Nina Cohen

Effect of antifungal therapy timing on mortality in cancer patients with candidemia.

ABSTRACT Prior studies have shown that delays in treatment are associated with increased mortality in patients with candidemia. The purpose of this study was to measure three separate time periods comprising the diagnosis and treatment of candidemia and to determine which one(s) is associated with hospital mortality. Patients with blood cultures positive for Candida spp. were identified. Subjects were excluded if no antifungal therapy was given or if there was preexisting antifungal therapy. Collected data included the time from blood culture collection to positivity (incubation period), the time from blood culture positivity to provider notification (provider notification period), and the time from provider notification to the first dose of antifungal given (antifungal initiation period). These times were assessed as predictors of inpatient mortality. A repeat analysis was done with adjustments for age, sex, race, underlying cancer, catheter removal, APACHE III score, acute renal failure, neutropenia, and non-Candida albicans species. A total of 106 episodes of candidemia were analyzed. The median incubation time was 32.1 h and was associated with mortality (univariate hazard ratio per hour, 1.025; P = 0.001). The median provider notification and antifungal initiation periods were 0.3 and 7.5 h, respectively, and were not associated with mortality. Adjusted analysis yielded similar results. For cancer patients with candidemia, the incubation period accounts for a significant amount of time, compared with the provider notification and antifungal initiation times, and is associated with in-hospital mortality. Strategies to shorten the incubation time, such as utilizing rapid molecularly based diagnostic methods, may help reduce in-hospital mortality.

Emergence of Daptomycin-Resistant VRE: Experience of a Single Institution

Recent surveillance from US hospitals shows that more than 99.5% of vancomycin-resistant enterococci (VRE) isolates remain susceptible to daptomycin. This report describes emergence of daptomycin-resistant VRE at a major cancer center. The percentage of patients with daptomycin-resistant VRE bacteremia increased from 3.4% in 2007 to 15.2% in 2009 ([Formula: see text]). Without susceptibility data, empiric daptomycin therapy for VRE infections should be used with caution.

Hepatic Safety of Voriconazole after Allogeneic Hematopoietic Stem Cell Transplantation

Voriconazole is increasingly used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis and treatment of fungal infections. Hepatic dysfunction is common in patients undergoing HSCT and may have an impact on the clinical decision to institute voriconazole. We conducted a retrospective review of all adult and pediatric HSCT recipients who received >2 consecutive doses of voriconazole between January 2005 and February 2008. Clinical hepatotoxicity was defined as the subjective attribution of liver enzyme elevation (even a mild one) to hepatotoxicity because of voriconazole by the treating physician and leading to discontinuation of voriconazole. Biochemical hepatotoxicity was defined as an elevation in one or more liver enzymes to >3 times the upper limit of normal or >3 times the baseline value if abnormal at baseline. Liver enzymes assessed included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Simple and multiple logistic regressions were used to define the risks for hepatic dysfunction. The Wilcoxon signed-rank test was used to assess the differences in liver function test values before, during, and after the use of voriconazole. Sixty-eight of 200 patients (34%) developed hepatotoxicity while on voriconazole. The median duration of voriconazole therapy was 72 days (range, 1-804 days). Biochemical hepatotoxicity occurred in 51 patients (75%); clinical hepatotoxicity, in 17 patients (25%). Thirty-five (51%) of the patients with hepatotoxicity required discontinuation of therapy. In simple logistic regression, acute graft-versus-host disease (GVHD) was a risk factor for hepatotoxicity, and receipt of a T-cell depleted allograft was protective. In multiple logistic regression, acute GVHD (P = .002) remained significant. There were no cases of liver failure or death attributed to voriconazole. In this cohort of patients undergoing allogeneic HSCT, the rate of hepatotoxicity while on voriconazole was 34%. In general, the hepatic dysfunction was mild and reversible. Voriconazole therapy with monitoring appears to be reasonably safe for use in HSCT recipients at high risk for invasive fungal infections.

Hematologic safety profile of linezolid in the early periengraftment period after allogeneic stem cell transplantation.

Vancomycin-resistant enterococci (VRE) are common pathogens of bloodstream infections in the peritransplantation period. Linezolid is approved by the FDA for treating VRE infections, but has been associated with low rates of hematologic toxicity in the general population; thus, there are concerns about its potential myelotoxicity in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. We examined the impact of linezolid treatment on the times to neutrophil and platelet engraftment in 33 patients who underwent HSCT. In this retrospective case-controlled study conducted from 2000 through 2007, cases received > or = 7 consecutive days of linezolid therapy, starting before day +8 post-HSCT. Controls received > or = 7 consecutive days of vancomycin therapy before day +8 and were matched to cases by age and conditioning regimen. The cumulative incidence function was used to estimate the probabilities for the times to neutrophil and platelet engraftment. A competing-risk regression model was used to determine whether times to engraftment differed for cases and controls. A total of 33 cases were compared with 33 controls. The median duration of treatment after stem cell infusion was 14 days (range, 7 to 34 days) for linezolid and 16 days (range, 8 to 33 days) for vancomycin. The rates of neutrophil and platelet engraftment were similar between the cases and controls. After adjusting for baseline characteristics, no difference in the times to neutrophil or platelet engraftment was seen between the 2 groups. Our findings demonstrate no adverse effect on the times to neutrophil or platelet engraftment with linezolid use. Larger prospective studies are needed to fully determine the hematologic safety of linezolid in patients undergoing HSCT.

Propofol infusion syndrome: case report and literature review.

PURPOSE A case of propofol infusion syndrome in a patient with respiratory failure and sepsis is reported. SUMMARY A 36-year-old Hispanic woman was admitted to the medical intensive care unit for treatment of respiratory failure and sepsis, likely secondary to pneumonia. Her medical history included human immunodeficiency virus infection and chronic hepatitis C virus infection. She was intubated and placed on mechanical ventilation. Empirical i.v. antimicrobial therapy was initiated with vancomycin, moxifloxacin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and micafungin, along with corticosteroids and vasopressors. Propofol 1.5 mg/kg per hour i.v. and midazolam i.v. were initiated for sedation, but the dosages of both propofol and midazolam needed to be increased due to persistent agitation. On hospital day 7, the patient developed a morbilliform rash on her neck, shoulders, and chest and multiple abnormal laboratory test values, including elevated levels of alanine transaminase, aspartate transaminase, amylase, lipase, creatine kinase, and triglycerides. Serial electrocardiograms revealed sinus tachycardia. Computed tomography of the abdomen showed hepatomegaly with fatty infiltration of the liver, no gallstones, and a normal pancreas. I.V. phenobarbital was added for sedation, and propofol was tapered and discontinued on the same day. The patient responded adequately to phenobarbital maintenance therapy and was eventually weaned off all other sedatives. The patients laboratory test values returned to normal within 72 hours after discontinuation of the propofol infusion, and the rash and tachycardia resolved. CONCLUSION Propofol infusion syndrome developed in a patient with respiratory failure and sepsis after a prolonged infusion of high-dose propofol.

Microbiological Profile of Organisms Causing Bloodstream Infection in Critically Ill Patients

Background Bloodstream infection (BSI) is the most frequent infection in critically ill patients. As BSI’s among patients in intensive care units (ICU’s) are usually secondary to intravascular catheters, they can be caused by both Gram-positive and Gram-negative microorganisms as well as fungi. Infection with multidrug-resistant (MDR) organisms is becoming more common, making the choice of empirical antimicrobial therapy challenging. The objective of this study is to evaluate the spectrum of microorganisms causing BSI’s in a Medical-Surgical Intensive Care Unit (MSICU) and their antimicrobial resistance patterns. Methods A prospective observational study among all adult patients with clinical signs of sepsis was conducted in a MSICU of an inner-city hospital in New York City between May 1, 2010 and May 30, 2011. Results A total of 722 adult patients with clinical signs of systemic inflammatory response syndrome (SIRS) and/or sepsis were admitted to the MSICU between May 1, 2010 and May 30, 2011. From those patients, 91 (12.6%) had one or more positive blood culture. A 122 isolates were identified: 72 (59%) were Gram-positive bacteria, 38 (31.1%) were Gram-negative organisms, and 12 (9.8%) were fungi. Thirteen (34.2%) Gram-negative organisms and 14 (19.4%) Gram-positive bacteria were classified as MDR. Conclusions Antimicrobial resistance, particularly among Gram-negative organisms, continues to increase at a rapid rate, especially in the ICU’s. Coordinated infection control interventions and antimicrobial stewardship policies are warranted in order to slow the emergence of resistance.

Safety and Efficacy of Intermittent Intravenous Administration of High-Dose Micafungin

BACKGROUND The use of mold-active azoles for antifungal prophylaxis after allogeneic stem cell transplantation (SCT) is hindered by adverse events and drug-drug interactions. Higher doses of echinocandins administered intermittently may be an alternative in this setting. METHODS This was a single-center, observational 5-year study to characterize the safety and efficacy of intermittent administration of high-dose intravenous micafungin (≥5 doses of ≥300 mg micafungin 2-3 times weekly) in patients with acute leukemia and allogeneic SCT recipients. RESULTS A total of 104 patients (84 allogeneic SCT recipients and 20 patients with leukemia) received intermittent high-dose intravenous micafungin, 83 (79.8%) as prophylaxis. Large variability in the micafungin dosing regimen was observed; 78 (75%) patients received >75% of their course as 300 mg micafungin 3 times weekly. Liver function tests decreased from baseline to end of treatment (EOT; P < .001). Patients with normal baseline liver function (n = 55 [52%]) maintained similar enzyme levels throughout the study. For patients with abnormal baseline liver function (n = 49 [47%]), liver function tests significantly improved from baseline to EOT (P ≤ .005). Duration and/or micafungin dosing algorithms were not associated with liver toxicity at EOT. There were no significant changes in renal function, and infusion-related reactions or deaths were not observed. Five of 83 (6.0%) patients in the prophylaxis group developed a breakthrough fungal infection. CONCLUSIONS In this largest cohort of patients to date, intermittent administration of high-dose micafungin was well tolerated, without any associated liver or renal function abnormalities, and may be considered an alternative antifungal prophylactic strategy. Prospective studies are needed to further validate these findings.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer

Background Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. Results We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Conclusions Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.

Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation

There are limited pediatric population pharmacokinetic data for voriconazole dosing, particularly in younger children. In a cohort of 34 patients younger than 3 years receiving voriconazole, the majority (n = 23, 68%) had a low initial serum concentration <1 mg/L. Among 23 children <2 years old, 19 (83%) had an initial trough <1 mg/L. There was large intra- and interindividual variability in trough levels. Dosing also varied from 3.3 to 19.6 mg/kg per dose. Only 2 of 34 patients had a documented adverse drug reaction attributable to voriconazole. More data are needed to establish optimal dosing in very young children.

Retrospective Analysis of Posaconazole Suspension Dosing Strategies in a Pediatric Oncology Population: Single-Center Experience

Limited data on optimal posaconazole dosing strategies for pediatric patients exist. In this study, we found that the median initial dose in patients who achieved a posaconazole plasma concentration of 0.7 μg/mL was 22.8 mg/kg per day whereas the median initial dose in those who did not reach the target concentration was 15.8 mg/kg per day; this result suggests that higher initial doses might be warranted.