Is Imipenem-Cilastatin Effective For the Treatment of UTI Caused by Pseudomonas aeruginosa with Difficult-to-Treat Resistance?

Summary • Imipenem-cilastatin (Primaxin) is a broad-spectrum carbapenem antibiotic used to treat many infectious diseases. • The CDC reports that there are roughly 2,700 deaths per year due to multi-drug resistant P. aeruginosa [1]. • MDR is defined as non-susceptibility to at least one antibiotic in at least three classes in which you would usually expect P. aeruginosa to be susceptible [2]. • Certain drugs in different classes are used to treat MDR P. aeruginosa such as fluoroquinolones, select cephalosporins, aminoglycosides, and carbapenems. • In 2018 the label of “difficult-to-treat” resistant (DTR) was suggested. DTR is defined as P. aeruginosa that is non-susceptible to our broader anti-pseudomonal antibiotics such as piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin [2]. • We will review the Infectious Diseases Society of America (IDSA) guidelines on treating this highly infective P. aeruginosa, as well as evaluate a study comparing imipenem-cilastatin plus relebactam and imipenem/cilastatin alone in the treatment of UTI’s caused by these organisms. Clinical Data Due to the significant clinical morbidity and mortality of infections caused by DTR P. aeruginosa, these infections must be treated promptly and with antimicrobial drugs with expected susceptibility [1]. The IDSA guidelines recommend ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, cefiderocol, or a single-dose of an aminoglycoside as the preferred treatment options for uncomplicated UTIs caused by DTR P. aeruginosa. The IDSA recommends these agents due to multiple studies that have shown them to be effective in treating UTIs per the IDSA. Imipenem-cilastatin is a common broad-spectrum option for treating these types of pathogens. Like other beta-lactams, imipenem can sometimes be paired with a drug from a class known as beta-lactamase inhibitors. These drugs work to inhibit the breakdown of the primary drug by enzymes produced by the pathogen. Relebactam is a beta-lactamase inhibitor that is sometimes used with imipenem when treating MDR or DTR pathogens. One study compared the efficacy of imipenem-cilastatin plus relebactam with imipenem-cilastatin alone in patients with complicated urinary tract infections that include P. aeruginosa. [3]. The study was randomized in a 1:1:1 fashion. Patients were placed into three different groups: imipenem-cilastatin plus 250mg of relebactam, imipenem-cilastatin plus relebactam 125mg, and imipenem-cilastatin alone. The primary endpoint for the study was an adequate microbial response rate (eradication of the pathogen), by the end of treatment. The researchers labeled non-inferiority of imipenem-cilastatin plus relebactam over imipenem-cilastatin as a treatment difference being no greater than 15%. At the time of discontinuation, clinical response rates were 97.1% in the imipenem-cilastatin plus 250mg of relebactam group, 98.7% in the imipenem-cilastatin plus 125mg relebactam group, and 98.8% in the imipenem-cilastatin alone group. Included below is Table 3 from the study that illustrates the pathogens that were identified in the study and their respective susceptibility in vitro to imipenem-cilastatin + relebactam vs imipenem-cilastatin alone. Interestingly, the susceptibility was higher in the imipenem-cilastatin plus relebactam group for P. aeruginosa compared to imipenem-cilastatin alone, however, the efficacy rates presented by the study of eradication of the pathogen were not statistically significant. The results of this study illustrated that in conclusion both imipenem-cilastatin plus relebactam, as well as imipenem-cilastatin alone, are viable options for the treatment of DTR P. aeruginosa. References 1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019. 2. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa) [published online ahead of print, 2020 Oct 27]. Clin Infect Dis. 2020;ciaa1478. doi:10.1093/cid/ciaa1478 3. Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother 2017; 72(9): 2616-26.