Daptomycin or teicoplanin in combination with gentamicin for treatment of experimental endocarditis due to a highly glycopeptide-resistant isolate of Enterococcus faecium

Enterococci are the third most frequent cause of infective endocarditis. A high-inoculum stationary-phase in vitro pharmacodynamic model with simulated endocardial vegetations was used to simulate the human pharmacokinetics of daptomycin at 6 or 10 mg/kg of body weight/day or linezolid at 600 mg every 12 h (q12h), alone or in combination with gentamicin at 1.3 mg/kg q12h or rifampin at 300 mg q8h or 900 mg q24h. Biofilm-forming, vancomycin-susceptible Enterococcus faecalis and vancomycin-resistant Enterococcus faecium (vancomycin-resistant enterococcus [VRE]) strains were tested. At 24, 48, and 72 h, all daptomycin-containing regimens demonstrated significantly more activity (decline in CFU/g) than any linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin to daptomycin (at 6 or 10 mg/kg) in the first 24 h significantly improved bactericidal activity. In contrast, the addition of rifampin delayed the bactericidal activity of daptomycin against E. faecalis, and the addition of rifampin antagonized the activities of all regimens against VRE at 24 h. Also, against VRE, the addition of gentamicin to linezolid at 72 h improved activity and was bactericidal. Rifampin significantly antagonized the activity of linezolid against VRE at 72 h. In in vivo Galleria mellonella survival assays, linezolid and daptomycin improved survival. Daptomycin at 10 mg/kg improved survival significantly over that with linezolid against E. faecalis. The addition of gentamicin improved the efficacy of daptomycin against E. faecalis and those of linezolid and daptomycin against VRE. We conclude that in enterococcal infection models, daptomycin has more activity than linezolid alone. Against biofilm-forming E. faecalis, the addition of gentamicin in the first 24 h causes the most rapid decline in CFU/g. Of interest, the addition of rifampin decreased the activity of daptomycin against both E. faecalis and VRE.

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confidence: 56%

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

Luther

Arvanitis

Mylonakis

et al. 2014

“…This is consistent with the results of previous studies, in which daptomycin was found to be active against GISA isolates. The results of animal model experiments for determination of the efficacy of daptomycin against IE infections caused by enterococci (6,24), as well as S. aureus and MRSA (5,30), have previously been published in the peer-reviewed literature, but there are limited data from animal models on its efficacy against GISA IE infections (23). The present study used a rabbit model simulating human-like PKs to investigate the efficacy of daptomycin against aortic valve IE caused by MRSA or GISA.…”

Section: Discussionmentioning

confidence: 99%

Daptomycin Is Effective in Treatment of Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus

Marco

Mària

Armero

et al. 2008

Methicillin-resistant Staphylococcus aureus (MRSA) strains are common causes of severe community-acquired and health care-associated infections, causing over one-quarter of all cases of S. aureus infective endocarditis (IE) (14). When vancomycin is used to treat IE caused by MRSA, vancomycin may exhibit slow bactericidal activity and diffuse poorly into bacterial vegetations (25,32). Over the years, the use of vancomycin has been associated with treatment failures in patients with IE and bacteremia, even in instances in which the patients' MRSA isolates remained in the susceptible MIC range (15,21). Furthermore, recent studies showed a shift in the vancomycin MIC for MRSA strains from Յ0.5 g/ml to MICs of 1 or 2 g/ml (20, 34). Sakoulas and colleagues found that clinical success correlated with vancomycin MICs: the failure of vancomycin for the treatment of MRSA bacteremia was significantly more likely when the vancomycin MIC was 1 to 2 g/ml than when it was Յ0.5 g/ml (31). Two other studies showed similar results (20,33). Moreover, the emergence of glycopeptideintermediate S. aureus (GISA) and heterogeneous GISA (in addition to vancomycin-resistant S. aureus) strains has mandated the development of alternatives to vancomycin for the clinical care of patients with drug-resistant S. aureus infections (1,10,35,36).Daptomycin is a cyclic lipopeptide antibiotic with rapid bactericidal activity against most antibiotic-resistant gram-positive pathogens in vitro, including GISA and MRSA strains (7,16). It is approved by the FDA and the EMEA for the treatment of complicated skin and skin structure infections and bacteremia, including those involving right-sided IE caused by methicillinsusceptible S. aureus and MRSA strains (Cubicin, daptomycin for injection, package insert, 2006; Cubist Pharmaceuticals, Lexington, MA). A randomized clinical study (13) found that

“…Quantitative autoradiography showed daptomycin to be homogenously distributed throughout the vegetations (8).…”

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confidence: 99%

Daptomycin Concentrations in Valve Tissue and Vegetation in Patients with Bacterial Endocarditis

Tascini

Paolo

Poletti

et al. 2013

In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 g/g, respectively, and 26 g/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 g/g in the valve and 18.1 g/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 (C min and C max , respectively) were collected shortly before and 30 min after drug administration. Every plasma sample (100 l) was added with methanol (200 l) 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 C max /MIC ratio of Ͼ100 or a C max of Ͼ60 mg/liter was used to predict efficacy (4), and a C min of Ͼ24 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 l/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 l) 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 C max and C min at day 5 were 36.6 and 8.5 mg/liter, respectively. The daily dose of daptomycin was increased to 700 mg on da...