Fluconazole concentrations in saliva from AIDS patients with oropharyngeal candidosis refractory to treatment with fluconazole

Abstract

Fluconazole (FCZ) has been extensively used as a primary therapy for oropharyngeal candidosis in AIDS patients. Clinical resistance to FCZ is now encountered, often related to decreased susceptibility of the isolate in vitro. We wondered if low levels in saliva play a role in the therapeutic failure, especially in patients complaining of dry mouth. Sixteen AIDS patients treated for oropharyngeal candidosis with FCZ were studied. MICs for the isolates were determined. Serum and saliva samples were collected to measure FCZ levels with a bioassay using paper disks loaded with the clinical specimens. We showed that (i) paper disks were convenient for collecting saliva in patients with dry mouth; (ii) levels in saliva depended on the FCZ dosage regimen but did not correlate with the response to therapy; (iii) correlation between concentrations in saliva and serum was poor and independent of clinical response to treatment, other therapies, or decreased salivation; and (iv) levels in saliva were always lower than MICs in patients who failed to respond to treatment. In conclusion, therapeutic failures are more likely to be related to in vitro resistance of the isolate to FCZ or insufficient dosage regimen than to decreased salivary secretion.Oropharyngeal candidosis (OPC) is a common mucosal infection among patients infected by the human immunodeficiency virus, occurring in 11 to 95% of these patients according to the degree of the immune defect (6, 7). Candida albicans is the most frequent opportunistic pathogen, responsible for more than 90% of the infections in this group of patients. However, other Candida species such as Candida tropicalis, Candida krusei, and Candida (Torulopsis) glabrata have emerged as significant pathogens (10, 21).The efficacy of fluconazole (FCZ) as a primary therapy for OPC in immunocompromised patients, especially AIDS patients (8), and even as prophylaxis of recurrent OPC (14), has been demonstrated. The rapid resolution of candidosis under FCZ therapy is probably related to the usual susceptibility of C. albicans to FCZ (3,12). Furthermore, studies have shown that levels in saliva are similar to those in plasma in healthy volunteers (4,12).Despite their usual efficacy, some FCZ treatments are considered to be clinical failures (persistence of clinical lesions despite adequate therapy) or mycological failures (culture of a Candida sp. showing in vitro resistance to FCZ) (17, 18). The clinical failures usually correlate with decreased susceptibility of the isolate to FCZ in vitro (5, 18) and are often related to previous treatments with this drug (18, 24). Explanations for this phenomenon include the mutation (2, 22, 27) or the selection of a resistant population (1,2,11,22,27) or local factors (17). Among these factors, diminution of FCZ concentration in saliva could alter FCZ efficacy. Xerostomia (dry mouth and diminished salivation) can modify the course of OPC not only by augmenting the risk of traumatic lesions of the oral mucosa but also by decreasing salivary constituents important i...

Salivary anticandidal activity and saliva composition in an HIV‐infected cohort

“…Fluconozole is a relatively inert fungistatic drug (9, 10) that is widely used to treat oral candidiasis in HIV patients, and many of the patients in this study were taking this drug. The mean concentration of fluconazole in saliva is approximately 2 to 12 μg/ml after ingesting 100 mg/day (8, 17). In this study, HIV patients who were taking the drug were taking 100 to 800 mg of fluconazole/day.…”

Contribution of molecular typing methods and antifungal susceptibility testing to the study of a candidemia cluster in a burn care unit

“…Since Candida septicemia is not unusual in burn patients, we attempted to determine whether the isolates responsible for candidemias in a burn care unit were genetically related. All C. albicans isolates were considered resistant to the azoles tested by a method that has been shown to correlate with treatment efficacy in AIDS patients with oropharyngeal candidiasis (5). Although the broth microdilution method is known to give higher values than the broth macrodilution method (15), the levels reached were high enough to be considered indicative of resistance.…”

“…Antifungal susceptibility testing. A broth microdilution method was used to determine the MICs (5). Stock solutions of antifungal agents were prepared in sterile distilled water for FCZ (Pfizer Central Research, Sandwich, United Kingdom) and in dimethyl sulfoxide for itraconazole (ITZ; Janssen Pharmaceuticals, Beerse, Belgium), ketoconazole (KTZ; Janssen), and amphotericin B (AmB; Squibb, Princeton, N.J.).…”

Comparison of microbiological assay and HPLC-UV for determination of fluconazole in capsules

“…A large number of strains have also been used as test organisms: Candida kefyr 706 (Garcia-Hermoso et al, 1995), Candida kefyr ATCC46764 (Perea et al, 2000), Candida albicans DSY1024 (Marchetti et al, 2001), Candida albicans ATCC95020 (Pascual et al, 2007) and Sacharomyces cerevisiae ATCC2601 (Adams, 2006). The strain C. albicans ATCC 18804 used in this work was considered to be adequate for fluconazole testing.…”