By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved a new antibacterial for the treatment of uncomplicated urinary tract infection (UTI) in female adults. Pivmecillinam is the synthetic prodrug of mecillinam, a beta-lactam antibacterial agent. It was granted a priority review and Qualified Infectious Disease Product Designation for the indication.1 Pivmecillinam has been available for decades in Scandinavia. It will be distributed in the United States by Utility Therapeutics, Ltd., as Pivya.
Indications
Pivmecillinam is indicated for the treatment of adult female patients (18 years of age and older) with uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus.2
Dosage
The recommended dose for pivmecillinam is one tablet orally three times per day for three to seven days as clinically indicated.2 It may be taken without regard to meals. It is available as 185 mg tablets.
Potential Advantages
Pivmecillinam showed in vitro activity against important urinary tract pathogens (Enterobacterales) as well as in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBL) of CTX-M, SHV, TEM, and AmpC.2,3 It has high selectivity for penicillin-binding protein (PBP)-2, in contrast to other beta-lactams that target PBP 1A, 1B, or -3.2 Pivmecillinam is mainly excreted unmetabolized in the urine, providing high urine concentrations. It has minimal effect on intestinal and vaginal microflora.4
Potential Disadvantages
Pivmecillinam is contraindicated in patients who have experienced serious hypersensitivity reaction to other beta-lactam antibacterials.2 Severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with pivmecillinam. Pivmecillinam may interfere with a newborn screening test for isovaleric acidemia.
Pivmecillinam is a pivalate-generating prodrug; therefore, valproic acid, valproate, or other pivalate-generating drugs should be avoided. It also is contraindicated in patients with carnitine deficiency or in patients with porphyria.2 As with nearly all systemic antibacterials, there is a risk of Clostridioides difficile-associated diarrhea.2 The most common adverse reactions are nausea and diarrhea.2 Adherence may be problematic because of a high pill burden (three times daily for three to seven days). In contrast, fosfomycin is a single-dose treatment for uncomplicated UTI.
Comments
The efficacy of pivmecillinam was evaluated in three controlled clinical trials.2,5 The first compared different doses of pivmecillinam to placebo, the second to cephalexin, and the third to ibuprofen (symptomatic treatment). All studies were in female adults (18 years of age or older) with uncomplicated UTI (with no structural abnormalities). Efficacy was assessed in the Microbiological Intent-to-Treat (micro-ITT) population, which included all randomized subjects with a positive baseline urine culture (≥ 105 colony-forming units/mL of a uropathogen) and no more than two species of microorganism regardless of the colony count.
No baseline pathogen was non-susceptible to the active comparator. The primary efficacy endpoint was the composite of clinical cure (i.e., resolution of symptoms) and microbiological response (negative or reduction [< 103] of bacteria in the urine culture) assessed approximately eight to 14 days after enrollment into the studies. In the first trial, pivmecillinam 185 mg three times daily for seven days, (n = 137) showed a composite response rate of 62% vs. 10% for placebo (n = 134). In the second trial, response rates were 72% for pivmecillinam (n = 127) and 76% for cephalexin (250 mg four times a day × seven days) (n = 132), and in the third trial, 66% for pivamecillinam (n = 105) and 22% for ibuprofen (600 mg three times daily × three days) (n = 119).5
Clinical Implications
Uncomplicated UTI is a very common condition affecting women and commonly leads to antibiotic use.1 Forty percent of women in the United States will develop a UTI during their lifetime.6 Many UTIs (about 20%) resolve spontaneously without treatment. The causative pathogens are most commonly E. coli (70% to 95%), Staphylococcus saprophylticus (5% to 19%), and occasional Proteus mirabilis and Klebsiella spp.7
In the United States, first-line agents for uncomplicated UTIs include nitrofurantoin, sulfamethoxazole/trimethoprim, fosfomycin, and first-generation cephalosporins.6 However, outside the United States, pivmecillinam is considered first-line. The new approval provides another effective option in the United States. Regardless, it is not recommended in pyelonephritis or suspected systemic infection due to inadequate tissue penetration.6 The cost for pivmecillinam was not available at the time of this review.
References
- U.S. Food and Drug Administration. FDA approves new treatment for uncomplicated urinary tract infections. April 24, 2024. https://www.fda.gov/news-event...
- Pivya Prescribing Information. Utility Therapeutics Ltd. April 2024. https://www.accessdata.fda.gov...
- Fuchs F, Hamprecht A. Results from a prospective in vitro study on the mecillinam (Amdinocillin) susceptibility of Enterobacterales. Antimicrob Agents Chemother 2019;63:e02402-18.
- Dewar S, Reed LC, Koerner RJ. Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria. J Antimicrob Chemother 2014;69:303-308.
- Vik I, Bollestad M, Grude N, et al. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women – a double-blind, randomized non-inferiority trial. PLOS Med 2018;15:e1002569.
- Bono MJ, Leslie SW, Reygaert WC. Uncomplicated urinary tract infections. In: StatPearls. StatPearls Publishing. Nov. 13, 2023. https://pubmed.ncbi.nlm.nih.gov/29261874/
- Wagenlehner FME, Naber KG. Urinary tract infections: Uncomplicated. Antimicrobe.org/e4a.asp
The U.S. Food and Drug Administration (FDA) has approved a new antibacterial for the treatment of uncomplicated urinary tract infection (UTI) in female adults.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content