure. Antimicrob Agents Chemother 1978; 13: 951–4. 10.1128/AAC.13.6.951 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B146] 146. Sarel R, Miskin A, Ashkenazi A. Penicillin VK absorption during fasting and after eating. Harefuah 1989; 117: 430–2. [PubMed] [Google Scholar]

[dkae028-B147] 147. Satterwhite JH, Cerimele BJ, Coleman DL et al. Pharmacokinetics of cefaclor AF: effects of age, antacids and H2-receptor antagonists. Postgrad Med J 1992; 68: S3–9. [PubMed] [Google Scholar]

[dkae028-B148] 148. Shiba K, Maezawa H, Yoshida M et al. Effects of antacids on pharmacokinetics of cefditoren pivoxil and its metabolism in humans. Chemotherapy 1992; 40: 1310–9. 10.11250/chemotherapy1953.40.1310 [DOI] [Google Scholar]

[dkae028-B149] 149. Shiiki K, Hara H Kanno K. Effect of food intake on pharmacokinetics of cefetamet pivoxil. Chemotherapy 1990; 38: 340–3. 10.11250/chemotherapy1953.38.Supplement1_340 [DOI] [Google Scholar]

[dkae028-B150] 150. Shimada K Oka S-I. Effect of food on bioavailability of cefdinir. Chemotherapy 1989; 37: 246–56. 10.11250/chemotherapy1953.37.Supplement2_246 [DOI] [Google Scholar]

[dkae028-B151] 151. Shimada J, Saito A, Shiba K et al. Effects of antacids on absorption, excretion and metabolism of cefteram pivoxil. Jpn J Antibiot 1990; 43: 1353–70. 10.11553/antibiotics1968b.43.1353 [DOI] [PubMed] [Google Scholar]

[dkae028-B152] 152. Shukla UA, Pittman KA, Barbhaiya RH. Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers. J Clin Pharmacol 1992; 32: 725–31. 10.1002/j.1552-4604.1992.tb03876.x [DOI] [PubMed] [Google Scholar]

[dkae028-B153] 153. Sutherland R, Robinson OP. Laboratory and pharmacological studies in man with hetacillin and ampicillin. Br Med J 1967; 2: 804–8. 10.1136/bmj.2.5555.804 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B154] 154. Shyu WC, Shah VR, Campbell DA et al. Excretion of cefprozil into human breast milk. Antimicrob Agents Chemother 1992; 36: 938–41. 10.1128/AAC.36.5.938 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B155] 155. Sidell S, Bulger RJ, Brodie JL et al. Cloxacillin, a new oral synthetic penicillin comparisons with oxacillin. Clin Pharmacol Ther 1964; 5: 26–34. 10.1002/cpt19645126 [DOI] [PubMed] [Google Scholar]

[dkae028-B156] 156. Sommers DK, van Wyk M, Moncrieff J et al. Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil. Br J Clin Pharmacol 1984; 18: 535–9. 10.1111/j.1365-2125.1984.tb02501.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B157] 157. Staniforth DH, Lillystone RJ, Jackson D. Effect of food on the bioavailability and tolerance of clavulanic acid/amoxycillin combination. J Antimicrob Chemother 1982; 10: 131–9. 10.1093/jac/10.2.131 [DOI] [PubMed] [Google Scholar]

[dkae028-B158] 158. Staniforth DH, Clarke HL, Horton R et al. Augmentin bioavailability following cimetidine, aluminum hydroxide and milk. Int J Clin Pharmacol 1985; 23: 154–7. [PubMed] [Google Scholar]

[dkae028-B159] 159. Tam YK, Kneer J, Dubach UC et al. Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers. Antimicrob Agents Chemother 1990; 34: 1556–9. 10.1128/AAC.34.8.1556 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B160] 160. Tateno M, Ito M, Iida M et al. Absorption and excretion studies of S6472 (sustained release preparations of cefaclor). Jpn J Antibiot 1985; 38: 834–48. 10.11553/antibiotics1968b.38.834 [DOI] [PubMed] [Google Scholar]

[dkae028-B161] 161. Tetzlaff TR, McCracken GH, Thomas ML. Bioavailability of cephalexin in children: relationship to drug formulations and meals. J Pediatr 1978; 92: 292–4. 10.1016/S0022-3476(78)80029-8 [DOI] [PubMed] [Google Scholar]

[dkae028-B162] 162. Thambavita DD, Galappatthy P, Jayakody RL. Pharmacokinetics and bioequivalence of two amoxicillin 500 mg products: effect of food on absorption and supporting scientific justification for biowaiver. J Pharm Sci 2021; 110: 3735–41. 10.1016/j.xphs.2021.06.011 [DOI] [PubMed] [Google Scholar]

[dkae028-B163] 163. Totsuka K, Shimizu K, Mori N et al. Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil. Int J Antimicrob Agents 2001; 18: 463–9. 10.1016/S0924-8579(01)00443-5 [DOI] [PubMed] [Google Scholar]

[dkae028-B164] 164. Toyonaga Y, Kurosu Y Sugita M. Fundamental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field. Jpn J Antibiot 1985; 38: 373–413. 10.11553/antibiotics1968b.38.373 [DOI] [PubMed] [Google Scholar]

[dkae028-B165] 165. Toyonaga Y, Imai H, Sugita M et al. Bacteriological, pharmacokinetic and clinical studies on cefteram pivoxil in the pediatric field. Jpn J Antibiot 1989; 42: 1799–814. 10.11553/antibiotics1968b.42.1799 [DOI] [PubMed] [Google Scholar]

[dkae028-B166] 166. Ueno K, Tanaka K, Tsujimura K et al. Impairment of cefdinir absorption by iron ion. Clin Pharmacol Ther 1993; 54: 473–5. 10.1038/clpt.1993.178 [DOI] [PubMed] [Google Scholar]

[dkae028-B167] 167. Wagatsuma Y, Takase A, Fukushima N et al. Clinical evaluation of cefteram pivoxil fine granules in pediatric infections. Jpn J Antibiot 1989; 42: 1735–44. 10.11553/antibiotics1968b.42.1735 [DOI] [PubMed] [Google Scholar]

[dkae028-B168] 168. Wagatsuma Y, Takase A, Fukushima N et al. A clinical study on cefpodoxime proxetil dry syrup in pediatric infections. Jpn J Antibiot 1989; 42: 1464–70. 10.11553/antibiotics1968b.42.1464 [DOI] [PubMed] [Google Scholar]

[dkae028-B169] 169. Wang C, Yang J. Effect of food intake on pharmacokinetics of sustained-release cefradine capsules in healthy volunteers. J China Pharm Univ 2005; 36: 556–8. [Google Scholar]

[dkae028-B170] 170. Wang Y, Fan L, Cheng Y et al. Diet-induced alterations in pharmacokinetics of cefuroxime axetil in healthy Chinese subjects. Indian J Pharm Sci 2019; 81: 966–70. 10.36468/pharmaceutical-sciences.592 [DOI] [Google Scholar]

[dkae028-B171] 171. Weitschies W, Friedrich C, Wedemeyer RS et al. Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying. Eur J Pharm Biopharm 2008; 70: 641–8. 10.1016/j.ejpb.2008.05.011 [DOI] [PubMed] [Google Scholar]

[dkae028-B172] 172. Welling PG, Huang H, Koch PA et al. Bioavailability of ampicillin and amoxicillin in fasted and nonfasted subjects. J Pharm Sci 1977; 66: 549–52. 10.1002/jps.2600660423 [DOI] [PubMed] [Google Scholar]

[dkae028-B173] 173. Williams PEO, Harding SM. The absolute bioavailability of oral cefuroxime axetil in male and female volunteers after fasting and after food. J Antimicrob Chemother 1984; 13: 191–6. 10.1093/jac/13.2.191 [DOI] [PubMed] [Google Scholar]

[dkae028-B174] 174. Xu S-M, Qin F, Zhang Y-D et al. Pharmacokinetics of amoxicillin and clavulanate potassium for suspension (200 mg/28.5 mg) in healthy subjects: sample add stabilizer study and food effects. Clin Pharmacol Drug Dev 2022; 11: 1314–21. 10.1002/cpdd.1143 [DOI] [PubMed] [Google Scholar]

[dkae028-B175] 175. Yamaguchi M, Satoh T, Kikuchi F et al. Comparative study on human blood concentration of oral cephem antibiotics CXM-AX vs CCL - effect of food on bioavailability. Oral Ther Pharmacol 1992; 11: 99–104. 10.11263/jsotp1982.11.99 [DOI] [Google Scholar]

[dkae028-B176] 176. Yang TY, Huang XX, Zhou JL et al. Effects of high-fat and high-calorie diets on pharmacokinetics of cefuroxime axetil tablets. Chin Pharm J 2017; 52: 1531–5. 10.11669/cpj.2017.17.011 [DOI] [Google Scholar]

[dkae028-B177] 177. Yaoguo S, Qin Z, Jichen Y et al. Pharmacokinetics of cefixime in healthy volunteers. Chin J Antibiotics 1994; 19: 293–8. [Google Scholar]

[dkae028-B178] 178. Yazdani-Brojeni P, Garcia-Bournissen F, Fujii H et al. Bioavailability of amoxicillin dissolved in human milk. J Popul Ther Clin Pharmacol 2012; 19: e295-6. [Google Scholar]

[dkae028-B179] 179. Zhang Z, Zhang X, Yang S et al. Bioequivalence of cefdinir capsules in Chinese healthy population under fasting/high-fat fed condition. Chin J Clin Pharmacol Therapeutics 2020; 25: 740–5. 10.12092/j.issn.1009-2501.2020.07.004 [DOI] [Google Scholar]

[dkae028-B180] 180. Wiesner A, Skrońska M, Gawlik G et al. Interactions of antiretroviral drugs with food, beverages, dietary supplements, and alcohol: a systematic review and meta-analyses. AIDS Behav 2023; 27: 1441–68. 10.1007/s10461-022-03880-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B181] 181. O’Shea JP, Holm R, O’Driscoll CM et al. Food for thought: formulating away the food effect—a PEARRL review. J Pharm Pharmacol 2019; 71: 510–35. 10.1111/jphp.12957 [DOI] [PubMed] [Google Scholar]

[dkae028-B182] 182. Gao P, Nie X, Zou M et al. Recent advances in materials for extended-release antibiotic delivery system. J Antibiot 2011; 64: 625–34. 10.1038/ja.2011.58 [DOI] [PubMed] [Google Scholar]

[dkae028-B183] 183. Gorria P, Revel J. Modified-release formulations: improving efficacy and patient compliance. Pharm Technol 2019; 2019: s6–8. [Google Scholar]

[dkae028-B184] 184. Zou P, Vaidyanathan J, Tran D et al. Predicting food effects on oral extended-release drug products: a retrospective evaluation. AAPS J 2023; 25: 36991196. 10.1208/s12248-023-00804-7 [DOI] [PubMed] [Google Scholar]

[dkae028-B185] 185. Bardal SK, Waechter JE, Martin DS. Pharmacokinetics. In: Applied Pharmacology. Elsevier, 2011; 17–34. [Google Scholar]

[dkae028-B186] 186. Wiesner A, Gajewska D, Paśko P. Levothyroxine interactions with food and dietary supplements—a systematic review. Pharmaceuticals 2021; 40: 206. 10.3390/ph14030206 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B187] 187. Batchelor HK, Marriott JF. Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol 2015; 79: 395–404. 10.1111/bcp.12267 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B188] 188. Smith PW, Zuccotto F, Bates RH et al. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect Dis 2018; 4: 1439–47. 10.1021/acsinfecdis.8b00160 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkae028-B189] 189. Smith DA, Beaumont K, Maurer TS et al. Volume of distribution in drug design. J Med Chem 2015; 58: 5691–8. 10.1021/acs.jmedchem.5b00201 [DOI] [PubMed] [Google Scholar]

[dkae028-B190] 190. Onetto AJ, Sharif S. Drug distribution. In: StatPearls. StatPearls Publishing, 2023; 2–5. [PubMed] [Google Scholar]

[dkae028-B191] 191. Boidin C, Moshiri P, Dahyot-Fizelier C et al. Pharmacokinetic variability of beta-lactams in critically ill patients: a narrative review. Anaesth Crit Care Pain Med 2020; 39: 87–109. 10.1016/j.accpm.2019.07.016 [DOI] [PubMed] [Google Scholar]

[dkae028-B192] 192. Williams L, Hill DP, Davis JA et al. The influence of food on the absorption and metabolism of drugs: an update. Eur J Drug Metab Pharmacokinet 1996; 21: 201–11. 10.1007/BF03189714 [DOI] [PubMed] [Google Scholar]

PERMALINK

Do dietary interventions exert clinically important effects on the bioavailability of β-lactam antibiotics? A systematic review with meta-analyses

Agnieszka Wiesner

Paweł Zagrodzki

Paweł Paśko

Abstract

Background

Methods

Results

Conclusions

Introduction

Background

Existing evidence

Objectives

Methods

Eligibility criteria

Types of studies

Types of participants

Types of interventions

Types of outcomes

Information sources and search strategy

Selection process

Data collection process

Assessment of risk of bias in individual studies

Data synthesis

The effect measures

Assessment of heterogeneity

Additional analyses

Judgement of clinical relevance

Results

Eligible studies

Figure 1.

Study characteristics

Table 1.

Risk-of-bias assessment

Quantitative synthesis

Table 2.

Subgroup analyses

Table 3.

Sensitivity analyses

Table 4.

Publication bias

Figure 2.

Qualitative synthesis

Table 5.

Summary of results

Clinically important interactions

Figure 3.

Figure 4.

Differences from recommendations in SmPCs

Discussion

Factors potentially affecting the interactions

Physicochemical properties of drugs

Figure 5.

Drug formulation

Drug dose

Type of dietary intervention

Patient age

Health state of patients

Secondary PK outcomes

Elimination half-life (t½)

Vd

CL

PK/PD indices

Amoxicillin

Cefaclor

Cefprozil

Cefalexin

Flucloxacillin

Limitations of studies included in the review

Actuality of studies

Methodology of studies

Concerns related to participants

Significant gaps in data

Limitations of the review

Summary

Supplementary Material

Contributor Information

Funding

Transparency declarations

Elimination half-life (t_½)

V_d