AUC/MIC Pharmacodynamic Target Is Not a Good Predictor of Vancomycin Efficacy in Methicillin-Resistant Staphylococcus aureus Experimental Endocarditis.

The aim of this in vivo study was to compare the efficacy of vancomycin at standard doses (VAN-SD) to that of VAN at adjusted doses (VAN-AD) in achieving a VAN area under the curve/MIC ratio (AUC/MIC) of ≥400 against three methicillin-resistant Staphylococcus aureus (MRSA) strains with different microdilution VAN MICs in an experimental endocarditis model. The valve vegetation bacterial counts after 48 h of VAN therapy were compared, and no differences were observed between the two treatment groups for any of the three strains tested. Overall, for VAN-SD and VAN-AD, the rates of sterile vegetations were 15/45 (33.3%) and 21/49 (42.8%) (P = 0.343), while the medians (interquartile ranges [IQRs]) for log10 CFU/g of vegetation were 2 (0 to 6.9) and 2 (0 to 4.5) (P = 0.384), respectively. In conclusion, this VAN AUC/MIC pharmacodynamic target was not a good predictor of vancomycin efficacy in MRSA experimental endocarditis.

Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis.

BACKGROUND: Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus bacteremia, and recent data point to a similar effect on methicillin-susceptible S. aureus bacteremia. We aimed to evaluate the effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin. METHODS: We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (<1.5 µg/mL) and high vancomycin MIC (≥1.5 µg/mL). The primary endpoint was in-hospital mortality. RESULTS: We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC < 1.5 µg/mL and 40 (43%) a vancomycin MIC ≥ 1.5 µg/mL. In-hospital mortality was 30% (n = 16/53) in patients with a low vancomycin MIC and 53% (n = 21/40) in those with a high vancomycin MIC (P = .03). No correlation was found between oxacillin MIC and vancomycin or daptomycin MIC. Logistic regression analysis showed that higher vancomycin MIC increased in-hospital mortality 3-fold (odds ratio, 3.1; 95% confidence interval, 1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and nonseptic complicated endocarditis. CONCLUSIONS: Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of antibiotics.

Early in vitro and in vivo development of high-level daptomycin resistance is common in mitis group Streptococci after exposure to daptomycin.

The development of high-level daptomycin resistance (HLDR; MIC of ≥ 256 mg/liter) after exposure to daptomycin has recently been reported in viridans group streptococcus (VGS) isolates. Our study objectives were as follows: to know whether in vitro development of HLDR after exposure to daptomycin was common among clinical isolates of VGS and Streptococcus bovis; to determine whether HLDR also developed during the administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible, penicillin-resistant Streptococcus mitis strain S. mitis 351; and to establish whether combination with gentamicin prevented the development of HLDR in vitro and in vivo. In vitro studies were performed with 114 VGS strains (mitis group, 92; anginosus group, 10; mutans group, 8; and salivarius group, 4) and 54 Streptococcus bovis strains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 h of exposure to daptomycin in 27% of the mitis group, including 27% of S. mitis isolates, 47% of S. oralis isolates, and 13% of S. sanguis isolates. In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 h of daptomycin administered at 6 mg/kg of body weight/24 h and 10 mg/kg/24 h, respectively. In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal against S. mitis 351 at tested concentrations of 0.5 and 1 times the MIC and prevented the development of HLDR. In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequently in vitro and in vivo among mitis group streptococci. Combining daptomycin with gentamicin enhanced its activity and prevented the development of HLDR in most cases.

High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis.

We describe 3 patients with left-sided staphylococcal endocarditis (1 with methicillin-susceptible Staphylococcus aureus [MSSA] prosthetic aortic valve endocarditis and 2 with methicillin-resistant S. aureus [MRSA] native-valve endocarditis) who were successfully treated with high-dose intravenous daptomycin (10 mg/kg/day) plus fosfomycin (2 g every 6 h) for 6 weeks. This combination was tested in vitro against 7 MSSA, 5 MRSA, and 2 intermediately glycopeptide-resistant S. aureus isolates and proved to be synergistic against 11 (79%) strains and bactericidal against 8 (57%) strains. This combination deserves further clinical study.

Daptomycin is effective in treatment of experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus.

Daptomycin is a lipopeptide antibiotic with potent in vitro activity against gram-positive cocci, including Staphylococcus aureus. This study evaluated the in vitro and in vivo efficacies of daptomycin against two clinical isolates: methicillin-resistant S. aureus (MRSA) 277 (vancomycin MIC, 2 microg/ml) and glycopeptide-intermediate S. aureus (GISA) ATCC 700788 (vancomycin MIC, 8 microg/ml). Time-kill experiments demonstrated that daptomycin was bactericidal in vitro against these two strains. The in vivo activity of daptomycin (6 mg/kg of body weight every 24 h) was evaluated by using a rabbit model of infective endocarditis and was compared with the activities of a high-dose (HD) vancomycin regimen (1 g intravenously every 6 h), the recommended dose (RD) of vancomycin regimen (1 g intravenously every 12 h) for 48 h, and no treatment (as a control). Daptomycin was significantly more effective than the vancomycin RD in reducing the density of bacteria in the vegetations for the MRSA strains (0 [interquartile range, 0 to 1.5] versus 2 [interquartile range, 0 to 5.6] log CFU/g vegetation; P = 0.02) and GISA strains (2 [interquartile range, 0 to 2] versus 6.6 [interquartile range, 2.0 to 6.9] log CFU/g vegetation; P < 0.01) studied. In addition, daptomycin sterilized more MRSA vegetations than the vancomycin RD (13/18 [72%] versus 7/20 [35%]; P = 0.02) and sterilized more GISA vegetations than either vancomycin regimen (12/19 [63%] versus 4/20 [20%]; P < 0.01). No statistically significant difference between the vancomycin HD and the vancomycin RD for MRSA treatment was noted. These results support the use of daptomycin for the treatment of aortic valve endocarditis caused by GISA and MRSA.

Epidemiology and prognosis of coagulase-negative staphylococcal endocarditis: impact of vancomycin minimum inhibitory concentration.

This study describes coagulase-negative staphylococcal (CoNS) infective endocarditis (IE) epidemiology at our institution, the antibiotic susceptibility profile, and the influence of vancomycin minimum inhibitory concentration (MIC) on patient outcomes. One hundred and three adults with definite IE admitted to an 850-bed tertiary care hospital in Barcelona from 1995-2008 were prospectively included in the cohort. We observed that CoNS IE was an important cause of community-acquired and healthcare-associated IE; one-third of patients involved native valves. Staphylococcus epidermidis was the most frequent species, methicillin-resistant in 52% of patients. CoNS frozen isolates were available in 88 patients. Vancomycin MICs of 2.0 µg/mL were common; almost all cases were found among S. epidermidis isolates and did not increase over time. Eighty-five patients were treated either with cloxacillin or vancomycin: 38 patients (Group 1) were treated with cloxacillin, and 47 received vancomycin; of these 47, 27 had CoNS isolates with a vancomycin MIC <2.0 µg/mL (Group 2), 20 had isolates with a vancomycin MIC ≥ 2.0 µg/mL (Group 3). One-year mortality was 21%, 48%, and 65% in Groups 1, 2, and 3, respectively (P = 0.003). After adjusting for confounders and taking Group 2 as a reference, methicillin-susceptibility was associated with lower 1-year mortality (OR 0.12, 95% CI 0.02-0.55), and vancomycin MIC ≥ 2.0 µg/mL showed a trend to higher 1-year mortality (OR 3.7, 95% CI 0.9-15.2; P=0.069). Other independent variables associated with 1-year mortality were heart failure (OR 6.2, 95% CI 1.5-25.2) and pacemaker lead IE (OR 0.1, 95%CI 0.02-0.51). In conclusion, methicillin-resistant S.epidermidis was the leading cause of CoNS IE, and patients receiving vancomycin had higher mortality rates than those receiving cloxacillin; mortality was higher among patients having isolates with vancomycin MICs ≥ 2.0 µg/mL.

Success of ampicillin plus ceftriaxone rescue therapy for a relapse of Enterococcus faecalis native-valve endocarditis and in vitro data on double beta-lactam activity.

We report a patient with Enterococcus faecalis native-valve endocarditis who relapsed after 4 weeks of treatment with ampicillin plus gentamicin. The relapse was cured with ampicillin plus ceftriaxone, which was introduced after gentamicin-induced acute renal failure. This double beta-lactam combination showed a bactericidal effect in time-killing curve studies.

Efficacy of telavancin in the treatment of experimental endocarditis due to glycopeptide-intermediate Staphylococcus aureus.

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate Staphylococcus aureus: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 microg/ml and 6 microg/ml, respectively, for telavancin and 46 microg/ml and 6 microg/ml, respectively, for vancomycin. In glycopeptide-intermediate S. aureus ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (P = 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (P = 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation; P = 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation; P = 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate S. aureus.