Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: a New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, we developed a dry powder formulation suitable for inhalation (AeroVanc). Here, we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In part I, 18 healthy subjects received a single dose of 16 mg, 32 mg, or 80 mg of AeroVanc. Two subjects also received a 250-mg dose of intravenous vancomycin. In part 2 of the study, 32 mg and 80 mg AeroVanc were administered to subjects with cystic fibrosis as single doses. There were no serious side effects. A small drop in forced expiratory volume in 1 s (FEV1) was observed in 3 subjects with cystic fibrosis, one of whom required salbutamol. Vancomycin was rapidly absorbed after inhalation. Peak and mean plasma concentrations of vancomycin were dose proportional. The average minimum concentration of vancomycin in sputum remained above the usual MIC values for MRSA for up to 24 h (minimum sputum concentration [Cmin], 32-mg dose = 3.05 µg/ml, 80-mg dose = 8.0 µg/ml). In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.

Low Serum Trough Concentrations and High Vancomycin Minimum Inhibitory Concentration in Methicillin-Sensitive Staphylococcus aureus From Hemodialysis Patients in Brazil.

BACKGROUND: The empiric antimicrobial therapy for bacteremia of long-term hemodialysis (HD) outpatients is currently based on the combination of vancomycin and gentamicin because of the high frequency of isolated Staphylococcus species. The vancomycin trough level range from 15 to 20 mcg/mL is expected for therapeutic success against methicillin-resistant Staphylococcus aureus with vancomycin minimum inhibitory concentration (MIC) ≥1.0 mcg/mL. Despite the availability of clinical practice guidelines for vancomycin therapeutic drug monitoring, these target serum concentrations are not reached in many patients. METHODS: In this study, the authors investigated the vancomycin trough levels in 20 HD patients with S. aureus bacteremia and the antimicrobial susceptibility pattern of 45 S. aureus strains isolated from 45 HD patients. The vancomycin serum concentration was determined by chemiluminescent assay. The MIC was determined by broth microdilution method. RESULTS: None of the HD patients included in this study had vancomycin trough concentrations within the therapeutic range. Also, the vancomycin MIC for most methicillin-sensitive S. aureus isolated from bacteremia was ≥1.0 mcg/mL. CONCLUSIONS: The therapeutic range of vancomycin was not achieved, and vancomycin MIC was surprisingly high in methicillin-sensitive S. aureus.

[Monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients].

OBJECTIVE: To investigate the relationship between the serum level of vancomycin and its clinical efficacy as well as adverse reactions in adult patient so as to provide recommendations for clinical management. METHODS: An open observational research was performed from 1st July 2013 to 31st December 2017 in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, which recruited the adult patients who were infected with Gram positive (G+) bacteria and treated with vancomycin. The initial dose was decided by the patient's creatinine clearance rate, and the treating dose was directed by the serum drug concentration and the patient's clinical response. By recording the associated clinical information (pathogen eradication, blood test results, adverse reactions, etc.), the clinical outcome and adverse reactions for vancomycin to treat G+ bacterial infections were analyzed. RESULTS: Eighty-nine cases who meet research standards were finally recruited, with 67.42% of male patients, and an average age of (50.5±17.9) years. The most common type of infection was bloodstream infection (61.80%), followed by low respiratory infection (17.98%). Infections caused by Staphylococcus aureus accounted for 39.33%. The bacterial eradication rate was 89.89% (80/89) and the total effective rate was 77.53% (69/89). The effective rate was 80.30% (53/66) with minimum inhibitory concentration (MIC) < 2 mg/L vs. 69.57% (16/23) with MIC ≥ 2 mg/L, the difference was not statistically significant (χ2 = 1.129, P = 0.288). The effective rate was 72.92% (35/48) with trough levels < 10 mg/L vs. 82.93% (34/41) with trough levels ≥ 10 mg/L, the difference was not statistically significant (χ2 = 1.272, P = 0.259). There were 4 cases of vancomycin associated nephrotoxicity, the incidence of nephrotoxicity was 4.49%, and the vancomycin serum trough levels were 17.22-28.53 mg/L. There were 33 cases of liver dysfunction, and elevated γ-glutamine transferase, alkaline phosphatase and aspartate aminotransferase were most common. There were 2 cases of neutropenia and 2 patients appeared rash during vancomycin period. CONCLUSIONS: Treatment outcomes were similar regardless of vancomycin MIC and serum trough level. The incidence of vancomycin associated nephrotoxicity rises apparently when serum trough level is over 15 mg/L. CLINICAL TRIAL REGISTRY: Chinese Clinical Trail Registry, ChiCTR-OPC-16007920.

Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy.

OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. METHODS: Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics®. The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. RESULTS: Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean ± standard deviation (SD) age, weight and body mass index (BMI) were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 per h and from peripheral to central compartment 5.29 ± 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. CONCLUSIONS: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring.

The ratio of pre-dialysis vancomycin trough serum concentration to minimum inhibitory concentration is associated with treatment outcomes in methicillin-resistant Staphylococcus aureus bacteremia.

BACKGROUND: Vancomycin is a standard treatment for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and its efficacy is closely linked to the recommended serum trough concentration of 15-20 mg/L. However, it is unknown how the pre-dialysis trough serum concentration (Cpre-HD) correlates with MRSA eradication in renal failure patients undergoing intermittent hemodialysis (HD). OBJECTIVE: To evaluate the relationship between Cpre-HD and the treatment outcomes in this population. MATERIALS AND METHODS: A retrospective study was conducted to enroll renal failure patients undergoing HD who had received vancomycin treatment for MRSA bacteremia during January 2013 to June 2016. Treatment failure was defined as persistent bacteremia after ≥ 7 days of vancomycin therapy or recurrent MRSA infection within 30 days. Patient characteristics, vancomycin dosing regimen, Cpre-HD, vancomycin minimum inhibitory concentration (MIC), and subsequent culture data were reviewed. The receiver operating characteristic (ROC) curve was used to find the optimal cut-off point of Cpre-HD. RESULTS: 42 patients were enrolled and 64% had treatment failure. Although there were no significant differences in demographics or Cpre-HD between the two groups, Cpre-HD/MIC was significantly higher in the success group than that in the failure group (22.80±10.90 vs. 14.94±6.11, p = 0.019). The area under the ROC curve was 0.74, while the sensitivity, specificity, positive predictive value, and negative predictive value were 67%, 78%, 62.5%, and 81%, respectively, at the optimal Cpre-HD/MIC of ≧ 18.6. CONCLUSIONS: Cpre-HD/MIC was associated with vancomycin treatment outcome in MRSA bacteremia, and targeting to achieve a Cpre-HD/MIC of ≧ 18.6 may improve treatment outcomes in renal failure patients who are on intermittent HD.

Optimizing the Clinical Use of Vancomycin.

The increasing number of infections produced by beta-lactam-resistant Gram-positive bacteria and the morbidity secondary to these infections make it necessary to optimize the use of vancomycin. In 2009, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists published specific guidelines about vancomycin dosage and monitoring. However, these guidelines have not been updated in the past 6 years. This review analyzes the new available information about vancomycin published in recent years regarding pharmacokinetics and pharmacodynamics, serum concentration monitoring, and optimal vancomycin dosing in special situations (obese people, burn patients, renal replacement therapy, among others). Vancomycin efficacy is linked to a correct dosage which should aim to reach an area under the curve (AUC)/MIC ratio of ≥400; serum trough levels of 15 to 20 mg/liter are considered a surrogate marker of an AUC/MIC ratio of ≥400 for a MIC of ≤1 mg/liter. For Staphylococcus aureus strains presenting with a MIC >1 mg/liter, an alternative agent should be considered. Vancomycin doses must be adjusted according to body weight and the plasma trough levels of the drug. Nephrotoxicity has been associated with target vancomycin trough levels above 15 mg/liter. Continuous infusion is an option, especially for patients at high risk of renal impairment or unstable vancomycin clearance. In such cases, vancomycin plasma steady-state level and creatinine monitoring are strongly indicated.

Vancomycin AUC24 /MIC Ratio in Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia.

BACKGROUND: Vancomycin is the treatment of choice for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. The area under the concentration-time curve from 0 to 24 hr (AUC24 )/minimum inhibitory concentration (MIC) ratio was recently introduced as a parameter for assessing clinical outcome by S. aureus. This study was purposed to apply the vancomycin AUC24 /MIC in patients with MRSA pneumonia. METHODS: Forty-seven patients with confirmed lower respiratory infection caused by MRSA during 2011 were enrolled. All patients were treated with vancomycin. Clinical characteristics and laboratory data were collected. AUC24 /MIC values were calculated as previously reported and patients were divided into two groups based on the bacteriologic response, which was eradicated or not, and an AUC24 /MIC value (above or below 400). RESULTS: MRSA infections were eradicated in 39 patients but 8 patients had persistent MSRA infection in the following cultures. The mean AUC24 /MIC values and vancomycin concentrations were not statistically different between patients with and without MRSA eradication. All 13 patients with a vancomycin MIC of 2 mg/L had an AUC24 /MIC below 400. CONCLUSION: AUC24 /MIC might not be a reliable indicator for assessing treatment response of vancomycin in MRSA pneumonia. Relationship between vancomycin AUC24 /MIC and therapeutic outcome needs to undergo further studies, including sufficiently large sample size.

Vancomycin Trough Concentration as a Predictor of Clinical Outcomes in Patients with Staphylococcus aureus Bacteremia: A Meta-analysis of Observational Studies.

STUDY OBJECTIVE: To determine the strength of evidence for better clinical outcomes in patients with Staphylococcus aureus bacteremia who had vancomycin trough levels of 15-20 mg/L. DESIGN: Meta-analysis of 14 observational cohort studies. PATIENTS: A total of 1677 patients, representing geriatric and unspecified inpatients, who received standard dosing of vancomycin for the treatment of S. aureus bacteremia and who had trough level goals of 15-20 mg/L. MEASUREMENTS AND MAIN RESULTS: The treatment variables examined in the analysis were vancomycin trough concentrations and 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC) values. The outcomes of interest were mortality, persistent bacteremia, and treatment failure. Mortality was defined as 30-day mortality, in-hospital mortality, or a comparable measure; persistent bacteremia was defined as bacteremia lasting at least 7 days after the initiation of vancomycin; treatment failure was defined as a composite end point that included at least persistent bacteremia and mortality, as previously defined. Higher vancomycin trough levels (15 mg/L or greater or based on MIC) were not associated with significantly reduced treatment failure, persistent bacteremia, or mortality. Higher AUC:MIC values were associated with significantly reduced treatment failure (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.31-0.53), persistent bacteremia (OR 0.53, 95% CI 0.33-0.86), and mortality (OR 0.47, 95% CI 0.33-0.65). The weighted mean ± SD AUC:MIC threshold defined by regression analyses in the included studies was 418 ± 88 hours, which supports the current goal of 400 hours or more. CONCLUSION: Vancomycin trough concentrations do not have sufficient evidence to support their use as the primary guide in vancomycin dosing. Dosing should instead focus on AUC:MIC values, which have strong evidence of benefit.

[Therapeutic monitoring of vancomycin in routine clinical practice]. / Terapeutické monitorování vankomycinu v rutinní klinické praxi.

Therapeutic drug monitoring (TDM) is specific method of clinical pharmacology for monitoring of the therapy using measurement of drug serum concentrations followed interpretation and good cooperation with clinician. TDM help clinicians to quickly optimize vancomycin dosing regimens to maximize the clinical effect and minimize the toxicity of the drugs. Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance, neverthelles trough concentrations > 20 mg/L are not recommended because of the risk of nephrotoxicity. For serious infections vancomycin trough concentrations of 15-20 mg/L are recommended and for a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC24/MIC 400 (area under the curve/minimal inhibitory concentration). In non-complicated infections trough concentrations of 10-15 mg/L should be sufficient. For continuous infusions of vancomycin target steady-state concentration values of 15-25 mg/L have been advocated for critically ill patients.Key words: therapeutic monitoring - trough concentration - vancomycin.

Inadequate vancomycin therapy in term and preterm neonates: a retrospective analysis of trough serum concentrations in relation to minimal inhibitory concentrations.

BACKGROUND: Vancomycin is effective against gram-positive bacteria and the first-line antibiotic for treatment of proven coagulase-negative staphylococcal infections. The aim of this study is bipartite: first, to assess the percentage of therapeutic initial trough serum concentrations and second, to evaluate the adequacy of the therapeutic range in interrelationship with the observed MIC-values in neonates. METHODS: In this study, preterm and term neonates admitted at a tertiary NICU in the Netherlands from January 2009 to December 2012 and treated with vancomycin for a proven gram-positive infection were included. Trough serum concentrations were measured prior to administration of the 5th dose. Trough concentrations in the range of 10 to 15 mg/L were considered therapeutic. Staphylococcal species minimal inhibitory concentrations (MIC's) were determined using the E-test method. Species identification was performed by matrix-assisted laser desorption/ionisation mass spectrometry. RESULTS: Of the 112 neonates, 53 neonates (47%) had sub-therapeutic initial trough serum concentrations of vancomycin, whereas 22% had supra-therapeutic initial trough serum concentrations. In all patients doses were adjusted on basis of the initial trough concentration. In 40% (23/57) of the neonates the second trough concentration remained sub-therapeutic. MIC's were determined for 30 coagulase-negative Staphylococcus isolates obtained from 19 patients. Only 4 out of 19 subjects had a trough concentration greater than tenfold the MIC. CONCLUSIONS: Forty-seven percent of the neonates had sub-therapeutic initial trough serum concentrations of vancomycin. The MIC-data indicate that the percentages of underdosed patients may be greater. It may be advisable to increase the lower limit of the therapeutic range for European neonates.

Impact of source of infection and vancomycin AUC0-24/MICBMD targets on treatment failure in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

Despite recent controversies about toxicity and reduced efficacy, vancomycin remains the current treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. The parameter associated with treatment success is the vancomycin 24-h area under concentration-time curve to MIC ratio (AUC0-24/MIC). We aimed to determine the utility of calculated AUCs and explore the optimal AUC0-24/MIC targets associated with treatment success. In this single-centre retrospective observational cohort study of 127 patients with MRSA bacteraemia, forty-five (35.4%) did not respond to vancomycin treatment. Patient characteristics were essentially the same between those who did not respond to vancomycin treatment and those with treatment success, with independent predictors of treatment failure being source of bacteraemia (odds ratio (OR), 4.29; 95% confidence interval (CI), 1.50-12.26; p 0.007) and not achieving an AUC0-24/MICBMD (using broth microdilution) target of ≥398 (OR, 11.4; 95% CI, 4.57-28.46; p< 0.001). Bacteraemic source-specific thresholds were observed with a higher AUC0-24/MICBMD target of 440 required for high-risk sources (e.g. infective endocarditis) compared with 330 for low-risk sources (line related bacteraemia). Overall treatment success in patients with MRSA bacteraemia was associated with a vancomycin AUC0-24/MICBMD target of ≥398, with source-specific targets observed. Future vancomycin practice guidelines will need to take into account MIC methodology, source of bacteraemia and patient populations prior to setting targets and monitoring recommendations.

Desired vancomycin trough serum concentration for treating invasive methicillin-resistant Staphylococcal infections.

Vancomycin area under the curve/minimal inhibitory concentration (AUC/MIC) >400 best predicts the outcome when treating invasive methicillin-resistant Staphylococcus aureus infection; however, trough serum concentrations are used clinically to assess the appropriateness of dosing. We used pharmacokinetic modeling and simulation to examine the relationship between vancomycin trough values and AUC/MIC in children receiving vancomycin 15 mg/kg every 6 hours and methicillin-resistant Staphylococcus aureus MIC of 1 µg/mL. A trough of 7-10 µg/mL predicted achievement of AUC/MIC >400 in >90% of children.

Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant staphylococcus aureus pneumonia.

BACKGROUND: We analyzed the pharmacokinetic-pharmacodynamic relationship of vancomycin to determine the drug exposure parameters that correlate with the efficacy and nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus pneumonia and evaluated the need to use peak concentration in therapeutic drug monitoring (TDM). METHODS: Serum drug concentrations of 31 hospitalized patients treated with vancomycin for methicillin-resistant S. aureus pneumonia were collected. RESULTS: Significant differences in trough concentration (Cmin)/minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC0-24)/MIC were observed between the response and non-response groups. Significant differences in Cmin and AUC0-24 were observed between the nephrotoxicity and non-nephrotoxicity groups. Receiver operating characteristic curves revealed high predictive values of Cmin/MIC and AUC0-24/MIC for efficacy and of Cmin and AUC0-24 for safety of vancomycin. CONCLUSIONS: These results suggest little need to use peak concentration in vancomycin TDM because Cmin/MIC and Cmin are sufficient to predict the efficacy and safety of vancomycin.

Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study.

OBJECTIVES: In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage. DESIGN: Prospective, observational, multicenter, pharmacokinetic study. SETTING: Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity. PATIENTS: Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy. INTERVENTIONS: We obtained trough blood samples and measured antibiotic concentrations. MEASUREMENTS AND MAIN RESULTS: We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8-18.4), 105.0 (74.4-204.0)/3.8 (3.4-21.8) for piperacillin/tazobactam, 12.0 (9.8-16.0) for vancomycin, and 3.7 (3.0-5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics. CONCLUSIONS: There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals.

Site of infection rather than vancomycin MIC predicts vancomycin treatment failure in methicillin-resistant Staphylococcus aureus bacteraemia.

BACKGROUND: Therapeutic use of vancomycin is characterized by decreased susceptibilities and increasing reports of clinical failures. Few studies have examined the clinical outcomes of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with vancomycin. The primary objective was to compare clinical outcomes of patients with MRSA bacteraemia treated according to standard of care practices. METHODS: Patients were included if: (i) admitted to University of New Mexico Hospital between 2002 and 2009; (ii) ≥18 years of age; (iii) had one blood culture positive for MRSA; and (iv) received vancomycin. Clinical outcomes were defined as cure, failure (relapse of infection 30 days after completion of therapy, death or change in therapy) or unevaluable. Patient demographics, source of bacteraemia, treatment regimen, and microbiological characteristics were determined. RESULTS: Two hundred patients with MRSA bacteraemia were included. Sixty-one patients were unevaluable, leaving 139 patients for the final analysis. Seventy-two (51.8%) patients were cured and 67 (48.2%) experienced vancomycin failure. Vancomycin MIC(90) was 2 mg/L for both groups by Etest. Patients with endocarditis (P = 0.02) or pneumonia (P = 0.02) were more likely to fail therapy. Panton-Valentine leucocidin, loss of agr functionality and strain type were not predictors of outcomes in this study. CONCLUSIONS: High failure rates were observed in patients with MRSA bacteraemia treated with vancomycin, despite high vancomycin troughs and low rates of nephrotoxicity. Predictors of vancomycin failure included endocarditis and pneumonia. In these situations, vancomycin provides suboptimal therapy.

Activity of simulated serum concentrations of daptomycin versus vancomycin during the first 24h of treatment in the presence of physiological albumin concentrations against vancomycin-susceptible, -tolerant or -intermediate-resistant Staphylococcus aureus.

In order to determine whether reduced susceptibility or tolerance to vancomycin in Staphylococcus aureus influences the activity of daptomycin by simulating serum concentrations in the first 24h of treatment in the presence of physiological concentrations of human albumin, a computerised pharmacodynamic simulation was performed using Mueller-Hinton broth with 4 g/dL human albumin concentrations. For daptomycin, the media was adjusted to physiological ionised calcium concentrations by adding 100 µg/mL Ca(2+). Protein binding was measured. Six S. aureus isolates were used, comprising one vancomycin-susceptible S. aureus (VSSA), three vancomycin-tolerant strains, one heteroresistant vancomycin-intermediate S. aureus (hVISA) and one homogeneous vancomycin-intermediate S. aureus (VISA). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of daptomycin increased eight times when determined in the presence of albumin (MIC(ALB) and MBC(ALB), respectively). Measured protein binding was 86.6% (C(max)) and 86.5% (C(min)) for daptomycin and 51.6% (C(max)) and 42.2% (C(min)) for vancomycin. Similar values were obtained for fAUC/MIC (where fAUC is the area under the concentration-time curve obtained with extrapolated concentrations using the highest protein binding rate experimentally obtained) and AUC/MIC(ALB) for each antibiotic. Daptomycin showed early (≤ 6 h) bactericidal activity [maximal effect (E(max)) >4 log(10) reductions in initial inocula] against all strains. Vancomycin produced an E(max) of 2.3 log(10) reductions at 8h against the VSSA and reductions ≤1.8 log(10) for the other strains in the 8-24h period. Pharmacodynamic parameters were fAUC/MBC from 8.0 to 15.6 (vancomycin) and from 56.0 to 111.6 (daptomycin) for tolerant strains, and fAUC/MIC of 126.8 and 63.3 for vancomycin and 222.6 and 113.2 for daptomycin against hVISA and VISA strains, respectively. Against the study strains (vancomycin-susceptible, -tolerant, heteroresistant or intermediate), daptomycin, in contrast to vancomycin, exhibited early bactericidal activity despite its high protein binding.

The efficacy of post-cardiopulmonary bypass dosing of vancomycin in cardiac surgery.

Objective. Vancomycin is administered widely to patients undergoing cardiac surgery as prophylaxis against resistant Gram-positive sternal wound and venous donor site infections. The purpose of this study was to determine the efficacy of a standardized prebypass and postbypass dosing regimen of vancomycin by assessing plasma concentrations in the immediate postoperative period and postoperative surgical site infections (SSIs). Design. Retrospective cohort study. Setting . Cardiothoracic surgical intensive care unit in a tertiary care academic medical center. Methods. A total of 34 consecutive adult patients who had undergone cardiac surgery with cardiopulmonary bypass (CPB) were analyzed retrospectively. Each patient received 1000 mg of vancomycin administered over 1 hour around the time of induction of anesthesia and 500 mg after discontinuation of CPB. Trough vancomycin levels were sampled in the intensive care unit 12 hours after the last dose given in the operating room. Along with patient characteristics, postoperative readmission rates and SSIs were recorded for 1 year after surgery. Results. The nadir serum vancomycin level before the next dose was 9.3 ± 4.5 µg/mL (mean ± standard deviation). One superficial SSI was noted. Readmission rate for SSIs was 2.94%. Conclusion . Vancomycin concentrations in the serum were greater than the minimum inhibitory concentration for most staphylococci ranging from 4 to 19.3 µg/mL producing acceptable therapeutic serum concentrations and low rate of infectious complications. Thus postbypass dosing is acceptable in vancomycin cardiac surgical prophylaxis.

Population pharmacokinetic and pharmacodynamic modeling of norvancomycin.

In this paper, population pharmacokinetics (PPK) and pharmacodynamics of norvancomycin in patients were investigated. The studied dataset was derived from 146 patients with confirmed or suspected gram-positive bacterial infections, as well as 20 healthy volunteers. A PPK model was developed and validated by the nonlinear mixed effect model (NONMEM) software. The norvancomycin minimum inhibitory concentrations (MICs) for the isolates from patients were determined by the agar dilution method. The best model was a two-compartment pharmacokinetic model with exponential inter-individual error and an additive residual error statistic model. The findings of the present study indicated that the change in CLcr values had different effects on drug clearance (CL). In patients with renal dysfunction (CLcr< or =85 ml/min), CL (L/h)=2.54.(CLcr /50)1.20, while in patients with normal renal function (CLcr>85 ml/min), CL=6.0.(WT/60)0.52. An increased volume of peripheral distribution (V2) was observed when norvancomycin was co-administered with diuretics. Inter-individual variability in CL, V1, Q, and V2 was 35.92%, 11.40%, 0, and 79.75%, respectively. Residual variability was 3.05 mg/L. The logistic stepwise analyses revealed that only the ratio of AUC24 /MIC was a major factor which could significantly predict the clinical outcome and bacterial eradication in patients. As the AUC24/MIC ratio was >579.90 for staphylococcal infection and >637.67 for enterococcal infections, approximately 95% of patients would be predicted to achieve a cured clinical outcome. In conclusion, AUC24/MIC should be a major pharmacokinetics/pharmacodynamics (PK/PD) parameter to predict the clinical efficacy of norvancomycin. An optimized regimen of norvancomycin can be simulated and developed for different subgroups of patients who have special physiologic and pathologic conditions.

Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci.

OBJECTIVES: Daptomycin was tested in vitro and in rats with experimental endocarditis against the ampicillin-susceptible and vancomycin-susceptible Enterococcus faecalis JH2-2, the vancomycin-resistant (VanA type) mutant of strain JH2-2 (strain JH2-2/pIP819), and the ampicillin-resistant and vancomycin-resistant (VanB type) Enterococcus faecium D366. METHODS: Rats with catheter-induced aortic vegetations were treated with doses simulating intravenously kinetics in humans of daptomycin (6 mg/kg every 24 h), amoxicillin (2 g every 6 h), vancomycin (1 g every 12 h) or teicoplanin (12 mg/kg every 12 h). Treatment was started 16 h post-inoculation and continued for 2 days. RESULTS: MICs of daptomycin were 1, 1 and 2 mg/L, respectively, for strains JH2-2, JH2-2/pIP819 and D366. In time-kill studies, daptomycin showed rapid (within 2 h) bactericidal activity against all strains. Daptomycin was highly bound to rat serum proteins (89%). In the presence of 50% rat serum, simulating free concentrations, daptomycin killing was maintained but delayed (6-24 h). In vivo, daptomycin treatment resulted in 10 of 12 (83%), 9 of 11 (82%) and 11 of 12 (91%) culture-negative vegetations in rats infected with strains JH2-2, JH2-2/pIP819 and D366, respectively (P < 0.001 compared to controls). Daptomycin efficacy was comparable to that of amoxicillin and vancomycin for susceptible isolates. Daptomycin, however, was significantly (P < 0.05) more effective than teicoplanin against the glycopeptide-susceptible strain JH2-2 and superior to all comparators against resistant isolates. CONCLUSIONS: These results support the use of the newly proposed daptomycin dose of 6 mg/kg every 24 h for treatment of enterococcal infections in humans.