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In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C +/- T), both agents being administered only if the initial granulocyte count was below 200/microliters, or ceftazidime plus piperacillin (C + P). The overall response rate was 71% (39 of 60 for C +/- T and 45 of 58 for C + P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C + P regimen (P = 0.06), there was no difference in response for patients with bacteremia and profound (< 100/microliters) sustained granulocytopenia. The double beta-lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced excellent serum bactericidal levels (C +/- T geometric mean peak 1:170; C + P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C + P and in 6 of 89 trials in the C +/- T group (P = 0.19). The incidence of secondary infections in patients with profound (< 100/microliters) sustained granulocytopenia was lower in the C +/- T group (P = 0.04). Alimentary canal anaerobic flora preservation with C +/- T, and suppression with C + P, was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Neutropenic patients with cancer are traditionally treated with empiric antibiotic combinations when they become febrile. The availability of broad-spectrum antibiotics such as ceftazidime and imipenem has made it possible to initiate therapy with a single agent (monotherapy). The objectives of this trial were to compare ceftazidime and imipenem as single agents for the therapy of febrile episodes in neutropenic patients and to ascertain whether the addition of an aminoglycoside (amikacin) to either of these agents would provide an advantage., Methods: A prospective clinical trial was conducted in which eligible neutropenic patients with cancer were randomized to one of four treatment arms: ceftazidime alone; imipenem alone; ceftazidime plus amikacin; and imipenem plus amikacin. Efficacy analysis was done for 750 assessable episodes. A multivariate logistic-regression analysis was also performed to examine the unique contribution of various prognostic factors., Results: The overall response rates were 76% with imipenem plus amikacin, 72% with imipenem, 71% with ceftazidime plus amikacin, and 59% with ceftazidime alone. Single-organism gram-positive infections occurred in 101 of 750 episodes. Without a change in antibiotics, the response rates were 50% with imipenem, 40% with imipenem plus amikacin, 39% with ceftazidime plus amikacin, and 38% with ceftazidime. Most responded to vancomycin or other antibiotics, and the mortality associated with gram-positive infections was only 5%. Regardless of the antibiotic regimen, the majority of uncomplicated gram-negative infections responded to therapy and the majority of complicated gram-negative infections failed to respond. Multivariate logistic-regression analysis showed that recovery of the neutrophil count was the most favorable prognostic factor in a patient's response to infection, whereas the presence of gram-positive infection, acute leukemia, pulmonary or enteric infection, and therapy with ceftazidime were unfavorable factors., Conclusions: Single-agent therapy with imipenem is as effective as more conventional combination antibiotic therapy for the empirical treatment of febrile episodes in neutropenic patients with cancer.

It has been suggested that empiric broad-spectrum antibiotics, instituted for fever in the presence of granulocytopenia, should continue to be administered, even when infection is not demonstrable, to those patients who remain persistently febrile and granulocytopenic. Therefore, the consequences of discontinuing antibiotics when the presence of infection is doubted in this setting were evaluated. In 16 (3.7 percent) of 429 episodes of fever and granulocytopenia for which empiric antibiotic therapy was instituted, after approximately four days, persistence of both fever and granulocytopenia was found, and yet infection was prospectively classified at that time as "doubtful." The initial empiric antibiotic regimen was therefore discontinued after a mean of 4.8 (median 5.0) days. Discontinuation of antibiotics proved appropriate for half of the patients; eight patients received no systemic therapeutic antibiotics with no evidence of infection during a period of at least two weeks. The other eight patients had antibacterial antibiotics reinstituted within a mean of 2.4 days; six infections were subsequently demonstrable. Six of these eight patients also required or were believed to require antifungal therapy with intravenous amphotericin B for presumed fungal infections. Patients with relapsed leukemia or lymphoma and those with a likelihood of continued profound granulocytopenia (counts below 100/microliters) or both were the ones who tended to require reinstitution of antibiotics. Discontinuation of antibiotics when infection was considered doubtful despite persistence of both fever and granulocytopenia was, therefore, successful in eight of 16 patients. Reinstitution of antibiotics was required in the eight remaining patients. No definite rule appears to be applicable to all patients.

15 patients with metastatic, nonhematopoietic neoplasms refractory to conventional means of treatment were given intensive chemotherapy followed by infusion of autologous noncryopreserved bone marrow which had been stored at 10 degrees C. This study has shown that the procurement of bone marrow from patients with advanced disease and reinfusion 12 h after high dose chemotherapy is tolerated without significant patient morbidity. The use of marrow stored at 10 degrees C leads to adequate recovery of granulocyte stem cells. The present data also suggest that autologous bone marrow transplantation is beneficial in shortening hematopoietic recovery time in patients receiving high dose chemotherapy and may improve response rates in patients with refractory neoplasms.

To determine whether antimicrobial synergism affects the outcome of gram-negative bacteremia among profoundly (less than 100/microliter) neutropenic cancer patients, the clinical courses of 75 such patients who received empiric therapy with combination, broad-spectrum antibiotics were analyzed. Twenty-nine of 34 (85 percent) patients whose granulocyte count increased to more than 100/microliter during therapy improved, whereas only 12 of 41 (29 percent) patients with no increase in granulocyte count showed improvement (p = 0.0002). The critical group for further analysis was, therefore, those patients with persistent, profound granulocytopenia. Among these 41 patients, synergism was associated with a substantially better response rate: eight of 18 (44 percent) improved compared with none of 13 in whom synergism was not detected (p = 0.005); presence or absence of synergism could not be assessed for the pathogens isolated from the remaining 10 patients because the organisms were exquisitely susceptible to one of the two antibiotics used. Further evaluation of these persistently neutropenic patients indicated that synergism appeared critical even when the pathogen was susceptible to both antibiotics. Thus, seven of 11 (64 percent) showed response when the two drugs were synergistic in activity, compared with none of six when synergism was not present (p = 0.01). These data again demonstrate the importance of granulocyte recovery to patient response and further indicate that synergistic combinations of antibiotics are indicated for cancer patients with gram-negative bacteremia and persistent, profound granulocytopenia.

The efficacy and safety of norfloxacin were compared with those of placebo, vancomycin-polymyxin, and trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis of bacterial infections in granulocytopenic patients. The study results showed that norfloxacin treatment, which was well tolerated and not associated with any serious systemic adverse effects, prevented acquisition of gram-negative bacillary organisms. Fewer norfloxacin-treated patients (38 of 108 patients, or 35 percent) experienced microbiologically documented infections compared with patients receiving placebo (27 of 40 patients, or 68 percent), vancomycin-polymyxin (16 of 30 patients, or 53 percent), or TMP/SMX (14 of 28 patients, or 50 percent). Gram-negative bacteremia developed in five of 108 norfloxacin-treated patients (5 percent), compared with 17 of 40 placebo-treated patients (43 percent), five of 30 treated with vancomycin-polymyxin (17 percent), and one of 28 patients treated with TMP/SMX (4 percent). The incidence of gram-positive bacteremia was similar in all study groups and was not affected by norfloxacin or any other oral prophylactic antibiotics. These results suggest that norfloxacin is both safe and effective for the prevention of serious gram-negative bacillary infections in granulocytopenic patients. More effective prophylaxis of gram-positive bacterial infections, however, is needed.

A program of nonfrozen autologous bone marrow rescue was used to treat patients with refractory nonhematological neoplasms. In vitro storage of bone marrow cells and CFU-C suggests that storage at 4 degrees or 10 degrees for periods up to five days can be undertaken with only minor loss of CFU-C. However, since the loss occurred in a gradual fashion, shorter duration of storage would probably be better. Hematological recovery after high dose chemotherapy occurred faster in patients given more CFU-C and those with shortest duration of storage prior to reinfusion.

The effects of newly available broad-spectrum antibiotics, used for infection prophylaxis and therapy in cancer patients, on faecal aerobic and anaerobic bacteria were investigated. Quantitative and qualitative aerobic and anaerobic cultures were performed in 34 patients before therapy and between the sixth and eleventh day of therapy. Of the two prophylactic regimens norfloxacin plus amphotericin-B eliminated Enterobacteriaceae and enterococci without encouraging growth of yeasts or Clostridium difficile whereas trimethoprim-sulphamethoxazole did not eliminate enterococci and colonization with toxin producing C. difficile occurred in two of ten patients. The effect of the two infection prophylaxis regimens on counts of faecal anaerobes was comparable. Monotherapy with ceftazidime and combination therapy with ceftazidime plus tobramycin did not result in major changes (greater than or equal to 3 log increase or decrease) in faecal anaerobic bacteria. Enterobacteriaceae were eliminated except in one patient treated with ceftazidime. The effect of these therapeutic regimens on enterococci was variable. Colonization by yeasts or by toxin negative C. difficile (two of three patients) were found in the ceftazidime group only. During combination therapy with piperacillin plus amikacin for fever during granulocytopenia signs of a disturbed faecal flora were found in one of three patients. Changes in faecal anaerobic bacteria were most marked in the ceftazidime plus piperacillin group. Moreover the isolation of a toxin positive C. difficile occurred in this group, in a patient who was colonized with toxin negative C. difficile before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

We prospectively evaluated the ability of the plugged telescoping catheter (PTC) brush and the single sheathed nonplugged catheter brush to provide sterile lower respiratory tract samples during fiberoptic bronchoscopy in 19 noninfected patients with cancer. Both brushes were evaluated, in random order, in each of the 19 patients. The PTC brush and the single sheath brush were sterile in 12 and 5 patients, respectively, and in 7 patients, the PTC brush alone was sterile (p = 0.016, two-sided). Patients were anesthetized by lidocaine administered through the bronchoscope (6 patients), via an aerosol (3 patients), or by transtracheal injection (10 patients). The advantage of the PTC brush was evident only when aerosol or transtracheal anesthesia were used; the PTC brush was sterile in 9 of 13 patients, whereas the single sheathed brush was sterile in only 2 of these 13 (p = 0.016, two-sided). The plugged telescoping catheter brush is therefore more suitable than the single sheathed brush catheter for delivering sterile brushes to the lower respiratory tract during fiberoptic bronchoscopy.

Infection remains a major cause of morbidity and mortality for the patient with cancer who experiences episodes of severe granulocytopenia. The search continues for new antimicrobial agents with improved efficacy and lower incidence of toxicity. Imipenem is a new carbapenem antibiotic which possesses a broad antibacterial spectrum with excellent activity against Pseudomonas aeruginosa and the other commonly recovered enteric gram-negative bacilli that infect the granulocytopenic patient with cancer. The combination of imipenem plus an aminoglycoside has shown in vitro synergy against P. aeruginosa and Staphylococcus aureus whereas the combination of imipenem plus piperacillin or the extended spectrum cephalosporins have frequently shown antagonism when tested against P. aeruginosa and Serratia marcescens. The use of a P. aeruginosa-infected neutropenic rat model has provided an in vivo system to evaluate the activity of new antibiotics or antibiotic combinations. Monotherapy with imipenem is as effective in this model as any of the currently available synergistic antibiotic combinations. This degree of activity has not been found with other broad-spectrum antibiotics when used alone. Imipenem provides serum bactericidal activity well above a 1:8 dilution for the four most commonly isolated pathogens: P. aeruginosa, Escherichia coli, Klebsiella species, and S. aureus. In addition, imipenem's post-antibiotic effect against P. aeruginosa may be pertinent. Imipenem is a unique antibiotic, with properties that make it well suited for study as monotherapy for fever and suspected infection in granulocytopenic patients with cancer. A prospective randomized, double-blind study comparing imipenem with a control regimen of piperacillin plus amikacin as empiric antibiotic therapy of febrile granulocytopenic patients with cancer is currently underway at the University of Maryland Cancer Center.

The suppression of pathogenic aerobes and the preservation of anaerobes provides a degree of infection prevention during granulocytopenia. Trimethoprim/sulfamethoxazole (TMP/SMZ) suppresses Enterobacteriaceae and probably maintains colonization resistance through sparing of anaerobes. TMP/SMZ (320/1600 mg/day) treatment was compared to placebo in a double-blind, randomized trial in patients with newly diagnosed small cell carcinoma of the lung during the initial courses of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. Infections were evaluated as microbiologically documented, with or without bacteremia, and clinically documented and were correlated to granulocytopenia. Of the 61 patients evaluated, 32 were given TMP/SMZ and 29 were given placebo; both groups had similar characteristics with regard to disease extent, performance status, age, sex, chemotherapy, and days of granulocytopenia. Incidence of infection at less than 100 granulocytes/microliters was significantly reduced in the TMP/SMZ group (2 infections/100 days) compared to placebo (11 infections/100 days, p = 0.005). Also reduced were the number of bacteremias and the mean proportion of study time on broad-spectrum antibiotics (p less than 0.01). Compared to placebo, TMP/SMZ provided infection prophylaxis without an increase in marrow suppression among patients with small cell carcinoma of the lung receiving intensive chemotherapy.

The double beta-lactam combination of moxalactam plus piperacillin was compared with the aminoglycoside-containing regimen of moxalactam plus amikacin in a prospective, randomized trial of empiric therapy for 302 febrile episodes in granulocytopenic cancer patients. The moxalactam/piperacillin regimen was found to be as effective as the moxalactam/amikacin regimen (70 percent overall responses); responses with moxalactam/piperacillin and moxalactam/amikacin were similar for microbiologically documented infections (24 of 37, 65 percent, versus 20 of 35, 57 percent), for the subgroup with bacteremias (19 of 32 versus 14 of 28), and for clinically documented infections (41 of 58, 71 percent, versus 40 of 48, 83 percent). Responses were similar also for bacteremia in patients with persistent, profound (less than 100/microliter) granulocytopenia. Among profoundly (less than 100/microliter) granulocytopenic patients with gram-negative bacteremia, an increase in the granulocyte count to more than 100/microliter during therapy and a peak bactericidal activity of 1:16 or more (the latter noted in seven of nine moxalactam/piperacillin trials and six of nine moxalactam/amikacin trials) correlated with a favorable clinical response in 85 percent (p less than or equal to 0.00003) and 92 percent (p less than or equal to 0.044), respectively. Although serious side effects were minimal with either regimen, the double beta-lactam combination was associated with significantly less frequent nephrotoxicity (two of 145 versus 12 of 130; p less than or equal to 0.003) and ototoxicity (none of 34 versus seven of 34; p less than or equal to 0.006). The double beta-lactam combination of moxalactam plus piperacillin was found to be as effective as moxalactam plus amikacin but to have significantly less nephro- and ototoxicity.