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Background: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza.Methods: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose.Results: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8-14.9) microg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257-900) microg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2=0.00, p=0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2=0.27, p<0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function.Interpretation: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary. [ABSTRACT FROM AUTHOR]

Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharmacokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CL(d) with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary. [ABSTRACT FROM AUTHOR]

Background: Although gentamicin is used extensively within the first week of life for suspected sepsis in neonates, little is known about the performance of gentamicin dosing nomograms in this population.Objective: The goal of our study was to retrospectively assess the performance of a gentamicin dosing nomogram in neonates given gentamicin during the first week after birth.Methods: In this retrospective study, gentamicin therapeutic drug monitoring data were collected during routine clinical care for all neonates who were born in St. Boniface General Hospital (Winnipeg, Manitoba, Canada) between January 1999 and April 2001 and given gentamicin during the first week after birth. We used Bayesian pharmacokinetic analysis to retrospectively assess the performance of our gentamicin dosing nomogram in neonates born at gestation ages <32 weeks, between 32 and 34 weeks, and >34 weeks. Bayesian pharmacokinetic values for parameters within groups were compared and used to explore predicted peak and trough serum gentamicin concentrations based on the institutional dosing nomogram.Results: In a total of 58 neonates, those neonates born at +/- 34 weeks' gestation had a weight-normalized apparent volume of gentamicin distribution 1.6 times larger than infants born after 34 weeks' gestation (P<0.001), as identified by Bayesian analysis. Weight-normalized gentamicin clearance was 22% lower in the youngest age category (P<0.01). Only 33% of predicted peak serum gentamicin concentrations were >6 mg/L for neonates born at 34 weeks' gestation, whereas 90% were therapeutic in neonates born at

Background: Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis., Methods: A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis., Results: Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen., Conclusions: The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appropriate surgical antimicrobial prophylaxis (SAP) is an important measure in preventing surgical site infections (SSIs). Although antimicrobial pharmacokinetics-pharmacodynamics (PKPD) is integral to optimizing antibiotic dosing for the treatment of infections, there is less research on preventing infections postsurgery. Whereas clinical studies of SAP dose, preincision timing, and redosing are informative, it is difficult to isolate their effect on SSI outcomes. Antimicrobial PKPD aims to explain the complex relationship between antibiotic exposure during surgery and the subsequent development of SSI. It accounts for the many factors that influence the PKs and antibiotic concentrations in patients and considers the susceptibilities of bacteria most likely to contaminate the surgical site. This narrative review examines the relevance and role of PKPD in providing effective SAP. The dose-response relationship i.e., association between lower dose and SSI in cefazolin prophylaxis is discussed. A comprehensive review of the evidence for an antibiotic concentration-response (SSI) relationship in SAP is also presented. Finally, PKPD considerations for improving SAP are explored with a focus on cefazolin prophylaxis in adults and outstanding questions regarding its dose, preincision timing, and redosing during surgery.

Purpose: To design an updated vancomycin dosing protocol for initiating therapy in patients undergoing chronic intermittent high-flux hemodialysis (iHFHD) that is congruent with the revised 2020 consensus guidelines for therapeutic drug monitoring (TDM)., Methods: Monte Carlo simulation methods were used to study vancomycin dosing for patients on iHFHD. Vancomycin regimens were constructed as intravenous infusions (for intradialytic administration) of a loading dose and maintenance doses 3 times weekly during subsequent dialysis sessions. Vancomycin plasma concentrations were simulated, and the probability of target attainment (PTA) for a 24-hour area under the time-concentration curve (AUC24) of 400 to 700 mg · h/L was determined. Standardized weight-based (ie, dose-banding) regimens were investigated, and an optimized protocol was selected based on TDM target attainment and practical considerations for use in the dialysis setting., Results: The proposed vancomycin dosing protocol (for intradialytic administration) specifies 3 regimens: (1) a 1,500-mg loading dose and 750-mg maintenance doses for patients weighing 50 kg to 69 kg; (2) a 2,000-mg loading dose and 1,000-mg maintenance doses for patients weighing 70 kg to 89 kg; and (3) a 2,500-mg loading dose and 1,250-mg maintenance doses for patients weighing 90 kg to 110 kg. In a simulated hemodialysis population (n = 5,000), the proposed protocol delivered median (interquartile range [IQR]) loading and maintenance doses of 25.0 (23.4-26.6) mg/kg and 12.5 (11.8-13.3) mg/kg, respectively. The PTA for an AUC24 of 400 to 700 mg · h/L was 74.7% on day 1 and 70.8% on day 8, with less than 10% of values exceeding the target range., Conclusion: Our proposed dosing protocol for patients undergoing iHFHD offers an updated and practical approach for initiating vancomycin therapy that can be optimized with early TDM., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given the morbidity and mortality associated with bloodstream infections in hemodialysis patients, understanding the microbiology is essential to optimizing treatment in this high-risk population., Objectives: To conduct a retrospective surveillance study of clinical blood isolates from adult hemodialysis patients, and to predict the microbiological coverage of empiric therapies for bloodstream infections in this population., Methods: Clinical blood isolate data were collected from the 4 main outpatient hemodialysis units in Winnipeg, Manitoba, from 2007 to 2014. The distribution of organisms and antimicrobial susceptibilities were characterized. When appropriate, changes over time were tested using time series analysis. Study data were used to predict and compare the microbiological coverage of various empiric therapies for bloodstream infections in hemodialysis patients., Results: The estimated annual number of patients receiving chronic hemodialysis increased steadily over the study period ( p < 0.001), whereas the number of blood isolates increased initially, then decreased significantly, from 180 in 2011 to 93 in 2014 ( p = 0.04). Gram-positive bacteria represented 72.6% (743/1024) of isolates, including Staphylococcus aureus (36.9%, 378/1024) and coagulase-negative staphylococci (23.1%, 237/1024). Only 26.1% (267/1024) of the isolates were gram-negative bacteria, the majority Enterobacteriaceae. The overall rate of methicillin resistance in S. aureus was 17.5%, and although annual rates were variable, there was a significant increase over time ( p = 0.04). Antibiotic resistance in gram-negative bacteria was relatively low, except in Escherichia coli , where 13.5% and 16.2% of isolates were resistant to ceftriaxone and ciprofloxacin, respectively. Empiric therapy with vancomycin plus an agent for gram-negative coverage was predicted to cover 98.8% to 99.7% of blood isolates from hemodialysis patients, whereas cefazolin plus an agent for gram-negative coverage would cover only 67.5% to 68.4%., Conclusions: In an era of increasing antimicrobial resistance, data such as these and ongoing surveillance are essential components of antimicrobial stewardship in the hemodialysis population., Competing Interests: Competing interests: Wolters Kluwer-Lexicomp has asked J Christine Davis to be a consultant (compensated) for drug dosing in kidney disease (outside the submitted work). No other competing interests declared., (2020 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

This study characterizes the pharmacodynamics of antimicrobial prophylaxis and sternal wound infections following cardiac surgery. Duration of surgery and cefazolin plasma concentration during wound closure were independently associated with surgical site infection at 30 days. Furthermore, a duration of surgery of >346 min and a total cefazolin closure concentration of <104 mg/liter were significant thresholds for an increased risk of infection. This study provides new data that informs dosing strategies for effective antimicrobial prophylaxis (AP) in patients undergoing cardiac surgery with cardiopulmonary bypass., (Copyright © 2018 American Society for Microbiology.)

Objectives: Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic-pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections., Methods: Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data., Results: Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects., Conclusions: Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients.

Objectives: Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L., Methods: Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥ 40 mg/L (≥8 mg/L unbound, assuming 80% protein binding)., Results: Fifty-five subjects (64.9 ± 10.4 years, 89.7 ± 16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of ≥ 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations., Conclusions: The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery.

Objectives: To evaluate the ability of body-weight-driven renal function assessment (RFA) formulae to predict on-target elimination rate ranges for gentamicin in patients with varying degrees of renal function., Methods: A 6 year retrospective pharmacokinetic study was conducted at a university teaching hospital., Results: A total of 85 patients met the inclusion criteria and 127 pharmacokinetic files were analysed from patients on medical-surgical wards (53%) and medical-surgical ICUs (13%) receiving intravenous gentamicin for treatment, as well as those for patients receiving it for surgical prophylaxis (34%). Each RFA formula was examined against standard dosing tables for gentamicin. A table of acceptable elimination rates was generated using a traditional peak of 8 mg/L and trough between 0.5 and 2 mg/L associated with each of the dosing interval extensions. The ability of each RFA formula to select on-target elimination rates was evaluated. The RFA formula assuming a normalized body weight of 72 kg and a modified creatinine reagent adjustment factor of 90% provided the most accurate on-target elimination rate selection. This method was superior to dosing interval selection based on the Modification in Diet Renal Disease (MDRD) formula, Sanford's guide method, as well as the Cockcroft-Gault formulae using total body weight, ideal body weight or lean body weight ( P  <   0.0001)., Conclusions: Based on the use of gentamicin as a surrogate guide for renally adjusted drugs, these results support dosing interval selection based on a normalized body weight method and a formula reagent adjustment factor of 90% within the Cockcroft-Gault formula., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

♦ BACKGROUND: Information related to the microbiology of peritonitis is critical to the optimal management of patients receiving peritoneal dialysis (PD). The goal was to characterize the microbiological etiology and antimicrobial susceptibilities of PD-related peritonitis (PDRP) from 2005 to 2014, inclusive. ♦ METHODS: The distribution of organisms in culture-positive PDRP was described for new episodes and relapse infections, and further detailed for monomicrobial and polymicrobial peritonitis. Annual and overall rates of PDRP were also characterized. Antimicrobial susceptibility rates were calculated for the most common and significant organisms. ♦ RESULTS: We identified 539 episodes of PDRP including 501 new and 38 relapse infections. New episodes of peritonitis were associated with a single organism in 85% of cases, and 44% of those involved staphylococci. Polymicrobial PDRP was more likely to involve gram-negative organisms, observed in 58% versus 24% of monomicrobial infections. Antimicrobial resistance was relatively stable from 2005 to 2014. Methicillin resistance was present in 57% of Staphylococcus epidermidis and 20% of other coagulase-negative staphylococci. Methicillin-resistant Staphylococcus aureus (MRSA) accounted for only 11% of S. aureus peritonitis compared with 2% in our previous study of PDRP from 1991 to 1998. Ciprofloxacin resistance in Escherichia coli increased from 3% in our previous study to 24% in 2005 - 2014. ♦ CONCLUSIONS: This study characterizes important differences in the distribution of organisms in new episodes of PDRP and relapse infections, as well as monomicrobial versus polymicrobial peritonitis. It also shows relatively stable rates of antimicrobial resistance from 2005 to 2014, but some increases compared with our previous study., (Copyright © 2017 International Society for Peritoneal Dialysis.)

Objectives: To use Monte Carlo simulation with an integrated pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate guideline-recommended antimicrobial prophylaxis (AP) regimens with anaerobic coverage in abdominal surgery., Methods: AP regimens were tested in simulated subjects undergoing elective abdominal surgery using relevant PK models and pathogen distributions in surgical site infections (SSIs). Predicted cumulative target attainment was the percentage of simulated subjects with free (unbound) antimicrobial plasma concentrations above the MICs for potential SSI pathogens., Results: Cefazolin plus metronidazole covered SSI aerobes in 70% and the Bacteroides fragilis group in 99% of subjects, whereas cefoxitin only covered aerobes and anaerobes in 63% and 27% of cases, respectively. The broad-spectrum ceftriaxone plus metronidazole covered aerobes in 82% and anaerobes in 99% of simulations, while ertapenem covered aerobes in 88% and anaerobes in 90% of cases. Clindamycin covered the B. fragilis group in only 11% of cases. For cefazolin, 2 g doses maintained target attainment in simulated subjects from 80 to 120 kg, whereas 1 g doses were associated with lower target attainment against potential Gram-negative pathogens even in those <80 kg. For gentamicin, 3 mg/kg doses were comparable to the suggested 5 mg/kg, but superior to the traditional 1.5 mg/kg., Conclusions: This study demonstrates the use of PK-PD to inform decisions regarding AP in abdominal surgery. In this case, the findings support avoiding cefoxitin, avoiding clindamycin for anaerobic coverage, selecting 2 g doses of cefazolin even in patients <80 kg and using 3 mg/kg doses of gentamicin., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To describe a case of successful treatment of severe pulmonary blastomycosis with amphotericin B deoxycholate after failure of liposomal amphotericin B., Case Summary: A 35-year-old male was exposed to damp decomposing wood while cleaning his basement. He subsequently developed a cough, malaise, fever, nausea, vomiting, and diarrhea. He was admitted to the hospital and intubated for worsening pulmonary symptoms. Microscopic examination of his sputum indicated Blastomyces dermatitidis. Liposomal amphotericin B was administered for 6 days, but the patient's temperature reached 39.6 °C and his white blood cell (WBC) count reached 52,300/μL. Extensive consolidation of both lungs fields was observed on chest X-ray. Because of progressive clinical deterioration, the treatment was switched to amphotericin B deoxycholate by continuous infusion. That change resulted in clinical improvement, with abrupt reductions (within 48 hours) in temperature and the WBC count. By day 14 of therapy (day 8 of amphotericin B deoxycholate), the chest X-ray showed improvement in diffuse airspace filling. After 16 days of amphotericin B treatment, intravenous followed by oral voriconazole was administered for 3 months. Eight months later the patient's strength had improved significantly, but he still had occasional episodes of shortness of breath., Discussion: The management of blastomycosis is challenging because of the lack of clinically supporting data. The gold standard for severe pulmonary blastomycosis had been amphotericin B deoxycholate; however, improved safety data with liposomal amphotericin B for other fungal infections has suggested this as an effective alternative. This report describes a patient with severe pulmonary blastomycosis failing 6 days of liposomal amphotericin B, yet he tolerated and clinically responded to continuous infusion of amphotericin B deoxycholate. Based on this case report and a simulated pharmacokinetic/pharmaco dynamic analysis, continuous infusion of amphotericin B deoxycholate may be a reasonable option for enhanced efficacy and minimal toxicity in patients with blastomycosis., Conclusions: Ours is the first case report to use continuous infusion of amphotericin B deoxycholate for the management of pulmonary blastomycosis. These results suggest that liposomal amphotericin B may not be adequate in some patients for the management of B. dermatitidis pulmonary infections.

Objectives: To study antimicrobial pharmacodynamic (PD) activity over time against clinical isolates of Pseudomonas aeruginosa in Canadian hospitals., Methods: Integrated pharmacokinetic (PK)/PD analyses with Monte Carlo simulations were used to study cefepime, meropenem, piperacillin/tazobactam, ciprofloxacin, amikacin, gentamicin and colistin. Profiles of P. aeruginosa infections were modelled using CANWARD data from January 2007 to June 2012 inclusive. The probability of target attainment (PTA) was the proportion of cases achieving a %ƒT>MIC ≥ 50% for cefepime, meropenem and piperacillin/tazobactam, an ƒAUC/MIC ≥ 90 for ciprofloxacin and the aminoglycosides, and a total AUC/MIC ≥ 60 for colistin., Results: Some 2126 P. aeruginosa isolates were identified. There were no significant trends over time in the PTA for cefepime (0.93-1.0), meropenem (0.89-0.92) or piperacillin/tazobactam (0.74-0.79) (data shown for the highest recommended doses). The PD activity for ciprofloxacin (PTA 0.48-0.64) was variable. There were notable improvements in the PTA for amikacin (from 0.21 to 0.55, P = 0.027), gentamicin (from 0.10 to 0.51, P = 0.035) and colistin (from 0.04 to ~0.20, P = 0.05), which were not reliably detected by MIC indices. There was a decline over time in the PTA for piperacillin/tazobactam from 0.73 to 0.61 against P. aeruginosa isolated from intensive care units (ICUs) (Pearson correlation coefficient -0.99, P = 0.003). Neither MIC50 nor MIC90 detected this reduction in PD activity., Conclusions: The overall PD activity against P. aeruginosa was stable from 2007 to 2012 for cefepime, meropenem and piperacillin/tazobactam, was variable and unreliable for ciprofloxacin, and improved significantly but remained relatively low for the aminoglycosides and colistin. There was a progressive reduction over time in the PD activity of piperacillin/tazobactam against ICU isolates, which was not detected by simply assessing MIC indices.

Background: Although recent consensus guidelines proposed more aggressive vancomycin troughs of >10 or 15-20 mg/L for complicated Staphylococcus aureus infections, dosing information to achieve these targets in patients undergoing hemodialysis (HD) is scarce., Methods: We used Monte Carlo simulation (MCS) methods with a previously published population-pharmacokinetic model and relevant patient demographics to evaluate and revise our existing vancomycin dosing protocol (1000-mg load followed by 500-mg maintenance dose, with doses infused during the last hour of dialysis). A new protocol (1000-mg load followed by 500-mg maintenance dose for patients <70 kg, 1250-mg followed by 750-mg for those 70-100 kg, and 1500-mg followed by 1000-mg for those >100 kg) was developed and prospectively validated to achieve therapeutic serum troughs in patients undergoing high-flux HD., Results: MCSs predicted that our existing protocol would be suboptimal in more than one-third of patients. Simulations predicted that the new vancomycin dosing protocol would achieve maintenance (pre-HD) troughs of 10-20 mg/L in 86.0% of cases including 15-20 mg/L in 35.2%. In prospective validation, the observed postload trough (pre-HD session 2) was 13.5 ± 3.4 mg/L with 76.9% of levels (20 of 26) between 10 and 20 mg/L. The observed maintenance trough was 17.3 ± 4.0 mg/L with 65.5% (19 of 29) between 10 and 20 mg/L and 89.7% (26 of 29) within 10% of the upper limit (ie, 10-22 mg/L)., Conclusions: In this study, a practical vancomycin dosing protocol for patients undergoing HD was developed and prospectively validated to achieve therapeutic serum concentrations in the clinical setting.

Purpose: To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function., Methods: Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges., Results: Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)-2 g q8h as 0.5-3 h infusions. Median estimates for volume of the central compartment, K₁₂ and K₂₁ were 0.24 L/kg, 0.49 h⁻¹, and 0.65 h⁻¹, respectively. K₁₀ was described by the equation: K₁₀= 0.3922 + 0.0025 × CrCl. Model bias and precision were -1.9 and 8.1 mg/L. R², bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30-49, and 10-29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions., Conclusions: This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.

Objectives: To evaluate, using Monte Carlo simulation, the pharmacodynamics (PD) of empirical antibiotic monotherapies for serious infections consistent with Canadian intensive care unit (ICU) surveillance data., Methods: Meropenem, piperacillin/tazobactam and cefepime, along with ceftobiprole, a broad-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), were tested at standard and highest recommended doses with and without prolonged infusion times (t'). Population pharmacokinetic models were used to simulate antibiotic serum concentrations (n = 5000). Cumulative target attainment (CTA) at >50%, >75% and 100% fT( > MIC) (percentage of time free concentrations exceed the MIC) targets were determined based on ICU surveillance data including 4798 pathogens, most commonly methicillin-susceptible S. aureus (20.1%), Escherichia coli (15.2%) and Pseudomonas aeruginosa (12.3%)., Results: With standard doses, ceftobiprole (500 mg every 8 h, t' 2 h) had 0.90 CTA at the >50% fT( > MIC) target while meropenem (1 g every 8 h, t' 0.5 h), piperacillin/tazobactam (3.375 g every 6 h, t' 0.5 h) and cefepime (2 g every 12 h, t' 0.5 h) reached >50% fT( > MIC) in 0.79-0.82 of the population (0.84-0.88 when MRSA was excluded). Piperacillin/tazobactam had the largest reduction in CTA at the >75% and 100% fT( > MIC) targets requiring prolonged infusions to maintain comparable PD. For all agents, prolonged infusions and/or high doses were required to achieve >0.9 CTA at the lowest target, to reach higher targets or to cover less susceptible pathogens such as P. aeruginosa., Conclusions: This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD.

Objectives: Given concerns regarding optimal therapy for serious Gram-negative infections, the goal was to characterize the pharmacodynamics of ciprofloxacin in the context of treating bloodstream infection., Patients and Methods: Data were collected from the medical records of 178 clinical cases. Blood isolates were retrieved and ciprofloxacin MICs were measured. Forty-two cases in which ciprofloxacin was initiated within 24 h of the positive blood culture were used in the pharmacodynamic analysis., Results: Significant factors with regard to treatment failure were low ciprofloxacin AUC(24)/MIC (P < 0.0001), high MIC (P = 0.001), male sex (P = 0.002) and low AUC(24) (P = 0.01). AUC(24)/MIC (P = 0.012) and MIC (P = 0.019) were significant variables in multivariate analyses; however, only the former remained significant (P = 0.038) after excluding two cases with ciprofloxacin-resistant isolates. An AUC(24)/MIC breakpoint of 250 was most significant, with cure rates of 91.4% (32/35) and 28.6% (2/7) in patients with values above and below this threshold, respectively (P = 0.001). The risk of ciprofloxacin treatment failure was 27.8 times (95% confidence interval, 2.1-333) greater in those not achieving an AUC(24)/MIC >or=250 (P = 0.011). Monte Carlo simulation of 5000 study subjects predicted that 0.88 of the population would achieve an AUC(24)/MIC >or=250 with standard-dose ciprofloxacin (400 mg intravenously every 12 h)., Conclusions: This study confirms the pharmacodynamic parameters of ciprofloxacin that are important for optimizing the treatment of serious infections, particularly the benefits of achieving an AUC(24)/MIC >or=250, rather than the conventional target of >or=125. It also shows the relevance of dose selection in optimizing target attainment, with important differences among pathogens, even those with MICs within the susceptible range.

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K(slope) pharmacokinetic model relating the elimination rate constant (K(10)) to renal function, as defined by creatinine clearance (CL(CR)), and central distribution volume (V(1)) to total body weight (TBW). The final model was described by the following equations: K(10) = 0.0027 x CL(CR) + 0.071 h(-1) and V(1) = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K(12) and K(21) were 0.780 h(-1) and 0.472 h(-1), respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 microg/ml, 24.0 microg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 microg/ml, 17.1 microg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Objectives: Antibiotic locks may be used to prevent haemodialysis catheter-related infections (CRIs). This in vitro study tested the effectiveness of a novel 30% ethanol/4% trisodium citrate lock solution in preventing biofilm formation by the most common pathogens causing haemodialysis CRIs., Methods: Ten clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli were tested. Bacterial suspensions of each isolate were prepared in a control solution of normal saline/Mueller-Hinton broth (MHB) and in a lock solution of 30% ethanol/4% trisodium citrate and MHB. The bacterial suspensions were placed into the wells of a Calgary Biofilm Device (CBD) and incubated with fresh solution every 24 h for 72 h. The biofilm formation was assessed by removing the CBD pegs, placing them in normal saline and sonicating them for 5 min. The resulting solution was sampled and the colony counts were determined after 24 h of incubation., Results: All controls demonstrated biofilm growth of between 6 x 10(6) and 7.4 x 10(7) cfu/mL over 72 h. In the 30% ethanol/4% trisodium citrate lock solution, no biofilm growth was observed after 72 h of incubation. These results were consistent among duplicates of all isolates., Conclusions: The 30% ethanol/4% trisodium citrate lock solution prevented the biofilm formation of all isolates of S. aureus, S. epidermidis, P. aeruginosa and E. coli in vitro. Further studies are necessary to determine its efficacy and safety in the haemodialysis population.

We conducted an in vitro study to assess the effect of a 30% ethanol/4% trisodium citrate (TSC) catheter locking solution on isolates of Candida albicans. Twelve isolates obtained from human blood cultures were tested in control solutions composed of broth and normal saline, and a test solution of 30% ethanol, 4% TSC, and broth. Colony counts were determined for control and test solutions at baseline and after 1, 24, and 48 hours of exposure. After 48 hours, the remaining test solution was filtered through a sterile filter funnel and rinsed with 10 mL of sterile water. Filters were aseptically transferred to agar plates and incubated for 24 hours. Control solutions grew well over the incubation period, as expected. In contrast, no viable growth was observed in test solutions 1 hour after instillation of the ethanol/TSC locking solution, or throughout the 48-hour study duration. Additionally, filters from test solutions displayed no growth. We conclude that a 30% ethanol/4% TSC catheter locking solution eradicated all isolates of C. albicans within 1 hour of exposure in this in vitro study, and shows promise as a new hemodialysis catheter locking solution.

Purpose: This in vitro study tested the effectiveness of a novel 30% ethanol/4% trisodium citrate (TSC) lock solution against the most common pathogens causing hemodialysis catheter-related infections., Methods: Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (n = 4), methicillin-sensitive S. aureus (MSSA) (n = 8), methicillin-resistant Staphylococcus epidermidis (MRSE) (n = 8), Pseudomonas aeruginosa (n = 4) and Escherichia coli (n = 4) were tested in duplicate. Bacterial suspensions of each isolate were made in a control solution of normal saline and Mueller-Hinton broth (MHB), and in a lock solution of ethanol 30%, TSC 4% and MHB. Suspensions were incubated at 37 degrees C for 48 h. Colony counts were determined from samples collected at t = 0 h (before exposure to the ethanol/TSC lock), t = 1 h (one hour after exposure to the ethanol/TSC lock), t = 24 h and t = 48 h. To confirm the absence of viable organisms in the lock solution, the remaining volume at 48 h was filtered through a 0.45 microm filter. The filter was rinsed with 15 mL sterile water and plated on tryptic soy agar (TSA)., Results: All controls demonstrated significant growth over 48 h. In the lock solutions, initial inocula were reduced to 0 viable colonies by t = 1 h (6-log kill), and there was no growth at t = 24 and 48 h. Filtering of lock solutions also showed no growth. These results were consistent among duplicates of all isolates., Conclusions: The 30% ethanol/4% TSC lock solution consistently eradicated MRSA, MSSA, MRSE, P. aeruginosa and E. coli within 1 h of exposure. Experiments are currently underway to test this novel lock solution on preventing biofilm production by these pathogens.

Background: Some investigators have recommended the convenient practice of administering vancomycin doses during the last hour of the hemodialysis treatment. Accepting that a greater amount of vancomycin is lost to dialysis with this recent approach, the objective of this study is to determine the pharmacokinetics of vancomycin and assess the adequacy of this dosing regimen in maintaining therapeutic predialysis concentrations., Methods: A sampling of 22 consecutive patients administered intradialytic vancomycin, 1 g, intravenously (IV) and maintenance doses of 500 mg during the last hour of high-flux dialysis sessions was studied. A population-modeling program and Bayesian pharmacokinetic analysis were used to identify all global and unique pharmacokinetic parameters of interest based on measured vancomycin predialysis concentrations., Results: For the 22 patients studied, this regimen achieved the targeted predialysis concentration range of 5 to 20 microg/mL for 96% of levels, whereas more narrowly within 5 to 15 microg/mL for 86% of levels. Average amount of vancomycin removed during a standardized 3- to 4-hour dialytic session ranged from 30% +/- 7% to 38% +/- 8%. Average elimination half-life of vancomycin on hemodialysis treatment was 5.4 hours (interquartile range, 5.0 to 5.9 hours). Patients showed an average predialysis plasma concentration of 11 +/- 3 microg/mL for the first 7 days of therapy., Conclusion: Our results indicate that intradialytic dosing with vancomycin using a 1-g IV load and 500 mg IV with subsequent high-flux dialysis sessions conveniently maintains adequate predialysis plasma concentrations. The lack of drug accumulation with this regimen provides convincing support for a limited blood sampling approach to plasma concentration determinations.

The goal of this study was to investigate clinical doses of trimethoprim-sulfamethoxazole (TMP-SMX) alone and in combination against Stenotrophomonas maltophilia in an in vitro pharmacodynamic infection model. A 1-compartment model was established using 4 clinical isolates of S. maltophilia susceptible to TMP-SMX and susceptible or intermediately susceptible to at least one other agent (ie, ceftazidime, ciprofloxacin, gentamicin, tobramycin). Antibiotics alone and in combination were tested by simulating unbound serum concentration profiles achieved with multiple-dose regimens in humans. Despite susceptible minimum inhibitory concentrations, TMP-SMX alone was bacteriostatic at best against all isolates. All antibiotic combinations were more active than monotherapy as determined by bacterial reductions at both 24 and 48 h (P < 0.0001). Significant benefit was observed even with agents inactive alone or only intermediately susceptible based on minimum inhibitory concentrations. These preclinical data support further investigation of antibiotic combinations in the management of serious S. maltophilia infections.

Background: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome., Objective: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality., Methods: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome., Results: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01)., Conclusions: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

The goal of this study was to investigate the effect of antibiotic sequence on combination regimens against Pseudomonas aeruginosa in an in vitro infection model. Ceftazidime plus ciprofloxacin and ceftazidime plus tobramycin were dosed every 12 h for 48 h using simultaneous or staggered administration. Simultaneous dosing and ceftazidime followed by ciprofloxacin or tobramycin were significantly more active at both 24 h (p = 0.03) and 48 h (p < 0.0001) than ciprofloxacin or tobramycin followed by ceftazidime. Final bacterial kill was sixfold greater with the former regimens. This study showed that antibiotic sequence had a significant and class dependent effect on antibacterial response. The clinical relevance of these observations warrants further investigations in animal models.

Standard microbiological tests (i.e., MIC) do not account for the unique factors of peritoneal dialysis (PD)-related peritonitis which can significantly influence treatment response. Our goals were to develop a peritoneal fluid titer (PFT) test and to conduct a pilot study of its association with clinical outcome. The methodology was developed by using spent dialysate collected from patients with bacterial PD-related peritonitis prior to the initiation of antibiotics. Dialysate was processed and spiked with antibiotic to simulate two standard intraperitoneal regimens: cefazolin plus tobramycin and cefazolin alone. Thirty-six clinical isolates, including Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, were tested. In the pilot study, dialysate was collected from 14 patients with bacterial PD-related peritonitis. Titers were determined by using each patient's dialysate and infecting pathogen. Titers were highly reproducible, with discrepancies in only 1% of cases. Overall, PFTs were notably higher against gram-positive bacteria (P < 0.0001). The addition of tobramycin increased titers significantly from zero to values of 1/16 to 1/64 against E. cloacae and P. aeruginosa (P < 0.0001). In the pilot study, peritoneal fluid inhibitory titers were significantly associated with clinical outcome, with a median value of 1/96 for patients who were cured compared to 1/32 for those who failed treatment (P = 0.036). In conclusion, this study provides preliminary support for the PFT as a pharmacodynamic index specific to the treatment of PD-related peritonitis. With further characterization and validation in patients, the PFT test may advance the study of antibiotic therapies for PD-related peritonitis.

Objectives: To conduct a retrospective study of antibiotic pharmacodynamics in the treatment of Pseudomonas aeruginosa bacteraemia, and to identify pharmacodynamic indices associated with clinical cure., Methods: Cases of P. aeruginosa bacteraemia were identified, and information related to patient demographics, clinical status, antibiotic treatment and clinical outcome were documented. Anti-pseudomonal therapy was assessed, and concentration versus time profiles were constructed using measured levels for aminoglycosides, or population pharmacokinetic models for other antibiotics. P. aeruginosa isolates from all patients were retrieved and MICs for the anti-pseudomonal agents used to treat the episode of bacteraemia were determined. Patient- and treatment-related factors were tested for associations with clinical outcome using univariate and multivariate analyses., Results: Fifty cases of P. aeruginosa bacteraemia were identified and 38 cases were included in the pharmacodynamic analysis. Eighty-seven percent of patients received an aminoglycoside or ciprofloxacin and 79% received piperacillin or ceftazidime. A majority of patients, 71%, were administered a combination of antibiotics. Treatment outcomes were documented as persistent infection in 21%, death within 2-30 days in 21% and clinical cure in 58% of cases. Peak/MIC (P=0.001) and AUC24/MIC (P=0.002) for aminoglycosides and ciprofloxacin were significant factors in univariate tests. Only peak/MIC was associated independently with treatment outcome (P=0.017) in logistic regression analysis. The predicted probability of cure was > or =90% when peak/MIC was at least 8., Conclusion: Pharmacodynamic considerations including aggressive dosing with targeted peak/MICs for aminoglycosides and ciprofloxacin are strongly associated with clinical outcome and essential to the appropriate management of P. aeruginosa bacteraemia.

Objective: To conduct a comprehensive pharmacodynamic analysis of moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro infection model., Methods: In dose escalation studies, single doses with peak concentrations equivalent to 1 x, 2 x, 4 x, 8 x, 16 x and 32 x MIC against two isolates of S. pneumoniae were studied over 24 h. Traditional pharmacodynamic indices, including peak concentration divided by MIC (peak/MIC), time of concentration above MIC (T > MIC) and AUC24/MIC, were estimated for all regimens. As a continuous index of fluoroquinolone exposure, AUC0-t/MIC was also calculated, as AUC from time 0 to 1, 2 and 6 h divided by MIC. Correlations between pharmacodynamic indices and antibacterial effects were examined using linear and non-linear methods. In validation experiments, the pharmacodynamic model was used to predict bacterial kill curves, produced by simulated clinical doses of moxifloxacin and levofloxacin against two other S. pneumoniae isolates., Results: Peak/MIC was most predictive of early bacterial kill, whereas T > MIC was significantly associated with final bacterial counts at 24 h. Antibacterial effects were bacteriostatic when T > MIC was 48% and bactericidal when values exceeded 55%. AUC0-t/MIC was strongly associated with bacterial kill throughout the dosing interval. Bactericidal activity and bacterial eradication were associated with AUC0-t/MICs of 28 and 135, respectively. AUC0-t/MIC was also highly predictive of bacterial kill curves produced by simulated clinical doses of moxifloxacin and levofloxacin (precision 0.36 log10 cfu/mL, bias 0.02 log10 cfu/mL)., Conclusion: This study demonstrated the novel application of AUC0-t/MIC as a continuous index of antibiotic activity, and provided extensive characterization of fluoroquinolone pharmacodynamics against S. pneumoniae.

The objective of this study was to characterize the relationship between gentamicin concentrations during surgery and the development of wound infection following colorectal operations. Despite decades of research in surgical prophylaxis, the relationship between intraoperative antibiotic concentrations and postoperative infection and the concentrations required for effective prophylaxis have not been established. A pharmacodynamic analysis was conducted using data from a previous prospective, randomized, double-blind clinical study which compared two dosage regimens of gentamicin plus metronidazole for prophylaxis in connection with elective colorectal surgery. Univariate and multivariate analyses of risk factors for postoperative wound infection were conducted, and the relationship between intraoperative gentamicin concentrations and surgical outcome was characterized. The gentamicin concentration at the time of surgical closure was one of the strongest independent risk factors for infection (P = 0.02), along with the presence of diabetes mellitus (P = 0.02), stoma (P = 0.04), and advanced age (P = 0.05). Gentamicin concentrations at closure of less than 0.5 mg/liter were associated with an infection rate of 80% (representing 8 of 10 patients with concentrations below that level) (P = 0.003). Receiver operating characteristic curve analysis identified a critical closure concentration of 1.6 mg/liter for effective surgical prophylaxis (P = 0.002; sensitivity, 70.8%; specificity, 65.9%). This study provides new and important information on antibiotic pharmacodynamics in surgical prophylaxis. It demonstrates the critical effect of the antibiotic concentration at closure on wound infection and suggests a significant association between the concentration and other well-established risk factors, like the timing of preoperative antibiotic administration and surgery duration.

Objectives: To analyze clinical outcomes of Staphylococcus epidermidis peritoneal dialysis peritonitis before and after an interventional switch from a vancomycin/ tobramycin to a cefazolin/tobramycin regimen for empiric treatment. To examine risk factors associated with clinical failure., Design: A retrospective study., Setting: A peritoneal dialysis program within a university-affiliated tertiary-care hospital., Patients: 93 episodes of S. epidermidis peritonitis over a 6-year period., Interventions: Clinical responses were compared between treatments using chi-square or Fisher's exact test. Univariate and multivariate analyses were used to identify significant risk factors for clinical failure., Measurements and Main Results: There was no difference in the overall response rates observed with vancomycin (40/49; 81.6%) and cefazolin (23/29; 79.3%) regimens for episodes of S. epidermidis peritonitis. Furthermore, the presence of methicillin resistance in 63 of 93 cases (67.7%) had no influence on clinical outcome, with response rates of 83.9% (26/31) and 82.4% (14/17) for empiric vancomycin and cefazolin regimens, respectively. Tobramycin therapy of less than 2 days was an independent risk factor for clinical failure in multivariate logistic regression analysis (odds ratio 4.44, 95% confidence interval 1.28 - 15.48; p = 0.02)., Conclusions: Empiric treatment with intraperitoneal cefazolin was as effective as vancomycin for S. epiderimidis peritonitis despite a high prevalence of methicillin resistance. Tobramycin therapy of less than 2 days was strongly associated with treatment failure.

This in vitro study investigated the ability of antibiotic/heparin locks to sterilize central venous haemodialysis catheters (CVCs) inoculated with methicillin-resistant Staphylococcus epidermidis (MRSE). Isolates of MRSE were incubated in broth inside CVCs. The catheters were then drained and filled with either vancomycin/gentamicin/heparin (VGH), cefazolin/gentamicin/ heparin (CGH) or control locks for 48 h. The catheters were drained, filled with fresh broth and again incubated. The final catheter solutions were sampled and the remaining volumes filtered. The samples, filters and catheter segments were examined for growth. For two isolates, both the VGH and CGH locks sterilized the catheters. Bacterial counts of the remaining two isolates were significantly reduced by >99%, but the catheters were not sterilized after the instillation of a single-antibiotic/heparin lock.

Single, high dose regimens of gentamicin plus metronidazole for colorectal surgical prophylaxis have not been adequately studied. Patients received single high dose gentamicin (4.5 mg/kg) plus metroni-dazole (500 mg) preoperatively or multiple standard dose gentamicin (1.5 mg/kg) plus metronidazole (500 mg) preoperatively and every 8h for 24h postoperatively. The deep surgical site infection (SSI) rates were 8.1% (6/74) and 6.9% (5/72) in the single high dose and multiple standard dose groups, respectively (P= 0.94). There was a trend towards fewer superficial SSIs in the single high dose group with infection rates of 18.9% (14/74) vs. 30.6% (22/72) (P= 0.05). Diabetes mellitus (odds ratio = 7.04) and surgery duration of longer than 3h (odds ratio = 5.46) were independent risk factors for the development of SSIs. A subset analysis of prolonged operations found significantly fewer superficial SSIs in the single high dose group than in the multiple standard dose group with rates of 22.2% (6/27) vs. 55% (11/20), respectively (P= 0.021). Single high dose gentamicin plus metronidazole preoperatively was at least as effective as the multiple standard dose regimen and may be more effective for prolonged operations., (Copyright 2000 The Hospital Infection Society.)

The pharmacodynamics of an investigational glycopeptide, LY333328 (LY), alone and in combination with gentamicin, against one vancomycin-susceptible and two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM). Dose-range data for the PDM studies were obtained from static time-kill curve studies. In PDM experiments conducted over 48 h, peak LY concentrations of 0.1x and 1x the MIC every 24 h and peak gentamicin concentrations of 18 micrograms/ml every 24 h (Gq24 h) and 6 micrograms/ml every 8 h (Gq8 h) were studied alone and in the four possible LY-gentamicin combinations. Compared to either antibiotic alone, LY-gentamicin combination regimens produced significantly higher apparent killing rates (KRs) calculated during the initial 2 h postdosing. The mean KRs for LY or gentamicin alone versus those for the LY-gentamicin combination regimens were 0.35 +/- 0.55 log10 CFU/ml/h (95% confidence interval [CI95%], 0 to 0.70) and 1.46 +/- 0.71 log10 CFU/ml/h (CI95%, 1.01 to 1.91), respectively (P < 0.0001). Bacterial killing at 48 h (BK48), which was calculated by subtracting the bacterial counts at 48 h from the initial inoculum, with a negative value indicating net growth, was also significantly greater. The mean BK48S were -0.69 +/- 0.44 log10 CFU/ml (CI95%, -0.41 to -0.97) and 3.72 +/- 2.28 log10 CFU/ml (CI95%, 2.28 to 5.17) for LY or gentamicin alone versus LY-gentamicin combination regimens, respectively (P < 0.0001). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the LY-gentamicin combination regimens were bactericidal. Eighty-three percent (10 of 12) of the LY-gentamicin combination regimens also demonstrated synergy. No significant differences between the pharmacodynamics of LY-gentamicin combination regimens containing Gq24 h versus those containing Gq8h were detected.

Fifty-two percent of stool specimens collected from 1,200 high-risk patients were colonized with yeasts, primarily Candida albicans (53. 6%) and Candida glabrata (35.7%). Susceptibilities to all antifungal agents tested, including LY303366, were similar to those reported previously for Candida species isolated from blood.

The purpose of this study was to compare once daily (To24) and thrice daily (To8) tobramycin dosing regimens alone and in combination with ceftazidime, ciprofloxacin and imipenem against a clinical and ATCC strain of Pseudomonas aeruginosa. A one-compartment in vitro pharmacodynamic model was used to simulate bacteremic infection. Pharmacodynamic parameters, including rate of bacterial kill following the first dose or time to achieve a 99.9% reduction in bacterial counts (T99.9%), extent of bacterial kill with subsequent doses and bacterial count at 24 h were characterized for each regimen. Compared to To8 alone, the combination regimens had a shorter T99.9% (p = 0.045) and greater extent of bacterial kill following the first dose (p = 0.045). Compared to To24 alone, the combination regimens demonstrated similar rates (p = 0.067) and extents of bacterial kill following the first dose (p = 0.32), however, produced lower bacterial counts at 24 h (p = 0.045). The various combination regimens appeared equally effective considering rate and extent of bacterial kill following the first dose and residual inocula at 24 h. Ciprofloxacin-containing regimens demonstrated the most bacterial kill with subsequent doses, however, bacterial counts at 24 h were similar to those of other combination regimens.

In vitro killing by a new semisynthetic echinocandin, LY-303366, was characterized using clinical isolates of fluconazole-sensitive (Y58) and -resistant (Y180) Candida albicans as well as Candida glabrata (Y7) and Candida krusei (Y171). The 24-h kill curves for Y58 and Y180 demonstrated dose-independent killing of between 1 and 2 log10 with LY-303366 at concentrations of 0.1, 1, 10, 50, 100, and 1,000 times the MIC. Regrowth did not occur at 24 h with either C. albicans isolate at the aforementioned LY-303366 concentrations. At their MICs, LY-303366 and amphotericin B produced similar killing kinetics in cultures of Y58, Y180, Y7, and Y171, while all cultures exposed to fluconazole at its MIC demonstrated stasis or growth over 24 h.

BMS-181184 is a water-soluble derivative of the pradimicin group of antifungal compounds. We determined the in vitro activities of BMS-181184 and comparator agents amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 184 systemic fungal isolates collected at the Health Sciences Centre in Winnipeg, Canada, between 1987 and 1995. BMS-181184 demonstrated MICs of between 1 and 8 micrograms/mL for all Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida lusitaniae, and Cryptococcus neoformans isolates tested. BMS-181184 was less active against Candida parapsilosis (MIC90 = 16 micrograms/mL) and Blastomyces dermatitidis (MIC90 = 32 micrograms/mL). Isolates of Candida species with fluconazole MICs of > or = 16 micrograms/mL and those with fluconazole MICs of < or = 8 micrograms/mL demonstrated similar BMS-181184 sensitivities.

Aminoglycoside adaptive resistance is defined as reduced antimicrobial killing in originally susceptible bacterial populations after initial incubation with aminoglycoside. It is observed in vitro and in vivo, most commonly with Pseudomonas aeruginosa. It appears to correlate with a marked reduction in intracellular aminoglycoside accumulation, although its specific mechanism and the cellular structures responsible remain unknown in P. aeruginosa. Recent work suggests that adaptive resistance develops coincident with cytoplasmic membranes protein changes and regulated expression of genes in the anaerobic respiratory pathway of the organism. It is clinically most relevant in immunocompromised patients and in those with serious infections, especially infections due to gram-negative rods. Treatment of these patients by targeting high peak concentration:minimum inhibitory concentration ratios with once-daily dosing may result in the best outcome. A major unresolved issue concerns the effect of combination therapy on the development of aminoglycoside adaptive resistance.

The in vitro activities of LY-303366, a new semisynthetic echinocandin, and comparators amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 205 systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species were determined. LY-303366 had MICs of < or = 0.32 microg/ml for all Candida albicans (n = 99), Candida glabrata (n = 18), and Candida tropicalis (n = 10) isolates tested. LY-303366 was also active against Aspergillus species (minimum effective concentration at which 90% of the isolates are inhibited, 0.02 microg/ml) (n = 20), was less active against Candida parapsilosis (MIC at which 90% of the isolates are inhibited [MIC90], 5.12 microg/ml) (n = 10), and was inactive against C. neoformans (MIC90, >10.24 microg/ml) (n = 15) and B. dermatitidis (MIC90, 16 microg/ml) (n = 29).