Emergence of methicillin-resistant Staphylococcus aureus with intermediate glycopeptide resistance: clinical significance and treatment options.

Methicillin-resistant Staphylococcus aureus is a pathogen that is associated with serious infections that pose a significant risk of morbidity and mortality because of their multidrug resistant nature. Until recently, therapeutic options were limited to vancomycin, making the use of this drug widespread. Unfortunately, the continued application of this drug has led to the emergence of glycopeptide intermediate susceptible S. aureus (GISA). By definition, these organisms demonstrated a vancomycin minimum inhibitory concentration (MIC) of >4 mg/L and <32 mg/L. However, although the mechanism of resistance is not fully elucidated at this time, GISA strains have demonstrated thickened or aggregated cell walls, an increase in penicillin binding proteins and greater autolytic activity. At present, the overall number of reported cases of GISA is relatively low. In most cases, thus far, prolonged courses of vancomycin were reported. A few cases reported monitoring serum vancomycin concentrations but because of limited information, no association with outcome can be made. Whether these GISA strains will become more widespread or evolve into fully glycopeptide resistant strains is unknown at this time. Although there are a number of new agents that possess activity against these pathogens, there is no consensus regarding specific recommendations for treatment. Strict infection control practices, routine screening for resistance and controlled use of antibacterial agents, especially vancomycin, are critical steps in preventing the further development of resistance among staphylococci.

Evaluation of empiric vancomycin therapy in children with fever and neutropenia.

A retrospective evaluation was conducted to determine which children admitted for fever and neutropenia required empiric vancomycin therapy, and to develop a clinical pathway for appropriate treatment. Chart review identified 109 admissions of 36 pediatric oncology patients for fever and neutropenia, of which 88 were eligible for analysis. Blood cultures isolated 17 gram-positive organisms; coagulase-negative staphylococci and viridans group streptococci were cultured most frequently (82%). We concluded that previous high-dose cytarabine therapy, inflamed central access site, and hypotension or septic shock are possible indicators of febrile, neutropenic patients at high risk for gram-positive pathogen isolation. These predictors then were used to determine which children would receive empiric vancomycin therapy.

In vitro activities of daptomycin, arbekacin, vancomycin, and gentamicin alone and/or in combination against glycopeptide intermediate-resistant Staphylococcus aureus in an infection model.

Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus, there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 microgram/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0. 125/0.5, and 0.125/0.25 microgram/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 microgram/ml and 128/128, 0.5/1.0, and 0.25/0.5 microgram/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) (P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth (P

Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations.

Daptomycin is an investigational lipopeptide antibiotic active against gram-positive organisms. The mechanism of action is unique, resulting in interference with cell membrane transport. The bactericidal activity of daptomycin was evaluated against glycopeptide-intermediate susceptible Staphylococcus aureus (GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant S. aureus (MRSA) in an in vitro infection model with simulated endocardial vegetations. Simulated regimens of daptomycin at 6 mg/kg/day (D6) and 10 mg/kg/day (D10) were utilized. MICs and MBCs for daptomycin were determined in the absence and in the presence of albumin with the following results (MIC/MBC): for GISA-992, 0.5/1.0 and 16/16; for VREF-590, 2.0/2.0 and 32/32; and for MRSA-494, 0.25/0.25 and 1.0/4.0 microg/ml, respectively. During the first 8 h daptomycin significantly reduced the inoculum for all organisms. Daptomycin at 6 mg/kg/day and 10 mg/kg/day had log(10) CFU/g reductions of 5 and 6, 3.4 and 5, and 6.4 and 6.5 by 8 h for GISA-992, VREF-590, and MRSA-494, respectively. Against both GISA-992 and VREF-590, the D10 regimen achieved the limit of detection at 72 h, with D6 regimens showing slight regrowth. A concentration-dependent killing effect was noted to occur, with daptomycin demonstrating a more rapid and greater kill from the D10 versus the D6 regimen. The results of this study suggest that daptomycin demonstrates significant (P < 0.05) activity against gram-positive organisms in a simulated sequestered infection site.