Diana Esaian

Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome.

Although animal studies have shown that the immunomodulator ipilimumab causes inflammation of the myocardium, clinically significant myocarditis has been observed only infrequently. We report a case of suspected acute coronary syndrome without a culprit lesion on cardiac angiography and takotsubo cardiomyopathy (TC)-like appearance on echocardiography in a patient with metastatic melanoma who received four standard doses of ipilimumab. Apical ballooning, hyperdynamic basal wall motion, systolic anterior motion of the mitral valve, and associated severe left ventricular outflow tract obstruction were present. Restaging with positron emission tomography-computed tomography done soon after discharge incidentally revealed increased fludeoxyglucose uptake in the apex. This case illustrates that a TC-like syndrome might be caused by autoimmune myocarditis after ipilimumab treatment although this was not biopsy-confirmed. Post-marketing surveillance should capture cardiac events occurring in patients treated with ipilimumab to better document and clarify a relationship to the drug, and biopsies should be considered. Physicians utilizing this novel agent should be aware of the potential for immune-related adverse events.

Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

ABSTRACT Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline, in vitro synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern.

Risk factors for nephrotoxicity onset associated with polymyxin B therapy

OBJECTIVES Polymyxin B is an active agent against many MDR Gram-negative bacteria, but nephrotoxicity is a major hindrance to its widespread use. To guide its optimal use, we determined the risk factors for nephrotoxicity onset associated with polymyxin B. METHODS In a multicentre, retrospective, cohort study, we evaluated adult patients with normal renal function who received ≥72 h of polymyxin B therapy. Pertinent information was retrieved from medical records; patients were followed for up to 30 days after therapy was started. The primary endpoint of this study was the onset of nephrotoxicity. A Cox proportional hazards model was used for analysis. RESULTS A total of 192 patients (52.1% male, 67.7% Caucasian) were evaluated. The mean ± SD age, actual body weight (ABW) and daily dose by ABW were 68.3 ± 17.2 years, 71.5 ± 20.4 kg and 1.5 ± 0.5 mg/kg, respectively. The median duration of therapy was 9.5 days. The overall prevalence rate of nephrotoxicity was 45.8% and the median onset of nephrotoxicity was 9 days. Independent risk factors for the onset of nephrotoxicity included daily dose by ABW (HR = 1.73; P = 0.022), concurrent use of vancomycin (HR = 1.89; P = 0.005) and contrast media (HR = 1.79; P = 0.009). Nephrotoxicity was seen earlier in the high-risk group (P = 0.003). CONCLUSIONS Risk factors for nephrotoxicity onset associated with polymyxin B were identified. In conjunction with susceptibility and other pharmacokinetic/pharmacodynamic data, our results can be used to optimize treatment for MDR Gram-negative infections.

Ketamine Continuous Infusion for Refractory Status Epilepticus in a Patient With Anticonvulsant Hypersensitivity Syndrome

Objective: Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. Case Summary: We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. Discussion: The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. Conclusion: This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis.

Effectiveness and Tolerability of a Polymyxin B Dosing Protocol

TO THE EDITOR: Optimal dosing of polymyxin B is not well defined. Limited in vitro pharmacodynamic data suggest that polymyxin B killing correlates most closely with an area under the curve/minimum inhibitory concentration (AUC/MIC) ratio.1 At our institution, historical conventional dosing of polymyxin B was based on 15,000-25,000 units/kg/day in 2 divided doses, with adjustment for renal function based on the physician’s discretion. We implemented a new polymyxin B dosing protocol to address observed clinical failures. All patients were given a loading dose of polymyxin B 25,000 units/kg on day 1. Subsequent doses and dosing interval were adjusted as follows: creatinine clearance (CrCl) >80 mL/min: 25,000 units/kg administered once every 24 hours; CrCl 30-80 mL/min: 15,000 units/kg once every 24 hours; CrCl <30 mL/min or continuous renal replacement therapy: 15,000 units/kg once every 48 hours; and CrCl <10 mL/min or hemodialysis: 10,000 units/kg once every 72 hours. Polymyxin B doses were calculated using ideal body weight.2 The objective of this study was to evaluate the effectiveness and tolerability of the new protocol as compared to conventional dosing. Methods. A retrospective chart review of sequential patients who received polymyxin B before and after protocol implementation was conducted. Patients 18 years of age or older with infections caused by multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii who were treated with polymyxin B for 72 hours or longer were included. An isolate was considered to be multidrug-resistant if it was nonsusceptible to 3 or more antimicrobial classes.3 Only the first treatment course of polymyxin B was included. Microbiologic clearance, clinical response at the end of therapy that was based on the physician’s assessment as stable/improved or deteriorating, mortality at end of therapy and at the end of hospitalization, and nephrotoxicity assessed by risk, injury, failure, loss, and end-stage kidney disease (RIFLE) criteria were evaluated.4 Results. Forty patients in each group were compared (Table 1). The mean single dose of polymyxin B was significantly higher in the protocol group compared to the conventional group, with no significant difference between groups for the mean daily dose. Microbiologic eradication was 73.3% versus 54.5% (p = 0.06) in the protocol group and conventional group, respectively, and 73.3% versus 44.4% (p = 0.01) after exclusion of catheter-related bloodstream infections (CRBSIs), since all patients with CRBSIs in the conventional group had their catheters removed with subsequent negative cultures. Microbiologic eradication was 66.7% versus 25% (p = 0.05) for respiratory infections in the protocol and conventional groups, respectively.5 Clinical response was 65% and 58% (p = 0.49) in the protocol and conventional groups, respectively. Mortality at end of therapy was 15% in the protocol group and 20% in the conventional dosing group (p = 0.56). Mortality at end of hospitalization was 30% and 38% (p = 0.48) in the protocol and conventional groups, respectively. In the protocol group, 58% of the patients met RIFLE criteria for nephrotoxicity at the time of peak serum creatinine (SCr) level compared to 20% in the conventional dosing group (p = 0.002). One week after the last polymyxin B dose, nephrotoxicity was 26.3% in the protocol group and 15.4% in the conventional group (p = 0.67). Among patients 70 years of age and older, the nephrotoxicity rate at peak SCr was 59% in the protocol group and 14% in the conventional dosing group (p = 0.008); 1 week after the last polymyxin B dose, nephrotoxicity was 30.8% in the protocol group and 0% in the conventional group (p = 0.13). In patients who developed nephrotoxicity, the mean time to peak SCr was 9 days in both groups. In this single-center retrospective evaluation, we observed a trend toward better microbiologic eradication in the protocol group, with no significant difference in clinical response and mortality. Using polymyxin B once daily for a prolonged duration may put patients at increased risk of nephrotoxicity, particularly the elderly. We also conclude that a loading dose did not correlate with nephrotoxicity, given that the time to peak SCr was identical in both groups, and might provide some benefits.

Treatment of Extended-Spectrum Beta-Lactamase Enterobacteriaceae With Cefepime: The Dose Matters, Too

To the Editor—We read Lee et als article in the 15 February 2013 issue of Clinical Infectious Diseases with great interest [1]. In this retrospective cohort, Lee et al showed that 17 propensity-score-matched patients had increased mortality when treated with cefepime, as compared to carbapenems, as definitive therapy for extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae. This finding was only relevant to organisms with minimum inhibitory concentrations (MICs) in the 2–8 µg/mL range. Based on their results, the authors conclude that cefepime therapy may only be appropriate to treat ESBL-producing organisms when the MIC is ≤1 µg/mL. Although we agree that there are limited data supporting the clinical use of cefepime for ESBL-producing organisms, we cannot entirely dismiss the efficacy of cefepime for pathogens with elevated but susceptible MICs based on these results. With the recent change in the Clinical and Laboratory Standards Institute recommendations to simply report MICs instead of performing confirmatory phenotypic testing for ESBL production, the assumption is that the organisms β-lactamase gene is irrelevant as long as pharmacodynamic targets remain attainable with the most commonly utilized dose of the drug [2]. Indeed, Andes and Craig have shown that maintaining a free cephalosporin concentration above the MIC for 70% of the dosing interval is associated with optimal microbial killing in both non-ESBL- and ESBL-producing organisms in the neutropenic mouse model, irrespective of genotype [3]. As Lee et al point out, several authors have described the difficulty in achieving meaningful pharmacodynamic probability of target attainment (PTA) for cefepime with organisms in the higher (2–8 µg/mL) MIC ranges. As shown in the Monte Carlo simulation performed by Roos et al, a dose of 2 g every 12 hours resulted in insufficient PTA for pathogen MICs of 4–8 µg/mL in the critically ill population, whereas 2 g every 8 hours was able to achieve meaningful PTA [4]. These data are in concordance with the findings of Bhat et al, who showed that a group of bacteremic patients with organism MICs of 8 µg/mL treated with cefepime 1–2 g every 12 hours had higher mortality compared to those with lower MICs [5]. As the present study only included 11 patients (5 of whom had died at 30 days) with MICs in the 2–8 µg/mL range [1], it is difficult to conclude that cefepime is ineffective, especially without specification of the MIC distribution and dosing regimens utilized. For instance, were all 5 failures treated with 1 g every 8 hours for organisms with an MIC of 8 µg/mL? Given the recent increase in prevalence of carbapenemase-producing organisms, it is essential to minimize the use of carbapenems whenever possible. There are data suggesting that traditional doses of cefepime (1 g every 8 hours or 2 g every 12 hours) may be inadequate to treat infections due to Enterobacteriaceae with elevated cefepime MICs (≥4 µg/mL), including ESBL-producing organisms; however, we are not aware of any trials evaluating aggressive cefepime doses (2 g every 8 hours, 1 g every 6 hours, or extended infusion strategies) to optimize the chances of achieving PTA and treat infections due to Enterobacteriaceae with higher cefepime MICs. Although carbapenems remain the drug of choice for ESBL-producing organisms, further clinical research evaluating cefepime dosing with pharmacodynamic optimization should be performed.