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.

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.

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.

Double-blind, placebo-controlled study on effects of diclofenac sodium and indomethacin on postprandial gastric motility in man.

Data from animal studies suggest that NSAIDs-induced gastric damage may be due to increased gastric motility. Such a mechanism, however, has never been tested or demonstrated in man. We evaluated the effects of two frequently prescribed NSAIDs, indomethacin and diclofenac sodium, on postprandial gastric motor activity (a physiologically reproducible stimulus) in healthy volunteers to see whether these compounds increase gastric motility. Twenty-four healthy volunteers of both sexes, 21-35 years of age, underwent a basal gastric motility recording. Thereafter, they were randomized in three groups to receive either placebo, indomethacin (50 mg three times a day) or diclofenac sodium (50 mg three times a day) for a week. At the end of the week, they underwent an identical manometric study. Analysis of the motility tracings showed no difference in gastric antral motility index and in amplitude of gastric antral contractions after NSAIDs with respect to the basal study and to the placebo group. About 50% of subjects (two in the placebo group) complained of side effects. These were transient and mild, except in two subjects taking indomethacin, in whom endoscopy was necessary; one of these had a small prepyloric ulcer. It is concluded that in man NSAID-related gastric damage is unlikely to be due to increased gastric motility.

Localization of aspergillosis to the central nervous system among patients with acute leukemia: report of 14 cases. Gruppo Italiano Malattie Ematologiche dell'Adulto Infection Program.

We retrospectively studied a consecutive series of 100 patients with acute leukemia and aspergillosis to evaluate the clinical findings and risk factors for colonization of the central nervous system (CNS) by Aspergillus species. The diagnosis of CNS aspergillosis was made in 14 patients on the basis of the following criteria: neurological signs of CNS involvement (13 of 14 patients); cerebral CT scan findings (9 of 12); microbiological findings (6 of 12); and histological findings at autopsy (11 of 11). The majority of patients had severe neurological complications (i.e., hemiparesis or seizures), due mainly to brain abscesses or mycetomas. Autopsies were performed on 11 of 14 patients and provided evidence that CNS localization was secondary to invasive aspergillosis; in each case, the most likely primary focus of infection was the lung. Although all patients had received oral antimycotic prophylaxis and had received timely empirical antifungal treatment, they all died within a median time of 5 days from the onset of neurological symptoms. Analysis of the characteristics of patients with invasive aspergillosis did not reveal any difference between those with CNS localization and those without CNS localization.

Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program.

Combinations of beta-lactams plus aminoglycosides have been standard therapy for suspected infections in granulocytopenic cancer patients, especially those with profound long-lasting granulocytopenia. With the advent of new broad-spectrum bactericidal antibiotics such as extended-spectrum cephalosporins or carbapenems, the need to combine beta-lactams with aminoglycosides became more controversial. The objective of this prospective randomized multicenter study was to compare the efficacy, safety, and tolerance of meropenem monotherapy with those of the combination of ceftazidime plus amikacin for the empirical treatment of fever in granulocytopenic cancer patients. Of 1,034 randomized patients, 958 were assessable in the intent-to-treat analysis for response to antibacterial therapy, including 483 in the meropenem group and 475 in the ceftazidime-plus-amikacin group. The median durations of neutropenia were 16 and 17 days, respectively. A successful outcome was reported in 270 of 483 (56%) patients treated with monotherapy compared with 245 of 475 (52%) patients treated with the combination group (P = 0.20). The success rates in the monotherapy group and the combination group were similar by type of infection (single gram-negative bacteremia, single gram-positive bacteremia, clinically documented infection, and possible infection). The occurrence of further infections assessed in patients for whom the allocated regimen was not modified did not differ between the two groups (12% in both groups). Mortality due to the presenting infection or further infection was relatively low (8 patients treated with the monotherapy compared with 13 patients treated with the combination). A total of 1,027 patients were evaluable for adverse events; the proportion of those who developed adverse effects was similar between the two groups (29% in both groups), and only 19 (4%) patients in the monotherapy group and 31 (6%) in the combination group experienced an adverse event related or probably related to the study drug. Allergic reactions were the only reason for stopping the protocol antibiotic(s) (3 and 5 patients, respectively). This study confirms that monotherapy with meropenem is as effective as the combination of ceftazidime plus amikacin for the empiric treatment of fever in persistently granulocytopenic cancer patients, and both regimens were well tolerated.

Empiric monotherapy in neutropenia: a realistic goal?

Infection remains the major cause of morbidity and mortality for cancer patients who become granulocytopenic as a result of chemotherapy. Treatment is instituted at the first sign of infection and before the identification of the causative pathogen (empiric treatment). For many years, standard empiric treatment has been combination therapy with beta-lactams and aminoglycosides. The advent of new broad spectrum antibiotics, such as ceftazidime, has introduced the possibility of empiric monotherapy. However, ceftazidime has only modest activity against infections due to Gram-positive organisms, which presently account for at least 50% of infections in neutropenic patients, and resistance to ceftazidime in Gram-negative organisms has been documented. Meropenem is a new carbapenem with a broad antibacterial spectrum with greater in vitro activity than ceftazidime against staphylococci, streptococci and many Gram-negative bacteria. A comparative study of intravenous meropenem (1 g 8-hourly) and ceftazidime (2 g 8-hourly) in the empiric treatment of febrile neutropenic patients with haematological malignancies has been conducted. In an open, randomised trial of the treatment of 338 febrile episodes, all patients survived to 72 hours on both treatments, and meropenem was found to be at least as clinically effective as ceftazidime in eradicating both Gram-positive and Gram-negative infections. Early modification of treatment (48-72 hours) was required for approximately 40% of patients but occurred less frequently in patients treated with meropenem than with ceftazidime. Tolerability of both treatments was good. Meropenem should be compared with standard combination therapy in a large randomised trial before adopting it as empiric monotherapy for febrile neutropenic patients.

Whipple's disease: a continuous challenge.

Whipple's disease is a rare disease with protean clinical manifestations, often mimicking those of other pathological conditions. We describe two new cases, one admitted to hospital only after Giardia lamblia infestation had drawn attention to gut symptoms, and the other who was treated for a long time with steroids for suspected Horton's arteritis. Once again, we stress the importance of bearing this polymorph disease in mind, especially in older people.

Effects of teicoplanin and those of vancomycin in initial empirical antibiotic regimen for febrile, neutropenic patients with hematologic malignancies. Gimema Infection Program.

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.

[Reduced ex vivo production of superoxide anion by polymorphonuclear leukocytes during therapy with omeprazole. A pharmacological effect?]. / Ridotta produzione "ex vivo" di anione superossido da parte dei leucociti polimorfonucleati durante terapia con omeprazolo. Un effetto farmacologico?

Among available drugs, omeprazole is the one that cures gastric acid secretion-related pathologies, including reflux oesophagitis which responds poorly to H2-receptor antagonists, most rapidly and efficaciously. This marked therapeutic action is thought to reflect the drug's capacity to adequately control parietal hydrochloric acid secretion. Our data suggest an omeprazole effect on human neutrophil function too. Neutrophils are more or less a constant, and often conspicuous anatomo-pathological component of the phlogistic processes associated with gastric acid secretion. A direct or indirect effect exerted by omeprazole on leukocyte function would be of great scientific-biological and therapeutic interest. Furthermore, it would contribute to marking the drug superior in terms of more rapid relief of the symptoms and range of therapeutic action.

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

OBJECTIVE: To compare the efficacy and tolerability of fluconazole and oral amphotericin B in preventing fungal infection in neutropenic patients with acute leukemia. DESIGN: A randomized, controlled, multicenter trial. SETTING: 30 hematologic units in tertiary care or university hospitals. PATIENTS: 820 consecutive, afebrile, adult patients with acute leukemia and chemotherapy-induced neutropenia. INTERVENTION: Patients were randomly assigned to receive fluconazole, 150 mg, as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours. MEASUREMENTS: An intention-to-treat analysis was done for 820 patients: 420 treated with fluconazole and 400 treated with oral amphotericin B. RESULTS: Definite systemic fungal infection occurred in 2.6% of fluconazole recipients and 2.5% of amphotericin B recipients; suspected systemic fungal infection requiring the empiric use of intravenous amphotericin B occurred in 16% of fluconazole recipients and 21% of oral amphotericin B recipients, a difference of 5 percentage points (95% CI for difference, -0.02% to 10%; P = 0.07). Superficial fungal infection was documented in 1.7% of fluconazole recipients compared with 2.7% of amphotericin B recipients, a difference of one percentage point (CI of difference, -0.9% to 3%; P > 0.2). The distribution of fungal isolates in systemic and superficial fungal infection was similar in both groups. The overall mortality rate accounted for 10% in both groups. An excellent compliance was documented for 90% of patients treated with fluconazole compared with 72% of those treated with amphotericin B suspension, a difference of 18 percentage points (CI for difference, 13% to 23%). Side effects were documented less frequently in fluconazole than in amphotericin B recipients (1.4% compared with 7%, a difference of 5.6 percentage points; CI for difference, 2% to 8%; P < 0.01). CONCLUSION: Fluconazole was at least as effective as oral amphotericin B in preventing systemic and superficial fungal infection and the empiric use of amphotericin B in neutropenic patients with acute leukemia but was better tolerated.

Effects of parenteral diclofenac sodium on upper gastrointestinal motility after food in man.

In experimental animal models nonsteroidal anti-inflammatory drugs may influence gastrointestinal motility, but as evidence is lacking in man. The effect of diclofenac sodium 75 mg i.m. on the motor response of the upper gastrointestinal tract to food has been studied by manometry in 9 healthy volunteers. Diclofenac had no effect on the motor activity of the stomach, duodenum, or jejunum after a 605 kcal meal.

Using teicoplanin for empiric therapy of febrile neutropenic patients with haematological malignancies.

The cumulative experience with teicoplanin in treating febrile neutropenic patients included in three different comparative clinical trials conducted at a single institution during a 3-year period, is presented. 152 febrile episodes in 129 neutropenic patients were treated with i.v. teicoplanin (6 mg/kg/d) combined with amikacin (15 mg/kg/d) plus ceftazidime (90 mg/kg/d). The study population comprised 75 patients with acute leukaemia and 77 marrow recipients: 53% (81/152) had a central venous catheter in place and 68% (103/152) had severe neutropenia (less than 100/mm3) at the beginning of the febrile episode. The overall response rate of the evaluable febrile episodes was excellent: 88% (107/122) improved. Bacteraemias due to Gram-positive cocci accounted for 75% of the total (42/56) and pathogens in the blood isolates were mostly staphylococci (coagulase-negative 14, coagulase-positive 13) and streptococci (13). The response rate of Gram-positive bacteraemias was good: 88% (37/42) improved and 75% (9/12) of Gram-positive bacteraemias having teicoplanin as the only antibiotic with in vitro activity against the infective strains were cured. Death due to infection accounted for 7% of total febrile episodes (11/152). Side effects were documented in 14% of the episodes. In a setting of high prevalence of Gram-positive infections caused by strains with a high rate of resistance to aminoglycoside and beta-lactam antibiotics, there may be an advantage in including teicoplanin in the initial empiric antibiotic regimen for febrile neutropenic cancer patients.

[Adverse effects of corticosteroids]. / Effetti indesiderati dei corticosteroidi.

Due to their anti-inflammatory and immunosuppressive properties, as well as their action on the hematopoietic system and the calcium phosphate turnover, corticosteroids are widely employed in the treatment of many diseases. However, the therapeutic use of these compounds is frequently associated with unwanted, mainly type A, effects that are directly dependent on the wide spectrum of their pharmacological activities. In this study these side effects are critically reviewed and classified on the basis of the organs and systems involved. Where possible, the incidence, pathogenesis, type of steroid, dose and schedule are reported, and the precautions that should prove useful in reducing the incidence and gravity of the side effects are given.

Ceftriaxone versus aztreonam plus cefazolin for infections in cancer patients with adequate neutrophil counts.

In a prospective randomized trial, 154 febrile episodes in cancer patients with adequate neutrophil counts (greater than 1,000 cells/mm3) were treated with either ceftriaxone (72 episodes) or aztreonam plus cefazolin (82 episodes). Documented infections represented almost half of the febrile episodes. The overall response rates among the 144 evaluable episodes were similar for the two regimens: 76% (51/67) with ceftriaxone versus 82% (63/77) with aztreonam plus cefazolin (p = 0.41, not significant). Although not statistically significant, the response rate of the microbiologically documented infections was slightly better in patients treated with the double beta-lactam combination (85% vs. 65%, p = 0.16) and clinically documented infections showed a better response in the group of patients receiving monotherapy (87% vs. 59%, p = 0.12). No serious adverse effects were observed during this study and both regimens were well tolerated. Ceftriaxone or the combination of aztreonam plus cefazolin showed a similar efficacy as empirical therapy for infections in cancer patients with adequate neutrophil counts.

Norfloxacin prophylaxis for neutropenic patients undergoing bone marrow transplantation.

To prevent bacterial infections in the neutropenic post-transplant period, norfloxacin 400mg twice daily was administered as oral prophylaxis to 44 marrow recipients isolated in laminar airflow rooms (LAFRs). Patients had a mean age of 30 years (8-50) and a male/female ratio of 29/15. The mean duration of prophylaxis was of 41 days (20-80), that of neutropenia (PMN less than 1000 x 10(6)/l) of 31 days (6-76) and that of severe neutropenia (PMN less than 100 x 10(6)/l) of 19 days (10-55). All but two patients developed one or more febrile episodes (total episodes: 71), 33 of which were documented infections. Eighteen bacteraemias occurred and all were caused by Gram-positive cocci: five by coagulase-negative staphylococci (three methicillin resistant), four by coagulase-positive (one methicillin resistant), seven by streptococci (four S. sanguis, one S. milleri, one group B, one group C), and two by enterococci. All streptococcal and enterococcal strains, but only one MR coagulase-positive staphylococcus, proved to be resistant to norfloxacin. Norfloxacin was well tolerated and no prophylactic course had to be interrupted because of side effects. In conclusion, norfloxacin adequately prevents infections caused by Gram-negative bacilli in bone marrow recipients isolated in LAFRs, but Gram-positive infections still remain a problem in these patients indicating the need for improving this prophylactic regimen.