The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported.

An experimental micellar formulation of amphotericin B (AMB) with sodium deoxycholate (DCH), AMB:DCH 1:1.5, was obtained and characterized to determine its aggregation state and particle size. Biodistribution, nephrotoxicity and efficacy against pulmonary aspergillosis in a murine model were studied and compared to the liposomal commercial amphotericin B after intravenous administration. The administration of 5 mg/kg AMB:DCH 1:1.5 presented 2.8-fold higher lung concentrations (18.125 ± 3.985 μg/g, after 6 daily doses) and lower kidney exposure (0.391 ± 0.167 μg/g) compared to liposomal commercial amphotericin B (6.567 ± 1.536 and 5.374 ± 1.157 μg/g, in lungs and kidneys, respectively). The different biodistribution of AMB:DCH micelle systems compared to liposomal commercial amphotericin B was attributed to their different morphology and particle size. The efficacy study has shown that both drugs administered at 5 mg/kg produced similar survival percentages and reduction of fungal burden. A slightly lower nephrotoxicity, associated to amphotericin B, was observed with AMB:DCH 1:1.5 than the one induced by the liposomal commercial formulation. However, AMB:DCH 1:1.5 reached higher AMB concentrations in lungs that could represents a therapeutic advantage over liposomal commercial amphotericin B-based treatment of pulmonary aspergillosis. These results are encouraging to explore the AMB:DCH 1:1.5 usefulness against this disease.

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis (CM). A PK study was conducted in n=42 patients receiving DAmB 1 mg/kg q24h. A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of CM patients treated with DAmB monotherapy and a meta-analysis was performed.The PK parameter means (standard deviation) were: clearance, 0.03 (0.01) x weight + 0.95 (0.02) litres/hour; volume, 0.89 (0.90) x weight + 1.54 (1.13) litres; first-order rate constant from central to peripheral compartment, 7.12 (6.50) hours-1; from peripheral to central compartment, 12.13 (12.50) hours-1 The meta-analysis suggested that DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility, but not in mortality outcomes. Simulations of area under concentration-time curve (AUC144-168) resulted in median (interquartile range) values 5.83 mg.h/litre (4.66-8.55), 10.16 (8.07-14.55) and 14.51 (11.48-20.42), with dosages of 0.4, 0.7 and 1.0 mg/kg q24h respectively.DAmB PK is described adequately by a linear model that incorporates weight on clearance and volume. Inter-patient PK variability is modest and unlikely to be responsible for variability in clinical outcome. There is a discord between the impact that drug exposure has on CSF sterility and on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy.

Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the name conventional amphotericin B and has been used for the treatment of invasive fungal infections for more than 50 years. It was first isolated as a natural product of a soil actinomycete.

Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D-AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3-13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 μmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 μmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option.