Andres Pascual

Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes

BACKGROUND Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. METHODS This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. RESULTS A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from <or=1 mg/L (the minimum inhibitory concentration at which, for most fungal pathogens, 90% of isolates are susceptible) in 25% of cases to >5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels <or=1 mg/L (6 [46%] of 13 patients, including 5 patients with aspergillosis, 4 of whom were treated orally with a median dosage of 6 mg/kg per day) than in those with voriconazole levels >1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels <or=5.5 mg/L presented with neurological toxicity (P=.002). Comedication with omeprazole possibly contributed to voriconazole accumulation in 4 patients. In all cases, discontinuation of therapy resulted in prompt and complete neurological recovery. CONCLUSIONS Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycoses.

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

The successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. As the population of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel (57). Despite recent advances in antifungal pharmacology, the morbidity and mortality due to invasive fungal infections remain unacceptably high. Numerous factors determine the outcome of these infections, including the host immune state, pathogen variables including drug susceptibility, location of the infection, timing of diagnosis relative to initiation of antifungal therapy, management of the infection source (e.g., surgery or vascular catheter removal), and effective administration of the appropriate dose of the most potent and safe antifungal drug (Fig. ​(Fig.1).1). Few of these variables are under the control of the clinician. The choices of antifungal drug and dosing regimen are among the factors which the clinician can dictate. However, even if the appropriate drug and regimen are initiated, drug exposure at the site of infection may be inadequate due to pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed those anticipated and may result in toxicity. Many antifungal drugs exhibit marked variability in drug blood concentrations due to inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. An understanding of the pharmacokinetics and pharmacodynamics of these drugs has been demonstrated to be important to optimize drug choice and dosing regimen design. One tool to detect drug exposures outside of the therapeutic window is monitoring of drug concentration in blood. The utility of this tool to inform drug choice and dosing decisions is being increasingly explored. FIG. 1. Determinants for outcome of invasive mycoses. Several factors must be considered in determining the role of therapeutic drug monitoring in patient management (32, 86, 88). An accurate, rapid, and cost-effective drug assay must be readily available to the clinician. Two pharmacological features then determine the relevance of monitoring of concentrations of drug in blood. The foremost variable is an unpredictable drug dose-exposure relationship. Next, there must be a clear relationship between concentrations of drug in blood and either toxicity or treatment efficacy. Consideration of these pharmacological variables for available antifungal compounds is the focus of this review.

Challenging Recommended Oral and Intravenous Voriconazole Doses for Improved Efficacy and Safety: Population Pharmacokinetics–Based Analysis of Adult Patients With Invasive Fungal Infections

BACKGROUND Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. METHODS A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. RESULTS A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. CONCLUSIONS Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

Variability of Voriconazole Plasma Levels Measured by New High-Performance Liquid Chromatography and Bioassay Methods

ABSTRACT Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Δ/cdr1Δ, cdr2Δ/cdr2Δ, flu1Δ/flu1Δ, and mdr1Δ/mdr1Δ) and calcineurin subunit A (cnaΔ/cnaΔ) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% ± 5.0%/96.5% ± 2.4% (HPLC) and 94.9% ± 6.1%/94.7% ± 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% ± 1.5%/5.4% ± 0.9% and 6.5% ± 2.5%/4.0% ± 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg · h/liter (range, 12.9 to 71.1) on the first and 27.4 mg · h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg · h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg · h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.

High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function.

ABSTRACT High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Reassessment of Recommended Imipenem Doses in Febrile Neutropenic Patients with Hematological Malignancies

ABSTRACT Imipenem plasma concentrations were analyzed in 57 febrile neutropenic patients using the NONMEM program. The recommended 2-g/day regimen achieved coverage of the most common bacteria (MIC90 = 1 mg/liter) during the whole dosing interval in only 53% of patients. This goal was achieved in 90% of patients with 3 g/day.

New Diagnostic Real-Time PCR for Specific Detection of Mycoplasma hominis DNA

Mycoplasma hominis is a fastidious micro-organism causing genital and extragenital infections. We developed a specific real-time PCR that exhibits high sensitivity and low intrarun and interrun variabilities. When applied to clinical samples, this quantitative PCR allowed to confirm the role of M. hominis in three patients with severe extragenital infections.

Mycoplasma hominis necrotizing pleuropneumonia in a previously healthy adolescent

BackgroundMycoplasma hominis is a fastidious micro-organism causing systemic infections in the neonate and genital infections in the adult. It can also be the cause of serious extra-genital infections, mainly in immunosuppressed or predisposed subjects.Case PresentationWe describe a case of severe pneumonia and pericarditis due to Mycoplasma hominis in a previously healthy adolescent who did not respond to initial therapy.ConclusionsMycoplasma hominis could be an underestimated cause of severe pneumonia in immunocompetent patients and should be particularly suspected in those not responding to standard therapy.

Ultra-Performance Liquid Chromatography Mass Spectrometry and Sensitive Bioassay Methods for Quantification of Posaconazole Plasma Concentrations after Oral Dosing

ABSTRACT Posaconazole (POS) is a new antifungal agent for prevention and therapy of mycoses in immunocompromised patients. Variable POS pharmacokinetics after oral dosing may influence efficacy: a trough threshold of 0.5 μg/ml has been recently proposed. Measurement of POS plasma concentrations by complex chromatographic techniques may thus contribute to optimize prevention and management of life-threatening infections. No microbiological analytical method is available. The objective of this study was to develop and validate a new simplified ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method and a sensitive bioassay for quantification of POS over the clinical plasma concentration range. The UPLC-MS/MS equipment consisted of a triple quadrupole mass spectrometer, an electrospray ionization (ESI) source, and a C18 analytical column. The Candida albicans POS-hypersusceptible mutant (MIC of 0.002 μg/ml) Δcdr1 Δcdr2 Δflu Δmdr1 Δcan constructed by targeted deletion of multidrug efflux transporters and calcineurin genes was used for the bioassay. POS was extracted from plasma by protein precipitation with acetonitrile-methanol (75%/25%, vol/vol). Reproducible standard curves were obtained over the range 0.014 to 12 (UPLC-MS/MS) and 0.028 to 12 μg/ml (bioassay). Intra- and interrun accuracy levels were 106% ± 2% and 103% ± 4% for UPLC-MS/MS and 102% ± 8% and 104% ± 1% for bioassay, respectively. The intra- and interrun coefficients of variation were 7% ± 4% and 7% ± 3% for UPLC-MS/MS and 5% ± 3% and 4% ± 2% for bioassay, respectively. An excellent correlation between POS plasma concentrations measured by UPLC-MS/MS and bioassay was found (concordance, 0.96). In 26 hemato-oncological patients receiving oral POS, 27/69 (39%) trough plasma concentrations were lower than 0.5 μg/ml. The UPLC-MS/MS method and sensitive bioassay offer alternative tools for accurate and precise quantification of the plasma concentrations in patients receiving oral posaconazole.

120 Monitoring of voriconazole (VRC) blood levels for prevention of serious neurological adverse events (SNAE)

Background: Voriconazote (VRC) is a widety used broad-spectrum antifunga[ agent. Non-linear pharmacokinetics, po[ymorphism of cytochrome CYP2C19, drug interactions and hepatic dysfunction may result in interand intra-individua[ variations of VRC brood revers. We reported SNAE probabty associated with protonged VRC overdosing (trough brood revers higher than 5.5 mg/L during more than 7d) (ICAAC 2005, M-2164). This observation suggested that VRC close adjustment based on monitoring of brood revers may hetp to prevent SNAE. Objective: To prospectivety evatuate the utitity of monitoring VRC brood revers for prevention of SNAE. Methods: VRC trough brood revers were measured by HPLC during the first week of therapy in 25 consecutive treatment courses during 2005. VRC dosing was adjusted if VRC trough brood revers were >5.5 mg/L. Clinical follow-up included surveillance for adverse events (NCI criteria). Occurrence of SNAE during VRC therapy in 2004 (no prospective close adjustment based on VRC brood revers) and 2005 (prospective close adjustment) was compared. Results: Indications for VRC therapy were aspergillosis (60%), candidiasis (16%), and suspected mycosis (24%). Median VRC close was 4 mg/kg bid (range 1.3-5.7). Median number of VRC trough brood revers measurements/ treatment course was 2.5 (range 1-5). Median clays to first measurement after starting VRC therapy were 2 (2-7). Nine pts (37%) presented transient self-limiting visual disturbances/hattucinations. Two patients (8%) presented severe hepatotoxicity. Occurrence of SNAE in 2004 and 2005 is compared in the tabte.