R. Brigg Turner

Role of Doxycycline in Clostridium difficile Infection Acquisition

Objective:To evaluate and review the literature surrounding the potential protective benefit of tetracyclines, particularly doxycycline, in reducing Clostridium difficile infection (CDI) acquisition. Data Sources: MEDLINE/PubMed, Google Scholar, and International Pharmaceutical Abstracts were searched through January 2014 using the search terms doxycycline, tetracycline, and Clostridium difficile. Study Selection and Data Extraction: Relevant studies, case reports, and review articles were screened for inclusion. Bibliographies of articles were extensively reviewed for additional sources. Data Synthesis: Doxycycline is a second-generation tetracycline antibiotic indicated for use in a variety of clinical syndromes and has activity against aerobic Gram-positive and -negative, anaerobic, and atypical bacteria as well as protozoan parasites. Although not used therapeutically to treat CDI, doxycycline may prevent or attenuate the virulence factors of toxigenic C difficile. Current literature does not indicate an increased risk of development of CDI with doxycycline use. In 3 retrospective studies, the use of doxycycline was associated with a protective effect. Conclusions: Doxycycline has been shown to have potential protective effects against the development of CDI. Although further randomized placebo-controlled studies are needed, available data suggest that the use of doxycycline in place of alternative antimicrobials, when appropriate, may be a useful antimicrobial stewardship strategy aimed at reducing the incidence of CDI.

Worsening renal function in patients with baseline renal impairment treated with intravenous voriconazole: A systematic review

The objective of this paper was to review the risk of worsening renal function in patients with pre-existing renal impairment receiving intravenous voriconazole (IVV). Controversy exists regarding the cause and risk of renal dysfunction in patients treated with IVV. Whilst some studies implicate renally excreted cyclodextrin, a pharmaceutical formulation stabiliser, as the cause of renal dysfunction following voriconazole administration, others provide contradicting evidence. Here we analyse the available literature to gain an insight into the significance of renal toxicity in patients treated with IVV. PubMed was searched for relevant studies to December 2014. To account for publication bias, abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Infectious Diseases Society of America/ID Week, and the European Congress of Clinical Microbiology and Infectious Diseases from 2008-2014 were reviewed. Bibliographies of all identified articles were reviewed and cross-referenced for additional sources. Seven retrospective studies were identified for inclusion in the review; no prospective studies were identified. Based on the available evidence, we conclude that there is no strong evidence suggesting an increased incidence of worsening renal function with IVV use. No study thus far has provided direct conclusive evidence for cellular and physiological renal toxicity due to IVV at clinically prevalent doses.

Ceftaroline for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus: a case series

Despite limited clinical data, ceftaroline is commonly used for treatment of complicated, invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). A retrospective chart review was conducted of adult patients receiving ceftaroline for MRSA osteomyelitis admitted between April 2011 and March 2016 at a five-hospital system. Twelve patients met the inclusion criteria. All patients received prior antimicrobial therapy with a median time to switch to ceftaroline of 45.5 days. Five of the 12 patients (41.7%) met criteria for ceftaroline failure. Patients with vertebral osteomyelitis (58%) had a longer length of stay, longer ceftaroline treatment, but similar success rates to those with non-vertebral osteomyelitis (57% vs. 60%). Ceftaroline is a viable alternative for a challenging patient population that has failed or are unable to receive other therapies.

Impact of rapid identification of Staphylococcus aureus bloodstream infection without antimicrobial stewardship intervention on antibiotic optimization and clinical outcomes

Few studies have evaluated the clinical impact of polymerase chain reaction (PCR) for Staphylococcus aureus bloodstream infections in resource-limited settings that lack direct antimicrobial stewardship intervention. This retrospective cohort study compared patients with standard microbiological identification (n=343) to those with additional identification by (PCR) (n=130). Time to initiation of optimal therapy was similar between groups but substantially shorter in the PCR group for those infected with methicillin susceptible S. aureus (median 40.0h vs. 28.3h, P=0.001). After controlling for confounding factors including infectious diseases consultation, the PCR group had a shorter time to initiation of optimal therapy by 9.7h (95% CI 4.3-15.0h). Clinical outcomes were similar in the non-PCR and PCR groups. While time to initiation of optimal therapy was shorter in the PCR group, greater reductions may be realized through additional education, direct antimicrobial stewardship intervention, or additional clinician notification.

Impact of an Antimicrobial Stewardship Program on Antibiotic Use at a Nonfreestanding Children's Hospital

Background Pediatric stewardship programs have been successful at reducing unnecessary antibiotic use. Data from nonfreestanding childrens hospitals are currently limited. This study is an analysis of antibiotic use after implementation of an antimicrobial stewardship program at a community nonfreestanding childrens hospital. Methods In April 2013, an antimicrobial stewardship program that consisted of physician-group engagement and pharmacist prospective auditing and feedback was initiated. We compared antibiotic use in the preintervention period (April 2012 to March 2013) with that in the postintervention period (April 2013 to March 2015) in all units except the neonatal intensive care unit and the emergency department. In addition, drug-acquisition costs, antibiotic-specific use, death, length of stay, and case-mix index were examined. Results Antibiotic use decreased by 16.8% (95% confidence interval, 18.0% to -9.2%; P < .001) in the postintervention period. Vancomycin use decreased by 38% (P = .001), whereas antipseudomonal β-lactam use was unaltered. Drug-acquisition cost savings were estimated to be

Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline

67 000/year over the 2-year postintervention period. Lengths of stay and mortality rates were unchanged in the postintervention period after adjusting for case-mix index. Conclusions Implementation of a simple stewardship initiative with limited resources at a community nonfreestanding childrens hospital effectively reduced antibiotic use without an overt negative impact on overall clinical outcomes. The results of this study suggest that nonfreestanding childrens hospitals can achieve substantial reductions in antibiotic use despite limited resources.

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Objectives Ceftaroline is often used in durations greater than that studied in clinical trials. Several retrospective, non-comparative studies have suggested a higher than anticipated incidence of neutropenia in patients receiving prolonged treatment with ceftaroline. We sought to determine if ceftaroline was associated with neutropenia by comparing the incidence with ceftaroline treatment with treatment with several comparative antibiotics. Methods Patients receiving 14 or more consecutive days of treatment with ceftaroline were compared with patients receiving cefazolin, daptomycin, linezolid, nafcillin or vancomycin (control group). The primary outcome was the development of neutropenia. Multivariate logistic regression and propensity score weighting using inverse probability weights with regression adjustment were used to control for confounding variables. Results A total of 753 patients were included (53 that received ceftaroline and 700 that received a comparative antibiotic). Ceftaroline was associated with a greater incidence of neutropenia as compared with the control group (17.0% versus 3.9%, P < 0.001). Several covariates were also associated with neutropenia and included younger age, lower baseline absolute neutrophil count, liver disease and bone and joint infections. After controlling for these confounders, receipt of ceftaroline continued to be associated with the development of neutropenia (adjusted OR 3.97, P = 0.003). Analysis after propensity score weighting confirmed this finding. Conclusions The results of this study suggest that prolonged treatment with ceftaroline is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. Careful monitoring of absolute neutrophil count is recommended in patients receiving >14 days of ceftaroline.

Clinical outcomes following hospital-wide implementation of prolonged-infusion cefepime and ceftazidime

ABSTRACT The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m2, respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)

Review and validation of Bayesian dose optimizing software and equations for calculation of the vancomycin area under the curve in critically ill patients

Prolonged infusion (3–4 h) of -lactam antibiotics may optiise the pharmacodynamic properties of these time-dependent gents [1]. Whilst clinical outcome data exist for some -lactam ntibiotics, limited data are available for cefepime and ceftazidime 2,3]. Our academic medical centre recently selected prolonged nfusion (PI) as the preferred infusion method for ceftazidime nd cefepime administration based on previously published pharacokinetic and pharmacodynamic data [4]. We conducted a uasi-experimental study to determine whether there was a clincal advantage or disadvantage to PI compared with standard nfusion (SI) in treating infections caused by Gram-negative orgaisms. Medication records at our academic medical centre for adult atients receiving ≥3 days of cefepime or ceftazidime from 1 anuary 2010 to 31 March 2013 were retrospectively searched. atients receiving either drug prior to 1 January 2012 received SI ver 30 min; after this date, all regimens were administered with a oading dose given over 30 min followed by PI over 180 min. Clinical utcomes were compared between the pre-intervention (SI) and ost-intervention (PI) groups. Only patients with a proven Gramegative organism identified in blood or respiratory cultures were ncluded in the study. The primary outcome was in-hospital morality. Secondary outcomes included clinical cure at 7 days as well as ospital and intensive care unit (ICU) length of stay. This study was ranted exempt status by the institutional review board of West irginia University Healthcare. A total of 2868 patients received cefepime or ceftazidime durng the study period, with 329 (11.5%) of these patients having culture meeting the inclusion criteria. Following other excluions, 108 patients were included in the final analysis. Overall, aseline characteristics were similar between the SI and PI groups, ith the exception that isolation of Pseudomonas aeruginosa was ore frequent in the PI group (40.6% vs. 63.6%; P = 0.03). Primary nd secondary outcomes were similar between groups (Table 1) ith the exception of longer ICU length of stay in the PI group P = 0.003). There was a non-statistically significant trend in inospital mortality favouring PI when limiting the analysis to atients admitted to the ICU [hazard ratio (HR) = 0.44, 95% confience interval (CI) 0.12–1.60] or those infected with P. aeruginosa HR = 0.38, 95% CI 0.10–1.46). Isolation of a resistant pathogen was he only variable independently predictive of in-hospital mortality adjusted HR = 4.04, 95% CI 1.03–15.85). After controlling for resisant pathogens, receipt of PI continued to be associated with longer CU length of stay (P = 0.03).

Prospective evaluation of vancomycin pharmacokinetics in a heterogeneous critically ill population

Vancomycin area under the concentration‐time curve (AUC) has been linked to efficacy and safety. An accurate method of calculating the AUC is needed.