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Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.

ABSTRACT: BACKGROUND:Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100mg to 2000mg/day have been used. Prevalence of fluconazole non-susceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentration and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy. METHODS:First, we conducted a systematic review using MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Second, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole's known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100mg to 2000mg via linear regression. Third, the fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review. RESULTS:We summarized 21 studies with 11,049 clinical Cryptococcus isolates. MICs were normally distributed with geometric mean of 3.4 ?g/mL, median (MIC50) of 4 ?g/mL, and 90th percentile (MIC90) of 16 ?g/mL. The median MIC50 trended upwards from 4 ?g/mL in 2000-2012 to 8 ?g/mL in 2014-2018. Predicted sub-therapeutic fluconazole concentrations (below MIC) would occur in 40% with 100mg, 21% with 200mg, and 9% with 400mg. AUC/MIC ratio >100 would occur in 53% for 400mg, 74% for 800mg, 83% for 1200mg, and 88% for 1600mg. CONCLUSIONS:Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.

SUBMITTER: Chesdachai S

PROVIDER: S-EPMC6767974 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.

Chesdachai Supavit S Rajasingham Radha R Nicol Melanie R MR Meya David B DB Bongomin Felix F Abassi Mahsa M Skipper Caleb C Kwizera Richard R Rhein Joshua J Boulware David R DR

Open forum infectious diseases 20191001 10

<h4>Background</h4>Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100mg to 2000mg/day have been used. Prevalence of fluconazole non-susceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentration and area under the curve (AUC) relative to MIC to propose a r ...[more]

PMID: 31420668

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Project description:Gram-negative bacteria possess stress responses to maintain the integrity of the cell envelope. Stress sensors monitor outer membrane permeability, envelope protein folding, and energization of the inner membrane. The systems used by Gram-negative bacteria to sense and combat stress resulting from disruption of the peptidoglycan layer are not well characterized. The peptidoglycan layer is a single molecule that completely surrounds the cell and ensures its structural integrity. During cell growth new peptidoglcyan subunits are incorporated into the peptidoglycan layer by a series of enzymes called the penicillin-binding proteins (PBPs). To explore how Gram-negative bacteria respond to peptidoglycan stress, global gene expression analysis was used to identify Escherichia coli stress responses activated following inhibition of specific PBPs by the β-lactam antibiotics mecillinam and cefsulodin. Inhibition of PBPs with different roles in peptidoglycan synthesis has different consequences for cell morphology and viability, suggesting that not all perturbations to the peptidoglycan layer generate equivalent stresses. We demonstrate that inhibition of different PBPs resulted in both shared and unique stress responses. The regulation of capsular synthesis (Rcs) phosphorelay was activated by inhibition of all of the PBPs tested. Furthermore, we show that activation of the Rcs phosphorelay increased survival in the presence of these antibiotics, independently of capsule synthesis. Both activation of the phosphorelay and survival required signal transduction via the outer membrane lipoprotein RcsF and the response regulator RcsB. We propose that the Rcs pathway responds to peptidoglycan damage and contributes to the intrinsic resistance of E. coli to β-lactam antibiotics. We used microarrays to identify changes in gene expression resulting from treatment of Escherichia coli with the β-lactam antibiotics cefsulodin, mecillinam, or the combination. Keywords: Dose response, stress response

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Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.

Publications

Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.

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