A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients.

Oral trimethoprim/sulfamethoxazole (TMP/SMZ) therapy was investigated in the prophylaxis of infections in granulocytopenia. Hospitalized granulocytopenic patients were allocated at random to receive TMP/SMZ (group 1) or to a control group (group 2). The percentage of febrile granulocytopenic days was significantly reduced in group 1, 19 per cent compared to 39 per cent in group 2 (P less than 0.01). In group 1, there were no bacteremias in 59 episodes of granulocytopenia (909 days). In group 2, there were nine bacteremias in 52 episodes of granulocytopenia (796 days)(P = 0.001). Disseminated candidiasis developed in two patients in each group. Candida occurred in similar numbers in surveillance cultures in both groups; Staphylococcus aureus and Pseudomonas aeruginosa were slightly decreased, and Enterobacteriaceae resistant to TMP slightly increased in group 1. This study suggest that oral prophylactic TMP/SMZ therapy is an effective, well tolerated, easily administered alternative to "gut sterilization" with nonabsorbable antibiotics.     

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer.

Early initiation of empiric antibiotic therapy in febrile cancer patients has become established practice, but the appropriate duration of antibiotic therapy when no infectious source can be identified is unknown. The complications of broad-spectrum antibiotics argue for brief treatment, but the risk of an inadequately treated infection in the granulocytopenic patient favors longer therapy. We prospectively studied 306 episodes of fever and granulocytopenia in 143 patients with leukemia or solid tumor (age one to 33 years) with respect to the duration of empiric antibiotic treatment. Eligible patients (fever > 38 °C three times/24 hours or > 38.5 °C once, plus polymorphonuclear leukocytes < 500/mm³) had an extensive diagnostic evaluation, including at least two preantibiotic blood cultures, and therapy was then started with a broad-spectrum antibiotic regimen— Keflin^®, gentamicin and carbenicillin (KGC). Initial evaluation failed to identify an infectious etiology for the fever in 142 of 306 (46 per cent) episodes. Fifty-six of 142 (39 per cent) of these fevers of unknown origin were associated with persistent granulocytopenia for more than seven days; in 33 of these, defervescence occurred while the patients received KGC. After seven days of empiric KGC therapy, the 33 patients with fevers of unknown origin who had become afebrile with empiric antibiotics but whose polymorphonuclear leukocytes remained less than 500/mm³ were randomized to either continue or discontinue ($\text{d}\text{c}$) to receive KGC. The patients who continued to receive KGC until their polymorphonuclear leukocytes were more than 500/mm³ had no infectious sequelae. However, in seven of 17 (41 per cent) of the patients randomized to $\text{d}\text{c}$ KGC infectious sequelae developed (p = 0.007) within a median of two days of discontinuing KGC (two with fever which again responded to KGC therapy, and five with a documented infection [two ultimately fatal]). In none of the patients did a resistant microbial flora or superinfection develop. These data suggest that the patient with a fever of unknown origin who becomes afebrile during empiric antibiotic therapy may profit from continued therapy while granulocytopenia persists.     

Can antibacterial therapy be discontinued in persistently febrile granulocytopenic cancer patients?

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.     

Bacteremia due to gram-positive cocci in patients with neoplastic disease.

Fifty-seven bacteremias caused by gram-positive cocci were observed over a four and a half year period in patients with a wide variety of malignant diseases. All patients had two or more positive antemortem blood cultures with the same microorganism. The number of bacteremic episodes were divided between Streptococcus pneumoniae (14), other streptococci (17) and Staphylococcus aureus (26). Seventy per cent, including 50 per cent of the pneumococcal bacteremias, were nosocomial. An identifiable portal of bacterial entry in the skin or the gastrointestinal or respiratory tract mucosa was present in 95 per cent, fever in 81 per cent and a prebacteremic performance status of less than 2 in 53 per cent. Granulocytopenia was present in only 18 per cent of the cases at the onset of the bacteremia. These bacteremias appeared to be responsive to antimicrobial therapy with an over-all immediate mortality rate of 23 per cent; 16 per cent in adequately treated patients. Poor outcome was associated with a prebacteremic performance status of 3 or 4, other than optimal antimicrobial therapy, a neutrophil count of less than 1,000/mm³ at the onset of the infection, and bacteremia due to Strep, pneumoniae. Hospitalized cancer patients, especially those with a poor performance status, should be monitored closely for breaks in the mucocutaneous host defense barriers and, if these are present in the face of suspected systemic infection, initial antimicrobial therapy should include drugs appropriate for the treatment of gram-positive coccal microorganisms.     

Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia

69 febrile granulocytopenic episodes without an initial focus of infection were assessed for empiric treatment either with high-dose amikacin plus piperacillin or ceftazidime. 90% of patients in each group survived the granulocytopenic episode; 15 (44 +/- 17%) episodes treated with the combination and 23 (66 +/- 16%) given ceftazidime responded without any modification of initial therapy and half defervesced within 72 h. Persistent fever was the most frequent reason for altering treatment which was done empirically in 90% of cases, but two-thirds of patients required further treatment modification. An infectious focus mainly involving the lung developed during granulocytopenia in 21 patients (30%), of which 17 occurred during antimicrobial therapy. Only 1 infection was shown to be due to bacteria, while 7 were due to fungi. Amikacin levels were similar to those expected following a normal dose (mean peak of 34.7 and mean trough of 12.6 mg/l). Therapy with the combination resulted in a higher serum creatinine (p less than 0.001) and a lower potassium level (p less than 0.001) in comparison with monotherapy. Potassium supplementation was required in 45 +/- 17% of patients given the combination compared with only 4 +/- 7% of those treated with ceftazidime. While both regimens appeared to be equally effective as initial therapy, the need for modification was high in both patient groups. Monotherapy being both simpler to administer and less toxic seems therefore to be the logical choice although the period of empiric therapy must be fully exploited in order to improve diagnosis and therefore antimicrobial management.     

Response to empiric amphotericin B during antileukemic therapy-induced granulocytopenia

We analyzed the initial and overall responses to empiric therapy with amphotericin B as they related to the rate of occurrence and the type of fungal infection and colonization during 264 consecutive episodes of prolonged, profound, chemotherapy-induced bone marrow aplasia (greater than 30 days, less than 100 polymorphonuclear leukocytes/mm3) in 160 adults with acute leukemia. Amphotericin B was administered during 248 (94%) of these granulocytopenic episodes; in 68 cases the drug was given because of documented infection with yeasts or filamentous fungi (DFI), and in 180 cases it was given because of refractory fever without DFI. The frequency of an initial response in patients with DFI (60%) was similar to that in non-DFI-infected patients (61%). Both the initial response rate and the overall survival rate were significantly decreased when therapy with amphotericin B was not initiated empirically before documentation of filamentous DFI. Given the comparatively high rates of initial and overall response (the latter being 74% and 71% for DFI and non-DFI, respectively) and the lack of alternative fungicidal agents, our data support prompt empiric treatment with amphotericin B for refractory fever in adults with acute leukemia who are compromised by severe, therapy-induced granulocytopenia.     

Oral trimethoprim/sulfamethoxazole in attempt to prevent infection after induction chemotherapy for acute leukemia

The efficacy of orally administered trimethoprim/sulfamethoxazole for infection prevention following induction chemotherapy was evaluated in 43 patients with acute leukemia. Twenty patients were randomly assigned to treatment with trimethoprim/sulfamethoxazole during 20 episodes of profound granulocytopenia; 23 patients in the control group were followed through 25 granulocytopenic episodes. The incidences of superficial skin and overall infections were significantly lower in those patients with multiple relapses who received trimethoprim/sulfamethoxazole (p = 0.008); however, there was no difference between the groups in regard to days of fever, days of antibiotic administration, days of hospitalization, or gram-negative rod bacteremia. As a result of this study, this regimen cannot be unequivocally recommended for infection prevention in neutropenic patients with acute leukemia undergoing induction or reinduction chemotherapy.     

Granulocytopenia in hospitalized patients: II. A prospective comparison of two antibiotic regimens in the empiric therapy of febrile patients

The results of empiric antibiotic therapy in 126 hospitalized patients with fever during 192 episodes of granulocytopenia were studied. Febrile granulocytopenic patients were randomly allocated to receive either carbenicillin, methicillin and gentamicin, or carbenicillin and cephalothin. The response rate for the two antibiotic regimens was similar, 49 (60 per cent) of 81 responded to the former and 42 (54 per cent) of 78 to the latter. The response rate in patients receiving other antibiotics because of specific indications or counterindications was 19 (58 per cent) of 33. Thirty-nine (35 per cent) of 110 patients who responded to initial antibiotic therapy had an increase in circulating granulocytes of one log₁₀ or more compared to only 10 (12 per cent) of 79 nonresponders with such an increase. The mortality rate in adult patients receiving carbenicillin, methicillin and gentamicin was eight (16 per cent) of 51, compared to 18 (37 per cent) of 49 in those receiving cephalothin and carbenicillin (P < 0.05). The significance of this difference in mortality rate is uncertain, as there was no difference in the initial response rate or mortality rate between patients treated with the two antibiotic regimens when only patients with documented bacterial infection were considered. Patients who responded to their initial antibiotic regimen, and patients for whose fever no explanation was found, had the best prognosis.     

Prophylactic use of ofloxacin in granulocytopenic patients with hematological malignancies during post-remission chemotherapy.

The prophylactic efficacy of ofloxacin (OFLX) therapy was evaluated in 51 granulocytopenic episodes in 22 patients with hematological malignancies during post-remission chemotherapy in a prospective, randomized, controlled trial. Oral administration of OFLX plus amphotericin-B (AMPH) and polymyxin-B (PL) reduced episodes of fever and infection more than did the control regimen with PL and AMPH alone (p less than 0.01), and the reduction in the incidence of infection was evident even in patients showing severe granulocytopenia (p less than 0.01). Furthermore, the first fever after the onset of granulocytopenia in the OFLX regimen developed later than that in the control regimen (p less than 0.05). Clinically, the prophylactic efficacy was 92% for the OFLX regimen and 40% for the control regimen (p less than 0.01). These findings suggest that OFLX is a promising prophylactic agent following post-remission chemotherapy. Patient hemomyelogram findings similar to those of patients with other malignancies may imply that OFLX is widely effective in granulocytopenic patients taking aggressive chemotherapy.     

Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing multiple courses of intensive chemotherapy

The records of 40 consecutive patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) were reviewed to determine the risk of recurrent fungal pneumonia during multiple episodes of chemotherapy-induced granulocytopenia. Fungal pneumonias were diagnosed as proven or probable using defined pathologic, microbiologic, radiologic, and clinical criteria. Sixteen patients died without a complete remission; of these, all 11 who underwent autopsy were found to have invasive fungal pneumonia. The 24 patients who achieved a complete remission received one to nine (median, four) additional courses of intensive chemotherapy for remission consolidation and/or relapse, and experienced 132 episodes of severe granulocytopenia. Seven patients never had a pulmonary infection despite 34 granulocytopenic episodes. However, fungal pneumonia complicated 32 (33 percent) of 98 granulocytopenic episodes in the other 17 patients. Fifteen of the patients who achieved a complete remission had at least one episode of fungal pneumonia; 12 received further chemotherapy, and nine (75 percent) of these had a subsequent fungal pneumonia. In all, 17 (52 percent) of 33 subsequent granulocytopenic episodes experienced by patients with a prior fungal pneumonia were complicated by another fungal pneumonia. All four patients with a probable fungal pneumonia diagnosed antemortem who subsequently underwent autopsy were found to have invasive fungal disease. It would appear that patients with ANLL who have had one episode of fungal pneumonia are at high risk for recurrence during subsequent episodes of granulocytopenia. Empiric or even prophylactic amphotericin B therapy may be warranted for such patients.     

Empiric use of vancomycin during prolonged treatment-induced granulocytopenia. Randomized, double-blind, placebo-controlled clinical trial in patients with acute leukemia

Because gram-positive infections cause morbidity following intensive antileukemic chemotherapy, the effects of vancomycin versus placebo were evaluated in a randomized, double-blind, placebo-controlled trial in 60 adult patients with acute leukemia and first infectious fever during prolonged (mean of 32 days) granulocytopenia. Gram-positive sepsis was associated with first fever in 17 (28 percent) of the 60 patients. None of 31 patients randomly assigned to receive vancomycin demonstrated gram-positive infection, whereas 16 of 22 patients randomly assigned to receive placebo subsequently had gram-positive infection (seven had sepsis, and nine had local infections; p less than 0.005). All patients with gram-positive infection were then given vancomycin, and all showed prompt clinical responses. The predominant gram-positive organism causing infection was beta-lactam-resistant Staphylococcus epidermis (19 of 44 isolates). Patients randomly assigned to receive vancomycin had more rapid resolution of first infectious fever and fewer total febrile days during the granulocytopenic course than did patients randomly assigned to receive placebo. Although vancomycin had no effect on the presence or absence of documented fungal infection, patients treated with vancomycin received empiric amphotericin B for recurrent or persistent fever later (mean of 14 days after initial antibiotic coverage was begun) than did patients receiving placebo (mean of 9.9 days; p less than 0.005), and thus received fewer total days of empiric amphotericin B therapy (mean of 16.3 days) than did patients given placebo (mean of 24.6 days; p less than 0.01). These data demonstrate that empiric use of vancomycin reduces the morbidity of gram-positive infections following intensive antileukemic therapy and decreases the need for empiric use of toxic amphotericin B.     

Soluble tumour necrosis factor receptors,tumour necrosis factor and interleukin-6 in serum in granulocytopenic patients with fever

Serum levels of TNF, IL-6 and soluble TNF receptors p55 and p75 (sTNFR-p55 and sTNFR-p75) were examined in 14 patients with acute myeloid leukaemia during 43 courses of chemotherapy. The patients experienced 30 episodes of fever which occurred during granulocytopenia (defined as granulocyte counts <0.2×10⁹/1) and six fever episodes when granulocyte counts were >1.0×10⁹/1. Febrile episodes were classified as microbiologically defined infection, clinically defined infection, and unexplained fever. Levels of bioactive IL-6 and immunoreactive TNF increased in response to fever during granulocytopenia, whereas bioactive TNF was not detected in any sample in this study. During granulocytopenia, both sTNFR rose significantly in microbiologically defined infection (P<0.01 for sTNFR-p55 and P<0.05 for sTNFR-p75), but not in the other two categories. The ratio of sTNFR-p55 to sTNFR-p75 was higher during febrile periods in granulocytopenia than in a non-granulocytopenic situation with granulocyte counts >1.0×10⁹/1 (P<0.01). We conclude that granulocytopenia affects release of the two sTNFR differently during febrile periods, and that release of sTNFR-p75 in response to fever is reduced during granulocytopenia, suggesting a role for the granulocytes in systemic release of sTNFR-p75.     

Cotrimoxazole prophylaxis in patients with leukemia and prolonged granulocytopenia

Sixty-three patients with acute nonlymphoid leukemia (ANLL) under cytostatic treatment were investigated in a randomized trial to determine whether oral administration of cotrimoxazole (TMP/STX) would reduce the rate of infection. Four significant differences were observed between the group given TMP/STX (30 patients) and the control group (33 patients): 1) the mean duration of severe granulocytopenia (less than or equal to 500 PMN/mm3) before the first febrile episode was longer in prophylaxis group, 14.26 days versus four in the control group (p less than 0.001); 2) the number of febrile episodes was 37 in TMP/STX group and 69 in control group (p less than 0.01); 3) 23 patients on prophylaxis presented at least one febrile episode versus 33 in the control group (p less than 0.01); 4) deaths due to infection were two in the TMP/STX group versus 11 in control group (p less than 0.05). Prophylaxis with TMP/STX appears to be useful since by reducing the number of febrile episodes and deaths due to infection, it increases the survival of leukemia patients under cytostatic drugs. Nevertheless, further studies on a larger number of patients are necessary in order to confirm the true efficacy of the drug in the reduction of sepsis and death due to infection.     

Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies

In a double blind study, oral prophylactic trimethoprim/sulfamethoxazole was evaluated for its utility in preventing serious infections in patients with hematologic malignancy. Of 58 evaluated granulocytopenic episodes in 47 patients, acute leukemia was the underlying malignancy in 46 episodes. Trimethoprim/sulfamethoxazole prophylaxis resulted in fewer microbiologically documented infections (seven versus 15; p = 0.029). This was primarily the result of a reduction in episodes of bacteremia in the trimethoprim/sulfamethoxazole-treated group as compared with the placebo-treated group (three versus nine episodes; p = 0.05). The combined frequency of disseminated candidiasis, candidemia, and esophagitis of presumed fungal etiology was greater in the trimethoprim/sulfamethoxazole-treated group (six) than in the placebo-treated group (two) but not significantly so (p = 0.13). Similarly, there were no significant differences between groups in the overall incidence of infectious complications, number of febrile days, use of parenteral antibiotics, or number of days following randomization to first infectious episode. Throat and rectal surveillance cultures more frequently revealed trimethoprim/sulfamethoxazole-resistant gramnegative bacilli and yeasts in the trimethoprim/sulfamethoxazole-treated group. More frequent emergence of yeast isolates from previously culture-negative patients was documented (p = 0.033). Thus, in this study, trimethoprim/sulfamethoxazole prophylaxis during granulocytopenia reduced the incidence of microbiologically documented infections. However, the emergence of resistant bacteria and of fungi may limit the potential usefulness of this approach.     

Approaching the controversies in antibacterial management of cancer patients

The principles for management of infectious complications in cancer patients are continuing to evolve. The critical element includes the prompt institution of broad-spectrum antibiotic(s) empirically when granulocytopenic patients become febrile and continuation and modification of the regimen in patients with persistent fever and granulocytopenia. The view is presented that antibiotics provide systemic prophylaxis as well as therapy in persistently granulocytopenic patients and that they should be continued until all signs of infection have cleared or the granulocyte count has recovered. Such aggressive therapy, supplemented by continued evaluation and monitoring of the patient, can significantly reduce infection-relation morbidity and mortality.     

Patterns of infection in 41 patients with idiosyncratic drug-induced agranulocytosis

Summary We examined the patterns of infection in 41 consecutive patients with idiosyncratic drug-induced agranulocytosis observed during the past 15 years. All patients were nursed in reverse isolation and treated prophylactically with oral antimicrobials and antifungal compounds. Nine of 41 patients remained without fever and did not need any parenteral antibiotic treatment for full recovery. The other 32 patients developed fever during the period of agranulocytosis and were treated with empirical antimicrobial therapy. Febrile episodes were documented microbiologically in 16 patients (eight with and eight without bacteremia) and clinically in six patients. In the other ten cases the fever was of unexplained origin. The observed pattern of infection was in accordance with the type of infection as reported in cancer patients during the granulocytopenic phase induced by cytotoxic drugs. Ten of 32 febrile patients showed improvement after empirical antimicrobial therapy, whereas three patients died, two of them of a lower respiratory tract infection and one of a massive hemorrhage due to necrosis of the carotid artery. In ten patients the signs and symptoms of infection resolved only after adjustment of the initial empirical scheme. In nine patients the fever persisted even after additional empirical antifungal therapy but subsided after recovery of the granulocytopenia.     

Randomized controlled trial comparing trimethoprim/sulfamethoxazole and trimethoprim for infection prophylaxis in hospitalized granulocytopenic patients

The clinical and microbiologic efficacy of trimethoprim alone and trimethoprim/sulfamethoxazole for infection prevention was evaluated in 75 patients during 92 episodes of granulocytopenia. Ultimately, 60 patients were evaluable during 77 episodes of granulocytopenia, 36 episodes in the trimethoprim group and 41 episodes in the trimethoprim/sulfamethoxazole group. The incidence of infection was higher in the trimethoprim group (50 percent) than in the trimethoprim/sulfamethoxazole group (39 percent), but this did not reach statistical significance. Trimethoprim did not appear to be as protective as trimethoprim/sulfamethoxazole when the granulocyte count was less than 100/mm³. In patients receiving trimethoprim/sulfamethoxazole, aerobic gram-negative bacilli cleared from fecal surveillance cultures more often and new aerobic gram-negative bacilli were acquired less often than in those receiving trimethoprim alone (p < 0.05). More myelosuppression was observed among patients receiving trimethoprim/sulfamethoxazole (p < 0.001). These observations suggest that trimethoprim alone may not be optimal for preventing colonization and infection in granulocytopenic patients and that combination with other agents may be necessary to increase the spectrum of activity. Trimethoprim/sulfamethoxazole itself may predispose toward an increased risk of infection by prolonging myelosuppression.     

Empiric antibiotic therapy for suspected infection in granulocytopenic cancer patients: a comparison between the combination of moxalactam plus amikacin and ticarcillin plus amikacin

Moxalactam is a new cephalosporin with a broad spectrum of activity which includes Pseudomonas aeruginosa in addition to Klebsiella species Escherichia coli, and Staphylococcus aureus. Moxalactam was combined with amikacin (M + A) compared to ticarcillin plus amikacin (T + A) in a prospective, randomized double-blind trial of empiric therapy for febrile episodes among granulocytopenic cancer patients. One hundred and ninety-one epidoses were evaluated; T + A, 93 episodes and M + A, 98 episodes. Median granulocyte count of initiation of therapy was less than 100/microliters. Overall response rates were good. In the T + A group, 21 of 29 (72 percent) microbiologically documented infections, including seven of 14 (50 percent) bacteremias, and 24 of 27 (89 percent) clinically documented infections improved. In the M + A group, 20 of 28 (71 percent) microbiologically documented infections, including 11 of 18 (61 percent) bacteremias, and 25 of 25 (96 percent) clinically documented infections resolved. Adverse effects were minimal and equivalent in both groups. Hypokalemia (decrease in serum potassium of greater than 11 mEq/liter from baseline) occurred in 14 of the 93 episodes in the T + A group and in 10 of the 98 episodes in the M + A group with decline in mean serum potassium level of 0.5 and 0.4 mEq/liter respectively. Nephrotoxicity (increase in serum creatinine greater than 0.04 mg/dl) occurred in only one patient in the T + A group and in two patients in the M + A group. Moxalactam plus amikacin has a broader in vitro spectrum, is as effective, and is no more toxic than ticarcillin plus amikacin as empiric therapy for febrile granulocytopenic cancer patients.     

A pilot study of piperacillin and ciprofloxacin as initial therapy for fever in severely neutropenic leukemia patients.

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.     

Norfloxacin versus cotrimoxazole for infection prophylaxis in granulocytopenic patients with acute leukemia. A prospective randomized study

Norfloxacin (NOR) or cotrimoxazole (TMP/SMX) were randomly administered to 59 granulocytopenic patients with acute leukemia for prevention of bacterial infections. Nineteen NOR patients (65%) and 22 TMP/SMX patients (73%) complained of febrile or infectious episodes during the study. The mean incidence of febrile complications per patient was higher in the TMP/SMX group: 1.05 vs 0.68 (p less than 0.05). Eleven of 16 microbiologically documented infections in the TMP/SMX group and 7 of 11 in the NOR group were caused by gram negative bacilli (GNB). NOR recipients had fewer days of fever, fewer days on parenteral antibiotics and a lower proportion of time spent febrile. Fecal surveillance cultures showed intestinal GNB colonization in 42/80 specimens in the TMP/SMX group (resistant strains: 93%) and in 8/75 specimens in the NOR group (1 resistant strain). Overall, NOR seems to be effective in eradicating GNB from the digestive tract without selection of resistant strains and in preventing febrile episodes in neutropenic patients.