Carbapenem Combinations for Infections Caused by Carbapenemase-Producing Pseudomonas aeruginosa: Experimental In Vitro and In Vivo Analysis

Abstract

In the context of difficult-to-treat carbapenem-resistant Pseudomonas aeruginosa infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven carbapenemase-producing P. aeruginosa isolates. According to the widespread global distribution of high-risk clones and carbapenemases, four representative isolates were selected: ST175 (OXA-2/VIM-20), ST175 (VIM-2), ST235 (GES-5), and ST111 (IMP-33), for efficacy studies using a sepsis murine model. Minimum inhibitory concentration (mg/L) ranges were 64–256 for imipenem and 16–128 for meropenem and doripenem. In vitro, imipenem plus meropenem was synergistic against 72% of isolates and doripenem plus meropenem or imipenem against 55% and 45%, respectively. All combinations were synergistic against the ST175, ST235, and ST155 clones. In vivo, meropenem diminished the spleen and blood bacterial concentrations of four and three isolates, respectively, with better efficacy than imipenem or doripenem. The combinations did not show efficacy compared with the more active monotherapies, except for imipenem plus meropenem, which reduced the ST235 bacterial spleen concentration. Mortality decreased with imipenem plus meropenem or doripenem for the ST175 isolate. Results suggest that carbapenem combinations are not an alternative for severe infections by carbapenemase-producing P. aeruginosa. Meropenem monotherapy showed in vivo efficacy despite its high MIC, probably because its dosage allowed a sufficient antimicrobial exposure at the infection sites.

Prevalence of meropenem-resistant Pseudomonas Aeruginosa in Ethiopia: a systematic review and meta‑analysis

“…The global landscape of public health faces a pressing and alarming threat in the form of antimicrobial resistance, a phenomenon that exacts a toll on mortality and morbidity rates, particularly in low- and middle-income countries where diagnostic access is constrained, and regulation of antimicrobial prescription and intake remains insufficiently established [ 2 ]. Within this context, carbapenems emerge as pivotal agents in the treatment of P. aeruginosa infections [ 45 ]. Our understanding deepens as we recognize that no single carbapenem exhibits superiority over another in preventing the emergence of carbapenem resistance [ 46 ].…”

Antibiotic Susceptibility Profile of Clinical Isolate of Carbapenem-Resistant Pseudomonas aeruginosa

“…Recently, it has been described as a pathogen that co-infects patients with COVID-19 [3,4]. The 2016 report by the European Center for Disease Control and Prevention (ECDC) on infections acquired in the ICU in 18 European countries showed that, in 2014, P. aeruginosa was the most common cause of ventilatorassociated pneumonia and the fifth most prevalent in ICU-acquired BSI [5,6]. P. aeruginosa infections are associated with elevated disease burden and mortality rates in the absence of optimal treatment [6,7].…”

“…The 2016 report by the European Center for Disease Control and Prevention (ECDC) on infections acquired in the ICU in 18 European countries showed that, in 2014, P. aeruginosa was the most common cause of ventilatorassociated pneumonia and the fifth most prevalent in ICU-acquired BSI [5,6]. P. aeruginosa infections are associated with elevated disease burden and mortality rates in the absence of optimal treatment [6,7]. The Pseudomonas aeruginosa accessory genome is often composed of genes involved in virulence to human hosts and antimicrobial resistance, resulting in a high risk of mortality and a high rate of multidrug resistance [8].…”

Antibiotic Resistance in Bacterial Pathogens

“…Finally, the development of new therapies, from antibiotic combinations [ 11 , 12 , 13 ] to the development of new antibiotics [ 14 ], is needed to combat AMR.…”