Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial

OBJECTIVE: To compare the efficacy of fluconazole with amphotericin B plus flucytosine in the treatment of cryptococcal meningitis. DESIGN: Patients were randomly assigned to oral fluconazole, 400 mg/d, for 10 weeks or to amphotericin B, 0.7 mg/kg body weight daily for 1 week, then three times weekly for 9 weeks combined with flucytosine, 150 mg/kg d, in four divided doses. SETTING: Los Angeles County-University of Southern California Medical Center. PATIENTS: Between 15 February and 7 December 1988, 42 patients had evidence of their first episode of cryptococcal meningitis, of whom 21 participated in the trial. All patients enrolled were men with the acquired immunodeficiency syndrome (AIDS) except one woman who was receiving prednisone therapy and was excluded from the final analysis. RESULTS: Of 14 patients with AIDS assigned to fluconazole, 8 (57%; 95% CI, 29% to 82%) failed; none of the 6 patients with AIDS failed who were assigned to amphotericin B plus flucytosine therapy (0%; CI, 0% to 46%) (Fisher exact test, P = 0.04). The mean duration of positive cerebrospinal fluid cultures was 40.6 +/- 5.4 days in patients receiving fluconazole and 15.6 +/- 6.6 days in patients receiving amphotericin B plus flucytosine (Mann-Whitney test, P = 0.02). Overall, 4 patients assigned to fluconazole therapy died whereas no patient assigned to amphotericin B plus flucytosine therapy died (Fisher exact test, P = 0.27). CONCLUSION: Amphotericin B used in combination with flucytosine has superior mycologic and clinical efficacy compared with fluconazole for the treatment of cryptococcal meningitis in patients with AIDS.     

Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: absence of significant pulmonary toxicity

One hundred and ninety-five series of granulocyte transfusions in 144 patients were evaluated with respect to possible severe pulmonary toxicity from concomitant administration of granulocytes and amphotericin B. Dyspnea as a side effect of granulocyte transfusion was equally common among patients receiving amphotericin B and those in a matched control group not receiving amphotericin B. Granulocyte transfusions and amphotericin B were given simultaneously in 35 transfusion series, involving 32 patients. Respiratory deterioration, defined as the appearance of new pulmonary infiltrates on chest x-ray, occurred in 11 of these 35 episodes. Patients developing respiratory deterioration were similar to those not developing respiratory deterioration in age, diagnosis, disease status, duration of concomitant therapy, and outcome, but more often had positive fungal cultures as an indication for treatment (91% versus 58%; p = 0.1). In 8 patients, the episodes of respiratory deterioration were readily explained by congestive heart failure, by simultaneous bacteremia or fungemia, or by fungal pneumonia discovered at autopsy. One patient had a leukoagglutinin reaction (responsive to steroids) and the other 2 had unexplained, but reversible respiratory deterioration. We concluded that concomitant administration of granulocyte transfusions and amphotericin B is not associated with unexpected or rapidly fatal pulmonary toxicity and when appropriate, can be safely accomplished.     

Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study Group.

BACKGROUND: Visceral leishmaniasis is common in patients with HIV infection living in endemic areas, but the most effective and safe treatment remains unknown. OBJECTIVE: To compare the efficacy and safety of meglumine antimoniate versus amphotericin B in HIV-infected patients with first episodes of visceral leishmaniasis (VL). DESIGN: An open, multicentre, prospective and randomized trial. SETTING: Twelve tertiary hospitals. PATIENTS: Eighty-nine consecutive HIV-infected patients diagnosed with VL. Patients were randomly assigned to treatment with either meglumine antimoniate (20 mg pentavalent antimony per kilogram of body weight per day) or amphotericin B (0.7 mg/kg per day) both for 28 days. Treatment was considered successful if a bone marrow aspirate performed 1 month after the end of therapy did not detect parasites. Relapse was defined as the reappearance of parasites after an initial cure. RESULTS: An initial cure was attained in 29 of 44 patients (65.9%) randomly assigned to treatment with meglumine antimoniate and 28 of 45 (62.2%) randomly assigned to treatment with amphotericin B. The incidence of moderate to severe adverse events was similar in both groups. The patients treated with meglumine antimoniate had higher incidences of cardiotoxicity (14 versus 0%, P = 0.02) and chemical pancreatitis (30 versus 0%, P < 0.01). However, in the amphotericin B group, nephrotoxicity was more frequent (36 versus 5%, P < 0.01). There was no difference in survival or relapse-free interval according to the allocated group of therapy. CONCLUSION: Treatment of VL with meglumine antimoniate or amphotericin B was shown to have similar efficacy and toxicity rates in Spanish HIV-infected patients. The differences in the toxicity patterns could be useful in choosing one of these agents as first-line treatment.     

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.     

Ciprofloxacin plus piperacillin is an equally effective regimen for empiric therapy in febrile neutropenic patients compared with standard therapy

The purpose of this study was to test the comparative efficacy and toxicity of empiric gentamicin and ciprofloxacin, in combination with piperacillin, in febrile patients with treatment-induced neutropenia. Fifty patients were prospectively randomized to receive piperacillin plus gentamicin (PG), and 46 were randomized to receive piperacillin plus ciprofloxacin (PC). The groups were similar in age, sex, diagnosis, duration of neutropenia, and incidence of positive cultures. The two antibiotic regimens were associated with comparable rates of defervescence in the patients with Gram-positive bacteremia. In the patients with Gram-negative bacteremia and those with negative cultures, however, defervescence was more prompt in the PC group. In particular, 27% of the culture-negative patients on PC, compared to only 5% of those on PG, defervesced within 72 hr (P = 0.015). Because of the more prompt defervescence in the PC group, amphotericin B was used less frequently; 78% of the patients on PG compared with only 56% of those on PC were started on amphotericin B (P J Biomed Mater Res, 41, = 0.025). PC is an effective alternative to the more traditional PG for treatment of febrile neutropenic hosts who have not been given prophylactic quinolones. More important, PC appears to hasten defervescence compared with PG, especially in culture-negative patients and those with Gram-negative bacteremia, and may decrease the necessity of additional antimicrobial agents such as amphotericin B. 1998. Am. J. Hematol. 58: 293–297, 1998. © 1998 Wiley-Liss, Inc.     

A study for candidemia during the six year period from 1993 to 1999 in St. Luke's International Hospital]

There were 71 patients with candidemia in our hospital from November 1, 1993 to October 31, 1999. We investigated the 59 patients from isolated species, route of infection, underlying disorders, risk factors, complications, treatment and prognosis. Candida albicans was the most commonly isolated species (52%), followed by Candida tropicalis (11%). Eighty eight percent of the patients developed candidemia from central venous catheter related infections. The risk factors to candidemia included keeping the catheter in place for more than 5 days, gastrointestinal tract malignancies, postoperative state of gastrointestinal tract surgery, administration of broad-spectrum or combination antibiotics for more than 5 days, and under corticosteroid therapy. About half of the patients (47%) had complications, including endophthalmitis (19 patients, 32%), septic shock (12 patients, 20%). Mortality rate associated with candidemia was 46%. Mortality rate was lower in 20 patients who were treated with amphotericin B (40%) than in 34 patients treated with only fluconazole (50%), but it was not statistically significant. In order to make an early diagnosis of candidemia, taking blood cultures and ophthalmologic examinations are essential, especially for patients who have those risk factors to candidemia mentioned above. If the patient was suspected of having catheter related infection, the catheter should be removed quickly and the catheter tip should be cultured. Once candidemia is found, ophthalmologic examination and systemic antifungal therapy are needed. Antifungal therapy with Amphotericin B should be used for patients with severe candidemia or with candidemia of non-albicans Candida species.     

Short-Course Treatment Regimen of Indian Visceral Leishmaniasis with an Indian Liposomal Amphotericin B Preparation (Fungisome?)

India bears the burden of about half of global visceral leishmaniasis (VL) cases with emerging problems of stibanate resistance. Liposomal preparations have improved treatment outcome through shorter duration of therapy and lower toxicity compared with conventional amphotericin B. We report the efficacy of two short-course regimens of an Indian preparation of liposomal amphotericin B (Fungisome™) for VL caused by Leishmania donovani in India. An open-label, randomized, single-center comparative study was undertaken from 2008 to 2011, involving 120 treatment naive non–human immunodeficiency virus VL patients randomly allocated to two groups. Fungisome™ was given, in groups A (N = 60), 5 mg/kg daily for 2 days and B (N = 60), 7.5 mg/kg daily for 2 days, as intravenous infusion. Initial cure rate was 100% in both the groups after 1 month posttreatment. At 6 months after completion of treatment, definitive cure rate was group A 90% (54/60, 95% confidence interval (CI): 80.55–95.72%); group B: 100% (95% CI: 95.92–100%); (P = 0.027). No serious adverse events occurred in either group. The short-course, 2-day regimen of 15 mg/kg Fungisome™ infusion is easy to administer, effective, and safe for treatment of VL caused by L. donovani in India.     

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.     

Candida tropicalis fungemia in a tertiary care hospital

Candida tropicalis is a frequent cause of fungemia in hospitals in Latin America. Candida albicans (33%) was the most frequently isolated species, followed by Candida parapsilosis (27%), and Candida tropicalis (24%) in tertiary care hospital in Brazil. We identified and retrospectively reviewed 27 cases of C. tropicalis fungemia that occurred at Hospital de Clinicas de Porto Alegre from 1996 to 1999. The mean age of the patients was 32 years (range 6 months to 88 years). Eight patients (29.6%) had hematological malignancy, and four (14.8%) had solid tumors. All the patients were taking broad-spectrum antibiotics, including vancomycin for at least 7 days. Antibiotics were given through a central venous catheter for the majority of the patients (77.7%). Relevant risk factors for candidemia in our patients included neutropenia (59.2%), and use of corticosteroids (37.0%) or cytotoxic drugs (40.7%). The onset of fever was the most frequent clinical manifestation (92.5%) of fungemia. Most of the patients (81.4%) were treated with amphotericin B or fluconazole. Overall mortality was 48.1%, and 7 (53.4%) of 13 deaths occurred within 10 days of the detection of candidemia. Results of the in vitro susceptibility testing of nine isolates of C. tropicalis from seven patients did not show resistance to fluconazole and amphotericin B.C. tropicalis presents as an important cause of fungemia in oncological and nononcological patients with central venous catheters taking broad-spectrum antibiotics. Although there was no evidence of resistance of C. tropicalis to amphotericin B and fluconazole, patients treated with antifungal agents presented with a high mortality rate in the hospital setting.     

Treatment of leishmaniasis in HIV-positive patients

Although, in southern Europe, there has been considerable experience in the treatment of visceral leishmaniasis (VL) in HIV-positive patients, the optimal therapy has yet to be established. Pentavalent antimony salts, free amphotericin B deoxycholate (ABD) and lipidic formulations of amphotericin B are the drugs most commonly used. Treatment with pentavalent antimonials requires daily injections for 28 days, is not well tolerated and leads to initial clinical cure in only 66% of the co-infected cases. Free ABD has to be given, intravenously, for just as long, has significant toxicity and leads to initial clinical cure in even fewer cases (62%). In a prospective, comparative trial, treatment of co-infected cases with a pentavalent antimonial was found to have similar efficacy and toxicity to treatment with free ABD. The duration of treatment and the associated toxicity may both be reduced by the use of lipidic formulations of amphotericin B. Anecdotal evidence and the results of non-randomized trials indicate that treatment with liposomal amphotericin B is highly effective. In a comparative trial, amphotericin B lipid complex was found to be not only as effective as a pentavalent antimonial but also better tolerated. At the moment, however, such lipidic formulations have only been tested against VL/HIV cases in Europe, not elsewhere in the world, and they remain very expensive. However successful the treatment in terms of initial clinical cure, almost all VL/HIV cases develop VL relapses. Although the data available on secondary prophylaxis are limited and often inconclusive, it appears that regular treatment with a pentavalent antimonial drug, liposomal amphothericin B or amphotericin B lipid complex can reduce the incidence of leishmanial relapses in HIV-positive patients with VL. The development of new regimens, use of new oral drugs (such as miltefosine) and the development of new antileishmanial drugs could all improve the treatment of HIV-related VL in the future.     

Effects of nosocomial candidemia on outcomes of critically ill patients

PURPOSE: To determine whether nosocomial candidemia is associated with increased mortality in intensive care unit (ICU) patients. SUBJECTS AND METHODS: We performed a retrospective (1992 to 2000) cohort study of 73 ICU patients with candidemia and 146 matched controls. Controls were matched based on disease severity as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score (+/- 1 point), diagnostic category, and length of ICU stay before onset of candidemia. RESULTS: In comparison with the control group, patients with candidemia developed more acute respiratory failure (97% [n = 71] vs. 88% [n = 129], P = 0.03) during their ICU stay. They were mechanically ventilated for a longer period (29 +/- 26 days vs. 19 +/- 19 days, P<0.01) and had a longer stay in the ICU (36 +/- 33 days vs. 25 +/- 23 days, P = 0.02) as well as in the hospital (77 +/- 81 days vs. 64 +/- 69 days, P = 0.04). There was no difference in in-hospital mortality between the groups (48% [n = 35] vs. 43% [n = 62], P = 0.44), a difference of 5% (95% confidence interval [CI]: -8% to 19%). In a multivariate analysis, older age (hazard ratio [HR] = 1.13 per 10 years; 95% CI: 1.04 to 1.23; P = 0.004), acute renal failure (HR = 1.4; 95% CI: 1.1 to 2.0; P = 0.02), and unfavorable APACHE II scores (HR = 1.10 per 5 points; 95% CI: 1.00 to 1.20; P = 0.05) were independent predictors of mortality. Candidemia was not associated with mortality in a model that adjusted for these factors (HR = 0.9; 95% CI: 0.7 to 1.2; P = 0.53). CONCLUSION: Nosocomial candidemia does not adversely affect the outcome in ICU patients in whom mortality is attributable to age, the severity of underlying disease, and acute illness.     

Retrospective study of candidemia in patients with hematological malignancies. Clinical features, risk factors and outcome of 76 episodes.

A retrospective study of 76 episodes of candidemia in 73 patients with underlying hematological malignancy, from 1988 until 1997, has been conducted to evaluate the clinical characteristics and to ascertain the variables related to the onset and the outcome of candidemia. The most frequent malignancy was acute myeloid leukemia (29 episodes). Candidemia developed mainly during aplasia in patients refractory to chemotherapy (42%). In 65 episodes (86%) the patients were neutropenic (ANC <1 x 10(9)/l) before the candidemia diagnosis for a median time of 13 d, and in 53 episodes (70%) at microbiological diagnosis of candidemia ANC was <1 x 10(9)/l. Candida albicans was the most frequently isolated etiologic agent (31 episodes), but C. non-albicans species sustained the majority of candidemia. Seventeen candidemias developed during azoles prophylaxis. One month after the diagnosis of candidemia, 26 patients died. In 19 cases, death was attributable to candidemia. The case-control study demonstrated, at univariate analysis, that the colonization with Candida. spp. (p=0.004), antimycotic prophylaxis (p=0.01), presence of central venous catheter (p=0.01), neutropenia (p=0.002), and the use of glycopeptide (p=0.0001) increased the risk of candidemia. Using multivariate regression analysis only colonization with Candida spp. and the previous therapy with glycopeptide were associated with a significantly increased risk. Acute mortality, expressed by a cumulative probability of survival at 30 d from diagnosis of candidemia, was 0.67 (95% C.I. 0.55-0.77) and was significantly reduced in patients with neutrophils <1 x 10(9)/l when compared to those with neutrophils >1 x 10(9)/l (p at Mantel-Cox=0.029). Overall cumulative probability of survival at 1 yr was 0.38 (95% C.I. 0.27-0.49) and only the treatment with Amfotericin B significantly reduced the risk of death.     

A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia

PURPOSE: Several studies have documented the efficacy of amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia. Amphotericin, however, is a toxic drug. Fluconazole has broad-spectrum antifungal activity with an excellent safety profile. Although prophylactic use of fluconazole is widespread, its efficacy as an empiric antifungal agent has not been extensively investigated.PATIENTS AND METHODS: We randomly assigned 106 patients with absolute neutropenia (≤500 cells μL) and persistent fever of undetermined origin (>38°C) despite 1 week of broad-spectrum antibiotic therapy to receive either fluconazole 400 mg orally daily or amphotericin B 0.5 mg/kg/day. Patients with obvious invasive fungal infections were excluded, as were those with abnormal renal or hepatic function. Success was defined as defervescence with the initially assigned antifungal regimen without development of clinically evident invasive fungal infection.RESULTS: Six patients were excluded from the analysis, mostly because they did not have severe neutropenia. Forty-eight patients received amphotericin B, and 52 received fluconazole. Baseline clinical characteristics and laboratory parameters as well as duration of neutropenia (7.7 versus 6.9 days), duration of fever (7.8 versus 8.1 days), and duration of hospitalization (10.4 versus 8.3 days) were similar between those receiving amphotericin and fluconazole. Treatment success rates and mortality rates were similar in the two groups: 22 (46%) patients in the amphotericin group and 29 (56%) patients in the fluconazole group responded successfully to therapy (P = 0.3), whereas 16 (33%) patients in the amphotericin group and 14 (27%) patients in the fluconazole group died during hospitalization (P = 0.5). Adverse events such as chills and fever (4 versus 1), bronchospasm (2 versus none), severe hypokalemia (25 versus 12) and nephrotoxicity (9 versus 3) were more frequently observed in patients receiving amphotericin. Adverse prognostic factors included prolonged duration of neutropenia and pneumonia.CONCLUSIONS: These results suggest that fluconazole is an equally effective but less toxic alternative to amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia.     

Treatment of pulmonary sporotrichosis

Pulmonary infection with Sporothrix schenckii is extremely rare. The small number of reported cases and lack of comparative clinical trials make assessment of treatment regimens difficult. Three modalities should be considered: Saturated solution of potassium iodide (SSKI), amphotericin B, and resective surgery. Available data suggest that SSKI is unlikely to be successful in cavitary disease or disease in immunocompromised hosts. Amphotericin B alone has been successfully used to cure cavitary pulmonary sporotrichosis, but overall cure rates probably are no higher than 50%, and the probability of cure in bilateral apical disease is dismal. Surgical resection has been successful when used alone in a small number of cases. The highest cure rates (70% to 80%) appear to be a result of management with amphotericin B or SSKI combined with resective pulmonary surgery. The dosage and duration of amphotericin B or SSKI to be used in conjunction with surgical resection is unknown.     

The management of uncomplicated adult gonococcal infection: should test of cure still be routine in patients attending genitourinary medicine clinics?

In this retrospective study of the outcome of treatment of 245 patients (87 females and 158 males) with a diagnosis of Neisseria gonorrhoeae infection seen between 1996 and 2002, 81% (95% confidence interval (CI) 74%-86.8%) of the males and 88.5% (95% CI 79.9%-94.3%) of the females attended for a test of cure. At initial presentation, 93% (95% CI 87.9%-96.5%) and 94.3% (95% CI 89.5%-97.4%) of males respectively, had symptoms and signs of gonococcal infection compared with 48.3% (95% CI 37.4%-59.2%) and 44.8% (95% CI 34.1%-55.9%) of females, and this difference was statistically significant (P = 0.005). Initial diagnosis at first visit was made by Gram-stained smear in 88.6% (95% CI 82.6%-93.1%) of males and 32.2% (95% CI 22.6%-43.1%) of females, a statistically significant difference P = 0.001. There were 12 (4.9%) cases of reinfection that rebooked to attend after failing to attend for their test of cure in two females and 10 males. There were two (0.8%) treatment failures amongst the 245 episodes in two males who still had symptoms when they returned for their test of cure. One male had a ciprofloxacin-resistant strain (CRNG) acquired locally and the other one had a betalactamase-producing CRNG/penicillinase-producing N. gonorrhoeae (PPNG) isolate acquired abroad in South America. These patients would have sought to return, as they still had signs and symptoms of gonococcal infection, and they would have been recalled following receipt of the antimicrobial susceptibility report. Post-gonococcal urethritis occurred in 36.3% (95% CI 27.8%-45.4%) of the males who attended for their test of cure, 74.8% (95% CI 67.2%-81.5%) received anti-chlamydial therapy with their standard treatment. In men who received anti-chlamydial therapy the odds ratio of having post-gonococcal urethritis was 0.42 (95% CI 0.17-1.06), P = 0.04. Co-infection with Chlamydia trachomatis was more likely to occur amongst females (43.9%), odds ratio 3.97 (95% CI 2.07-7.67), P < 0.001 than males (16.5%). We have now discontinued routine attendance for a test of cure and encourage our patients to telephone for their results with recall only of patients whose antimicrobial susceptibility indicate inappropriate first line therapy or who are still symptomatic.     

Three days of pivmecillinam or norfloxacin for treatment of acute uncomplicated urinary infection in women

Pivmecillinam is a unique beta-lactam antimicrobial that has been used for the treatment of acute uncomplicated urinary infection for > 20 y. Since this agent was introduced, the quinolone antimicrobials have become widely used for the same indication. This study compared the efficacy of a 3-d regimen of pivmecillinam 400 mg b.i.d. with norfloxacin 400 mg b.i.d. Women aged between 18 and 65 y presenting with symptoms of acute cystitis of < 7 d duration were eligible for enrollment; 483 were randomized to receive pivmecillinam and 471 to receive norfloxacin. In each group, 30% of women had negative urine cultures prior to therapy. Bacteriologic cure at early post-therapy follow-up was achieved in 222/298 (75%) pivmecillinam patients and 276/302 (91%) norfloxacin patients [p < 0.001; 95% confidence interval (CI) 12.0-21.8]. Clinical cure/improvement at Day 4 following initiation of therapy was observed in 434/457 (95%) women who received pivmecillinam and 425/442 (96%) who received norfloxacin (p = 0.39; 95% CI 1.5-3.9). Early post-therapy (11 +/- 2 d) clinical cure was achieved in 360/437 women (82%) who received pivmecillinam and 381/433 (88%) who received norfloxacin (p = 0.019; 95% CI 0.9-10.3). In women aged < or = 50 y, early clinical cure rates were 294/351 (84%) for pivmecillinam and 299/340 (88%) for norfloxacin (p = 0.11; 95% CI 1.0-9.4). Adverse effects were similar for both regimens, and there was no evidence of the emergence of organisms of increasing resistance with therapy. Short-course therapy with norfloxacin was superior to that with pivmecillinam in terms of bacteriologic outcome, although differences in clinical outcome were less marked. In conclusion, short-course therapy with pivmecillinam is an effective empirical treatment for pre-menopausal women.     

Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study

In this randomized, double-blind, dose-ranging, multicenter trial, 84 patients with visceral leishmaniasis refractory to antimony therapy were administered liposomal amphotericin B (AmBisome) at cumulative doses of 3.75, 7.5, and 15.0 mg/kg for 5 consecutive days. Posttreatment apparent cure and definite cure were assessed at 2 weeks and 6 months after the end of therapy, respectively. Mild to moderate infusion-related fever and rigors were seen in 29 and 44% of patients, respectively. One patient each in the 3.75- and 7.5-mg groups had detectable parasites on splenic smear at posttreatment evaluation. At 6 months' follow-up, however, 2, 1, and 1 patients relapsed in the 3.75-, 7.5-, and 15.0-mg groups, resulting in definite cure rates of 89, 93, and 97%, respectively. There was no significant difference in the cure rates of the 3 groups. Low-dose liposomal amphotericin B given for 5 days can cure most patients with Indian kala-azar.     

Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women

BACKGROUND: There is a paucity of data on the efficacy of nitrofurantoin for the treatment of acute uncomplicated cystitis in regimens shorter than 7 days. Evidence-based use of this drug is increasingly important as trimethoprim-sulfamethoxazole resistance among uropathogens increases. METHODS: To assess the efficacy of nitrofurantoin vs trimethoprim-sulfamethoxazole, 338 women aged 18 to 45 years with acute uncomplicated cystitis were randomized to open-label treatment with either trimethoprim-sulfamethoxazole, 1 double-strength tablet twice daily for 3 days, or nitrofurantoin, 100 mg twice daily for 5 days. Clinical cure 30 days after therapy was the main outcome measure. Secondary outcomes included clinical and microbiological cure rates 5 to 9 days after therapy and, for trimethoprim-sulfamethoxazole-treated women, clinical cure stratified by the trimethoprim-sulfamethoxazole susceptibility of the uropathogen. RESULTS: Clinical cure was achieved in 79% of the trimethoprim-sulfamethoxazole group and in 84% of the nitrofurantoin group, for a difference of -5% (95% confidence interval, -13% to 4%). Clinical and microbiological cure rates at the first follow-up visit were also equivalent between the 2 groups. In the trimethoprim-sulfamethoxazole arm, 7 of 17 women (41%) with a trimethoprim-sulfamethoxazole-nonsusceptible isolate had a clinical cure compared with 84% of women with a trimethoprim-sulfamethoxazole-susceptible isolate (P < .001). CONCLUSION: A 5-day course of nitrofurantoin is equivalent clinically and microbiologically to a 3-day course of trimethoprim-sulfamethoxazole and should be considered an effective fluoroquinolone-sparing alternative for the treatment of acute cystitis in women.     

Liposomal Amphotericin B (AmBisome) in the Treatment of Neonatal Candidiasis in Very Low Birth Weight Infants

Summary AmBisone (2.5–7 mg/kg/day as a continuous 1 h infusion) was evaluated prospectively from September 1994 to January 1998 in 24 very low birth weight infants (mean birth weight 847±244 g, mean gestational age 26 weeks) with systemic candidiasis. Mean age at onset of candidemia was 17 days. One patient had two episodes of candidiasis. Thirteen infants failed previous antifungal therapy with amphotericin B (with or without 5-flucytosine). Candida spp. were isolated from the blood in all 25 episodes and from skin abscesses and urine in four infants each, respectively. There were 13 isolates of Candida albicans, ten of Candida parapsilosis, two of Candida tropicalis and one of Candida glabrata. One infant had a mixed infection with C. albicans and C. parapsilosis. The mean duration of therapy was 21 days; the cumulative AmBisome dose was 94 mg/kg. Fungal eradication was achieved in 92% of the episodes; mean duration of AmBisome therapy until achieving eradication was 9 days. Twenty (83%) infants were considered clinically cured at the end of treatment. No major adverse effects were recorded; one infant developed increased bilirubin and hepatic transaminases levels during therapy. Four (17%) infants died; in two of them (8%) the cause of death was directly attributed to systemic candidiasis. Conclusion: AmBisome represents an effective, safe and convenient antifungal agent in the therapy of systemic fungal infections in very low birth weight infants. Received: March 21, 1999 · Revision accepted: March 3, 2000     

A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.