Outpatient therapy with oral ofloxacin for patients with low risk neutropenia and fever: a prospective, randomized clinical trial. Outpatient, sequential, parenteral-oral antibiotic therapy for lower risk febrile neutropenia in children with malignant disease: a single-center, randomized, controlled trial in Argentina. Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. Multicenter, randomized trial of ciprofloxacin plus azlocillin versus ceftazidime plus amikacin for empiric treatment of febrile neutropenic patients. Randomised comparison of oral ofloxacin alone with combination of parenteral antibiotics in neutropenic febrile patients. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer. Randomized trial of oral versus intravenous antibiotics in low-risk febrile neutropenic patients with lung cancer. Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Oral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: randomized prospective trial. Oral administration of cefixime to lower risk febrile neutropenic children with cancer. Monotherapy with intravenous followed by oral high-dose ciprofloxacin versus combination therapy with ceftazidime plus amikacin as initial empiric therapy for granulocytopenic patients with fever.
Hospitalization and treatment with broad-spectrum intravenous antibiotics is the standard care for patients with neutropenia and fever. This randomized clinical trial evaluated the feasibility and efficacy of ambulatory care with oral ofloxacin for patients with low risk, chemotherapy-induced neutropenia and fever.
                Patients with solid tumors who were treated with conventional dose chemotherapy, presented with fever (axillary temperature >38 degrees C on 2 occasions or >38.5 degrees C on a single occasion) and neutropenia (absolute neutrophil count, <500 cells/microL), and met low risk criteria were eligible for this study. They were randomized either to hospitalization and treatment with broad-spectrum intravenous antibiotics, which consisted of a combination of cefazidime and amikacin, or to outpatient treatment with oral ofloxacin. The definitions of fever of unknown origin, clinical and microbiologic infection, success, success with modification, and failure were the usual ones for this type of study.
                One hundred episodes were randomized, and 95 were evaluable (47 were randomized to ceftazidime/amikacin and 48 to ofloxacin). Baseline characteristics, as well as the proportion of patients with microbiologic and clinical infections, were similar in the two groups. In 91% of episodes in the inpatient group and 89% in the ofloxacin group, patients recovered uneventfully (P=1; 95% CI for the difference, -0.09 to 0.13), with 2 and 5 patients requiring modification of the antibiotics, respectively. Eight percent of episodes in the control group and 10.4% in the experimental group resulted in treatment failure. Eight patients (16%) in the outpatient group experienced failure with ambulatory care and were admitted to the hospital.
                Outpatient oral antibiotic therapy with oral ofloxacin for patients with low risk neutropenia and fever is safe and similar in efficacy to hospitalization and treatment with broad-spectrum parenteral antibiotics. Recent reports and previous randomized trials conducted at the authors' institution suggested that children with lower risk febrile neutropenic (LRFN) may benefit from substitution of oral antibiotic therapy for parenteral therapy. The objective of this study was to determine the efficacy of parenteral-oral outpatient therapy in the management of children with LRFN who were receiving treatment for malignant disease.
                From August 2000 to April 2002, 135 children with a median age of 7.5 years (range, 1.6-15.8 years) who had a total of 177 episodes of LRFN were included in a prospective, randomized, single-institution trial. Children with LRFN received a single dose of ceftriaxone and amikacin and completed a risk-assessment work-up. All patients were discharged immediately and, at 24 hours, were allocated randomly to two groups: Group A (89 episodes) received oral ciprofloxacin, and Group B (88 episodes) received intravenous ceftriaxone.
                Most patients (61% in Group A and 51% in Group B) were receiving treatment for leukemia (P value not significant [NS]). Twenty-eight children (31%) in Group A and 22 children (25%) in Group B displayed unexplained fever (P value NS). No significant differences in sites of initial infection were found between the two groups. The median duration of neutropenia was 4.2 days and 4.7 days for Group A and Group B, respectively (P value NS); the median duration of fever was 2.3 days and 2.6 days, respectively (P value NS); and the median duration of antibiotic treatment was 4.5 days and 4.8 days, respectively (P value NS). The overall results of the study were excellent. Only four treatment failures in Group A (5%) and 6 treatment failures in Group B (7%) were observed. These patients were readmitted to the hospital and did well with appropriate treatment.
                In children with LRFN who are receiving treatment for malignant disease, outpatient oral ciprofloxacin after 24 hours of a single dose of intravenous ceftriaxone and amikacin was as safe and efficacious as parenteral ceftriaxone. Outpatient management and early antibiotic withdrawal were safe for both groups.
                Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11251 Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer. Recent work suggests that a low-risk population exists who might benefit from an alternate approach.
                A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer.
                The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19). Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study. Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03).
                This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective. Better oral regimens are needed. In a multicenter, randomized clinical trial, the efficacy of ciprofloxacin plus azlocillin was compared with that of a standard regimen of ceftazidime plus amikacin for the initial empiric treatment of fever in neutropenic cancer patients. In addition, the efficacy of early conversion from intravenous therapy to orally administered ciprofloxacin was compared with that of continued ceftazidime plus amikacin. Seventy-one oncology patients with 79 episodes of fever and neutropenia were randomly assigned to receive initial empiric antibiotic therapy with either intravenously administered ciprofloxacin and azlocillin followed by orally administered ciprofloxacin (regimen 1, 25 episodes); ceftazidime and amikacin (regimen 2, 30 episodes); or ceftazidime and amikacin followed by oral ciprofloxacin (regimen 3, 24 episodes). Microbiologically documented infections were the cause of fever in 10 (40 percent), seven (23 percent), and nine (38 percent) episodes in regimens 1, 2, and 3, respectively, including six, five, and four episodes of bacteremia. Patient survival was 90 to 92 percent in each regimen; however, some modification of antimicrobial therapy occurred in 65, 44, and 41 percent of surviving patients in regimens 1, 2, and 3, respectively. The rate of clearance of initial bacteremia was 67 percent (four of six) in regimen 1, 100 percent (five of five) in regimen 2 and 50 percent (two of four) in regimen 3. Patients in regimens 1 and 3 were able to convert to orally administered ciprofloxacin in 32 (65 percent) of 49 episodes after a mean of six days of intravenous therapy. Superinfections occurred in 24, 10, and 12 percent of patients receiving regimens 1, 2, and 3, respectively, and occurred similarly for patients receiving orally administered ciprofloxacin, 12 percent (four of 32), and intravenous therapy, 17 percent (eight of 47). Parenteral ciprofloxacin was generally well tolerated. One (4 percent) of 25 patients receiving regimen 1 experienced oto- or nephrotoxicity, compared with eight (15 percent) of 54 patients receiving regimens 1, 2, and 3 (p = 0.15), including three patients who required premature termination of aminoglycoside therapy. Our data suggest that the combination of ciprofloxacin and azlocillin is an effective alternative to ceftazidime and amikacin for the initial empiric therapy of febrile neutropenic patients, is generally well tolerated, and avoids the oto- and nephrotoxicity associated with aminoglycoside use. In addition, a majority of patients could change to orally administered ciprofloxacin alone after six days of parenteral therapy. Prompt treatment with empirical antibiotics in neutropenic febrile patients reduces morbidity and mortality. Most patients have been treated with parenteral combination antibiotics, but newer antibiotics with broad-spectrum bactericidal activity have made monotherapy feasible. Ofloxacin, a broad-spectrum fluoroquinolone, has the additional advantage that bactericidal concentrations can be achieved with oral administration. We have compared ofloxacin as an oral single agent with standard parenteral combination antibiotics for the management of neutropenic febrile patients in a prospective, randomised trial. Patients with severe neutropenia (absolute neutrophil count less than or equal to 0.5 x 10(9)/l), fever above 38 degrees C, and ability to take drugs by mouth were eligible for the study. After initial investigations, 60 patients were randomly assigned to oral ofloxacin 400 mg twice daily and 62 to parenteral combination antibiotic therapy (amikacin 15 mg/kg daily, plus, at various times in the trial, carbenicillin, cloxacillin, or piperacillin). Patients were examined 72 h and 7 days after the start of treatment and when neutropenia resolved. 24 (40%) ofloxacin-treated and 26 (42%) combination-treated patients had pyrexia of unknown origin (PUO). In both treatment groups, the treatment success rate was higher for such patients than for those with clinically or microbiologically documented infections (92% vs 67% [p less than 0.05] for ofloxacin; 85% vs 64% for combination). There were no significant differences in success rates of ofloxacin and combination treatment for these subgroups or overall (77% vs 73%). Patients with neutropenia for less than 1 week had better responses to both treatments than patients with longer-lasting neutropenia. There were 4 (7%) deaths in the ofloxacin group and 6 (10%) in the combination group. Both regimens were well tolerated. We conclude that oral single-agent ofloxacin is as effective as parenteral combination antibiotic therapy in neutropenic febrile patients, especially those expected to have short durations of neutropenia. Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment.
                We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved.
                A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patient's inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07).
                In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective. Empiric oral antibiotic therapy for febrile neutropenic cancer patients has been suggested as a means to decrease hospitalization, but the safety of this approach has not been adequately studied in children. We compared continued iv antibiotic therapy with switching treatment to orally administered cefixime in a group of selected febrile neutropenic children for whom blood cultures were sterile after 48 h of incubation. Two hundred episodes of febrile neutropenia were studied (156 patients), and 100 episodes were randomized to receive each treatment. Failure to respond to therapy was defined by documented or suspected bacterial infection, recurrent fever, or discontinuation of assigned therapy for any reason before neutropenia resolved. Rates of treatment failure were similar in the oral cefixime group (28%) and in the iv antibiotic group (27%; P=1.0). Results support the safety of oral cefixime therapy for low-risk febrile neutropenic children, a therapeutic approach that would facilitate earlier outpatient management and decrease the costs of treatment. Neutropenic fever is one of the most serious adverse effects of cancer chemotherapy. Neutropenia may cause a life-threatening bacterial infection. Therefore, febrile neutropenic inpatients are empirically treated with intravenous broad-spectrum antibiotics. Recently, several studies have suggested the presence of low-risk groups among febrile neutropenic patients.
                A prospective randomized trial was conducted to compare treatment with oral ciprofloxacin (200 mg) and amoxicillin-clavulanate (375 mg) administered every 8 h against that with intravenous ceftazidime (1 g) administered every 12 h in low-risk febrile neutropenic patients with lung cancer. All patients received chemotherapy and antibiotic therapy while being hospitalized.
                A total of 177 patients with lung cancer agreed to participate in this study prior to undergoing chemotherapy. Among them, a total of 36 neutropenic patients with 42 febrile episodes were enrolled in the study. Treatment was successful without the need for modification in 91% of the episodes in patients receiving the oral regimen and 79% of the episodes in patients receiving the intravenous regimen. No treatment-related deaths occurred. One patient developed nausea while receiving the oral regimen, so the oral regimen was changed to the intravenous regimen in this patient.
                This prospective study suggested that treatment with oral antibiotics ciplofloxacin plus amoxicillin-clavulanate was effective for low-risk febrile neutropenic patients after chemotherapy. Fever and neutropenia (F&N) is a common complication of cancer chemotherapy. It is conveniently managed by hospitalization and empiric administration of parenteral antibiotics. This study attempted to determine whether pediatric cancer patients with F&N identified as low risk for morbidity and mortality by clinical criteria at the time of presentation could be treated safely as outpatients.
                Seventy-three episodes of F&N in 41 patients were studied prospectively over 2 years. Eligibility criteria included age > or =2 years, reliable caretakers, and residence within 1 hour of the hospital. Exclusion criteria included hemodynamic instability, dehydration, severe mucositis, pneumonia, leukemia/lymphoma induction therapy, bone marrow transplantation, or other serious comorbidity. Patients were evaluated, received a single dose of intravenous ceftazidime, and were observed for 3-16 hours. They were randomized to receive either oral ciprofloxacin or intravenous ceftazidime as outpatients. Patients were seen daily until they had been afebrile for at least 48 hours and had a rising absolute phagocyte count of >500 cells/microL.
                Sixty-three of 73 episodes (86%) were successfully managed on an outpatient basis. For 31 of 33 episodes in the ceftazidime arm, the patients remained outpatients, compared with 32 of 40 in the ciprofloxacin arm; this difference was not statistically significant. On average, patients remained febrile for 2.7 days and were treated for 4.7 days. Seventy-seven percent of episodes required no modification of initial antibiotic therapy. Of the 10 patients who were hospitalized, 4 had prolonged fever and 3 had emesis. Protracted neutropenia was associated with the need for hospitalization. There were no deaths, intensive care unit transfers, or serious complications.
                Carefully selected low risk children with fever and neutropenia can be treated safely as outpatients. Close daily medical scrutiny is required. Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost.
                In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less.
                Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency.
                In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy. Infections are one of the major complications in children undergoing chemotherapy. Monotherapy with either ciprofloxacin or ceftriaxone is safe and efficient in low-risk patients (solid tumors and stage I/II lymphomas). The same drugs may be used in an outpatient setting, decreasing costs and the risk of nosocomial infections.
                Low-risk patients (N = 70) with episodes of fever and neutropenia (N = 116) were randomized to receive either oral ciprofloxacin or intravenous ceftriaxone as outpatients. Only one patient had a central venous catheter.
                Episodes of fever and neutropenia were classified as fever of unknown origin (41% vs. 32%) or clinically documented infection (56% vs. 63%) in the ciprofloxacin and ceftriaxone groups, respectively. Most of these infections were of upper respiratory tract, skin, or gastrointestinal origin. The mean duration of neutropenia was 5 vs. 6 days. Fever persisted for 1-9 days (mean 2 vs. 3 days). Therapy was successful with no modifications in 83% vs. 75% of the episodes. Patients were admitted in 7% vs. 4% of the episodes. No bone or joint side effects were seen in either group. All patients survived.
                Outpatient therapy with either oral ciprofloxacin or intravenous ceftriaxone for fever and neutropenia is effective and safe in pediatric patients with solid tumors and stage I/II non-Hodgkin lymphoma (low-risk patients).
                Copyright 2000 Wiley-Liss, Inc. Febrile neutropenia is a heterogeneous condition. Recently, several risk factors have been defined, permitting the definition of a lower risk group of patients who may benefit form less aggressive therapy. The use of an oral antibiotic approach was tested in the current trial.
                From May 1997 to March 1998, 154 episodes of lower risk febrile neutropenia in 128 children with a mean age of 62 (range, 8-200) months were enrolled in this randomized, single-institution trial. Inclusion criteria were fever (> 38 degrees C), neutropenia (absolute neutrophil count < 500/mm(3)), lower risk features (i.e., absence of severe comorbidity factors, good clinical condition, negative blood cultures, control of local infection, no fever during the last 24 hours), and compliance of parents. After 3 days of ceftriaxone (100 mg/kg/day administered intravenously [i.v.]) every 12 hours plus amikacin (15 mg/kg/day i.v.) every 24 hours for 3 days, all patients were discharged and randomized to be allocated to 2 treatment arms. Group A (n = 74) received ceftriaxone cefixime (8 mg/kg/day administered orally) every 24 hours for 4 days, whereas Group B (n = 80) was treated with ceftriaxone plus amikacin for 7 days. Failure was defined as the need for second hospitalization during the same episode of neutropenia, or fever during the 7 days after discharge.
                Most of the patients (49% in Group A and 55% in Group B) had acute leukemia. Fifty-four (72%) children in Group A and 46 (56%) in Group B had fever of unknown origin (P = not significant [NS]). No significant differences were found in the sites of initial infection between the two groups. Overall results were outstanding, with a favorable outcome in 73 of 78 cases (98.6%) in Group A and 78 of 80 cases (97.5%) in Group B (P = NS). Three patients needed a second hospitalization due to failure of the initial therapy: one in Group A and two in Group B. All three did well with secondary treatment.
                In lower risk febrile neutropenic children receiving anticancer therapy, the efficacy of oral cefixime, given for 4 days after 72 hours of intravenous ceftriaxone plus amikacin, was similar to that of 7 days of parenteral ceftriaxone plus amikacin. The oral outpatient therapy approach to the treatment of lower risk febrile neutropenia after chemotherapy is safe and may be cost-saving. This strategy might be adopted as standard therapy in the future.
                Copyright 2000 American Cancer Society. The aim of the present study was to obtain clinical experience with the use of high-dose ciprofloxacin as monotherapy for the treatment of febrile neutropenia episodes (granulocyte count, <500/mm(3)) compared to a standard regimen and to clarify whether ciprofloxacin administration may be switched to the oral route. In a prospective randomized study ciprofloxacin was given at 400 mg three times a day (t.i.d.) for at least 72 h followed by oral administration at 750 mg twice a day (b.i.d). That regimen was compared with ceftazidime given intravenously at 2 g t.i.d. plus amikacin given intravenously at 500 mg b.i.d. The frequency of successful clinical response without modification at the end of therapy was almost identical for ciprofloxacin (50% [62 of 124 patients]) compared with that for ceftazidime plus amikacin (50.8% [62 of 122 patients]) in an intent-to-treat analysis; the frequencies were 48.3% (57 of 118 patients) versus 49.6% (56 of 113 patients), respectively, in a per-protocol analysis (P values for one-sided equivalence, 0.0485 and 0.0516, respectively; delta = 10%), with no significant differences among patients with bacteremia and other microbiologically or clinically documented infections and fever of unknown origin. For 82 (66.1%) patients, it was possible to switch from parenteral ciprofloxacin to the oral ciprofloxacin, and the response was successful for 61 (74.4%) patients. The efficacies of the regimens against streptococcal bacteremias were 16.6% (one of six patients) for the ciprofloxacin group and 33.3% (one of three patients) for the combination group (it was not statistically significant), with one breakthrough streptococcal bacteremia observed among the ciprofloxacin-treated patients. Adverse events were mostly self-limited and were observed in 27 (20.6%) ciprofloxacin-treated patients and 26 (19.7%) patients who were receiving the combination. This study demonstrates that high-dose ciprofloxacin given intravenously for at least 3 days and then by the oral route is therapeutically equivalent to the routine regimen of intraveneous ceftazidime plus amikacin even in febrile patients with severe neutropenia (polymorphonuclear leukocyte count, <100 mm(3)). However, it is very important that before an empirical therapy is chosen each hospital determine bacteriologic predominance and perform resistance surveillance.
Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, not having pneumonia, infection of a central line or a severe soft-tissue infection. The wide CI for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.