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Abstract
Introduction Complicated urinary tract infections (cUTIs) are associated with poor prognosis. The widespread infection of multidrug-resistant Gram-negative uropathogens such as extended-spectrum beta-lactamase-producing bacteria has limited the efficacy of antibiotics used for treating cUTI. Considering the existence of antimicrobial-resistant (AMR) uropathogens, carbapenem is the last-resort antibiotic for cUTI. Given that carbapenem overuse has facilitated the spread of carbapenem-resistant Gram-negative bacteria, carbapenem dependence should be urgently reduced. However, improvement on the clinical outcomes of alternative antibiotics against cUTI caused by AMR uropathogens has not yet been systematically evaluated. Thus, this systematic review and meta-analysis aims to explore and compare the clinical outcomes of cUTI caused by AMR uropathogens between carbapenem and non-carbapenem antibiotics.
Methods and analysis The study inclusion criteria will be considered based on the PICO model consisting the following elements: population—adult patients with cUTIs caused by Gram-negative uropathogens; intervention—non-carbapenem class of antimicrobial agents with in vitro activities against Gram-negative uropathogens; comparison—treatment of carbapenem class antibiotics; outcome—a clinical and microbiological cure. Relevant articles published until December 2022 will be systematically searched in February 2023, using electronic databases such as PubMed, the Cochrane Library, EMBASE and ClinicalTrials.gov. Two independent reviewers will screen the select literature and then assess the full-text article to meet the inclusion criteria. The risk of bias will be assessed using the Cochrane risk-of-bias assessment tool. The treatment effects of antibiotics will be estimated as a risk ratio with a 95% CI, using the random-effects model.
Ethics and dissemination This protocol and systematic review will not include direct patient data; thus, informed consent will be waived. The results of this study will be published in an international peer-reviewed journal for wider information dissemination.
PROSPERO registration number CRD42022356064.
- Urinary tract infections
- INFECTIOUS DISEASES
- Pyelonephritis
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This new protocol will only include randomised controlled trials and endeavour to address a gap in the current evidence by focusing on complicated urinary tract infections caused by antimicrobial-resistant uropathogens.
The protocol method is conducted robustly in accordance with the Cochrane Handbook for Systematic Reviews.
Given that the inclusion criteria will include articles published and uploaded to the database, studies such as those in conference presentations and not written in English may be missed.
Introduction
Complicated urinary tract infections (cUTIs) are associated with morbidity, mortality and excessive healthcare costs.1–4 Guidelines for cUTIs recommend that the empirical treatment should target Gram-negative uropathogens, including Escherichia coli, Klebsiella pneumoniae and non-Enterobacterales. Therefore, broad-spectrum antibiotics are frequently selected for empirical treatment.5
Over the past few decades, the widespread use of multidrug-resistant Gram-negative bacteria has been limiting the efficacy of antibiotics in cUTI treatment.6 In particular, the burden of a disease caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria, which have become resistant to almost all beta-lactam antibiotics, is alarming.7 Carbapenems as a representative of beta-lactam antibiotics exhibit an in vitro activity against most of the Gram-negative bacteria, including antimicrobial-resistant (AMR) uropathogens such as the ESBL-producing bacteria. In fact, carbapenem is the last-resort antibiotic for cUTI caused by AMR uropathogens, including ESBL-producing E. coli and K. pneumoniae.8 Consequently, carbapenems have been increasingly used, but their widespread use has facilitated the proliferation of carbapenem-resistant Gram-negative bacteria.9 The global spread of carbapenem-resistant bacteria reinforces the urgent need to reduce carbapenem dependence. An important strategy to reduce carbapenem overuse is to evaluate alternative antibiotics.10 Several systematic reviews and meta-analyses were conducted to evaluate and compare the efficacy between carbapenems and alternative antibiotics for the treatment of cUTIs.11–14 The study results consistently indicated that the efficacy of alternative antibiotics was non-inferior to that of carbapenem in patients with cUTIs. Nevertheless, the population of these meta-analyses included both resistant and non-resistant strains. Considering that various antibiotics can treat cUTI caused by non-resistant bacteria, focusing on resistant bacteria is needed to evaluate the efficacy of carbapenem and its alternative antibiotics.
Presently, specific data on the efficacy of alternative antibiotics for cUTIs caused by AMR uropathogens remain unavailable. In addition, improvement of the clinical outcomes of patients taking alternative antibiotics for cUTI caused by AMR uropathogens has not yet been systematically evaluated. Thus, we would like to conduct a systematic review and meta-analysis of the clinical outcomes of cUTI caused by AMR uropathogens between carbapenem and non-carbapenem antibiotics. Our meta-analysis will provide useful information for the proper selection of antibiotics used for treating cUTI in a clinical setting, as well as a future direction for the development of alternative antibiotics for AMR cUTI.
Methods and analysis
This protocol adheres to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines. We prepared this protocol manuscript according to the PRISMA-P checklist.15 16
Population
For the study population, we will include adult patients with cUTIs, including acute pyelonephritis, caused by Gram-negative uropathogens that are resistant to third-generation cephalosporin.17
Interventions
The intervention involves the non-carbapenem class of antimicrobial agents with in vitro activities against Gram-negative uropathogens that are resistant to third-generation cephalosporin.
Controls
The control is the treatment of carbapenem class antibiotics.
Outcomes
The primary outcome will be the composite outcome of clinical and microbiological cure defined by the US Food and Drug Administration as follows: resolution of cUTI symptoms present at trial entry (and no new symptoms) and the reduction of bacterial pathogens found at trial entry to fewer than 103 CFU/mL on urine culture.18 The secondary outcomes will be the microbiological outcome responses and death at each endpoint.
Study designs
This review will only include individual and cluster randomised controlled trials.
Search strategy
Literature published until December 2022 will be searched in February 2023 in the following databases: MEDLINE/PubMed, the Cochrane Library (Cochrane Central Register of Controlled Trials, CENTRAL), EMBASE and ClinicalTrials.gov. The comprehensive search strategies will use the developed search terms shown in table 1 and online supplemental file 1.
Supplemental material
Comprehensive search strategy methods for MEDLINE/PubMed
Screening of the retrieved articles
Two independent researchers will screen the retrieved articles. The title and abstract will be screened and scrutinised to meet the study criteria, using the online software Rayyan, which helps to conduct systematic reviews.19 Two researchers will independently review the full-text manuscripts according to the eligibility criteria for this review. If they differ in the decision on whether or not the study meets the inclusion criteria, another reviewer will resolve the conflicts.
Data extraction
The selected data will be extracted by two independent researchers using Microsoft Excel, conforming to guidelines of the Cochrane Handbook for Systematic Reviews.20 The following data will be extracted from the selected studies: author names, publication year, study population, baseline characteristics, study settings, intervention details, outcomes and subgroup analysis stratified by AMR pathogens.
Assessment of risk of bias
Two independent researchers will assess the risk of bias using the Cochrane risk-of-bias assessment tool. The assessment domain consists of the following: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment of self-reported outcomes and reaction time (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other biases, such as imbalance of baseline characteristics and overdiagnosis bias.21 The included studies will be divided into low risk, high risk and unclear risk according to the reviewers’ judgement. Any discord will be resolved through a discussion between them.
Data analysis
For dichotomous data, the treatment effects will be estimated as a risk ratio with a 95% CI, using the random-effects model. We will use the random-effects model to address the possible between-studies heterogeneity. We cannot assess how statistical heterogeneity exists before seeing the datasets; thus, we will adopt the random-effects model for the primary statistical analyses. Heterogeneity will be assessed using the Χ2 test and I2 statistics. The heterogeneity will be addressed through meta-regression and subgroup analyses. We will conduct a sensitivity analysis to determine the impact of the exclusion of studies at an overall high risk of bias and outliers for the primary outcome. Publication bias will be assessed in forest plots using Egger’s test. Forest plots and funnel plots will be generated using the Review Manager (RevMan) software. We will perform the synthesis analyses when at least four studies are eligible. After the preliminary assessments of publication biases, we will perform the meta-analyses if there are no serious systematic biases. We will present summary data and assess individual studies in detail if a meta-analysis is not feasible.20
Grading of evidence
The strength of the body of evidence will be assessed by two independent researchers using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to judge the quality of evidence for outcomes.22 GRADE will then be assessed according to the risk of bias among studies, inconsistency, imprecision, indirectness and publication bias. We will generate a summary of the findings table using the GRADEpro software.
Patient and public involvement
No patients or citizens will be involved in this research. Only data that are already published will be used. For this systematic review, the estimation of the efficacy of the treatment will benefit patients with cUTI.
Ethics and dissemination
This systematic review and meta-analysis will not include direct patient data because it will only use studies that are already published. Therefore, informed consent will be waived. The results of this study will be published in an international peer-reviewed journal for wider information dissemination. This work will influence the national guidelines for the treatment of cUTIs.17
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors Conception of the study—MM. Statistical concept—TH, HN and EO. Construction of search strategy—MM. Drafting the manuscript—MM and TH. Review and finalisation—TH, HN and EO. All authors reviewed and approved the final version of the manuscript. Guarantor of the review—MM.
Funding This work was supported by JSPS KAKENHI (grant number 19K03092).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.