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

• Main Authors: Soraya Herrera-Espejo (Author), Ester Del Barrio-Tofiño (Author), Tania Cebrero-Cangueiro (Author), Carla López-Causapé (Author), Rocío Álvarez-Marín (Author), José Miguel Cisneros (Author), Jerónimo Pachón (Author), Antonio Oliver (Author), María Eugenia Pachón-Ibáñez (Author)
• Format: Book
• Published: MDPI AG, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics11091212; 2079-6382
• Keywords: carbapenemase-producing <i>Pseudomonas aeruginosa</i>; doripenem; efficacy studies; imipenem; meropenem; murine sepsis model; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 11, Iss 9, p 1212 (2022)

In the context of difficult-to-treat carbapenem-resistant <i>Pseudomonas aeruginosa</i> infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven carbapenemase-producing <i>P. aeruginosa</i> 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 <i>P. aeruginosa</i>. Meropenem monotherapy showed in vivo efficacy despite its high MIC, probably because its dosage allowed a sufficient antimicrobial exposure at the infection sites.