Novel Antibiotic Combinations of Diverse Subclasses for Effective Suppression of Extensively Drug-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA).

Shumyila Nasir,Saadia Andleeb,Khalid Mehmood,Maira Aleem,Umm E Swaiba,Danish Gul,Muhammad Sufyan Vohra,Faham Khamesipour

doi:10.1155/2020/8831322

Abstract

The emergence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), the chief etiological agent for a range of refractory infections, has rendered all β-lactams ineffective against it. The treatment process is further complicated with the development of resistance to glycopeptides, primary antibiotics for treatment of MRSA. Antibiotic combination therapy with existing antimicrobial agents may provide an immediate treatment option. Minimum inhibitory concentrations (MICs) of 18 different commercially available antibiotics were determined along with their 90 possible pairwise combinations and 64 triple combinations to filter out 5 best combinations. Time-Kill kinetics of these combinations were then analyzed to find collateral bactericidal combinations which were then tested on other randomly selected MRSA isolates. Among the top 5 combinations including levofloxacin-ceftazidime; amoxicillin/clavulanic acid-tobramycin; amoxicillin/clavulanic acid-cephradine; amoxicillin/clavulanic acid-ofloxacin; and piperacillin/tazobactam-tobramycin, three combinations were found to be collaterally effective. Levofloxacin-ceftazidime acted synergistically in 80% of the tested clinical MRSA isolates. First-line β-lactams of lower generations can be used effectively against MRSA infection when used in combination. Antibiotics other than glycopeptides may still work in combination.

Highlights

Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been a predominant agent for skin and nosocomial infections for several years [1,2,3]
Methicillin resistance in Staphylococcus aureus is mediated by SCCmec gene, which encodes polypeptide penicillinbinding-protein 2a (PBP2a) [6, 7] and provides insertion sites for plasmids and transposons which assist in transmission of resistance to non-β-lactam antibiotics [8, 9]
Glycopeptides remain the major class of antibiotics for treatment of MRSA, but indiscriminate use of these antimicrobial agents has led to the emergence of vancomycin-resistant S. aureus (VRSA) [10]

Summary

Introduction

Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been a predominant agent for skin and nosocomial infections for several years [1,2,3]. Methicillin resistance in Staphylococcus aureus is mediated by SCCmec gene, which encodes polypeptide penicillinbinding-protein 2a (PBP2a) [6, 7] and provides insertion sites for plasmids and transposons which assist in transmission of resistance to non-β-lactam antibiotics [8, 9]. Glycopeptides (mainly vancomycin) remain the major class of antibiotics for treatment of MRSA, but indiscriminate use of these antimicrobial agents has led to the emergence of vancomycin-resistant S. aureus (VRSA) [10]. Since other therapeutic interventions such as phage therapies are still in development, antibiotic combination therapy with existing antimicrobial agents provides an immediate treatment option

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Conclusion