Biomedical subjects

Michael J Rybak

Publications and source records attributed to Michael J Rybak.

At least 19 recordsLinked to original sources

PubMed2004

Pulsatile delivery of amoxicillin against Streptococcus pneumoniae.

OBJECTIVE: Beta-Lactam antimicrobials are dosed intermittently or continuously based on their short half-lives and concentration-independent activity. Based on the relationship between antimicrobial killing and bacterial growth cycle, the pharmacodynamics of a unique pulsatile strategy was investigated. METHODS: In vitro pharmacodynamic models with initial inocula of 6 log(10) cfu/mL were utilized to simulate amoxicillin regimens against two Streptococcus pneumoniae isolates: 16891 (MIC = 4 mg/L) and ATCC 49150 (MIC = 0.016 mg/L). Time-kill profiles of pulsatile dosing of amoxicillin (total daily dose fractionated equally and given at 0, 2, 4 and 6 h for each 24 h cycle) were compared with regimens of every 8 h and every 12 h with the same 24 h drug exposure. Each regimen targeted cumulative peak concentrations of 30, 15 and 5 mg/L for each 24 h cycle. A t(1/2) of 1 h was simulated for all experiments. Bacterial density was quantified over 96 h. RESULTS: Against 16891, every 8 h and every 12 h regimens exhibited minimal bacterial kill at all dosing levels. In contrast, pulsatile dosing at 30 mg/L/24 h resulted in an initial modest approximately 1 log(10) cfu/mL kill with regrowth to growth control levels at 24 h but was immediately followed by a rapid approximately 2 log(10) cfu/mL kill by 32 h. This pattern of kill and regrowth repeated at the same magnitude for each 24 h cycle for the 96 h study duration. Against the susceptible strain (ATCC 49150), both pulse and traditional dosing of amoxicillin resulted in rapid and significant kill to our detection limits for the entire study duration. A pattern of kill and regrowth was only observed at the lowest dose (0.05 mg/L) against ATCC 49150. At therapeutic levels, all regimens rapidly achieved undetectable limits against this strain for the study duration. No significant alterations in post-exposure MICs were noted. Overall bacterial density reduction was similar between the regimens for the susceptible isolate and greater with pulsatile regimens against the less susceptible strain. CONCLUSION: Pulsatile dosing, which involves administration of the total daily dose over the first 6 h of the day, may represent a unique and alternative strategy for dosing beta-lactam antimicrobials.

Amoxicillin↗

PubMed2004

The importance of bactericidal drugs: future directions in infectious disease.

BACKGROUND: Although a considerable amount of research has gone into the study of the role of bactericidal versus bacteriostatic antimicrobial agents in the treatment of different infectious diseases, there is no accepted standard of practice. METHODS: A panel of infectious diseases specialists reviewed the available literature to try to define specific recommendations for clinical practice. RESULTS: In infections of the central nervous system, the rapidity with which the organism is killed may be an important determinant, because of the serious damage that may occur during these clinical situations. The failure of bacteriostatic antibiotics to adequately treat endocarditis is well documented, both in human studies and in animal models. CONCLUSION: The bulk of the evidence supports the concept that, in treating endocarditis and meningitis, it is important to use antibacterial agents with in vitro bactericidal activity. This conclusion is based on both human and animal data. The data to support bactericidal drugs' superiority to bacteriostatic drugs do not exist for most other clinical situations, and animal models do not support this concept in some situations. Clinicians should be aware that drugs that are bacteriostatic for one organism may in fact be bactericidal for another organism or another strain of the same organism.

Animals↗

PubMed2004

Increased bacterial resistance: PROTEKT US--an update.

Community-acquired respiratory tract infections (CARTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis, remain substantial sources of morbidity and mortality in the US. The increasing prevalence of antimicrobial-resistant strains among the common respiratory pathogens, particularly Streptococcus pneumoniae, has complicated the choice of antimicrobials and threatens the efficacy of treatment for CARTIs. This highlights the need both for ongoing surveillance efforts to track current resistance patterns and for the development of new antimicrobial agents effective against resistant organisms. To provide current and ongoing antimicrobial resistance surveillance data, including comparisons of telithromycin (the first ketolide to undergo clinical development and be approved by the Food and Drug Administration) with other agents, a longitudinal global surveillance study--Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT)--was launched in 1999. A US component of this study was initiated in 2000, and results from the first respiratory infection tracking season (2000-2001) are discussed in this article. Providing resistance data on the national, regional, and local levels, PROTEKT US has thus far confirmed the increasing prevalence of resistant S. pneumoniae isolates to beta-lactams and macrolides, as well as the emergence of fluoroquinolone resistance in the US. Importantly, telithromycin was highly active against S. pneumoniae, including resistant isolates.

Community-Acquired Infections↗

PubMed2004

Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model.

OBJECTIVE: Daptomycin exhibits bactericidal activity against clinically significant Gram-positive bacteria despite being highly bound to human proteins. Evaluations characterizing the effect of protein on daptomycin pharmacodynamics are warranted. METHODS: We utilized an in vitro pharmacodynamic model to simulate daptomycin regimens of 6 mg/kg/day under controlled conditions of pH, calcium and/or protein. Free concentrations were simulated in broth, whereas total concentrations were simulated in broth supplemented with human albumin. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA) and two vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. RESULTS: Daptomycin exhibited bactericidal activity against both MRSA isolates, with time to 99.9% killing occurring at 0.5 h and 8 h in broth and in albumin-supplemented broth, respectively. Initial kill was observed against both VREF isolates followed by regrowth. There was no statistical difference (P>0.05) in extent of bacterial kill at 24 or 48 h between the different media. CONCLUSIONS: Although delayed, the extent of kill for daptomycin was unaltered against all isolates in albumin-supplemented broth. Further antimicrobial studies that incorporate protein are warranted to assess the influence of protein in the pharmacodynamic evaluation of antimicrobials.

Anti-Bacterial Agents↗

PubMed2004

Clinical glycopeptide-intermediate staphylococci tested against arbekacin, daptomycin, and tigecycline.

We examined the activity of arbekacin, daptomycin, tigecycline, and vancomycin against various Staphylococci isolates with glycopeptide-intermediate (n = 25) and heterogeneous susceptibilities (n = 22) (GISS and hGISS). The minimum inhibitory concentrations (MIC) of each antimicrobial was evaluated in time-kill experiments by using 4 randomly selected GISS isolates tested at 2 and 4 times their respective MIC. The MIC(90) microg/mL ranges for arbekacin, daptomycin, tigecycline, and vancomycin were 2 (0.25-4), 1 (0.0625-2), 0.5 (0.0625-2), and 8 (4-8), respectively. Time kill at 2 times the MIC demonstrated a mean log(10) colony forming units (CFU)/mL change of -2.98 +/- 0.708, -3.6 +/- 0.509, -2.48 +/- 0.647, and +1.14 +/- 0.1 arbekacin, daptomycin, tigecycline, and vancomycin, respectively. At 4 times the MIC, significant activity for all compounds was noted with a log(10) CFU/mL decrease range from 3.68 to 2.74 +/- 0.66. Overall, all the antimicrobials tested (with the exception of vancomycin) exhibited significant in vitro activity against GISS. These compounds may offer therapeutic options for the treatment of GISS.

Aminoglycosides↗

PubMed2004

In vitro activities of mutant prevention concentration-targeted concentrations of fluoroquinolones against Staphylococcus aureus in a pharmacodynamic model.

To test the validity of the mutant selection window, we simulated mutant prevention concentration-targeted fluoroquinolone concentrations using an in vitro model with infected fibrin clots. Therapeutic ciprofloxacin (peak 5 microg/mL; t(1/2) 4 h), gatifloxacin (3.5 microg/mL; 8h), gemifloxacin (1.25 microg/mL; 8 h), levofloxacin (6 microg/mL; 6 h) and moxifloxacin (4.5 microg/mL; 12 h) were tested against methicillin-susceptible and -resistant Staphylococcus aureus, as were mutant prevention concentration (MPC)-targeted regimens achieving a trough of 1/4x or 2x MPC. MIC/MPC for MSSA K553 were 0.125/2, 0.03/0.125, 0.03/0.063, 0.125/1 and 0.015/0.25 microg/mL for ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, respectively. Corresponding values for MRSA 494 were 0.125/1, 0.063/0.125, 0.03/0.063, 0.125/0.5 and 0.063/0.125 microg/mL. All regimens produced efflux mutants of MSSA K553. For MRSA 494, therapeutic and 1/4x MPC levofloxacin regimens produced resistance, whereas only 1/4x MPC regimens of gatifloxacin, gemifloxacin, and moxifloxacin produced resistance. All ciprofloxacin regimens produced resistance. Ciprofloxacin 1/4x MPC and therapeutic levofloxacin caused outgrowth of GrlA mutants (S80Y amino acid substitution); efflux mutants were isolated in all other cases. Overall, gatifloxacin, gemifloxacin, and moxifloxacin displayed a lesser propensity to select resistant isolates of S. aureus than ciprofloxacin and levofloxacin. The mutant selection window premise appeared valid for MRSA only. Additional studies are necessary to define the applicability of the MPC.

Anti-Infective Agents↗

PubMed2004

Antimicrobial susceptibility of Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae collected from patients across the USA, in 2001-2002, as part of the PROTEKT US study.

BACKGROUND: The PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) surveillance programme was started in 2000, to chart the emergence and spread of antimicrobial resistance among isolates of Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae from across the USA. METHODS: In 2001-2002 (Year 2 of PROTEKT US) 242 centres from 46 states and the territory of Puerto Rico submitted a total of 10 012 S. pneumoniae, 4508 S. pyogenes and 3296 H. influenzae isolates from community-acquired respiratory tract infections (CARTIs). Susceptibility testing was performed and interpreted using NCCLS methodology and criteria. RESULTS: Overall, 35.4% of S. pneumoniae were non-susceptible to penicillin (14.2% intermediate, MIC 0.12-1 mg/L; 21.2% resistant, MIC > or =2 mg/L) and 27.9% were resistant to erythromycin (MIC > or =1 mg/L) (0.2% intermediate, MIC 0.5 mg/L). A total of 105 (1.0%) isolates were resistant to levofloxacin (MIC > or =8 mg/L). More than 99.2% of isolates were susceptible to telithromycin (MIC < or =1 mg/L) irrespective of penicillin and/or erythromycin resistance. All S. pyogenes isolates were susceptible to penicillin (MIC < or =0.12 mg/L) and 5.7% were resistant to erythromycin (MIC > or =1 mg/L) (0.3% intermediate, MIC 0.5 mg/L). The MIC90 of telithromycin for S. pyogenes was 0.03 mg/L. A total of 27.5% of H. influenzae isolates were beta-lactamase producers. Overall, 27.8% were resistant (MIC > or =4 mg/L) and 1.1% were intermediate to ampicillin (MIC 2 mg/L). A total of 96.3% of H. influenzae isolates were susceptible to telithromycin (MIC < or =4 mg/L). CONCLUSIONS: Antimicrobial resistance continues to be a problem in the USA. The ketolide telithromycin continues to show high activity against common CARTI pathogens, including those resistant to beta-lactams and macrolides.

Anti-Infective Agents↗

PubMed2004

Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model.

We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 +/- 1.1, 3.28 +/- 0.4, and 3.34 +/- 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 +/- 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.

Acetamides↗

PubMed2004

In vitro activities of a novel cephalosporin, CB-181963 (CAB-175), against methicillin-susceptible or -resistant Staphylococcus aureus and glycopeptide-intermediate susceptible staphylococci.

We examined the activity of CB-181963, a novel cephalosporin, against methicillin-resistant Staphylococcus aureus (MRSA) (n = 200), methicillin-susceptible S. aureus (MSSA) (n = 50), glycopeptide-intermediate Staphylococcus species (GISS) (n = 47), and VRSA (n = 2) isolates. CB-181963 exhibited MIC profiles similar to those of linezolid against MRSA and GISS; however, activity against MSSA was similar to that of vancomycin. Time-kill study results of investigations of activity against MRSA, MSSA, and GISS at 24 h were as follows: CB-181963 activity = vancomycin activity > linezolid activity (P < 0.001); CB-181963 = quinupristin-dalfopristin = vancomycin > linezolid (P < 0.05); CB-181963 > linezolid (P = 0.003); and CB-181963 = quinupristin-dalfopristin = vancomycin. CB-181963 may provide an alternative treatment for multidrug-resistant staphylococci.

Anti-Bacterial Agents↗

PubMed2004

Daptomycin - a novel antibiotic against Gram-positive pathogens.

Daptomycin is a novel member of a new class of antimicrobial agents used in treating resistant Gram-positive infections. These infections are becoming more commonplace and treatment options are limited. At present, daptomycin is approved for use in the US for complicated skin and skin-structure infections that are a common complication of surgery, diabetic foot ulcers, and burns. The most common causative organisms in these types of infections are Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Group C and G streptococci. Traditionally, these infections have been treated with penicillin and cephalosporins, but resistance to these agents is widespread and increasing. Of particular concern is the rapid increase in methicillin-resistant S. aureus (MRSA). The SENTRY Antimicrobial Surveillance Programme reported that approximately 30% of S. aureus isolates from skin and skin-structure infections were MRSA. The standard treatment for MRSA infections is vancomycin but resistance to this agent is also developing. There is a continuing need for the development of new antibiotics with Gram-positive activity, to combat multi-drug-resistant Gram-positive infections.

Animals↗

PubMed2004

Daptomycin.

Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used for the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and -resistant S. aureus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms.

Animals↗

PubMed2003

Structural features of piperazinyl-linked ciprofloxacin dimers required for activity against drug-resistant strains of Staphylococcus aureus.

We previously demonstrated that piperazinyl-linked fluoroquinolone dimers possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus. In this study, we report the preparation and evaluation of a series of incomplete dimers toward ascertaining structural features of piperazinyl-linked ciprofloxacin dimers that render these agents refractory to fluoroquinolone-resistance mechanisms in Staphylococcus aureus.

Anti-Infective Agents↗

PubMed2003

Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia.

The objective of this study was to determine the effect of delayed therapy on morbidity and mortality associated with nosocomial Staphylococcus aureus bacteremia. The study included all episodes of S. aureus bacteremia that developed >2 days after hospital admission during 1999 to 2001. Classification and regression tree analysis (CART) was used to select the mortality breakpoint between early and delayed treatment. During the 25-month study period, 167 patients met the inclusion criteria. The breakpoint between delayed and early treatment derived using CART was 44.75 hours. On multivariate analysis, delayed treatment was found to be an independent predictor of infection-related mortality (odds ratio, 3.8; 95% confidence interval, 1.3-11.0; P=.01) and was associated with a longer hospital stay than was early treatment (20.2 days versus 14.3 days; P=.05). These findings support the notion that delay of therapy has deleterious effects on clinical outcomes, and efforts should be made to ensure that appropriate therapy is initiated promptly.

Anti-Bacterial Agents↗

PubMed2003

Piperazinyl-linked fluoroquinolone dimers possessing potent antibacterial activity against drug-resistant strains of Staphylococcus aureus.

The synthesis of symmetric and asymmetric piperazinyl-linked dimers of the fluoroquinolone class of antibiotics is described. Specific dimers are shown to possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus, including strains possessing resistance due to the NorA multidrug efflux pump and a mutation in the quinolone resistance-determining region of topoisomerase IV.

Anti-Bacterial Agents↗

PubMed2003

Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations.

Daptomycin is a lipopeptide antibiotic that exhibits bactericidal activity against Gram-positive bacteria. In pursuit of potential clinical dosing regimens for endocarditis, we evaluated two, once-daily daptomycin regimens against multiple, drug-resistant Gram-positive pathogens. Daptomycin susceptibility was determined in the absence and presence of physiologic concentrations of albumin. An in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein was used to simulate regimens of daptomycin at 6 and 8 mg/kg/day and vancomycin at 1 g every 12 h against methicillin-resistant S. aureus (MRSA-67 and 494) and S. epidermidis (MRSE-R227 and R617), glycopeptide-intermediate S. aureus and S. epidermidis (GISA-992 and GISE-12333), and vancomycin-resistant E. faecium (VREF-SF12047 and 12366). Bacterial quantification occurred over 72 h. Daptomycin MIC results for study isolates in the absence or presence of albumin ranged from 0.125 to 4 and 1 to 8, respectively. Both daptomycin regimens achieved greater than 99.9% kill by 8 h and demonstrated greater bacterial reduction than vancomycin against all tested isolates at 24, 48, and 72 h (p < 0.05). Undetectable limits of bacterial quantification was achieved and maintained by 8 mg/kg/day against MRSA-494 and 67, GISA-992, and VREF-590 for the study duration. Although slight regrowth was noted only for 6 mg/kg/day against MRSA-67, 99.9% kill was maintained throughout the study period without development of resistance. Pharmacodynamic profiles and drug exposure of daptomycin at 6 mg/kg/day corresponds to previously reported AUC/MIC requirements. These results suggest that 6 and 8 mg/kg/day of daptomycin represent potential regimens for further clinical evaluation in drug-resistant Gram-positive endocarditis.

Anti-Bacterial Agents↗

PubMed2003

Effect of linezolid versus vancomycin on length of hospital stay in patients with complicated skin and soft tissue infections caused by known or suspected methicillin-resistant staphylococci: results from a randomized clinical trial.

BACKGROUND: Complicated skin and soft tissue infections are common surgical indications usually requiring patients to be hospitalized, and are often caused by gram-positive bacteria, including methicillin-resistant staphylococci such as MRSA. Vancomycin has been the standard treatment for methicillin-resistant staphylococcal infections in many countries, but its intravenous-only formulation for systemic infections often confines patients to the hospital for the treatment. Linezolid, a novel oxazolidinone antibiotic available in intravenous and 100% bioavailable oral forms, was shown in a randomized trial to be as efficacious as vancomycin for suspected or proven methicillin-resistant staphylococcal infections. To determine if oral linezolid can reduce length of hospital stay (LOS) when compared to vancomycin, we compared the LOS for the 230 complicated skin and soft tissue infection patients enrolled in this trial. MATERIALS AND METHODS: Patients received up to four weeks of linezolid (intravenous followed by optional oral) or vancomycin (intravenous only), followed by up to four weeks of observation. Unadjusted LOS was estimated using Kaplan-Meier survival functions, whereas the log-logistic survival analysis model was used to estimate the multivariate-adjusted LOS controlling for patient demographics and selected baseline clinical variables. Analysis was done on the intent-to-treat (n = 230) sample as well as on two subsamples of the clinically evaluable (n = 144) and surgical site infection (n = 114) patients. RESULTS: The unadjusted Kaplan-Meier median LOS was five days shorter for the linezolid group than the vancomycin group in the intent-to-treat sample (9 vs. 14 days, p = 0.052). It was eight days shorter (8 vs. 16 days, p = 0.0025) in the clinically evaluable sample, but the difference in the surgical site infection sample was not significant (10 vs. 14 days; p = 0.29). The linezolid group's unadjusted mean LOS was 1.7, 5.3 and 0.8 days shorter in the intentto-treat, clinically evaluable, and surgical site infection samples, respectively. After adjusting for age, gender, race, geographic region, bacteremia, type of inpatient location, and number of concurrent medical conditions using the log-logistic model, between-treatment differences in the multivariate-adjusted median LOS decreased to 3, 6, and 3 days, whereas the differences in mean LOS increased to 3.1, 6.5 and 2.5 days for the intent-to-treat, clinically evaluable, and surgical site infection samples (p < 0.01, < 0.01, and < 0.10), respectively. When the between-treatment differences in LOS were expressed as odds ratio of hospital discharges, multivariate-adjustment increased the odds ratios in favor of linezolid for all the three samples. CONCLUSION: Results from this randomized trial show that linezolid can significantly reduce LOS for patients with complicated skin and soft tissue infections from suspected or confirmed methicillin-resistant staphylococci.

Acetamides↗

PubMed2003

Bactericidal activities of daptomycin, quinupristin-dalfopristin, and linezolid against vancomycin-resistant Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations.

In search of treatment alternatives against vancomycin-resistant S. aureus (VRSA), an in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein and a high inoculum was used to simulate daptomycin, linezolid, quinupristin-dalfopristin, and vancomycin against the Michigan VRSA strain. Daptomycin and quinupristin-dalfopristin exhibited the greatest bacterial reductions, and all tested agents except vancomycin exhibited bactericidal activity against the VRSA.

Acetamides↗

PubMed2003

Daptomycin dose-effect relationship against resistant gram-positive organisms.

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.

Animals↗