mk-7655 and Respiratory-Tract-Infections

To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies.. P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS.. Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance.. Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Humans; Imipenem; Intensive Care Units; Microbial Sensitivity Tests; Portugal; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Spain

β-lactam- and multi-drug-resistant (MDR) Gram-negative bacilli frequently cause lower respiratory tract infections (LRTIs) in patients housed in intensive care units (ICUs). Relebactam, a novel diazabicyclooctane inhibitor of Ambler class A and C β-lactamases, in combination with imipenem-cilastatin was approved by the US Food and Drug Administration in July 2019 for the treatment of adults with complicated intra-abdominal infections and complicated urinary tract infections. A phase III study of imipenem/relebactam for the treatment of patients with respiratory tract infections, including antimicrobial-resistant Gram-negative infections, has also been completed. The Clinical and Laboratory Standards Institute's broth microdilution methodology was used to determine minimum inhibitory concentrations against non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa collected from ICU patients with LRTIs at 26 US hospitals in 2015-2017. Percent susceptibilities to imipenem/relebactam were 97.0%, 66.4% and 98.1%, respectively, for all NPE (n=1298), imipenem-non-susceptible NPE (n=113, of which 71% were Serratia marcescens) and MDR NPE (n=206), and 92.2%, 77.2% and 79.6%, respectively, for all P. aeruginosa (n=638), imipenem-non-susceptible P. aeruginosa (n=219) and MDR P. aeruginosa (n=225). Percent susceptibilities to imipenem/relebactam were 98.0-98.6% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible NPE and 77.8-82.5% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible P. aeruginosa. Generally, only slight variations in susceptibility were observed across US census regions. Imipenem/relebactam may provide a valuable therapeutic option for the treatment of ICU patients with LRTI caused by Gram-negative bacilli resistant to commonly used β-lactams, as it demonstrated potent in-vitro activity against the majority of tested β-lactam-non-susceptible and MDR Gram-negative bacilli from ICU patients with LRTIs in US hospitals.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Enterobacteriaceae; Gram-Negative Bacteria; Humans; Imipenem; Intensive Care Units; Intraabdominal Infections; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Respiratory Tract Infections; United States; Young Adult

Imipenem resistance in Pseudomonas aeruginosa most often entails loss of the 'carbapenem-specific' porin OprD; more rarely it reflects acquired carbapenemases. Loss of OprD only confers resistance to imipenem if AmpC β-lactamase is expressed, and we investigated whether this mechanism was overcome by relebactam, a developmental diazabicyclooctane β-lactamase inhibitor.. Consecutive P. aeruginosa isolates causing bacteraemia or hospital-onset lower respiratory tract infections were collected between 2014 and 2016 under the aegis of the BSAC Resistance Surveillance Programme. Imipenem MICs were determined centrally by BSAC agar dilution, with relebactam at a fixed concentration (4 mg/L).. For most imipenem-susceptible P. aeruginosa (726/759, 95.7%), the MICs of imipenem alone were 0.5-2 mg/L and were decreased 3- to 4-fold by addition of relebactam, as based on geometric means or modes. For most imipenem-resistant P. aeruginosa (82/92, 89%), imipenem MICs were 8-16 mg/L, and were reduced to 1-2 mg/L by relebactam. These patterns applied regardless of whether the isolates were susceptible to penicillins and cephalosporins or had phenotypes suggesting derepressed AmpC or up-regulated efflux. Imipenem MICs for five P. aeruginosa with MBLs remained high (≥16 mg/L) regardless of relebactam.. Potentiation of imipenem by relebactam was almost universal, in accordance with the view that endogenous pseudomonal AmpC ordinarily protects against this carbapenem to a small degree. Imipenem MICs were reduced to the current breakpoint, or lower, except for MBL producers. Potentiation was not compromised by derepression of AmpC or up-regulation of efflux.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacteremia; Drug Resistance, Bacterial; Drug Synergism; Humans; Imipenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections