National Amoxicillin-Clavulanate Formulation Use Pattern: A Survey

Abstract

OBJECTIVE

Five commercially available amoxicillin-clavulanate (AMC) ratio formulations contribute to ratio selection variability with efficacy and toxicity implications. The objective of this survey was to determine AMC formulation use patterns across the United States.

METHODS

A multicenter practitioner survey was distributed to multiple listservs (American College of Clinical Pharmacy pediatrics, infectious diseases, ambulatory care, pharmacy administration; American Society of Health-System Pharmacists; Pediatric Pharmacy Association members), and selected pediatric Vizient members in June 2019. Responses were screened for multiples within institutions. Repeated organization responses were identified (n = 37) and excluded if the duplicate matched another response from the same organization exactly (n = 0).

RESULTS

One hundred ninety independent responses were received. Nearly 62% of respondents represented a children's hospital within an acute care hospital; remainder being from stand-alone children's hospitals. Around 55% of respondents indicated prescribers were responsible for choosing the patient-specific formulation for inpatients. Nearly 70% of respondents indicated multiple formulations were available due to clinical need (efficacy, toxicity, measurable volume), whereas over 40% responded that the number of liquid formulations were limited to decrease the potential for error. Variability was demonstrated among institutions using ≥ 2 different formulations for acute otitis media (AOM), sinusitis, lower respiratory tract infection, skin and soft tissue infection, and urinary tract infection (33.6%, 37.3%, 41.5%, 35.8%, and 35.8%, respectively). The 14:1 formulation was the most common, but not exclusive, for AOM, sinusitis, and lower respiratory tract infections with 2.1%, 2.1%, and 2.6% of respondents indicating use of the 2:1 formulation and 10.9%, 15%, and 16.6% of respondents indicating use of the 4:1 formulation.

CONCLUSIONS

Significant AMC formulation selection variability exists across the United States.

Introduction

Medication safety is a vital component of patient care and it carries significant implications within pediatric practice. A Sentinel Event Alert issued by the Joint Commission describes that adverse drug events are 3 times more likely to occur in pediatric patients compared with adults.¹ Estimates indicate 1% to 10% of medication errors lead to harm.²

Amoxicillin-clavulanate (AMC) is an oral combination beta-lactam/beta lactamase inhibitor antibiotic introduced into the US market in the mid-1980s. Subsequently, the number of commercially available ratio formulations have increased, resulting in 5 currently available amoxicillin to clavulanate ratios (i.e., 2:1, 4:1, 7:1, 14:1, 16:1) among 11 dosage formulations on the US market.

There is perceived variability in ratio selection approach per observation and conversations with pediatric clinicians. Choosing an incorrect ratio has efficacy and toxicity implications. The potential for decreased effectiveness against beta-lactamase producing pathogens exists if using traditional/lower/standard dosing (e.g., ≤45 mg/kg/day) and a high ratio formulation (e.g., 14:1) as the clavulanate dose delivered may not achieve pharmacodynamic targets and would not be consistent with labeled dosing (Table 1).^3–5 Using a lower than optimal amoxicillin to clavulanate ratio has the potential to induce gastrointestinal toxicity, specifically diarrhea.^6–8 Anecdotally, practitioners may choose a ratio solely based on whichever formulation will produce a convenient volume for administration (e.g., 5 mL, 7.5 mL).

Table 1.

Amoxicillin Dose and Delivered Clavulanate Dose

AMC Ratio (AMC Formulation Examples)	Delivered Clavulanate Dose (mg/kg/day)
Amoxicillin dose: 45 mg/kg/day
4:1 (125 mg/5 mL, 250 mg/5 mL, 500 mg tablet)	11.25*
7:1 (200 mg/5 mL, 400 mg/5 mL, 875 mg tablet)	6.43†
14:1 (600 mg/5 mL)	3.21‡
Amoxicillin dose: 90 mg/kg/day
4:1 (125 mg/5 mL, 250 mg/5 mL, 500 mg tablet)	22.5*
7:1 (200 mg/5 mL, 400 mg/5 mL, 875 mg tablet)	12.86*
14:1 (600 mg/5 mL)	6.43†

AMC, amoxicillin-clavulanate

^* Potentially supratherapeutic clavulanate dose.

^† Intended (labeled) clavulanate dose.

^‡ Potentially subtherapeutic clavulanate dose.

Commonly used dosing references include AMC dosing recommendations which, because of the references' language on formulation selection and depending on the formulation chosen, could deliver anywhere from 1.8 to 12.9 mg/kg/day of clavulanate.⁹ Interestingly, when the combination parenteral antibiotic ticarcillin-clavulanate potassium, used primarily for infections caused by resistant Gram-negative organisms, was available on the US market, dosing recommendations of 200 to 300 mg/kg/day would deliver 6.7 to 10 mg/kg/day of clavulanate. Existing gaps in the literature, with respect to the optimal mg/kg clavulanate dose needed to achieve pharmacodynamic targets when in combination with amoxicillin, may compound challenges associated with appropriate AMC formulation selection.

There are additional challenges when using these formulations when caring for children within an adult hospital as compared with a stand-alone children's hospital. Clinicians may cross cover adult and pediatric areas, and formulary choices may be influenced by the wider patient population age set. Because of the complexity, clinical repercussions, and medication safety implications of inappropriate ratio use, we set out to determine AMC formulation use patterns across the United States.

Materials and Methods

This was a cross-sectional descriptive survey of health-system practitioners. A 12-question (~5 minutes) electronic Qualtrics (Provo, UT) survey was distributed via listservs (American College of Clinical Pharmacy pediatrics, infectious diseases, ambulatory care, pharmacy administration; American Society of Health-System Pharmacists; Pediatric Pharmacy Association members), and to selected pediatric Vizient members. Survey data were collected for an 8-week period between June and August 2019. Total number of surveys distributed was not available due to listserv management by external organizations and potential for duplication or overlap of recipients. The survey instrument used conditional logic and included a maximum of 12 questions to assess respondent demographics, AMC formulation availability, and formulation selection rationale. Survey questions were multiple choice, brief response, multiple response, and multiple response with an other text-text box option.

Participation was voluntary and anonymous aside from a question asking the name of the respondent's organization. This was included to identify and reconcile duplicate responses submitted from the same organization. A repeated response was defined as ≥ 2 responses from the same organization and a duplicate response was defined as matching another response from the same organization exactly. Participants were encouraged to answer all survey questions but were able to skip questions.

Descriptive statistics were calculated using Statistical Package for Social Sciences version 26 (SPSS, Inc, Chicago, IL).

Results

One hundred ninety independent responses were received and included in analysis. Although there were repeated responses (n = 37), there were no instances of the duplicate responses identified (n = 0) exactly matching another from the same organization. Most respondents (61.7%) identified their institutions as a children's hospital within an acute care hospital while the remainder (38.3%) were from stand-alone children's hospitals. The survey tool did not further determine if stand-alone children's hospitals were independent or a part of a larger health system.

Respondents reported a median (IQR) pediatric bed capacity of 130 (71, 253) with as few as < 10 and large as > 650. Responsibility for choosing specific AMC ratio formulations within institutions rested with prescribers (55%) more so than pharmacists (45%).

Ninety-eight percent and 21% of respondents indicated their institutions supplied multiple AMC formulations for pediatric and neonatal patients, respectively. Institutions indicating multiple formulations, supplied a mean ± SD of 5.1 ± 1.7 and 1.3 ± 0.6 formulations for pediatric and neonatal patients, respectively. Table 2 describes the formulation availability, by hospital type, among pediatric and neonatal patients.

Table 2.

Formulation Availability Among Hospital Types ^*

	Number of Formulations
	1	2–4	5–7	8–9	10
Children’s hospital within acute care hospital
Pediatric patients	1.7	32.8	56.9	7.8	0.9
Neonatal patients	83.9	16.1	0	0	0
Stand-alone children’s hospital
Pediatric patients	2.8	40.8	50.7	4.2	1.4
Neonatal patients	69.7	28.8	1.5	0	0

^* Data reported in %.

The 875-mg and 500-mg tablets were the most common tablet formulations for pediatric patients with 91.6% and 72.6% of respondents indicating availability, respectively. Fewer than 30% of respondents indicated pediatric availability for other tablet forms. Among liquid formulations for pediatric patients, the 600 mg/5 mL and 400 mg/5 mL were most commonly reported. Table 3 displays liquid formulation availability for pediatric and neonatal patients.

Table 3.

Liquid Formulation Availability for Pediatric Patients and Neonatal Patients ^*

	125 mg/5 mL	250 mg/5 mL	200 mg/5 mL	400 mg/5 mL	600 mg/5 mL
Pediatric (1 mo–18 yr)	23.2	37.9	18.9	74.2	87.4
Neonatal (0–29 days)	28.2	28.2	9.4	36.5	22.1

* Data reported in %.

Table 4 describes formulation availability by indication. Roughly one-third of respondents reported using at least 2 different formulations for the treatment of acute otitis media (AOM; 28.1%), sinusitis (31.2%), lower respiratory tract infection (36.5%), skin and soft tissue infection (30.3%), or urinary tract infection (29.1%).

Table 4.

Formulation Availability by Indication ^*

Formulation	Indication
	AOM	Sinusitis	LRTI	SSTI	UTI
2:1	2.2	2.3	2.8	6.2	4.6
4:1	11.8	16.5	18	30.9	37.7
7:1	30.9	52.8	52.2	80.9	76
14:1	80.9	62.5	68	24.7	18.3
16:1	15.7	11.9	15.7	5.1	3.2

AOM, acute otitis media; LRTI, lower respiratory tract infection; SSTI, skin and soft tissue infection; UTI, urinary tract infection

^* Data reported in %.

Respondents reported a variety of rationales influencing the availability of liquid formulations. Roughly two-thirds (69.5%) indicted stocking multiple formulations due to clinical need, which encompassed efficacy and toxicity considerations as well as dosage volume measurability. This was followed by rationales of limiting formulations due to error concerns (42.8%) and to comply with US Food and Drug Administration labeling (12.8%). Less than 10% of respondents chose additional rationales including don't know (9.1%), local resistance patterns (8.6%), no difference in formulations (5.3%), and no rationale (1.6%).

Discussion

This is the first evaluation of AMC formulation use patterns across the United States, with respondents from each of the 9 Centers for Disease Control and Prevention geographical regions, despite the growth of AMC formulations since initial marketing. Significant AMC formulation selection variability, both in terms of formulary availability and selection, exists. A limitation of our survey is the response rate was not available as the total number of surveys distributed was not known. Our findings highlight that along with varied ratio availability, institutions stock multiple different formulations with clinical need cited as the most common reason. This is an important consideration as practitioners often use AMC for infections primary caused by Streptococcus pneumoniae and those caused by beta-lactamase producing Gram-negative pathogens. Optimizing AMC's pharmacokinetic and pharmacodynamic characteristics to meet the myriad of anticipated infections challenges an institution's approach to streamline product availability.

A question becomes how many different ratios an institution should make available. One consistent approach across institutions, including free-standing children's hospitals and adult-focus health systems caring for pediatric patients, is unrealistic. Clinical need may drive formulation availability, but data supporting optimal indication-specific clavulanate dosing are lacking. This issue is highlighted among data on formulation availability by indication. There appears to be an inclination toward a higher ratio for AOM where S pneumoniae is arguably the most concerning causative organism. With alteration of penicillin binding site proteins, the primary mechanism of antibiotic resistance encountered with S pneumoniae associated otitis media, the need for beta-lactamase inhibition is diminished. The trends are less clear with infections more likely stemming from beta-lactamase producing Gram-negative bacteria (Table 4).

The implication of our data is clear. Potential exists for the selection of a lower AMC ratio for a condition when a higher ratio is warranted to optimate drug properties and limit adverse effects. A corresponding potential exists for the selection of a higher AMC ratio in conditions where a lower ratio would be needed to optimize efficacy, through the delivery of a higher mg/kg clavulanate dose. Further study of AMC pharmacodynamics, while the desire may be low, could contribute to the collective knowledge and answer the question of how much clavulanate is required.

In the free text comments, 2 respondents indicated use of AMC as a pro-motility agent since the clavulanate component is known to cause increased intestinal motility and diarrhea.^6–8 While antibiotics are occasionally used for non-antimicrobial indications (e.g., macrolides or tetracyclines for inflammation or macrolides for gastrointestinal motility), there are concerns regarding the induction of antimicrobial resistance, specifically S pneumoniae and Enterobacteriaceae (common pediatric pathogens), with long-term AMC use for this indication.^10,11 Practices like these provide reminders of the importance of local antimicrobial stewardship efforts even for drugs like AMC, which may not garner as much attention as others.

Conclusion

Education opportunities exist to ensure optimal use, formulation availability, and selection in order to yield desired clinical outcomes and avoid unnecessary errors and adverse events. Based on the results of this survey, the authors recommend the following:

1. Organizations may consider limiting the number of formulations available to encourage safe medication practices and decrease confusion by leveraging an individualized approach based on local needs, patient factors, and clinician preference.

2. A broad and continuous educational campaign will support appropriate efficacy, mitigate toxicity or adverse events, and encourage the safe and effective use of various formulations. This may include formalized didactic activity (prescribers, nurses, and pharmacy staff), electronic health record prompts, learning management system modules, patient education, and clinical decision support.

3. Limit the use of AMC for chronic use outside of the antimicrobial setting.

ABBREVIATIONS

AMC

amoxicillin-clavulanate;

AOM

acute otitis media;

UTI

urinary tract infection