Major publications in the critical care pharmacotherapy literature: January-December 2016.

PURPOSE: To summarize select critical care pharmacotherapy guidelines and studies published in 2016. SUMMARY: The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 31 journals monthly for relevant pharmacotherapy articles and selected 107 articles for review over the course of 2016. Of those included in the monthly CCPLU, three guidelines and seven primary literature studies are reviewed here. The guideline updates included are as follows: hospital-acquired pneumonia and ventilator-associated pneumonia management, sustained neuromuscular blocking agent use, and reversal of antithrombotics in intracranial hemorrhage (ICH). The primary literature summaries evaluate the following: dexmedetomidine for delirium prevention in post-cardiac surgery, dexmedetomidine for delirium management in mechanically ventilated patients, high-dose epoetin alfa after out-of-hospital cardiac arrest, ideal blood pressure targets in ICH, hydrocortisone in severe sepsis, procalcitonin-guided antibiotic de-escalation, and empiric micafungin therapy. CONCLUSION: The review provides a synopsis of select pharmacotherapy publications in 2016 applicable to clinical practice.

Ceftolozane/Tazobactam: A Novel Cephalosporin/ß-Lactamase Inhibitor Combination.

Ceftolozane/tazobactam is a novel antipseudomonal ß-lactam/ß-lactamase inhibitor combination that is currently approved by the United States Food and Drug Administration for the treatment of complicated intraabdominal infections (cIAI) and complicated urinary tract infections (cUTI). It exhibits bactericidal properties through inhibition of bacterial cell wall biosynthesis, which is mediated through penicillin-binding proteins (PBPs). Ceftolozane is a potent PBP3 inhibitor and has a higher affinity for PBP1b compared with other ß-lactam agents. Ceftolozane/tazobactam differs from other cephalosporins due to its increased activity against some AmpC ß-lactamases and Pseudomonas aeruginosa. The addition of tazobactam provides enhanced activity against extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and certain anaerobic organisms. Population pharmacokinetic studies for ceftolozane and ceftolozane/tazobactam are best described by a two-compartment model with zero-order input and linear elimination. Similar to other cephalosporins, the best pharmacodynamic property to predict efficacy for ceftolozane/tazobactam is a concentration that remains above the minimum inhibitory concentration (MIC) for 40-50% of the dosing interval. For Enterobacteriaceae and P. aeruginosa strains, the time above the MIC (T > MIC) needed to produce bactericidal activity was much less with ceftolozane than other cephalosporins, with T > MIC requirements of approximately 30%. For currently approved indications, the dose of ceftolozane/tazobactam is 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) intravenously every 8 hours given as a 1-hour infusion. Ceftolozane has low plasma protein binding (20%) and is predominantly excreted unchanged in the urine (≥ 92%). Dosage adjustments are required for moderate-to-severe renal impairment and in patients receiving hemodialysis. Based on data from clinical trials, adverse effects due to ceftolozane/tazobactam do not differ considerably from other cephalosporins, with the most common being nausea, diarrhea, headache, and pyrexia. Ceftolozane/tazobactam is a promising new agent for the treatment of cIAI and cUTI, including those caused by multidrug-resistant gram-negative organisms.

Assessment of a modified 4T scoring system for heparin-induced thrombocytopenia in critically ill patients.

PURPOSE: The purpose of the study is to determine if a modified 4T (m4T) scoring system, which omits clinical evaluation of other thrombocytopenic etiologies, is different from the 4T scoring system's probability to predict a positive heparin-induced thrombocytopenia (HIT) laboratory test in the intensive care unit. MATERIALS AND METHODS: This is a single-centered retrospective analysis of critically ill adults who had an enzyme-linked immunosorbent assay antiplatelet factor 4 antibody (ELISA anti-PF4 Ab) ordered. Patients were identified as HIT positive (optical density, ≥0.40) or HIT negative (optical density, <0.40) based on the ELISA anti-PF4 Ab. Both 4T and m4T scores were calculated, and the diagnostic accuracy was compared using paired receiver operating characteristic curves. RESULTS: A total of 1487 adult intensive care unit patients with an ELISA anti-PF4 Ab ordered between January 2007 and December 2009 were eligible for study enrollment. Application of exclusion criteria and random selection yielded a total of 232 patients included for analysis (58 HIT-positive and 174 HIT-negative patients). The area under the curve for the 4T and m4T scores were 0.683 (95% confidence interval, 0.604-0.762) and 0.680 (95% confidence interval, 0.600-0.759), respectively (P=.065). CONCLUSION: This study does not show a difference in the probability of the m4T and 4T scoring systems to predict a positive ELISA anti-PF4 Ab test in the critically ill patient population. Further prospective studies are needed to validate the m4T scoring system.

Clinical epidemiology of carbapenem-intermediate or -resistant Enterobacteriaceae.

OBJECTIVES: Despite the increasing incidence of carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), risk factors associated with CIRE infections have not been well defined. This study characterizes factors associated with CIRE among two different source populations. METHODS: A case-control study was performed at a tertiary care medical centre between January 2005 and December 2009. Cases were adults with a culture-confirmed Enterobacteriaceae infection with reduced susceptibility to meropenem or ertapenem. The CIRE cases were matched 1:1 to patients from two different control series: (i) those with carbapenem-susceptible Enterobacteriaceae (CSE) infections; and (ii) inpatients residing on the same ward within 30 days of CIRE culture date. Logistic regression was used to identify variables independently associated with CIRE among each source population. Restricted multivariate analyses were performed to determine if covariates predictive of CIRE varied by infecting organism or presence of the bla(KPC) gene. RESULTS: There were 102 cases of CIRE during the study period. The only covariate independently associated with CIRE in all multivariate analyses was the cumulative number of prior antibiotic exposures. Compared with CSE controls, the odds ratios (95% confidence interval) were 1.43 (1.19-1.72), 2.05 (1.70-2.47) and 2.93 (2.43-3.53) for 1, 2 and ≥ 3 antibiotic exposures, respectively. The strength of this association was comparable for the hospitalized control group and analyses stratified by organism and presence of the bla(KPC) gene. CONCLUSIONS: A patient's cumulative antibiotic exposure history is likely to be more important than any one specific exposure when determining the likelihood of developing a CIRE infection.