Carbapenem-Nonsusceptible Pseudomonas aeruginosa Isolates from Intensive Care Units in the United States: a Potential Role for New β-Lactam Combination Agents

Abstract

Pseudomonas aeruginosa, a frequent pathogen in the intensive care unit (ICU), has the propensity to develop antibiotic resistance. In particular, carbapenem-nonsusceptible (NS) P. aeruginosa poses tremendous challenges, and new antibiotics will be needed to treat this phenotype. Here we determine carbapenem nonsusceptibility rates for contemporary P. aeruginosa isolates from U.S. ICUs and in vitro activities of new β-lactam combination agents. Between July 2017 and June 2018, consecutive nonduplicate P. aeruginosa isolates from blood and respiratory tract sources were recovered from patients admitted to the ICUs of 36 geographically diverse U.S. hospitals. Antimicrobial susceptibility to the following antipseudomonal agents was tested: ceftazidime, imipenem, meropenem, ceftazidime-avibactam, and imipenem-relebactam (an investigational β-lactam/β-lactamase inhibitor). MICs and susceptibility rates were measured using Clinical and Laboratory Standards Institute reference broth microdilution methodology. Among the 538 consecutive ICU P. aeruginosa isolates collected, carbapenem nonsusceptibility was observed for 35% of the isolates and was more common among respiratory tract versus bloodstream specimens. Susceptibility rates, MIC50 values, and MIC90 values were as follows: ceftazidime-avibactam, 92.8%, 2 μg/ml, and 8 μg/ml; imipenem-relebactam, 91.5%, 0.25 μg/ml, and 2 μg/ml; ceftazidime, 77.1%, 4 μg/ml, and 64 μg/ml; meropenem, 72.7%, 1 μg/ml, and 16 μg/ml; imipenem, 67.1%, 2 μg/ml, and 16 μg/ml. Most (>75%) of the carbapenem-NS isolates were susceptible to ceftazidime-avibactam and imipenem-relebactam. In these U.S. hospital ICUs, carbapenem-NS P. aeruginosa isolates from respiratory sources were frequently observed. Novel β-lactam combination agents appear to retain active in vitro susceptibility profiles against these isolates and may play a role in the treatment of infections caused by carbapenem-NS P. aeruginosa strains.

It’s Not Easy Being Green: A Narrative Review on the Microbiology, Virulence and Therapeutic Prospects of Multidrug-Resistant Pseudomonas aeruginosa

“…While there have been advances in the marketing authorization of novel antibiotics and combination therapy in the recent decade, their price and availability may hinder their widespread use in the near future. Additionally, it is questionable how long the new agents can manage the worsening resistance situation [146,157,[249][250][251][252][253][254]. With the daunting increase in antimicrobial resistance rates in all types of bacteria, one of the main aims of antimicrobial research is the exploration for new approaches past conventional antibiotics, such as bacteriophages, antimicrobial peptides with diverse structures and mechanisms of action, virulence inhibitors, siderophores, compounds from natural origins (like essential oils), and other adjuvants (e.g., efflux pump inhibitors, monoclonal antibodies) (Table 3) [118,[255][256][257][258][259][260][261][262][263][264][265][266][267][268][269][270].…”

In Vitro Activity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin against Pseudomonas aeruginosa

“…Paired with imipenem, relebactam has potent in vitro activity against class A ␤-lactamases, including KPC-type carbapenemases, and class C ␤-lactamases (11,18). In a recent intensive care unit (ICU)-based surveillance study with 538 P. aeruginosa isolates, the respective susceptibility rates of meropenem, imipenem, and imipenem-relebactam were 72.7%, 67.1%, and 91.5% (9). The carbapenem-nonsusceptible and MDR P. aeruginosa isolates utilized in this study are representative of isolates that may be encountered in a critically ill population and where antimicrobial agents such as imipenemrelebactam would be considered for treatment.…”

“…become conventional at many hospitals in North America. Recent surveillance studies report P. aeruginosa carbapenem nonsusceptibility rates of 20% to 25% and up to 35% in the intensive care unit setting (7)(8)(9); furthermore, carbapenem nonsusceptibility generally mirrors the prevalence of MDR isolates. As a result, new treatments for carbapenem-resistant and MDR P. aeruginosa are needed (10).…”

<p>A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date</p>

“…22,23 Pseudomonas aeruginosa There are several in vitro studies that evaluated activity of I-R against Pseudomonas aeruginosa (Table 1). [5][6][7][8]17,21,22,[33][34][35][36][37] Rates of susceptibility were approximately 90% for all P. aeruginosa isolates tested. Relebactam restored susceptibility to imipenem to 80% of imipenem-non-susceptible isolates of P. aeruginosa.…”