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Meta-Analysis
16 January 2025

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

Authors: Florian Wagenlehner, Verónica Rico Caballero [email protected], Vikalp Maheshwari, Ayantika Biswas, Priyanka Saini, Juan Quevedo, Juergen Polifka, Leonardo Ruiz, and Sandrine CureAuthor Info & Affiliations
Volume 14, Number 3
https://doi.org/10.57264/cer-2024-0214
PDFFormats

Abstract

Aim: Compared with uncomplicated urinary tract infections (UTIs), complicated UTIs (cUTIs) including acute pyelonephritis (AP) present with 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®, MEDLINE® 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 master NMA network. 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.

Plain language summary

What is this article about?

Complicated urinary tract infections (cUTIs) including acute pyelonephritis (AP, kidney infections) have a high risk of treatment failure, requiring longer courses of antibiotic treatment. The emergence of drug-resistant organisms poses a considerable global challenge in the treatment of patients with cUTIs/AP due to the limited antibiotic options such as carbapenem antibiotics. Although several established and novel antibiotic treatment options are available, direct comparative data is lacking. This article compares the effectiveness of different antibiotic treatments for complicated urinary tract infections (cUTIs) and acute pyelonephritis (kidney infections). The study performed a systematic review of randomized clinical trials and used a statistical method called network meta-analysis to compare multiple treatments across the identified individual studies.

What were the results?

For overall treatment success, several antibiotics such as cefepime + enmetazobactam, ceftolozane + tazobactam, cefiderocol, levofloxacin or plazomicin performed better than standard carbapenem antibiotics. While for full elimination of the bacterial infection from the urine, cefepime + enmetazobactam, plazomicin, cefiderocol, fosfomycin, meropenem + vaborbactam and ceftazidime + avibactam were more effective than carbapenems. Cefepime + enmetazobactam showed considerably better results than several established and newer treatments for overall success, bacterial elimination and clinical cure.

What do the results of the study mean?

The findings suggest that some newer antibiotic treatments, particularly cefepime + enmetazobactam, may be more effective than standard carbapenem antibiotics for treating cUTIs and APs (kidney infections). This is important because it provides more treatment options for patients and healthcare providers, especially as bacteria are becoming resistant to commonly used antibiotics. The study concludes that cefepime + enmetazobactam could be an effective alternative to carbapenems, potentially helping to reduce overuse of these last-resort antibiotics and combat the growing problem of antibiotic resistance.

Shareable abstract

New network #meta-analysis shows cefepime + enmetazobactam outperforms several #antibiotics for treating complicated #UTIs, including #carbapenems. Could be an effective carbapenem-sparing option against #drug-resistant #infections. #AntibioticResistance #UTI

Supplementary Material

File (supplementary materials.docx)

References

1.
Öztürk R, Murt A. Epidemiology of urological infections: a global burden. World J. Urol. 38(11), 2669–2679 (2020).
PubMed
Google Scholar
2.
Yang X, Chen H, Zheng Y, Qu S, Wang H, Yi F. Disease burden and long-term trends of urinary tract infections: a worldwide report. Front. Public Health 10, 888205 (2022).
PubMed
Google Scholar
3.
Sabih A, Leslie S. Complicated urinary tract infections. StatPearls Publishing, FL, USA (2023). Available from: https://www.ncbi.nlm.nih.gov/books/NBK436013/
Google Scholar
4.
Singh KP, Li G, Mitrani-Gold FS et al. Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection. Antimicrob. Agents Chemother. 57(11), 5284–5290 (2013).
PubMed
Google Scholar
5.
Zilberberg MD, Nathanson BH, Sulham K, Shorr AF. Multiple antimicrobial resistance and outcomes among hospitalized patients with complicated urinary tract infections in the us, 2013–2018: a retrospective cohort study. BMC Infectious Diseases 21(1), 159 (2021).
PubMed
Google Scholar
6.
Bonkat G. EAU Guidelines on Urological Infections. (2022).
Google Scholar
7.
Tandoğdu Z, Bartoletti R, Cai T et al. Antimicrobial resistance in urosepsis: outcomes from the multinational, multicenter Global Prevalence of Infections in Urology (GPIU) Study 2003–2013. World J. Urol. 34(8), 1193–1200 (2016).
PubMed
Google Scholar
8.
Liu YX, Le KJ, Shi HY et al. Efficacy and safety of tigecycline for complicated urinary tract infection: a systematic review. Transl. Androl. Urol. 10(1), 292–299 (2021).
PubMed
Google Scholar
10.
FDA. Exblifep - full prescribing information. Available at: Https://www.Accessdata.Fda.Gov/drugsatfda_docs/label/2024/216165s000lbl.Pdf
Google Scholar
11.
Kaye KS, Belley A, Barth P et al. Effect of cefepime/enmetazobactam vs piperacillin/tazobactam on clinical cure and microbiological eradication in patients with complicated urinary tract infection or acute pyelonephritis: a randomized clinical trial. JAMA 328(13), 1304–1314 (2022).
PubMed
Google Scholar
12.
NICE. Nice process and methods. Appendix c: methodology checklist: Randomised controlled trials. (Accessed: March 2024). https://www.nice.org.uk/process/pmg6/resources/the-guidelines-manual-appendices-bi-2549703709/chapter/appendix-c-methodology-checklist-randomised-controlled-trials
Google Scholar
13.
Ezure Y, Rico V, Paterson DL et al. Efficacy and safety of carbapenems vs new antibiotics for treatment of adult patients with complicated urinary tract infections: a systematic review and meta-analysis. Open Forum Infect. Dis. 9(5), ofaa480 (2022).
PubMed
Google Scholar
14.
Rebelo A, Schlicht L, Kleeff J, Michalski CW, Heckler M. Carbapenem antibiotics versus other antibiotics for complicated intra-abdominal infections: a systematic review and patient-level meta-analysis of randomized controlled trials (PROSPERO crd42018108854). J. Gastrointest. Surg. 27(6), 1208–1215 (2023).
PubMed
Google Scholar
15.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 327(7414), 557–560 (2003).
PubMed
Google Scholar
16.
Dias S, Welton NJ, Sutton AJ, Ades A. NICE DSU Technical Support Document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. (2011).
Google Scholar
17.
Dias S, Sutton AJ, Welton NJ, Ades A. NICE DSU Technical Support Document 3: heterogeneity: Subgroups, meta-regression, bias and bias-adjustment. (2011).
Google Scholar
18.
Ouwens MJ, Philips Z, Jansen JP. Network meta-analysis of parametric survival curves. Res. Synth. Methods 1(3–4), 258–271 (2010).
PubMed
Google Scholar
19.
Watt J, Tricco A, Straus S, Veroniki A, Naglie G, Drucker A. Research techniques made simple: network meta analysis. J. Investig. Dermatol. 139, 4–12 (2019).
PubMed
Google Scholar
20.
Seo YB, Lee J, Kim YK et al. Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing escherichia coli. BMC Infect. Dis. 17(1), 404 (2017).
PubMed
Google Scholar
21.
FDA. Complicated urinary tract infections: developing drugs for treatment. (Accessed: March 2024). https://www.fda.gov/media/71313/download
Google Scholar
22.
EMA. Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. (Accessed: March 2024). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-medicinal-products-indicated-treatment-bacterial-infections-revision-3_en.pdf
Google Scholar
23.
Kadry N, Natarajan M, Bein E, Kim P, Farley J. Discordant clinical and microbiological outcomes are associated with late clinical relapse in clinical trials for complicated urinary tract infections. Clin. Infect. Dis. 76(10), 1768–1775 (2023).
PubMed
Google Scholar
24.
Zollner-Schwetz I, König E. Treatment options for multidrug-resistant gram-negatives in urinary tract infections. Curr. Opin. Urol. 33(3), 173–179 (2023).
PubMed
Google Scholar
25.
Zilberberg MD, Nathanson BH, Sulham K, Shorr AF. Multiple antimicrobial resistance and outcomes among hospitalized patients with complicated urinary tract infections in the us, 2013–2018: a retrospective cohort study. BMC Infect. Dis. 21, 1–10 (2021).
PubMed
Google Scholar
26.
Tompkins K, van Duin D. Treatment for carbapenem-resistant enterobacterales infections: recent advances and future directions. Eur. J. Clin. Microbiol. Infect. Dis. 40(10), 2053–2068 (2021).
PubMed
Google Scholar
27.
Doi Y. Treatment options for carbapenem-resistant gram-negative bacterial infections. Clin. Infect. Dis. 69(Suppl. 7), S565–S575 (2019).
PubMed
Google Scholar
28.
Han R, Teng M, Zhang T, Wang T, Dong Y, Wang Y. Choosing optimal antibiotics for the treatment of patients infected with enterobacteriaceae: a network meta-analysis and cost-effectiveness analysis. Front. Pharmacol. 12, 656790 (2021).
PubMed
Google Scholar
29.
Bilsen MP, Conroy SP, Schneeberger C et al. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect. Dis. 24(8), e513–e521 (2024).
PubMed
Google Scholar
|