XDR-Klebsiella pneumoniae isolates harboring bla_OXA-48: In vitro and in vivo evaluation using a murine thigh-infection model

Abstract

Blood stream infection with extensively drug-resistant-carbapenamase producing Klebsiella (K.) pneumoniae usually represents a major threat with medical challenges among hospitalized cancer patients with poor functional status and underlying diseases. Accordingly, the aim of the study was to evaluate the efficacy of different antibiotics either alone or in combinations against extensively drug-resistant-OXA-48 producing K. pneumoniae clinical isolates that were previously recovered from febrile neutropenic pediatric cancer patients. The antimicrobial activity of amikacin, gentamicin, colistin, ertapenem, imipenem, meropenem and tigecycline was assessed by broth microdilution method. The results revealed that all the tested OXA-48 producing K. pneumoniae isolates exhibited extensively drug-resistant phenotype and all of them were susceptible to tigecycline. Checkerboard method was used to determine the fraction inhibitory concentration index, to further classify the effect of antibiotic combination as synergistic, additive, indifferent, or antagonistic effect. The results revealed that in vitro dual carbapenem combination of ertapenem with meropenem had shown synergistic effect against all of the tested isolates. Additionally, synergistic effect of meropenem with colistin was detected among three of four isolates tested. Herein we investigated the in vivo activity of colistin, meropenem alone and in combination in a rat thigh infection model. The results showed that addition of meropenem to colistin was not effective at reduction of bacterial count as compared to colistin alone at 24 h post treatment. Accordingly, we can conclude that in vitro antibiotic combinations of dual carbapenems (ertapenem plus meropenem) and meropenem plus colistin showed synergism in 100% and 75% of the tested isolates, respectively. Colistin alone had significantly reduced bacterial count while its combination with meropenem was not superior to monotherapy in murine thigh infection model. Impact statement The present study aimed to evaluate the effectiveness of various antibiotics both in vitro and in vivo using murine animal model either alone or in combination against various strains of extensively drug-resistant (XDR) Klebsiella pneumoniae, life-threatening pathogens of relevant medical importance isolated from febrile neutropenic pediatric cancer patients. This work also emphasizes how to select the appropriate antibiotics options and help the physicians to choice the appropriate antibiotic for the treatment of such superbugs (extensively drug-resistant (XDR) Klebsiella pneumoniae). The results showed that in vitro dual carbapenem combination of ertapenem with meropenem had shown synergistic effect against all of the tested XDR isolates. Antibiotic combinations of dual carbapenems and meropenem plus colistin showed synergism in 100% and 75% of the testes isolates, respectively. Results of the in vivo evaluation, colistin alone had significantly reduced bacterial count while its combination with meropenem was not superior to monotherapy.

Evaluation of fortimicin antibiotic combinations against MDR Pseudomonas aeruginosa and resistome analysis of a whole genome sequenced pan-drug resistant isolate

“…Briefly, FTM was serially diluted along the abscissa (rows), and the other antibiotic in combination was serially diluted along the ordinate (column). Thereafter, plates were inoculated with adjusted bacterial inoculum (5 × 10 5 CFU/ml) and the fraction inhibitory concentration index (FICI) was determined after overnight incubation of plates at 35 °C [ 21 , 22 ]. Fraction inhibitory concentration (FIC) of each drug was calculated by dividing each drug’s MIC when used in combination by each drug’s MIC when used alone.…”

New Insights on the Carbapenem-resistant Gram Negative-associated-Infections: Challenges and Opportunities

“…It is strongly advised that various antimicrobial combinations with synergistic effects be tested due to the nature of MDR. Combination therapy can also increase effectiveness by broadening its spectrum, reducing resistance, and perhaps even reducing mortality rates [96,97]. The evidence supporting combination therapy versus monotherapy for CR GNB involving Enterobacteriaceae, Pseudomonas, and Acinetobacter spp.…”

Genomic Characterization of Multidrug-Resistant Pathogenic Enteric Bacteria from Healthy Children in Osun State, Nigeria

“…Antimicrobial resistance (AMR) has been established to be a significant driver for the persistence and spread of enteric diseases, particularly in cases where the causative agents are multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens [ 10 , 11 ] as MDR pathogens are known to be non-susceptible to one or more drugs in three antibiotics classes, while XDR pathogens are non-susceptible to at least one drug in all but two or fewer antibiotics classes. The overuse and misuse of antibiotics have been identified as significant causes of AMR in enteric bacteria, as these create selective pressure and promote the emergence of resistance, leading to an alarming increase in the prevalence of MDR enteric bacteria among healthy individuals [ 12 ].…”