Article

Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity

Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 08/2012; 56(10):5296-302. DOI: 10.1128/AAC.00797-12
Source: PubMed

ABSTRACT

Antistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistant Staphylococcus aureus (MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. An in vitro pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivity in vivo and resulted in clearance of persistent blood cultures. Daptomycin susceptibility in vitro was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Both in vivo- and in vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial in vivo isolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

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    • "In fact, ceftaroline retains potent activity against MRSA even in the presence of reduced vancomycin susceptibility (MIC >2 mg ml –1 ), linezolid resistance (MIC >8 mg ml –1 ) and daptomycin non-susceptibility (MIC >2 mg ml –1 ) (Sader et al., 2013). Several published case reports and series (Ho et al., 2012; Jongsma et al., 2013; Lin et al., 2013; Polenakovik & Pleiman, 2013; Rose et al., 2012) have described the potential utility of ceftaroline as a viable therapeutic option for invasive MRSA infections; however, none of the published literature has included a pregnant patient. "

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    • "Reports of off-label use of ceftaroline are also emerging. Prompt sterilization of blood following the addition of ceftaroline salvage therapy was documented in a review of six cases of persistent or recurrent MRSA bacteremia/endocarditis being treated with vancomycin or daptomycin [87, 88]. Interestingly, the five patients treated with a more aggressive regimen of ceftaroline 600 mg administered every 8 h all survived, while the patient who received ceftaroline every 12 h succumbed to other complications [87]. "
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