Doxycycline for Multidrug-Resistant Gram-Negative Bacterial Infection Treatment: A Scoping Review

Abstract

Introduction:

Multidrug-resistant bacterial infections limit available therapeutic options. Doxycycline is an old antibiotic from the tetracycline class that exhibits a wide antibacterial action, including Gram-negative bacteria (GNB), and could be an alternative for the treatment of multidrug-resistant (MDR) Enterobacteriaceae. The study aimed to systematically identify, evaluate, and summarize the results of studies related to outcomes of treatments for MDR-GNB infections in patients treated with doxycycline.

Methods:

This review was conducted in four databases during weeks 41–52 of 2022: PubMed, Medline, Scopus, and Web of Science, from the earliest year available on each database to December 2022. Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines were followed in conducting this study, and PICO was used for the research question of this review.

Results:

This scoping review found 8 retrospective studies that included 59 patients. Of these, 69% were treated for ventilator-associated pneumonia (VAP), 27% for urinary tract infections, 2% for bloodstream infections, and 2% for wound infections, both of which were associated with VAP. The usual dosage of doxycycline was 100 mg intravenously or orally. Clinical and microbiologic improvements were achieved in 81.3% and 87% of all patients, respectively. The mortality rate was 17.3% and was exclusively due to VAP.

Conclusions:

Doxycycline showed promising results in this review; however, randomized clinical trials or prospective cohorts are recommended to demonstrate the efficacy of doxycycline in the treatment of MDR infections with GNB.

INTRODUCTION

Bacterial antimicrobial resistance is a reality in most health scenarios around the world, occurring mainly due to the widespread and abusive use of antibiotics.[1,2]

Limited treatment options are available in the context of multidrug-resistant bacterial infections, resulting in a threat to public health, increasing costs, morbidity, and mortality. New antibiotics take an average of 7–8 years to develop, which is the same time that takes an organism to develop resistance to a drug.[3] Another option, until new classes of antimicrobials emerge or are on the market, old drugs can be rescued.[4,5]

Doxycycline is an ancient antibiotic that shows good activity against Gram-positive and Gram-negative bacteria (GNB)[6,7] and has been observed in vitro[8] remaining active against multidrug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli ESBL, KPC, which are the most critical group of multidrug-resistant bacteria considered by the WHO for the development of new antibiotics.[9]

However, data on the clinical efficacy of doxycycline are still scarce in the literature on this topic.[10] Therefore, the aim was to systematically identify, evaluate, and summarize the results of studies related to outcomes of treatments for MDR-GNB infections in patients treated with doxycycline.

METHODS

This scoping review was structured according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and the Cochrane Collaboration. The research question of this review was formulated on the basis of PICO: “Is doxycycline a therapeutic option for the treatment of multidrug-resistant Gram-negative bacteria?” In this case, the population (P) consisted of adult patients infected with multidrug-resistant Enterobacteriaceae (Enterobacter resistant to 1^st to 3^rd generation cephalosporins and carbapenems, Acinetobacter resistant to carbapenems, Pseudomonas resistant to carbapenems), the intervention (I) was the use of doxycycline, the comparison (C) was no restriction, and the outcome (O) was the clinical and microbiological cure.

Electronic searches for articles were performed in the PubMed, Medline, Scopus, and Web of Science databases from the earliest year available on each database to December 2022 during weeks 41–52 of 2022.

The search was performed using the following terms: (“ESBL” OR “carbapenemases” OR “Klebsiella pneumoniae” OR “Acinetobacter” OR “Pseudomonas” OR “Gram-negative resistance” OR “carbapenem-resistant Enterobacteriaceae”) AND doxycycline. The retrieved articles were exported to the Rayyan digital platform (Qatar Computing Research Institute, Doha, Qatar). Table 1 provides an overview of the database search strategy. No restrictions were placed on language or year of publication.

Table 1.

Search strategy

Database	Search strategy	n
Scopus	[TITLE-ABS (doxycycline) AND TITLE-ABS (“ESBL” OR “Carbapenemases” OR “Klebsiella pneumoniae” OR “Acinetobacter” OR “Pseudomonas” OR “gram negative resistance” OR “Carbapenem-resistant Enterobacteriaceae”]	477
Web of science	“ESBL” OR “Carbapenemases” OR “Klebsiella pneumoniae” OR “Acinetobacter” OR “Pseudomonas” OR “gram negative resistance” OR Carbapenem-resistant Enterobacteriaceae (topic) AND doxycycline (topic)	204
Pubmed	(“ESBL”[All Fields] OR “Carbapenemases”[All Fields] OR “Klebsiella pneumoniae”[All Fields] OR “Acinetobacter”[All Fields] OR “Pseudomonas”[All Fields] OR “gram negative resistance”[All Fields] OR “Carbapenem-resistant Enterobacteriaceae”[All Fields]) AND (“doxycycline”[MeSH Terms] OR “doxycycline”[All Fields] OR “doxycyclin”[All Fields])	425

n: Number of articles identified from database

Two independent reviewers selected the studies and extracted the data. Disagreements were resolved with a third reviewer or by consensus. Thus, articles were selected on the basis of titles and abstracts (screening step), and for studies with insufficient data, the manuscript was obtained and read in full. Studies that did not meet the established eligibility criteria were excluded. The second selection was made by reading the full text (selection step). Disagreements in article selection were resolved by discussion between independent authors.

Furthermore, Table 2 describes the inclusion and exclusion criteria adopted in this review.

Table 2.

Eligibility criteria adopted for this scoping review

Eligibility criteria
Inclusion criteria	Studies that met the PICO acronym were included
	Patients (P): Adult patients infected with MDR enterobacteria (Eterobacter resistant to 1st–3rd generation cephalosporins and carbapenems, Acinetobacter resistant to carbapenems, Pseudomonas resistant to carbapenems)
	Intervention (I): Doxycycline
	Comparator (C): Another antimicrobial that covers MDR Outcome (O): Clinical and microbiological cure
Exclusion criteria	Studies focusing on in vitro activity and animal models

MDR: Multiple drug resistance

RESULTS

Figure 1 shows the selection process for the included studies. Eight retrospective studies were included in this scoping review.[11,12,13,14,15,16,17,18] These articles mostly consist of case reports, whereas there are only a few studies (2 cohort studies, 3 case series, and 3 case reports). Table 3 provides a summary of the author/year of study, study design, number of patients, clinical manifestation, and results for each included paper.

Figure 1.

PRISMA flowchart

Table 3.

Clinical and microbiological characteristics and outcomes of selected studies

Author year	Study design	Number patients	Site infection	Bacteria	Duration of treatment and antibiotic regimen	Clinical success (%)	Microbiological success (%)	Mortality (%)
Wood et al. (2003)[11]	Case series	3	VAP	AB-MDR	DOX: 100 mg IV bid Patient 1: AMI + DOX, 14 days Patient 2: AMP-SUL + DOX, 9 days Patient 3: AMI + TFX + DOX, 13 days	67	100 (2 tested patients)	33
Holloway et al. (2006)[12]	Case series	4	2 VAP 1 BSI 1 SSI	AB-MDR	DOX: 100 mg IV bid 7 days	2 in 4 (50), BSI and SSI	67 (2/3 patients)	75 (death not associated with treatment)
Chan et al. (2010)[13]	Cohort	36	VAP	CR-AB	DOX or MIN (loading dose 200 mg) followed by 200 mg bid (n=17) or DOXI 100 mg IV bid (n=19), either alone (n=11) or in combination: AMI, TIG or PMX (n=25) 13.3 days	81 MIN + DOX 75 AMI + MIN/DOX	48.5	NA
Alexander et al. (2012)[14]	Cohort	3	UTI	CRKP	DOX: 100 mg VO qd Patient 1=6.5 days Patient 2=13 days Patient 3=7 days	100	67	0
Cicora et al. (2013)[15]	Case series	2	UTI	CRKP	NA Patient 1=28 days 1° e 2° treatments Patient 2=14 days	67 Patient 1=Success and later relapse Patient 2=Success	NA	0
Qureshi et al. (2014)[16]	Cohort	9	UTI	CRKP	NA 13 days	100	100	0
Cunha et al. (2015)[17]	Case report	1	Chronic prostatitis	E. coli ESBL	DOXI: 100 mg VO bid + FOF 3 g VO each 72 h 14 days	100	100	0
White et al. (2017)[18]	Case report	1	UTI	K. pneumoniae ESBL + E. coli MS	DOXI: 100 mg VO bid 14 days	100	NA	0

AB-MDR: A. baumanni multi drug resistant, AMI: Amikacin, AMP + SUL: Ampicillin-sulbactam, bid: Twice a day, BSI: Bloodstream infections, CR-AB: Carbapenem-resistant A. baumanni, CRKP: Carbapenem resistant K. pneumonia, DOX: Doxycycline, E. coli: Escherichia coli, ESBL: Extended-spectrum B-lactamase, FOF: Fosfomycin, K. pneumoniae: Klebsiella pneumonia, MIN: Minocycline, MS: Multi-susceptible, NA: Not available, PMX: Polymyxin, qd: Once a day, SSI: Surgical site infection, TIG: Tigecycline, UTI: Urinary tract infection, VAP: Ventilator-associated pneumonia, A. baumanni: Acinetobacter baumanni, IV: Intravenous, TFX: Trovafloxacin

A total of 59 patients, from all 8 studies, were included and treated for 61 different types of infections: 43 cases of ventilator-associated pneumonia (VAP), 15 cases of urinary tract infection (UTI), 1 prostatitis, 1 bloodstream infection secondary to VAP, and 1 burn infection associated with VAP. The most common bacterium isolated in these studies was Acinetobacter baumannii, which was found in 43 lower respiratory tract infections, and 2 of these, 1 VAP was associated with 1 burn infection and another VAP was associated with 1 bloodstream infection, followed by carbapenem-resistant Klebsiella pneumoniae in 14 patients treated for UTI and cephalosporin-resistant Enterobacteriaceae of the 1^st to 4^th generation in 2 patients (1 chronic prostatitis and 1 UTI).

In 29 cases, most of which were VAP (n = 28) and only 1 UTI, doxycycline was used in combination with another agent: Ampicillin/sulbactam, aminoglycosides (mainly amikacin), and fosfomycin. On the other hand, doxycycline was prescribed as monotherapy in most cases from UTI (n = 15), followed by VAP (n = 15). In 6 of the 8 articles, the dosage of doxycycline was given. The usual doses of doxycycline were 100 mg intravenously (IV) or orally (p. o.) twice daily (b. i. d.) or 100 mg once daily (q. d.). Oral doxycycline was most commonly used for the treatment of UTI. The duration of treatment was reported in all studies; the median ranged from 6.5 days to 14 days. The median treatment duration for UTI was 6 days and for VAP was 7.6 days. Clinical outcomes were presented in all studies. Clinical improvement was achieved in 48 (81.3%) of 59 patients: 93.4% reported UTI and 65.8% for respiratory infections. Microbiologic outcomes were reported in five studies[8,10,11,12,13,14,15] with microbiologic success in 16 (87%) of 18 available cases. Clinical and microbiologic outcomes are listed in Table 3. The definition of clinical or microbiologic resolution of the studies analyzed is shown in Table 4. Mortality was mentioned in seven articles. Of 23 patients in these studies, four deaths (17.3%) were reported, all of which were related to VAP. In the available data from studies of VAP, 4 deaths (57%) occurred in 7 patients with respiratory infections. No deaths occurred from UTI.

Table 4.

Definition of clinical or microbiological resolution of the analyzed studies

Author, year	Clinical success definition	Microbiological success definition
Wood et al. (2003)[11]	Clinical improvement and survival until hospital discharge	A. baumannii negative culture in (BAL)
Holloway et al. (2006)[12]	At least one criterion: Reduction or normalization of leukocytes, resolution of fever, reduction of vasopressor, extubating, reduction of inspired O2 fraction or sputum production, or clinical judgment. If a criterion was met, clinical cure was determined as a consensus decision by investigators in case of confusion	Negative follow-up cultures
Chan et al. (2010)[13]	Improvement and resolution of signs and symptoms of VAP	Microbiological eradication of Acinetobacter from BAL or sputum culture at the end of therapy
Alexander et al. (2012)[14]	Complete response: Who have resolved fever, leukocytosis, and all signs of infection Partial response: Who had reduced abnormalities in the above parameters without complete resolution Failure: Who had no reduction or deterioration in any clinical parameters Uncertain: Who had signs and symptoms that were not clearly attributable to infection	Positive: KPC-producing eradication of the organism from a repeated urine culture Assumed: Response to clinical treatment, no follow-up cultures obtained to verify production of KPC, eradication of the organism, and no readmissions within 30 days with a positive culture for the same KPC strain Negative: Persistence of KPC-producing organism despite 3-day treatment with appropriate antibiotics or undocumented
Cicora et al. (2013)[15]	NA	NA
Qureshi et al. (2014)[16]	Cure: Resolution of clinical signs and symptoms of UTI+negative urine culture Presumed cure: Signs and symptoms of UTI without urine culture Failure: Persistent growth of CRKP in urine cultures, with no improvement in signs and symptoms of infection or recurrence of UTI with CRKP within 30 days of initial resolution	Negative culture
Cunha et al. (2015)[17]	Favorable outcome in 2 weeks	Negative culture at 2 weeks
White et al. (2017)[18]	Favorable outcome without recurrence in 90 days	NA

K. pneumoniae: Klebsiella pneumonia, BAL: Bronchoalveolar lavage, CRKP: Carbapenem resistant K. pneumonia, KPC: K. pneumoniae carbapenemase, NA: Not available, UTI: Urinary tract infection, VAP: Ventilator-associated pneumonia

DISCUSSION

The aim of this scoping review was to evaluate clinical data from patients treated with doxycycline for infections with Gram-negative MDR bacteria.

Most of these studies focused on two main sites of infection, the lower respiratory tract, and the urinary tract, with favorable outcomes for most of these patients. The mean clinical cure for VAP was achieved in 55.6% of patients, and the mean microbiological cure was 71.8%. These values were slightly lower than those described by Falagas et al.[10] Mortality was described in only 2 of the 3 studies and was 33%, slightly higher than the values described by the same authors. However, the authors also considered the use of minocycline. In cases of VAP mainly due to Acinetobacter baumannii, therapy was combined with other antimicrobial agents in most patients, and it is not possible in these situations to know the isolated contribution of doxycycline to clinical or microbiological cure. Using an animal model of experimental pneumonia caused by Acinetobacter baumannii, the efficacy of imipenem, doxycycline, and amikacin in monotherapy and the combination of imipenem plus amikacin and doxycycline plus amikacin were compared. Doxycycline and amikacin had synergistic effects in vitro after 24 h of incubation. The number of sterile lungs and lung clearance of Acinetobacter baumannii was greater in the imipenem-treated group, but doxycycline plus amikacin proved to be an alternative to imipenem in the treatment of Acinetobacter baumannii pneumonia.[19]

Clinical and microbiologic success was achieved in 94.5% and 89% of UTIs, respectively. No deaths were reported among these patients. In this scenario, doxycycline was most commonly used as monotherapy.

The explanation for its good performance in UTIs may be related to its pharmacokinetic and pharmacodynamic data. Doxycycline has good oral absorption with a bioavailability of over 80%. It is lipid soluble with a high volume of distribution of 0.7 L/kg, with concentrations higher in the liver, kidneys, and digestive tract (the organs of excretion). Doxycycline is excreted unchanged by the kidneys and bile ducts.[6,20,21] The concentration in bile may be 10–25 times higher than in serum. Therefore, it may be a therapeutic option for the treatment of infections at these sites.

In the respiratory setting, there are few human studies of lung penetration and respiratory secretions dating back more than 40 years.[22,23,24] Three studies have quantified the ability of doxycycline to concentrate in sputum and lung tissue. In one study based on estimates at a single point in time, the penetration of doxycycline into sputum was 8%–28%, estimated over 16 h.[22] In a study estimating penetration into the lung at a single point in time, the overall serum-to-tissue ratio in the lung for doxycycline was estimated to be 0.68.[23] In another study, doxycycline concentrations in lung tissue (1.03–12.30 µg/ml) were high or higher than doxycycline serum levels (0.94–7.82 mug/ml) in the majority of cases.[24]

The usual dosage of doxycycline is 100 mg b. i. d.; however, in some cases, it is possible to use 100 mg to 400 mg q. d. The dosage of doxycycline used in most articles was 100 mg twice daily, intravenously or orally. In many countries, an intravenous formulation of doxycycline is not available. A single dose of oral doxycycline 200 mg achieves peak serum concentrations of approximately 3.0–5.0 µg/ml, and a single dose of intravenous doxycycline at the same dosage achieves peak serum concentrations of 4–10 µg/ml.[21] These concentrations are sufficient to achieve the concentration for most GNB, especially in tissue infections.

The strength of this review article is that it is the second work in the literature that we are aware of, that includes data from clinical studies of doxycycline for the treatment of infections with Gram-negative MDR bacteria and extends the study that has been done previously.[10] The weakness of this article is the quality and the different designs of the studies, which were mostly retrospective and with few samples. Unfortunately, there is a lack of studies with the best quality evidence as trials or prospective cohorts in this topic.

CONCLUSIONS

Doxycycline showed good clinical e microbiologic results in this review, particularly in UTI infections. However, randomized clinical trials or prospective cohorts are recommended to determine the efficacy of doxycycline as monotherapy or in combination with other antimicrobial agents for the treatment of infections with Gram-negative MDR bacteria.

Research quality and ethics statement

This study followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the PRISMA guidelines, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.