Harry A. Gallis

A Comparison of Amphotericin B Alone and Combined with Flucytosine in the Treatment of Cryptoccal Meningitis

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis

BACKGROUND Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Prospective Multicenter Surveillance Study of Funguria in Hospitalized Patients

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.

Fungal Peritonitis in Patients on Continuous Ambulatory Peritoneal Dialysis

Fungal peritonitis is a rare complication in patients on continuous ambulatory peritoneal dialysis. We report five recent cases and their management. The fungi isolated were Candida albicans, C. parapsilosis, Exophiala jeanselmei, Drechslera spicifera, and a Fusarium species. Chemotherapy was attempted with various regimens including oral ketoconazole, intravenous or intraperitoneal amphotericin B, and oral flucytosine. Pharmacokinetic studies were done in two patients receiving treatment with one of these drugs. Three patients were cured of their fungal infection. Three patients whose Tenckhoff catheters were left in situ died, whereas two patients whose catheters were removed survived. Our experience suggests that removal of the peritoneal catheter should be considered once the diagnosis of fungal peritonitis is established.

Single and multiple pyogenic liver abscesses. Natural history, diagnosis and treatment, with emphasis on percutaneous drainage.

The presenting features, modes of treatment and clinical course were reviewed for 55 patients with pyogenic liver abscess, seen at Duke University Medical Center over a 15-year period. Thirty-three patients had a solitary abscess and 22 had multiple abscesses. Most patients were between the ages of 40 and 60 years. Males predominated, 2.4:1. Major underlying conditions included biliary tract disease, malignancy and colonic disease. Eight patients, each with a solitary abscess, had no identifiable underlying condition. Symptoms and signs were nonspecific: fever, chills, focal abdominal tenderness and hepatomegaly were common. A raised serum alkaline phosphatase level was the most consistent abnormal laboratory finding. CT with contrast enhancement, radioisotope scanning and ultrasonography all accurately defined solitary hepatic abscesses. However, CT scan was more successful than other imaging techniques in detecting multiple abscesses. In seven patients the diagnosis was made only at laparotomy. Overall, a diagnosis of liver abscess was made in 50 living patients (91%). Microorganisms were recovered from pus and/or blood cultures of 44 patients (80%). Most common were enteric gram-negative facultative rods, anaerobic gram-negative rods, and microaerophilic streptococci. Single abscesses were more likely than multiple abscesses to contain more than one organism. All patients received antibiotics; the choice of antibiotic does not appear to be critical provided the regimen has a broad spectrum including activity against anaerobes. Surgical or percutaneous drainage was successful when attempted in all patients with a single abscess, but the outcome was less favorable in those with multiple abscesses. Percutaneous drainage is currently replacing open operative drainage as the method of choice. Overall mortality in patients with single abscesses was 15% (5/33) and in those with multiple abscesses 41% (9/22).

Treatment of Systemic Mycoses with Ketoconazole: Emphasis on Toxicity and Clinical Response in 52 Patients: National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.

Observations on Spiraling Empiricism: Its Causes, Allure, and Perils, with Particular Reference to Antibiotic Therapy

Spiralicy empiricism describes the inappropriate treatment, or the unjustifiable escalation of treatment, of suspected but un documented infections diseases

Pharmacokinetics and safety of levofloxacin in patients with human immunodeficiency virus infection.

Levofloxacin, the bacteriologically active isomer of ofloxacin, has microbiologic activity against many pathogens common in human immunodeficiency virus (HIV)-infected patients, including Mycoplasma species which may be cofactors in the progression of HIV disease. The purpose of this phase I, double-blind, randomized (1:1), placebo-controlled trial was to evaluate the pharmacokinetics and safety of levofloxacin hemihydrate in 10 asymptomatic HIV-infected males. Plasma concentrations by chiral high-performance liquid chromatography (HPLC) were evaluated for 48 h after a single 350-mg oral dose, at morning predose during the multiple-dosing phase, and for 72 h at steady state after a week of 350 mg every 8 h orally. Mean +/- standard deviation levofloxacin pharmacokinetic parameters (by noncompartmental moment method) after multiple dosing were as follows: area under the concentration-time curve, 31.24 +/- 5.60 mg.h/liter; apparent total body clearance, 11.18 +/- 1.76 liters/h; renal clearance, 8.63 +/- 2.82 liters/h; steady-state volume of distribution, 104.10 +/- 12.48 liters; and effective half-life, 6.50 +/- 0.51 h. Single-dose parameters were not significantly different from the multiple-dose parameters, with the exception of peak concentrations in plasma, which were 4.79 +/- 1.00 and 6.92 +/- 1.56 mg/liter for single- and multiple-dose data, respectively. Essentially identical parameter values were obtained from curve-fitting analysis when the entire 13-day plasma concentration profiles of the subjects were analyzed simultaneously by a two-compartmental distribution model. Levofloxacin pharmacokinetics in HIV-infected patients remained linear upon multiple dosing. The dosing regimen studied provides levels in plasma and urine well above those found to be effective in vitro against pathogens common in HIV-infected patients. Levofloxacin was well- tolerated in this group of asymptomatic HIV-infected males: there were no statistically significant differences in adverse effects in the two groups (P = 0.22). Use of placebo control helped to differentiate disease-related adverse effects from those related to the study drug.

OFLOXACIN, ITS PHARMACOLOGY, PHARMACOKINETICS AND POTENTIAL FOR CLINICAL APPLICATION

Ofloxacin is a 4‐quinolone antibiotic with rapid bactericidal activity against a wide variety of organisms. Its proposed mechanism of activity is interference with DNA gyrase, an enzyme essential for the replication of bacterial DNA. In vitro activity of ofloxacin includes a variety of aerobic and anaerobic bacteria. Enteric gram‐negative bacilli and cocci are generally sensitive to ofloxacin; nonaeruginosa strains of Pseudomonas are less so. Numerous bacterial pathogens of the gastrointestinal tract are also sensitive to the drug. Although its MIC values for gram‐positive aerobic organisms are generally higher, ofloxacins bactericidal activity against these organisms is considered by some to be adequate, and superior to that of most other fluoroquinolones. Ofloxacin is well absorbed after oral administration. Wide tissue and body fluid distribution is demonstrated. Urinary excretion is thought to be the primary route of elimination, with 80% of the dose recovered in the urine within 24 hours. The serum half‐life ranges between 2.9 and 9 hours in a dose‐dependent manner. Only modest accumulation is reported after multiple‐dose administration. Clinical trials using daily dosages of 100–800 mg/day in single or divided doses have been reported in the treatment of a variety of conditions such as skin and soft tissue infections, tonsillitis, sexually transmitted disease, respiratory tract infections, cystitis, and complicated and uncomplicated urinary tract infections. English reports of these trials, however, are generally limited to abstract form, making evaluation of trial design difficult. Side effects most frequently encountered include gastrointestinal and central nervous system reactions.

Phycomycosis of the vulva

A necrotic ulcerative lesion of the vulva in a patient with diabetic ketoacidosis initially resembled necrotizing fasciitis. Debridement and histologic examination led to a diagnosis of phycomycosis. The condition responded to surgical debridement without antifungal therapy.