Robert E. Ariano

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.

Background: Tranexamic acid (TXA) reduces transfusion in a wide range of surgical populations, although its real‐world use in non‐cardiac surgeries has not been well described. The objective of this study was to describe prophylactic TXA use in non‐cardiac surgeries at high risk for transfusion.Methods: This is a retrospective cohort study of all adult patients undergoing major non‐cardiac surgery at ≥5% risk of perioperative transfusion at five Canadian hospitals between January 2014 and December 2016. Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database were linked to transfusion and laboratory databases. TXA use was ascertained electronically from The Ottawa Hospital Data Warehouse and via manual chart review for Winnipeg hospitals. For each surgery, we evaluated the percentage of patients who received TXA as well as the specifics of TXA dosing and administration.Results: TXA use was evaluable in 14 300 patients. Overall, 17% of surgeries received TXA, ranging from 0% to 68% among individual surgeries. TXA use was more common in orthopaedic (n = 2043/4942; 41%) and spine surgeries (n = 239/1322; 18%) compared to other surgical domains (n = 109/8036; 1%). TXA was commonly administered as a bolus (n = 2097/2391; 88%). The median TXA dose was 1000 mg (IQR 1000–1000 mg).Conclusion: TXA is predominantly used in orthopaedic and spine surgeries, with little uptake in other non‐cardiac surgeries at high risk for red blood cell transfusion. Further studies are needed to evaluate the effectiveness and safety of TXA and to understand the barriers to TXA administration in a broad range of non‐cardiac surgeries.

Carfentanil and related fentanyl analogs have been linked to a number of overdose deaths from drug users in several cities across North America. Diagnosis of carfentanil exposure requires a very high index of clinical suspicion, especially because available laboratory narcotic screens do not detect this agent. We describe a 34‐year‐old man admitted with depressed level of consciousness and in respiratory failure after recreational exposure to a white powder later inferred to contain carfentanil. Urine and whole blood samples were obtained for conventional preliminary drug screen immunoassays for unknown exposures, in addition to utilizing a high‐pressure liquid chromatography–tandem mass spectrometry assay for quantification of carfentanil and its metabolite. The patient was intubated and required mechanically assisted ventilation for 31 hours until he was able to breathe safely on his own. Pharmacokinetic modeling of three timed blood samples identified the elimination half‐life as 5.7 hours for carfentanil and 11.8 hours for the norcarfentanil metabolite. Awakening and breathing spontaneously corresponded to an interpolated blood carfentanil concentration of 0.52 ng/ml. This is the first pharmacokinetic and pharmacodynamic case report on the recreational use of carfentanil. Critical care clinicians should anticipate long periods of ventilatory support in the care of patients exposed to carfentanil.

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. 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). Fifty-five subjects (64.9 ± 10.4 years, 89.7 ± 16.5 kg, CL_CR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations dosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. 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.

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.

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. 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. 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. 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.