Supplementary materials: Efficacy of treatment options for complicated urinary tract infections including acute pyelonephritis: a systematic literature review and network meta-analysis

These are peer-reviewed supplementary materials for the article 'Efficacy of treatment options for complicated urinary tract infections including acute pyelonephritis: a systematic literature review and network meta-analysis' published in the Journal of Comparative Effectiveness Research.TablesTable 1A: Embase and Medline search strategy run on 15th June 2022 through Embase.comTable 1B: MEDLINE® In-Process search strategy run on 15th June 2022 through Pubmed.com interfaceTable 1C: Cochrane search strategy run on 15th June 2022 through Cochrane libraryTable 2: PICOTS criteria for study inclusionTable 3: Summary of randomized controlled trials included (n = 40)Table 4: Risk of bias assessment (using Jadad score and NICE appraisal checklists)Table 5: Definitions reported for complicated urinary tract infection and acute pyelonephritis across included studiesTable 6: Heterogeneity assessment results by outcomeFiguresFigure 1A: Clinical cure at TOC network diagram – Base caseFigure 1B: Clinical cure at TOC network diagram – Sensitivity analysisFigure 1C: Clinical cure at EOT network diagramFigure 2A: Microbiological eradication at TOC network diagram – Base caseFigure 2B: Microbiological eradication at TOC network diagram – Sensitivity analysisFigure 2C: Microbiological eradication at EOT evidence network diagramFigure 3A: Overall response rate at TOC network diagramFigure 3B: Overall response rate at EOT network diagramFigure 4: Summary plots for composite outcome (A), clinical cure (B), microbiological eradication (C) at EOT (FEM)Figure 5: Summary plots for clinical cure (A) and microbiological eradication (B) at EOT (FEM) – Sensitivity analysisFigure 6: Funnel plots for composite outcome (A), clinical cure (B) and microbiological eradication (C) at TOCFigure 7: Funnel plots for composite outcome (A), clinical cure (B) and microbiological eradication (C) at EOTReferencesAim: Compared with uncomplicated urinary tract infections (UTIs), complicated UTIs (cUTIs) including acute pyelonephritis (AP) presentwith significant morbidity, a higher risk of treatment failure and typically require longer courses of treatment, or alternative antibiotics. The emergence of drug-resistant organisms represents a considerable challenge in the treatment of patients with cUTIs/AP and has limited antibiotic options. Carbapenems are considered the current last line of therapy, however, carbapenem resistance represents a growing problem. Although several established and novel treatment options are available, direct comparative evidence is lacking. Methods: Randomized controlled trials (RCTs) were identified by systematic literature review of Embase R ? , MEDLINER ? and Cochrane databases (database inception to 15th June 2022). Relevant conference proceedings (2020–2022) were also reviewed. Following feasibility assessment to verify network connectivity at an overall level, outcome specific networks were prepared. Bayesian network meta-analysis (NMA) was performed (using R version 4.2.1) to determine the relative efficacy of various treatments for cUTI/AP, including cefepime + enmetazobactam. Convergence was assessed by visual inspection of trace plots. The accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter. Published study results were included in the synthesis of the relative risk (RR) of efficacy end points, using a logit link with binomial likelihood distribution. Results: Feasibility assessment was conducted for 40 RCTs identified, to assess the viability of constructing a network of interlinked RCTs. Of those, 28 studies were included in the masterNMAnetwork. A fixed effects model (FEM) was selected due to low statistical heterogeneity, according to I2 values. For composite outcome at test of cure (TOC), ceftolozane + tazobactam, cefepime + enmetazobactam, cefiderocol, levofloxacin and plazomicin demonstrated significantly higher RRs versus carbapenems. For microbiological eradication at TOC, cefepime + enmetazobactam, plazomicin, cefiderocol, fosfomycin, meropenem + vaborbactam and ceftazidime + avibactam demonstrated significantly higher RRs versus carbapenems. RRs for cefepime + enmetazobactam were also significantly higher versus several established and novel treatment options for composite outcome, microbiological eradication and clinical cure. Conclusion: Against the backdrop of increasing bacterial resistance, these findings suggest that cefepime + enmetazobactam may represent an effective carbapenem-sparing treatment option in patients with cUTI including AP.