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In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 μg/g, respectively, and 26 μg/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 μg/g in the valve and 18.1 μg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase.
Daptomycin concentrations were measured in plasma, valve tissues, and vegetations obtained from 2 patients with bacterial endocarditis requiring surgery. Diagnosis of endocarditis was done according to the Duke criteria (1). The blood culture system used was Bactec 9240 (Becton, Dickinson, Milano, Italy). Tissues and vegetations were cultured directly on solid media (chocolate agar, MacConkey agar, mannitol salt agar, and Sabouraud agar). Microorganisms were identified by an automated system (API, Bio-Merieux, Marcy L'Etoile, France).
Daptomycin susceptibility was determined by the Etest method (AB-Biodisk, Solna, Sweden). Resistance phenotype was classified according to the breakpoints indicated by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2).
Daptomycin (dose range, 500 to 700 mg/day) was administered intravenously over a 2-min period. Blood samples for the measurement of minimum and maximum drug plasma concentrations (Cmin and Cmax, respectively) were collected shortly before and 30 min after drug administration. Every plasma sample (100 μl) was added with methanol (200 μl) and centrifuged, and the clear supernatant was analyzed. A validated high-performance liquid chromatographic (HPLC) method was applied to measure plasma concentrations of daptomycin (3). A target value of a Cmax/MIC ratio of >100 or a Cmax of >60 mg/liter was used to predict efficacy (4), and a Cmin of >24 mg/liter was considered predictive of toxicity (5).
Portions of surgically removed valve tissues and mitral vegetation were weighted and disrupted in cold phosphate-buffered saline (500 μl/sample) using a refrigerated ground-glass pestle. Homogenized samples were then collected in Eppendorf tubes and centrifuged for 15 min at 12,000 rpm and 4°C (Sigma 1K15 centrifuge). For every sample, clear supernatant (100 μl) was processed as described above for plasma samples and finally analyzed using the available HPLC method (3).
A 61-year-old male (body weight, 72 kg) was diagnosed with a mitro-aortic native-valve Streptococcus oralis endocarditis. Transthoracic echocardiography (TTE) revealed two vegetations on the mitral (25 by 12 mm) and aortic (8 by 6 mm) valves, respectively. Daptomycin (500 mg/day intravenously [IV]) was empirically started and continued because of its favorable Streptococcus oralis MIC (0.094 mg/liter). Daptomycin Cmax and Cmin at day 5 were 36.6 and 8.5 mg/liter, respectively. The daily dose of daptomycin was increased to 700 mg on day 7, and at day 15, Cmax and Cmin increased to 81.8 and 14.8 mg/liter, respectively.
Despite rapid defervescence and persistently negative blood cultures, TTE documented an increase in mitral valve vegetation (30 by 14 mm) with severe mitral regurgitation.
The patient underwent surgical replacement of mitral and aortic valves with mechanical prostheses. Daptomycin concentrations in the aortic and mitral valves were 8.6 and 30.8 μg/g of tissue, respectively, and 26.0 μg/g in the mitral vegetation. The vegetation culture grew Streptococcus oralis with a MIC of up to 0.38 mg/liter. The patient was treated with IV ceftriaxone at 2 g/day for 30 days (MIC, 0.016 mg/liter), and at the 6-month follow-up visit, he was considered cured.
The second patient was a 69-year-old male (body weight, 70 kg) with an early methicillin-resistant Staphylococcus epidermidis endocarditis on a Carpentier-Edwards aortic porcine bioprosthesis. Several blood cultures were positive for S. epidermidis (MIC for daptomycin, 0.38 mg/liter), but no vegetations were documented upon examination by either TTE or transesophageal echocardiography (TEE). Daptomycin (500 mg/daily) was administered IV. At day 5, Cmax and Cmin were 45.3 and 9.9 mg/liter, respectively. Daptomycin was administered for 30 days until the patient's discharge. Four weeks later, the patient was readmitted for relapsing fever; blood cultures were negative, but TEE revealed a para-aortic prosthetic abscess. Daptomycin (500 mg/day) was empirically started again, and the patient underwent prosthetic aortic valve replacement. Cultures of aortic root abscess and aortic graft tissue were negative. Biomolecular analysis (FISH [fluorescence in situ hybridization] and PCR sequencing [6, 7]) of valve samples was also negative. Daptomycin concentrations were 53.1 and 18.1 μg/g of tissue in the prosthetic aortic valve and in the perivalvular tissue, respectively. Daptomycin was continued for 10 weeks, and the patient was considered cured after 6 months of follow-up.
The main clinical, microbiological, and pharmacokinetic/pharmacodynamic (PK/PD) data from the two reported cases are summarized in Table 1.
To our knowledge, these are the first data reporting daptomycin cardiac valve concentrations in patients treated for bacterial endocarditis.
In an experimental rabbit model of endocarditis due to vancomycin-resistant Enterococcus faecium, daptomycin concentrations in cardiac vegetations were directly related to the dose: 11.6 ± 10.8 μg/g of tissue with 10 mg/kg twice a day and 22.5 ± 1.4 μg/g of tissue with 12 mg/kg three times a day. Quantitative autoradiography showed daptomycin to be homogenously distributed throughout the vegetations (8).
Our data seem to deserve some comments and considerations.
The direct relationship between daptomycin dose and serum levels does not appear to be confirmed for concentration in infected cardiac tissue and vegetation.
The different microbiological outcomes observed in these two patients may be related to the presence and size of vegetation (larger bacterial inoculum). The activity of daptomycin against viridans group streptococci seems to be variable: in a large survey of blood isolates, the only resistant strain was a strain of S. oralis (MIC, 2 mg/liter) (9); accordingly, in our case we observed a 4-fold increase of the daptomycin MIC for S. oralis during treatment and lack of valve sterilization.
Daptomycin confirmed its efficacy and bactericidal effect in endocarditis due to S. epidermidis. Daptomycin was in fact more effective than vancomycin in reducing the bacterial density in valve vegetations in an experimental model of endocarditis due to methicillin-resistant and glycopeptides-intermediate S. epidermidis (10).
More data on the penetration of antimicrobials in vegetations and valve tissues and its correlation with clinical efficacy are needed to optimize the management of bacterial endocarditis.
In the past 2 years, C.T. has been paid for lectures on behalf of Pfizer, Novartis, Merck, and Astellas.
Published ahead of print 22 October 2012