Biomedical subjects

M J Rybak

Publications and source records attributed to M J Rybak.

At least 19 recordsLinked to original sources

PubMed2006

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.

Anti-Bacterial Agents↗

PubMed2001

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.

Acetamides↗

PubMed2001

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.

Anti-Bacterial Agents↗

PubMed2001

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.

Anti-Bacterial Agents↗

PubMed2001

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.

Anti-Infective Agents↗

PubMed2001

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.

Journal Article↗

PubMed2001

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.

AIDS-Related Opportunistic Infections↗

PubMed2001

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.

Acinetobacter Infections↗

PubMed2001

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.

Acetamides↗

PubMed2001

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.

Anti-Bacterial Agents↗

PubMed2000

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.

Ampicillin↗

PubMed2000

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.

Anti-Bacterial Agents↗

PubMed2000

Activities of trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin against penicillin-resistant Streptococcus pneumoniae in an in vitro infection model.

We adapted an in vitro pharmacodynamic model of infection to incorporate infected fibrin clots. The bactericidal activities of various fluoroquinolones against two strains of penicillin-resistant Streptococcus pneumoniae were studied over a 48-h period. Bacteria were prepared in Muller-Hinton broth by using colonies from a 24-h tryptic soy agar plus 5% sheep blood plate and were added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 10(6) CFU of organism per fibrin clot. The fibrin clots were suspended into the models and removed, in triplicate, at various time points over 48 h. Control models were also conducted to characterize the growth of S. pneumoniae in the growth medium without antibiotic. Trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were administered to simulate their pharmacokinetic profiles in humans. Fibrin clot samples were also plated onto antibiotic-containing tryptic soy agar plus 5% lysed horse blood to detect resistance. The newer fluoroquinolones demonstrated better activity than ciprofloxacin against both isolates. In conclusion, the newer quinolones demonstrated significant activity against penicillin-resistant S. pneumoniae, with standard dosing resulting in area under the concentration-time curve/MIC ratios and peak concentration/MIC ratios that resulted in 99.9% killing against these isolates.

Anti-Infective Agents↗

PubMed2000

In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains.

The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus (VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing > or =3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

Acetamides↗

PubMed2000

Activities of trovafloxacin and ampicillin-sulbactam alone or in combination versus three strains of vancomycin- intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model.

The recent isolation of clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) with intermediate susceptibility (MICs, 8 microg/ml) to vancomycin (vancomycin-intermediate S. aureus [VISA]) emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment. We studied the activities of ampicillin-sulbactam and trovafloxacin alone or in combination against three unique strains of VISA in an in vitro infection model. Two VISA strains were trovafloxacin susceptible (MICs, < or =2 microg/ml); one VISA strain was trovafloxacin resistant (MIC, 4 microg/ml). Trovafloxacin was administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam was administered to simulate a dose of 3 g every 6 h. Samples were removed from the infection models over 48 h, and reductions in colony counts were compared between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA strain over the 48-h experiment but produced only slight killing of all three VISA strains. The higher dose of trovafloxacin improved killing but did not produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid bactericidal activity against all four strains tested, and colony counts at 8 h were at the limits of detection. However, regrowth occurred by 48 h for each strain. The combination of ampicillin-sulbactam and trovafloxacin provided additive activity against two of the three VISA strains. In conclusion, trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity against the VISA strains for the 48-h evaluation period, but the combination could help improve activity against some strains of VISA.

Ampicillin↗

PubMed2000

Comparison of a rabbit model of bacterial endocarditis and an in vitro infection model with simulated endocardial vegetations.

Animal models are commonly used to determine the efficacy of various antimicrobial agents for treatment of bacterial endocarditis. Previously we have utilized an in vitro infection model, which incorporates simulated endocardial vegetations (SEVs) to evaluate the pharmacodynamics of various antibiotics. In the present study, we compared four experimental rabbit endocarditis protocols to an in vitro infection model in an effort to determine if these models are comparable. We have evaluated the activity of clinafloxacin, trovafloxacin, sparfloxacin, and ciprofloxacin in rabbit models against Staphylococcus aureus and Enterococcus spp. In vitro models were performed simulating the antibiotic pharmacokinetics obtained in the in vivo studies. Models were dosed the same as rabbit models, and SEVs were evaluated at the same time the rabbit vegetations were examined. Clinafloxacin and trovafloxacin were evaluated against methicillin-susceptible (MSSA1199) and -resistant (MRSA494) strains of S. aureus. Ciprofloxacin was studied against MSSA1199 and MSSA487. Sparfloxacin and clinafloxacin were evaluated against Enterococcus faecium SF2149 and Enterococcus faecalis WH245, respectively. We found that reductions in SEV bacterial density obtained in the in vitro model were similar to those obtained in rabbit vegetations, indicating that the SEV model may be a valuable tool for assessing antibiotic potential in the treatment of bacterial endocarditis.

Animal Testing Alternatives↗

PubMed2000

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 </= 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C(max)/MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.

Aminoglycosides↗

PubMed2000

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.

Anti-Infective Agents↗