In this prospective multicenter trial, treatment strategies for 1573 patients with neutropenia < 1000/microliters and fever > or = 38.5 degrees C after cytotoxic chemotherapy were compared. Patients with unexplained fever were randomized to a three-phase sequential study for different established drug regimens. If an infection could be defined microbiologically or clinically, treatment modifications were determined. In phase I, treatment for all patients consisted of acylaminopenicillin (PEN) plus aminoglycoside (AMG); or third-generation cephalosporin (CEPH) plus AMG; or PEN plus CEPH. In 800 patients with unexplained fever the response rates were: PEN/AMG (n = 258): 74.4%, CEPH/AMG (n = 252): 73.4%; PEN/CEPH (n = 290): 70.0%. Total response rate was 72.5%. In phase II, patients not responding after 3 days received PEN/CEPH/vancomycin (n = 70) or PEN/CEPH/AMG (n = 74). The respective response rates were 52.9% and 55.4%, total 54.2%. If fever did not resolve, the patients received either PEN/CEPH (n = 40) or imipenem/cilastatin (n = 59) both in combination with amphotericin-B/5-flucytosin/rifampin. The response rates were 62.5% and 79.7%, respectively (p = 0.07), total 72.7%. No significant differences between the treatment modalities compared were found. Analyzing all three phases together, 91.3% of patients with unexplained fever were cured. The response rate was also analyzed according to patients with gram-positive bacteremia (n = 183), response rate = 82.5%; gram-negative organisms (n = 145) 78.6%; fungemia (n = 51) 43.1% (p < 0.001); lung infiltrates (n = 269) 61.3% (p < 0.001); clinically documented infections (n = 198) 84.4%; and clinically and microbiologically documented infections (n = 84) 82.1%. If infections were diagnosed after at least 5 febrile days, more lung infiltrates and fungal infections occurred (p < 0.001). Leukocytes rising above 500/mu during the infection predicted better response rates (p < 0.001): in unexplained fever 97.8% vs 86.5% and lower death rates 1.5% vs 8.5%. In documented infections the response rates were then 89.9% vs 62.3% and the death rates 7.0% vs 20.5%. Therapy of neutropenic fever and infections must be adapted according to risk factors and should include early empiric antifungal therapy. The therapeutic and prophylactic use of hematopoietic growth factors to overcome neutropenia should be evaluated.
The pharmacokinetics of caffeine, including formation of its major metabolite paraxanthine in plasma, has been investigated in 12 healthy males (age 20-40 years) alone and during co-administration of the 4-quinolones ofloxacin, norfloxacin, pipemidic acid, ciprofloxacin, and enoxacin; ciprofloxacin and enoxacin were given in 3 different dose levels. The naphthyridine derivative enoxacin and the pyrido-pyrimidine derivative pipemidic acid had caused marked inhibition of caffeine and paraxanthine metabolism, whereas the genuine quinolone derivatives norfloxacin and ciprofloxacin had little effect, and the pyrido-benzoxacine derivative ofloxacin had no detectable effect. The different molecular and spatial structures of the compounds appear to be responsible for the differences in inhibitory potency.
The effect of the aminoglycosides amikacin, gentamicin, netilmicin sisomicin and tobramycin on the proximal tubule of the human kidney was investigated in 78 healthy subjects. Fifteen adults were each given gentamicin, sisomicin or tobramycin 3 mg/kg bodyweight, 10 subjects received netilmicin 3 mg/kg or amikacin 15 mg/kg additionally seven subjects amikacin 10 mg and six subjects netilmicin 6 mg on three consecutive days. The principal enzyme of the brush border membrane of the proximal tubule, alanine aminopeptidase (AAP), was determined enzymatically and immunologically in 24-hour urines. The effects of the various aminoglycosides on the membranes were different. Less of membrane AAP was greatest after amikacin and was least after tobramycin. There was no difference between gentamicin, netilmicin, and sisomicin, which had an effect intermediate between the other two compounds. The elimination of AAP occurred at intervals which might possibly have been caused by impairment of cell cycles.
The efficacy of oral itraconazole 2 x 200 mg capsules daily for prevention of systemic mycoses was investigated in granulocytopenic patients with haematological malignancies. Of 241 patients, 197 were evaluable for prophylactic efficacy, and 214 for adverse events. Patients with similar characteristics receiving oral amphotericin B as antifungal prophylaxis, observed over 15 months before introduction of itraconazole, served as control group (n = 223). With itraconazole prophylaxis, 13 cases of aspergillosis (9 proven, 1 probable, 3 possible; 7%) and no systemic yeast infection occurred, compared with 14 episodes of aspergillosis (9 proven, 2 probable, 3 possible; 6%) and 3 proven systemic yeast infections (Candida albicans, Candida norvegensis, Trichosporon beigelii) in the historical group. Adverse events were observed in 13% of evaluable patients receiving itraconazole. In four patients with acute lymphoblastic leukaemia receiving itraconazole and vincristine simultaneously, severe vinca alkaloid-induced neurotoxicity occurred. Plasma concentrations of itraconazole and hydroxyitraconazole were measured in 64 patients. After eight days of itraconazole the median drug concentration was adequate (700 ng/mL), but there was a marked individual variation (229-2861 ng/mL). In comparison with a historical group, antifungal prophylaxis with itraconazole reduced the incidence of systemic yeast infections, but the frequency of aspergillosis was similar. However, a general increasing incidence of aspergillus infections at our hospital over the last four years should be considered in the assessment of study results.
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