The Activity of Antimicrobial Surfaces Varies by Testing Protocol Utilized.

BACKGROUND: Contaminated hospital surfaces are an important source of nosocomial infections. A major obstacle in marketing antimicrobial surfaces is a lack of efficacy data based on standardized testing protocols. AIM: We compared the efficacy of multiple testing protocols against several "antimicrobial" film surfaces. METHODS: Four clinical isolates were used: one Escherichia coli, one Klebsiella pneumoniae, and two Staphylococcus aureus strains. Two industry methods (modified ISO 22196 and ASTM E2149), a "dried droplet", and a "transfer" method were tested against two commercially available antimicrobial films, one film in development, an untreated control, and a positive (silver) control film. At 2 (only ISO) and 24 hours following inoculation, bacteria were collected from film surfaces and enumerated. RESULTS: Compared to untreated films in all protocols, there were no significant differences in recovery on either commercial brand at 2 or 24 hours after inoculation. The silver surface demonstrated significant microbicidal activity (mean loss 4.9 Log10 CFU/ml) in all methods and time points with the exception of 2 hours in the ISO protocol and the transfer method. Using our novel droplet method, no differences between placebo and active surfaces were detected. The surface in development demonstrated variable activity depending on method, organism, and time point. The ISO demonstrated minimal activity at 2 hours but significant activity at 24 hours (mean 4.5 Log10 CFU/ml difference versus placebo). The ASTEM protocol exhibited significant differences in recovery of staphylococci (mean 5 Log10 CFU/ml) but not Gram-negative isolates (10 fold decrease). Minimal activity was observed with this film in the transfer method. CONCLUSIONS: Varying results between protocols suggested that efficacy of antimicrobial surfaces cannot be easily and reproducibly compared. Clinical use should be considered and further development of representative methods is needed.

Surface microbiology of the iPad tablet computer and the potential to serve as a fomite in both inpatient practice settings as well as outside of the hospital environment.

BACKGROUND: The use of tablet computers and other touch screen technology within the healthcare system has rapidly expanded. It has been reported that these devices can harbor pathogens in hospitals; however, much less is known about what pathogens they can harbor when used outside the hospital environment compared to hospital practice. METHODS: Thirty iPads belonging to faculty with a variety of practice settings were sampled to determine the presence and quantity of clinically-relevant organisms. Flocked nylon swabs and neutralizer solution were used to sample the surface of each iPad. Samples were then plated on a variety of selective agars for presence and quantity of selected pathogens. In addition, faculty members were surveyed to classify the physical location of their practice settings and usage patterns. Continuous variables were compared via an unpaired Student's t test with two-tailed distribution; categorical variables were compared with the Fisher's exact test. RESULTS: Of the iPads sampled, 16 belonged to faculty practicing within a hospital and 14 belonged to a faculty member practicing outside a hospital. More faculty within the hospital group used their iPads at their practice sites (78.6% vs. 31.3%; p = 0.014) and within patient care areas (71.4% vs. 18.8%; p = 0.009) than the non-hospital group. There were no differences in the presence, absence, or quantity of, any of the pathogens selectively isolated between groups. Problematic nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and P. aeruginosa were isolated from both hospital and non-hospital faculty iPads. CONCLUSIONS: Gram positive and Gram negative organisms were recovered from the surfaces of iPads regardless of practice setting; these included problematic multidrug-resistant pathogens like MRSA, VRE, and Pseudomonas aeruginosa. Healthcare personnel in all settings should be aware of the potential for tablet computers to serve as a nidus for microorganism transmission.

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.

Comparative activities of telavancin combined with nafcillin, imipenem, and gentamicin against Staphylococcus aureus.

Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and telavancin, we investigated the activity of telavancin combined with nafcillin and imipenem compared to the known synergistic combination of telavancin and gentamicin. Thirty strains of Staphylococcus aureus, 10 methicillin-susceptible S. aureus (MSSA), 10 methicillin-resistant S. aureus (MRSA), and 10 heterogeneously vancomycin-intermediate S. aureus (hVISA), were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of 10 mg/kg of body weight of telavancin once daily alone and combined with 2 g nafcillin every 4 h, 500 mg imipenem every 6 h, or 5 mg/kg gentamicin once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of telavancin and gentamicin, 70% with telavancin and nafcillin, and 63% with telavancin and imipenem. In the PK/PD model, the activities of all three combinations against MRSA and hVISA were superior to all individual drugs alone (P ≤ 0.002) and were similar to each other (P ≥ 0.187). The activities of all three combinations against MSSA were generally similar to each other except for one strain where the combination of telavancin and imipenem was superior to all other regimens (P ≤ 0.011). The activity of the combination of telavancin and beta-lactam agents was similar to that of telavancin and gentamicin against S. aureus, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than telavancin plus gentamicin, these beta-lactam combinations may have clinical utility.

Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus.

OBJECTIVES: Continued selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including vancomycin-intermediate S. aureus (VISA). Though relatively uncommon, VISA presents a particularly difficult clinical challenge when it arises. Pertinent to this investigation is the correlation between vancomycin intermediacy and daptomycin non-susceptibility. The aim of this study was to evaluate the potential for synergy between daptomycin and nafcillin against VISA. METHODS: Twenty VISA strains were evaluated for daptomycin and nafcillin MICs by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 0.5× MIC in triplicate. Four strains displaying synergy in time-kill analysis were analysed in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model in duplicate over 72 h. RESULTS: In time-kill experiments, 55% of strains (11/20) displayed synergy with the combination. In the PK/PD model, no differences between daptomycin-alone and combination regimens were observed for the strain with the lowest daptomycin MIC (0.5 mg/L). For the strain with a daptomycin MIC of 1 mg/L, 6 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin alone (P=0.002) and 10 mg/kg daptomycin+nafcillin was superior to all other regimens (P ≤ 0.004). When the daptomycin MIC increased to 2 mg/L, 10 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin+nafcillin, which was superior to both 6 and 10 mg/kg daptomycin alone (P ≤ 0.019). CONCLUSIONS: Daptomycin and nafcillin in combination significantly improved antibacterial activity against VISA. This effect was more pronounced as the daptomycin susceptibility of the strain declined.

An introductory review module for an anti-infectives therapeutics course.

OBJECTIVE: To determine whether an introductory review module using a hybrid-learning approach helped students learn infectious disease management in an anti-infectives therapeutics course. DESIGN: An introductory module consisting of an online pharmacology review, pre-class assignment, 2 classroom lectures, and 1 case-based lecture was developed and implemented. ASSESSMENT: Among the 110 students who completed pre- and post-tests on the material covered, average scores increased from 71% to 83% (p<0.0001). Performance on knowledge-based question improved for 8 out of 10 questions (p<0.05) and student confidence increased from the first lecture to completion of the module (p<0.001 for all comparisons). Of the 129 students who completed an evaluation of the introductory module, 98% strongly agreed or agreed that the content was essential for course success. CONCLUSION: The addition of an introductory module using a hybrid-learning approach to review and solidify concepts of medical microbiology and pharmacology provided the foundation necessary for success in an infectious diseases module.

Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.

INTRODUCTION: Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. METHODS: Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. RESULTS: In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA. CONCLUSIONS: The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.

Validation of the effectiveness of a vancomycin nomogram in achieving target trough concentrations of 15-20 mg/L suggested by the vancomycin consensus guidelines.

STUDY OBJECTIVE: To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L. DESIGN: Prospective multicenter study. SETTING: Five tertiary care teaching hospitals. PATIENTS: A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L. INTERVENTION: The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed. MEASUREMENTS AND MAIN RESULTS: Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater. CONCLUSION: Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.

Comparative in vitro activity of telavancin, vancomycin and linezolid against heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA).

Selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including heterogeneously vancomycin-intermediate S. aureus (hVISA). Treatment of hVISA infections with vancomycin has been associated with treatment failure, therefore new treatments are required. The objective of this study was to evaluate the activity of telavancin, vancomycin and linezolid against hVISA clinical strains. Twenty-five hVISA isolates were evaluated for minimum inhibitory concentrations (MICs) by microdilution and for bactericidal activity by time-kill analysis [starting inoculum ca. 10(6)colony-forming units (CFU)/mL and ca. 10(8)CFU/mL] against telavancin, vancomycin and linezolid. MICs for 50% and 90% of the organisms (MIC(50) and MIC(90) values, respectively) were, respectively, 0.5mg/L and 1mg/L for telavancin and 2mg/L and 2mg/L for both vancomycin and linezolid. In time-kill studies, telavancin was bactericidal against all strains at plasma peak and trough concentrations and at low and high inocula. At low inoculum, the time to bactericidal activity (defined as 99.9% kill from initial inoculum) (T(99.9)) for telavancin was 5.6 ± 3.2 h at peak concentration and 12.3 ± 5.2 h at trough concentration. This was superior to vancomycin (P<0.001), which had a T(99.9) of 18.8 ± 2.1 h at peak concentration and 19.1 ± 2.2 h at trough concentration. At high inoculum, telavancin had a T(99.9) of 16.3 ± 3.2 h at peak concentration and 21.4 ± 2.5 h at trough concentration, whilst vancomycin did not consistently achieve bactericidal activity. Linezolid was not bactericidal against any strain at either concentration or inoculum. In conclusion, the killing activity of telavancin against hVISA was found to be superior to vancomycin and linezolid.

Heterogeneous vancomycin resistance in Staphylococcus aureus: a review of epidemiology, diagnosis, and clinical significance.

OBJECTIVE: To provide an overview of heterogeneously glycopeptide intermediate Staphylococcus aureus, its epidemiology, methods of diagnosis, and clinical relevance. DATA SOURCES: Literature was retrieved in December 2009 through Academic Search Premier, Alt-Health Watch, MEDLINE, OVID, and PubMed, using the search terms heterogeneous glycopeptide-intermediate Staphylococcus aureus, hGISA, hVISA, vancomycin-intermediate Staphylococcus aureus, GISA, and VISA (from 2003 to December 2009). Additional references were obtained through review of publication citations. STUDY SELECTION AND DATA EXTRACTION: All articles retrieved through the literature search and reference review were evaluated for inclusion in this review. DATA SYNTHESIS: Heterogeneously glycopeptide-intermediate S. aureus (hGISA) has been shown to significantly complicate treatment for patients with bacteremia and often escapes detection in clinical laboratories. Population analysis profile area under the curve ratio (PAP-AUC) is considered to be the gold standard of hGISA detection; however, it is labor-intensive, expensive, and not feasible in a clinical setting. The Etest macromethod is a reasonable alternative to PAP, yielding high sensitivity and specificity, and has potential for routine use in clinical laboratories. Due to these difficulties in detection, an exact prevalence is difficult to obtain though, based on available data, it appears that approximately 5-15% of isolates display this phenotype. hGISA is associated with prolonged bacteremia, high bacterial load infections, prolonged antibiotic therapy, prolonged hospitalization, treatment failure, and potential for increased mortality. CONCLUSIONS: Overall, hGISA is associated with a poor clinical course in patients with bacteremia. Information is still lacking regarding the actual prevalence of hGISA as well as the extent of its clinical impact. A uniform method of diagnosis must be established in order to better account for all cases of hGISA. More studies must be conducted to assess clinical outcomes of hGISA.

Activity of telavancin against Staphylococcus aureus strains with various vancomycin susceptibilities in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations.

We investigated the activity of telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log(10) CFU/g, at 96 h were 2.8 +/- 0.5 for MRSA 494, 2.8 +/- 0.3 for MSSA 1199, 4.2 +/- 0.2 for hGISA 1629, and 4.1 +/- 0.3 for GISA NJ 992. Combinations of telavancin with gentamicin significantly enhanced killing compared to telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log(10) CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in telavancin susceptibilities were observed. These results suggest that telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.

Evaluation of the Etest GRD for the detection of Staphylococcus aureus with reduced susceptibility to glycopeptides.

OBJECTIVES: Continued glycopeptide-selective pressure has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). The gold standard for identification of hVISA is the population analysis profile area under the curve ratio (PAP-AUC), though this method is time-consuming and labour-intensive. The objective of this study was to compare a new method for detection of hVISA, the Etest GRD, to PAP-AUC and to macro Etest. METHODS: One hundred clinical hVISA and 50 clinical fully vancomycin-susceptible S. aureus (VSSA), confirmed by PAP-AUC, were evaluated. Microtitre and Etest MICs were determined by standard testing procedures on all isolates. Macro Etest was performed according to referenced procedures. The Etest GRD was tested using a 0.5 McFarland standard on Mueller-Hinton agar + 5% blood and read at 24 and 48 h. If either the vancomycin or the teicoplanin end of the GRD strip was >or=8 and the vancomycin Etest was

Evaluation of vancomycin and daptomycin against methicillin-resistant Staphylococcus aureus and heterogeneously vancomycin-intermediate S. aureus in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations.

OBJECTIVES: Glycopeptides have historically been the drugs of choice for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the continued selective pressure has led to the emergence of non-susceptible strains including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA have been associated with poor outcomes including vancomycin treatment failures. The objective of this study was to evaluate vancomycin and daptomycin against vancomycin-susceptible MRSA and hVISA in a pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. METHODS: Six clinical isolates obtained from patients at the Detroit Medical Center were used: MRSA 494, MRSA 67, hVISA R1720, hVISS R2295, hVISA R3640 and hVISA R1629. All heteroresistant strains were confirmed by a population analysis profile ratio, with Mu3 as a control strain. Vancomycin regimens of 1 g every 12 h and 2 g every 12 h and daptomycin regimens of 6, 10 and 12 mg/kg daily were utilized in a PK/PD model over 72 h. RESULTS: Against MRSA isolates, vancomycin displayed minimal activity and minimal-to-no activity against hVISA. In general, the use of high dose vancomycin over standard dose vancomycin did not improve activity except against one of six isolates (MRSA 494). Daptomycin was bactericidal against both MRSA and hVISA isolates, although the rate of kill was slower against hVISA. CONCLUSIONS: Overall, daptomycin achieved rapid and effective kill against both MRSA and hVISA while vancomycin displayed slow and minimal kill against MRSA and minimal-to-no activity against hVISA, regardless of high dose exposure.

Impact of inoculum size and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) on vancomycin activity and emergence of VISA in an in vitro pharmacodynamic model.

The activity of vancomycin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and non-hVISA isolates, using an in vitro pharmacodynamic model, was reduced in the presence of a high inoculum amount (10(8) CFU/ml). A high bacterial load of >10(5) CFU/ml persisted for all strains with doses up to 5 g every 12 h against high inoculum amounts. No change in the vancomycin MIC was detected in any isolate at a moderate inoculum amount (10(6) CFU/ml), and bactericidal activity occurred only against the non-hVISA isolate (time to 99% kill, 7.5 h; P = 0.001).

Synergy between gemifloxacin and trimethoprim/sulfamethoxazole against community-associated methicillin-resistant Staphylococcus aureus.

OBJECTIVES: The rapid emergence of methicillin-resistant Staphylococcus aureus from the community (CA-MRSA) presents difficulties in making treatment choices. We evaluated whether combining another orally available agent commonly used to treat CA-MRSA with gemifloxacin would enhance gemifloxacin activity against CA-MRSA. METHODS: Fifty strains of SCCmec IV, agr group 1, Panton-Valentine leucocidin-positive CA-MRSA were evaluated for susceptibilities to gemifloxacin, trimethoprim/sulfamethoxazole, doxycycline, levofloxacin, rifampicin, clindamycin and erythromycin. Twenty of these strains were evaluated for the potential for synergy between gemifloxacin and trimethoprim/sulfamethoxazole, clindamycin and rifampicin by time-kill analysis. Two strains were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. RESULTS: In time-kill analyses, gemifloxacin combined with trimethoprim/sulfamethoxazole produced additivity (6/20) or synergy (11/20) in 85% of the isolates tested. The addition of clindamycin to gemifloxacin showed additivity (3/20) or synergy (2/20) in 25% of the isolates. All isolates displayed indifference to the combination of gemifloxacin and rifampicin. In the PK/PD model, combining gemifloxacin and trimethoprim/sulfamethoxazole provided potent and sustained bactericidal activity to detection limits of 2 log(10) cfu/mL by 48 h; gemifloxacin combined with clindamycin or with rifampicin killed to detection limits by 56 h or later. One isolate developed efflux-mediated resistance to gemifloxacin at 96 h with gemifloxacin monotherapy. All combinations prevented the emergence of this resistance. CONCLUSIONS: Synergy or additivity was demonstrated by time-kill analysis between gemifloxacin and trimethoprim/sulfamethoxazole in most isolates tested. In the PK/PD model, the addition of trimethoprim/sulfamethoxazole, clindamycin and rifampicin enhanced the activity of gemifloxacin against CA-MRSA and suppressed the emergence of resistance to gemifloxacin.

Evaluation of daptomycin pharmacodynamics and resistance at various dosage regimens against Staphylococcus aureus isolates with reduced susceptibilities to daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations.

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard- and high-dose daptomycin in combination with gentamicin or rifampin against daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the daptomycin-susceptible strains. Concentration-dependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose daptomycin. These results suggest that high-dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.

Activities of ceftobiprole, linezolid, vancomycin, and daptomycin against community-associated and hospital-associated methicillin-resistant Staphylococcus aureus.

We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC(50) and MIC(90) values were 1 and 2 microg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.

Activities of clindamycin, daptomycin, doxycycline, linezolid, trimethoprim-sulfamethoxazole, and vancomycin against community-associated methicillin-resistant Staphylococcus aureus with inducible clindamycin resistance in murine thigh infection and in vitro pharmacodynamic models.

Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh infection models, we evaluated and compared several antimicrobial compounds against CA-MRSA. Strains with inducible macrolide lincosamide-streptogramin type B (iMLS(B)) resistance and strains in which resistance was noninducible were evaluated. Two levels of inocula (10(5) and 10(7)) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate, and bacterial quantification occurred over 72 h, with drug doses that were designed to simulate the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLS(B) strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of > or =10(6) in the in vivo models. However, at a low inoculum (10(5)) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLS(B) strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

Telavancin: an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infections.

Telavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin. It has broad-spectrum activity against gram-positive bacteria, including strains with reduced susceptibility to vancomycin. Telavancin's multifunctional mechanism of action, including inhibition of peptidoglycan synthesis and disruption of membrane potential, account for this enhanced activity as well as rapid bactericidal properties. In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae, as well as methicillin-resistant, glycopeptide-intermediate, and vancomycin-resistant Staphylococcus aureus. The agent also displays activity against many gram-positive anaerobic organisms. Predictable linear pharmacokinetics have been demonstrated over a wide range of doses, with the most common adverse effects being taste disturbance and nausea. Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins, and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication. Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens, including drug-resistant pathogens. Further clinical experience will clarify its role in therapy.

Evaluation of daptomycin, telavancin, teicoplanin, and vancomycin activity in the presence of albumin or serum.

We evaluated the calculated protein binding based on arithmetic means of MIC values in the presence and absence of protein for daptomycin, telavancin, vancomycin, and teicoplanin against 5 Staphylococcus aureus isolates. The extent of protein binding was lower than expected, particularly for daptomycin and telavancin. These drugs may be more active than predicted based on unbound drug concentrations alone.