Implementation of an Automated Antibiotic Time-out at a Comprehensive Cancer Center.

Background: Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established. Methods: An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center. Physicians were to discontinue the antimicrobial if unnecessary or document a rationale for continuation. This is a quasi-experimental, interrupted time series analysis assessing antimicrobial use during the following times: period 1 (before time-out: January 2007-June 2010) and period 2 (after time-out: July 2010-March/2015). The primary antimicrobial consumption metric was mean duration of therapy. Days of therapy per 1000 patient-days were also assessed. Results: Implementation of the time-out was associated with a significant decrease in mean duration of therapy for the following antimicrobials; daptomycin: -0.89 days (95% confidence interval [CI], -1.38 to -.41); linezolid: -0.89 days (95% CI, -1.27 to -.52); meropenem: -0.97 days (95% CI, -1.39 to -.56); tigecycline: -1.41 days (95% CI, -2.19 to -.63); P < .001 for each comparison. Days of therapy/1000 patient-days decreased significantly for meropenem (-43.49; 95% CI, -58.61 to -28.37; P < .001), tigecycline (-35.47; 95% CI, -44.94 to -26.00; P < .001), and daptomycin (-9.47; 95% CI, -15.25 to -3.68; P = .002). Discussion: A passive day 5 time-out was associated with reduction in targeted antibiotic use in a cancer center and could potentially be successfully adopted to several settings and electronic health records.

The growing threat of NDM-producing E. coli with penicillin-binding protein 3 mutations in the United States - is there a potential role for durlobactam?

We report identification of 5 patients with infections caused by NDM-5-producing E. coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane ß-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.

Aminoglycoside Pharmacokinetics in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

BACKGROUND: There are few studies describing aminoglycoside pharmacokinetics during continuous renal replacement therapy (CRRT). OBJECTIVE: To characterize the effect of CRRT on aminoglycoside clearance and volume of distribution (Vd). METHODS: Retrospective observational pharmacokinetic study of adult critically ill oncologic patients who received a first dose of amikacin or tobramycin during CRRT between February 2012 and May 2017. Study outcomes included aminoglycoside clearance, Vd, and attainment of the target peak: MIC (minimum inhibitory concentration) ratio as a surrogate for dosing appropriateness. RESULTS: In total, 80 patients were included, sustained low-efficiency dialysis (SLED), n = 49; continuous venovenous hemodialysis (CVVHD), n = 19; continuous venovenous hemofiltration (CVVH), n = 12. Fifty-one patients received amikacin at a median dose of 14.5 mg/kg per actual body weight and achieved a median peak level of 26.7 mg/L. Twenty-nine patients received tobramycin at a median dose of 6.5 mg/kg actual body weight and achieved a median peak level of 10.3 mg/L. The median aminoglycoside clearance was 63.1 mL/min and was similar between CRRT modality groups (P = 0.97). The median Vd was 0.47 L/kg and was different between the SLED and CVVH groups (P = 0.007). Attainment of target peak: MIC occurred in 29% in the total study population and 44% in the subgroup of 23 patients with isolates tested for aminoglycoside susceptibility. CONCLUSION AND RELEVANCE: Critically ill oncology patients undergoing CRRT exhibited reduced clearance and expanded Vd that was not significantly different between CRRT modalities. Current dosing regimens led to low peak concentrations and poor attainment of pharmacokinetic targets.

Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists.

The purpose of this narrative review is to bring together the most recent epidemiologic, preclinical, and clinical findings to offer our perspective on best practices for managing patients with A. baumannii infections with an emphasis on carbapenem-resistant A. baumannii (CRAB). To date, the preferred treatment for CRAB infections has not been defined. Traditional agents with retained in vitro activity (aminoglycosides, polymyxins, and tetracyclines) are limited by suboptimal pharmacokinetic characteristics, emergence of resistance, and/or toxicity. Recently developed and US Food and Drug Administration (FDA)-approved ß-lactam/ß-lactamase inhibitor agents do not provide enhanced activity against CRAB. On balance, cefiderocol and eravacycline demonstrate potent in vitro activity and are well tolerated, but clinical data for patients with CRAB infections do not yet support widespread use. Given that CRAB has the capacity to infect vulnerable patients and preferred regimens have not been identified, we advocate for combination therapy. Our preferred regimen for critically ill patients infected, or considered to be at high risk for CRAB, includes meropenem, polymyxin B, and ampicillin/sulbactam. Importantly, site of infection, severity of illness, and local epidemiology are essential factors to be considered in selecting combination therapies. Molecular mechanisms of resistance may unveil preferred combinations at individual centers; however, such data are often unavailable to treating clinicians and have not been linked to improved clinical outcomes. Combination strategies may also pose an increased risk for antibiotic toxicity and Clostridioides difficile infection, and should therefore be balanced by understanding patient goals of care and underlying health conditions. Promising therapies that are in clinical development and/or under investigation include durlobactam-sulbactam, cefiderocol combination regimens, and bacteriophage therapy, which may over time eliminate the need for the continued use of polymyxins. Future goals for CRAB management include pathogen-focused treatment paradigms that are based on molecular mechanisms of resistance, local susceptibility rates, and the availability of well-tolerated, effective treatment options.

Effect of High-Dose Posaconazole on Serum Levels in Adult Patients with Hematologic Malignancy.

Posaconazole (POS) appears to have dose-proportional pharmacokinetics; however, there is a paucity of real-life data. We retrospectively evaluated 67 patients with hematologic cancer who had POS dose increases from 300 mg/day to either 400 mg/day (n = 52) or 300 mg twice daily (BID) (n = 15) and for whom POS serum levels were measured. Median POS levels were 840 ng/ml, 1,625 ng/ml, and 2,710 ng/ml for the dosages of 300 mg/day, 400 mg/day, and 300 mg BID, respectively. Significant interpatient variability in serum levels was noted.

Clinical Outcomes Associated With Linezolid Resistance in Leukemia Patients With Linezolid-Resistant Staphylococcus epidermidis Bacteremia.

BACKGROUND: Coagulase-negative staphylococci, including Staphylococcus epidermidis, are the most common cause of bloodstream infection in cancer patients. Linezolid resistance is increasingly identified in S. epidermidis, but whether such resistance alters the clinical course of S. epidermidis infections is unknown. The purpose of this study was to assess the clinical impact of linezolid resistance in leukemia patients with S. epidermidis bloodstream infection. METHODS: This was a retrospective, single-center cohort study of all adult leukemia patients with S. epidermidis bacteremia treated with empiric linezolid between 2012 and 2015. The primary end point was adverse clinical outcome on day 3, defined as a composite of persistent bacteremia, fever, intensive care unit admission, or death. Fourteen- and 30-day mortality were also assessed. RESULTS: Eighty-two unique leukemia patients with S. epidermidis were identified. Linezolid resistance was identified in 33/82 (40%). Patients with linezolid-resistant S. epidermidis were significantly more likely to have persistent bacteremia (41% vs 7%; adjusted relative risk [aRR], 5.15; 95% confidence interval [CI], 1.63-16.30; P = .005); however, adverse short-term clinical outcomes overall were not more common among patients with linezolid-resistant S. epidermidis (61% vs 33%; aRR, 1.46; 95% CI, 0.92-2.32; P = .108). No differences were observed in 14- or 30-day mortality. CONCLUSIONS: Leukemia patients with linezolid-resistant S. epidermidis bacteremia who were treated with linezolid were significantly more likely to have persistent bacteremia compared with those with linezolid-sensitive isolates. Interventions to limit the clinical impact of linezolid-resistant S. epidermidis are warranted.

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses.

Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayed-release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received ≥3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (<700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (<700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of >1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of >700 ng/ml, and a posaconazole level of >1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.

Daptomycin non-susceptible Enterococcus faecium in leukemia patients: Role of prior daptomycin exposure.

OBJECTIVES: We sought to determine the association between previous daptomycin exposure and daptomycin non-susceptible Enterococcus faecium (DNSEf) bloodstream infections (BSI) in adult leukemia patients. METHODS: We retrospectively identified adult (≥18 years old) leukemia patients with Enterococcus spp. bacteremia at The University of Texas MD Anderson Cancer Center (MDACC) from 6/1/2013 to 7/22/2015. Antimicrobial susceptibility and previous antibiotic exposure within the 90 days prior to bacteremia were collected. Classification and Regression Tree (CART) analysis was used to identify the most significant breakpoint between daptomycin exposure and DNSEf. RESULTS: Any amount of daptomycin received within the 90 days preceding BSI was significantly associated with isolation of DNSEf compared to daptomycin susceptible E. faecium (DSEf) (88% vs. 44%, respectively, p < 0.01). CART analysis identified receiving ≥13 days of daptomycin in the preceding 90 days as most significantly correlated with DNSEf (60% vs. 11%, relative risk [RR] 5.31, 95% Confidence interval [CI] 2.36-11.96, p < 0.01). CONCLUSIONS: Prior daptomycin exposure for ≥13 days within 90 days preceding BSI was significantly associated with isolation of DNSEf BSI in adult leukemia patients at our institution. Antimicrobial stewardship initiatives aimed at minimizing daptomycin exposure in high-risk patients may be of significant benefit in limiting the emergence of DNSEf.

Predicting the risk of nephrotoxicity in patients receiving colistimethate sodium: a multicentre, retrospective, cohort study.

OBJECTIVES: With increasing rates of infections caused by MDR Gram-negative organisms, clinicians resort to older agents such as colistimethate sodium (CMS) despite a significant risk of nephrotoxicity. Several risk factors for CMS-associated nephrotoxicity have been reported, but they have yet to be validated. We compared the performance of published mathematical models in predicting the risk of CMS-associated nephrotoxicity. METHODS: In a multicentre, retrospective, cohort study, adult patients (≥18 years of age) were evaluated from five large academic medical centres in the USA. Patients with normal renal function (baseline serum creatinine ≤1.5 mg/dL) who received intravenous CMS for ≥72 h were followed for up to 30 days. The development of nephrotoxicity was as defined by the RIFLE criteria. Each published model was conditioned using patient-specific variables to predict the risk of nephrotoxicity. The predictive performance of the models was evaluated using the observed-to-expected (O/E) ratio. The most significant cut-off threshold for stratifying patients into high and low risk of nephrotoxicity was identified using classification and regression tree analysis. RESULTS: A total of 106 patients were examined (mean age 53.3 ±â€Š14.9 years, 66% male); the overall observed nephrotoxicity rate was 52.8%. We identified a simple model demonstrating reasonable overall nephrotoxicity risk assessment [O/E ratio of 1.07 (95% CI = 0.81-1.39)] and high sensitivity (92.9%) in predicting nephrotoxicity development in patients on CMS therapy. CONCLUSIONS: We identified a model that could be incorporated into patient management strategies to reduce the risk of nephrotoxicity in patients requiring CMS therapy.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Use of Ceftolozane/Tazobactam in the Treatment of Multidrug-resistant Pseudomonas aeruginosa Bloodstream Infection in a Pediatric Leukemia Patient.

Multidrug-resistant Pseudomonas aeruginosa is of increasing concern in pediatric patients. Ceftolozane/tazobactam is a novel cephalosporin/ß-lactamase inhibitor combination with activity against multidrug-resistant Pseudomonas; however, no data exist on its use in children. This report summarizes the treatment of a multidrug-resistant P. aeruginosa bloodstream infection in a pediatric leukemia patient with ceftolozane/tazobactam and provides the first description of its pharmacokinetics in pediatrics.

Antifungal agents and liver toxicity: a complex interaction.

INTRODUCTION: The number of antifungal agents has sharply increased in recent decades. Antifungals differ in their spectrum of activity, pharmacokinetic/pharmacodynamic properties, dosing, safety-profiles and costs. Risk of developing antifungal associated hepatotoxicity is multifactorial and is influenced by pre-existing liver disease, chemical properties of the drug, patient demographics, comorbidities, drug-drug interactions, environmental and genetic factors. Antifungal related liver injury typically manifests as elevations in serum aminotransferase levels, although the clinical significance of these biochemical alterations is not always clear. Incidence rates of hepatotoxicity induced by antifungal therapy range widely, occurring most frequently in patients treated with azole antifungals for documented fungal infections. AREAS COVERED: This review provides an update regarding the hepatotoxicity profiles of the modern systemic antifungals used in treatment of invasive fungal infections. Expert commentary: Understanding the likelihood and pattern of hepatotoxicity for all suspected drugs can aid the clinician in early detection of liver injury allowing for intervention and potential mitigation of liver damage. Therapeutic drug monitoring is emerging as a potential tool to assess risk for hepatotoxicity.

Probable Nonconvulsive Status Epilepticus With the Use of High-Dose Continuous Infusion Ceftazidime.

Multidrug resistant (MDR) bacterial infections are a major concern of health care providers due to their increasing incidence and associated mortality. In some cases, few or no antibiotics have preserved activity. Beta-lactam administration via continuous infusion can optimize time over minimum inhibitory concentration (MIC). In some cases, use of high-dose continuous infusion (HDCI) may be necessary to achieve serum levels in excess of nonsusceptible MIC values. The use of HDCI beta-lactams is not without risk, specifically neurotoxic adverse effects, which appear dose related. We describe a 64-year-old male who experienced myoclonus and nonconvulsive status epilepticus while receiving HDCI ceftazidime for treatment of multidrug resistant Pseudomonas aeruginosa bacteremia. This report serves as a cautionary example of the potential toxicities associated with HDCI beta-lactams and supports the importance of risk-benefit analysis prior to and during treatment. Additionally, the use of serum drug level monitoring may be necessary to better prevent or predict toxicity.

Development of a combination antibiogram for Pseudomonas aeruginosa bacteremia in an oncology population.

PURPOSE: Development of a combination antibiogram to identify combinations of antibiotics that have the highest likelihood of attaining one active agent in the empiric management of presumed Pseudomonas aeruginosa bacteremia. METHODS: Patients with cancer and P. aeruginosa bacteremia from January 1 to December 31, 2012 were included in this analysis. The primary outcome was identification of effective combinations of beta-lactam and non-betalactam agents. An effective combination was defined as one which achieved in-vitro activity to greater than or equal to 85% of isolates collected. Furthermore, the addition of the non-beta-lactam agent was required to increase the in-vitro activity by at least 5% over beta-lactam monotherapy. Multiple secondary outcomes were evaluated. RESULTS: One hundred and twenty-three P. aeruginosa isolates were included from 99 patients. Single agent beta-lactam sensitivities ranged from 72.4 to 79.7%. Combination regimen sensitivities ranged from 73.5 to 96.7%. All combination regimens that included a beta-lactam plus an aminoglycoside were found to be effective per the study definition. Independent risk factors for MDR P. aeruginosa were receipt of intravenous (IV) antibiotics within 90 days and hospital length of stay (LOS) greater than or equal to five days. Increasing the number of antibiotics received was associated with a decrease in survival to hospital discharge. CONCLUSIONS: Effective combination regimens included all beta-lactam aminoglycoside regimens. Receipt of IV antibiotics within 90 days and hospital LOS greater than or equal to five days were independent risk factors for MDR isolates.

Switching to anidulafungin from caspofungin in cancer patients in the setting of liver dysfunction is associated with improvement of liver function tests.

BACKGROUND: Anidulafungin does not undergo hepatic metabolism like the other echinocandins. Therefore, there is a perception that anidulafungin may be less hepatotoxic or less likely to exacerbate existing liver damage. This has not been substantiated in the literature. METHODS: We retrospectively reviewed all cancer patients in whom anidulafungin treatment was immediately preceded by treatment with caspofungin and there existed clinical or laboratory evidence of hepatic damage or dysfunction at M. D. Anderson Cancer Center from January 2010 to December 2013. RESULTS: Sixty-one patients were included in the study. Most patients had haematological malignancies (58, 95%), and the patients were administered hepatotoxic agents such as chemotherapeutic agents (47, 77%) and other medications (38, 62%) simultaneously. There were significant decreases in AST and ALT (P < 0.029 and P < 0.0017, respectively) between two timepoints (switch from caspofungin to anidulafungin and end of anidulafungin therapy). The median changes in AST, ALT and total bilirubin during anidulafungin therapy were -43 IU/L, -25 IU/L and -0.15 mg/dL, respectively. Over 70% of patients had favourable changes in hepatic enzymes or function, and values were stable and decreased at the end of anidulafungin therapy. On average, the percentage of patients with laboratory results meeting common terminology criteria for adverse events (CTCAE) grade ≥2 at the time of switching to anidulafungin was decreased at the end of treatment. CONCLUSIONS: Median serum values and trajectory of hepatic enzymes and hepatotoxicity usually decreased after switching to anidulafungin treatment in patients with abnormal liver function tests. Anidulafungin could be useful in the management of cancer patients with hepatotoxicity occurring during caspofungin therapy.

First-dose pharmacokinetics of aminoglycosides in critically ill haematological malignancy patients.

The primary objective of this study was to determine the volume of distribution (Vd) (L/kg) of intravenous aminoglycosides (AGs) in critically ill haematological malignancy patients. Secondary objectives were to determine the body weight (actual, ideal, adjusted or lean) that yields the most precise estimate of Vd when normalised in L/kg as well as the frequency that current first-dose strategies result in post-distributional peak concentrations (C(peak)) within the target range (tobramycin 16-24 mg/L; amikacin 32-48 mg/L). In total, 58 AG doses were included (tobramycin, n = 34; amikacin, n = 24). Median Vd was 0.38 L/kg normalised per the most precise dose weight, which was actual body weight (ABW). The median dose was 445 mg (5.8 mg/kg ABW) for tobramycin and 1200 mg (13.8 mg/kg ABW) for amikacin. Target C(peak) (tobramycin 20mg/L; amikacin 40 mg/L) was achieved in only 25% of all AG episodes, with 4% exceeding the target and 71% falling below the target. Twenty-four organisms were isolated in the study sample; target C(peak) achievement (tobramycin 20 mg/L; amikacin 40 mg/L) would yield a peak:minimum inhibitory concentration of 10 in 75% and 52% of organisms, respectively. In conclusion, an increased Vd of AGs was identified in this critically ill haematological malignancy patient sample, and current dosing yielded a suboptimal C(peak) in the majority of patients.

Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity.

We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity.

The use of fidaxomicin for treatment of relapsed Clostridium difficile infections in patients with cancer.

OBJECTIVES: To report our experience with the use of fidaxomicin (FDX), an oral macrocyclic antibiotic, in cancer patients with Clostridium difficile infection (CDI). METHODS: A single-center retrospective case series was conducted at The University of Texas MD Anderson Cancer Center. Patients with CDI treated with FDX from May 2011 to January 2013 were identified via the pharmacy database. Clinical response and recurrence after FDX initiation were evaluated. RESULTS: Twenty-two patients were included, most of whom were male (55%) with a mean age of 58 years (range: 20-83 yrs). The most common underlying malignancies were nine patients with lymphoma (41%), seven with leukemia (32%), and six with solid tumors (27%). Indications for FDX included recurrent CDI in 16 patients (72%) and failure of both metronidazole and oral vancomycin in 6 patients (28%). Nineteen patients (86%) were on concomitant antimicrobials during CDI treatment. Clinical response to FDX was 91%, and overall sustained clinical response was 82%. FDX was well tolerated with no major adverse events that were FDX related or discontinuations due to drug-related adverse events. CONCLUSION: In cancer patients, FDX is effective treatment for the first episode of CDI after failure of standard therapies and treatment of recurrent CDI. This was interesting given the large number of high-risk patients who continued to receive concomitant antimicrobial therapy, which is common in this immunocompromised patient population.

The safety of amphotericin B lipid complex in patients with prior severe intolerance to liposomal amphotericin B.

The tolerability of amphotericin B lipid complex in patients with previous severe infusion reactions to liposomal amphotericin B is unclear. We reviewed the charts of 40 such patients at a tertiary care cancer center and found that amphotericin B lipid complex administration was uneventful in 34 patients (85% [95% confidence interval, 69%-93%]).