Previous studies employing time-kill methods have observed synergistic effects against methicillin-resistant Staphylococcus aureus (MRSA) when a -lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. ) were evaluated in an in vitro pharmacodynamic model with a starting inoculum of 10 6 or 10 8 CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 10 6 CFU/ml studies, combination therapy achieved greater log 10 CFU/ml changes than vancomycin alone at 12 h (؊4.31 ؎ 0.58 versus ؊2.80 ؎ 0.59, P < 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ؎ 14) compared with vancomycin alone (148 ؎ 22, P ؍ 0.017). Similar results were observed during 10 8 CFU/ml studies, where combination therapy achieved greater log 10 CFU/ml changes at 12 h than vancomycin alone (؊4.00 ؎ 0.20 versus ؊1.10 ؎ 0.04, P < 0.001) and significantly reduced the AUBC (275 ؎ 30 versus 429 ؎ 37, P < 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments. Staphylococcus aureus causes serious infections in both the hospital and community settings, and the growing prevalence of methicillin-resistant S. aureus (MRSA) isolates as a cause of these infections has increased the use of glycopeptide antibiotics such as vancomycin. Although vancomycin is almost universally accepted as the drug of choice for the treatment of most MRSA infections, it is less rapidly bactericidal than -lactams against S. aureus, especially at higher inocula (34). Additionally, the recent emergence of decreased vancomycin susceptibility in S. aureus, including isolates with vancomycin MICs of 2 g/ml, heterogenous vancomycin-intermediate S. aureus (hVISA), and vancomycinintermediate S. aureus (VISA), presents a significant clinical problem (26,37,39). Sakoulas and colleagues reported a significant correlation between vancomycin susceptibilities of S. aureus isolates from blood and patient outcomes (29), and some studies revealed that patients infected with MRSA isolates having vancomycin MICs of 1 to 2 g/ml are less likely to be successfully treated with vancomycin than patients infected with isolates demonstrating lower MICs (14,18,21,23,36). Similarly, significantly higher rates of morbidity were observed in patients infected with hVISA and VISA during vancomycin treatment (3,15,16).With few antibiotics historically available to treat MRSA infections, combination therapy with a -lactam and vancomycin has previously been e...
Ceftaroline exhibits in vitro activity against extended-spectrum -lactamase (ESBL)-, AmpC-, and KPCproducing Enterobacteriaceae when combined with the novel -lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against Enterobacteriaceae in a murine thigh infection model.Twelve Enterobacteriaceae isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log 10 CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of <0.015 to 1 g/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to >2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of <1 g/ml and could be useful in combating the growing threat of resistant Enterobacteriaceae.
Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ؎ standard deviations (SD) for the maximum concentration in serum (C max ), the volume of distribution at terminal phase (V z ), and the half-life (t 1/2 ) for linezolid in plasma were 11.99 ؎ 3.67 g/ml,
Enterobacteriaceae producing the novel carbapenemase New Delhi metallo--lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was <8 g/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing Enterobacteriaceae under certain conditions, and this warrants further in vivo exploration.
e Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent-and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced >1-log 10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, >1-log 10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae. New Delhi metallo--lactamase (NDM-1) is a novel carbapenemase that was first identified in a Klebsiella pneumoniae isolate in India in 2008 (1). Since then, it has disseminated at a high rate among Enterobacteriaceae isolates both within the Indian subcontinent and worldwide (2-4). The treatment options for infections caused by NDM-1-producing isolates are extremely limited, as these enzymes are known to hydrolyze penicillins, cephalosporins, and carbapenems while typically retaining susceptibility to only colistin and tigecycline (2), neither of which has been shown to be a dependable option on the basis of in vitro time-kill data and case reports (5-8). Aztreonam is not readily inactivated by metallo--lactamases, including NDM-1, and may represent another potential option for therapy (1, 9). However, NDM-1-producing strains often coproduce other -lactamases, such as CTX-M-and CMY-type enzymes, that possess the ability to hydrolyze aztreonam, further limiting the utility of all -lactam antibiotics (1). Furthermore, in vivo efficacy data evaluating potential treatment options for NDM-1-producing isolates are sparse and clinical experience in treating inf...
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