Richard M. Tucker

Treatment of invasive aspergillosis with itraconazole

PURPOSE Invasive aspergillosis in the immunocompromised host is one of the most difficult therapeutic problems. Itraconazole, a new oral triazole, is inhibitory as well as fungicidal against Aspergillus species in vitro. It is active against Aspergillus infections in animal models. We present our experience with itraconazole therapy of 21 patients with aspergillosis. PATIENTS AND METHODS Eighteen of the 21 patients received 400 mg of itraconazole orally per day; the other three received 100 to 200 mg daily. Serum concentrations of itraconazole were measured and susceptibility testing was performed according to previously described methods. RESULTS Of 15 evaluable patients, responses were produced in 12. Four of five with invasive pulmonary disease, two of two with skeletal disease, one of two with pleural disease, one of one with pericardial, sinus, mastoid, or hepatosplenic aspergillosis, and one of one with onychomycosis responded. One patient with carotid artery disease did not show a response, although results of cultures were negative at autopsy. One responder with joint disease had a possible relapse three months after completing 12 months of therapy. Ten of these patients were immunocompromised (including four with neutropenia and two renal transplant recipients) and eight of these responded. Side effects with itraconazole, in contrast to previously available therapy, were rare. CONCLUSION This experience suggests itraconazole may be an important advance in the therapy of aspergillosis.

Itraconazole treatment of phaeohyphomycosis.

Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these, 17 were assessable for clinical outcome. Of these, two had received no prior therapy, five had failed amphotericin B therapy, four had failed ketoconazole or miconazole therapy, and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients, soft tissue in nine, sinuses in eight, bone in five, joints in two, and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment, one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis, including patients refractory to other antifungal agents.

A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/sulfamethoxazole for the treatment of acute urinary tract infection in women

PURPOSE Bladder infections are very common in otherwise healthy women, and short-course antimicrobial treatment appears effective for many episodes of cystitis. This study reports the results of short-course ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole therapy. PATIENTS AND METHODS We performed a randomized, double-blind study of the efficacy and safety of a 3-day course of oral ciprofloxacin 100 mg twice daily, ofloxacin 200 mg twice daily, or trimethoprim/sulfamethoxazole 160/800 mg twice daily in women with acute, uncomplicated, symptomatic lower urinary tract infection. RESULTS A total of 866 patients were enrolled, of whom 688 (79%) were evaluated for the efficacy of treatment (229 treated with ciprofloxacin, 228 treated with trimethoprim/sulfamethoxazole, and 231 treated with ofloxacin). The most frequent reason for exclusion was the failure to identify a pretreatment pathogen. The most commonly isolated pathogen was Escherichia coli (81%). Eradication of the pretreatment pathogen at the end of therapy occurred in 94% of ciprofloxacin, 93% of trimethoprim/sulfamethoxazole, and 97% of ofloxacin-treated patients. At follow-up evaluation at 4 to 6 weeks, recurrence rates (relapse or reinfection) were 11% in the ciprofloxacin, 16% in the trimethoprim/sulfamethoxazole, and 13% in the ofloxacin treatment group. Clinical success at the end of therapy was 93% in the ciprofloxacin, 95% in the trimethoprim/sulfamethoxazole, and 96% in the ofloxacin treatment groups. The frequency of all adverse events was 31% for ciprofloxacin, 41% for trimethoprim/sulfamethoxazole, and 39% for ofloxacin-treated patients (P = 0.03). Premature discontinuation of study drug due to an adverse event was more common in trimethoprim/sulfamethoxazole-treated patients (n = 9) compared with those given ciprofloxacin (n = 2) or ofloxacin (n = 1; P = 0.02). CONCLUSION Ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole had similar efficacy when given for 3 days to treat acute, symptomatic, uncomplicated lower urinary tract infection in women.

Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis.

The pharmacokinetics of fluconazole, a new oral azole, were evaluated in cerebrospinal fluid and sera of eight patients with coccidioidal meningitis. At a dose of 50 mg/day, peak concentrations of 2.5 to 3.5 and 2.0 to 2.3 micrograms/ml occurred at 2 to 6 and 4 to 8 h in serum and cerebrospinal fluid, respectively. At 100 mg/day, peak concentrations of 4.5 to 8.0 and 3.4 to 6.2 micrograms/ml occurred at 2 to 4 and 4 to 12 h, respectively. The mean ratios of the concentration in cerebrospinal fluid to that in serum were 73.8% at 50 mg/day and 88.7% at 100 mg/day. Results suggested that there was a prolonged half-life in both cerebrospinal fluid and serum and that it was slightly longer in the former. Minimal toxicity was noted in 34 patient months of therapy (12 months on 50 mg daily; 22 months on 100 mg daily). After a mean of 4.5 months of therapy, five patients responded to therapy and three were unevaluable. The penetration of fluconazole into cerebrospinal fluid was substantial, toxicity was minimal, and early clinical experience was encouraging. Fluconazole holds promise as the sole or adjunctive therapy for fungal meningitis.

Cyclosporine and Itraconazole Interaction in Heart and Lung Transplant Recipients

Excerpt Itraconazole is a new triazole antifungal (1-3). The infrequency of serious toxicity makes it particularly appropriate in patients receiving cyclosporine therapy, in whom nephrotoxicity is ...

Itraconazole Therapy for Chronic Coccidioidal Meningitis

STUDY OBJECTIVE To assess the efficacy of orally administered itraconazole in the treatment of coccidioidal meningitis. DESIGN Prospective, nonrandomized open trial. SETTING Multicenter trial at an urban county hospital, a university referral center, and referring institutions. PATIENTS Ten patients with culture or serologic evidence of coccidioidal meningitis refractory to standard therapy. Patients receiving other systemic antifungal therapy were excluded. INTERVENTION Itraconazole was administered orally at doses of 300 to 400 mg/d for a median duration of 10 months. Disease activity and drug efficacy were evaluated at initiation of therapy and at the most recent follow-up using a standardized scoring system. MEASUREMENTS AND MAIN RESULTS Eight of ten patients are evaluable. Of five patients receiving itraconazole as sole therapy, four have responded. All three patients receiving intrathecal amphotericin B have had that therapy discontinued and have no evidence of active disease in the absence of intrathecal therapy. Toxicity has been minimal; one patient had mild nausea. CONCLUSIONS Itraconazole shows impressive activity in this series of patients with refractory coccidioidal meningitis. Itraconazole in this and other fungal meningitides should be evaluated further.

Itraconazole therapy for nonmeningeal coccidioidomycosis: Clinical and laboratory observations

Itraconazole, a new oral triazole antifungal agent, was administered in 75 courses to patients with chronic coccidioidomycosis at dosages of 50 to 400 mg/day for a median duration of 10 months. Assessment of efficacy was made with a standardized scoring system. Responses were seen in 42 of 58 assessable courses (72%). Nonresponse occurred exclusively in patients who had failed previous therapy and was most common in pulmonary disease. Toxicity was minimal at the doses studied. Pharmacokinetic analysis of itraconazole in serum at steady state showed negligible circadian variation; differences in serum concentrations among patients were large. Clinical isolates of Coccidioides immitis showed uniform in vitro susceptibility to itraconazole. Itraconazole shows impressive activity in this series of patients with refractory coccidioidomycosis. Further evaluation of itraconazole in this and in other systemic mycoses is in order.

Itraconazole in opportunistic mycoses: Cryptococcosis and aspergillosis

Striking results were obtained with oral itraconazole therapy in two opportunistic mycoses. Of 28 patients with cryptococcal meningitis, 18 achieved complete responses, including 16 of 24 patients with acquired immunodeficiency syndrome. Other manifestations of cryptococcosis were similarly responsive. In aspergillosis 12 of 15 patients responded, including 8 of 10 immunocompromised hosts. These patients included those with invasive pulmonary disease (4/5), skeletal disease (2/2), pleural disease (1/2), and pericardial, sinus, mastoid, hepatosplenic, or nail disease (1/1). These results with itraconazole compare favorably to conventional (parenteral) therapy, and toxicity was minimal. This suggests that comparative trials are now in order.

Oral Itraconazole Therapy of Cryptococcal Meningitis and Cryptococcosis in Patients with AIDS

We studied the efficacy of oral itraconazole in 57 AIDS patients with cryptococcosis. Diagnoses included cryptococcal meningitis (48 patients), cryptococcemia (28 patients), cryptococcuria (16 patients), pulmonary cryptococcosis (12 patients), and 2 patients who were symptomatic, antigen positive and culture negative. Patients received itraconazole 200 mg b.i.d. orally given as sole therapy in 55 of 57 (96%); five patients with low serum concentrations received 200 mg t.i.d. Therapy was monitored by clinical and radiological response, culture and cryptococcal antigen testing. Twenty three of 36 (64%) evaluable patients with cryptococcal meningitis had complete responses (clinical resolution and negative cultures), 8 (22%) a partial response and 5 (14%) failed therapy. In those not previously treated, only 2 of 29 (7%) failed therapy. Meningitis recrudesced on therapy in 13 of 31 (42%) responding patients; the median time to recrudescence in these 13 patients was 4 months after starting itraconazole. Cryptococcemia was abolished in 17 of 19 (89%) evaluable patients together with clinical resolution. Among the 9 evaluable patients with pulmonary cryptococcosis, 8 have responded to therapy (89%). Cryptococcuria was abolished in 4 of 10 (40%) evaluable patients. Among the whole group of 57 patients, relapse occurred in 4 of 7 (57%) patients discontinuing therapy. Prior or concurrent therapy with rifampin (for mycobacterial disease) was associated with one patient failing therapy and another having to be withdrawn with no response at eight days. Our response rates compare favorably to amphotericin B therapy with or without flucytosine. Eighty-five of 96 (91%) isolates of C. neoformans were susceptible in vitro to itraconazole (MIC≤3.13 mcg/ml), 6 were borderline (MIC 6.25 mcg/ml) and 3 were resistant (≥12.5 mcg/ml). Oral itraconazole is promising for the primary or salvage therapy of cryptococcal meningitis and other forms of cryptococcosis in patients with AIDS.

Hyphal forms in the central nervous system of patients with coccidioidomycosis.

Coccidioides immitis is a dimorphic fungus that grows as a filamentous mold in soil and as a spherule at human body temperature. The hyphal or soil form is found rarely in human tissue. We report 5 cases of coccidioidomycosis in which hyphae were found in brain tissue or spinal fluid. The presence of central nervous system plastic devices appears to be associated with morphological reversion to the saprophytic form. This reversion has implications for diagnosis and therapy and may increase the risk of obstruction of the device(s).