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Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

ABSTRACT: BACKGROUND:Posaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs). METHODS:Bibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut-off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA). RESULTS:Twenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR?=?1.98, 95% confidence interval, CI 1.09-3.58, P?=?0.02) while the threshold, 0.7 mg/L showed no significant difference (OR?=?1.84, 95% CI 0.94-3.63, P?=?0.08). The TSA results showed that there was sufficient information to support these findings. CONCLUSIONS:An optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L.

SUBMITTER: Chen L

PROVIDER: S-EPMC5879730 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

Chen Lu L Wang Yan Y Zhang Tao T Li Ying Y Meng Ti T Liu Leichao L Hao Ruifang R Dong Yalin Y

BMC infectious diseases 20180402 1

<h4>Background</h4>Posaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs).<h4>Methods</h4>Bibliographic data ...[more]

PMID: 29609553

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Project description:Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Project description:Invasive fungal infections (IFIs) are one of the most important infectious complications after liver transplantation, determining morbidity and mortality. Antimycotic prophylaxis may impede IFI, but a consensus on indication, agent, or duration is still missing. Therefore, this study aimed to investigate the incidence of IFIs under targeted echinocandin antimycotic prophylaxis in adult high-risk liver transplant recipients. We retrospectively reviewed all patients undergoing a deceased donor liver transplantation at the Medical University of Innsbruck in the period from 2017 to 2020. Of 299 patients, 224 met the inclusion criteria. We defined patients as being at high risk for IFI if they had two or more prespecified risk factors and these patients received prophylaxis. In total, 85% (190/224) of the patients were correctly classified according to the developed algorithm, being able to predict an IFI with a sensitivity of 89%. Although 83% (90/109) so defined high-risk recipients received echinocandin prophylaxis, 21% (23/109) still developed an IFI. The multivariate analysis identified the age of the recipient (hazard ratio-HR = 0.97, p = 0.027), split liver transplantation (HR = 5.18, p = 0.014), massive intraoperative blood transfusion (HR = 24.08, p = 0.004), donor-derived infection (HR = 9.70, p < 0.001), and relaparotomy (HR = 4.62, p = 0.003) as variables with increased hazard ratios for an IFI within 90 days. The fungal colonization at baseline, high-urgency transplantation, posttransplant dialysis, bile leak, and early transplantation showed significance only in a univariate model. Notably, 57% (12/21) of the invasive Candida infections were caused by a non-albicans species, entailing a markedly reduced one-year survival. The attributable 90-day mortality rate of an IFI after a liver transplant was 53% (9/17). None of the patients with invasive aspergillosis survived. Despite targeted echinocandin prophylaxis, there is still a notable risk for IFI. Consequently, the prophylactic use of echinocandins must be critically questioned regarding the high rate of breakthrough infections, the increased occurrence of fluconazole-resistant pathogens, and the higher mortality rate in non-albicans Candida species. Adherence to the internal prophylaxis algorithms is of immense importance, bearing in mind the high IFI rates in case algorithms are not followed.

Dataset Information

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

Publications

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

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