Pharmacological Studies with 5-Fluorocytosine

Block, Edward R.; Bennett, John E.

doi:10.1128/aac.1.6.476

Cited by 108 publications

(44 citation statements)

References 13 publications

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“…This level was achieved for periods up to 3 h after a single dose of 5-FC in this study. The serum concentrations of 5-FC achieved in dogs were roughly equivalent to those expected in humans given similar milligram-per-kilogram doses (3). Therefore, the excellent penetration of 5-FC into bronchial secretions indicates potential clinical efficacy for 5-FC in intrabronchial candida therapy.…”

Section: Discussionsupporting

confidence: 54%

5-Fluorocytosine and Amphotericin B in Bronchial Secretions

Pennington

Block

Reynolds

1974

Antimicrob Agents Chemother

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The penetration into and clearance from bronchial secretions of 5-fluorocytosine and amphotericin B were studied in a dog model. After a single intravenous dose of 35 mg/kg, 5-fluorocytosine intrabronchial concentrations were greater than the minimal inhibitory concentration for 80 to 90% of Candida species. These inhibitory concentrations persisted up to 3 h. In contrast, amphotericin B in intravenous doses of 0.6 and 1.2 mg/kg penetrated the blood-bronchus barrier poorly.Colonization of the tracheobronchial tree with Candida species (usually C. albicans) is not uncommon in debilitated and immunosuppressed patients. Endotracheal intubation or tracheostomy (9), and the use of broad-spectrum antibiotics (18), render patients especially prone to candida colonization. The incidence of candidemia or invasive pulmonary infection which results from this colonization is unkiiown. However, an increasing problem with disseminated candidiasis and candida pneumonia in these patients has been reported (7,8).Antibiotics, administered to respiratory mucosal surfaces via aerosal spray, have been effective in reducing the incidence of gram-negative bacterial colonization of the respiratory tract in certain groups of patients (6, 9). Attempts at eradicating oropharyngeal candida using local nystatin therapy have been less successful, particularly in leukopenic patients (8). Effective control of mucosal candida colonization and infection may depend upon using systemic therapy in such patients (8).Although low-dose amphotericin B therapy has been advocated for certain superficial candida infections (14), use of this potentially toxic drug in a debilitated patient is usually reserved for life-threatening fungal infection. Fivefluorocytosine (5-FC) has proven to be clinically useful in treating candida infections and is relatively nontoxic (1). To assess the potential value of 5-FC in controlling respiratory tract colonization with candida, a study of 5-FC penetration into bronchial secretions was done, using a dog model. For comparison, amphotericin B concentrations in bronchial secretions were also evaluated.MATERIALS AND METHODS Animal studies. A dog model (15) for the study of antibiotic diffusion into and clearance from normal bronchial secretions was used in this study. American foxhounds (approximately 20 kg) were anesthetized with 2.5% sodium thiamylal and intubated with a rubber endotracheal tube. Subcutaneous pilocarpine HCl was given (0.5 mg/kg every 45 min) to stimulate an adequate flow of bronchial secretions (about 1 ml/h) for specimen collection. Volumes were small so that significant dilution did not occur. Previous work has demonstrated little change in the constituents of bronchial secretions after pilocarpine administration (15). Bronchial secretion specimens were aspirated via the endotracheal tube using a small-bore (1.25 mm) plastic catheter inserted to maximal depth within a mainstem bronchus. A syringe attached to the catheter provided adequate suction. Bronchial secretion specimens were each approximately 0....

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Section: Discussionsupporting

confidence: 54%

5-Fluorocytosine and Amphotericin B in Bronchial Secretions

Pennington

Block

Reynolds

1974

Antimicrob Agents Chemother

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“…The concentrations of 5FC in human CSF are similar to its corresponding serum concentrations (91,96,250), and a combination of 5FC with AmBd or L-AMB is a recognized first-line induction therapy for cryptococcal meningitis (97).…”

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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“…5-Flucytosine does not bind to plasma proteins and possesses excellent penetration into the CSF: 1 to 2 h after dosing, CSF concentrations amounted to 74.4% Ϯ 5.6% of the corresponding serum levels (23).…”

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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Pharmacological Studies with 5-Fluorocytosine

Cited by 108 publications

References 13 publications

5-Fluorocytosine and Amphotericin B in Bronchial Secretions

5-Fluorocytosine and Amphotericin B in Bronchial Secretions

Tissue Penetration of Antifungal Agents

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

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