mk-7655 and Urinary-Tract-Infections

Infections due to multidrug-resistant (MDR) Gram-negative bacteria are challenging to treat because of limited treatment options and potential side effects of less frequently used anti-infectives. In the past few years, several new antimicrobial agents effective against MDR Gram-negatives have become available. This review focuses on the treatment options for complicated urinary tract infections (cUTIs) caused by MDR Gram-negatives.. The novel combinations, betalactam or carbapenem and betalactamase inhibitor, ceftazidime/avibactam and meropenem/vaborbactam, are effective for infections caused by KPC-carbapenemase-producing pathogens. Imipenem/relebactam, another carbapenem/betalactamase inhibitor combination, has been approved for the treatment of cUTI. However, data on the efficacy of imipenem/relebactam against carbapenem-resistant pathogens is still limited. Ceftolozane/tazobactam is mainly used for the treatment of MDR Pseudomonas aeruginosa infections. For the treatment of cUTI caused by extended-spectrum betalactamases producing Enterobacterales aminoglycosides or intravenous fosfomycin should be considered.. To ensure prudent use and to avoid the development of resistance to novel anti-infective substances, an interdisciplinary approach, including urologists, microbiologists, and infectious disease physicians, is strongly advised.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; Carbapenems; Gram-Negative Bacterial Infections; Humans; Imipenem; Urinary Tract Infections

The addition of the β-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice.. In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium.. With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Humans; Imipenem; Male; Microbial Sensitivity Tests; Urinary Tract Infections

Relebactam, a novel class A/C β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens.. This phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5-14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis.. Of 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT.. A favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin; Cilastatin, Imipenem Drug Combination; Humans; Imipenem; Intraabdominal Infections; Japan; Urinary Tract Infections

The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens.. To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%.. At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache.. Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634).

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Cilastatin; Cilastatin, Imipenem Drug Combination; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Male; Middle Aged; Prospective Studies; Pyelonephritis; Urinary Tract Infections; Young Adult

Antimicrobial resistance due to β-lactamase production is a worldwide issue, and β-lactamase inhibitors have been developed to overcome the growing problem. This study aimed to evaluate the in vitro activities of two recently introduced carbapenem/β-lactamase inhibitor combinations - imipenem/relebactam and meropenem/vaborbactam - and their comparators against Enterobacterales from patients with urinary tract infections (UTIs).. Enterobacterales isolates from patients with UTIs in Taiwan and participating in the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 2020 were included. Minimum inhibitory concentrations (MICs) for various antibiotics were determined using the broth microdilution method. Susceptibility was interpreted based on the MIC breakpoints of the Clinical and Laboratory Standards Institute 2022. Genes encoding common β-lactamases, including extended-spectrum β-lactamases, AmpC β-lactamases and carbapenemases, were detected using multiplex polymerase chain reaction.. A total of 309 Enterobacterales isolates were included, against which both imipenem/relebactam and meropenem/vaborbactam exerted excellent efficacy (275 of 309, 95% and 288 of 309, 99.3%, respectively). Among imipenem non-susceptible isolates, 17 of 43 (39.5%) and 39 of 43 (90.7%) were susceptible to imipenem/relebactam and meropenem/vaborbactam, respectively.. Imipenem/relebactam and meropenem/vaborbactam may be appropriate choices for treating UTIs due to Enterobacterales resistant to commonly used antibiotics. Continuous monitoring of antimicrobial resistance is crucial.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Drug Combinations; Drug Resistance, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Taiwan; Urinary Tract Infections

Antimicrobial resistance, including multidrug-resistance (MDR), is increasing, especially among Gram-negative bacilli. New agents are needed to treat infections caused by these pathogens. This report assessed the activity of imipenem/relebactam against Gram-negative bacilli from intraabdominal infections (IAIs) and urinary tract infections (UTIs) submitted to the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance programme in the United States from 2015 to 2017.. Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa (P. aeruginosa). Imipenem/relebactam MICs were interpreted using United States Food and Drug Administration (FDA) breakpoints.. 99.5% of NPE isolates collected from patients with IAIs (n=3633) and UTIs (n=3038) were susceptible to imipenem/relebactam, as were 77.9% of imipenem-nonsusceptible, 96.3% of Klebsiella pneumoniae carbapenemase (KPC)-positive, and 98.7% of MDR isolates from IAIs and UTIs combined. A total of 96.7% of IAI isolates (n=486) and 96.4% of UTI isolates (n=360) of P. aeruginosa were susceptible to imipenem/relebactam, as were 85.0% of imipenem-nonsusceptible and 87.3% of MDR isolates from IAIs and UTIs combined. Percent susceptibility to imipenem/relebactam for cefepime-, ceftazidime-, and piperacillin-tazobactam-nonsusceptible isolates was 98.3-98.8% for NPE and 87.3-90.0% for P. aeruginosa.. Imipenem/relebactam demonstrated potent in vitro activity against NPE and P. aeruginosa isolates from IAIs and UTIs, including against resistant subsets, and will provide important coverage for IAIs and UTIs caused by β-lactam-resistant, MDR, and KPC-positive Gram-negative bacilli.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Enterobacteriaceae; Humans; Imipenem; Pseudomonas aeruginosa; United States; Urinary Tract Infections

Imipenem/cilastatin sodium/relebactam is a combination of imipenem/cilastatin, a U.S. Food and Drug Administration (FDA)-approved antibiotic, and β-lactamase inhibitor relebactam which has been developed for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) due to drug-resistant bacterial pathogens. The combination (Recarbrio) has been designated as a qualified infectious disease product (QIDP) and obtained FDA approval in 2019 for the treatment of cUTI and cIAI caused by susceptible Gram-negative microorganisms in adult patients with limited or no alternative treatment options. The product was also approved by the European Medicines Agency (EMA) in 2020 for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.

Topics: Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Cilastatin, Imipenem Drug Combination; Humans; Intraabdominal Infections; Urinary Tract Infections

Imipenem/cilastatin/relebactam is a β-lactam/β-lactamase inhibitor that has been recently FDA approved for complicated intra-abdominal and urinary tract infections under the brand name Recarbrio®. It has activity against imipenem non-susceptible Pseudomonas species as well as KPC-producing Enterobacteriaceae. Optimization of PK/PD of antimicrobials particularly in critically-ill patients is essential, but unfortunately, is hindered by separate administration that requires significant resources. The objective of the study is to investigate the compatibility of Y-site administration of imipenem/cilastatin/relebactam with a wide range of antimicrobials. After admixture, physical characteristics, pH changes and turbidity were measured for each 2-drug combination at a time. With the exception of amphotericin B deoxycholate, and posaconazole, imipenem/cilastatin/relebactam was compatible with a variety of antimicrobial agents. The compatibility profile described, will facilitate incorporation into hospital protocols, contribute to therapy optimization and guide clinicians to avoid successive administration, consequently resulting in reduction of total infusion time, optimization of PK/PD, economizing nursing time and cost containment.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Cilastatin; Drug Combinations; Drug Therapy, Combination; Humans; Hydrogen-Ion Concentration; Imipenem; Microbial Sensitivity Tests; Urinary Tract Infections

Considering the increasing incidence of carbapenem-resistant Enterobacteriaceae in China, this study aimed to establish the in vitro effectiveness of imipenem/relebactam (IMI/REL) on clinical Enterobacteriaceae isolates derived from intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs) in China between 2015 and 2018.. In total, 8781 Enterobacteriaceae isolates from IAI, RTI, and UTI samples were collected from 22 hospitals across 7 geographic regions of China. Susceptibility to antimicrobial drugs was tested using the Clinical and Laboratory Standards Institute broth microdilution and breakpoints, and IMI/REL activity was assessed using United States Food and Drug Administration guidelines.. In 2015-2018, the most frequently identified Enterobacteriaceae species was Escherichia coli (n = 4676 [53.3%]), followed by Klebsiella pneumoniae (n = 2949 [33.6%]) and Enterobacter cloacae (n = 542 [6.2%]). The Enterobacteriaceae isolates showed 95.2% overall susceptibility to IMI/REL, of which the susceptibility rates in isolates from IAI, RTI, and UTI were 95.8%, 91.4%, and 96.6%, respectively. Overall, the susceptibilities of both intensive care unit (ICU) and non-ICU Enterobacteriaceae isolates to colistin were 92.9%, followed by IMI/REL (90.7% [95.9%]) and amikacin (83.3% [92.3%]). In addition, IMI/REL restored 66.3% susceptibility in imipenem-nonsusceptible Enterobacteriaceae.. Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; China; Drug Resistance, Bacterial; Enterobacteriaceae; Humans; Imipenem; Intraabdominal Infections; Microbial Sensitivity Tests; Respiratory System; United States; Urinary Tract Infections