Is it time to move away from polymyxins?: evidence and alternatives.

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins 'intermediate' breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2 mg/L, implying limited clinical efficacy even for isolates with the MIC value 2 mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important clinical concern in patients, and is often associated with significant disease burden and metastatic infections. There is an increasing evidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) associated treatment failure. In this study, we aim to understand the molecular mechanism of teicoplanin resistant MRSA (TR-MRSA) and hVISA. A total of 482 MRSA isolates were investigated for these phenotypes. Of the tested isolates, 1% were identified as TR-MRSA, and 12% identified as hVISA. A highly diverse amino acid substitution was observed in tcaRAB, vraSR, and graSR genes in TR-MRSA and hVISA strains. Interestingly, 65% of hVISA strains had a D148Q mutation in the graR gene. However, none of the markers were reliable in differentiating hVISA from TR-MRSA. Significant pbp2 upregulation was noted in three TR-MRSA strains, which had teicoplanin MICs of 16 or 32 µg/ml, whilst significant pbp4 downregulation was not noted in these strains. In our study, multiple mutations were identified in the candidate genes, suggesting a complex evolutionary pathway involved in the development of TR-MRSA and hVISA strains.