Multicenter Study of the Real-World Use of Ceftaroline versus Vancomycin for Acute Bacterial Skin and Skin Structure Infections.

The objective of this study was to determine if real-world ceftaroline treatment in adults hospitalized for acute bacterial skin and skin structure infections (ABSSSI) is associated with decreased infection-related length of stay (LOSinf) compared to that with vancomycin. This was a retrospective, multicenter, cohort study from 2012 to 2017. Cox proportional hazard regression, propensity score matching, and inverse probability of treatment weighting (IPTW) were used to determine the independent effect of treatment group on LOSinf The patients were adults hospitalized with ABSSSI and treated with ceftaroline or vancomycin for ≥72 h within 120 h of diagnosis at four academic medical centers and two community hospitals in Arizona, Florida, Michigan, and West Virginia. A total of 724 patients were included (325 ceftaroline treated and 399 vancomycin treated). In general, ceftaroline-treated patients had characteristics consistent with a higher risk of poor outcomes. The unadjusted median LOSinf values were 5 (interquartile range [IQR], 3 to 7) days and 6 (IQR, 4 to 8) days in the vancomycin and ceftaroline groups, respectively (hazard ratio [HR], 0.866; 95% confidence interval [CI], 0.747 to 1.002). The Cox proportional hazard model (adjusted HR [aHR], 0.891; 95% CI, 0.748 to 1.060), propensity score-matched (aHR, 0.955; 95% CI, 0.786 to 1.159), and IPTW (aHR, 0.918; 95% CI, 0.793 to 1.063) analyses demonstrated no significant difference in LOSinf between groups. Patients treated with ceftaroline were significantly more likely to meet criteria for discharge readiness at day 3 in unadjusted and adjusted analyses. Although discharge readiness at day 3 was higher in ceftaroline-treated patients, LOSinf values were similar between treatment groups. Clinical and nonclinical factors were associated with LOSinf.

Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis.

Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be ß-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs) S. mitis/S. oralis strain and its daptomycin-resistant (DAPr) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAPr variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPs strain following treatment with daptomycin. The parental strain and the DAPr variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPr variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.

Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis.

Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance (Dapr) in enterococci. Daptomycin simulations of 4 to 12 mg/kg/day (maximum concentration of drug in serum [Cmax] of 57.8, 93.9, 123.3, 141.1, and 183.7 mg/liter; half-life [t1/2] of 8 h) were tested against one Enterococcus faecium strain (S447) and one Enterococcus faecalis strain (S613) in a simulated endocardial vegetation pharmacokinetic/pharmacodynamic model over 14 days. Samples were plated on media containing 3× the MIC of daptomycin to detect Dapr. Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in Dapr derivatives. Dapr derivatives were assessed for changes in susceptibility, surface charge, membrane depolarization, cell wall thickness (CWT), and growth rate. Strains S447 and S613 developed Dapr after simulations of 4 to 8 mg/kg/day but not 10 to 12 mg/kg/day. MICs for Dapr strains ranged from 8 to 256 mg/liter. Some S613 derivatives developed mutations in liaF or cls. S447 derivatives lacked mutations in these genes. Dapr derivatives from both strains exhibited lowered growth rates, up to a 72% reduction in daptomycin-induced depolarization and up to 6-nm increases in CWT (P<0.01). Peak/MIC and AUC0-24/MIC ratios (AUC0-24 is the area under the concentration-time curve from 0 to 24 h) associated with Dapr prevention were 72.1 and 780 for S447 and 144 and 1561 for S613, respectively. Daptomycin doses of 10 mg/kg/day may be required to prevent Dapr in serious enterococcal infections.

Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA.

We demonstrated a significant inverse correlation between vancomycin and beta-lactam susceptibilities in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) isolates. Using time-kill assays, vancomycin plus oxacillin or ceftaroline was synergistic against 3 of 5 VISA and 1 of 5 hVISA isolates or 5 of 5 VISA and 4 of 5 hVISA isolates, respectively. Beta-lactam exposure reduced overall vancomycin-Bodipy (dipyrromethene boron difluoride [4,4-difluoro-4-bora-3a,4a-diaza-s-indacene] fluorescent dye) binding but may have improved vancomycin-cell wall interactions to improve vancomycin activity. Further research is warranted to elucidate the mechanism behind vancomycin and beta-lactam synergy.

Independent risk factors for the co-colonization of vancomycin-resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus in the region most endemic for vancomycin-resistant Staphylococcus aureus isolation.

In the majority of cases of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant Enterococcus faecalis (VR E. faecalis) served as the vanA donor to S. aureus. Previous studies that evaluated the risk factors for co-colonization with VRE and MRSA did not differentiate between VR E. faecalis and VR E. faecium. This study aimed to identify variables associated with VR E. faecalis and MRSA co-colonization. A retrospective case-control study from January 2008 to December 2009 was conducted at the Detroit Medical Center. Data were extracted from charts and pharmacy records. Unique patients co-colonized with VR E. faecalis and MRSA (defined as isolation of MRSA within 7 days of VR E. faecalis isolation) were compared with patients with VR E. faecalis who were not co-colonized with MRSA. A total of 546 patients with VR E. faecalis isolation were identified. 85 (15.6 %) VR E. faecalis patients were co-colonized with MRSA and 461 (84.4 %) VR E. faecalis patients were not co-colonized with MRSA. The mean age of the study cohort was 65.9 ± 16.4 years, 424 (77.7 %) were African-American, and 270 (49.5 %) were residing in long-term care institutions. Independent predictors of co-colonization of VR E. faecalis and MRSA were male gender, impaired consciousness, ICU stay prior to VR E. faecalis isolation, indwelling devices, and isolation of VR E. faecalis from wounds. MRSA was frequently isolated from the same culture specimen as VR E. faecalis (n = 39, 45.9 %), most commonly from wounds. This large study of patients with VR E. faecalis identified the severity of illness, indwelling devices, and chronic wounds as independent predictors of co-colonization with VR E. faecalis and MRSA.

Successful treatment of a left ventricular assist device infection with daptomycin non-susceptible methicillin-resistant Staphylococcus aureus: case report and review of the literature.

Recipients of left ventricular assist devices (LVADs) are highly susceptible to the development of infections with multidrug-resistant (MDR) organisms. We describe the case of a patient with an LVAD who developed a device-related, daptomycin non-susceptible, methicillin-resistant Staphylococcus aureus infection, highlighting this patient population as highly vulnerable to the development of such antimicrobial resistance. This report includes a thorough review of the literature on the mechanisms of development of daptomycin non-susceptibility and suggests ways to prevent its emergence. We also provide and underscore the appropriate guidelines to abide by when attempting to control infections with such resistant isolates. This case also demonstrates the importance of definitive treatment with LVAD removal and transplantation as a component of appropriate management of invasive LVAD infections. In addition, we suggest that even infections with MDR organisms may not adversely affect post-transplant outcomes.

The efficacy and safety of daptomycin: first in a new class of antibiotics for Gram-positive bacteria.

In the face of increasing resistance to currently available antibiotics, there is a continued interest in the development of new drugs to treat Gram-positive infections. One such agent is the cyclic lipopeptide daptomycin-licensed in the USA for treatment of Gram-positive complicated skin and skin structure infections (cSSSIs) in 2003 and currently awaiting European approval for a similar indication (complicated skin and soft tissue infections). Daptomycin exerts its rapid bactericidal effect through insertion into and subsequent depolarisation of the bacterial cell membrane, a mode of action unlike that of any other available antibiotic. This novel mechanism of action makes the development of cross-resistance between daptomycin and other antibiotic classes unlikely. Daptomycin is highly active in vitro against a range of Gram-positive pathogens, including both susceptible and multidrug-resistant staphylococci and enterococci. Bactericidal activity has also been demonstrated against both growing and stationary-phase organisms, suggesting potential utility in the treatment of deep-seated infections. Two pivotal clinical studies comparing daptomycin 4 mg/kg per day intravenously with vancomycin or oxacillin-class antibiotics demonstrated the efficacy of daptomycin for treatment of cSSSIs. Daptomycin was well tolerated, with most adverse events considered to be unrelated to study medication, of mild-to-moderate intensity, and with a frequency and distribution similar to those associated with comparator antibiotics. The favourable clinical profile and low potential for development of resistance combine to make daptomycin a promising alternative to current agents for treatment of Gram-positive bacterial infections.

Rhodococcus equi pneumonia in a patient with human immunodeficiency virus: case report and review.

Rhodococcus equi is a facultative, intracellular, gram-positive coccobacillus increasingly reported as an opportunistic pathogen in patients positive for human immunodeficiency virus (HIV). An HIV-positive man developed R. equi pneumonia and sepsis. He failed to improve despite surgical drainage of localized infection and many empiric antibiotics. Time-kill studies of R. equi isolated from the patient were performed against various antimicrobial agents to optimize therapy. Levofloxacin seemed to offer excellent in vitro bactericidal activity. Antagonism was observed with certain antibiotic combinations. Our anecdotal case report suggests that fluoroquinolones such as levofloxacin may offer superior efficacy to standard therapy in rhodococcal infections; their clinical utility deserves further investigation. In view of potential antagonism, prospective susceptibility testing for various drugs and drug combinations should be considered when clinically indicated.

Activities of newer fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae.

The incidence of ciprofloxacin resistance in Streptococcus pneumoniae is low but steadily increasing, which raises concerns regarding the clinical impact of potential cross-resistance with newer fluoroquinolones. To investigate this problem, we utilized an in vitro pharmacodynamic model and compared the activities of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin to that of ciprofloxacin against two laboratory-derived, ciprofloxacin-resistant derivatives of S. pneumoniae (strains R919 and R921). Ciprofloxacin resistance in these strains involved the activity of a multidrug efflux pump and possibly, for R919, a mutation resulting in an amino acid substitution in GyrA. Gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin achieved 99.9% killing of both R919 and R921 in < or =28 h. With respect to levofloxacin, significant regrowth of both mutants was observed at 48 h (P < 0.05). For gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin, regrowth was minimal at 48 h, with each maintaining 99.9% killing against both mutants. No killing of either R919 or R921 was observed with exposure to ciprofloxacin. During model experiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin did not develop but the MICs of ciprofloxacin and levofloxacin increased 1 to 2 dilutions for both R919 and R921. Although specific area under the concentration-time curve from 0 to 24 h (AUC(0--24))/MIC and maximum concentration of drug in serum (C(max))/MIC ratios have not been defined for the fluoroquinolones with respect to gram-positive organisms, our study revealed that significant regrowth and/or resistance was associated with AUC(0-24)/MIC ratios of < or =31.7 and C(max)/MIC ratios of < or =3.1. It is evident that the newer fluoroquinolones tested possess improved activity against S. pneumoniae, including strains for which ciprofloxacin MICs were elevated.

Comparison of length of hospital stay for patients with known or suspected methicillin-resistant Staphylococcus species infections treated with linezolid or vancomycin: a randomized, multicenter trial.

STUDY OBJECTIVE: To compare hospital length of stay (LOS), weekly discharges, and days of antibiotic treatment with linezolid (intravenous with oral follow-up) and vancomycin (intravenous only). DESIGN: Multinational, randomized, phase III trial. SETTINGS: Hospitals in North America, Latin America, and Europe. PATIENTS: Four hundred sixty hospitalized patients with infections of known or suspected methicillin-resistant Staphylococcus species. INTERVENTION: Administration of linezolid or vancomycin. MEASUREMENTS AND MAIN RESULTS: For linezolid recipients, median LOS was 5 and 8 days shorter (p=0.05 and 0.003) in the complicated skin and soft tissue infection intent-to-treat (230 patients) and clinically evaluable (144) samples, and slightly but not significantly shorter in the overall intent-to-treat (460) and clinically evaluable (254) samples. In all samples, linezolid recipients had more discharges in the first week of treatment and fewer days of intravenous therapy than vancomycin recipients. CONCLUSION: Our results support linezolid's ability to reduce medical resource use.

Epidemiology, resistance, and outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam.

STUDY OBJECTIVE: To evaluate epidemiology, resistance, and treatment outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam for 72 hours or longer. DESIGN: Retrospective analysis. SETTING: University teaching hospital. PATIENTS: Forty-eight patients with A. baumannii bacteremia. INTERVENTION: Evaluation of susceptibility and clinical data from 48 patients treated with either ampicillin-sulbactam or imipenem-cilastatin from 1987-1999. MEASUREMENTS AND MAIN RESULTS: Comparing ampicillin-sulbactam and imipenem-cilastatin, there were no differences between days of bacteremia (4 vs 2 days, p=0.05), days to resolution of temperature or white blood cell count, success or failure during or at end of treatment, or intensive care unit total or antibiotic-related length of stay (13 vs 10 days, p=0.05). Patients treated with ampicillin-sulbactam had significantly decreased antibiotic treatment costs (1500 dollars vs 500 dollars, p=0.004). CONCLUSION: Ampicillin-sulbactam is at least as effective as imipenem-cilastatin based on clinical response at days 2, 7, and end of treatment and is a cost-effective alternative for treatment of A. baumannii infections.

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.

Activity of oritavancin (LY333328), an investigational glycopeptide, compared to that of vancomycin against multidrug-resistant Streptococcus pneumoniae in an in vitro pharmacodynamic model.

In the past 2 decades, multidrug-resistant Streptococcus pneumoniae has been encountered with increasing frequency around the world. This has led to the need for newer agents in the treatment of S. pneumoniae infections. Oritavancin (LY333328) is a new glycopeptide antibiotic with activity against gram-positive organisms; however, there is limited information on the pharmacodynamics of oritavancin with respect to the treatment of S. pneumoniae. We utilized an in vitro pharmacodynamic model to compare the activity of oritavancin to that of vancomycin against two penicillin-, macrolide-, and ciprofloxacin-resistant S. pneumoniae isolates (R919 and R921) over a 48-h period. Both oritavancin and vancomycin achieved 99.9% (3-log) kill, with oritavancin achieving the limit of detection (10(2) CFU/ml) within 1 h and vancomycin achieving this limit at 24 h for both isolates. Detection of resistance was not observed for oritavancin or vancomycin during the 48-h experiments. The key pharmacodynamic parameter for oritavancin has not been well defined. In our experiment, the ratios of the area under the curve from 0 to 24 h to the MIC of oritavancin, oritavancin plus albumin, and vancomycin for both isolates were greater than 944.5, and the ratios of the maximum concentration of drug in serum to the MIC ranged from 73.7 to 7188.5. T>MIC was 100% for oritavancin and vancomycin for both isolates. Oritavancin is a unique and potent antimicrobial that warrants further investigation against multidrug-resistant S. pneumoniae.

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.

Therapeutic options for Gram-positive infections.

Gram-positive infections impose a major burden on patients and the healthcare systems globally. The need to treat these infections correctly in an empirical fashion is of paramount importance. Further complicating this changing aetiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus new agents such as linezolid have been developed to assist with initial empirical prescribing in infections where Gram-positive pathogens may be present. The characteristics of linezolid, including spectrum of activity, pharmacodynamic profile, tolerablility and overall efficacy should strengthen confidence when considering initial antimicrobial therapy in patients in risk areas. Future agents also being developed to fight multi-resistant Gram-positive infections include oritavancin, daptomycin and the glycylcyclines; however, these are still in the development phase.

Oxazolidinones: new players in the battle against multi-resistant Gram-positive bacteria.

For many years the pharmaceutical industry did not pursue the development of antimicrobial agents that specifically targeted Gram-positive bacteria. Semi-synthetic penicillins and vancomycin were the mainstays of therapy for methicillin-susceptible and -resistant strains of staphylococci, respectively, as was penicillin for Streptococcus pneumoniae and beta-lactam-aminoglycoside combinations for serious enterococcal infections. In the 1980s enterococci resistant to glycopeptides emerged, followed shortly thereafter by a dissemination of penicillin-insensitive S. pneumoniae and, more recently, the occurrence of vancomycin-intermediately susceptible Staphylococcus aureus. The emergence of fully glycopeptide-resistant S. aureus is clearly on the horizon. Multi-resistant Gram-positive bacteria now pose an important therapeutic challenge for clinicians. New drugs with activity against some of these dangerous pathogens have recently been pursued, and linezolid, the first member of the oxazolidinone class, has now been licensed for clinical use in many countries. This drug has excellent in vitro and in vivo activity against all clinically relevant multi-resistant Gram-positive cocci and fills an important void in infectious disease chemotherapy.

Activities of LY333328 and vancomycin administered alone or in combination with gentamicin against three strains of vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model.

Staphylococcus aureus with intermediate glycopeptide susceptibility (glycopeptide-intermediate S. aureus [GISA]) has been isolated from patients with apparent therapy failures. We studied the killing activity of vancomycin over a range of simulated conventional doses (1 to 1.5 g every 12 h) against three of these GISA strains in an in vitro pharmacodynamic infection model. We also studied the activity of a new glycopeptide (LY333328) at a simulated dose of 3 mg/kg of body weight every 24 h or 5 mg/kg every 24 h, as well as the potential for vancomycin and gentamicin synergy against these GISA strains. Four doses of vancomycin with or without gentamicin or two doses of LY333328 were administered over the 48-h study period. The vancomycin and LY333328 MICs and minimal bactericidal concentrations (MBCs) for the three GISA strains (strains 14379, 992, and Mu50) were 8 and 8 microgram/ml and 1 and 2 microgram/ml, respectively, for GISA 14379, 6 and 6 microgram/ml and 1 and 1 microgram/ml, respectively, for GISA 992, and 8 and 12 microgram/ml and 2 and 8 microgram/ml, respectively, for GISA Mu50. Vancomycin and LY333328 MICs and MBCs were 0.75 and 1.0 microgram/ml and 1 and 1 microgram/ml, respectively for a vancomycin-susceptible comparator strain (methicillin-resistant S. aureus [MRSA] 494). The addition of albumin to the growth medium increased the LY333328 MICs and MBCs approximately 8- to 16-fold. Vancomycin was bacteriostatic against the three GISA strains at doses of 1, 1.125, and 1.25 g every 12 h. Vancomycin was bactericidal at the dose of 1.5 g every 12 h against all strains; bactericidal activity occurred against the GISA strains at 8- to 10-fold lower ratios of the peak concentration to the MIC and the area under the concentration-time curve from time zero to 24 h (AUC(0-24)) to the MIC compared to those for the vancomycin-sensitive control strain. Overall, vancomycin activity was significantly correlated with the AUC(0-24) (R(2) = 0.79; P < 0.001) by multiple stepwise regression analyses. The addition of gentamicin did not significantly affect killing activity against any strain. LY333328 was bactericidal against GISA strains 14379 and 992 and against MRSA 494 only with the 5-mg/kg/day dose simulations. The higher dose of LY333328 also prevented regrowth over the 48-h experiments for all strains tested. Higher doses of vancomycin (1.5 g every 12 h) and LY333328 (5 mg/kg every 24 h) may represent potential treatment options for infections caused by GISA strains.

Once-daily aminoglycoside in the treatment of Enterococcus faecalis endocarditis: case report and review.

Once-daily administration of aminoglycosides (ODA) is effective and safe for many indications. By optimizing pharmacodynamic principles, it enhances bactericidal activity and minimizes toxicity. Its use for the treatment of enterococcal infection is controversial, however, and results of in vitro studies and animal models of endocarditis are conflicting. To date, no case reports or clinical trials have examined its utility in human enterococcal endocarditis. A patient with right-sided endocarditis caused by Enterococcus faecalis was managed by once-daily gentamicin. Clinical and bacteriologic cures of this patient raise questions as to whether enterococcal endocarditis should be regarded as contraindication to ODA. The clinical utility of ODA in this disease deserves further investigation.

Influence of platelets and platelet microbicidal protein susceptibility on the fate of Staphylococcus aureus in an in vitro model of infective endocarditis.

Several lines of evidence indicate that platelets protect against endovascular infections such as infective endocarditis (IE). It is highly likely that a principal mechanism of this platelet host defense role is the release of platelet microbicidal proteins (PMPs) in response to agonists generated at sites of endovascular infection. We studied the ability of platelets to limit the colonization and proliferation of Staphylococcus aureus in an in vitro model of IE. Three isogenic S. aureus strains, differing in their in vitro susceptibility to thrombin-induced platelet microbicidal protein-1 (tPMP), were used: ISP479C (parental strain; highly susceptible to tPMP [tPMP(s)]); ISP479R (transposon mutant derived from ISP479; tPMP resistant [tPMP(r)]); or 757-5 (tPMP(r) transductant of the ISP479R genotype in the ISP479 parental background). Time-kill assays and in vitro IE models were used to examine the temporal relationship between thrombin-induced platelet activation and S. aureus killing. In time-kill studies, early platelet activation (30 min prior to bacterial exposure) correlated with a significant bactericidal effect against tPMP(s) ISP479C (r(2) > 0.90, P < 0.02) but not against tPMP(r) strains, ISP479R or 757-5. In the IE model, thrombin activation significantly inhibited proliferation of ISP479C within simulated vegetations compared to strains ISP479R or 757-5 (P < 0.05). The latter differences were observed despite there being no detectable differences among the three S. aureus strains in initial colonization of simulated vegetations. Collectively, these data indicate that platelets limit intravegetation proliferation of tPMP(s) but not tPMP(r) S. aureus. These findings underscore the likelihood that platelets play an important antimicrobial host defense role in preventing and/or limiting endovascular infections due to tPMP(s) pathogens.

Pharmacodynamics of vancomycin and ampicillin alone and in combination with gentamicin once daily or thrice daily against Enterococcus faecalis in an in vitro infection model.

We compared the pharmacodynamic activities of vancomycin and ampicillin with or without gentamicin once daily or thrice daily in an in vitro infection model with fibrin-platelet clots (FPCs) infected with Enterococcus faecalis. Antibiotics were administered as a bolus to simulate human pharmacokinetics with regimens consisting of vancomycin 1 g q12h, ampicillin 2 g q6h and gentamicin 1.3 mg/kg q8h and 5 mg/kg qd. Model experiments were performed in duplicate over 72 h. FPCs were removed from the models in triplicate at 0, 8, 24, 32, 48 and 72 h, weighed, homogenized, diluted and plated to determine colony counts. Additional FPCs were removed at over 72 h post-antibiotic dose to determine antibiotic concentrations. The inoculum density at 72 h was used to compare bactericidal activity between the regimens. Overall, all antibiotic regimens containing either ampicillin or vancomycin significantly (P < 0.01) decreased the bacterial load at 72 h compared with the growth control although monotherapy regimens with either vancomycin or gentamicin had little impact. Ampicillin was superior to vancomycin with or without the addition of gentamicin (P < 0.01). There were no significant differences in reduction of bacterial density at 72 h between the combination of ampicillin or vancomycin plus gentamicin q8h and ampicillin or vancomycin plus gentamicin once daily. This was despite achieving unmeasurable FPC gentamicin concentrations after the 8 h time point during the once-daily aminoglycoside regimen. Vancomycin plus gentamicin either every 8 h or once daily was significantly (P < 0.01) better than vancomycin alone. Ampicillin plus either of the two gentamicin regimens was also better than ampicillin alone but this did not reach statistical significance. Our data suggest that once-daily gentamicin in combination with ampicillin or vancomycin demonstrates equivalent bacterial reductions to combination therapy with thrice-daily gentamicin. Once-daily aminoglycoside combination therapy for the treatment of enterococcal endocarditis warrants further investigation.