Comparison of imipenem versus cefuroxime plus tobramycin as empirical therapy for febrile granulocytopenic patients and efficacy of vancomycin and aztreonam in case of failure.

143 aplastic episodes with fever in 91 haematological patients with granulocytopenia were treated empirically in a randomized prospective study using either imipenem (Imi) or a combination of tobramycin and cefuroxime (T/C). Response after 72 h was significantly better in patients receiving Imi (44/75 vs 27/68, p < 0.05). This was seen especially in patients with bacteriologically proven infections where the isolated staphylococci and streptococci were more susceptible to Imi. In both groups, patients who failed to respond to the initial antibiotic therapy were given vancomycin and aztreonam (V/A). The response rate after another 72 h, measured using the same criteria as after the first 72 h, did not differ statistically between the groups. One patient in each study group died from the bacterial infection, both from Gram-positive bacteraemia. Duration of fever was significantly shorter in the Imi group (4 days vs 7 days, p < 0.04). Serum peak and trough concentrations of the antibiotics were comparable. Both regimens were well tolerated. Our results show that monotherapy with imipenem is superior to the combination of tobramycin and cefuroxime during the first 72 h of therapy and can be safely administered to neutropenic patients with predominantly Gram-positive infections. A combination of vancomycin and aztreonam, given when initial imipenem treatment has failed, was effective in only a few patients. Adjuvant glycopeptide therapy from the outset in the treatment of febrile granulocytopenic patients did not seem worthwhile.

The release of endotoxin from antibiotic-treated Escherichia coli and the production of tumour necrosis factor by human monocytes.

The influence of antibiotic-induced release of endotoxin from in-vitro grown Escherichia coli on the production of tumour necrosis factor-alpha (TNF) by human monocytes was studied. Antibiotics tested were: cefuroxime (7.5 and 75 mg/L); ceftazidime (10 and 100 mg/L); aztreonam (10 and 100 mg/L); imipenem (10 and 100 mg/L); and tobramycin (8 mg/L). The effect of the combination of cefuroxime plus tobramycin, and the effect of taurolidine, an endotoxin-binding agent, on TNF production was also tested. After incubation for 4 h, all antibiotic-treated cultures (high-dose) induced a similar rise in extracellular TNF production when compared to the controls. However, after incubation for 24 h, a significant rise in TNF production was noticed in the cefuroxime and aztreonam-treated cultures (6440 and 5969 ng/L, respectively) compared to the ceftazidime and imipenem-treated cultures (846 and 381 ng/L, respectively). The cefuroxime-induced release of TNF could be reduced by addition of tobramycin (from 6440 to 1615 ng/L). Similar differences in TNF production were noticed in cell-associated TNF. Dose-response curves did not demonstrate differences in TNF production in aztreonam or imipenem-treated cultures. However, for both cefuroxime and ceftazidime-treated cultures, low-dose treatment resulted in significantly higher production of TNF. The differences in TNF production between these antibiotics could be explained by the production of filaments following treatment with cefuroxime, aztreonam and low-dose ceftazidime, resulting in late bacterial lysis with high levels of endotoxin, whereas treatment with imipenem or high-dose ceftazidime resulted in the formation of spheroplasts, resulting in early lysis of the bacteria and much lower levels of endotoxin. The addition of taurolidine to either imipenem or aztreonam-treated cultures prevented a rise in TNF production as a result of nearly complete neutralization of the released endotoxin. It was concluded that the observed differences in TNF production by human monocytes in vitro were related to differences in the mechanisms and amount of antibiotic-induced release of endotoxin.

Prevention of infection in acute leukemia.

In a randomized study comparing cotrimoxazole plus colistin with ciprofloxacin, each in combination with nonabsorbable antimycotics, the incidence of major infections in terms of septicemias and pneumonias as well as of minor infections and episodes of unexplained fever (FUO) was higher in patients treated with ciprofloxacin. In cases of microbiologically documented infections, gram-positive cocci dominated by far. In surveillance cultures of oral washings and of feces, gram-negative enterobacteria were only rarely detected; however, large numbers of cultures were positive for Acinetobacter species. There were four cases of documented Pneumocystis carinii pneumonia in patients not receiving cotrimoxazole. The incidence of documented mycotic infections as well as the detection of fungi in surveillance cultures was similar in both treatment groups. A decrease in the number of adverse events, especially of allergic reactions, could not be achieved by the administration of ciprofloxacin. In conclusion, cotrimoxazole plus colistin in combination with nonabsorbable antimycotics remains the standard regimen for prevention of infection in patients with acute leukemia undergoing aggressive remission induction therapy. A detailed analysis of study II will be prepared for publication.

Ciprofloxacin and norfloxacin for selective decontamination in patients with severe granulocytopenia.

In a randomized multicenter study, ciprofloxacin and norfloxacin, each in two different dose regimens and in combination with non-absorbable antimycotics, were administered to 51 patients with acute leukaemia undergoing aggressive remission induction chemotherapy for infection prevention. Both drugs showed an effective elimination of gram-negative potential pathogens and Staphylococcus aureus not affecting the anaerobic flora of the gastrointestinal tract. A low incidence of side effects and a satisfactory patient compliance could be observed. A daily dosage of 1,000 mg ciprofloxacin or 800 mg norfloxacin is recommended for infection prevention in severely granulocytopenic patients.