Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review

Sinnollareddy, Mahipal G.; Peake, Sandra; Roberts, Michael S.; Lipman, Jeffrey; Roberts, Jason A.

doi:10.1016/j.ijantimicag.2011.07.013

Cited by 49 publications

(33 citation statements)

References 80 publications

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“…In addition to resistance issues, the effectiveness of a particular antifungal agent depends on its pharmacokinetic and pharmacodynamic properties (2,38,39). Because new triazoles frequently have unpredictable pharmacokinetics and often interact with other drugs (2), and because TDM has been rarely performed during PAP (3, 9), we cannot rule out that some breakthrough IFIs with azoles were due to suboptimal drug exposure.…”

Section: Discussionmentioning

confidence: 99%

Incidence Density of Invasive Fungal Infections during Primary Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Patients in a Tertiary Cancer Center, 2009 to 2011

Gomes

Mulanovich

Jiang

et al. 2014

Antimicrob Agents Chemother

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Although primary antifungal prophylaxis (PAP) is routinely administered in patients with acute myeloid leukemia (AML) during remission-induction and consolidation chemotherapy, the impact of PAP on the incidence of invasive fungal infections (IFIs) is not well described. We retrospectively analyzed the incidence of IFIs in 152 patients with AML who had been admitted to a tertiary cancer center between August 2009 and March 2011 and received PAP within 120 days after first remission-induction chemotherapy. We excluded patients who had undergone stem cell transplantation. Patients received a PAP drug with antiAspergillus activity during 72% (7,660/10,572) of prophylaxis-days. The incidence of documented IFIs (definite or probable according to revised European Organization for Research and Treatment of Cancer [EORTC] criteria) was 2.0/1,000 prophylaxisdays (95% confidence interval [CI], 1.23 to 3.04). IFIs due to molds were more common than IFIs due to yeasts (1.5/1,000 prophylaxis-days versus 0.4/1,000 prophylaxis-days; P ‫؍‬ 0.01). Echinocandin-based PAP (8.6 and 7.1/1,000 prophylaxis-days, respectively) was associated with higher rates of documented IFIs than anti-Aspergillus azoles (voriconazole or posaconazole) (2.4 and 1.1/1,000 prophylaxis-days, respectively) at both 42 days (P ‫؍‬ 0.03) and 120 days (P < 0.0001) after first remission-induction chemotherapy. The incidence of overall (documented and presumed) IFIs (P < 0.001), documented IFIs (P < 0.01), and empirical antifungal therapies (P < 0.0001) was higher during the first 42 days than after day 42. Despite the broad use of PAP with anti-Aspergillus activity, IFIs, especially molds, remain a significant cause of morbidity and mortality in AML patients, predominantly during the remission-induction phase. Patients receiving echinocandin-based PAP experienced higher rates of IFIs than did those receiving anti-Aspergillus azoles.

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Section: Discussionmentioning

confidence: 99%

Incidence Density of Invasive Fungal Infections during Primary Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Patients in a Tertiary Cancer Center, 2009 to 2011

Gomes

Mulanovich

Jiang

et al. 2014

Antimicrob Agents Chemother

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“…In critically ill nonobese patients, fluconazole PK appears to be different from that of healthy subjects (16). This is likely due to organ dysfunction, renal and/or hepatic, as well as fluid shifts and capillary permeability changes that can alter fluconazole clearance and V. There is little or no data about the PK of fluconazole in obese patients, particularly critically ill obese patients.…”

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confidence: 99%

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2016

Antimicrob Agents Chemother

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“…For antifungals where this parameter is known, dosing regimens may be adapted to maximize antifungal activity (19). Despite this, it is clear that terbinafine is increasingly used at high doses (1), and thus, a practical approach is warranted for the selection of high-dose terbinafine regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacodynamic parameters that are predictive of drug efficacy, in- cluding AUC/MIC, time above the MIC, and C max /MIC, have been established for most antifungal agents (19); however, to our knowledge, no studies have investigated pharmacodynamic parameters for terbinafine. Therefore, the AUC/MIC and C max /MIC ratios and time above the MIC were investigated in this study, with each of these parameters being assessed for both total terbinafine plasma concentration (bound to plasma proteins and unbound) and unbound terbinafine plasma concentration (free).…”

Section: Methodsmentioning

confidence: 99%

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

Dolton

Perera

Pont

et al. 2014

Antimicrob Agents Chemother

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dTerbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of highdose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (C max ), and minimum concentration (C min ) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.T he allylamine antifungal terbinafine is a well-established agent in the treatment of onychomycosis (1). Due to its broad antifungal spectrum, interest in terbinafine has expanded to include its use in a range of cutaneous and subcutaneous mycoses, such as sporotrichosis, eumycetoma, and chromoblastomycosis (2-4), as well as in combination with other antifungal agents to treat resistant or refractory invasive fungal infections (IFIs), as described in numerous case reports (1, 5). In support of the latter indication, synergistic in vitro antifungal activity has been demonstrated with terbinafine in combination with azole antifungals for many important fungal pathogens, including Aspergillus spp., zygomycetes, Fusarium spp., Paecilomyces spp., Candida albicans, dematiaceous molds, and the highly resistant Scedosporium prolificans (6-11).High dose is a consistent feature of terbinafine use in these indications, with daily doses of up to 1,000 mg daily (1) used to boost the plasma concentrations of terbinafine, which are known to be low following standard dosing, such as the standard dosing regimen of 250 mg daily in onychomycosis, due to extensive accumulation in skin and adipose tissue (12). However, no studies have assessed the systemic exposure of higher-dose terbinafine treatment (Ͼ250 mg daily) or divided daily doses (every 12 h [q12h] or q8h), factors that are likely to be crucial to the utility of terbinafine in effectively treating systemic mycoses in combination with other antifungals. This pauci...

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Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review

Cited by 49 publications

References 80 publications

Incidence Density of Invasive Fungal Infections during Primary Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Patients in a Tertiary Cancer Center, 2009 to 2011

Incidence Density of Invasive Fungal Infections during Primary Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Patients in a Tertiary Cancer Center, 2009 to 2011

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

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