Jerry Altshuler

Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02-0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.

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.

Combination Therapy With Vancomycin and Ceftaroline for Refractory Methicillin-resistant Staphylococcus aureus Bacteremia: A Case Series

PURPOSE Although vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline. METHODS Between January 2014 and August 2016, 5 patients were identified who received vancomycin and ceftaroline combination therapy due to persistent bacteremia or deterioration of their clinical status on vancomycin alone (despite a vancomycin MIC within the susceptible range). FINDINGS Five patients presented with MRSA bacteremia secondary to endocarditis (n = 2), epidural abscess (n = 2), or left iliopsoas abscess (n = 1). Four of the 5 patients experienced microbiologic cure, and 1 patient transitioned to palliative care. IMPLICATIONS This case series serves to describe additional clinical experience with vancomycin and ceftaroline combination therapy. This combination may be considered when vancomycin monotherapy does not lead to microbiological and/or clinical improvement in patients with metastatic MRSA bacteremia. Additional studies are warranted to further define its role in salvage therapy for persistent MRSA bacteremia.

Efficacy of Intravenous Chlorothiazide for Refractory Acute Decompensated Heart Failure Unresponsive to Adjunct Metolazone

To assess the efficacy of intravenous chlorothiazide in patients with acute decompensated heart failure (ADHF) who were determined to be loop diuretic resistant and refractory to metolazone.

Clinical Outcomes in Patients With Gram-Negative Infections Treated With Optimized Dosing Cefepime Over Various Minimum Inhibitory Concentrations

Background: The Clinical and Laboratory Standards Institute (CLSI) revised cefepime interpretive criteria, introducing the susceptible dose-dependent category for Enterobacteriaceae with a minimum inhibitory concentration (MIC) of 4 to 8 μg/mL in 2014. Limited clinical data support these new categories. This study compares outcomes of patients treated with standard and high-dose cefepime across various MICs. Methods: We retrospectively reviewed cases of pneumonia or bacteremia caused by gram-negative organisms treated with adequate doses of cefepime for ≥48 hours. Outcomes were compared for MICs of ≤2 (low), 4 (medium), and 8 μg/mL (high). The primary end point was clinical failure, the secondary end point was microbiological failure. Results: Ninety cases met the inclusion criteria: 46, 25, and 19 patients with low, medium, or high MIC, respectively. Multivariate logistic regression revealed that the medium (odds ratio [OR]: 9.13, P < .01) and high (OR: 6.79, P = .01) MIC groups had increased clinical failure. Conclusion: Cefepime therapy, even at CLSI-recommended doses, had an increased risk of clinical failure for gram-negative pathogens with MICs of 4 or 8 μg/mL. This finding suggests that higher dosing regimens (2 g every 8 hours or 1 g every 6 hours) may be necessary to treat serious gram-negative infections with elevated MICs.

Amiodarone versus digoxin for rate control in critically ill patients with rapid atrial fibrillation or flutter

Background: In critically ill patients with atrial fibrillation (AF) with rapid ventricular rate (RVR), first-line agents may be due to hemodynamically unfavorable. Amiodarone and digoxin are alternatives, however, there is a paucity of literature comparing their effectiveness. This study compared the effectiveness of these agents in critically ill patients in AF with RVR. Methods: This retrospective chart review included critically ill adults between June 2014 and December 2016 who experienced AF with RVR (HR ≥110 bpm) and were initiated on digoxin or amiodarone. The primary endpoint was time until ventricular rate control (HR <110 bpm) within 24 hours. Secondary endpoints included maintenance of target heart rate, time to sinus rhythm conversion, need for rescue therapy, ICU length of stay, 30-day in-hospital mortality, and safety. Results: Thirty-two patients were included in the amiodarone group and 54 patients in the digoxin group. There was no statistically significant difference in time to ventricular rate control between amiodarone and digoxin [4 (IQR, 2–4) vs. 5.5 h (IQR, 2–11), P=0.46], and both agents were similarly efficacious in maintaining rate control (74% vs. 78%, P=0.18). Digoxin was less effective in patients requiring catecholamines in lowering heart rate at 24 hours (107±12 vs. 95±16 bpm, P=0.02). Conclusions: Both groups were similar in time to rate control and rate control at 24 hours. Digoxin was less effective at lowering HR in patients requiring catecholamines.

Risk Factors for Bleeding Events with Enoxaparin, Dabigatran andFondaparinux in Hospitalized Patients with Varying Levels of RenalImpairment

Background: Anticoagulants with renal elimination may accumulate in patients with renal impairment and potentially increase the risk of bleeding. Limited data are available to elucidate the potential bleeding risk present in patients with moderate renal impairment defined as creatinine clearance of 30-50 mL/min. Objective: To evaluate potential risk factors for bleeding over various renal function ranges in patients on enoxaparin, fondaparinux, or dabigatran. Methods: Retrospective chart review from 2010 until 2011 identified patients who incurred a bleeding episode on therapeutic dosed enoxaparin, dabigatran, or fondaparinux stratified according to renal function and presence of pre-defined potential risk factors for bleeding. Bleeding episodes identified using UHC Safety Intelligence, a selfreporting database used to identify safety improvement opportunities. Results: A total of 27 (2.16%) bleeding episodes were identified, 20 occurring during enoxaparin pharmacotherapy and 7 during treatment with dabigatran. There were no fondaparinux bleeds identified. Patients with normal renal function, moderate renal impairment and severe renal impairment incurred 9, 12 and 6 bleeds, respectively. Conclusion: A similar number of patients incurred bleeding episodes on enoxaparin in the normal renal function group and moderate renal impairment group. Patients experiencing bleeding episodes in the enoxaparin group with moderate renal impairment were of advanced age and female. Enoxaparin bleeding episodes were noted in patients with hypertension in all renal function ranges. Patients who bled on dabigatran had some degree of renal impairment and were of advanced age. Concomitant p-glycoprotein inhibitor use was observed in patients with bleeding episodes on dabigatran in patients with renal impairment.

Extended Versus Short-Course Corticosteroid Taper Regimens in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Critically Ill Patients:

Background: Previous literature has suggested that a short course of corticosteroids is similarly effective as an extended course for managing an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there are limited data regarding the optimal corticosteroid regimen in critically ill patients and the dosing strategies remain highly variable in this population. Methods: This retrospective cohort study evaluated patients with AECOPD admitted to the intensive care unit within a 2-year period. Patients were divided into short-course (≤5 days) or extended-course (>5 days) corticosteroid taper groups. The primary end point was treatment failure, defined as the need for intubation, reintubation, or noninvasive mechanical ventilation. Secondary end points included the duration of mechanical ventilation, hospital and intensive care unit length of stay, and adverse events. Results: Of the 151 patients who met the inclusion criteria, 94 received an extended taper and 57 received a short taper. Treatment failure occurred in 3 patients, who were all in the extended taper group (P = .17). In a propensity score-matched cohort, the hospital length of stay was 7 days in the short taper group compared to 11 days in the extended taper group (P < .0001). No differences in adverse events were observed. Conclusion: A short-course corticosteroid taper in critically ill patients with AECOPD is associated with reduced hospital length of stay and decreased corticosteroid exposure without increased risk of treatment failure. A prospective randomized trial is warranted.

CorrespondenceThe Unsung Hero: Role of Thiamine in the ‘Vitamin C Cocktail’

To the Editor: The study by Marik and colleagues, published in the June issue of CHEST, is thought-provoking and exciting. Combining intravenous vitamin C with corticosteroids and thiamine reduced mortality by 31.9% in a beforeand-after cohort. This research has sparked much interest and debate regarding the efficacy of this “cocktail,” with the majority of focus placed on the vitamin C component. The effects of corticosteroids in sepsis have long been discussed and debated, and the potential synergism between corticosteroids and vitamin C is interesting. However, we believe that the contribution of thiamine in this “cocktail” may have been underappreciated.

Refractory Toxic Shock-Like Syndrome from Streptococcus dysgalactiae ssp. equisimilis and Intravenous Immunoglobulin as Salvage Therapy: A Case Series.

Infections from Streptococcus dysgalactiae ssp. equisimilis (SDSE) can cause a wide variety of infections, ranging from mild cellulitis to invasive disease, such as endocarditis and streptococcal toxic shock-like syndrome (TSLS). Despite prompt and appropriate antibiotics, mortality rates associated with shock have remained exceedingly high, prompting the need for adjunctive therapy. IVIG has been proposed as a possible adjunct, given its ability to neutralize a wide variety of superantigens and modulate a dysregulated inflammatory response. We present the first reported cases of successful IVIG therapy for reversing shock in the treatment of SDSE TSLS.