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1.  Prospective Evaluation of the Effect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity 
The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for ≥72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P ≤ 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (P ≤ 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.
PMCID: PMC89322  PMID: 10390201
2.  Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection 
The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P < 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P < 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity.
doi:10.1128/AAC.00380-13
PMCID: PMC3754327  PMID: 23796929
3.  Multicenter Study of High-Dose Daptomycin for Treatment of Enterococcal Infections 
Enterococci are among the leading pathogens isolated in hospital-acquired infections. Current antimicrobial options for vancomycin-resistant enterococci (VRE) are limited. Prior data suggest that daptomycin at >6 mg/kg of body weight/day may be used to treat enterococcal infections. We retrospectively evaluated the effectiveness and safety of high-dose daptomycin (HD-daptomycin) therapy (>6 mg/kg) in a multicenter cohort of adult patients with enterococcal infections to describe the characteristics and outcomes. Two hundred forty-five patients were evaluated. Enterococcus faecium was identified in 175 (71%), followed by Enterococcus faecalis in 49 (20%) and Enterococcus spp. in 21 (9%); overall, 204 (83%) isolates were VRE. Enterococcal infections included bacteremia (173, 71%) and intra-abdominal (35, 14%) and bone and joint (25, 10%) infections. The median dosage and duration of HD-daptomycin were 8.2 mg/kg/day (interquartile range [IQR], 7.7 to 9.7) and 10 days (IQR, 6 to 15), respectively. The overall clinical success rate was 89% (193/218), and microbiological eradication was observed in 93% (177/191) of patients. The median time to clearance of blood cultures on HD-daptomycin was 3 days (IQR, 2 to 5). The 30-day all-cause mortality rate was 27%, and 5 (2%) patients developed daptomycin-nonsusceptible enterococcal strains while on HD-daptomycin. Seven patients (3%) had creatine phosphokinase (CPK) elevation, yet no HD-daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic. Overall, there was a high frequency of clinical success and microbiological eradication in patients treated with HD-daptomycin for enterococcal infections, even in patients with complicated and difficult-to-treat infections. No adverse event-related discontinuation of HD-daptomycin was noted. HD-daptomycin may be an option for the treatment of enterococcal infections.
doi:10.1128/AAC.00526-13
PMCID: PMC3754344  PMID: 23774437
4.  Evaluation of Vancomycin Susceptibility Testing for Methicillin-Resistant Staphylococcus aureus: Comparison of Etest and Three Automated Testing Methods 
Journal of Clinical Microbiology  2013;51(7):2077-2081.
We evaluated the ability of four commercial MIC testing systems (MicroScan, Vitek 2, Phoenix, and Etest) to detect vancomycin MIC values of ≤1 to ≥2 in 200 methicillin-resistant Staphylococcus aureus (MRSA) strains compared to the Clinical and Laboratory Standards Institute broth microdilution (BMD) reference methods. Compared to the BMD method, absolute agreement (0 ± dilution) was highest for the Phoenix system (66.2%) and the MicroScan turbidity method (61.8%), followed by the Vitek 2 system (54.3%). The Etest produced MIC values 1 to 2 dilutions higher than those produced by the BMD method (36.7% agreement). Of interest, the MicroScan system (prompt method) was more likely to overcall an MIC value of 1 mg/liter (74.1%), whereas the Phoenix (76%) and Vitek 2 (20%) systems had a tendency to undercall an MIC of 2 mg/liter. The ability to correctly identify vancomycin MIC values of 1 and 2 has clinical implications and requires further evaluation.
doi:10.1128/JCM.00448-13
PMCID: PMC3697692  PMID: 23596249
5.  Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the “Seesaw Effect” 
A “seesaw effect” in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fCmax], 15.2 μg/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18 μg/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ∼107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.
doi:10.1128/AAC.02308-12
PMCID: PMC3716128  PMID: 23545533
7.  Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model 
New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fCmax], 15.2 mg/liter; half-life [t1/2], 2.3 h), daptomycin at 10 mg/kg/day (fCmax, 11.3 mg/liter; t1/2, 8 h), vancomycin at 2 g q12h (fCmax, 30 mg/liter; t1/2, 6 h), ceftaroline plus daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10 CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.
doi:10.1128/AAC.01586-12
PMCID: PMC3535972  PMID: 23070161
8.  Evaluation of Telavancin Activity versus Daptomycin and Vancomycin against Daptomycin-Nonsusceptible Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model 
Daptomycin-nonsusceptible (DNS) Staphylococcus aureus strains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNS S. aureus strains, CB1814, R6212, and SA-684, were evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 108.5 CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter; t1/2, 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter; t1/2, 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter; t1/2, 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3-log10 CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; −4.31 log10 CFU/g), SA-684 (56 to 120 h; −3.06 log10 CFU/g), and CB1814 (48 to 120 h; −4.9 log10 CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P < 0.05). Telavancin displayed bactericidal activity in vitro against DNS S. aureus isolates.
doi:10.1128/AAC.05849-11
PMCID: PMC3264278  PMID: 22123693
9.  Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents 
Several thieno[2,3-d]pyrimidinediones have been synthesized and examined for antibacterial activity against a range of Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2–16 mg/L) against multi-drug resistant Gram-positive organisms, including methicillin, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus (MRSA, VISA, VRSA) and vancomycin-resistant enterococci (VRE). Only one of these agents possessed moderate activity (16–32 mg/L) against Gram-negative strains. An examination of the cytotoxicity of these agents revealed that they displayed low toxicity (40–50 mg/L) against mammalian cell and very low hemolytic activity (2–7%). Taken together, these studies suggest that thieno[2,3-d]pyrimidinediones are interesting scaffolds for the development of novel Gram-positive antibacterial agents.
doi:10.1016/j.ejmech.2012.02.035
PMCID: PMC3340521  PMID: 22405289
10.  Evaluation of the Novel Combination of High-Dose Daptomycin plus Trimethoprim-Sulfamethoxazole against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations 
Antimicrobial Agents and Chemotherapy  2012;56(11):5709-5714.
Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (109 CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log10 CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P < 0.05) and trimethoprim-sulfamethoxazole monotherapy (P < 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections.
doi:10.1128/AAC.01185-12
PMCID: PMC3486589  PMID: 22908167
11.  Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Vertebral Osteomyelitis Cases Complicated by Bacteremia Treated with High-Dose Daptomycin and Trimethoprim-Sulfamethoxazole 
Antimicrobial Agents and Chemotherapy  2012;56(11):5990-5993.
We report two cases of daptomycin (DAP)-nonsusceptible (DNS) vancomycin-intermediate Staphylococcus aureus (VISA) vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole. Both patients responded rapidly and favorably to this combination. The clinical isolates from the two patients were tested post hoc in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to confirm the bactericidal activity and enhancement of daptomycin and trimethoprim-sulfamethoxazole. The combination of high-dose daptomycin and trimethoprim-sulfamethoxazole should be explored further for the treatment of DNS VISA strains.
doi:10.1128/AAC.01046-12
PMCID: PMC3486608  PMID: 22869580
12.  Heterogeneous Vancomycin-Intermediate Susceptibility Phenotype in Bloodstream Methicillin-Resistant Staphylococcus aureus Isolates from an International Cohort of Patients with Infective Endocarditis: Prevalence, Genotype, and Clinical Significance 
The Journal of infectious diseases  2009;200(9):1355-1366.
Background
The significance of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is unknown. Using a multinational collection of isolates from methicillin-resistant S. aureus (MRSA) infective endocarditis (IE), we characterized IE patients with and without hVISA, and genotyped the infecting strains.
Methods
MRSA bloodstream isolates from 65 patients with definite IE from 8 countries underwent PCR for 31 virulence genes, pulsed-field gel electrophoresis, and multilocus sequence typing. hVISA was defined using population analysis profiling (PAP).
Results
Nineteen (29.2%) of 65 MRSA IE isolates exhibited hVISA by PAP. Isolates from Oceania and Europe were more likely to exhibit hVISA than isolates from the United States (77.8% vs. 35.0% vs. 13.9%; P < .001). The prevalence of hVISA was higher among isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (P = .026). hVISA-infected patients were more likely to have persistent bacteremia (68.4% vs. 37.0%; P = .029) and heart failure (47.4% vs. 19.6%; P = .033). Mortality of hVISA- and non-hVISA-infected patients did not differ (42.1% vs. 34.8%, P = .586). hVISA and non-hVISA isolates were genotypically similar.
Conclusions
In these analyses, hVISA occurred in over one-quarter of MRSA IE isolates, was associated with certain IE complications, and varied in frequency by geographic region.
doi:10.1086/606027
PMCID: PMC3600359  PMID: 19811099
hVISA; Methicillin-resistant Staphylococcus aureus; endocarditis; genotype
13.  Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations 
Daptomycin MICs for enterococci are typically 1- to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥3 log10 CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log10 CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P ≤ 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.
doi:10.1128/AAC.06439-11
PMCID: PMC3370794  PMID: 22470111
14.  Evaluation of Ceftaroline Activity versus Ceftriaxone against Clinical Isolates of Streptococcus pneumoniae with Various Susceptibilities to Cephalosporins in an In Vitro Pharmacokinetic/Pharmacodynamic Model 
Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fCmax] is 15.2 μg/ml, and half-life [T1/2] is 2.5 h) versus ceftriaxone at 1 g q24h (fCmax = 23 μg/ml, T1/2 = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 107 CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3 log10 CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, −5.49 log10 CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, −2.03 log10 CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [−5.91 log10 CFU/ml, P ≤ 0.002], SP 90 [−5.26 log10 CFU/ml, P ≤ 0.008], and SP1466 [−5.14 log10 CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.
doi:10.1128/AAC.06185-11
PMCID: PMC3346590  PMID: 22354289
15.  Characterizing Vancomycin-Resistant Enterococcus Strains with Various Mechanisms of Daptomycin Resistance Developed in an In Vitro Pharmacokinetic/Pharmacodynamic Model▿ 
Antimicrobial Agents and Chemotherapy  2011;55(10):4748-4754.
Two daptomycin (DAP) regimens were evaluated in a pharmacokinetic/pharmacodynamic (PK/PD) model, and the mutants recovered were examined for changes in phenotypic characteristics. Three Enterococcus faecium strains (vancomycin-resistant Enterococcus [VRE] ATCC 51559, VRE 12311, and VRE SF 12047) were utilized in a 7-day, 1-compartment in vitro PK/PD model. The simulated dosing regimens were DAP at 6 mg/kg/day (free Cmax [fCmax] = 7.9 μg/ml, half-life [t1/2] = 8 h) and DAP at 10 mg/kg/day (fCmax = 13.17 μg/ml, t1/2 = 8 h). Samples were plated daily on Mueller-Hinton agar containing DAP at 16 μg/ml and 50 mg/liter Ca2+ to assess the emergence of DAP resistance. For each strain, the mutant with the highest DAP MIC was then evaluated for changes in relative surface charge, cell wall thickness, and cytoplasmic membrane depolarization induced by DAP. The initial DAP MICs were 4 μg/ml for all 3 strains. A dose-dependent response and regrowth were observed for DAP 6 mg/kg/day and DAP 10 mg/kg/day against all 3 strains. Mutants of VRE ATCC 51559 (MIC = 128 and 64 μg/ml) and VRE 12311 (MIC = 256 and 32 μg/ml) were recovered from the DAP 6 mg and DAP 10 mg regimen, respectively. For VRE SF 12047, a mutant (MIC = 64 μg/ml) was recovered from the DAP 6 mg model. All mutants displayed an increase in relative surface charge compared to those of their respective parent strains. The DAP-resistant mutants displayed a 43 to 58% increase in cell wall thickness (P < 0.0001), while DAP membrane depolarization decreased by 53 to 65% compared to that of the susceptible strains. VRE with DAP resistance displayed increased surface charge, increased cell wall thickness, and decreased depolarization induced by DAP, consistent with previous observations in Staphylococcus aureus with reduced DAP susceptibility. Further characterization of DAP-resistant VRE is warranted.
doi:10.1128/AAC.00084-11
PMCID: PMC3186956  PMID: 21788457
16.  Pharmacokinetics of Single-Dose Daptomycin in Patients with Suspected or Confirmed Neurological Infections ▿ 
There are currently few or no published data on the amount of cerebrospinal fluid (CSF) penetration of daptomycin in patients with suspected or documented neurosurgical infections. We conducted a prospective study, assessing the pharmacokinetics and CSF penetration of a single intravenous daptomycin dose administered at 10 mg/kg, based on total body weight (TBW), in six neurosurgical patients with indwelling external CSF shunts with suspected or documented meningitis or ventriculitis. Each patient had four blood and CSF samples drawn simultaneously at specific times after the end of infusion: 30 min, 6 h, 12 h, and 24 h. Pharmacokinetic parameters of daptomycin in serum were calculated using standard noncompartmental methods, and daptomycin was assayed using high-performance liquid chromatography (for serum) or liquid chromatography with mass spectrometry (for CSF). The mean (± standard deviation [SD]) maximum measured daptomycin concentrations were 93.7 ± 17.3 mg/liter in serum at 0.5 h postinfusion and 0.461 ± 0.51 mg/liter in CSF at 6 h postinfusion. The mean (± SD) daptomycin minimum concentrations were 13.8 ± 4.8 mg/liter in serum at 24 h postinfusion and 0.126 ± 0.12 mg/liter in CSF at 0.5 h postinfusion. The mean daptomycin penetration, determined by the area under the concentration-time curve in CSF (AUCCSF)/(AUCserum ratio), was 0.8%. Corrected for protein binding, the overall CSF penetration was 11.5%. Additional pharmacokinetic studies evaluating multiple and/or higher dosages of daptomycin are necessary in human subjects to better characterize the CSF penetration of daptomycin in neurosurgical patients.
doi:10.1128/AAC.01741-10
PMCID: PMC3122430  PMID: 21502620
17.  Impact of Dose De-Escalation and Escalation on Daptomycin's Pharmacodynamics against Clinical Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Model▿ 
De-escalation and escalation therapeutic strategies are commonly employed by clinicians on the basis of susceptibility results and patient response. Since no in vitro or in vivo data are currently available to support one strategy over the other for daptomycin, we attempted to evaluate the effects of dose escalation and de-escalation on daptomycin activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. Three clinical MRSA isolates, including one heterogeneous vancomycin-intermediate S. aureus (hVISA) isolate and one vancomycin-intermediate S. aureus (VISA) isolate, were exposed to daptomycin at 10 or 6 mg/kg of body weight/day for 8 days using a starting inoculum of ∼109 CFU/g of vegetations, with dose escalation and de-escalation initiated on the fourth day. Daptomycin MIC values ranged from 0.5 to 1 μg/ml. In the PK/PD model, high-dose daptomycin (10 mg/kg/day) and de-escalation simulation (10 to 6 mg/kg/day) appeared to be the most efficient regimens against the three tested isolates, exhibiting the fastest bactericidal activity (4 to 8 h) compared to that of the standard regimen of 6 mg/kg/day and the escalation therapy of 6 to 10 mg/kg/day. The differences in the numbers of CFU/g observed between dose escalation and de-escalation were significant for the hVISA strain, with the de-escalation simulation exhibiting a better killing effect than the escalation simulation (P < 0.024). Although our results need to be carefully considered, the use of high-dose daptomycin up front demonstrated the most efficient activity against the tested isolates. Different therapeutic scenarios including isolates with higher MICs and prolonged drug exposures are warranted to better understand the outcomes of escalation and de-escalation strategies.
doi:10.1128/AAC.01291-10
PMCID: PMC3088203  PMID: 21321148
18.  Evaluation of Ceftaroline Activity versus Daptomycin (DAP) against DAP-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model ▿ † 
The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediate S. aureus) and R5995 (vancomycin-intermediate S. aureus) were evaluated in a two-compartment hollow-fiber in vitro pharmacokinetic/pharmacodynamic model at a starting inoculum of 107 CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [fCmax], 15.2 μg/ml; serum half-life [t1/2], 2.3 h), daptomycin at 6 mg/kg q24h (fCmax, 7.9 μg/ml; t1/2, 8 h), and daptomycin at 10 mg/kg q24h (fCmax, 15.2 μg/ml; t1/2, 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log10 CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, −3.1 log10 CFU/ml; R5563, −2.5 log10 CFU/ml; R5996, −5.77 log10 CFU/ml; R5995, −6.38 log10 CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains, P ≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains, P ≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.
doi:10.1128/AAC.00347-11
PMCID: PMC3122384  PMID: 21576449
19.  Novel Daptomycin Combinations against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations▿  
Antimicrobial Agents and Chemotherapy  2010;54(12):5187-5192.
Reduced susceptibility to daptomycin has been reported in patients with infections due to methicillin-resistant Staphylococcus aureus (MRSA). Although infections with daptomycin-nonsusceptible (DNS) MRSA are infrequent, optimal therapy of these strains has not been determined. We investigated the killing effects of novel antibiotic combinations with daptomycin (DAP) against two clinical DNS MRSA isolates (SA-684 and R6003) in a 72-h in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (SEV). Simulated regimens included DAP at 6 mg/kg every 24 h (q24h) alone or in combination with trimethoprim-sulfamethoxazole (TMP/SMX) at 160/800 mg q12h, linezolid (LIN) at 600 mg q12h, cefepime (CEF) at 2 g q12h, and nafcillin (NAF) at 4 g q4h. Bactericidal activity was defined as a ≥3-log10 CFU/g kill. Differences in CFU/g were evaluated between 4 and 72 h by analysis of variance with the Bonferroni post hoc test. DAP MICs were 4 and 2 mg/liter for SA-684 and R6003, respectively. In the PK/PD model, DAP alone was slowly bactericidal, achieving a 3-log10 kill at 24 and 50 h for SA-684 and R6003, respectively. Against SA-684, DAP plus TMP/SMX, CEF, LIN, or NAF was bactericidal at 4, 4, 8, and 8 h, respectively, and maintained this activity for the 72-h study duration. DAP plus TMP/SMX or CEF exhibited superior killing than DAP alone against SA-684 between 4 and 72 h, and overall this was significant (P < 0.05). Against R6003, DAP plus TMP/SMX was bactericidal (8 h) and superior to DAP alone between 8 and 72 h (P < 0.001). The unique combination of DAP plus TMP/SMX was the most effective and rapidly bactericidal regimen against the two isolates tested and may provide a clinical option to treat DNS S. aureus infections.
doi:10.1128/AAC.00536-10
PMCID: PMC2981245  PMID: 20921318
20.  Activities of High-Dose Daptomycin, Vancomycin, and Moxifloxacin Alone or in Combination with Clarithromycin or Rifampin in a Novel In Vitro Model of Staphylococcus aureus Biofilm▿  
Antimicrobial Agents and Chemotherapy  2010;54(10):4329-4334.
Biofilm formation is an important virulence factor that allows bacteria to resist host responses and antibacterial agents. The aim of the study was to assess the in vitro activities of several antimicrobials alone or in combination against two Staphylococcus aureus isolates in a novel pharmacokinetic/pharmacodynamic (PK/PD) model of biofilm for 3 days. One methicillin-susceptible S. aureus strain (SH1000) and one methicillin-resistant S. aureus strain (N315) were evaluated in a modified biofilm reactor with polystyrene coupons. Simulated regimens included vancomycin (VAN) plus rifampin (RIF), moxifloxacin (MOX), and high doses (10 mg/kg of body weight/day) of daptomycin (DAP) alone or combined with RIF or clarithromycin (CLA). Against viable planktonic bacteria (PB) and biofilm-embedded bacteria (BB) of SH1000, neither DAP nor MOX alone was bactericidal. In contrast, the combination of DAP or MOX with CLA significantly increased the activity of the two agents against both PB and BB (P < 0.01), and DAP plus CLA reached the limit of detection at 72 h. Against PB of N315, DAP alone briefly achieved bactericidal activity at 24 h, whereas sustained bactericidal activity was observed at 32 h with VAN plus RIF. Overall, only a minimal reduction was observed with both regimens against BB (<2.8 log10 CFU/ml). Finally, the combination of DAP and RIF was bactericidal against both PB and BB, achieving the limit of detection at 72 h. In conclusion, we developed a novel in vitro PK/PD model to assess the activities of antimicrobials against mature bacterial biofilm. Combinations of DAP or MOX with CLA were the most effective regimens and may represent promising options to treat persistent infections caused by S. aureus biofilms.
doi:10.1128/AAC.00455-10
PMCID: PMC2944618  PMID: 20696880
21.  In Vitro Activity of the New Multivalent Glycopeptide-Cephalosporin Antibiotic TD-1792 against Vancomycin-Nonsusceptible Staphylococcus Isolates▿  
TD-1792 is a glycopeptide-cephalosporin heterodimer antibiotic with activity against a broad spectrum of Gram-positive pathogens that includes methicillin-susceptible and -resistant Staphylococcus aureus. The objective of the present study was to evaluate the in vitro activity of TD-1792 against a collection of clinical isolates of vancomycin-intermediate Staphylococcus spp. (VISS), heteroresistant VISS (hVISS), and vancomycin-resistant S. aureus (VRSA). The TD-1792, vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin MICs and minimum bactericidal concentrations (MBCs) were determined for 50 VISS/hVISS isolates and 3 VRSA isolates. Time-kill experiments (TKs) were then performed over 24 h with two vancomycin-intermediate S. aureus strains and two VRSA strains, using each agent at multiples of the MIC. TD-1792 and daptomycin were also evaluated in the presence and absence of 50% human serum to determine the effects of the proteins on their activities. Most of the VISS/hVISS isolates were susceptible to all agents except vancomycin. TD-1792 exhibited the lowest MIC values (MIC90 = 0.125 μg/ml), followed by quinupristin-dalfopristin and daptomycin (MIC90 = 1 μg/ml) and then linezolid (MIC90 = 2 μg/ml). The presence of serum resulted in a 2- to 8-fold increase in the TD-1792 and daptomycin MIC values. In TKs, QD demonstrated bactericidal activity at multiples of the MIC that simulated therapeutic levels, whereas linezolid was only bacteriostatic. Both TD-1792 and daptomycin demonstrated rapid bactericidal activities against all isolates tested. The presence of proteins had only a minimal impact on the activity of TD-1792 in TKs. TD-1792 exhibited significant in vitro activity against multidrug-resistant Staphylococcus isolates and represents a promising candidate for the treatment of infections caused by Gram-positive organisms.
doi:10.1128/AAC.00452-10
PMCID: PMC2935031  PMID: 20585126
22.  Synthesis and Antibacterial Properties of (–)-nor-Platencin 
Organic letters  2009;11(22):5334-5337.
An asymmetric Diels–Alder reaction between acrolein and 1-benzyloxymethyl-1,3-cyclohexadiene affords a bicyclic aldehyde that was elaborated in 11 steps to nor-platencin. nor-Platencin is 4–16 times less active than platencin against several resistant strains of Staphylococcus aureus, macrolide-resistant Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium.
doi:10.1021/ol902194q
PMCID: PMC2789445  PMID: 19845392
24.  Epidemiology of Vancomycin-Resistant Enterococcus faecalis: a Case-Case-Control Study 
Although much is known about vancomycin-resistant (VR) Enterococcus faecium, little is known about the epidemiology of VR Enterococcus faecalis. The predilection of VR E. faecalis to transfer the vancomycin resistance determinant to Staphylococcus aureus is much greater than that of VR E. faecium. The epidemiology of VR E. faecalis has important implications regarding the emergence of vancomycin-resistant S. aureus (VRSA); 8 of 13 reported VRSA cases have been from Michigan. A retrospective case-case-control study was conducted at the Detroit Medical Center, located in southeastern Michigan. Unique patients with VR E. faecalis infection were matched to patients with strains of vancomycin-susceptible (VS) E. faecalis and to uninfected controls at a 1:1:1 ratio. Five hundred thirty-two VR E. faecalis cases were identified and were matched to 532 VS E. faecalis cases and 532 uninfected controls. The overall mean age of the study cohort (n = 1,596) was 63.0 ± 17.4 years, and 747 (46.8%) individuals were male. Independent predictors for the isolation of VR E. faecalis (but not VS E. faecalis) compared to uninfected controls were an age of ≥65 years, nonhome residence, diabetes mellitus, peripheral vascular disease, exposure to cephalosporins and fluoroquinolones in the prior 3 months, and immunosuppressive status. Invasive procedures and/or surgery, chronic skin ulcers, and indwelling devices were risk factors for both VR E. faecalis and VS E. faecalis isolation. Cephalosporin and fluoroquinolone exposures were unique, independent predictors for isolation of VR E. faecalis. A majority of case patients had VR E. faecalis present at the time of admission. Control of VR E. faecalis, and ultimately VRSA, will likely require regional efforts focusing on infection prevention and antimicrobial stewardship.
doi:10.1128/AAC.01271-12
PMCID: PMC3535915  PMID: 23070173
25.  In Vitro Activity of Ceftaroline against Methicillin-Resistant Staphylococcus aureus and Heterogeneous Vancomycin-Intermediate S. aureus in a Hollow Fiber Model▿  
Antimicrobial Agents and Chemotherapy  2009;53(11):4712-4717.
Ceftaroline is a broad-spectrum injectable cephalosporin exhibiting bactericidal activity against a variety of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Using a two-compartment in vitro pharmacokinetic/pharmacodynamic (PK/PD) model, we evaluated the activity of ceftaroline at 600 mg every 8 h (q8h) and q12h in comparison with that of vancomycin at 1,000 mg q12h over a 72-h time period against six clinical MRSA isolates, including two heterogeneous vancomycin-intermediate S. aureus (hVISA) isolates. The MIC and minimum bactericidal concentration ranged between 0.125 to 2 and 0.5 to 2 μg/ml for ceftaroline and vancomycin, respectively. In the PK/PD model, ceftaroline was superior to vancomycin against all isolates (P < 0.05), except one to which it was equivalent. No difference in activity was observed between both q8 and q12h dosing regimens of ceftaroline. Bacterial regrowth was observed after 32 h for two isolates treated with ceftaroline. This regrowth was uncorrelated to resistance, instability of the drug, or tolerance. However, subpopulations with higher MICs to ceftaroline were found by population analysis for these two isolates. Finally, and in contrast to ceftaroline, MIC elevations up to 8 to 12 μg/ml were observed with vancomycin for the hVISA isolates. In conclusion, in addition to a lower potential to select resistant mutants, ceftaroline demonstrated activity equal to or greater than vancomycin against MRSA isolates. Although further in vitro and in vivo investigations are warranted, ceftaroline appears to be a promising alternative for the treatment of MRSA infections.
doi:10.1128/AAC.00636-09
PMCID: PMC2772315  PMID: 19738009

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