An inquiry into the virulence, antimicrobial resistance genes, and susceptibility to newer antimicrobials of extremely and pan drug-resistant Gram-Negative Bacilli isolated from urinary tract infections.

Antimicrobial resistance (AMR) among Gram-negative bacilli (GNB) is evolving so rapidly that the specter of the dreaded post-antibiotic era is closer than ever before. Antimicrobial-resistant bacteria contribute significantly to patient morbidity and mortality and rising health care costs. This resistance was initially confined to Pseudomonas and Acinetobacter spp. However, carbapenem and colistin resistance are increasingly observed in members of Enterobacterales family. Much of this is due to spread of Ambler class A (KPC, TEM, CTX-M type ), Class B (MBL- IMP,VIM, NDM type ) and Class D (OXA-48 type) type of resistance to which is now added colistin resistance mediated by mutations in phoPQ, pmr AB, mgrB or mcr A and B.1 OXA-48 is the predominant genotype circulating in Oman. The emergence of carbapenemases and colistin resistance in Gram- negative bacilli has caused global concern among the scientific, medical and public health communities. Both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) consider carbapenem-resistant Enterobacteriaceae (CRE) to constitute a significant threat that necessitates immediate action. Urinary tract infections are one of the leading bacterial infections worldwide and, with escalating AMR, are becoming increasingly difficult to treat. The treatment of choice in such extremely resistant organisms is usually colistin. Recently introduced antimicrobials like cefiderocol, plazomicin and eravacycline, meropenem-vaborbactam need to be tested in Oman against our XDR and PDR isolates and assess the feasibility of their introduction and utility in our region. It is essential to assess the feasibility of these new antibiotics, alone and in combination, to treat carbapenem and colistin-resistant bacteria. Clinical data from prospective, randomized trials are lacking for combination therapy for carbapenem resistant Gram negative bacteria (CRGNB); however, in vitro studies and accumulated retrospective experience suggest that combination therapy, including a carbapenem (eg, polymyxin-carbapenem or aminoglycoside-carbapenem), may have a mortality benefit in both CRGNB and Colistin resistant (CoR) bacteria. Since resistance determinants vary from region to region, it is essential to map these in each area to develop evidence-based prescribing etiquettes. A proactive approach to exploring effective antimicrobial combinations by in vitro synergy should take place at local, regional, national, and international levels to facilitate effective patient management. In this study, we will evaluate the clinical profile, antimicrobial and virulence factors in the region, assess the in-vitro effectiveness of various combinations of colistin and carbapenem with the new antimicrobial agents against CRGNB and CoR clinical isolates of Gram negative bacilli using the checkerboard, time-kill and Etest assays. Whole -genome sequence (WGS) analysis will shed light on the predominant multilocus sequence types circulating in this region and their resistance determinants. Additionally, we will shed light on the bacterial determinants that enable antimicrobials to attain synergy. WGS will enable us to study a large number of resistance determinants like colistin resistance, carbapenem resistance, aminoglycoside and fluoroquinolone resistance. Characterization of antibiotic resistance determinants at the genomic level will play a critical role in understanding and potentially controlling the spread of pan drug -resistant (PDR) pathogens. Of particular concern in not only Oman, but worldwide is the spread of pan drug- resistant strains of Escherichia coli, K. pneumoniae, Acinetobacter baumanii and Pseudomonas aeruginosa. The circulating clonal types of these bacteria will be identified, their movement traced within the hospital. This will help to initiate control and preventive measures. Thus, this study will shed light on synergistic antimicrobial combinations, resistance markers, and dominant MLST types, which will go a long way in optimising patient management and identifying alternate management plans.