Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin-Nonsusceptible Strains of Methicillin-Resistant Staphylococcus aureus with Evolving Oxacillin Susceptibility (the “Seesaw Effect”)

Abstract

In vivo development of daptomycin resistance (DAP r ) among Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA) strains, in conjunction with clinical treatment failures, has emerged as a major problem. This has raised the question of DAP-based combination regimens to enhance efficacy against such strains. We studied five recent DAP-susceptible (DAP s )/DAP r clinical MRSA strain pairs obtained from patients who failed DAP monotherapy regimens, as well as one DAP s /DAP r MRSA strain pair in which the resistant strain was generated by in vitro passage in DAP. Of note, we identified a DAP-oxacillin (OX) "seesaw" phenomenon in vitro in which development of DAP r was accompanied by a concomitant fall in OX resistance, as demonstrated by 3-to 4-fold decreases in the OX MIC, a susceptibility shift by population analyses, and enhanced early killing by OX in time-kill assays. In addition, the combination of DAP and OX exerted modest improvement in in vitro bactericidal effects. Using an experimental model of infective endocarditis and two DAP s /DAP r strain pairs, we demonstrated that (i) OX monotherapy was ineffective at clearing DAP r strains from any target tissue in this model (heart valve, kidneys, or spleen) and (ii) DAP-OX combination therapy was highly effective in DAP r strain clearances from these organs. The mechanism(s) of the seesaw effect remains to be defined but does not appear to involve excision of the staphylococcal cassette chromosome mec (SCCmec) that carries mecA.

Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

“…The mechanisms for this are not fully understood, but some ␤-lactams have been observed to increase binding of DAP to bacterial cell membranes (3,4) or to target binding to membrane regions where DAP is most effective (5). This is consistent with reports of a DAP-␤-lactam "seesaw effect," whereby S. aureus frequently gains susceptibility to ␤-lactams upon acquisition of the DAP-nonsusceptible (DNS) phenotype (6). Collectively, these in vitro observations have been translated to antimicrobial therapy combinations to successfully manage difficult-to-treat MRSA infections (1,3,6,7).…”

“…This is consistent with reports of a DAP-␤-lactam "seesaw effect," whereby S. aureus frequently gains susceptibility to ␤-lactams upon acquisition of the DAP-nonsusceptible (DNS) phenotype (6). Collectively, these in vitro observations have been translated to antimicrobial therapy combinations to successfully manage difficult-to-treat MRSA infections (1,3,6,7).…”

Stepwise Decrease in Daptomycin Susceptibility in Clinical Staphylococcus aureus Isolates Associated with an Initial Mutation in rpoB and a Compensatory Inactivation of the clpX Gene

“…We demonstrated that a single mutation in rpoB resulting in an A 477 D substitution in the ␤ subunit of RNA polymerase (RNAP) significantly decreased susceptibility not only to daptomycin but also to vancomycin, ␤-lactams, and rifampin. These results demonstrate that decreased susceptibility to daptomycin is acquired by a pathway conferring high levels of resistance to ␤-lactams, in contrast to other pathways leading to DAP-NS, which have been shown to cause a concomitant fall in ␤-lactam resistance, a phenomenon designated the daptomycin/␤-lactam "seesaw effect" (43). rpoB mutations are common in DAP-NS strains, but to our knowledge, the A 477 D variation has not previously been selected after daptomycin exposure.…”

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

“…Most available data exist on combination therapy with daptomycin and b-lactam antibiotics [95,96]. Oxacillin, in particular, appears to be very efficacious [97,98]. bLactams improve the binding of daptomycin by increasing the net negative charge of the cell membrane [96].…”