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Assessment of In-Vitro Synergy of Fosfomycin with Meropenem, Amikacin and Tigecycline in Whole Genome Sequenced Extended and Pan Drug Resistant <i>Klebsiella Pneumoniae</i>: Exploring A Colistin Sparing Protocol
oleh: Manawr AL-Quraini, Meher Rizvi, Zaaima AL-Jabri, Hiba Sami, Muna AL-Muzahmi, Zakariya AL-Muharrmi, Neelam Taneja, Ibrahim AL-Busaidi, Rajeev Soman
Format: | Article |
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Diterbitkan: | MDPI AG 2022-01-01 |
Deskripsi
Fosfomycin has emerged as a very useful antimicrobial in management of extremely drug resistant (XDR) and pan drug resistant (PDR) <i>Klebsiella pneumoniae</i>. In this study, we assessed in-vitro synergy of colistin sparing combinations of fosfomycin (FOS) with meropenem (MEM), tigecycline (TGC) and amikacin (AK) against XDR and PDR <i>Klebsiella pneumoniae</i>. Method: Non-replicate fully characterised 18 clinical isolates of <i>K. pneumoniae</i> (15 XDR and 3 PDR strains) were subjected to in-vitro synergy testing by checkerboard and time kill assay. Combinations tested were FOS-MEM, FOS-TGC and FOS-AK with glucose-6-phosphate being incorporated in all runs.WGS was carried out on the Illumina next-generation sequencing platform. Results: FOS-MEM and FOS-AK both demonstrated excellent synergy against all PDRs and all but one XDR. Synergy led to lowering of MICs to susceptible breakpoints. FOS-TGC demonstrated antagonism. MLST-231 <i>K. pneumoniae</i> predominated (14), followed by ST-395 (3) and ST147 (1). Majority harboured OXA-232 (n = 15), while n = 2 carried NDM-1 type and n = 1 co-carried NDM-5 + OXA-232. Mortality was high in both ST-231 (57.1%) and ST-395 (66.6%). Synergy was observed despite widespread presence of resistance markers against aminoglycosides [aph(3′)-Ic, aacA4, and rmtf], beta-lactams [blaSHV-11, blaTEM-1b, blaCTX-M-15, and blaOXA-232], fosfomycin [fosA6 and fosA5] and presence of porin proteins OmpK37, OmpA and <i>K. pneumoniae</i> antibiotic efflux pumps Kpn F, H, G, and E. Conclusion: FOS + MEM and FOS + AK are excellent colistin sparing combinations against ST 231, ST-395 and ST-147 XDR and PDR <i>K. pneumoniae</i>. FOS with fewer side effects than colistin, excellent tissue distribution and minimal side effects may be recommended in combination with meropenem.