Kristen L. Bunnell

Nephrotoxicity Associated with Concomitant Use of Ledipasvir-Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection

Direct‐acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon‐based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)‐coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir‐sofosbuvir (LDV‐SOF). A 56‐year‐old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV‐SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9–1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV‐SOF and TDF were discontinued, and the patients serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV‐SOF is commonly prescribed in patients with HIV‐HCV coinfection, as patients who received LDV‐SOF– and TDF‐containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV‐SOF and TDF. Clinicians prescribing LDV‐SOF to HCV‐HIV–coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF.

Exposure of Cyclosporin A in Whole Blood, Cerebral Spinal Fluid, and Brain Extracellular Fluid Dialysate in Adults with Traumatic Brain Injury

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.

Economic Barriers in the Treatment of Clostridium difficile Infection With Oral Vancomycin.

Abstract Vancomycin is an increasingly important option for the treatment of Clostridium difficile infection, but economic barriers to its use remain significant in the outpatient setting. Generic vancomycin capsules are still inexplicably expensive and not universally covered by insurers. This report highlights the potential adverse consequences of cost-related nonadherence to vancomycin therapy and the challenges that clinicians face when prescribing oral vancomycin.

Effectiveness of Probiotic for Primary Prevention of Clostridium difficile Infection: A Single-Center Before-and-After Quality Improvement Intervention at a Tertiary-Care Medical Center

OBJECTIVETo evaluate probiotics for the primary prevention of Clostridium difficile infection (CDI) among hospital inpatients.DESIGNA before-and-after quality improvement intervention comparing 12-month baseline and intervention periods.SETTINGA 694-bed teaching hospital.INTERVENTIONWe administered a multispecies probiotic comprising L. acidophilus (CL1285), L. casei (LBC80R), and L. rhamnosus (CLR2) to eligible antibiotic recipients within 12 hours of initial antibiotic receipt through 5 days after final dose. We excluded (1) all patients on neonatal, pediatric and oncology wards; (2) all individuals receiving perioperative prophylactic antibiotic recipients; (3) all those restricted from oral intake; and (4) those with pancreatitis, leukopenia, or posttransplant. We defined CDI by symptoms plus C. difficile toxin detection by polymerase chain reaction. Our primary outcome was hospital-onset CDI incidence on eligible hospital units, analyzed using segmented regression.RESULTSThe study included 251 CDI episodes among 360,016 patient days during the baseline and intervention periods, and the incidence rate was 7.0 per 10,000 patient days. The incidence rate was similar during baseline and intervention periods (6.9 vs 7.0 per 10,000 patient days; P=.95). However, compared to the first 6 months of the intervention, we detected a significant decrease in CDI during the final 6 months (incidence rate ratio, 0.6; 95% confidence interval, 0.4-0.9; P=.009). Testing intensity remained stable between the baseline and intervention periods: 19% versus 20% of stools tested were C. difficile positive by PCR, respectively. From medical record reviews, only 26% of eligible patients received a probiotic per the protocol.CONCLUSIONSDespite poor adherence to the protocol, there was a reduction in the incidence of CDI during the intervention, which was delayed ~6 months after introducing probiotic for primary prevention.Infect Control Hosp Epidemiol 2018;765-770.

Levetiracetam-induced neutropenia following traumatic brain injury

Abstract Background: Levetiracetam is being increasingly utilized for post-traumatic brain injury seizure prophylaxis, in part because of its more favourable adverse effect profile compared to other anti-epileptics. This report highlights an unusual, clinically significant adverse drug reaction attributed to levetiracetam use in a patient with blunt traumatic brain injury. Methods: This study describes a case of isolated neutropenia associated with levetiracetam in a 52-year-old man with traumatic brain injury. Results: The patient developed neutropenia on day 3 of therapy with levetiracetam, with an absolute neutrophil count nadir of 200. There were no other medications that may have been implicated in the development of this haematological toxicity. Neutropenia rapidly resolved upon cessation of levetiracetam therapy. Conclusions: Clinicians should be aware of potentially serious adverse reactions associated with levetiracetam in patients with neurological injury.

Clinical use of the polymyxins: the tale of the fox and the cat

BACKGROUND There is a need to identify practice patterns of polymyxin use, quantify gaps in knowledge, and recognize areas of persistent confusion. METHODS A structured electronic survey was distributed to physicians, pharmacists and microbiologists. Demographic information was obtained, along with data regarding availability, stewardship principles, therapeutic usage, dosing, microbiological testing, and knowledge, attitudes and beliefs regarding the polymyxins. RESULTS In total, there were 420 respondents with a median of 8 (interquartile range 4-15) years of experience in infectious diseases (52.5%) and critical care (35%). Of the respondents who reported that only one polymyxin was available for use, 17.1% used polymyxin B. Over half (52.5%) of the respondents utilized a loading dose very often/always, and 66.8% dosed both polymyxins in milligrams, with the most common doses of colistin and polymyxin B being 2.5 mg/kg twice daily (60.3%) and 1.5 mg/kg twice daily (65%), respectively, for patients with normal renal function. Polymyxins were most often used for respiratory infections (63%) in combination with a carbapenem (63.6%). Approximately 85% of respondents reported their knowledge level to be fair, good or very good, although 34.9% answered two of the three knowledge questions incorrectly. More than 70% of respondents agreed that confusion exists in all surveyed areas of polymyxin use. Almost all respondents (91.2%) agreed that a polymyxin guideline would be a helpful resource. CONCLUSIONS This survey revealed objective and subjective variability in the use and perception of the polymyxins, and identified several areas in which they were being used contrary to the available evidence. The information provided herein lays the framework to harmonize clinical practice, guide future research and shape consensus guidelines.

Pharmacokinetics of telavancin at fixed doses in normal- body-weight and obese (classes I, II, and III) adult subjects

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects (n = 32) received a single, weight-stratified, fixed dose of 500 mg (n = 4), 750 mg (n = 8), or 1,000 mg (n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC0–∞) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)

Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration

ABSTRACT Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (Cmax), 61.10 and 14.54 mg/liter; minimum plasma concentration (Cmin), 31.96 and 8.45 mg/liter; half-life (t1/2), 6.07 and 6.78 h; apparent volume of distribution at the steady state (Vss), 27.23 and 30.81 liters; total clearance at the steady state (CLss), 2.87 and 2.95 liters/h; area under the concentration-time curve from 0 to 8 h (AUC0–8), 347.87 and 85.69 mg · h/liter. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/liter) throughout the 8-h dosing interval. Mean CVVH extraction ratios for ceftazidime and avibactam were 14.44% and 11.53%, respectively, and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 liters/h and for avibactam was 1.59 liters/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data that include multiple patients and dialysis modes are needed to verify the optimal ceftazidime-avibactam dosing strategy during critical illness and CVVH.

Immunologic and Virologic Outcomes of Obese and Nonobese Incarcerated Adults on Antiretroviral Therapy for HIV Infection

Background: Obesity is common among patients with HIV. The objective of this study was to characterize response to antiretroviral therapy (ART) in a cohort of obese incarcerated adults compared to a nonobese cohort. Methods: A retrospective matched cohort study was conducted in an HIV telemedicine clinic. Patients with body mass index (BMI) >30 kg/m2 who received the same ART with >95% adherence for at least 6 months were matched to nonobese patients by age, gender, ART, CD4 count, and viral load at baseline. Results: Twenty pairs were included, with an average BMI of 24 kg/m2 in the nonobese cohort and 35 kg/m2 in the obese cohort. No difference was observed in the proportion of patients who achieved virologic suppression or the change in CD4 count from baseline to 6 to 12 months. Conclusion: This study revealed no differences in immunologic recovery or virologic suppression between obese and nonobese patients in an adult correctional population.

1362: EVALUATION OF CLEARANCE EQUATIONS IN CONTINUOUS RENAL REPLACEMENT THERAPY WITH AN IN VITRO MODEL

www.ccmjournal.org Critical Care Medicine • Volume 46 • Number 1 (Supplement) Learning Objectives: Several inconsistencies in clearance estimation equations are noted in the continuous renal replacement therapy (CRRT) literature. Specifically, it is unclear if an averaged preand post-filter plasma concentration is more accurate than only pre-filter concentration in calculating saturation coefficient (SA) in continuous dialysis (CVVHD), and if correction factors (CF) for pre-filter dilution in continuous hemofiltration (CVVH) should be incorporated into the sieving coefficient (SC) or CVVH clearance equation (CL CVVH,pre ). The objective of this pilot study was to use modeled CRRT to clarify SA and CL CVVH,pre calculations. Methods: Modeled CRRT was performed with bovine blood (200 mL/min) and a Prismaflex unit with polysulfone filter (HF1400). Ceftazidime or vancomycin were added to simulate human plasma concentrations. In SA experiments, CVVHD ran at 2 and 4 L/h, with pre-filter, post-filter, and dialysate antibiotic concentrations assessed at 10 and 45 mins. SA was calculated with averaged and pre-filter concentrations. In CF experiments, CVVH ran at 2 and 4 L/h with pre-filter replacement. Concentrations were determined before and after the dilution point and in effluent serially after drug addition. CL CVVH,pre equations incorporating SC and CF were compared to CL CVVH derived from regression of pre-filter concentration-time data. Results: The SA of ceftazidime during CVVHD at 2 and 4 L/h calculated with averages was marginally higher than with prefilter only (+ 0.10 and 0.06, respectively). Similarly, the SA of vancomycin at 2 L/h was 0.04 higher when averaged compared to pre-filter only. In pre-filter dilution CVVH experiments, CL CVVH of vancomycin by linear regression at 2 and 4 L/h was 1.42 and 2.52 L/h, respectively. The use of a correction factor within the SC equation, and not the CL equation, more closely represented regression clearance (1.43 and 2.62 L/h, respectively) than did the use of a correction factor in the CL equation (1.06 and 1.48 L/h, respectively). Conclusions: Our pilot results suggest that SA may reasonably be calculated with pre-filter concentrations only, which could minimize the number of assays required for SA calculations in research. In addition, our results suggest that CL CVVH,pre equations that incorporate a correction factor may underestimate true clearance compared to correction only in the SC calculation.