Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Donor-derived tuberculosis (TB): isoniazid-resistant TB transmitted from a lung transplant donor with inadequately treated latent infection.

Donor-derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid-resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required.

Support for the EUCAST and revised CLSI fluconazole clinical breakpoints by Sensititre® YeastOne® for Candida albicans: a prospective observational cohort study.

OBJECTIVES: Species-specific clinical breakpoints (CBPs) for Candida spp. were established following consideration of clinical outcomes in patients with oesophageal candidiasis. We sought to further determine the validity of the current CBPs based on data from a prospective candidaemia study. PATIENTS AND METHODS: All Candida albicans candidaemia episodes in patients enrolled in the Australian Candidaemia Study and who were treated with fluconazole monotherapy were included. Fluconazole MICs were established using Sensititre(®) YeastOne(®). RESULTS: Two hundred and seventeen evaluable episodes were identified, 93.5% of which occurred in adult patients. Fluconazole was commenced within 72 h of blood culture positivity in 96.3% (209/217) of episodes. Fluconazole doses were appropriate in 89.9% (195/217) of episodes and the median duration of therapy was 14 days (IQR 8-21 days) for the whole cohort. The all-cause 30 day mortality was 19.8% (43/217), with 37.2% (16/43) of deaths attributed to candidaemia. Classification and regression tree (CART) analysis identified a fluconazole MIC target of ≥2 mg/L for infection-related mortality and ≥4 mg/L for overall 30 day mortality. Overall mortality was no different in episodes with isolates above or below the identified MIC target, although there was a trend towards significance (P = 0.051). On univariate analysis, infection-related mortality was significantly increased in C. albicans episodes with an MIC ≥2 mg/L compared with those below this MIC target (20.6% versus 4.9%; P = 0.001). This target remained an independent predictor of infection-related mortality (OR 8.2; 95% CI 2.3-29.7; P = 0.001). CONCLUSIONS: We observed a direct relationship between infection-related mortality and rising fluconazole MIC for C. albicans candidaemia; overall, the data support the EUCAST and revised CLSI fluconazole clinical breakpoints.

Candidaemia with uncommon Candida species: predisposing factors, outcome, antifungal susceptibility, and implications for management.

The risk factors for and clinical features of bloodstream infection with uncommon Candida spp. (species other than C. albicans, C. glabrata, C. parapsilosis, C. tropicals and C. krusei) are incompletely defined. To identify clinical variables associated with these species that might guide management, 57 cases of candidaemia resulting from uncommon Candida spp. were analysed in comparison with 517 episodes of Candida albicans candidaemia (2001-2004). Infection with uncommon Candida spp. (5.3% of candidaemia cases), as compared with C. albicans candidaemia, was significantly more likely to be outpatient-acquired than inpatient-acquired (15 of 57 vs. 65 of 517 episodes, p 0.01). Prior exposure to fluconazole was uncommon (n=1). Candida dubliniensis was the commonest species (n=22, 39%), followed by Candida guilliermondii (n=11, 19%) and Candida lusitaniae (n=7, 12%).C. dubliniensis candidaemia was independently associated with recent intravenous drug use (p 0.01) and chronic liver disease (p 0.03), and infection with species other than C. dubliniensis was independently associated with age<65 years (p 0.02), male sex (p 0.03) and human immunodeficiency virus infection (p 0.05). Presence of sepsis at diagnosis and crude 30-day mortality rates were similar for C. dubliniensis-related, non-C. dubliniensis-related and C. albicans-related candidaemia. Haematological malignancy was the commonest predisposing factor in C. guilliermondii (n=3, 27%) and C. lusitaniae (n=3, 43%) candidaemia. The 30-day mortality rate of C. lusitaniae candidaemia was higher than the overall death rate for all uncommon Candida spp. (42.9% vs. 25%, p not significant). All isolates were susceptible to amphotericin B, voriconazole, posaconazole, and caspofungin; five strains (9%) had fluconazole MIC values of 16-32 mg/L. Candidaemia due to uncommon Candida spp. is emerging among hospital outpatients; certain clinical variables may assist in recognition of this entity.

Rhizopus microsporus var. rhizopodiformis sinus-orbital zygomycosis in an immunosuppressed patient: successful treatment with posaconazole after a complicated clinical course.

A case of sinus-orbital Rhizopus microsporus var. rhizopodiformis infection in a patient with graft versus host disease following allogeneic blood stem cell transplantation is reported. Commercially available pea straw compost used for gardening was suspected to be the source of the infection. After an initial relapse, treatment with surgical debridement, liposomal amphotericin B and posaconazole was successful.