Efficacy of meropenem and amikacin combination therapy against carbapenemase-producing Klebsiella pneumoniae mouse model of pneumonia

Abstract

Background: The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) is a global health problem due to its high mortality and limited treatment options. Combination antimicrobial therapy is reported to be effective against CRE in vitro; however, its efficacy in vivo has not been thoroughly evaluated. Thus, this study assessed the efficacy of combination therapy of meropenem (MEPM) and amikacin (AMK) in a carbapenem-resistant Klebsiella pneumoniae (CR-Kp) mouse model of pneumonia. Materials and methods: Agar-based bacterial suspension of CR-Kp clinical isolates was inoculated into the trachea of BALB/c mice. Treatment was initiated 6 h post infection, with 100 mg/kg MEPM every 6 h, 100 mg/kg AMK every 12 h, or in combination; survival was evaluated for 7 days. The number of viable bacteria in the lungs, lung histopathology, and neutrophil counts in broncho-alveolar lavage fluid (BALF) were evaluated 42 h after infection. Results: All mice in the untreated control group died in 48 h, while all the mice in treatment groups survived past 7 days following infection. The bacterial count in the lungs (log 10 CFU/mL, mean ± SEM) in the combination group (2.00 ± 0.00) decreased significantly compared to that in control (10.19 ± 0.11, p < 0.0001), MEPM (6.38 ± 0.17, p < 0.0001), and AMK (6.17 ± 0.16, p < 0.0001) groups. BALF neutrophil count reduced only in the combination therapy group. Combination therapy prevented the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. Conclusions: This study demonstrates in vivo efficacy of MEPM and AMK combination therapy against CR-Kp pneumonia.

Bergenin Monohydrate Attenuates Inflammatory Response via MAPK and NF-κB Pathways Against Klebsiella pneumonia Infection

“…Klebsiella pneumonia is a crucial type of bacteria in the genus Klebsiella and accounts for more than 95% of Klebsiella infections ( Raetz et al, 1991 ; Geetha et al, 2020 ; Ota et al, 2020 ). Kp infection is acknowledged to be severe and challenging to treat, causing a high mortality rate.…”

Rapid Detection of Multiple Classes of β-Lactam Antibiotics in Blood Using an NDM-1 Biosensing Assay

“…To verify whether combination with fosfomycin or amikacin interferes with the NDM-1 biosensor in the detection of meropenem, activity responses of the NDM-1 biosensor to meropenem alone and meropenem mixed with fosfomycin or amikacin were compared. The combined antibiotics were prepared with mass ratios of meropenem to fosfomycin and amikacin of 1:4 and 1:1, respectively, as reported previously [28,30]. It was observed that within the concentration range from 12.5 to 200 mg/L, the activity responses of the NDM-1 biosensor to fosfomycin or amikacin were very low, and the correlation of the activity responses with the antibiotic concentrations was not significant for either antibiotic (Supplementary Figure S1A).…”

“…Multiple lines of evidence support that the combination of one β-lactam antibiotic with another antibiotic exhibits synergism in antimicrobial activity in vitro [27]. Moreover, it was reported that combination therapy using carbapenem with fosfomycin, amikacin or another antibiotic has a synergistic effect on the alleviation of lung inflammation and enhancement of survival [28][29][30][31]. To verify whether combination with fosfomycin or amikacin interferes with the NDM-1 biosensor in the detection of meropenem, activity responses of the NDM-1 biosensor to meropenem alone and meropenem mixed with fosfomycin or amikacin were compared.…”

Recurrent emergence of carbapenem resistance in Klebsiella pneumoniae mediated by an inhibitory ompK36 mRNA secondary structure

“…dH2O alone was administered to vehicle control animals. Doses were delivered at 6 hourly intervals as previously employed in a murine carbapenemase producing KP model (Ota et al, 2020). The drug mixture was delivered by intraperitoneal infection (BD Microlance 27G 13mm needles) to animals at 6 hourly intervals and the iliac fossa used was alternated between doses.…”