Altering the Proclivity towards Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Using Combinations with Other Antibiotics

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Daptomycin (DAP) is increasingly used as a part of combination therapy, particularly in complex methicillin-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Staphylococcus aureus</jats:named-content>(MRSA) infections. While multiple studies have reported the potential for synergy between DAP and adjunctive anti-infectives, few have examined the influence of adjunctive therapy on the emergence of DAP resistance. This study examined eight adjunctive antimicrobial combinations with DAP<jats:italic>in vitro</jats:italic>and the emergence of DAP resistance over time (up to 4 weeks) using clinical isolates of DAP-susceptible MRSA (MIC, 0.5 μg/ml) in which DAP resistance subsequently developed during patient therapy (MIC, 3 μg/ml). In addition to DAP susceptibility testing, selected strains were examined for phenotypic changes associated with DAP resistance, including changes to cell wall thickness (CWT) and cell membrane alterations. The addition of either oxacillin or clarithromycin in medium containing DAP significantly inhibited the development of DAP resistance through the entirety of the 4-week exposure (10- to 32-fold MIC reduction from that of DAP alone). Combinations with rifampin or fosfomycin were effective in delaying the emergence of DAP resistance through the end of week one only (week one MIC, 0.5 μg/ml; week four MIC, 24 μg/ml). Cell wall thickening was observed for all antibiotic combinations regardless of their effect on the DAP MIC (14 to 70% increase in CWT), while changes in cell membrane fluidity were variable and treatment dependent. DAP showed reduced activity against strains with DAP MICs of 1 to 12 μg/ml, but cell membrane integrity was still disrupted at concentrations achieved with doses greater than 10 mg/kg of body weight. The emergence of DAP resistance in MRSA is strongly influenced by the presence of subinhibitory concentrations of adjunctive antimicrobials. These data suggest that combining DAP with oxacillin or clarithromycin may delay the development of DAP resistance in cases requiring prolonged antibiotic therapy.</jats:p>

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

“…An in vitro evaluation of DAP in combination with OXA noted that this regimen prevented the emergence of DAP resistance with prolonged exposure but resulted in significantly thicker cell walls than DAP alone (38). This effect of thickened cell walls but enhanced DAP susceptibility in the presence of antistaphylococcal beta-lactam antibiotics is similar to our current findings with CPT.…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Of interest, the fosfomycin-containing regimens prevented the emergence of daptomycin nonsusceptibility in 2/3 daptomycin-susceptible strains, whereas an increase in MIC was seen with daptomycin alone. Similar effects have been seen in methicillin-resistant S. aureus, where the addition of fosfomycin to daptomycin delayed the emergence of resistance to daptomycin in vitro (43). Fosfomycin exposure appeared to reduce cell surface charge, which suggests that the mechanism of synergy is similar to that seen with beta-lactams and daptomycin against enterococci and Staphylococcus aureus (27,44,45).…”

Daptomycin combinations as alternative therapies in experimental foreign-body infection caused by meticillin-susceptible Staphylococcus aureus

“…By contrast, high doses of DAP alone showed little effect and did not protect against resistance. These results are in line with the risk for emergence of DAP-resistant strains when using it alone even at high doses [28]. In fact, the present results support the current recommendations for using DAP in combination against severe staphylococcal infections, which should include those caused by MSSA strains [10,29,30].…”