Therapeutic Drug Monitoring of Voriconazole in a Child With Invasive Aspergillosis Requiring Extracorporeal Membrane Oxygenation

Brüggemann, Roger J. M.; Antonius, Tim; Heijst, Arno van; Hoogerbrugge, Peter M.; Burger, David M.; Warris, Adilia

doi:10.1097/ftd.0b013e3181898b0c

Cited by 46 publications

(28 citation statements)

References 12 publications

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“…Using therapeutic drug monitoring the authors increased the voriconazole dosing two fold to achieve adequate plasma levels. They found a decreased clearance compared to non ECMO pediatric patients [72]. Similar findings are reported in the adult population [73][74].…”

Section: Voriconazolesupporting

confidence: 57%

Pharmacotherapy in Neonatal and Pediatric Extracorporeal Membrane Oxygenation (ECMO)

Wildschut

Ahsman²,

Houmes³

et al. 2012

CDM

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ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research.

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Section: Voriconazolesupporting

confidence: 57%

Pharmacotherapy in Neonatal and Pediatric Extracorporeal Membrane Oxygenation (ECMO)

Wildschut

Ahsman²,

Houmes³

et al. 2012

CDM

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“…Based on our data, our present practice is to target voriconazole troughs during prophylaxis to a range of Ͼ1.5 to 4 g/ml. This range encompasses our efficacy cutoff, allows some cushion for variations in levels over time, and acknowledges previous reports of increased toxicity at higher troughs (6,8). At the same time, our experience highlights the challenges of achieving and maintaining serum troughs of Ͼ1.5 g/ml.…”

Section: Discussionmentioning

confidence: 62%

“…A trough of Ͼ1 g/ml was also protective against IFI or colonization, although the association was less robust. Our data suggest that the target trough for optimizing the efficacy of voriconazole prophylaxis in lung transplant recipients is within the range of targets previously advocated for the treatment of IFIs (6,19,28,31,32). To date, there are limited data for voriconazole TDM during antifungal prophylaxis.…”

Section: Discussionmentioning

confidence: 88%

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Mitsani

Nguyen

Shields

et al. 2012

Antimicrob Agents Chemother

118

125

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ABSTRACTVoriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n= 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n= 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P= 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P= 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P= 0.01) and among patients with no trough of >1.5 μg/ml (P= 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P= 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.

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“…76 This is compared to the recommended standard dosing of a 10–12 mg/kg every 12 hours for two doses followed by 8–9 mg/kg every 12 hours. 50 The authors felt that it was unclear if ECMO contributed to the patient’s higher dosing requirement but hypothesized that an increased V may have played a role.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature

Sherwin

Heath

Watt

2016

Clinical Therapeutics

121

120

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Purpose Extracorporeal Membrane Oxygenation (ECMO) is a cardiopulmonary bypass device that is used to temporarily support the most critically ill of patients with respiratory and/or cardiac failure. Infection and its sequelae may be an indication for ECMO or infections may be acquired while on ECMO, and are associated with a mortality of greater than 50%.1 Effective therapy requires optimal dosing. However, optimal dosing can be different in patients on ECMO, because the ECMO circuit can alter drug pharmacokinetics. This review assessed the current literature for pharmacokinetic data and subsequent dosing recommendations for anti-infective drugs in patients on ECMO. Methods We searched the PubMed and EMBASE databases (1965 to February 2016) and included case reports, case series, or studies that provided pharmacokinetic data for anti-infective drugs including antibiotics, antifungals, and antivirals being used to treat patients of all age groups on ECMO. Pharmacokinetic parameters and dosing recommendations based on these data are presented. Findings The majority of data on this topic come from neonatal studies of antibiotics from the 1980s and 1990s. These studies generally demonstrate a larger volume of distribution (V) due to ECMO and therefore, higher doses are needed initially. More adult data is now emerging, but with a predominance of case reports and case series without comparison to critically ill controls. The available pharmacokinetic analyses do suggest that V and clearance (CL) are unchanged in the adult population and therefore dosing recommendations largely remain unchanged. There are a lack of data in children >1 year of age. The data support the importance of therapeutic drug monitoring (TDM) when available in this population of patients. Implications This review found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infectives. In order to better determine optimal dosing on ECMO, a systematic approach is needed. Approaches that combine ex vivo ECMO experiments, animal studies, specialized pharmacokinetic modeling, and human clinical trials are being developed.

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Therapeutic Drug Monitoring of Voriconazole in a Child With Invasive Aspergillosis Requiring Extracorporeal Membrane Oxygenation

Abstract: We describe a patient with invasive pulmonary aspergillosis on extracorporeal membrane oxygenation therapy in which therapeutic drug monitoring and individualization of therapy by measuring voriconazole plasma concentrations were performed.

Cited by 46 publications

References 12 publications

Pharmacotherapy in Neonatal and Pediatric Extracorporeal Membrane Oxygenation (ECMO)

Pharmacotherapy in Neonatal and Pediatric Extracorporeal Membrane Oxygenation (ECMO)

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature

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