Urinary tract infections in women - Emerging treatments

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 UTI, including pyelonephritis, caused by susceptible gram-negative microorganisms (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex in adults. A randomized clinical trial showed cefepime/enmetazobactam to be noninferior to, and even superior to, piperacillin/tazobactam for clinical cure and microbiologic eradication in cases of complicated UTI and acute pyelonephritis.[88]

Meropenem/vaborbactam

Meropenem, a carbapenem antibiotic, has been combined with vaborbactam, a novel beta-lactamase inhibitor, to treat infections caused by bacteria resistant to currently available carbapenems.[89] It is approved by the FDA and EMA for the treatment of adults with complicated UTI, including pyelonephritis, caused by designated susceptible gram-negative microorganisms Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex). Meropenem/vaborbactam was shown to be noninferior to piperacillin/tazobactam for complete resolution along with microbial eradication in complicated UTIs in adults.[90]

Plazomicin

Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance.[91][92] It has been approved by the FDA for the treatment of adults with complicated UTIs, including pyelonephritis, that are caused by certain Enterobacteriaceae in patients who have limited or no alternative treatment options. Clinical studies have shown plazomicin to be noninferior to meropenem in the treatment of complicated UTI.[93]

Sulopenem

Sulopenem is a broad-spectrum penem antibiotic developed for the treatment of multi-drug resistant gram-negative infections. It is recently approved by the FDA to treat uncomplicated UTIs in adult women with limited or no available alternative oral antibiotic options. It is the first oral penem approved in the US, specific to the treatment of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. In a recent phase 3, randomized trial, treatment of UTIs with sulopenem was found noninferior to ciprofloxacin in ciprofloxacin-susceptible pathogens and superior in ciprofloxacin-nonsusceptible pathogens.[94] Sulopenem is coformulated with probenecid (a uricosuric agent) to reduce renal clearance of sulopenem and increase plasma sulopenem levels.

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.[95] The FDA and EMA have approved ceftolozane/tazobactam for the treatment of complicated UTIs in adults and children. A meta-analysis showed ceftolozane/tazobactam to be more effective in treating complicated UTIs than piperacillin/tazobactam.[96]

Cefiderocol

Cefiderocol is a novel siderophore cephalosporin which has broad activity against Enterobacteriaceae and nonfermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. It has been approved by the FDA for the treatment of adults with complicated UTIs including kidney infections caused by susceptible gram-negative microorganisms, who have limited or no alternative options. It is also approved by the EMA for the treatment of infections due to aerobic gram-negative organisms, including complicated UTIs, in adults with limited treatment options. A phase 2 double-blind, noninferiority trial (n=448) found that treatment with cefiderocol was noninferior compared with imipenem/cilastatin for the treatment of complicated UTIs in people with multidrug-resistant gram-negative infections.[97]

Imipenem/cilastatin/relebactam

This three drug combination includes relebactam, a beta-lactamase inhibitor, together with the previously approved carbapenem antibiotic imipenem/cilastatin. Relebactam can restore imipenem activity against many imipenem-resistant strains of Enterobacteriaceae and P aeruginosa. The new combination has been approved by the FDA for the treatment of adults with complicated UTIs, who have limited or no alternative options. It is also approved by the EMA for the treatment of infections due to aerobic gram-negative organisms, including complicated UTIs, in adults with limited treatment options. A prospective, randomized, double-blind, phase 2 dose-ranging study (n=298) compared the efficacy and safety of imipenem/cilastatin/relebactam with imipenem/cilastatin alone in patients with complicated UTIs. Imipenem/cilastatin/relebactam was shown to be as effective as imipenem/cilastatin alone, was well tolerated and may cover highly resistant pathogens.[98]

Pivmecillinam

The FDA has approved pivmecillinam, an oral beta-lactam antibiotic, for the treatment of uncomplicated UTIs in adults. It has been shown to have specific activity against gram-negative organisms such as Escherichia coli and other Enterobacteriaceae, such as Proteus mirabilis and Staphylococcus saprophyticus.[99] Pivmecillinam has been available in other countries, including the UK, for many years.

Vaccines

Vaccines against Escherichia coli and other uropathogens are a promising emerging treatment. Mucosal and parenteral vaccines targeted at E coli and other uropathogens are being investigated.[100][101][102][103] 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.[104]

Lactobacillus

Vaginal lactobacilli are an important host defense against UTI. In healthy premenopausal women, the vaginal environment is acidic, with Lactobacillus species as the predominant bacteria. Studies to evaluate the probiotic capacity of Lactobacillus species administered by the vaginal route have been carried out in women with UTIs, with mixed but promising results.[105] A study showed that oral daily lactobacillus may be as effective as daily trimethoprim/sulfamethoxazole in preventing infections in patients with recurrent UTI.[106] Currently there is no reliable product for urogenital application of lactobacillus to prevent UTIs.[107][108]

D-mannose

D-mannose, found in several fruits and vegetables including cranberries, is a simple sugar that may hinder bacterial adhesion to the urothelium. Small studies have looked at D-mannose as a potential UTI prevention strategy.[109][110] 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.[111] In a recent RCT, D-mannose did not reduce the proportion of women with recurrent UTI in primary care settings who experienced a subsequent clinically suspected UTI, and the conclusion was that D-mannose should not be recommended for prophylaxis in this patient group.[112]

Cranberry

Cranberry has been used to prevent recurrent UTI (rUTI) among healthy women. Efﬁcacy of cranberry for the prevention of rUTI remains controversial, in part because of the conﬂicting conclusions from meta-analyses. The key issues that contribute to the conflicting evidence are the variability of participants (i.e., nursing home vs. ambulatory adult women) and outcome measures (including the threshold for UTI diagnosis, bacteriuria vs. symptomatic, culture positive UTI). Heterogeneity is also seen when complicated and uncomplicated UTIs are combined in the analysis.[113][114] Efficacy has been observed in clinical trials assessing prevention of rUTI in generally healthy women.[115] The American Urological Association Guidelines (AUA) on rUTI state that, “Clinicians may offer cranberry prophylaxis for women with recurrent UTIs (Evidence Level: Grade C).”[2] This analysis included five randomized clinical trials. Cranberry was associated with decreased risk of experiencing at least one UTI recurrence over placebo or no cranberry (RR 0.67, 95% CI 0.54 to 0.83). Limitations included lack of adverse effects reported and that formulation (juice vs. extract) could not be recommended. Overall, cranberry is a low-risk preventive strategy. There is evidence to support soluble cranberry with a high level of proanthocyanidins (PACs) in the prevention of rUTI in ambulatory adult women.[116] However, more studies in this area are needed.[117]

Intravesical therapy

The intravesicular installation of a combination of sodium hyaluronate and chondroitin sulfate is considered a possible nonantibiotic option for recurrent UTI. It works by restoring the integrity of the bladder lining and potentially inhibiting bacterial adhesion. A meta-analysis showed significantly decreased UTI rate, and significantly longer mean UTI recurrence time, in patients using this method compared to placebo. However, more large studies are needed, as evidence regarding the use of nonantibiotic instillations is still considered generally low.[73][118][119]