Are we missing opportunities to confirm the diagnosis of tuberculosis by microbial culture?

SummarySettingTuberculosis (TB) incidence is rising globally, with drug resistance becoming increasingly problematic. Microbiological confirmation ensures correct anti-tuberculous chemotherapy.Objective/designWe retrospectively analysed all TB cases diagnosed in Central Manchester in 2009 investigating how often we are not achieving microbiological diagnosis, factors influencing this and whether opportunities to obtain microbiological samples are missed.Results128/156 (82%) cases had samples sent for microbiology. Factors affecting this included disease site, with ocular disease least likely to be sampled (p < 0.0001), and patient age (with children less likely to be sampled p = 0.002). Ethnicity did not affect sampling (n.s.). Overall, 92/156 (59%) cases were culture positive. Negative culture was related to specimen type (p < 0.0001) and patient age (p = 0.019), with children significantly less likely to have a positive culture. Ethnicity and disease site did not affect culture results. There was a trend towards culture positivity being more common in pulmonary (75%) than non-pulmonary (46%) disease (n.s.). In only 7 (4%), could samples have been sent where they were originally absent (3) or further samples obtained where the cultures proved to be negative (4).ConclusionDespite an overall culture positive rate of 59%, opportunities to achieve microbiological confirmation are seldom missed. In our centre, which is typical of UK practice, this lack of capacity to increase microbiological confirmation, particularly in an era of increasing importance of extra-pulmonary TB, is concerning. Improvements in sample acquisition and laboratory methods are urgently required

Pharmacodynamics of itraconazole against Aspergillus fumigatus in an in vitro model of the human alveolus: Perspectives on the treatment of triazole-resistant infection and utility of airway administration

Itraconazole is used for the prevention and treatment of infections caused by Aspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. An in vitro model of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity

Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints.

Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used