The Pharmacokinetics and Pharmacodynamics of Micafungin in Experimental Hematogenous<i>Candida</i>Meningoencephalitis: Implications for Echinocandin Therapy in Neonates

Hope, William; Mickiene, Diana; Petraitis, Vidmantas; Petraitienė, Rūta; Kelaher, Amy M.; Hughes, Joanna E.; Cotton, Margaret P.; Bacher, John; Keirns, James J.; Buell, Donald N.; Heresi, Gloria P.; Benjamin, Daniel K.; Groll, Andreas H.; Drusano, George L.; Walsh, Thomas J.

doi:10.1086/524063

Cited by 163 publications

(124 citation statements)

References 27 publications

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“…Similarly, the CSF/plasma concentration ratios of three patients receiving micafungin were low and variable, ranging from 0.002 to 0.54, while in the brain tissue of another patient, the tissue/plasma concentration ratio was only 0.17 (106,107,252). Micafungin penetration into rabbit brains is dose dependent, and significantly higher concentrations are measurable in the meninges than in either the cerebrum or cerebellum (108). However, the concentrations in these various subcompartments are also sufficient to achieve a significant anti-Candida effect.…”

Section: Brain and Cerebrospinal Fluidmentioning

confidence: 93%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

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Section: Brain and Cerebrospinal Fluidmentioning

confidence: 93%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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“…Micafungin concentrations determined for several subcompartments of the CNS after intravenous administration in experimental rabbits with Candida meningoencephalitis were highest in the meninges and the choroid plexus, but micafungin was not reliably detected in CSF. Based on pharmacokinetic-pharmacodynamic data and Monte Carlo simulations, the appropriate dose to induce a near-maximum effect in a majority of infants with Candida meningoencephalitis was estimated to lie between 9 and 15 mg/kg (95).…”

Section: Antifungal Agentsmentioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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“…There are limited data to guide dosing of anidulafungin. Neonatal data are needed for all the echinocandins in four major areas: optimal dose, resistance patterns with regards to C parapsilosis, safety, and central nervous system penetration 31,35,36 . Their role in treatment or prophylaxis will depend on these findings and the general principle to use one agent for prophylaxis and a different agent for treatment.…”

Section: Treatment Of Invasive Fungal Infectionsmentioning

confidence: 99%

Challenging issues in neonatal candidiasis

Kaufman

2010

Current Medical Research and Opinion

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In an era of quality improvement and 'getting to zero (infections and/or related mortality),' neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution's invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants51000 g and/or 27 weeks, because this group has high infection-related mortality and neurodevelopmental impairment in 57% of survivors. Antifungal prophylaxis has been shown to nearly eliminate infection-related mortality. Interventions start with prenatal initiatives, with women being treated for vaginal candidiasis, especially with preterm labor or complications. Targeting modifiable risk factors, including restriction policies for use of third-and fourth-generation cephalosporins, carbapenems, H2-antagonists, proton pump inhibitors, and postnatal steroids; guidelines for CVC care and removal; and feeding practices, with promotion of early feedings and breast milk, may also reduce risk. A few studies have emerged on empiric antifungal therapy with sepsis evaluations for preterm infants 51500 g and other high-risk patients that have shown favorable effects of eliminating mortality, but these have not been compared to appropriate antifungal therapy and central line removal. Further study of empiric therapy, prospective treatment studies with higher targeted dosing of amphotericin B preparations, fluconazole, and new antifungals with prompt CVC removal may contribute to a 100% survival rate for those infants41000 g and 28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.

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The Pharmacokinetics and Pharmacodynamics of Micafungin in Experimental HematogenousCandidaMeningoencephalitis: Implications for Echinocandin Therapy in Neonates

Abstract: These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Cited by 163 publications

References 27 publications

Tissue Penetration of Antifungal Agents

Tissue Penetration of Antifungal Agents

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

Challenging issues in neonatal candidiasis

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