Albano Del Favero

Itraconazole Oral Solution as Prophylaxis for Fungal Infections in Neutropenic Patients with Hematologic Malignancies: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases

A retrospective study of 37 patients with haematological malignancy (21 acute myeloid leukaemia, 11 acute lymphoid leukaemia, two lymphoma, two hairy cell leukaemia, one Hodgkins disease) and histologically documented mucormycosis was conducted to evaluate the clinical characteristics and ascertain the factors which influenced the outcome from mycotic infection. Patients were admitted to 18 haematology divisions in tertiary care or university hospitals in Italy between 1987 and 1995.

A Multicenter, Double-Blind, Placebo-Controlled Trial Comparing Piperacillin-Tazobactam with and without Amikacin as Empiric Therapy for Febrile Neutropenia

In a prospective, multicenter, double-blind, randomized clinical trial, we compared the efficacy of piperacillin-tazobactam (4.5 g 3 times daily intravenously) plus placebo versus piperacillin-tazobactam plus amikacin (7.5 mg/kg twice daily intravenously) for the treatment of 760 febrile, adult patients with cancer with chemotherapy-induced profound (<500 neutrophils/mm3) and prolonged (>10 days) neutropenia. A total of 733 patients were assessable for efficacy of the drug regimens, and an overall successful outcome was reported in 49% (179 of 364) of the patients who received monotherapy, compared with 53% (196 of 369) of patients who received combination therapy (P=.2). Response rates were similar with both regimens, as were incidences of bacteremia and clinically documented and possible infections. In our epidemiological setting, the initial empiric combination therapy was not associated with improved outcomes when compared with initial monotherapy.

Preventing fungal infection in neutropenic patients with acute leukemia : fluconazole compared with oral amphotericin B

Superficial and systemic fungal infections are a major problem among neutropenic patients with acute leukemia [1] or those having bone marrow transplantation [2]. It remains a leading cause of morbidity and mortality, and many centers administer amphotericin B empirically to patients with neutropenia and fever refractory to antibacterial treatment [3, 4]. Antifungal prophylaxis is also used widely, but its efficacy in reducing systemic fungal infection is debated [5]. However, oral polyene antibiotics, usually poorly tolerated because of their bitter taste, have been shown to reduce oral candidiasis, and, in a placebo-controlled study, oral amphotericin B was shown to decrease autopsy-proven systemic candidiasis [6]. Among the imidazoles, ketoconazole and miconazole have been used with contrasting results in the prevention of systemic fungal infections, but because of their toxicities and the emergence of fungal-resistant strains, they are rarely used. Fluconazole, an oral triazole with systemic activity, tested in placebo-controlled trials in a daily oral dose of 400 mg, was found to be effective in reducing systemic fungal infections in marrow recipients [7] but did not show the same benefit in patients with acute leukemia receiving therapy to induce remission [8]. Our aim was to clarify the role of systemic and topical antifungal prophylactic agents in neutropenic patients with acute leukemia by doing a large, randomized, multicenter trial that compared the efficacy and tolerability of oral fluconazole with high-dose amphotericin B suspension. Methods Eligible patients included consecutive adults who had acute leukemia, were hospitalized at participating centers, and were receiving cytotoxic therapy likely to induce neutropenia (neutrophil count < 1000/mm3) within 7 days. Patients received remission-induction or reinduction therapy according to the GIMEMA protocols [9, 10]. We excluded from the study before randomization patients younger than 14 years, patients with a history of hypersensitivity to triazoles, patients treated with antifungal therapy in the previous 15 days, patients with evidence of a preexisting systemic fungal infection, and patients who had nasal colonization with Aspergillus spp. Study Protocol After informed consent was obtained, the patients were randomly assigned to receive either fluconazole, 150 mg as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours. Patients were randomly assigned to treatments using random permuted blocks of 10 containing different and balanced sequences of the two regimens. Antifungal prophylaxis was started 1 to 3 days before the administration of cytotoxic chemotherapy and continued until the neutrophil count returned to 1000/L or a systemic fungal infection was proved or suspected. All patients received oral ciprofloxacin, 500 mg twice daily, as antibacterial prophylaxis [11]; antiviral prophylaxis and central venous catheters were used according to autonomous decisions made at each participating center. The patients were treated under conventional ward conditions or in single rooms, depending on the center. Prophylactic granulocyte transfusions and colony-stimulating factors were not used. All patients were examined daily for clinical signs of fungal infection. When axillary temperature increased to more than 38 C or infection was suspected, samples for microbiological cultures, including at least three separate blood specimens, were obtained, prophylactic therapy with ciprofloxacin was discontinued, and treatment with amikacin, ceftazidime, and a glycopeptide antibiotic (teicoplanin or vancomycin) was started; if fever persisted despite 4 to 6 days of systemic antibiotics, empiric intravenous amphotericin B was administered. Documented systemic fungal infections were treated with systemic antifungal agents (mainly intravenous amphotericin B), and superficial fungal infections were treated with topical antifungal agents. To compare the efficacy and tolerability of the two prophylactic regimens, the following variables were measured: documented systemic fungal infection; suspected systemic fungal infection; superficial fungal infection; the interval to the development of documented systemic fungal infection or to the use of empiric antifungal therapy; compliance; treatment interruption caused by side effects; and mortality. Definition of Fungal Infection Superficial fungal infection was defined as clinically apparent infection of the oropharynx or skin, along with positive cultures; a suspected case of systemic fungal infection was defined as any episode of fever that persisted despite 4 to 6 days of empiric antibiotic therapy, for which empiric intravenous amphotericin B therapy was administered; definite systemic fungal infection was defined as one in which there was both clinical evidence of blood or tissue infection and a culture or biopsy specimen from the involved site showing a pathogenic fungal organism [7]. Compliance Compliance was monitored by the nurse who counted capsules of fluconazole and measured the volume of amphotericin B oral suspension each day and recorded these data on the clinical report form. Compliance was defined as excellent if the patient took all the drug doses, as good if the patient missed fewer than three consecutive doses or took more than 80% of the total number of doses, and as poor if the patient missed more than three consecutive doses or took less than 80% of the total number of doses. Statistical Analysis Statistical analysis was done at the GIMEMA Infection Program Data Center with the SAS package (SAS Institute, Inc., Cary, North Carolina). Results are reported for all patients enrolled in the study (intention-to-treat analysis). Except for three patients randomly assigned to fluconazole and two patients assigned to amphotericin B who did not receive the study drugs and six additional patients in the fluconazole group and five in the amphotericin B group who had a duration of neutropenia of less than 7 days, all other patients were evaluable for the clinical efficacy analysis. The chi-square test with a correction for continuity, or the Fisher exact test when appropriate, was used to compare differences in proportions between the two groups. The log-rank test was used to compare the Kaplan-Meier survival curves. The Student unpaired t-test was used to compare the means. Confidence intervals (CIs) of 95% are given where appropriate. Results A total of 820 patients with acute leukemia and neutropenic episodes from 30 centers were studied; 420 were randomly assigned to receive fluconazole, and 400 were randomly assigned to receive oral amphotericin B. The two groups of patients were similar in sex, age, underlying diseases, type of chemotherapy, protective environment, use of central venous catheters, and duration and severity of neutropenia. Patients receiving first-induction chemotherapy were equally distributed in the two treatment groups (Table 1). Table 1. Patient Characteristics according to Treatment Group Systemic Fungal Infection Proven systemic fungal infection occurred in 11 (2.6%) fluconazole recipients and in 10 (2.5%) amphotericin B recipients (P > 0.2). The distribution of fungal isolates was similar in both groups (Table 2): Candida spp. caused 55% of systemic infections in fluconazole recipients and 70% in amphotericin B recipients; no difference was found in the isolation of different Candida spp., including C. krusei, between the two groups. Rates of infections caused by Aspergillus spp. were 45% in fluconazole recipients and 30% in amphotericin B recipients, a difference of 15 percentage points (95% CI for difference, 25% to 56%, P > 0.2), and the Aspergillus isolates were equally distributed. Fungemia caused by Candida spp. was documented in five patients receiving fluconazole and in three treated with amphotericin B. The characteristics of the patients with proven cases of systemic fungal infection and their clinical outcomes are summarized in Table 3. Table 2. Types of Fungi Isolated in Systemic Infections according to Treatment Group* Table 3. Characteristics and Outcomes of the Definite Cases of Systemic Fungal Infection according to Treatment Group Overall, the sites of infection between the two treatment groups were similar (P > 0.2). Simple fungemia caused by Candida isolates was documented in three patients in each group (two cases of C. krusei and one of C. parapsilosis in fluconazole recipients; one case each of C. albicans, C. krusei, and C. parapsilosis in amphotericin B recipients), and tissue infection was documented in three fluconazole recipients (C. tropicalis, C. albicans, and C. parapsilosis), and two amphotericin recipients (Candida spp., C. albicans). In patients receiving amphotericin B, esophagitis caused by Candida spp. and urinary tract infection caused by C. tropicalis were also documented. Tissue infection caused by Aspergillus spp. occurred in five fluconazole recipients (four cases of pneumonia and one disseminated infection) and in three amphotericin B-treated patients (two cases of pneumonia and one case of disseminated infection). Deaths from fungal infection were similar. Candida krusei fungemia and C. albicans and C. parapsilosis tissue infections caused death in three fluconazole recipients; C. albicans fungemia and Candida spp. tissue infection caused death in two amphotericin B recipients. Aspergillus pneumonia caused two deaths in the fluconazole group and one death in the amphotericin B group. The interval to the documented systemic fungal infection was 21 days in fluconazole recipients and 15 days in amphotericin B recipients, a nonstatistically significant difference (95% CI for difference, 3 to 15 days; P = 0.15). Superficial Fungal Infection Superficial infections were reported in 7 of the 420 patients receiving fluconazole (1.7%) and in 11 of 400 of those receiving amphotericin B (2.7%), a difference of 1 percentage point (CI for di

Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis

We set out to compare the efficacy of antibiotic monotherapy with that of combination therapy including an aminoglycoside for empirical treatment of febrile neutropenic cancer patients. We did a meta-analysis of 29 randomised clinical trials pooling data from 4795 febrile episodes and a subset of 1029 bacteraemic episodes by both fixed and random effects models. Outcome measure was clinical failure of antibiotic treatment, defined as modification of the initially allocated regimen or death during treatment. In febrile episodes, the pooled odds ratio (OR) of clinical failure with monotherapy versus combination therapy was 0.88, with 95% CI from 0.78 to 0.99 by the fixed effects model, and 0.87 with 95% CI from 0.75 to 1.01 by the more conservative random effects model. For bacteraemic episodes, the pooled OR of failure with monotherapy was 0.70 (0.54 to 0.92) by the fixed effects model, and 0.72 (0.54 to 0.95) by the random effects model. We conclude that monotherapy has been as effective as aminoglycoside-containing combinations for empirical treatment of febrile neutropenia.

Ondansetron clinical pharmacokinetics.

SummaryOndansetron is a potent and highly selective serotonin 5-HT3-receptor antagonist which has demonstrated important antiemetic activity and good tolerability in the prevention of chemotherapy-induced nausea and vomiting.Ondansetron is completely and rapidly absorbed from the gastrointestinal tract after oral administration, and does not accumulate with repeated oral administration. Owing to hepatic first-pass metabolism, its bioavailability is only about 60% compared with ondansetron administered by infusion over 15 minutes. Bioavailability is slightly increased when administered after a standard meal, and is not influenced by coadministration of antacids; a slightly enhanced bioavailability has been observed in patients with cancer. Since the time to reach peak concentration is 0.5 to 2 hours after oral ingestion, the drug should be administered at least 30 minutes before chemotherapy. Possible alternative ways of administration of ondansetron include intramuscular, subcutaneous and rectal administration, and oral controlled-release formulations.Ondansetron is widely distributed (volume of distribution approximately 160L) and binds moderately (70 to 76%) to plasma proteins; the elimination half-life averages approximately 3.8 ± 1 hours. Clearance occurs by hepatic metabolism (95%) rather than renal excretion. Metabolites do not play a role in the activity of the drug, and there is no evidence of genetic polymorphic metabolism.Although aging is associated with decreased clearance and increased bioavailability, dosage adjustments are not required for the elderly, and may be necessary only in patients with severe hepatic impairment. Chemotherapeutic agents do not seem to modify the pharmacokinetics of ondansetron.There remains the question of whether control of emesis is related to systemic availability of ondansetron and, in consequence, the optimal dose and schedule of ondansetron is still to be identified with certainty.

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres

Summary. A retrospective survey was conducted over a 10‐year period (1990–99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non‐Hodgkins lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non‐productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar–interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0·006) and a radiological picture of diffuse lung involvement (P < 0·003) were negative diagnostic factors.

Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone : a randomized single-blind study

To prevent delayed emesis induced by cisplatin (mean dose 90 mg/m2), 120 consecutive patients were randomized to receive, in a 7-day crossover design, oral metoclopramide (20 mg q.i.d.), dexamethasone (1 mg q.i.d.) or placebo (two tablets q.i.d.) starting 24 hours after the end of chemotherapy. Complete protection from nausea, but not from vomiting. was significantly increased by both dexamethasone and metoclopramide with respect to placebo. Important prognostic factors favoring the appearance of delayed emesis were incomplete protection from vomiting during the first 24 hours after cisplatin, female gender, and highest cisplatin doses. Tolerability of both drugs was good. Larger and randomized controlled trials are necessary to identify better preventive treatment of delayed emesis induced by cisplatin.

Fatal haemoptysis in pulmonary filamentous mycosis: An underevaluated cause of death in patients with acute leukaemia in haematological complete remission. A retrospective study and review of the literature

A retrospective study on a consecutive series of 116 patients affected by acute leukaemia with documented pulmonary filamentous mycosis (FM) admitted between 1987 and 1992 to 14 tertiary‐care hospitals in Italy was made in order to evaluate the characteristics of those patients who developed fatal massive haemoptysis.

Pharmacokinetics of vincristine in cancer patients treated with nifedipine

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium‐entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least‐square regression program (SAS‐NLIN). A tri‐exponential model fitted the raw data better than a bi‐exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2α was shorter in NIF‐treated patients, whereas the T 1/2γ was longer in the NIF‐treated group. The NIF‐treated group showed an increase in the AUC O‐∞ and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7‐day urinary excretion of VCR was reduced in the NIF‐treated patients. These data suggest that, when VCR is administered to NIF‐treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.