cilastatin--imipenem-drug-combination and Agranulocytosis

One hundred febrile episodes in 89 neutropenic patients after cytotoxic chemotherapy were randomized to be treated with either ceftazidime or imipenem as initial monotherapy. The clinical characteristics of the two groups of patients were comparable. The response of the fever in patients who received imipenem was significantly better than that in those who received ceftazidime (77 versus 56%, respectively; P = 0.04), especially in those with microbiologically documented infection (81 versus 33%, respectively; P = 0.02). The in vitro susceptibilities and the clinical responses suggested that, with the possible exception of Pseudomonas spp., imipenem was more effective than ceftazidime in treating neutropenic infections caused by both gram-positive and -negative organisms. An additional 23 and 21% of the patients in the ceftazidime and imipenem groups, respectively, responded to the addition of cloxacillin and amikacin following failure of monotherapy. The majority of the treatment failures, relapses, and superinfections were related to resistant infective organisms such as methicillin-resistant Staphylococcus spp. and Pseudomonas spp. or disseminated fungal infections.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Ceftazidime; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Fever; Humans; Imipenem; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Prospective Studies; Randomized Controlled Trials as Topic

In a prospective, randomized study we compared ceftriaxone (active ingredient of Rocephin) plus amikacin, ceftazidime plus amikacin and imipenem/cilastatin in the empiric therapy of febrile granulocytopenic (less than 500/mm3) patients with cancer or aplastic anemia. Of 27 evaluable episodes, 12 were treated with ceftriaxone plus amikacin, 5 with ceftazidime plus amikacin and 10 with imipenem/cilastatin. 56% were culture-positive. Septicemia was the most frequent site of infection and Escherichia coli was the most frequently isolated organism. The efficacy of the three regimens was comparable. One failure occurring in each treatment group was successfully treated with an alternative antibiotic regimen. A second failure in the first treatment group did not respond to the alternative treatment either. No major adverse effects occurred. This study demonstrates that the three regimens are excellent in the empiric therapy of febrile granulocytopenic patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Ceftazidime; Ceftriaxone; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Fever; Humans; Imipenem; Male; Middle Aged; Prospective Studies; Random Allocation; Remission Induction

Seventy-eight patients with cancer experienced 88 episodes of fever while neutropenic and were randomly assigned to receive empiric antibiotic therapy with cefoperazone 2 g intravenously every 12 hours and mezlocillin 4 g intravenously every six hours or imipenem/cilastatin 500 mg intravenously over 30 to 60 minutes every six hours. Within 96 hours of starting antibiotic treatment, 24 patients (57 percent) treated with cefoperazone and mezlocillin and 34 patients (74 percent) receiving imipenem/cilastatin became afebrile. One half of the patients in each arm required changes in the antibiotic regimen because of side effects, persistent fever with a site suspicious for infection, resistant organisms, or breakthrough bacteremias. Forty patients (95 percent) receiving cefoperazone and mezlocillin and 43 patients (93 percent) receiving imipenem/cilastatin recovered from the neutropenic episode. Two patients in each regimen group died of their underlying disease. One patient in the imipenem/cilastatin arm died of Pseudomonas aeruginosa sepsis. Although the two regimens are comparable in efficacy, the incidence of side effects favored the cefoperazone and mezlocillin group. No seizures or bleeding were seen in either arm; however, 19 patients (41 percent) receiving imipenem/cilastatin required pretreatment antiemetic drugs for nausea.

Topics: Adult; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Cefoperazone; Cilastatin; Cilastatin, Imipenem Drug Combination; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Fever; Humans; Imipenem; Male; Mezlocillin; Neoplasms; Neutropenia; Thienamycins

In this open, controlled, randomized multi-clinic trial, monotherapy with imipenem/cilastatin was compared to amikacin plus piperacillin as empiric antibacterial therapy in 210 neutropenic cancer patients. Of patients randomized, 53 (25%) had bacteriologically documented infections and of those 30 had septicemia. A further 80 patients (38%) were evaluable for clinical efficacy but did not have documented infections. Seventy-seven patients (37%) were non-evaluable due to effective antibiotic treatment before the trial, early institution of other antibiotics during the trial, verified non-bacterial infections, no neutropenia or other reasons. There were no significant differences in terms of efficacy between imipenem/cilastatin and amikacin plus piperacillin but a consistent trend towards higher rates of clinical cure or improvement and of elimination of causative pathogens was noted in the imipenem/cilastatin group. In patients who were severely neutropenic (less than 0.1 x 10(9) granulocytes/l), similar cure rates were obtained in the two treatment groups--again with a tendency towards better results in the imipenem/cilastatin group. Among evaluable patients with septicemia, one patient in the imipenem/cilastatin group had persistent Staphylococcus aureus bacteremia during treatment. Five patients in the amikacin plus piperacillin group had persistent bacteremia during treatment; all but one (a Pseudomonas aeruginosa) caused by strains resistant to amikacin or piperacillin. Clinical and laboratory adverse effects were mild in the imipenem/cilastatin group although nausea was significantly more common than in the amikacin plus piperacillin group. Among patients on amikacin plus piperacillin, one died in renal failure, possibly related to treatment. Drug-related serious adverse events were reported in two additional amikacin plus piperacillin patients; one with drug fever and one with hearing loss. Microbiological adverse effects occurred in similar frequencies in the two groups. It is concluded that imipenem/cilastatin is a promising candidate for monotherapy of bacterial infections in neutropenic cancer patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Anti-Bacterial Agents; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Drug Resistance, Microbial; Female; Humans; Imipenem; Male; Middle Aged; Neutropenia; Penicillin Resistance; Piperacillin; Prospective Studies; Random Allocation; Thienamycins

Antibiotic-induced severe neutropenia and less frequently agranulocytosis has been reported. In most of these cases a relatively normal myelopoiesis is found. We report on the first case of agranulocytosis with histological evidence of pure white cell aplasia associated with imipenem-cilastatin treatment.

Topics: Aged; Agranulocytosis; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Leukocyte Count

A 46-year-old woman is described with a clozapine-induced agranulocytosis. She was treated with a broad-spectrum antibiotic and supportive care was provided with granulocyte colony-stimulating factor (G-CSF). Immune-mediated mechanisms of clozapine-induced agranulocytosis and the role of haematopoietic growth factors are discussed.

Topics: Agranulocytosis; Antipsychotic Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Clozapine; Disease-Free Survival; Drug Combinations; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Imipenem; Leukocyte Count; Middle Aged; Netherlands; Schizophrenia

The pharmacokinetics of imipenem/cilastatin were studied in febrile neutropenic patients with haematological malignancies. The peak plasma concentrations (36.4 +/- 4.96 mg/l), plasma half-life (60 min), volume of distribution (0.28 +/- 0.02 l/kg) and plasma clearance (3.23 +/- 0.38 ml/min/kg) were comparable with those in normal healthy volunteers suggesting that the drug handling is not appreciably altered in this group of patients. The administration of 12.5 mg/kg (max 1 g), 6-hourly achieved levels that were up to 3.5 times MICs of most relevant bacteria. The drug therefore has a potential use as empirical monotherapy in febrile neutropenic patients.

Topics: Acute Disease; Adult; Agranulocytosis; Blood Preservation; Chromatography, High Pressure Liquid; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Female; Half-Life; Humans; Imipenem; Leukemia; Lymphoma, Non-Hodgkin; Male; Metabolic Clearance Rate; Middle Aged; Neutropenia

We treated 20 febrile episodes in 14 patients with granulocytopenia under 1.0 x 10(9)/L. 6 episodes were pretreated, in 14 Imipenem/Cilastatin was the initial therapy. The age was between 36 and 78 years, mean 57 years. Predominant underlying disease was acute leukemia. 8 out of 20 episodes became afebrile. Counting only proven bacterial infections the response rate was 6 out of 12. There was a statistical difference between not pretreated and pretreated patients. The treatment had no success in the latter. There was also a significant difference between febrile episodes of patients with granulocytes increasing under treatment to those remaining unchanged. 5 of 6 of the first group but none of the 9 episodes of the second group resolved. 7 patients died while on treatment between the 9th and 32nd day after therapy had started. There was no connection between the Imipenem treatment and the deaths. Tolerance of therapy was good. The most common side effect was nausea, which was reversible with reduction of the infusion rate. Most important advantage of imipenem is the easy handling and the low inconvenience to the patient. We had only moderate efficacy in our series.

Topics: Adult; Aged; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Fever of Unknown Origin; Humans; Imipenem; Male; Middle Aged; Neutropenia; Prospective Studies