Pivmecillinam and mecillinam –poised to meet the critical need for treatment of UTIs
Resistant strains of Enterobacteriaceae, including E coli, are rapidly eroding the effectiveness of currently available antibiotics
Enterobacteriaceae is a gram-negative family of bacteria, including E coli, that are a common cause of numerous infections in humans.1,2 Over the past decade, a growing number of ESBLs, a group of enzymes that render some antibiotics ineffective, have been emerging and spreading throughout the world.3,4
ESBLs are associated with resistance to penicillin, cephalosporin, trimethoprim-sulfamethoxazole (TMP-SMX), and quinolone.1,3-5 In the United States, ESBL-producing Enterobacteriaceae increased by more than 33% over a 5-year period, compromising the efficacy of antibiotics that were routinely used to treat gram-negative infections.3,5
5-year increase in ESBL-producing Enterobacteriaceae5
As antibiotic resistance increases, effective options for UTI treatment are becoming more and more limited
Most UTIs are caused by E coli. Since the mid-1980s, the rate of E coli resistance has steadily grown. Today, most commonly used antibiotics for UTIs exhibit high rates of resistance, resulting in treatment failure.3,6
Antibiotic-resistant (ESBL-producing) E coli in UTIs3
Antibiotic resistance compromises treatment outcomes and drives up healthcare costs
In the outpatient setting, antibiotic-resistant UTIs are associated with a high rate of treatment failure, requiring additional rounds of treatment and/or hospitalization.6 Furthermore, over a period of 13 years, as the rate of resistance continued to grow, the number of UTIs requiring hospitalization increased by 76%, dramatically driving up treatment costs.7 The rising rate of treatment failures, hospitalizations, and treatment costs underscores the need for treatment options that are effective against resistant ESBL-producing bacteria.
Mecillinam and its pro-drug pivmecillinam are a unique class of antibiotics with potent in vitro activity against the most common bacteria in UTI, including resistant strains8
UTILITY therapeutics has acquired 2 European-approved antibiotics for the treatment of UTIs, and is working to make these available to the US market. Mecillinam and its pro-drug pivmecillinam are highly active against gram-negative Enterobacteriaceae, including ESBL-producing strains of E coli.8 Pivmecillinam, an oral formulation, is an appropriate choice for therapy in regions where it is available.9 Based on strong evidence showing consistent activity against key resistant pathogens, well-established clinical data, and extensive real-world experience in treating UTIs, UTILITY therapeutics acquired exclusive US rights to both drugs and is currently developing a program to help bring them to market.
The path to approval
The FDA has already granted Qualified Infectious Disease Product (QIDP) designation for pivmecillinam for the treatment of uncomplicated UTIs.10
UTILITY therapeutics is on track to achieve several key milestones for pivmecillinam in 2021 and beyond:
- Scientific engagement with Key Opinion Leaders
- Pre-NDA meeting with the FDA in the first half of 2021
- NDA submission and establish commercial readiness for product launch
UTILITY therapeutics is also pursuing approval of mecillinam IV for complicated UTIs and other gram-negative infections.
Product Pipeline
Pivmecillinam offers an exceptional combination of clinical attributes for treatment of uncomplicated UTIs:
- Extensive experience, with no emerging issues with efficacy or safety after decades of use outside of the United States8,11
- A high level of activity (95.8%) against E coli, including ESBL-producing strains8
- ≤5% E coli resistance rates12
- Minimal effect on normal intestinal microflora, with little potential for overgrowth of resistant strains of Enterobacteriaceae or Clostridium difficile8
Pivmecillinam is positioned for potential rapid adoption and success
Despite concerted efforts with antimicrobial stewardship to curb resistance, the United States is facing an urgent crisis as resistance continues to rise. With steady increases in ESBL-producing Enterobacteriaceae and antibiotic-resistant UTIs, healthcare professionals have fewer and fewer effective treatments for resistant infections.3,5
With the high rate of resistance and the necessity for better treatment options for uncomplicated UTIs, pivmecillinam would be a welcome newcomer to the United States
UTIs are one of the most common bacterial infections in the world. In the United States, more than 45 million courses of antibiotics are prescribed each year for UTIs. More than 32 million courses are prescribed in an office setting for uncomplicated UTIs.13
Research shows that physicians are in favor of pivmecillinam as a first-line treatment for UTIs and expect to use it for a large number of their patients. Likewise, payers indicate that they are likely to provide unrestricted access to a majority of patients.13 Guidelines from both the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommend pivmecillinam as a first-line treatment of uncomplicated UTIs. As the IDSA has stated that pivmecillinam is an appropriate choice for therapy in regions where it is available (not currently available in the United States), UTILITY therapeutics expects widespread adoption of pivmecillinam by healthcare providers and payers, if approved.9
US physicians are motivated to prescribe pivmecillinam as a first-line treatment option for UTIs, based on its real-world experience13
As part of our commitment to conquering the challenge of antibiotic resistance in uncomplicated and complicated UTIs, UTILITY therapeutics is continuing to advance our program to gain FDA approval of IV mecillinam for treatment of complicated UTIs in the hospital setting, and step-down therapy transitioning from IV mecillinam to oral pivmecillinam so that patients can continue treatment at home.
References: 1. Rawat D, Nair D. Extended-spectrum ß-lactamases in gram negative bacteria. J Glob Infect Dis. 2010;2(3):263-274. doi:10.4103/ 0974-777X.68531 2. Patients: information about CRE. Centers for Disease Control and Prevention. November 13, 2019. Accessed January 14, 2021. https://www.cdc.gov/hai/organisms/cre/cre-patients.html 3. Critchley IA, Cotroneo N, Pucci MJ, Mendes R. The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017. PLoS One. 2019;14(12):e0220265. doi:10.1371/journal.pone.0220265 4. Kumar D, Singh AK, Ali MR, Chander Y. Antimicrobial susceptibility profile of extended spectrum ß-lactamase (ESBL) producing Escherichia coli from various clinical samples. Infect Dis Res Treat. 2014;7:1-8. doi:10.4137/IDRT.S13820 5. Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. Centers for Disease Control and Prevention. Accessed January 18, 2021. https://www.cdc.gov/drugresistance/pdf/threats-report/esbl-508.pdf 6. Dunne MW, Snow K, Mehta R. Failure of empiric treatment of uncomplicated urinary tract infection (UTI) associated with resistant pathogens. Poster presented at: American Society of Microbiology and Infectious Diseases; June 20-24, 2019; San Francisco, CA. 7. Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011. Open Forum Infect Dis. 2017;4(1):ofw281. doi:10.1093/ofid/ofw281 8. 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(2):303-308. doi:10.1093/jac/dkt368 9. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. doi:10.1093/cid/ciq257 10. Data on File. UTILITY therapeutics. 11. Selexid® Product Monograph Version 2.0. February 6, 2018. LEO Pharma, Inc. Thornhill, Ontario. 12. Cordoba G, Holm A, Hansen F, Hammerum AM, Bjerrum L. Prevalence of antimicrobial resistant Escherichia coli from patients with suspected urinary tract infection in primary care, Denmark. BMC Infect Dis. 2017;17(1):670. doi:10.1186/s12879-017-2785-y 13. IQVIA/IMS Market Analysis. April 5, 2018.