Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a New
            <i>In Vitro</i>
            Pharmacokinetic/Pharmacodynamic Model

Meletiadis, Joseph; Al-Saigh, Rafal; Velegraki, Aristea; Walsh, Thomas J.; Roilides, Emmanuel; Zerva, Loukia

doi:10.1128/aac.00662-11

Cited by 42 publications

(41 citation statements)

References 37 publications

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“…The in vitro pharmacokinetic simulation model consisted of (i) a glass beaker containing 700 ml medium (external compartment [EC]) in which was placed (ii) a dialysis tube of a 10-ml volume (internal compartment [IC]) made of a permeable cellulose membrane, which allowed free diffusion of molecules with a molecular mass of Ͻ20 kDa, and (iii) a peristaltic pump (Minipuls Evolution, Gilson, France), which removed the content of EC and added fresh medium within it at a rate equivalent to drug removal from human serum (17). The conidial suspension was inoculated in the IC, where it remained trapped together with the galactomannan (molecular mass of 20 kDa to 60 kDa) produced by the growing mycelia, while nutrients and drug diffused freely between the IC and EC.…”

Section: Methodsmentioning

confidence: 99%

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Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

Elefanti

Mouton

Verweij

et al. 2014

Antimicrob Agents Chemother

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Invasive aspergillosis is a life-threatening disease among patients with leukemia and bone marrow and solid-organ transplantation (1). Aspergillus fumigatus is the most common pathogen causing invasive aspergillosis, accounting for Ͼ70% of the cases, followed by Aspergillus flavus, Aspergillus terreus, and Aspergillus niger (2). Conventional amphotericin B was for many years the drug of choice and is still used against invasive aspergillosis. Despite its in vitro potent antifungal activity against Aspergillus spp., clinical trials have shown that conventional amphotericin B therapy is associated with Ͻ60% survival in patients with invasive aspergillosis (3-6). Although underlying disease, immunosuppression, toxicity, and timing of antifungal therapy affect the mortality of these infections, pathogen susceptibility and drug serum concentrations also represent important contributing factors. In vivo studies have shown that the best efficacy was achieved when the maximum concentration of amphotericin B in serum exceeded 2.4 times the MIC of the A. fumigatus isolate (7). However, in vitro antifungal susceptibility testing of amphotericin B is challenged by the lack of reliable susceptibility breakpoints for each Aspergillus species.The epidemiological cutoff values 2, 2, and 4 mg/liter for the CLSI method and 1, 4, and 4 mg/liter for the EUCAST method were determined for A. fumigatus, A. flavus, and A. terreus, respectively, in order to detect isolates with extreme MICs (8, 9). The current susceptibility breakpoints for Aspergillus spp. with the CLSI and EUCAST methodologies are Յ1 mg/liter (9, 10). However, the supporting clinical and experimental in vivo data are poor, and no pharmacokinetic-pharmacodynamic (PK-PD) studies have validated this breakpoint (9). In a retrospective case-control study of 29 patients, 22/23 patients with isolate MICs of Ն2 mg/liter died, whereas 6/6 patients with isolate MICs of Յ1 mg/ liter survived (11). Of note, 5/6 survivors with isolate MICs of Յ1 mg/liter underwent surgery or resolved their neutropenia. In two other large retrospective studies of 160 and 40 patients, no correlation was found between an Aspergillus MIC of Ն2 mg/liter and clinical outcome in patients with invasive aspergillosis treated with conventional amphotericin B (12, 13). Notably, more than 95% of A. fumigatus isolates have MICs of Յ1 mg/liter (8). Therefore, the majority of the isolates would be considered wild-type susceptible based on the 1-mg/liter cutoff, while conventional amphotericin B therapy has been associated with Ͻ60% of survival in all clinical trials (3,4,14). Furthermore, treatment failure was observed in patients infected with A. fumigatus and A. flavus isolates with CLSI MICs of 0.25 to 0.5 mg/liter and 1 mg/liter, respectively, when treated with the standard dose of 1 mg/kg of conventional amphotericin B (15, 16). Thus, a clinically relevant and

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Section: Methodsmentioning

confidence: 99%

“…simulating pharmacokinetics of antifungal drugs (17). This model revealed considerable pharmacodynamic differences among Aspergillus isolates reflecting differences in time-and concentration-dependent inhibitory and fungicidal activity that were not captured by the MIC (18).…”

mentioning

confidence: 99%

Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

Elefanti

Mouton

Verweij

et al. 2014

Antimicrob Agents Chemother

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“…These effects can be quantified by a surrogate marker of fungal growth based on galactomannan production kinetics which captures any difference on the above antifungal effects. Differential antifungal activity against three Aspergillus species with identical MICs of voriconazole, amphotericin B, and caspofungin was recently found, emphasizing the importance of studying nonconstant drug concentrations (11). The growth rate may be an important determinant of antifungal activity.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of decreasing drug concentrations on Aspergillus spp. was unknown until recently, when we developed an in vitro model simulating human pharmacokinetics of antifungal drugs, including voriconazole (11). This novel pharmacokinetic/pharmacodynamic (PKPD) model demonstrated a differential activity of simulated standard dosages of antifungals against Aspergillus isolates with identical MICs.…”

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confidence: 99%

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

Al-Saigh

Elefanti

Velegraki

et al. 2012

Antimicrob Agents Chemother

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The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with C max values of 7, 3.5, and 1.75 mg/liter and a t 1/2 of 6 h. The area under the galactomannan index-time curve (AUC GI ) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC 0-24 -AUC GI followed a sigmoid pattern (global R 2 ‫؍‬ 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC 0-24 (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. terreus (F test; P < 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage. Invasive aspergillosis is the most serious infection caused by Aspergillus species, particularly in patients with hematological malignancies or bone marrow transplantation (16). These infections are characterized by high morbidity and mortality despite available antifungal therapy (7), among which voriconazole is the drug of choice (24). Several factors may influence the clinical outcome, related to the host (underlying condition and immunosuppression), drug (timing of administration and suboptimal exposure), and pathogen (resistance and virulence). Although voriconazole-resistant isolates have been described, their low prevalence (Ͻ10%) cannot explain the high mortality of these infections (10, 21). Testing of large sets of Aspergillus isolates showed that more than half of them exhibited similar in vitro susceptibilities to voriconazole, with a MIC of 0.5 mg/liter (5, 17). Furthermore, the most frequently isolated species, A. fumigatus, A. flavus, and A. terreus, demonstrated similar in vitro susceptibilities, although in vivo experimental and clinical data show that the efficacy of voriconazole differs for these species (22)(23)(24)26). T...

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“…The in vitro closed diffusion-dialysis PK-PD model consisted of two compartments, the internal and the external compartment, as previously described (Meletiadis et al, 2012). The external compartment consisted of a 750 ml flask placed on a 37 uC magnetic heating stirrer, whereas the internal compartment consisted of a 10 ml dialysis tube made of semi-permeable cellulose with membrane molecular weight cutoff of 1000 kDa (Float-A-Lyzer; Spectrum Labs).…”

mentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

Tsala

Vourli

Kotsakis

et al. 2016

Journal of Medical Microbiology

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VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l 21) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log 10 CFU/ml reduction of ,1 for the VIM-producing (MIC 16 mg l 21) and .2 for the WT (MIC 0.031 mg l 21) isolates, with %f T .MIC 25 and 100 %, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T.MIC and attained in .90 % of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l 21. For isolates with MICs of 2-8 mg l 21 , prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l 21 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.

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Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a New In Vitro Pharmacokinetic/Pharmacodynamic Model

Cited by 42 publications

References 37 publications

Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

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