Vancomycin in the treatment of methicillin-resistant Staphylococcus aureus – a clinician’s guide to the science informing current practice

Abstract

Clinicians treating an infection assess a patient in terms of disease manifestation, causative organism and available antibiotic options with the aim of devising a therapeutic strategy under the creed of ‘first, do no harm’. It is often only when treatment is failing or options are limited, as in the scenario of multidrug-resistant organisms, that consideration is given to the interplay that occurs between the microbe and the host. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin provides a prime example of these dynamic interactions. This review shall explore these concepts in relation to vancomycin for the treatment of methicillin-resistant S. aureus, with the aim of providing an informed approach to the utilization of this drug.

Keywords:

• antibiotic resistance
• MRSA
• rifampicin
• Staphylococcus aureus
• vancomycin

Financial & competing interests disclosure

BP Howden was supported by an NHMRC Career Development Fellowship (APP1023526). JYH Lee was supported by the Basser Research Entry Scholarship from the Royal Australasian College of Physicians. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Vancomycin remains the first-line drug for the treatment of methicillin-resistant Staphylococcus aureus (MRSA).

• Vancomycin MICs can vary depending on the methodology implemented.

• Vancomycin Etest MIC of >1.5 μg/ml has been demonstrated as an independent predictor of mortality in both MRSA and methicillin-susceptible S. aureus bacteremia, irrespective of antibiotic treatment.

• Heteroresistant vancomycin-intermediate S. aureus (hVISA) isolates have MICs within the susceptible range for vancomycin when tested by routine methods, but possess subpopulations capable of growth within the intermediate range and are associated with glycopeptide treatment failure. Considered a precursor to VISA, their presence should prompt consideration of alterative therapy.

• MRSA resistance mechanisms against vancomycin are complex and pleiotropic, frequently involving mutations in key regulatory loci that can push bacterial evolution toward increased resistance and compensatory mutations that improve survival.

• Persistent infection can promote the development of MRSA resistance against endogenous host defense peptides, which can be associated with cross-resistance with daptomycin and vancomycin.

• Adjuvant use of rifampicin with vancomycin (and daptomycin) is cautioned against. The combination does not protect against the development of rifampicin resistance and a single point mutation in rpoB is sufficient to create high-level rifampicin resistance and a hVISA phenotype.

• The addition of β-lactams to daptomycin for the treatment of MRSA is synergistic and protective against the development of daptomycin resistance. This may also apply for vancomycin, but requires further study.

• Clinical resistance has been reported for all the established alternative agents to vancomycin, plus the newer agent ceftaroline.

• Four new drugs were approved for the treatment of MRSA acute bacterial skin and soft tissue infections in 2014: three lipoglycopeptides that were non-inferior to vancomycin and a linezolid derivative which was non-inferior to linezolid and with a lower rate of hematological side effects.