Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

Dorsthorst, D. T. A. Te; Verweij, Paul E.; Meis, Jacques F.; Mouton, Johan W.

doi:10.1128/aac.49.10.4220-4226.2005

Cited by 25 publications

(16 citation statements)

References 24 publications

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“…[31][32][33] Although increasing the administration frequency raises concerns about toxicity, 5FC has been used experimentally as an antifungal agent at doses up to 200 mg kg À1 every 6 h for 7 days without signs of toxicity. 35 The current regimen of 500 mg kg À1 four times a day for 4 days did not reveal any signs of toxicity, and permitted a correlation between maximal 5FC bioavailability and high level expression of CD::UPRT at the tumor. The modified VSV/5FC prodrug combination inhibited tumor growth better than either treatment alone, and increased animal survival, relative to the previously published combination approach in the TSA syngenic tumor model.…”

Section: Discussionmentioning

confidence: 75%

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MD51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MD51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.

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Section: Discussionmentioning

confidence: 75%

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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“…This could explain the increased activity of flucytosine against A. fumigatus at pH 5.0, due to the increased uptake of the drug. In IA, the pH at the site of infection might be less than 7.4 due to the metabolism of glucose by Aspergillus and the subsequent formation of organic acids, as suggested before (9).…”

mentioning

confidence: 87%

“…1). The efficacy of flucytosine against this isolate was compared with that against an isolate (isolate AZN 8196, which was flucytosine susceptible) that was previously shown to respond to flucytosine monotherapy (9). This isolate showed a decrease in the MIC from 512 mg/liter at pH 7.0 to 0.125 mg/liter at pH 5.0.…”

mentioning

confidence: 99%

In Vitro Activities at pH 5.0 and pH 7.0 and In Vivo Efficacy of Flucytosine against Aspergillus fumigatus

Verweij

Dorsthorst

Janssen

et al. 2008

Antimicrob Agents Chemother

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The antifungal agent flucytosine was found to be active in vitro against Aspergillus fumigatus isolates when the MIC was determined at pH 5.0 instead of pH 7.0. The in vitro MIC at pH 5.0 corresponded to the in vivo efficacy of flucytosine monotherapy in a murine model of invasive aspergillosis.The efficacy of flucytosine for the treatment of invasive aspergillosis (IA) has been controversial, although the evidence supporting its use for this condition is limited (5, 10, 11). Most guidelines do not recommend the use of the drug for the treatment of IA (1, 13), although use of the combination of amphotericin B and flucytosine for the treatment of Aspergillus osteomyelitis and joint infection was recommended previously (5).Most isolates of Aspergillus species are not susceptible to flucytosine, with MICs typically being Ͼ64 mg/liter (8). However, we previously demonstrated that the activity of flucytosine against Aspergillus species increased when the pH of the medium was lowered from 7.0 to 5.0 (8). Viviani et al. (12) showed that the in vitro activity of flucytosine against Cryptococcus neoformans at pH 5.4 correlated well with the clinical outcome. We investigated the flucytosine MIC distribution of Aspergillus fumigatus at pH 7.0 and pH 5.0 and determined which condition of MIC testing best corresponded with in vivo efficacy in a nonneutropenic murine model of IA.The in vitro activity of flucytosine against 50 clinical A. fumigatus isolates from our private fungus culture collection was determined by using the microdilution format of the CLSI (formerly the NCCLS) M38-A protocol (6). The isolates were cultured from clinical specimens from patients admitted to the Radboud University Medical Center and other Dutch hospitals between 1999 and 2005. All isolates were tested in duplicate at pH 7.0 and pH 5.0, and the MIC was read as the 50% inhibition of growth compared to the growth for the control. The pH was adjusted to 5.0 by using 100 mM citrate buffer.Female CD-1 outbred mice (weight, 20 to 29 g; Charles River Laboratories, Sulzfeld, Germany) were used. The animal studies were conducted in accordance with the recommendations of the European Community (Directive 86/609/EEC, 24 November 1986) and were approved by the institutional animal care and use committee of Radboud University. Inocula were prepared as conidial suspensions in saline containing 0.05% Tween 80, counted microscopically, and adjusted to the required concentration. Mice were infected with the 90% lethal dose (LD 90 ) by injection of 0.1 ml of the conidial suspension into the orbital vein.Flucytosine was dissolved in distilled water, according to the instructions of the manufacturer, and administered intraperitoneally. Treatment was begun 2 h after infection. Groups of 10 mice each were treated for 7 days with 100 mg/kg of body weight every 6 h (q6h), 100 mg/kg every 12 h (q12h), 200 mg/kg q6h, and 200 mg/kg q12h. Control mice were infected but received only distilled water. Animals were checked twice daily for clinical signs and mortality. Mort...

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“…once a day. Due to the short half-life in mice and the known time-dependent effect of the drug (1,31), FC (Ancotil; ICN Pharmaceuticals, Orsay, France) was given in the drinking water (orally [p.o.]) to ensure a more stable concentration of the drug over time.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis

Schwarz

Dromer

Lortholary

et al. 2006

Antimicrob Agents Chemother

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Whether or not flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 g/ml) to flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the flucytosinesusceptible isolate and in brain and spleen for the flucytosine-resistant isolate. For the flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the flucytosinesusceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to flucytosine.

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Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

Cited by 25 publications

References 24 publications

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

In Vitro Activities at pH 5.0 and pH 7.0 and In Vivo Efficacy of Flucytosine against Aspergillus fumigatus

Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis

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