Infectious esophagitis is a leading cause of esophagitis worldwide. While esophageal infections have traditionally been associated with immunocompromised patients, these disorders are becoming increasingly recognized in immunocompetent individuals. The three most common etiologies of infectious esophagitis are Candida, herpes simplex virus, and cytomegalovirus. Human papilloma virus infection can also involve the esophagus in the form of ulcerative lesions and papillomas. Less common etiologies include various other fungal, bacterial, and viral organisms. This review provides a comprehensive update on risk factors, diagnosis, and management of both common and less common infections of the esophagus.

Esophageal candidiasis is a frequent cause of morbidity in immunocompromised patients. Isavuconazole is a novel, broad-spectrum antifungal developed for the treatment of opportunistic fungal infections. This phase 2 trial compared the efficacy and safety of three oral dosing regimens of isavuconazole with an oral fluconazole regimen in the primary treatment of uncomplicated esophageal candidiasis. The isavuconazole regimens were as follows: 200 mg on day 1 and then 50 mg once daily (arm A), 400 mg on day 1 and then 400 mg once-weekly (arm B), and 400 mg on day 1 and then 100 mg once daily (arm C). Patients in arm D received fluconazole at 200 mg on day 1 and then 100 mg once daily. The minimum treatment duration was 14 days. The primary endpoint was the rate of endoscopically confirmed clinical response at end of therapy. Safety and tolerability were also assessed. Efficacy was evaluated in 153 of 160 enrolled patients. Overall, 146 (95.4%) achieved endoscopically confirmed clinical success. Each of the isavuconazole regimens was shown to be not inferior to fluconazole, i.e., arm A versus D, -0.5% (95% confidence interval [CI] -10.0 to 9.4), arm B versus D, 3.5% (95% CI, -5.6 to 12.7), and arm C versus D, -0.2% (95% CI, -9.8 to 9.4). The frequency of adverse events was similar in arm A (n = 22; 55%), arm B (n = 18; 45%), and arm D (n = 22; 58%), but higher in arm C (n = 29; 71%). In summary, efficacy and safety of once-daily and once-weekly isavuconazole were comparable with once-daily fluconazole in the primary treatment of uncomplicated esophageal candidiasis.

Mucosal candidiasis is frequent in immunocompromised HIV-infected highly active antiretroviral (HAART) naive patients or those who have failed therapy. Mucosal candidiasis is a marker of progressive immune deficiency. Because of the frequently marked and prompt immune reconstitution induced by HAART, there is no recommendation for primary antifungal prophylaxis of mucosal candidiasis in the HIV setting in Europe, although it has been evidenced as effective in the pre-HAART era. Fluconazole remains the first line of therapy for both oropharyngeal candidiasis and oesophageal candidiasis and should be preferred to itraconazole oral solution (or capsules when not available) due to fewer side effects. For patients who still present with fluconazole-refractory mucosal candidiasis, oral treatment with any other azole should be preferred based on precise Candida species identification and susceptibility testing results in addition to the optimization of HAART when feasible. For vaginal candidiasis, topical therapy is preferred.

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs.

Mucocutaneous candidiasis is frequently one of the first signs of human immunodeficiency virus (HIV) infection. Over 90% of patients with AIDS will develop oropharyngeal candidiasis (OPC) at some time during their illness. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole, voriconazole, posaconazole) have replaced older topical antifungals (gentian violet and nystatin) in the management of oropharyngeal candidiasis in these patients. The systemic azoles, are generally safe and effective agents in HIV-infected patients with oropharyngeal candidiasis. A constant concern in these patients is relapse, which is dependent on the degree of immunosuppression commonly seen after topical therapy, rather than with systemic azole therapy. Candida esophagitis (CE) is also an important concern since it occurs in more than 10% of patients with AIDS and can lead to a decrease in oral intake and associated weight loss. Fluconazole has become the most widely used antifungal in the management of mucosal candidiasis. However, itraconazole and posaconazole have similar clinical response rates as fluconazole and are also effective alternative agents. In patients with fluconazole-refractory mucosal candidiasis, treatment options now include itraconazole solution, voriconazole, posaconazole, and the newer echinocandins (caspofungin, micafungin, and anidulafungin).

Gastrointestinal (GI) opportunistic infections (OIs) are commonly encountered at various stages of human immunodeficiency virus (HIV) disease. In view of the suppressive nature of the virus and the direct contact with the environment, the GI tract is readily accessible and is a common site for clinical expression of HIV. The subject is presented based on information obtained by electronic searches of peer-reviewed articles in medical journals, Cochrane reviews and PubMed sources. The spectrum of GI OIs ranges from oral lesions of Candidiasis, various lesions of viral infections, hepatobiliary lesions, pancreatitis and anorectal lesions. The manifestations of the disease depend on the level of immunosuppression, as determined by the CD4 counts. The advent of highly active antiretroviral therapy has altered the pattern of presentation, resorting mainly to features of antimicrobial-associated colitis and side effects of antiretroviral drugs. The diagnosis of GI OIs in HIV/acquired immunodeficiency syndrome patients is usually straightforward. However, subtle presentations require that the physicians should have a high index of suspicion when given the setting of HIV infection.

Oral candidiasis is one of the common diseases seen in HIV/AIDS patients. It is rare if CD4+ cell counts are above 500 microl. Outbreaks are more common as the count drops to 100 microl. It may be more difficult to treat when CD4+ cell counts fall below 50 microl.

A retrospective review of 112 HIV/AIDS patients with lesions in the mouth, head, and neck seen at the oral and maxillofacial surgery units of two public hospitals in eastern Nigeria was carried out between 2000 and 2003. The focus was on oral candidiasis patients. Twenty-nine of these patients, made up of 11 males and 18 females, had oral candidiasis. To compare the action of two drugs, namely, nystatin (a topical antifungal drug) and ketoconazole (a systemic antifungal drug), we treated 15 of the patients with nystatin in the first 2 years and the remaining 14 with ketoconazole in the following 2 years.

Amongst the 15 patients treated with topical drugs, 7 (46.7%) had complete remission, 2 (13.3%) had partial response, 4 (26.7%) remained stationary, and 2 (13.3%) died. Out of the 14 cases treated with systemic drugs, 11 (78.6%) had complete remission, 2 (14.3%) had partial response, and 1 (7.1%) died.

Despite the huge advance that highly active antiretroviral therapy has represented for the prognosis of infection by human immunodeficiency virus (HIV), opportunistic infections continue to be a cause of morbidity and mortality in HIV-infected patients. This is often the case because of severe immunodepression, poor adherence to antiretroviral therapy, failure of therapy, or the fact that patients are unaware of their HIV-positive status and debut with an opportunistic infection. This article updates the guidelines on treatment of acute episodes of various opportunistic infections in HIV-infected patients, including infections due to parasites, fungi, viruses, mycobacteria, and bacteria. This edition has a new chapter on imported parasite infections as well as additional information on endemic mycoses in the chapter on fungal infections, taking into account the growing number of immigrants in our setting. Lastly, the chapter on the immune reconstitution syndrome has also been updated, providing relevant data on a phenomenon that has clinical and diagnostic repercussions in patients who start antiretroviral therapy while they are severely immunodepressed (English version available at http://www.gesida.seimc.org).

This article reviews risk factors, prevention and management of oesophageal candidiasis (OC) in the elderly. Putative risk factors for OC in the elderly include old age itself, malignant disease, antibacterial and corticosteroid use, chronic obstructive pulmonary disease, acid suppression treatment, oesophageal dysmotility and other local factors, diabetes mellitus and HIV/AIDS. We have found evidence for a risk association between OC in the elderly and malignant disease (both haematological and non-haematological), antibacterial therapy and corticosteroid (including inhaled corticosteroids) use. We also found evidence of an association between OC in the elderly and oesophageal dysmotility or HIV/AIDS, but little direct evidence of an association between diabetes or old age per se. The literature on OC in the elderly is not large. The published series evaluating OC in this age group are small in size, often do not contain controls and mostly contain only limited information about the age of the patients. Prevention of OC is mainly the avoidance of exposure to the risk factors wherever possible. Specific measures such as highly active antiretroviral therapy in AIDS, prophylactic fluconazole when receiving chemotherapy for malignancy, using spacing devices, mouth rinsing soon after inhalation of corticosteroids and avoiding the use of cortiocosteroids just before bedtime are useful. OC is often responsive to a 2- to 3-week course of oral fluconazole, but resistance may be encountered in AIDS or in the presence of uncorrected anatomical factors in the oesophagus. Itraconazole solution, voriconazole or caspofungin may be used in refractory cases. Use of amphotericin B is restricted because of its narrow therapeutic index.

Infections caused by yeasts and molds continue to be associated with high rates of morbidity and mortality in both immunocompromised and immunocompetent patients. Many antifungal drugs have been developed over the past 15 years to aid in the management of these infections. However, treatment is still not optimal, as the epidemiology of the fungal infections continues to change and the available antifungal agents have varying toxicities and drug-interaction potential. Several investigational antifungal drugs, as well as nonantifungal drugs, show promise for the management of these infections.

Fungal infections are a significant cause of HIV-related morbidity and mortality, particularly in the developing world, but also in countries with access to highly active antiretroviral therapy. New agents are essential to improve present efficacy rates, particularly in cases of drug resistance. Caspofungin is a new antifungal from the echinocandin class and is licensed for the treatment of candidal infections and as a second-line therapy for invasive aspergillosis. In this paper, the pharmacology, interaction and susceptibility data for this agent are reviewed and studies supporting the use of this agent in HIV-infected individuals are examined. Finally, evidence for the use of caspofungin for the treatment of Pneumocystis jiroveci pneumonia, an unlicensed indication, including a case series from our own unit is explored.

Gastrointestinal opportunistic infections, primarily oral and esophageal candidiasis, are common in persons infected with the human immunodeficiency virus (HIV) and contribute significantly to morbidity and mortality. Research early in the AIDS epidemic established a strong association between the presence of oral and esophageal candidiasis in patients complaining of odynophagia, demonstrated the diagnostic efficacy of a therapeutic trial with anti-fungal medicines, and defined the indications for endoscopy in HIV-infected persons with upper gastrointestinal complaints. Resulting diagnostic and treatment strategies with anti-fungal agents were very effective in preventing and treating mycotic infections of the gastrointestinal tract. Now, robust data from the United States and Europe indicate that recent advances in the development and use of highly active anti-retroviral therapy (HAART) are associated with a striking decline in the prevalence of oro-esophageal candidiasis in HIV-infected persons. In addition to developing more effective, safer antiviral agents, an HIV vaccine, and other novel approaches to combating this illness, a major challenge is to provide HAART to those without access to these life-saving drugs.

Esophageal disease is a common complication and cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Opportunistic infections are the leading cause of esophageal complaints and may be a predictor of poor long-term prognosis, presumably as a reflection of severe underlying HIV immunodeficiency. The esophagus may be the site of the first acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness in a large number of patients. Barium esophagography and upper gastrointestinal endoscopy are diagnostic modalities, commonly used to evaluate esophageal complaints in patients with AIDS. Treatment for most etiologies of esophagitis generally has a high degree of success, with a resultant improvement in quality of life. In addition to optimizing antiretroviral therapy, a thorough diagnostic assessment of every HIV-infected patient with esophageal complaints is warranted, followed by timely and appropriate treatment.

In countries where highly active antiretroviral therapy (HAART) is widely available, a decrease in the incidence of fungal infections has been observed in the last 5 years compared with countries that cannot afford this treatment. Even refractory fungal infections may be controlled when HAART is given to patients, and end-stage AIDS infections, such as aspergillosis, are now only infrequently seen. In contrast, fungal infections in certain regions, such as penicilliosis in Southeast Asia or cryptococcosis in Sub-Saharan Africa, are a growing problem. Antifungal therapy for documented infections has not changed very much during recent years; however, new drugs such as caspofungin and voriconazole may be more effective in the treatment of opportunistic fungal infections, in particular, those involving resistant organisms. Secondary antifungal prophylaxis for many opportunistic pathogens can now be temporarily or even permanently discontinued in many HIV-positive patients who have a marked improvement in immune function parameters, such as CD4(+) cell counts, after initiation of HAART. The link between effective virustatic control of HIV infection and a decreasing incidence of fungal infections has been recognised; and so, despite the availability of very effective new antifungal drugs, the cornerstone of treatment and prevention of opportunistic fungal infections in patients with HIV infection is effective antiretroviral therapy including protease inhibitors.

Candida esophagitis is a frequent infection in immunocompromised patients. This study was designed to determine its characteristics in non- human immune deficiency virus (HIV) infected patients attending a teaching hospital.

Clinical records of all patients coded by international classification of diseases 9th revision with clinical modifications' (ICD-9-CM), with candida esophagitis diagnosed by esophagogastroduodenoscopy (EGD) and histopathology over a period of 5 years were studied.

Fifty-one patients (27 males, 24 females, range 21-77 years old and mean age 52.9 years) fulfilled the criteria (0.34% of the EGD). The common predisposing factors were carcinoma (OR 3.87, CI 1.00-14.99) and diabetes mellitus (OR 4.39, CI 1.34-14.42). The frequent clinical symptoms were retrosternal discomfort, dysphagia and epigastric abdominal pain with endoscopic appearance of scattered mucosal plaques. Another endoscopic lesion was associated with candida esophagitis in 15% patients.

Carcinomas, diabetes mellitus, corticosteroid and antibiotic therapy are major risk factors for candida esophagitis in Pakistan. It is an easily managed complication that responds to treatment with nystatin.

This paper describes the workings of the workshop dedicated to oral and dental care and treatment protocols for the management of HIV-infected patients. The questions addressed were: 1) What are the current ethical issues in dental care of HIV patients, do they need to be addressed? 2) Do we need to modify the dental care we give HIV-positive patients? 3) When is it necessary to give antibiotic prophylaxis to HIV-positive patients? 4) What is the evidence for the effective treatment of oral lesions associated with HIV? 5) What is the most successful palliative treatment for KS? 6) Can we provide clinical treatment that has a scientific basis rather being trial based? 7) Is ddI + hydroxy-urea an effective African alternative to HAART? 8) What is the influence of protease inhibitors and HAART on the excretion of HIV in saliva? 9) What is the effect of anti-HIV therapy on the oral mucosa and oral health? This workshop did not fully cover the issue of ddI and hydroxy-urea as an alternative HIV therapy as this was considered to be the remit of general physicians caring for patients with HIV and AIDS rather than that of oral health care workers.

The efficacy, safety, and tolerability of voriconazole and fluconazole were compared in 391 immunocompromised patients with mycology- and biopsy-proven esophageal candidiasis. Primary efficacy analysis (256 patients) of esophageal treatment as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole. The 95% confidence interval for the difference in success rates ranged from -1.0% to 7.5%. The overall safety and tolerability of both antifungals were acceptable. Fewer patients discontinued voriconazole treatment because of insufficient clinical response (4 patients [2.0%] vs. 5 patients [2.6%]). More patients discontinued voriconazole than fluconazole treatment because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). The most frequent adverse events (23%) with voriconazole were mild, transient visual disturbances. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as fluconazole in the treatment of biopsy-proven esophageal candidiasis in immunocompromised patients.

The effect of fluconazole on the susceptibility of Candida isolates recovered from women infected with human immunodeficiency virus (HIV) was evaluated in a randomized, double-blind, placebo-controlled trial. Women with CD4(+) cell counts of < or =300 cells/mm(3) received either fluconazole (200 mg/week) or placebo as prophylaxis. The antifungal susceptibility of specimens was evaluated. One patient who received fluconazole and 2 patients assigned to placebo had Candida albicans isolates recovered that were resistant to fluconazole (MIC, > or =64 microg/mL). Eleven patients assigned fluconazole and 4 patients assigned placebo had non-albicans Candida strains (all Candida glabrata) recovered that were resistant to fluconazole. There was significant azole cross-resistance among the non-albicans Candida species isolates. Although the rate of azole resistance did not significantly increase after fluconazole prophylaxis, there was a trend toward more in vitro azole resistance in C. glabrata isolates from patients assigned fluconazole. Moreover, the majority of resistant vaginal isolates of Candida species were recovered after initiation of open-label fluconazole use.

At least 30% of patients with AIDS experience esophageal symptoms at some point during the course of HIV infection. The aim of this review is to provide a practical approach to the evaluation and therapy of esophagitis in AIDS.

An open multicentre, non-comparative study was conducted in three countries to investigate the efficacy, safety and tolerance of fluconazole suppositories in the treatment of oropharyngeal candidosis. Patients received fluconazole 100 mg day-1 in the form of suppositories or capsules. Minimum duration of total treatment was 7 days, maximum total treatment duration was 14 days, and median duration of total treatment was 9.5 (7-14) days. After having received suppository-based treatment for at least 5 days, patients could be switched to oral treatment. Eighty-two male and 19 female patients with a mean age of 43 years were enrolled in the study. The median duration of suppository treatment was 8.9 (5-14) days. Patients were evaluated clinically and mycologically at regular intervals during and at the end of treatment. Seventy-nine of 101 patients enrolled in the study were considered efficacy-evaluable. Clinical cure was achieved in 75 of 79 (95%) patients and improvement was seen in four of 79 (5%) at the end of therapy. At follow-up after 1 month, clinical cure was observed in 48 of 63 (76%) patients. The results of this study demonstrates that the fluconazole suppository formulation is effective, safe and well tolerated.

Oropharyngeal candidiasis may be the first manifestation of human immunodeficiency viral (HIV) infection, and more than 90% of patients with the acquired immunodeficiency syndrome (AIDS) develop the disease. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole), have largely replaced older topical antifungals (gentian violet, nystatin) in the management of the disease in these patients. A concern in these patients is clinical relapse, which appears to be dependent on degree of immunosuppression and is more common with clotrimazole and ketoconazole than with fluconazole or itraconazole. Candida esophagitis is also of concern, since it occurs in more than 10% of patients with AIDS. Fluconazole is an integral part of management. A cyclodextrin oral solution formulation of itraconazole has similar clinical response rates as fluconazole and is an effective alternative. In patients with fluconazole-resistant mucocutaneous candidiasis, treatment options include itraconazole and amphotericin B oral suspension and parenteral preparation.

A randomized cross-over clinical and endoscopic evaluation of 85 Ugandan patients showed that esophageal candidiasis in AIDS patients with oral candidiasis could be managed without endoscopy and biopsies. Oral lesions, especially when accompanied by esophageal symptoms, were sufficient for diagnosis. Miconazole was more effective than nystatin in treating esophageal candidiasis and could be a valid alternative to more expensive azolic drugs in developing countries.

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.

Patients with HIV infection often present with symptoms suggesting esophageal disease: these include odynophagia (pain with swallowing), dysphagia (difficulty in swallowing), and retrosternal chest pain. Esophageal symptoms rank second only to diarrhea in frequency of gastrointestinal complaints among patients with AIDS. Also, esophageal opportunistic infections have been associated with a poor outcome, the mean survival after diagnosis being less than 6 months in one study. Such short survival may be explained by the underlying immunosuppression, as well as a decrease in nutritional intake due to difficulty swallowing.

A randomized, double-blinded, placebo-controlled pharmacokinetic and safety trial was conducted to determine the effect of fluconazole on methadone disposition. Volunteers receiving methadone maintenance therapy were randomized to receive either 200 mg/day oral fluconazole (n = 13) or placebo (n = 12). After 14 days there was a 35% average increase in serum methadone area under the curve relative to baseline among patients receiving fluconazole (p = 0.0008). At the same time, mean serum methadone peak and trough concentrations increased by 27% (p = 0.0076) and 48% (p = 0.0023), respectively, and oral clearance of methadone was reduced by 24% (p = 0.0007). In contrast, the pharmacokinetics of methadone were unaltered in the placebo group. Renal clearance of methadone was not significantly affected by fluconazole or placebo therapy. Although exposed to increased concentrations of methadone, patients treated with fluconazole did not exhibit signs or symptoms of significant narcotic overdose.

To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis.

Multicentre open study.

HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more.

Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7.

Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall.

D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Pain as a symptom is common to many pathologic conditions. At its most elementary level, it is a signal from peripheral nerves with specialized receptors that there is a change in the local environment, such as pressure, pH, temperature, or some other noxious stimulus, that can be detrimental to function. Pain is particularly prevalent in patients with HIV infection. The assessment, evaluation, and treatment of pain should be an integral part of comprehensive patient care.

Fluconazole shows good penetration into the tissues and body fluids examined and a rapid equilibrium is achieved between the concentrations in the various compartments. The pharmacokinetics of fluconazole after intravenous or oral administration are proportional to the dose. This finding, together with the slow elimination of the triazole (t1/2 30 h), makes it easier to forecast the therapeutically effective dosage. Measurements of fluconazole concentration in blood can be used to predict levels in some tissues (lung, brain, gynaecological samples), body fluids (sputum, saliva, vaginal secretions) or exudates. Concentrations in cerebrospinal fluid and vitreous humour of the eye reach approximately 80% of the levels found in blood. A very high proportion of fluconazole is excreted unchanged in the urine, where concentrations of the drug are 10-20-fold higher than in blood. Whilst this pharmacokinetic profile is valuable in the treatment of fungal infections of the urinary tract, it also means that the dosage may need to be decreased in patients with renal impairment. The susceptibility of fungi to fluconazole in vitro and in vivo correlates well with the concentrations of the drug measured in various compartments of the body.

We report three cases of deep-seated and systemic Candida albicans infection in which inadequate dosages of fluconazole were used, leading to breakthrough fungaemia, candidal osteomyelitis and endocarditis. The need to modify fluconazole dosage in patients receiving continuous venovenous haemofiltration is discussed.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN

Fungal infections represent a major source of morbidity and mortality in patients with almost all types of immunodeficiencies. These infections may be nosocomial (aspergillosis) or community acquired (cryptococcosis), or both (candidiasis). Endemic mycoses such as histoplasmosis, coccidioidomycosis, and penicilliosis may infect many immunocompromised hosts in some geographic areas and thereby create major public health problems. With the wide availability of oral azoles, antifungal prophylactic strategies have been extensively developed. However, only a few well-designed studies involving strict criteria have been performed, mostly in patients with hematological malignancies or AIDS. In these situations, the best dose and duration of administration of the antifungal drug often remain to be determined. In high-risk neutropenic or bone marrow transplant patients, fluconazole is effective for the prevention of superficial and/or systemic candidal infections but is not always able to prolong overall survival and potentially selects less susceptible or resistant Candida spp. Primary prophylaxis against aspergillosis remains investigative. At present, no standard general recommendation for primary antifungal prophylaxis can be proposed for AIDS patients or transplant recipients. However, for persistently immunocompromised patients who previously experienced a noncandidal systemic fungal infection, prolonged suppressive antifungal therapy is often indicated to prevent a relapse. Better strategies for controlling immune deficiencies should also help to avoid some potentially life-threatening deep mycoses. When prescribing antifungal prophylaxis, physicians should be aware of the potential emergence of resistant strains, drug-drug interactions, and the cost. Well-designed, randomized, multicenter clinical trials in high-risk immunocompromised hosts are urgently needed to better define how to prevent severe invasive mycoses.

Although there have been dramatic strides in the therapy of human immunodeficiency virus infection over the last few years, the number of infected people world-wide is tremendous and, at least in developing countries, continues to expand. Complications which involve the gastrointestinal tract are common in these patients, because the gut is a major site for involvement by opportunistic infections and neoplasms in patients with the acquired immunodeficiency syndrome. It is important to recognize the clinical spectrum of gastrointestinal diseases, as well as the appropriate and most cost-effective diagnostic strategies, as therapies for a number of these disorders are both widely available and high effective. This review summarizes the major gastrointestinal infections which are seen in patients with the acquired immunodeficiency syndrome, and their treatment.

This article focused on the approach to oral and esophageal disorders in patients with AIDS. Most of these disorders respond to various therapeutic regimens. Some of the oral complications can be prevented with dental prophylaxis, whereas recurrent esophageal disease in some patients may require long-term suppressive therapy. As patients with AIDS live longer with lower CD4 counts, gastroenterologists need to become familiar with the approach to and management of the more common lesions of the mouth and esophagus.

The purpose of this prospective, open-label, noncomparative, multicentre study was to evaluate the efficacy and safety of fluconazole in the treatment of hospitalised patients with mycoses. A total of 587 patients with diagnosed fungal infections were enrolled. Fluconazole was given orally or intravenously in a 200 or 400 mg loading dose, followed by 100 or 200 mg once daily. The most common candidal infections were fungemia, esophageal candidiasis, bronchopulmonary candidiasis, peritonitis, oropharyngeal candidiasis, urinary tract infection and deep wound infection. Meningitis was the most common cryptococcal infection. Of the 291 evaluable patients with candidiasis, 96% (70/73) of AIDS patients and 79% (171/218) of non-AIDS patients were clinically cured or improved. Of the 36 evaluable patients with cryptococcosis, 69% (20/29) of AIDS patients and 100% (7/7) of non-AIDS patients responded clinically. The overall mycological eradication rate was 85%; eradication was similar in patients with and without AIDS. Most adverse events during fluconazole therapy were mild to moderate in severity. This investigation confirms the results of previous studies demonstrating high response rates to fluconazole therapy in AIDS and non-AIDS patients with fungal infections. Even during long-term therapy treatment-limiting adverse events were uncommon with fluconazole.

The incidence and severity of fungal infections appear to increase with progression of HIV disease. Because of the significant morbidity and mortality associated with the mycoses discussed, knowledge of the clinical syndromes, early diagnosis, and prompt institution of therapy are crucial for a favorable outcome. For disseminated or invasive fungal infections, suppressive therapy must be continued to prevent relapse.

The AIDS epidemic has led to the emergence of several disease entities which in the pre-AIDS era were rare or seemingly innocuous. Experience of treating these diseases varies. In some instances, such as Pneumocystis carinii pneumonia, there is an abundance of published literature to direct our course of action. However, for many of these newly recognised diseases our treatment experience is limited. Furthermore, in many instances, well controlled trials evaluating treatment modalities in the AIDS population are lacking. We have identified 13 disease entities (P. carinii pneumonia, toxoplasmosis, cryptococcosis, histoplasmosis, Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus, coccidioidomycosis, isosporiasis, candidosis, Kaposi's sarcoma, herpes simplex virus, and varicella zoster virus) and have reviewed the current literature with regard to their treatment.

To determine the etiologies of esophageal symptoms in human immunodeficiency virus (HIV)-infected patients failing antifungal treatment.

Between August 1, 1990 and December 31, 1994, all HIV-infected patients seen at a large inner-city hospital who had esophageal complaints despite being on antifungal therapy were prospectively evaluated for the cause of symptoms. Thus, the population studied included patients given empiric antifungal therapy for esophageal symptoms and patients who developed symptoms while on long-term antifungal therapy. Endoscopy was performed in all patients. The cause of symptoms was determined by the clinical, endoscopic, and pathologic findings, and follow-up after treatment.

Over the 53-month study period, 74 patients failing empiric antifungal therapy were identified. The majority (77%) of these patients had esophageal ulcers; 25 patients had idiopathic ulcers and 24 had cytomegalovirus. In 2 patients, Candida was present with other causes of ulcerative esophagitis. Candida esophagitis alone was diagnosed in only 3 patients. No endoscopic abnormalities were observed in 14 patients (19%). An additional 24 patients developed esophageal symptoms while receiving antifungal therapy; endoscopic findings in these patients included ulceration in 16 (67%), Candida esophagitis alone in 2, and normal in 6. Empirically treated patients in whom odynophagia was not the only symptom, those with dysphagia alone, and those with a CD4 count > 100/mm3 were less likely to have an endoscopic diagnosis.

Esophageal ulceration is the most common cause of esophageal symptoms in HIV-infected patients failing empiric antifungal therapy and those developing symptoms while receiving antifungal agents. Given these findings, endoscopy should be the test of choice for these nonresponders, rather than escalating the dose of antifungal agent, adding other empiric treatments, or performing barium esophagography.

To assess the role and the therapeutic efficacy of fluconazole and itraconazole-flucytosine association compared with placebo, in the treatment of endoscopically diagnosed esophageal candidiasis in a selected population of AIDS patients.

Double-blind, placebo-controlled study.

University Hospitals and AIDS Centers.

Eighty-five HIV-positive patients (53 men and 32 women; mean age, 28 years) at first episode of esophageal candidiasis diagnosed by endoscopy (grades I to II of Kodsi's endoscopic classification and grades I to IIa of Barbaro's clinical classification). All the patients selected for the study provided informed consent.

The patients have been double blindly randomized in 3 groups of patients in relation to pharmacologic therapy: (1) the patients of the first group (n = 30) received fluconazole (3 mg/kg daily orally) and placebo (100 mg/kg/daily orally); (2) the patients of the second group (n = 30) received itraconazole (3 mg/kg daily orally) and flucytosine (100 mg/kg daily orally); and (3) the patients of the third group (n = 25) received placebo (3 mg/kg daily orally) and placebo (100 mg/kg daily orally). After 2 weeks of treatment, the patients previously randomized to receive placebo only were double blindly randomized to receive fluconazole+placebo or itraconazole+flucytosine. To evaluate the efficacy of pharmacologic therapy, clinical and endoscopic examinations were performed at weeks 2 and 4 and at the end of follow-up (3 months).

At week 2, endoscopic cure (grade 0) was observed in 68.9% of the fluconazole+placebo group and in 72.4% of the itraconazole+flucytosine group (relative risk, 0.95; 95% confidence interval [CI], 0.68 to 1.33; p = 0.772); partial endoscopic response (grade I) was observed in 22.7% of the placebo group. Clinical cure (grade 0) was observed in 75.8% of fluconazole+placebo group and in 72.4% of itraconazole+flucytosine group (relative risk, 1.05; 95% CI, 0.77 to 1.42; p = 0.764), with a difference statistically significant for both treatments in comparison to placebo group (p < 0.001). Partial clinical response (grade I) was observed in 27.3% of the placebo group. At the end of follow-up, endoscopic cure was observed in 89.8% of the fluconazole+placebo group and in 94.8% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.83 to 1.08; p = 0.695). Clinical cure was observed in 94.8% of the fluconazole+placebo group and in 97.3% of the itraconazole+flucytosine group (relative risk, 0.97; 95% CI, 0.89 to 1.07; p = 0.981).

The results of this study have demonstrated that both fluconazole and itraconazole+flucytosine association are efficacious in short-term treatment of esophageal candidiasis in AIDS patients with a statistically significant difference in comparison to placebo. Both therapeutic regimens demonstrated a good therapeutic efficacy, without statistically significant difference, between them, in the rate of endoscopic and clinical cure. Itraconazole+flucytosine association may represent an alternative therapeutic regimen for patients with fluconazole-resistant Candida esophagitis.

Gastrointestinal disease is a common problem in the setting of HIV-1 infection. As patients live longer and other opportunistic pathogens are suppressed, these problems are becoming even more important in the quality of life.

Although Candida esophagitis is one of the most common opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), there has been no systematic study of the endoscopic and pathologic manifestations of this disease. During a 53-month period, 141 patients with AIDS and Candida esophagitis were studied. All patients had the severity of esophagitis graded prospectively and esophageal mucosal biopsies performed. Tissue biopsies were evaluated for histologic evidence of ulceration, extent of candidiasis, and presence of viral cytopathic effect. Follow-up was obtained. There appeared to be a uniform endoscopic appearance; with increasing severity, the scattered mucosal plaques coalesced, resulting in circumferential disease and luminal impingement. The pathologic pattern of Candida esophagitis was homogenous. Plaque material was composed primarily of desquamated superficial hyperplastic hyperkeratotic squamous epithelium and inflammatory cells, with infiltration by fungal elements and bacteria consistent with superinfection. Although endoscopic and histopathologic ulcer was commonly seen in these patients (32%), only four patients had ulcer believed secondary to Candida esophagitis alone. In conclusion, in patients with AIDS, Candida esophagitis is a superficial mucosal infection resulting in characteristic endoscopic and histopathologic patterns.