Cefepime/enmetazobactam
Cefepime/enmetazobactam is a combination of the fourth-generation cephalosporin cefepime with the beta-lactamase inhibitor enmetazobactam. The Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved cefepime/enmetazobactam for the treatment of adults with complicated urinary tract infections (UTIs), including pyelonephritis, caused by susceptible gram-negative microorganisms (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex) in adults. One randomized clinical trial (RCT) showed cefepime/enmetazobactam to be noninferior to, and even superior to, piperacillin/tazobactam for clinical cure and microbiologic eradication in cases of complex UTI and acute pyelonephritis.[105]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. 2022 Oct 4;328(13):1304-14.
http://www.ncbi.nlm.nih.gov/pubmed/36194218?tool=bestpractice.com
Ceftolozane/tazobactam
Ceftolozane/tazobactam is a combination of the fifth-generation cephalosporin ceftolozane with tazobactam (a beta-lactamase inhibitor). It is active against Pseudomonas, including multidrug-resistant strains, as well as many extended spectrum beta-lactamases Enterobacterales.[106]López Montesinos I, Montero M, Sorlí L, et al. Ceftolozane-tazobactam: when, how and why using it? Rev Esp Quimioter. 2021 Sep;34 Suppl 1(suppl1):35-7.
https://seq.es/abstract/rev-esp-quimioter-2021-september-10
http://www.ncbi.nlm.nih.gov/pubmed/34598422?tool=bestpractice.com
The FDA and EMA have approved ceftolozane/tazobactam for the treatment of complicated UTIs (cUTIs) in adults and children. One meta-analysis showed ceftolozane/tazobactam to be more effective in treating cUTIs than piperacillin/tazobactam.[107]Saeed MW, Gillani SW, Mahmood RK, et al. A meta-analysis on clinical outcomes of ceftolozane versus piperacillin in combination with tazobactam in patients with complicated urinary tract infections. Biomed Res Int. 2022 Aug 8:2022:1639114.
https://onlinelibrary.wiley.com/doi/10.1155/2022/1639114
http://www.ncbi.nlm.nih.gov/pubmed/35978637?tool=bestpractice.com
The 2024 Infectious Diseases Society of America guidelines noted that newer data indicate that ceftolozane/tazobactam is likely to be effective against extended-spectrum beta-lactamase producing Enterobacterales; however, it suggested that this drug be preserved for the treatment of difficult-to-treat aeruginosa or polymicrobial infections.[81]Tamma PD, Heil EL, Justo JA, et al. Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 2024 Aug 7:ciae403.
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciae403/7728556
http://www.ncbi.nlm.nih.gov/pubmed/39108079?tool=bestpractice.com
Tebipenem
Tebipenem is an oral carbapenem antibiotic with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. In one recent phase 3 trial, tebipenem was noninferior to ertapenem (an intravenous carbapenem antibiotic) in the treatment of cUTI and acute pyelonephritis.[108]Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. N Engl J Med. 2022 Apr 7;386(14):1327-38.
https://www.nejm.org/doi/10.1056/NEJMoa2105462
http://www.ncbi.nlm.nih.gov/pubmed/35388666?tool=bestpractice.com
The FDA has granted fast-track designation to the drug, but states further clinical trials are needed. Tebipenem (formulated as tebipenem pivoxil) is currently only approved in Japan.
Cefepime/taniborbactam
Cefepime/taniborbactam is an investigational combination of the fourth-generation cephalosporin cefepime with taniborbactam (a beta-lactamase inhibitor). Studies have demonstrated activity against Enterobacterales species and Pseudomonas. In one phase 3 RCT, cefepime/taniborbactam was superior to meropenem (a carbapenem antibiotic) for the treatment of cUTI that included acute pyelonephritis, with a safety profile similar to that of meropenem.[109]Wagenlehner FM, Gasink LB, McGovern PC, et al. Cefepime-taniborbactam in complicated urinary tract infection. N Engl J Med. 2024 Feb 15;390(7):611-22.
https://www.nejm.org/doi/10.1056/NEJMoa2304748
http://www.ncbi.nlm.nih.gov/pubmed/38354140?tool=bestpractice.com
Vaccines
Vaccines against E coli and other uropathogens are a promising emerging treatment. Mucosal and parenteral vaccines targeted at E coli and other uropathogens are being investigated, and oral immunostimulation with E coli extracts has proven to be a safe and effective method for preventing recurrent UTIs compared with placebo at short-term follow-up.[49]Cruz F, Dambros M, Naber KG, et al. Recurrent urinary tract infections: Uro-Vaxom, a new alternative. Eur Urol Suppl. 2009;8:762-8.[110]Krebs J, Fleischli S, Stoyanov J, et al. Effects of oral immunomodulation therapy on urinary tract infections in individuals with chronic spinal cord injury-a retrospective cohort study. Neurourol Urodyn. 2019 Jan;38(1):346-52.
http://www.ncbi.nlm.nih.gov/pubmed/30350886?tool=bestpractice.com
[111]Stapleton A. Novel approaches to prevention of urinary tract infections. Infect Dis Clin North Am. 2003 Jun;17(2):457-71.
http://www.ncbi.nlm.nih.gov/pubmed/12848479?tool=bestpractice.com
[112]Huttner A, Hatz C, van den Dobbelsteen G, et al. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect Dis. 2017 May;17(5):528-37.
http://www.ncbi.nlm.nih.gov/pubmed/28238601?tool=bestpractice.com
[113]Yang B, Foley S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune(®). BJU Int. 2018 Feb;121(2):289-92.
http://www.ncbi.nlm.nih.gov/pubmed/29171130?tool=bestpractice.com
There is a high level of patient interest in vaccines for the prevention of UTIs. Vaccines targeted at E coli are not yet available for widespread clinical use in the US. MV140 (also known as Uromune®) is a polyvalent, bacterial, whole cell-based, sublingual vaccine that has been developed for prevention of recurrent UTI and is currently available under special access programs or is approved for use in some countries.[114]Nickel JC, Kelly KL, Griffin A, et al. MV140 sublingual vaccine reduces recurrent urinary tract infection in women results from the first North American clinical experience study. Can Urol Assoc J. 2024 Feb;18(2):25-31.
https://cuaj.ca/index.php/journal/article/view/8455
http://www.ncbi.nlm.nih.gov/pubmed/37931282?tool=bestpractice.com
One systematic review looking at vaccines for the treatment of recurrent UTI noted that vaccines do seem to have a short-term role in their prevention. However, more studies are needed along with inclusion of other high-risk patient groups.[115]Prattley S, Geraghty R, Moore M, et al. Role of vaccines for recurrent urinary tract infections: a systematic review. Eur Urol Focus. 2020 May 15;6(3):593-604.
http://www.ncbi.nlm.nih.gov/pubmed/31806578?tool=bestpractice.com
D-mannose
D-mannose, found in several fruits and vegetables including cranberries, is a simple sugar that may hinder bacterial adhesion to the urothelium. One meta-analysis found D-mannose to be more effective in preventing recurrent UTIs in women than placebo and similar to antibiotic prophylaxis.[116]Lenger SM, Bradley MS, Thomas DA, et al. D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020 Aug;223(2):265.e1-13.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7395894
http://www.ncbi.nlm.nih.gov/pubmed/32497610?tool=bestpractice.com
More studies are needed to determine whether D-mannose can be an effective aid in acute cystitis symptom management and/or as a successful prophylactic agent in a selected population.[117]Cooper TE, Teng C, Howell M, et al. D-mannose for preventing and treating urinary tract infections. Cochrane Database Syst Rev. 2022 Aug 30;8(8):CD013608.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013608.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/36041061?tool=bestpractice.com
Cranberry
At this time there are no quality studies that show conclusive evidence on the use of cranberries for the treatment of UTIs. More studies in this area are needed.[118]Jepson RG, Mihaljevic L, Craig JC. Cranberries for treating urinary tract infections. Cochrane Database Syst Rev. 2023 Dec 14;12(12):CD001322.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001322.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/38096261?tool=bestpractice.com
Note that cranberry studies are difficult to interpret due to variability in the cranberry formulation, variable study populations, and varying outcome measures. There is some evidence to support soluble cranberry with a high level of proanthocyanidins in the prevention of recurrent UTIs.[119]Howell AB, Dreyfus JF, Chughtai B. Differences in urinary bacterial anti-adhesion activity after intake of cranberry dietary supplements with soluble versus insoluble proanthocyanidins. J Diet Suppl. 2022;19(5):621-39.
https://www.tandfonline.com/doi/full/10.1080/19390211.2021.1908480
http://www.ncbi.nlm.nih.gov/pubmed/33818241?tool=bestpractice.com