Economic evaluation of voriconazole compared with conventional amphotericin B for the primary treatment of aspergillosis in immunocompromised patients.

OBJECTIVE: The objective of this study was to conduct an economic evaluation of voriconazole compared with conventional amphotericin B deoxycholate (CAB) using data from a recently reported randomized comparative trial in patients with various underlying immunosuppressive conditions. This trial demonstrated the superiority of voriconazole in terms of clinical response, survival and safety when used as primary therapy for invasive aspergillosis. METHODS: A decision analytic model was designed using an expert panel and populated primarily with efficacy and resource utilization data collected prospectively during the clinical trial. The analysis was carried out from the perspective of the health care system and all costs are reported in 2002 US dollars. RESULTS: Average total treatment costs per patient were 10% lower in the voriconazole arm ($30 664) than in the CAB arm ($34 144), resulting from reduced consumption of hospital resources and fewer changes in antifungal therapy. In the base case analysis, voriconazole provided an average saving of $3481 per treated patient, resulted in a lower cost per survivor ($43 310 versus $58 971) and a lower cost per successfully treated patient ($58 100 versus $108 124) compared with CAB. Sensitivity analyses demonstrated that the cost savings observed were maintained over a wide range of alternative values for both unit costs and resource utilization, including length of hospital stay, time spent in intensive care units, bed day costs and the cost of lipid formulations of amphotericin B. CONCLUSION: Incremental cost-effectiveness analysis indicated the dominance of voriconazole because of both lower costs and greater efficacy.

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.

Infections caused by filamentous fungi in patients with hematologic malignancies. A report of 391 cases by GIMEMA Infection Program.

BACKGROUND AND OBJECTIVES: To evaluate the clinical characteristics of patients with hematologic malignancies developing a filamentous fungi infection (FFI) and to define the prognostic factors for their outcome. DESIGN AND METHODS: A retrospective study, conducted on patients admitted to 14 Hematology divisions of tertiary care or university hospitals, participating in the GIMEMA Infection Program, over a ten-year period (1988-1997). The study included patients with hematological malignancies and a histologically and/or microbiologically proven or probable FFI. RESULTS: We included 391 patients (male/female: 262/129, median age 49 years) with hematologic malignancies (225 acute myeloid leukemia, 67 acute lymphocytic leukemia, 30 chronic myeloid leukemia, 22 non-Hodgkin's lymphoma, 12 myelodysplastic syndrome, 10 aplastic anemia, 7 Hodgkin's disease, 8 chronic lymphocytic leukemia, 5 multiple myeloma, and 5 hairy cell leukemia) who developed a proven FFI. Eighty percent of the patients had been neutropenic for an average of 14 days before the infection, and 71% had an absolute neutrophil count lower than 0.5 x 10(9)/L at the time of FFI diagnosis. The primary sites of infection were: lungs (85%), nose and paranasal sinus (10%), and other sites (5%). The diagnosis was made while still alive in 310 patients (79%), and at autopsy in the remaining 81 patients (21%). Chest X-ray was diagnostic in 77% of patients with pulmonary FFI, while computed tomography (CT) scan of the thorax was positive in 95% of cases. A significant diagnostic advantage for CT scan was observed in 145 patients who had both a chest X-ray and CT scan. Aspergillus was identified as the cause of FFI in 296 patients, Mucorales in 45 patients, Fusarium in 6 patients and other filamentous fungi species in 4 patients, while in a further 40 patients no agent was identifiable. The overall mortality rate three months after the diagnosis of FFI was 74%, and fungal infection had been the cause of death in 51% of patients. INTERPRETATION AND CONCLUSIONS: Our retrospective study shows that FFI still remains a life-threatening complication in neutropenic patients. Despite appropriate treatment, half of the patients die due to this complication. The use of glucocorticoids and recovery from neutropenia are the most important prognostic factors. Mucorales infections are associated with a significantly poorer prognosis than those due to Aspergillus spp.

The epidemiology of fusariosis in patients with haematological diseases. Gimema Infection Programme.

Fusariosis has been considered an emerging infection in patients with haematological malignancies. In a multicentre retrospective study on filamentous fungi infections in patients with haematological diseases over a period of 10 years in Italy, fusariosis was documented in six patients from two of the 14 centres with a 0.06% incidence in acute leukaemia. A literature search yielded 177 cases of Fusarium infections in haematological diseases and acute leukaemia accounted for 71% of the underlying conditions. An increase from 0.5 to 3.8 cases per year was observed at the M.D. Anderson Cancer Center of Houston in the periods 1975-85 and 1986-95 respectively. Conversely, only 5.1 and 6.3 cases per year have been reported in the periods 1981-90 and 1991-96, respectively, from the other centres in the world. Half of the cases have been observed in the USA. In Europe, most of the cases have been observed in France and Italy. Invasive fusariosis is a rare complication in haematological diseases, as its overall frequency does not seem to be significantly increased within the last 20 years. However, its epidemiological distribution is not homogeneous and the possibility of local clusters of infections by this deadly pathogen should be carefully considered.

Management of fungal infections in neutropenic patients: more doubts than certainties?

An evidence based approach to prophylaxis and therapy of invasive fungal infections depends on the knowledge of epidemiology and of risk factors for these infections, as well as on the appreciation of merits and limitation of the available clinical trials. A progressive increase in the incidence of systemic fungal infections, most often caused by Candida and Aspergillus, in patients with cancer and neutropenia has been observed in recent years. This increase of systemic fungal infections recognizes a multifactorial origin, including host defense impairment and type of underlying disease. The various combinations of these different risk factors make the patients affected by systemic fungal infections a non-homogeneous population and, therefore, the transferability of the results of many clinical trials from one population to another is difficult. Clinical trials on prophylaxis and treatment of systemic fungal infections moreover have many limitations: they are often of small size, are frequently non-comparative, enrol population at different risk for infection, use different criteria to define success or failure of therapy. These limitations make the interpretation of the trial results difficult. As randomised clinical trials and metanalysis are considered the most valuable sources of information on new treatments, it dearly appears that the mentioned difficulties in interpreting available data from the literature may expose patients to an increased risk of receiving an inappropriate or non-optimal treatment. Better designed studies are needed to clarify the many controversial questions in antifungal prophylaxis and therapy.

Pattern of antibiotic use in primary health care in Italy.

OBJECTIVE: The overuse and misuse of antibiotics have been related to the growing emergence of bacterial resistance. The aim of the present study was to assess the pattern of antibiotic use by Italian general practitioners (GPs) in the treatment of the most frequent infectious problems. METHODS: The study was performed with 131 GPs recruited on a voluntary basis from among the 181 GPs contacted in two Italian regions, Emilia Romagna and Umbria. GPs were requested to report all the infectious events encountered during six sample weeks on a special form, whether an antibiotic was administered or not. RESULTS: The GPs reported 7095 infectious cases, of which 5036 (77%) were respiratory-tract infections (RTIs) and 749 (11%) were urinary-tract infections (UTIs). Antibiotics were prescribed in 71% of the cases. The proportion of antibiotic-treated cases was highest in UTIs (97%), followed by lower respiratory-tract infections (LRTIs; 93%) and upper respiratory-tract infections (URTIs; 54%). Drugs belonging to 16 Anatomical Therapeutical Chemical groups (fourth level) were used. Wide-spectrum penicillins and macrolides ranked first (23%), followed by penicillins plus beta-lactamase inhibitors (15%), cephalosporins (15%) and fluoroquinolones (10%). The most prescribed antibiotics for the major disease groups were wide-spectrum penicillins for URTIs (36%), macrolides and cephalosporins for LRTIs (27% each) and fluoroquinolones for UTIs (46%). CONCLUSIONS: The present survey showed a high level of inappropriate use. In fact, a large number of infectious diseases, including infections commonly caused by viral agents, were treated with an anti-bacterial drug. Italian GPs had a tendency to preferentially prescribe wide-spectrum antibiotics and to use, in many cases, antibiotics that are rarely of choice in primary health care, such as cephalosporins and fluoroquinolones. In order to attain a more evidence-based prescription, local guidelines shared by specialists and GPs should be implemented.

Ceftriaxone versus beta-lactams with antipseudomonal activity for empirical, combined antibiotic therapy in febrile neutropenia: a meta-analysis.

The object of this work was to compare the efficacy of antibiotic combinations including ceftriaxone with that of combinations including an antipseudomonal beta-lactam for the empirical treatment of febrile neutropenia in cancer patients. We identified all published randomised trials comparing two antibiotic combinations differing only in the beta-lactam, being ceftriaxone in one treatment group and an antipseudomonal beta-lactam in the other. The quality of individual trials was formally evaluated. A meta-analysis was performed using the Peto-modified Mantel-Haenszel method for combining binary data. Primary analysis was done, for both febrile episodes and bacteraemic episodes, using failure of empirical antibiotic treatment defined as modification of the initial allocated regimen or death during treatment. Secondary analysis was done using death from any cause in the two treatment groups. Data relating to 1,537 febrile neutropenic episodes recorded in eight randomised clinical trial were pooled s. Overall, there were 256 treatment failures out of 782 febrile episodes treated with ceftriaxone-containing combinations (32.7%), and 243 out of 755 treated with antipseudomonal beta-lactam regimens (32.1%). The pooled odds ratio of failure for ceftriaxone-containing combinations for febrile episodes was 1.04, with the 95% confidence interval ranging from 0.84 to 1.29, and that for bacteraemic episodes was 0.93 (95% confidence interval 0.58-1.49). With regard to overall mortality, there were 54 deaths among 782 febrile episodes treated with ceftriaxone-containing combinations (6.9%) and 62 deaths among 755 febrile episodes treated with antipseudomonal beta-lactam-containing regimens (8.2%). The pooled odds ratio of death for ceftriaxone regimens was 0.84 (95% confidence interval 0.57-1.24). Results of this meta-analysis show that in the empirical treatment of febrile neutropenia, antibiotic combinations containing ceftriaxone are as effective as those in which the beta-lactam has specific activity against Pseudomonas aeruginosa, such as ureidopenicillin or ceftazidime.

In vitro effects of meropenem and imipenem/cilastatin on some functions of human natural effector cells.

Meropenem, a new carbapenem antibiotic, was assessed to evaluate its effects on some functional parameters of human polymorphonuclear (PMN) and natural killer (NK) cells in comparison with imipenem/cilastatin. Both drugs significantly inhibited PMN phagocytosis and chemotaxis at concentrations of 2,000 and 4,000 microg/ml. They affected PMN microbicidal activity, evaluated against Candida albicans, only at 4,000 microg/ml. A study of the effects of both drugs on peripheral NK populations and the human NK line (NK-92) showed that even at 4,000 microg/ml there was no effect on antitumor activity. These data indicate that meropenem can reduce some PMN antimicrobial functions only at very high concentrations like imipenem/cilastatin, whereas no concentration influenced NK activity.

[Clinical and molecular epidemiology of an outbreak of infusion-related Acinetobacter baumannii bacteremia in an Intensive Care Unit] / Epidemiologia clinica e molecolare di una epidemia di batteriemie da Acynetobacter baumannii correlate ad infusioni in una Unita di Terapia Intensiva.

Objective: To describe the clinical and molecular epidemiology of an outbreak of infusion-related Acinetobacter baumannii bacteremia in an intensive care unit (ICU). Methods: Six cases of A. baumannii bacteremia identified in the Foligno Hospital ICU, Italy, were peer reviewed. Antibiotic susceptibility and genotyping (PFGE and RAPD) of A. baumannii isolates were carried out. Results: All A. baumannii blood isolates and a strain isolated from parenteral solution had an identical genotype. The strains were susceptible to carbapenems and the combination of meropenem plus amikacin or piperacillin/ tazobactam plus netilmicin was synergistic. A. baumannii bacteremia persisted for several days in almost all patients; catheter tip cultures were always positive for A. baumannii. Three patients, with an elevated Apache II score, died of sepsis. Conclusions: The outbreak was related to contaminated parenteral solutions improperly prepared in the ward. Aseptic preparation in the hospital pharmacy allowed for an interruption of the outbreak.

Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy.

Nausea and vomiting induced by chemotherapy are a major cause of distress to patients and reduce compliance with potentially beneficial treatment. Itasetron hydrochloride is a new 5-hydroxytryptamine3 (5-HT3) antagonist with potent antiemetic properties. It is more potent than ondansetron in animal models and in early clinical studies it demonstrates a long half-life and does not undergo hepatic biotransformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given intravenously (i.v.) to patients due to receive high-dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i.v. infusion of itasetron hydrochloride at a dose of 17-280 microg/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2). Antiemetic protection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not effective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Adverse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians' and patients' assessments of efficacy and tolerability of itasetron hydrochloride were similar, the majority rating the treatment as 'good' or 'very good'. In conclusion, itasetron hydrochloride is effective in the dose range 35-280 microg/kg in preventing cisplatin-induced emesis. Taken together with results from a larger dose-finding study, a dose corresponding to 35 microg/kg (equivalent to 2.5 mg itasetron, calculated as free base) has been pursued in Phase III studies with the i.v. formulation.

Cost analysis of 2 empiric antibacterial regimens containing glycopeptides for the treatment of febrile neutropenia in patients with acute leukaemia.

OBJECTIVE: Patients with cancer-associated neutropenia are at high risk of developing severe infections which can be fatal if treatment is not promptly administered. For this reason, fever is treated as soon as possible with broad spectrum antibacterial therapy. The objective of this study was to conduct a cost analysis in Italy comparing 2 empiric glycoprotein-containing antibacterial regimens for the treatment of febrile neutropenia in patients with acute leukaemia. DESIGN AND SETTING: A retrospective cost analysis was conducted, using the records of 527 febrile neutropenic patients with acute leukaemia who participated in an 18-month multicentre (29 Italian haematological units) randomised trial during 1991. All patients received either of the following 2 empiric intravenous regimens, each containing 3 antibacterial agents: ceftazidime (2 g, 3 times daily) and amikacin (15 mg/kg/day, in 3 separate doses) plus teicoplanin (6 mg/kg, in a single dose) or vancomycin (30 mg/kg/day, in 2 separate doses). Economic analyses were carried out from a hospital perspective. Only the direct costs per patient, i.e. mean antibacterial treatment and management cost, mean overall treatment failure cost and mean cost of adverse effects, were included. MAIN OUTCOME MEASURES AND RESULTS: No differences were found in the clinical response, defined as the improvement in the rate of fever or infection (if documented), between the 2 regimens. However, tolerability, defined as the incidence of adverse effects probably or definitely related to the assigned treatment, was reported to be better with the teicoplanin-rather than the vancomycin-containing regimen. CONCLUSIONS: Thus retrospective cost analysis showed that despite the higher acquisition cost of teicoplanin relative to vancomycin, the lower incidence of adverse effects associated with teicoplanin and its ease of administration (single daily dose) resulted in equivalent overall treatment costs between teicoplanin- and vancomycin containing regimens.

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment.

Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable.

Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell' Adulto.

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.