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.

cWe 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. Despite concerns of poor bioavailability, posaconazole (POSA) suspension has been used effectively as prophylaxis and as a salvage treatment of invasive fungal infections with rare clinical hepatotoxicity (1). Higher serum concentrations of POSA suspension were associated with higher response rates in treatment of invasive aspergillosis (2). Recent studies (3-6) have suggested that the absorption of the new formulation of POSA delayed-release tablets is minimally affected by food, mucositis, or increased gastric pH and impaired motility and that the new tablet formula also attains higher average concentrations than the suspension does and is well tolerated in healthy subjects. However, no studies about patients who were "bridged" from POSA suspension to tablets have been published to date. We report our early experience in leukemia patients who switched from POSA suspension to delayed-release tablets.Pharmacy databases were queried for adult cancer (Ͼ18 years of age) patients who were switched from POSA suspension (400 mg twice daily or 200 mg 4 times daily) to tablets (300 mg once daily) at The University of Texas MD Anderson Cancer Center from December 2013 to January 2014. Once POSA tablets were added to the formulary, a general trend seen in our hematologic malignancy patient population was that physicians would independently transition almost all current and future patients to tablets despite suspension remaining on the formulary. We identified 12 patients with leukemia who were treated as such. Validated high-performance liquid chromatography (HPLC) assay-tandem mass spectrometry (performed at Mayo Clinic Department of Laboratory Medicine and Pathology, Rochester, MN) was used to measure posaconazole concentrations in blood (7). All patients who had serum POSA levels recorded during both the POSA suspension and tablet periods were identified. POSA concentrations were included in the analysis only if the data were obtained 7 days after POSA administration, as steady state of the drug should be reached at this time for both suspension and tablet (4, 8). The patients' medical records were reviewed for demographic, clinical, and laboratory characteristics (Table 1). Target serum POSA levels were defined as greater than 700 ng/ml for prophylaxis and greater than 1,000 ng/ml for treatment (9). Clinically relevant Underlying condition at the time of sampling, a n (%) ANC of Ͻ500/l 6 (50) Graft-versus-host disease 3 a For measurement of serum POSA levels.

Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayedrelease 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 Ն3 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 (Ͻ700 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 (Ͻ700 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 Ͼ1,830 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 Ͼ700 ng/ml, and a posaconazole level of Ͼ1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.KEYWORDS posaconazole, hematological malignancy, prophylaxis, cancer, antifungal I nvasive fungal infections (IFIs) continue to be a significant cause of morbidity and death among patients with hematological malignancy (1). The triazole posaconazole (PCZ) has in vitro, preclinical, and clinical activities against a variety of yeasts and molds (2). Since its introduction 15 years ago, PCZ has been widely used for the prevention and treatment of IFIs in patients with leukemia and in hematopoietic stem cell

Resistance to the novel β-lactam/β-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-β-lactamase in diverse Enterobacteriaceae species.

Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort.