Re Channel 5 News - Prince Harry and Elton John, Diana's legacy, we can beat it, if the link between Candidiasis and HIV is made

Introduction

Mucocutaneous candidiasis occurs in 3 forms in persons with HIV infection: oropharyngeal, esophageal, and vulvovaginal disease. Oropharyngeal candidiasis (OPC) was among the initial manifestations of HIV-induced immunodeficiency to be recognized (1,2) and typically affects the majority of persons with advanced untreated HIV infection. Presenting months or years before more severe opportunistic illnesses, OPC may be a sentinel event indicating the presence or progression of HIV disease.(3-5) Although usually not associated with severe morbidity, OPC can be clinically significant. Severe OPC can interfere with the administration of medications and adequate nutritional intake, and may spread to the esophagus.(6) Esophageal candidiasis remains one of the most common opportunistic infections in countries where combination antiretroviral therapy (ART) is a routine part of the standard of care.(7) Vulvovaginal candidiasis is an important concern for women with HIV infection, although the relationship of vulvovaginal candidiasis to HIV infection remains unclear.(8) In resource-poor nations, mucocutaneous candidiasis is a formidable problem.(9,10) Despite the frequency of mucosal disease, disseminated or invasive infections with Candida and related yeasts are surprisingly uncommon.

Microbiology and Epidemiology

Yeasts are fungi that grow as single cells and reproduce by budding. They are distinguished from one another on the basis of the presence or absence of capsules, their size and shape, the mechanism of daughter formation, the formation of true hyphae or pseudohyphae, and the presence or absence of sexual spores, along with physiologic data from biochemical testing. Candida albicans is the predominant causative agent of all forms of mucocutaneous candidiasis. Less frequently, C glabrata, C parapsilosis, C tropicalis, C krusei, and several other species may cause disease. C dubliniensis, a species that is phenotypically similar to C albicans, may cause approximately 15% of infections previously ascribed to C albicans.(11-14) Candida are normal inhabitants of the human gastrointestinal (GI) tract and may be recovered from up to one third of the mouths of normal individuals and two thirds of those with advanced HIV disease.(15,16) Oral colonization with inherently drug-resistant organisms is more common in advanced HIV infection (CD4 lymphocyte counts <50 cells/µL).(16) Although vaginal colonization is more prevalent among HIV-infected women compared with HIV-negative women, no association of colonization rate with CD4 counts is apparent.(17) The majority of disease is caused by organisms that are part of the normal flora of an individual, although rare cases of person-to-person transmission have been documented.(18) The individual Candida strains affecting persons with HIV infection are not different from those in other immunosuppressed hosts.(19) C dubliniensis is more commonly identified in HIV-infected persons, though it is currently indistinguishable from C albicans in its clinical presentation.(11-13) There are no detectable differences in the virulence of strains isolated from HIV-infected or HIV-uninfected persons. Recurrent disease can result from the same or from different species or strains of Candida.(20-23) The emergence of different strains or species is more likely in persons with lower CD4 lymphocyte counts and exposure to antifungal therapy.(19) Oropharyngeal and vulvovaginal disease are the most common forms of mucocutaneous candidiasis. Up to 90% of persons with advanced untreated HIV infection develop OPC, with 60% having at least 1 episode per year with frequent recurrences (50-60%).(16,21,24-32) Esophageal candidiasis occurs less frequently (10-20%) but is the leading cause of esophageal disease.(33-35) Vaginal candidiasis has been noted in 27-60% of women, similar to the rates of oropharyngeal disease.(36-38) However, the incidence appears to be similar in HIV-infected and HIV-uninfected women.(8) Of note, 75% of all women of childbearing age develop vaginal candidiasis and 40% will have a second occurrence. Few women (<5%) experience frequent recurrences (defined as >=4 infections in a 12-month period). The use of combination ART results in a significant decline in the incidence of a number of opportunistic illnesses (eg, Pneumocystis jiroveci pneumonia and cytomegalovirus).(39-41) Thus, in resource-rich nations, the incidence of mucocutaneous candidiasis has declined precipitously. For example, a significant difference has been found in the incidence of recurrent OPC in patients treated with protease inhibitors compared with those not treated with protease inhibitors (7% vs 36%).(42) Similarly, a decline in the incidence of OPC from 30% to 4% over a 1-year period was reported in persons on ART.(43) More frequent use of antifungal medications for secondary prevention also may have reduced the prevalence of mucocutaneous disease. A number of factors are important in the development of mucocutaneous candidiasis.(44) The level of immunosuppression is paramount.(45) Other host factors important in the defense of Candida infections include blood group secretor status (such as presence or absence of specific Lewis antigens), salivary flow rates, condition of the epithelial barrier, antimicrobial constituents of saliva, presence of normal bacterial flora, and local immunity.(27,46) Several studies suggest an impairment in a number of anti-Candida host defense mechanisms in persons with HIV infection.(27,29,30) Higher levels of HIV-1 RNA in the plasma also have been associated with increased rates of mucocutaneous candidiasis and colonization with Candida.(42,47) Of note, the correlation between the level of immunosuppression and vaginal candidiasis may not be as strong. In a cross-sectional study of 833 HIV-infected and 427 HIV-uninfected women, the annual incidence of vaginal candidiasis in the 2 groups was similar (9%).(38)

Clinical Presentation

Symptoms of OPC may include burning pain, altered taste sensation, and difficulty swallowing liquids and solids. Many patients are asymptomatic. Most persons with OPC present with pseudomembranous candidiasis or thrush (white plaques on the buccal mucosa, gums, or tongue) and less commonly with acute atrophic candidiasis (erythematous mucosa) or chronic hyperplastic candidiasis (leukoplakia, distinct from "hairy leukoplakia"; see chapter on Oral Manifestations) involving the tongue, or angular cheilitis (inflammation and cracking at the corners of the mouth). Esophageal candidiasis usually is accompanied by the presence of OPC. Typically, dysphagia and odynophagia are described. In as many as 40% of patients with OPC, esophageal involvement may be asymptomatic.(6) Occasionally, esophageal disease may occur in the absence of clinically detectable oropharyngeal disease. Vulvovaginal candidiasis generally presents with marked itching, watery to curdlike discharge, vaginal erythema with adherent white discharge, dyspareunia, external dysuria, erythema, and swelling of labia and vulva with discrete pustulopapular peripheral lesions. The cervix usually appears normal. Symptoms typically exacerbate the week preceding menses with some relief once menstrual flow begins. Vaginal candidiasis frequently is associated with pregnancy, high-estrogen oral contraceptives, uncontrolled diabetes mellitus, tight-fitting clothes, antibiotic therapy, dietary factors, intestinal colonization, and sexually transmitted disease. Specific additional risk factors for recurrent vulvovaginal candidiasis have not been identified.(48) Female-to-male transmission remains questionable, although male sexual partners may experience a transient rash, erythema, pruritus, or burning sensation of the penis minutes to hours after unprotected sexual intercourse. Occasionally, Candida balanitis may occur.

Diagnosis

The diagnosis of OPC usually is made by its characteristic clinical appearance; recovery of an organism is not required. Oropharyngeal cultures often demonstrate Candida species, but alone are not diagnostic because colonization is common.(24) The diagnosis of OPC can be confirmed by examining a 10% potassium hydroxide (KOH) slide preparation of a scraping from an active lesion. Pseudohyphae and budding yeast are characteristic findings. The appearance of the lesion and presence of yeast forms on microscopic examination of the oropharynx are sufficient to confirm the diagnosis. A KOH preparation is not mandatory for diagnosing OPC. A presumptive diagnosis of OPC can be made by visual detection of characteristic lesions with resolution of those lesions in response to antifungal therapy. Culture usually is not necessary unless the lesions fail to clear with appropriate antifungal therapy. In patients with poorly responsive OPC, a culture should be obtained to look for inherently drug-resistant yeast or those that respond poorly to certain azoles (eg, C krusei or C glabrata). Clinicians should note that many microbiology laboratories report yeast cultures as either C albicans or non-albicans species based upon the germ tube test, and further characterization requires making a specific request. Biopsy of oral lesions rarely is helpful or indicated for the diagnosis of oral candidiasis. A presumptive diagnosis of Candida esophagitis can be made in a patient with dysphagia and/or odynophagia who has OPC. Barium swallow or upper GI endoscopy can confirm a suspicion of esophageal involvement. These studies are not uniformly required, however, unless a patient fails to improve with appropriate systemic antifungal therapy.(35) If esophageal symptoms in a patient with OPC do not resolve despite resolution of the oral lesions, endoscopy is indicated to exclude other causes of esophagitis (eg, cytomegalovirus, herpes simplex virus, aphthous ulcers) in persons with HIV infection. The diagnosis of Candida esophagitis is confirmed by the presence of yeast forms on histologic examination of esophageal lesions. Cultures to look for drug-resistant yeast are warranted for patients who require endoscopy. Barium swallow rarely is indicated in HIV-infected patients with esophageal disease because it usually is not possible to determine the cause of an abnormality by its radiologic appearance alone. The diagnosis of Candida vulvovaginitis is made by the presence of a characteristic clinical appearance and observation of yeast forms on microscopic examination. A KOH preparation of the vaginal discharge should be made to confirm the diagnosis of candidiasis and to differentiate from a number of other conditions that can be similar in appearance (eg, trichomoniasis). Because yeast are normal inhabitants of the vaginal mucosa, routine fungal cultures rarely are helpful when the KOH preparation is negative. A fungal culture should be obtained if a patient fails to respond to standard antifungal therapy. Antifungal susceptibility testing has improved over the past few years but remains problematic. In 2002, the National Committee on Clinical Laboratory Standards (NCCLS) published standardized methods and definitions for in vitro susceptibilities to selected agents (Table 1).(49,50) The most common methods for in vitro testing are the macrotube and microtiter broth dilution assays. Alternative methods such as agar-based assays and flow cytometry are under evaluation.(51) In vitro susceptibilities should not be used routinely to guide the choice of antifungal agents because the correlation between clinical response and susceptibility testing is not clear. Despite the technical limitations, a number of studies have documented that in vitro resistance to antifungal medications is common.(16,52-64) The incidence of resistance varies widely in these studies. Overall, the rates of fluconazole resistance vary from 5% to 56%.(16,52-57) The rates of ketoconazole and itraconazole resistance have been reported less frequently but vary from 0% to 25%.(58-60) Amphotericin B resistance is extremely uncommon but has been reported.(64) Resistance to newer agents including echinocandins and triazoles (eg, voriconazole and posaconazole) is less common but has been documented.(65,66) Much of the variance in the rates of in vitro resistance can be explained by several factors: differences in the level of host immunosuppression, prior exposure to antifungal agents, the design of the study (longitudinal vs cross-sectional), the prevalence of non-albicans species of yeast, and differences in the in vitro methods used. Several mechanisms may contribute to in vitro resistance to antifungals. Some yeasts have single-drug resistance, whereas others are multidrug resistant. Azole resistance has been demonstrated in yeasts that contain alterations in the enzymes that were the target of azole action or were involved in ergosterol biosynthesis. The cytochrome P450-dependent 14alpha-sterol demethylase (P450DM) and the delta5,6 sterol desaturase are enzymes that, when altered, result in azole resistance.(67,68) Reduced cell permeability is another mechanism of azole resistance.(69) Finally, active efflux of drug also has been observed.(70) The prevalence of these mechanisms, however, is unknown. Further, it is not clear whether certain mechanisms of resistance may be overcome by increasing the dosage of the drug.

Therapy

A wide variety of agents are effective for the treatment of candidiasis (Table 2). Important factors that determine clinical response, besides the choice of antifungal agent, include the extent and severity of disease, patient adherence, and the pharmacokinetic properties of the drug. Treatment of OPC and vaginal candidiasis is relatively simple, with most types responding to therapy. Overall, randomized studies show little difference between topical and systemic therapy. Mild OPC or vulvovaginal disease often can be treated with topical therapy. Moderate and severe episodes typically require systemic therapy. Esophagitis always requires systemic therapy. Classes of antifungal agents include polyenes (nystatin and amphotericin B), which bind to ergosterol in the fungal cell membrane and induce osmotic instability and loss of membrane integrity; azoles, including the imidazoles (clotrimazole) and triazoles (ketoconazole, itraconazole, fluconazole, voriconazole, ravuconazole, and posaconazole), which inhibit fungal cytochrome P450-dependent enzymes, resulting in the impairment of ergosterol biosynthesis and depletion of ergosterol from the fungal cell membrane; pyrimidine synthesis inhibitors, including 5-fluorocytosine (flucytosine), which inhibits DNA and RNA synthesis in fungal organisms; and the echinocandins (caspofungin, micafungin and anidulafungin), cyclic lipopeptides that inhibit beta-1:3 glucan synthase, an enzyme involved in fungal wall cell biosynthesis. Nystatin is used in a topical preparation. The oral form is not absorbed and has minimal side effects other than dysgeusia. Flucytosine is available as a tablet and is associated with such side effects as nausea, vomiting, diarrhea, GI bleeding, renal insufficiency, hepatitis, thrombocytopenia, anemia, and leukopenia. Although the manufacturer recommends maintaining flucytosine levels between 25 and 100 µg/mL, most clinicians monitor laboratory parameters (complete blood count, liver function tests, and renal function tests) and the patient for adverse effects. Clotrimazole is available as a spray, solution, and troche for oral use. Clotrimazole has few side effects, and is absorbed from the GI tract poorly. Ketoconazole is available as a tablet or cream. Oral absorption is enhanced when the gastric pH is <4.0. Achlorhydria has been documented in HIV-infected patients and, when present, may interfere with ketoconazole absorption.(71) Itraconazole is available in a cyclodextrin oral solution, capsule, and parenteral form. The suspension and intravenous formulations have enhanced bioavailability compared with the capsule formulation. Absorption is improved when itraconazole is taken after a meal. Fluconazole, the first triazole compound released in the United States, is absorbed more completely than itraconazole or ketoconazole because absorption is not dependent on gastric acidity or food intake. Fluconazole is available in suspension, tablet, and parenteral form. In general, the side effects of ketoconazole, itraconazole, fluconazole, posaconazole, and voriconazole are similar, the more common being headache, dyspepsia, diarrhea, nausea, vomiting, hepatitis, and skin rash.(72) Voriconazole can cause reversible mild abnormal vision.(73) Prolonged administration of azoles may require surveillance of liver enzymes to monitor for hepatotoxicity. Significant drug interactions with each of these medications are provided in Table 3. The echinocandins are available only in parenteral forms. Caspofungin and micafungin are approved by the U.S. Food and Drug Administration (FDA) for the treatment of esophageal candidiasis. Adverse events including fever, nausea, infused-vein complications, and vomiting typically are mild.(74) Most antifungal treatment studies for mucocutaneous candidiasis are difficult to interpret, given the small numbers of patients, heterogeneous populations, short follow-up, and nonblinded design. Specifically, no study has stratified patients by CD4+ lymphocyte count. This point is important because persons with low CD4+ lymphocyte counts may respond more slowly to treatment, have lower rates of fungal eradication, and have higher relapse rates than persons with less advanced disease. No treatment trials for vulvovaginal candidiasis in women with HIV infection have been published. Recommendations for the treatment of vulvovaginal disease are made based on data from the non-HIV-infected population. Most of the published controlled trials for the treatment of oral and esophageal candidiasis are listed in Table 4. Response rates range from 34% to 100% in studies of treatment for oral and esophageal disease.(31,75-82) In clinical experience, the response rates to standard antifungal treatments are on the order of 75-95%. There are few significant differences in response rates between topical and systemic therapies or among the different systemic therapies for OPC. Thus, it is reasonable to conclude that clotrimazole, ketoconazole, fluconazole, and itraconazole probably are equivalent in the acute treatment of most cases of OPC. The treatment of esophageal candidiasis has not been studied so well as the treatment of OPC. Most experts recommend systemic therapy because of the significant morbidity of esophageal candidiasis and the absence of evidence supporting the use of topical therapy. Response rates to systemic therapies generally are quite good. Fluconazole has proved to be more effective than ketoconazole in one trial.(80) There have been no comparative studies of itraconazole in tablet or solution vs fluconazole. Itraconazole solution probably is equivalent to fluconazole for treating esophageal candidiasis. The cure rates for vulvovaginal candidiasis range from 72% to 98% in most trials of persons without HIV infection.(83-87) In the past, the standard treatment for vulvovaginal candidiasis typically consisted of topical clotrimazole or miconazole for 7 days. However, shorter courses have proved effective. Topical therapy for 3 days generally is equivalent to treatment with 7 days of topical medication. In a study comparing a 1-time dose of fluconazole (150 mg orally) with 7 days of topical clotrimazole therapy (100-mg vaginal suppositories), the clinical cure rate (75%) in the 2 groups was equivalent by day 35.(87) Mycologic eradication rates at day 35 were 63% for the fluconazole group and 57% for the clotrimazole group. Either topical or systemic therapy generally is effective in women with HIV infection, but relapse rates may be quite high.(38) There are no prospective trials using real-time, in vitro susceptibility testing to guide the choice of antifungal therapy. A likely explanation is that most Candida infections respond to empiric therapy, and in vitro testing for antifungal resistance is not yet as reliable as antibiotic susceptibility testing of bacterial isolates. Some clinical fungal isolates found to be "resistant" by in vitro testing nevertheless respond to therapy. Less commonly, some patients fail to respond to therapy despite having a relatively "sensitive" organism isolated. Thus, despite the determination of standard definitions for what constitutes in vitro resistance, more work must be done in this area before susceptibility testing can be used as a guide to antifungal therapy. There are a number of newer antifungals in varying phases of clinical development, including triazoles, echinocandins, sordarins, chitin synthase inhibitors, and topoisomerase inhibitors. Several new agents in the former 2 categories are now approved in the United States. In vitro activity of 3 new triazoles (posaconazole, ravuconazole, and voriconazole) appears to be quite good for Candida species, the latter agent having been licensed by the FDA in 2002.(88-94) A blinded, randomized study of voriconazole (200 mg twice daily) vs fluconazole (200 mg daily) for the treatment of esophageal candidiasis found no difference in the number of persons with endoscopically proven cure after 2-6 weeks of therapy: 94.8% of the voriconazole group (n = 115) vs 90.1% of the fluconazole group (n = 141).(73) Posaconazole (100 mg suspension/day) compared favorably to fluconazole (100 mg suspension/day) in the treatment of OPC in persons with HIV infection.(93) The clinical cure rate was 92% (n = 169) for posaconazole vs 93% (n = 160) for fluconazole. Similarly, posaconazole compared favorably to fluconazole in a dose-ranging study for the treatment of oral candidiasis in HIV infection.(94) Caspofungin, micafungin, and anidulafungin are members of the echinocandins, a novel class of antifungals. These agents also show promise in the treatment of Candida infections but are limited to parenteral administration at present.(95-97) In a study of 21 persons with esophageal or oral candidiasis, most of whom had HIV infection, who were treated with caspofungin, a favorable response was noted in 82% with esophageal disease and 100% with oral disease.(65) In a randomized trial comparing caspofungin with fluconazole for esophageal candidiasis, response rates and relapses at 4 weeks were similar. In the caspofungin group, 81% (n = 81) responded vs 85% (n = 94) in the fluconazole group.(98) Similarly, micafungin at a dose of 150 mg/day (n = 59) was similar in efficacy to fluconazole 200 mg/day (n = 60) for esophageal candidiasis (89.8% vs 86.7% response rate, respectively) in a randomized, double-blinded, multicenter study.(99)

Refractory Candidiasis

Reports of refractory OPC and esophageal disease began emerging in 1990.(16,58,59,100-114) Refractory vaginal candidiasis has remained relatively uncommon.(115) Refractory disease is defined as the failure to respond to antifungal treatment with appropriate doses for a standard duration of time (eg, 14 days).(16,115) Fluconazole-refractory disease has received particular attention because of significant morbidity, treatment often requiring the use of parenteral agents, and the frequency with which fluconazole has been prescribed. The annual incidence of fluconazole-refractory OPC was reported to be 4-5% in advanced HIV infection in developed countries prior to the introduction of combination ART.(16,37) Like most other opportunistic infections, fluconazole-refractory OPC is less common with the widespread use of effective ART. Candidiasis refractory to amphotericin B is exceedingly uncommon.(116-120) Of note, clinical failures also may result from inadequate drug absorption or drug interactions that decrease the levels of some antifungal medications.(71,121,122) Refractory candidiasis tends to occur in persons with advanced HIV disease (CD4 lymphocyte counts <50 cells/µL) who have been exposed to antifungal therapy on a continuous, chronic basis.(16) A longer median duration of exposure to antifungal therapy (419 vs 118 days, p < .001) and to systemic azole therapy (272 vs 14 days, p < .001) has been reported in comparing persons who had fluconazole-refractory OPC with matched controls.(104) In a randomized trial of episodic vs continuous use of fluconazole to determine which strategy for the prevention and treatment of mucocutaneous candidiasis would more likely lead to refractory candidiasis, no difference was observed in the rates of refractory disease (4.3% vs 4.1%, respectively).(123) Other factors that may predict the development of refractory candidiasis include use of prophylactic trimethoprim-sulfamethoxazole and a history of prior opportunistic illnesses such as Mycobacterium avium complex disease.(16) Similarly, chronic exposure to itraconazole results in higher rates of in vitro resistance, but these isolates typically remain susceptible to fluconazole.(124) Refractory candidiasis often is difficult to treat and may become increasingly unresponsive to therapy over time. The most important step is to determine what medications and dosages have been tried and whether adherence to therapy has been adequate. Removing any interacting medications or increasing the dose of the antifungal agent may be curative in some persons. In general, persons with OPC that is unresponsive to clotrimazole, nystatin, ketoconazole, or itraconazole tablets will respond to fluconazole. Persons with OPC unresponsive to fluconazole 200 mg daily given for 2 weeks are less likely to respond to higher doses but sometimes do respond. Additionally, flucytosine may be added for synergy. Options for managing fluconazole-refractory disease are listed in Table 5. There have been few controlled, comparative studies of these approaches. Parenteral amphotericin B (or liposomal preparations of amphotericin B) remains the drug of choice for persons with severe disease or esophageal involvement. For mild to moderate fluconazole-refractory OPC, amphotericin B oral suspension, itraconazole solution, or the addition of flucytosine are reasonable therapeutic strategies.(125-131) Overall, the response rate is 50-60% for itraconazole solution and slightly lower for oral amphotericin B solution. Other options for treating fluconazole-resistant isolates include voriconazole, caspofungin, micafungin, and anidulafungin.(88,89) ART should be optimized in persons with refractory candidiasis. Treatment with protease inhibitors has been noted to result in clinical improvement in difficult-to-treat cases.(132) Protease inhibitors have been shown to inhibit Candida secretory aspartic proteases, demonstrating direct antifungal activity against Candida.(133-135) The duration of antifungal treatment for refractory disease is based upon the response, but typically a course of 14 days for OPC or vaginal disease, and 21-28 days for esophageal disease, is necessary. Relapse rates are high in persons with refractory disease, and maintenance suppressive therapy is universally required.(131) In challenging cases, therapy 2-3 times weekly, or daily suppressive therapy on occasion, may be needed to avoid relapse.

Invasive Candidiasis

Despite the frequency of mucosal candidiasis, invasive disease is uncommon in persons with HIV infection. There are few studies describing the incidence and prevalence of nonesophageal invasive candidiasis in HIV-infected persons. Most studies are restricted to case series or anecdotal reports. A retrospective review found the incidence of candidemia to be 0.09 episodes per 100 person-years from 1992 to 1996 compared with 1.1 episodes per 100 person-years from 1997 to 2001, suggesting a decrease following the advent of effective ART.(136) Overall, the incidence of candidemia in AIDS is probably <1%.(137,138) Individuals who develop candidemia usually have risk factors known to be associated with invasive candidiasis (eg, indwelling intravenous catheter, neutropenia, chemotherapy, parenteral alimentation).(136) The explanation for the lack of invasive disease in persons with HIV infection may be that the pathogenesis of invasive candidiasis usually involves disruption of a mucosal or skin surface barrier with subsequent hematogenous dissemination secondary to neutrophil and macrophage dysfunction--conditions that are not characteristic of HIV disease.(139,140) In a review of 14 cases of Candida meningitis in HIV-infected patients, a history of at least 1 predisposing risk factor was noted in 10 of the patients, 9 of whom were intravenous drug users.(140) Of interest, 4 of the patients had no risk factors identified. Candida meningitis remains a rare entity, even among other immunosuppressed patients, and optimal therapy is unknown. It seems prudent for HIV-infected patients with Candida meningitis to continue chronic suppressive therapy with fluconazole on a regimen similar to that used in the management of cryptococcal meningitis.

Prevention

The most important method of preventing mucocutaneous candidiasis is reversal of the immunodeficiency associated with HIV infection. Combination ART is the single best intervention to reduce the incidence of mucocutaneous candidiasis. Several studies demonstrate a decline in the rate of colonization and clinical disease with the use of potent ART.(42,43,47) This decline has been correlated with reduction in HIV-1 RNA levels in the plasma. Other possible interventions include smoking cessation, good oral hygiene, avoidance of unnecessary antibiotics and steroids, and specific antifungal medications. Although recurrent mucocutaneous candidiasis is frequent in persons with untreated advanced HIV infection, the indications for prophylactic antifungal therapy remain uncertain. A randomized study comparing clotrimazole and fluconazole demonstrated that fluconazole can prevent invasive fungal infections such as cryptococcosis and esophageal candidiasis.(141) However, that study found no survival advantage. Weekly fluconazole prophylaxis also has been studied for the prevention of OPC and vulvovaginal disease.(38,142,143) Another study reported decreases in the incidence of both OPC (relative risk [RR] = 0.50; 95% confidence interval [CI], 0.33-0.71) and vulvovaginal disease (RR = 0.56; 95% CI, 0.41-0.77) in a group of 323 women with moderately advanced HIV infection who took weekly doses of fluconazole 200 mg (median follow-up, 29 months).(38) Thus, although prophylaxis can reduce the risk of mucocutaneous candidiasis, there is no associated survival advantage. Furthermore, several studies have demonstrated that continuous, long-term exposure to antifungals such as fluconazole can lead to the emergence of resistance and refractory infections.(16) Consequently, most experts do not recommend universal primary antifungal prophylaxis. The use of secondary prophylaxis should be individualized. In a randomized study of continuous fluconazole prophylaxis vs episodic treatment with fluconazole in persons with prior mucosal candidiasis, continuous fluconazole resulted in fewer cases of OPC or esophageal disease (0.29 vs 1.08 per patient-year; p < .001) and invasive fungal infections (15 vs 28 episodes; p = .04) though there was no difference in survival.(123) There was no increase detected in resistance among the continuous usage arm. The proportion of patients in whom the final candidal isolate was resistant to fluconazole was 50 of 110 (45%) in the continuous fluconazole arm and 79 of 218 (36%) in the episodic fluconazole arm (p = .11). Some experts recommend prophylaxis in persons with a prior episode of esophageal candidiasis.(144,145) In general, persons with occasional disease or infrequent recurrences of OPC (fewer than 3 episodes per year) can be treated for each episode. An alternative approach is to provide the patient with a supply of antifungal medications that can be initiated at the earliest sign of recurrence. This alternative may be useful for adherent, well-educated patients with frequent or disabling episodes, particularly at low CD4+ lymphocyte counts. Some experts recommend prophylaxis in persons with advanced HIV disease when prescribing antibiotics or corticosteroids, such as in a patient with Pneumocystis jiroveci pneumonia. If the decision is made to use prophylaxis, daily, thrice-weekly, or weekly fluconazole are the options most frequently cited in published studies. Ketoconazole and itraconazole probably are useful as well but have not been evaluated in controlled trials. Topical therapy may be useful in some patients. In summary, reserving continuous use of antifungal agents to those persons with frequent or severe recurrences of mucosal candidiasis is recommended in order to avoid the emergence of drug resistance, avoid drug interactions, simplify already complex drug regimens, avoid drug toxicity, and lower the cost of treatment.

References 1.   Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981; 305:1425-31. 2.   Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, Wormser G, Brettman L, Lange M, Murray HW, Cunningham-Rundles S. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981; 305:1431-8. 3.   Klein RS, Harris CA, Small CB, Moll B, Lesser M, Friedland GH. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984; 311:354-8. 4.   Dodd CL, Greenspan D, Katz MH, Westenhouse JL, Feigal DW, Greenspan JS. Oral candidiasis in HIV infection: pseudomembranous and erythematous candidiasis show similar rates of progression to AIDS. Aids 1991; 5:1339-43. 5.   Katz MH, Greenspan D, Westenhouse J, Hessol NA, Buchbinder SP, Lifson AR, Shiboski S, Osmond D, Moss A, Samuel M, et al. Progression to AIDS in HIV-infected homosexual and bisexual men with hairy leukoplakia and oral candidiasis. Aids 1992; 6:95-100. 6.   Tavitian A, Raufman JP, Rosenthal LE. Oral candidiasis as a marker for esophageal candidiasis in the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104:54-5. 7.   Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med 1996; 124:633-42. 8.   White MH. Is vulvovaginal candidiasis an AIDS-related illness? Clin Infect Dis 1996; 22 Suppl 2:S124-7. 9.   Schmidt-Westhausen AM, Bendick C, Reichart PA, Samaranayake LP. Oral candidosis and associated Candida species in HIV-infected Cambodians exposed to antimycotics. Mycoses 2004; 47:435-41. 10.   Sanchez-Vargas LO, Ortiz-Lopez NG, Villar M, Moragues MD, Aguirre JM, Cashat-Cruz M, Lopez-Ribot JL, Gaitan-Cepeda LA, Quindos G. Oral Candida isolates colonizing or infecting human immunodeficiency virus-infected and healthy persons in Mexico. J Clin Microbiol 2005; 43:4159-62. 11.   Tintelnot K, Haase G, Seibold M, Bergmann F, Staemmler M, Franz T, Naumann D. Evaluation of phenotypic markers for selection and identification of Candida dubliniensis. J Clin Microbiol 2000; 38:1599-608. 12.   Schorling SR, Kortinga HC, Froschb M, Muhlschlegel FA. The role of Candida dubliniensis in oral candidiasis in human immunodeficiency virus-infected individuals. Crit Rev Microbiol 2000; 26:59-68. 13.   Jabra-Rizk MA, Falkler WA, Jr., Merz WG, Baqui AA, Kelley JI, Meiller TF. Retrospective identification and characterization of Candida dubliniensis isolates among Candida albicans clinical laboratory isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected individuals. J Clin Microbiol 2000; 38:2423-6. 14.   Binolfi A, Biasoli MS, Luque AG, Tosello ME, Magaro HM. High prevalence of oral colonization by Candida dubliniensis in HIV-positive patients in Argentina. Med Mycol 2005; 43:431-7. 15.   Odds FC. Candida and Candidosis. London: Bailliere Tindall; 1988; p. 117. 16.   Fichtenbaum CJ, Koletar S, Yiannoutsos C, Holland F, Pottage J, Cohn SE, Walawander A, Frame P, Feinberg J, Saag M, Van der Horst C, Powderly WG. Refractory mucosal candidiasis in advanced human immunodeficiency virus infection. Clin Infect Dis 2000; 30:749-56. 17.   Schuman P, Sobel JD, Ohmit SE, Mayer KH, Carpenter CC, Rompalo A, Duerr A, Smith DK, Warren D, Klein RS. Mucosal candidal colonization and candidiasis in women with or at risk for human immunodeficiency virus infection. HIV Epidemiology Research Study (HERS) Group. Clin Infect Dis 1998; 27:1161-7. 18.   Barchiesi F, Hollis RJ, Del Poeta M, McGough DA, Scalise G, Rinaldi MG, Pfaller MA. Transmission of fluconazole-resistant Candida albicans between patients with AIDS and oropharyngeal candidiasis documented by pulsed-field gel electrophoresis. Clin Infect Dis 1995; 21:561-4. 19.   Powderly WG, Robinson K, Keath EJ. Molecular typing of candida albicans isolated from oral lesions of HIV-infected individuals. Aids 1992; 6:81-4. 20.   Powderly WG. Mucosal candidiasis caused by non-albicans species of Candida in HIV-positive patients. Aids 1992; 6:604-5. 21.   Bruatto M, Vidotto V, Marinuzzi G, Raiteri R, Sinicco A. Candida albicans biotypes in human immunodeficiency virus type 1-infected patients with oral candidiasis before and after antifungal therapy. J Clin Microbiol 1991; 29:726-30. 22.   Schmid J, Odds FC, Wiselka MJ, Nicholson KG, Soll DR. Genetic similarity and maintenance of Candida albicans strains from a group of AIDS patients, demonstrated by DNA fingerprinting. J Clin Microbiol 1992; 30:935-41. 23.   Korting HC, Ollert M, Georgii A, Froschl M. In vitro susceptibilities and biotypes of Candida albicans isolates from the oral cavities of patients infected with human immunodeficiency virus. J Clin Microbiol 1988; 26:2626-31. 24.   Feigal DW, Katz MH, Greenspan D, Westenhouse J, Winkelstein W, Jr., Lang W, Samuel M, Buchbinder SP, Hessol NA, Lifson AR, et al. The prevalence of oral lesions in HIV-infected homosexual and bisexual men: three San Francisco epidemiological cohorts. Aids 1991; 5:519-25. 25.   Pindborg JJ. Oral candidiasis in HIV infection. In: Robertson PB, Greenspan JS (eds): Perspectives on Oral Manifestations of AIDS. Littleton, MA: PSG Publishing; 1988; p. 23. 26.   Holmstrup P, Samaranayake LP: Acute and AIDS-related oral candidosis. In: Samaranayake LP, MacFarlane TW eds. Oral Candidosis. London: Wright; 1990; p. 133. 27.   McCarthy GM, Mackie ID, Koval J, Sandhu HS, Daley TD. Factors associated with increased frequency of HIV-related oral candidiasis. J Oral Pathol Med 1991; 20:332-6. 28.   Epstein JB, Truelove EL, Izutzu KT. Oral candidiasis: pathogenesis and host defense. Rev Infect Dis 1984; 6:96-106. 29.   McCarthy GM. Host factors associated with HIV-related oral candidiasis. A review. Oral Surg Oral Med Oral Pathol 1992; 73:181-6. 30.   Yeh CK, Fox PC, Ship JA, Busch KA, Bermudez DK, Wilder AM, Katz RW, Wolff A, Tylenda CA, Atkinson JC, et al. Oral defense mechanisms are impaired early in HIV-1 infected patients. J Acquir Immune Defic Syndr 1988; 1:361-6. 31.   Pons V, Greenspan D, Debruin M. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. The Multicenter Study Group. J Acquir Immune Defic Syndr 1993; 6:1311-6. 32.   Smith DE, Midgley J, Allan M, Connolly GM, Gazzard BG. Itraconazole versus ketaconazole in the treatment of oral and oesophageal candidosis in patients infected with HIV. Aids 1991; 5:1367-71. 33.   Selik RM, Starcher ET, Curran JW. Opportunistic diseases reported in AIDS patients: frequencies, associations, and trends. Aids 1987; 1:175-82. 34.   Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med 1996; 124:633-42. 35.   Wilcox CM, Alexander LN, Clark WS, Thompson SE, 3rd. Fluconazole compared with endoscopy for human immunodeficiency virus-infected patients with esophageal symptoms. Gastroenterology 1996; 110:1803-9. 36.   Duerr A, Sierra M, Clarke L, et al: Vaginal candidiasis among HIV-infected women. In: Proceedings of the IX International Conference on AIDS, Berlin, 1993, Vol I, Abstract No. PO-B01-0880:282. 37.   Sha B, Benson C, Pottage J, et al: HIV infection in women: a six year longitudinal, observational study. In: Proceedings of the IX International Conference on AIDS, Berlin, 1993, Vol I, Abstract No. PO-B01-0891:283. 38.   Schuman P, Capps L, Peng G, Vazquez J, el-Sadr W, Goldman AI, Alston B, Besch CL, Vaughn A, Thompson MA, Cobb MN, Kerkering T, Sobel JD. Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. Ann Intern Med 1997; 126:689-96. 39.   Mouton Y, Alfandari S, Valette M, Cartier F, Dellamonica P, Humbert G, Lang JM, Massip P, Mechali D, Leclercq P, Modai J, Portier H. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. Federation National des Centres de Lutte contre le SIDA. Aids 1997; 11:F101-5. 40.   Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853-60. 41.   Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ, Jr., Feinberg JE, Balfour HH, Jr., Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725-33. 42.   Cauda R, Tacconelli E, Tumbarello M, Morace G, De Bernardis F, Torosantucci A, Cassone A. Role of protease inhibitors in preventing recurrent oral candidosis in patients with HIV infection: a prospective case-control study. J Acquir Immune Defic Syndr 1999; 21:20-5. 43.   Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin Infect Dis 1998; 27:1291-4. 44.   de Repentigny L, Lewandowski D, Jolicoeur P. Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection. Clin Microbiol Rev 2004; 17:729-59, table of contents. 45.   Steele C, Leigh J, Swoboda R, Fidel PL, Jr. Growth inhibition of Candida by human oral epithelial cells. J Infect Dis 2000; 182:1479-85. 46.   Diz Dios P, Ocampo A, Otero I, Iglesias I, Martinez C. Changes in oropharyngeal colonization and infection by Candida albicans in human immunodeficiency virus-infected patients. J Infect Dis 2001; 183:355-356. 47.   Gottfredsson M, Cox GM, Indridason OS, de Almeida GM, Heald AE, Perfect JR. Association of plasma levels of human immunodeficiency virus type 1 RNA and oropharyngeal Candida colonization. J Infect Dis 1999; 180:534-7. 48.   Sobel JD. Pathogenesis and treatment of recurrent vulvovaginal candidiasis. Clin Infect Dis 1992; 14 Suppl 1:S148-53. 49.   Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-Ingroff A, Ghannoum MA, Lancaster M, Odds FC, Rinaldi MG, Walsh TJ, Barry AL. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis 1997; 24:235-47. 50.   National Committee for Clinical Laboratory Standards. 2002 Reference method for broth dilution antifungal susceptibility testing of yeasts. M27-A2. National Committee for Clinical Laboratory Standards, Wayne, Pa. 51.   Chaturvedi V, Ramani R, Pfaller MA. Collaborative study of the NCCLS and flow cytometry methods for antifungal susceptibility testing of Candida albicans. J Clin Microbiol 2004; 42:2249-51. 52.   Heinic GS, Stevens DA, Greenspan D, MacPhail LA, Dodd CL, Stringari S, Strull WM, Hollander H. Fluconazole-resistant Candida in AIDS patients. Report of two cases. Oral Surg Oral Med Oral Pathol 1993; 76:711-5. 53.   Quereda C, Polanco AM, Giner C, Sanchez-Sousa A, Pereira E, Navas E, Fortun J, Guerrero A, Baquero F. Correlation between in vitro resistance to fluconazole and clinical outcome of oropharyngeal candidiasis in HIV-infected patients. Eur J Clin Microbiol Infect Dis 1996; 15:30-7. 54.   Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE. Infection due to fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis 1997; 24:28-34. 55.   Pfaller MA, Rhine-Chalberg J, Redding SW, Smith J, Farinacci G, Fothergill AW, Rinaldi MG. Variations in fluconazole susceptibility and electrophoretic karyotype among oral isolates of Candida albicans from patients with AIDS and oral candidiasis. J Clin Microbiol 1994; 32:59-64. 56.   Laguna F, Rodriguez-Tudela JL, Martinez-Suarez JV, Polo R, Valencia E, Diaz-Guerra TM, Dronda F, Pulido F. Patterns of fluconazole susceptibility in isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis due to Candida albicans. Clin Infect Dis 1997; 24:124-30. 57.   Barchiesi F, Colombo AL, McGough DA, Fothergill AW, Rinaldi MG. In vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1994; 38:1530-3. 58.   He X, Tiballi RN, Zarins LT, Bradley SF, Sangeorzan JA, Kauffman CA. Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1994; 38:2495-7. 59.   Fan-Havard P, Capano D, Smith SM, Mangia A, Eng RH. Development of resistance in candida isolates from patients receiving prolonged antifungal therapy. Antimicrob Agents Chemother 1991; 35:2302-5. 60.   St-Germain G, Dion C, Espinel-Ingroff A, Ratelle J, de Repentigny L. Ketoconazole and itraconazole susceptibility of Candida albicans isolated from patients infected with HIV. J Antimicrob Chemother 1995; 36:109-18. 61.   Cameron ML, Schell WA, Bruch S, Bartlett JA, Waskin HA, Perfect JR. Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1. Antimicrob Agents Chemother 1993; 37:2449-53. 62.   Chavanet P, Lopez J, Grappin M, Bonnin A, Duong M, Waldner A, Buisson M, Camerlynck P, Portier H. Cross-sectional study of the susceptibility of Candida isolates to antifungal drugs and in vitro-in vivo correlation in HIV-infected patients. Aids 1994; 8:945-50. 63.   Sangeorzan JA, Bradley SF, He X, Zarins LT, Ridenour GL, Tiballi RN, Kauffman CA. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med 1994; 97:339-46. 64.   Ruhnke M, Eigler A, Tennagen I, Geiseler B, Engelmann E, Trautmann M. Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. J Clin Microbiol 1994; 32:2092-8. 65.   Kartsonis NA, Saah A, Lipka CJ, Taylor A, Sable CA. Second-line therapy with caspofungin for mucosal or invasive candidiasis: results from the caspofungin compassionate-use study. J Antimicrob Chemother 2004; 53:878-81. 66.   Gerzenshtein L, Patel SM, Scarsi KK, Postelnick MJ, Flaherty JP. Breakthrough Candida infections in patients receiving voriconazole. Ann Pharmacother 2005; 39:1342-5. 67.   Hitchcock CA. Resistance of Candida albicans to azole antifungal agents. Biochem Soc Trans 1993; 21:1039-47. 68.   Vanden Bossche H, Marichal P, Odds FC. Molecular mechanisms of drug resistance in fungi. Trends Microbiol 1994; 2:393-400. 69.   Ryley JF, Wilson RG, Barrett-Bee KJ. Azole resistance in Candida albicans. Sabouraudia 1984; 22:53-63. 70.   Parkinson T, Falconer DJ, Hitchcock CA. Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata. Antimicrob Agents Chemother 1995; 39:1696-9. 71.   Lake-Bakaar G, Tom W, Lake-Bakaar D, Gupta N, Beidas S, Elsakr M, Straus E. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 109:471-3. 72.   Munoz P, Moreno S, Berenguer J, Bernaldo de Quiros JC, Bouza E. Fluconazole-related hepatotoxicity in patients with acquired immunodeficiency syndrome. Arch Intern Med 1991; 151:1020-1. 73.   Ally R, Schurmann D, Kreisel W, Carosi G, Aguirrebengoa K, Dupont B, Hodges M, Troke P, Romero AJ. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001; 33:1447-54. 74.   Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, Sable CA, Kartsonis NA, Ngai A, Taylor A, Patterson TF, Denning DW, Walsh TJ. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39:1563-71. 75.   Lim SG, Lee CA, Hales M, O'Doherty M, Winter M, Kernoff PB. Fluconazole for oropharyngeal candidiasis in anti-HIV positive haemophiliacs. Aliment Pharmacol Ther 1991; 5:199-205. 76.   De Wit S, Urbain D, Rahir F, Weerts D, Clumeck N. Efficacy of oral fluconazole in the treatment of AIDS associated oesophageal candidiasis. Eur J Clin Microbiol Infect Dis 1991; 10:503-5. 77.   Chave JP, Francioli P, Hirschel B, Glauser MP. Single-dose therapy for esophageal candidiasis with fluconazole. Aids 1990; 4:1034-5. 78.   De Wit S, Weerts D, Goossens H, Clumeck N. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet 1989; 1:746-8. 79.   Koletar SL, Russell JA, Fass RJ, Plouffe JF. Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1990; 34:2267-8. 80.   Laine L, Dretler RH, Conteas CN, Tuazon C, Koster FM, Sattler F, Squires K, Islam MZ. Fluconazole compared with ketoconazole for the treatment of Candida esophagitis in AIDS. A randomized trial. Ann Intern Med 1992; 117:655-60. 81.   Barchiesi F, Giacometti A, Arzeni D, Branchesi P, Crescenzi G, Ancarani F, Scalise G. Fluconazole and ketoconazole in the treatment of oral and esophageal candidiasis in AIDS patients. J Chemother 1992; 4:381-6. 82.   de Repentigny L, Ratelle J. Comparison of itraconazole and ketoconazole in HIV-positive patients with oropharyngeal or esophageal candidiasis.Human Immunodeficiency Virus Itraconazole Ketoconazole Project Group. Chemotherapy 1996; 42:374-83. 83.   Kutzer E, Oittner R, Leodolter S, Brammer KW. A comparison of fluconazole and ketoconazole in the oral treatment of vaginal candidiasis; report of a double-blind multicentre trial. Eur J Obstet Gynecol Reprod Biol 1988; 29:305-13. 84.   van Heusden AM, Merkus HM, Corbeij RS, Oosterbaan HP, Stoot JE, Ubachs HM, Verhoeff A. Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis. Acta Obstet Gynecol Scand 1990; 69:417-22. 85.   Woolley PD, Higgins SP. Comparison of clotrimazole, fluconazole and itraconazole in vaginal candidiasis. Br J Clin Pract 1995; 49:65-6. 86.   A comparison of single-dose oral fluconazole with 3-day intravaginal clotrimazole in the treatment of vaginal candidiasis. Report of an international multicentre trial. Br J Obstet Gynaecol 1989; 96:226-32. 87.   Sobel JD, Brooker D, Stein GE, Thomason JL, Wermeling DP, Bradley B, Weinstein L. Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole Vaginitis Study Group. Am J Obstet Gynecol 1995; 172:1263-8. 88.   Ruhnke M, Schmidt-Westhausen A, Trautmann M. In vitro activities of voriconazole (UK-109,496) against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997; 41:575-7. 89.   Hegener P, Troke PF, Fatkenheuer G, Diehl V, Ruhnke M. Treatment of fluconazole-resistant candidiasis with voriconazole in patients with AIDS. Aids 1998; 12:2227-8. 90.   Pfaller MA, Messer SA, Hollis RJ, Jones RN, Doern GV, Brandt ME, Hajjeh RA. In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole. Antimicrob Agents Chemother 1998; 42:3242-4. 91.   Chavez M, Bernal S, Valverde A, Gutierrez MJ, Quindos G, Mazuelos EM. In-vitro activity of voriconazole (UK-109,496), LY303366 and other antifungal agents against oral Candida spp. isolates from HIV-infected patients. J Antimicrob Chemother 1999; 44:697-700. 92.   Cacciapuoti A, Loebenberg D, Corcoran E, Menzel F, Jr., Moss EL, Jr., Norris C, Michalski M, Raynor K, Halpern J, Mendrick C, Arnold B, Antonacci B, Parmegiani R, Yarosh-Tomaine T, Miller GH, Hare RS. In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida. Antimicrob Agents Chemother 2000; 44:2017-22. 93.   Vazquez JA, Northland R, Miller S, Dickinson G, Wright G: Posaconazole compared to fluconazole for oral candidiasis in HIV-positive patients. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 1107. 94.   Nieto L, Northland R, Pittisuttithum P, et al. Posaconazole equivalent to fluconazole in the treatment of oropharyngeal candidiasis. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 1108. 95.   Pettengell K, Mynhardt J, Kluyts T, Lau W, Facklam D, Buell D. Successful treatment of oesophageal candidiasis by micafungin: a novel systemic antifungal agent. Aliment Pharmacol Ther 2004; 20:475-81. 96.   Brown GL, White RJ, Turik M: Phase II, randomized, open label study of two intravenous dosing regimens of V-Echinocandid in the treatment of esophageal candidiasis. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 1106. 97.   Hicks PS, Dorso KL, Gerckens LS, et al: Comparative in vitro susceptibility of clinical trial isolates to the echinocandin antifungal caspofungin (CancidasTM, MK-0991). In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 193. 98.   Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, Smietana JM, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002; 113:294-9. 99.   De Wet NTE, Llanos-Cuentas A, Suleiman H, et al. Micafungin (FK463) dose response and comparison with fluconazole in oesophageal candidiasis. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago. Abstract M-1754. 100.   Baily GG, Perry FM, Denning DW, Mandal BK. Fluconazole-resistant candidosis in an HIV cohort. Aids 1994; 8:787-92. 101.   Boken DJ, Swindells S, Rinaldi MG. Fluconazole-resistant Candida albicans. Clin Infect Dis 1993; 17:1018-21. 102.   Newman SL, Flanigan TP, Fisher A, Rinaldi MG, Stein M, Vigilante K. Clinically significant mucosal candidiasis resistant to fluconazole treatment in patients with AIDS. Clin Infect Dis 1994; 19:684-6. 103.   White A, Goetz MB. Azole-resistant Candida albicans: report of two cases of resistance to fluconazole and review. Clin Infect Dis 1994; 19:687-92. 104.   Maenza JR, Keruly JC, Moore RD, Chaisson RE, Merz WG, Gallant JE. Risk factors for fluconazole-resistant candidiasis in human immunodeficiency virus-infected patients. J Infect Dis 1996; 173:219-25. 105.   Fox R, Neal KR, Leen CL, Ellis ME, Mandal BK. Fluconazole resistant candida in AIDS. J Infect 1991; 22:201-4. 106.   Kitchen VS, Savage M, Harris JR. Candida albicans resistance in AIDS. J Infect 1991; 22:204-5. 107.   Smith D, Boag F, Midgley J, Gazzard B. Fluconazole resistant candida in AIDS. J Infect 1991; 23:345-6. 108.   Willocks L, Leen CL, Brettle RP, Urquhart D, Russell TB, Milne LJ. Fluconazole resistance in AIDS patients. J Antimicrob Chemother 1991; 28:937-9. 109.   Arilla MC, Carbonero JL, Schneider J, Regulez P, Quindos G, Ponton J, Cisterna R. Vulvovaginal candidiasis refractory to treatment with fluconazole. Eur J Obstet Gynecol Reprod Biol 1992; 44:77-80. 110.   Sanguineti A, Carmichael JK, Campbell K. Fluconazole-resistant Candida albicans after long-term suppressive therapy. Arch Intern Med 1993; 153:1122-4. 111.   Redding S, Smith J, Farinacci G, Rinaldi M, Fothergill A, Rhine-Chalberg J, Pfaller M. Resistance of Candida albicans to fluconazole during treatment of oropharyngeal candidiasis in a patient with AIDS: documentation by in vitro susceptibility testing and DNA subtype analysis. Clin Infect Dis 1994; 18:240-2. 112.   Troillet N, Durussel C, Bille J, Glauser MP, Chave JP. Correlation between in vitro susceptibility of Candida albicans and fluconazole-resistant oropharyngeal candidiasis in HIV-infected patients. Eur J Clin Microbiol Infect Dis 1993; 12:911-5. 113.   Cartledge JD, Midgley J, Gazzard BG. Relative growth measurement of Candida species in a single concentration of fluconazole predicts the clinical response to fluconazole in HIV infected patients with oral candidosis. J Antimicrob Chemother 1996; 37:275-83. 114.   Horn CA, Washburn RG, Givner LB, Peacock JE, Jr., Pegram PS. Azole-resistant oropharyngeal and esophageal candidiasis in patients with AIDS. Aids 1995; 9:533-4. 115.   Arilla MC, Carbonero JL, Schneider J, Regulez P, Quindos G, Ponton J, Cisterna R. Vulvovaginal candidiasis refractory to treatment with fluconazole. Eur J Obstet Gynecol Reprod Biol 1992; 44:77-80. 116.   Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 1998; 26:556-65. 117.   Berman S, Ho M: Highly resistant esophageal candidiasis in patients with AIDS. In: Proceedings of the IX International Conference on AIDS, Berlin, 1993, Vol I, Abstract No. PO-B09-1405:369. 118.   Dick JD, Merz WG, Saral R. Incidence of polyene-resistant yeasts recovered from clinical specimens. Antimicrob Agents Chemother 1980; 18:158-63. 119.   Kwon-Chung KJ, Bennett JE. Principles of antifungal therapy. In: Medical Mycology. Philadelphia, Lea & Febiger, 1992, p 81. 120.   Powderly WG, Kobayashi GS, Herzig GP, Medoff G. Amphotericin B-resistant yeast infection in severely immunocompromised patients. Am J Med 1988; 84:826-32. 121.   Blum RA, D'Andrea DT, Florentino BM, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, Goldstein H, Schentag JJ. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991; 114:755-7. 122.   Kaltenbach G, Leveque D, Peter JD, Salmon J, Elkhaili H, Cavalier A, Salmon Y, Monteil H, Jehl F. Pharmacokinetic interaction between itraconazole and rifampin in Yucatan miniature pigs. Antimicrob Agents Chemother 1996; 40:2043-6. 123.   Goldman M, Cloud GA, Wade KD, Reboli AC, Fichtenbaum CJ, Hafner R, Sobel JD, Powderly WG, Patterson TF, Wheat LJ, Stein DK, Dismukes WE, Filler SG. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40. Clin Infect Dis 2005; 41:1473-80. 124.   Goldman M, Cloud GA, Smedema M, LeMonte A, Connolly P, McKinsey DS, Kauffman CA, Moskovitz B, Wheat LJ. Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? The National Institute of Allergy and Infectious Diseases Mycoses study group. Antimicrob Agents Chemother 2000; 44:1585-7. 125.   Dewsnup DH, Stevens DA. Efficacy of oral amphotericin B in AIDS patients with thrush clinically resistant to fluconazole. J Med Vet Mycol 1994; 32:389-93. 126.   Nguyen MT, Weiss PG, Labarre RC, et al: Oral amphotericin B in the treatment or oral candidiasis due to azole-resistant Candida species. In: Program and abstracts of the Annual Meeting of the Infectious Diseases Society of America; October 7-9, 1994; Orlando, FL. Abstract 287. 127.   Fichtenbaum CJ, Zackin R, Rajicic N, Powderly WG, Wheat LJ, Zingman BS. Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295. Aids 2000; 14:845-52. 128.   Cartledge JD, Midgley J, Youle M, Gazzard BG. Itraconazole cyclodextrin solution--effective treatment for HIV-related candidosis unresponsive to other azole therapy. J Antimicrob Chemother 1994; 33:1071-3. 129.   Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM. Itraconazole cyclodextrin solution for fluconazole-refractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility. Aids 1996; 10:1369-76. 130.   Saag MS, Fessel WJ, Kaufman CA, Merrill KW, Ward DJ, Moskovitz BL, Thomas C, Oleka N, Guarnieri JA, Lee J, Brenner-Gati L, Klausner M. Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients. AIDS Res Hum Retroviruses 1999; 15:1413-7. 131.   Moskovitz B, Wu J, Baruch A, et al. Long term safety and efficacy of itraconazole oral solution for the treatment of fluconazole refractory oropharyngeal candidiasis in HIV positive patients. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26, 1997; Washington. Abstract 325. 132.   Zingman BS. Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir. N Engl J Med 1996; 334:1674-5. 133.   Borg-von Zepelin M, Meyer I, Thomssen R, Wurzner R, Sanglard D, Telenti A, Monod M. HIV-Protease inhibitors reduce cell adherence of Candida albicans strains by inhibition of yeast secreted aspartic proteases. J Invest Dermatol 1999; 113:747-51. 134.   Naglik JR, Newport G, White TC, Fernandes-Naglik LL, Greenspan JS, Greenspan D, Sweet SP, Challacombe SJ, Agabian N. In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis. Infect Immun 1999; 67:2482-90. 135.   Korting HC, Schaller M, Eder G, Hamm G, Bohmer U, Hube B. Effects of the human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on in vitro activities of secreted aspartyl proteinases of Candida albicans isolates from HIV-infected patients. Antimicrob Agents Chemother 1999; 43:2038-42. 136.   Bertagnolio S, de Gaetano Donati K, Tacconelli E, Scoppettuolo G, Posteraro B, Fadda G, Cauda R, Tumbarello M. Hospital-acquired candidemia in HIV-infected patients. Incidence, risk factors and predictors of outcome. J Chemother 2004; 16:172-8. 137.   Launay O, Lortholary O, Bouges-Michel C, Jarrousse B, Bentata M, Guillevin L. Candidemia: a nosocomial complication in adults with late-stage AIDS. Clin Infect Dis 1998; 26:1134-41. 138.   Tumbarello M, Tacconelli E, de Gaetano Donati K, Morace G, Fadda G, Cauda R. Candidemia in HIV-infected subjects. Eur J Clin Microbiol Infect Dis 1999; 18:478-83. 139.   Bodey GP. Disseminated candidiasis in neutropenic patients. Int J Infect Dis 1997; 1:S2-6. 140.   Casado JL, Quereda C, Oliva J, Navas E, Moreno A, Pintado V, Cobo J, Corral I. Candidal meningitis in HIV-infected patients: analysis of 14 cases. Clin Infect Dis 1997; 25:673-6. 141.   Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster ME, Carey J, Waskin H, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995; 332:700-5. 142.   Leen CL, Dunbar EM, Ellis ME, Mandal BK. Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind placebo-controlled study. J Infect 1990; 21:55-60. 143.   Marriott DJ, Jones PD, Hoy JF, Speed BR, Harkness JL. Fluconazole once a week as secondary prophylaxis against oropharyngeal candidiasis in HIV-infected patients. A double-blind placebo-controlled study. Med J Aust 1993; 158:312-6. 144.   Esposito R, Castagna A, Uberti Foppa C. Maintenance therapy of oropharyngeal candidiasis in HIV-infected patients with fluconazole. Aids 1990; 4:1033-4. 145.   Agresti MG, de Bernardis F, Mondello F, Bellocco R, Carosi GP, Caputo RM, Milazzo F, Chiodo F, Giannini V, Minoli L, et al. Clinical and mycological evaluation of fluconazole in the secondary prophylaxis of esophageal candidiasis in AIDS patients. An open, multicenter study. Eur J Epidemiol 1994; 10:17-22.