Antifungal agents. Part II. The azoles

Before 1978, amphotericin B and flucytosine were the only drugs available for the treatment of systemic fungal infections. The imidazoles, miconazole and ketoconazole, were introduced during the next 3 years. Intravenously administered miconazole served a limited therapeutic role and is no longer available. Orally administered ketoconazole, an inexpensive, effective, and convenient option for treating mucosal candidiasis, was widely used for a decade because it was the only available oral therapy for systemic fungal infections. During the 1990s, use of ketoconazole diminished because of the release of the triazoles--fluconazole and itraconazole. Fluconazole is less toxic and has several pharmacologic advantages over ketoconazole, including penetration into the cerebrospinal fluid. In addition, it has superior efficacy against systemic candidiasis, cryptococcosis, and coccidioidomycosis. Despite a myriad of drug interactions and less favorable pharmacologic and toxicity profiles in comparison with fluconazole, itraconazole has become a valuable addition to the antifungal armamentarium. It has excellent activity against sporotrichosis and seems promising in the treatment of aspergillosis. Itraconazole has replaced ketoconazole as the therapy of choice for nonmeningeal, non-life-threatening cases of histoplasmosis, blastomycosis, and paracoccidioidomycosis and is effective in patients with cryptococcosis and coccidioidomycosis, including those with meningitis. Further investigation into the development of new antifungal agents is ongoing.     

Curative treatment with fluconazole in 5 cases of invasive candidiasis

BACKGROUND: Amphotericin B is the treatment of choice for invasive and disseminated Candida sp. infections. Fluconazole is an antifungal drug with less toxicity. Because of its pharmacokinetic properties, fluconazole can be specially useful in the treatment of invasive candidiasis. Although it is useful in several forms of candidiasis, its efficacy in deep-seated candidal infections is not totally proved due to the lack of comparative studies with amphotericin. In order to contribute new data about the usefulness of fluconazole in the treatment of invasive candidiasis, we report 5 patients which cured with this antifungal drug. METHODS: The clinical records of those patients with invasive candidiasis that cured with fluconazole were retrospectively reviewed. RESULTS: Fluconazole was used in 2 patients after detecting toxicity to amphotericin. Fluconazole was used from the beginning in the other 3 patients. None of the patients were neutropenic. All the patients cured without recurrence. CONCLUSIONS: In this series, the employment of fluconazole was a non-toxic and effective alternative to amphotericin B in nonneutropenic patients with invasive candidiasis.     

Successful treatment with fluconazole of protothecosis developing at the site of an intralesional corticosteroid injection

We report a case of cutaneous protothecosis treated successfully with oral fluconazole. Fluconazole appears to be an effective alternative to conventional drugs for the treatment of cutaneous protothecosis. Cutaneous protothecosis is an uncommon infection due to achlorophyllic, saprophytic, algae-like unicellular organisms of the genus Prototheca that occurs mainly in immunocompromised patients. To date there is no standard treatment regimen. Surgical excision, oral ketoconazole, intravenous amphotericin B alone or in combination with oral tetracycline have been reported to be effective in the management of protothecosis. We report a 55-year-old immunocompetent woman with cutaneous protothecosis which developed at the site of intralesional triamcinolone acetonide injection, who was successfully treated with oral fluconazole.     

Systemic candidiasis in infants: a case presentation and literature review

A 4 1/2-month-old male infant with systemic candidiasis had anuria secondary to Candida albicans fungus balls impacted in the renal pelves. The patient was treated with temporary urinary diversion, amphotericin B, and flucytosine. Six weeks after therapy had been concluded, the patient had C albicans arthritis of the right hip and responded to a second course of amphotericin B and flucytosine therapy. This article discusses immunologic evaluation and presents a literature review.     

Safety of intrauterine contraceptive devices during MR imaging

OBJECTIVE: We report a case of candidiasis of the upper urinary tract that presented as acute renal failure associated with septic syndrome. The patient initially required hemodialysis. Right hydronephrosis and perirenal collection were observed on ultrasound examination. METHODS: A percutaneous nephrostomy was performed. Nephrostomy urine cytology and cultures were positive for Candida tropicalis. An anterograde pyelography showed a 'fungus ball' in the urinary tract. RESULTS: Therapy with oral fluconazole and percutaneous amphotericin B achieved excellent results. CONCLUSIONS: Candidiasic urinary infection of the upper urinary tract often produces obstructive uropathy requiring percutaneous nephrostomy, which can also be used to instill amphotericin B. Combination therapy with amphotericin B and fluconazole can achieve excellent results.     

Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .     

Reduction of amphotericin B nephrotoxicity with mannitol

Amphotericin B in combination with mannitol was given to a patient who had mucocutaneous candidiasis and moderate renal insufficiency. Previously, amphotericin B alone had induced an abrupt increase in serum creatinine and urea nitrogen, but when mannitol was given concurrently there was no worsening of renal function. Thus, amphotericin B with mannitol appears to offer a less nephrotoxic but equally candicidal therapeutic regimen in the renal compromised patient requiring parenteral candicidal therapy.     

Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis

The interactions of amphotericin B and itraconazole were studied in murine invasive candidiasis. Candida albicans-infected mice were treated for 10 consecutive days, 24 h after infection. Survival was monitored over 30 days and kidney cultures were done. Mice treated with amphotericin B (0.2 mg/kg/day intraperitoneally) or itraconazole (100 mg/kg/day by oral gavage in two divided doses/ day) had a 30-day survival of 20% or 40%. Concomitant administration of both drugs resulted in 100% mortality; 90% of mice treated with amphotericin B (1 mg/kg/day) survived. With the combination, 100% were dead by day 28 (P < or = .001 vs. amphotericin B). With sequential therapy (i.e., 5 days with one drug and then 5 days with the other), survival was inferior to that with amphotericin B alone but similar to that with itraconazole alone. Kidney culture results confirmed the antagonism of the combination compared with amphotericin B alone. In treatment of murine invasive candidiasis, the concomitant or sequential use of amphotericin B and itraconazole results in a negative interaction.     

Comparison of itraconazole and ketoconazole in HIV-positive patients with oropharyngeal or esophageal candidiasis. Human Immunodeficiency Virus Itraconazole Ketoconazole Project Group

The efficacy of oral itraconazole and ketoconazole in the treatment of oropharyngeal and/or esophageal candidiasis, and the rate of post-treatment relapse, were compared in a multicenter, prospective, double-blind, double-dummy, randomized, parallel-group trial. A total of 143 adult HIV-positive patients with oropharyngeal and/or esophageal candidiasis were assigned to receive either itraconazole or ketoconazole (200 mg/day). Patients with oropharyngeal and esophageal candidiasis were treated for 2 and 4 weeks, respectively. Patients were evaluated clinically and mycologically after 1, 2 and 4 (for esophageal patients) weeks of therapy, and relapses were compared in a 6-week post-treatment follow-up period. Of 129 evaluable patients, 98 had oropharyngeal candidiasis and 31 esophageal infection. CDC classification, CD4+ cell counts, and number of previous episodes of oropharyngeal or esophageal candidiasis were comparable in both groups. Oropharyngeal infection was cleared clinically at 21 days in 71% of patients receiving itraconazole and 60% receiving ketoconazole, and esophageal candidiasis was cleared at 41 days in 100% of patients receiving itraconazole and 91% receiving ketoconazole. Marginally significant differences were found between itraconazole and ketoconazole in rates of clearing of infection clinically in patients with oropharyngeal and esophageal candidiasis (p = 0.0614 and 0.0781, respectively). Mean rates of infection relapse were not statistically different in the two treatment groups. Adverse events were generally mild and not considered drug related. Itraconazole is marginally more efficacious than ketoconazole in the treatment of oropharyngeal and esophageal candidiasis in HIV-positive patients and both drugs appear safe and well tolerated.     

Cryptococcal meningitis: the place of itraconazole

Itraconazole, an orally active broad-spectrum triazole antimycotic, has demonstrated anti-Cryptococcus activity in vitro and in animal models of cryptococcal meningitis. The drug has been used by a number of clinical groups for the treatment of cryptococcal meningitis, predominantly in AIDS patients. A problem that has been found with ketoconazole is the relatively low absorption of the drug in AIDS patients. This has resulted in ketoconazole plasma levels below the MIC90 (1-5 micrograms ml-1) needed to eliminate Cryptococcus neoformans. In addition, tissue levels of ketoconazole are lower than plasma levels. For itraconazole, the required MIC90 for Cr. neoformans is 0.1 microgram ml-1, and the plasma levels in AIDS patients receiving 200-400 mg daily, even in the case of reduced absorption, are well above this MIC90. The itraconazole levels in the brain and in the meninges are higher than the plasma levels. Consequently, itraconazole has been considered a valid candidate for studies in patients with cryptococcal meningitis. Various treatment modalities have been used: primary oral therapy alone or in combination with amphotericin B or 5-fluorocytosine (5-FC); maintenance oral therapy after initial treatment with amphotericin B (with or without 5-FC); and first-line intravenous treatment in severely ill patients. The results were evaluated in four different groups. When the drug was given as primary oral therapy without combination with amphotericin B or 5-FC, the results depended greatly on the dose administered and on the life expectancy of the patient at inclusion. In general, daily doses of 400 mg were better than 200-mg doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adhesion of oral Candida albicans isolates to denture acrylic following limited exposure to antifungal agents

Candidal adherence to denture acrylic surfaces is implicated as the first step in the pathogenesis of Candida-associated denture stomatitis, the most prevalent form of oral candidosis in the West. This condition is treated by topically administered antifungal agents, mainly belonging to the polyenes and azoles. As the intraoral concentrations of antifungals fluctuate considerably due to the dynamics of the oral environment, the effect of short exposure to sublethal concentrations of antifungals on the adhesion of Candida albicans to denture acrylic surfaces was investigated. Seven oral C. albicans isolates were exposed to four-eight times minimum inhibitory concentrations (MIC) of five antifungal drugs, nystatin, amphotericin B, 5-fluorocytosine, ketoconazole and fluconazole, for 1 h. After removing the drug (by repeated washing) the adhesion of these isolates to acrylic strips was assessed by an in vitro adhesion assay. Exposure to antifungal agents significantly reduced the adherence of all seven C. albicans isolates to denture acrylic. The mean percentage reductions of adhesion after limited exposure to nystatin, amphotericin B, 5-fluorocytosine, ketoconazole and fluconazole were 86.48, 90.85, 66.72, 65.88 and 47.42%, respectively. These findings indicate that subtherapeutic doses of antifungals may modulate oral candidal colonization. Further, these results may have an important bearing on dosage regimens currently employed in treating oral candidosis.     

Assessment of antifungal activities of fluconazole and amphotericin B administered alone and in combination against Candida albicans by using a dynamic in vitro mycotic infection model

We evaluated the pharmacodynamic activities of fluconazole and amphotericin B given alone and in combination against Candida albicans by using an in vitro model of bloodstream infection that simulates human serum pharmacokinetic parameters for these antifungals. Fluconazole was administered as a bolus into the model to simulate regimens of 200 mg every 24 h (q24 h) and 400 mg q24 h. Amphotericin B was administered at doses producing the peak concentration (2.4 micrograms/ml) observed with a regimen of 1 mg/kg of body weight q24 h. A combination regimen of fluconazole (400 mg q24 h) and amphotericin B (1 mg/kg q24 h) administered simultaneously and as a staggered regimen (amphotericin B bolus given 8 h after fluconazole bolus) was also simulated in the model to characterize possible antagonism between these agents. Fluconazole alone and amphotericin B alone demonstrated fungistatic (< 99.9% reduction in numbers of CFU per milliliter from the starting inoculum) and fungicidal (> 99.9% reduction) activity, respectively. When fluconazole and amphotericin B were administered simultaneously, fungicidal activity similar to that observed with amphotericin B alone was observed. Staggered administration of fluconazole and amphotericin B, however, resulted in a substantial reduction of the fungicidal activity of amphotericin B, producing fungistatic activity similar to that observed with noncombination fluconazole regimens. These results demonstrate the usefulness of this model for comparing the in vitro pharmacodynamic characteristics of different antifungal regimens and support the theory of azole-polyene antagonism. The effects of this antagonism on the in vivo activity and clinical usefulness of combination antifungal therapy, however, remain to be determined.     

Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs

Quinolone antibacterial drugs inhibit DNA gyrase, a type 2 topoisomerase. Since topoisomerases are present in eukaryotic cells, it was of interest to evaluate the antifungal activities of two clinically available quinolones, ciprofloxacin and trovafloxacin, alone and in combination with amphotericin B or fluconazole, in vitro against Candida albicans and in a murine model of invasive candidiasis. The in vitro activity of trovafloxacin was also tested against other yeasts and molds. In vitro, trovafloxacin exhibited no antifungal activity against any of the fungi (MIC, >250 microg/ml). There was also no effect of the quinolone on the in vitro activity of either antifungal drug. Marked antifungal effects were seen, however, in the murine model of candidiasis. In all experiments, control mice infected intravenously with C. albicans were dead by day 24. While either quinolone had minimal effects on survival of mice when used alone in oral doses of up to 40 mg/kg twice daily, the combination of the quinolone with fluconazole (40 or 80 mg/kg given twice daily by oral gavage) was more effective in prolonging survival than was fluconazole alone. Colony counts of kidneys on days 12 and 30 showed similar reductions in C. albicans recovered from mice treated with fluconazole with or without trovafloxacin or amphotericin B with or without trovafloxacin. Survival of mice treated with a suboptimal dose of amphotericin B (0.2 mg/kg/day) was also improved when trovafloxacin (40 mg/kg) given twice daily was included (0 versus 27%, respectively; P < 0.05). While the mechanisms of action of the combination of trovafloxacin and amphotericin B or fluconazole are unclear, further work focused on fungal topoisomerase inhibition and the mechanism of the antifungal effect of quinolone antibacterial drugs is warranted.     

Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions

A total of 167 human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis were randomly assigned to receive 14 days of therapy with liquid suspension fluconazole (100 mg once daily) or liquid nystatin (500,000 U four times daily). At day 14, 87% of the fluconazole-treated patients were clinically cured, as opposed to 52% in the nystatin-treated group (P < .001). Fluconazole eradicated Candida organisms from the oral flora in 60%, vs. a 6% eradication rate with nystatin (P < .001). The fluconazole group had fewer relapses noted on day 28 (18%, vs. 44% in the nystatin group; P < .001). This relapse difference no longer existed by day 42. Fluconazole oral suspension as a systemic therapy was more effective than liquid nystatin as a topical therapy in the treatment of oral candidiasis in HIV-infected patients and provided a longer disease-free interval before relapse.     

Triangular osteosynthesis of vertically unstable sacrum fractures: a new concept allowing early weight-bearing

Multilocus enzyme electrophoresis (MEE) and in vitro antifungal susceptibility testing were used to investigate the Candida albicans strain diversity in twenty nine AIDS patients from Abidjan (Ivory Coast). All patients were monitored for a first episode of oropharyngeal candidiasis and were randomly clustered into three groups of therapy: ketoconazole, amphotericin B or nystatin. Oral swabs were collected before every treatment, 14 and 30 days after the initiation of the therapy; a total of 67 isolates were investigated. No resistant or less susceptible isolate to any antifungal agent was found despite the emergence of clinical relapses, mainly for patients treated with nystatin or amphotericin B. The MEE analysis revealed 27 different electrophoretic types (ETs). Genetic distances between ETs were statistically analyzed and represented on a dendrogram. The 27 ETs clustered into three groups; in each group, ETs represented variants of the same strain. A segregation of the C. albicans isolates seemed to be as a function of the serotype.     

Neurological form of cryptococcosis. Apropos of 2 atypical cases in non HIV-infected patients

Cryptococcal infection is the most common fungal infection of the central nervous system. More than 50% of the cases of cryptococcal infection are superimposed on an immunosuppressive or other general debilitating condition. Cerebral cryptococcosis usually presents as meningitis or meningoencephalitis, although cerebral granuloma has also been reported. Hydrocephalus is the most common neurosurgical complication of cerebral cryptococcosis. The majority of patients require only medical treatment with antifungal drugs. However, when complications ensue, surgical intervention is mandatory. We suggest that chronic meningitis be ruled out in all patients prior to the placement of shunts. In the two cases reported here treatment of cryptococcal meningitis was a combination of amphotericin B and flucytosine for six weeks. Fluconazole is a new alternative and at least as effective as amphotericin B.     

Candida infections in patients with acute leukemia: ineffectiveness of nystatin prophylaxis and relationship between oropharyngeal and systemic candidiasis

Ninety-three hospitalizations of 70 patients, who underwent induction chemotherapy for acute leukemia to determine the effectiveness of oral nystatin in preventing oropharyngeal and systemic candidiasis were reviewed. Sixty-two percent of patients who received prophylactic nystatin and 58% of patients who did not receive nystatin developed oropharyngeal candidiasis; 11% of patients who received prophylaxis and 21% of those who did not receive prophylaxis developed systemic candidiasis. The use of oral nystatin did not significantly diminish the risk of developing either type of Candida infection. Oropharyngeal candidiasis occurred more commonly in patients who had severe and prolonged leukopenia, had received more parenteral antibiotics, and had developed chemotherapy-induced mucositis. Systemic candidiasis developed almost exclusively in patients who had prior oropharyngeal candidiasis. Guidelines for the empiric use of amphotericin B in these patients are provided.     

Meta-analysis of prophylactic or empirical antifungal treatment versus placebo or no treatment in patients with cancer complicated by neutropenia

OBJECTIVE: To determine whether antifungal agents given prophylactically or empirically decrease morbidity and mortality in patients with cancer complicated by neutropenia. DESIGN: Meta-analysis of randomised trials of amphotericin B, various lipid soluble formulations of amphotericin B (for example, AmBisome), fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment. SETTING: Trials conducted anywhere in the world. SUBJECTS: Patients with cancer complicated by neutropenia. MAIN OUTCOME MEASURES: Mortality, invasive fungal infection (defined as positive blood culture, oesophageal candidiasis, or lung or deep tissue infection), and colonisation. RESULTS: 24 trials with 2758 randomised patients were reviewed; the total number of deaths was 434. Prophylactic or empirical treatment with antifungals as a group bad no effect on mortality (odds ratio 0.92; 95% confidence interval 0.74 to 1.14). Amphotericin B decreased mortality significantly (0.58; 0.37 to 0.93) but the studies were small and the difference in number of deaths was only 15. Antifungal treatment decreased the incidence of invasive fungal infection (0.47; 0.35 to 0.64) and fungal colonisation (0.45; 0.30 to 0.69). For every 73 patients treated (95% confidence interval to 48 to 158) one case of fungal invasion was prevented in surviving patients. CONCLUSIONS: There seems to be no survival benefit of antifungal agents given prophylactically or empirically to patients with cancer complicated by neutropenia. These agents should be restricted to patients with proved infection and those in randomised trials. A large, definitive placebo controlled trial of amphotericin B is needed.     

Potential utility of recombinant human GM-CSF as adjunctive treatment of refractory oropharyngeal candidiasis in AIDS patients

The aim of the study was to investigate the use of granulocyte macrophage-colony stimulating factor (GM-CSF) as an adjunctive treatment for clinically refractory mucosal candidiasis in patients with advanced AIDS. Three patients with advanced AIDS and oropharyngeal candidiasis clinically refractory to azoles or amphotericin B received GM-CSF for 14 days along with either fluconazole or amphotericin B. All three patients showed clinical improvement and mycological improvement without any adverse events. Thus, GM-CSF may be a possible alternative as adjunctive therapy in the management of refractory mucosal candidiasis in patients with advanced AIDS.     

Current and emerging azole antifungal agents

Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.