Envolving treatment of fever and neutropenia in cancer patients

Management of febrile neutropenia is evolving as we learn to prospectively identify risk factors influencing outcome. High risk patients should still be promptly hospitalized and treated with parenteral antibiotics and colony-stimulating factors until resolution of the febrile neutropenia episode. A number of broad spectrum antibiotics can be safely used in monotherapy, although initial combination antibiotic treatment is recommended in patients presenting clinical signs predictive of gram-negative sepsis. The incorporation of glycopeptides to initial therapeutic regimens shall be used only in clinical situations associated with increased risk of fulminant gram-positive bacterial infections. Validated risk-assessment models are now available and have enabled clinicians to identify patients at low risk of complications who may benefit from therapeutic approaches associated with reduced toxicity and cost, such as oral antibiotic therapy, early hospital discharge and outpatient care. Hospital-based oral antibiotic therapy has proven to be safe and effective in low-risk populations. Early hospital discharge and outpatient care may be also appropriate in low-risk febrile neutropenic patients in selected settings. However, the safety of these treatment strategies in the general medical community remains to be proven. A risk-based approach should also be applied to the use of colony-stimulating factors in this setting. While the routine use of growth factors in neutropenic patients with uncomplicated febrile episodes is not warranted, recent data support their use in populations with high risk neutropenic fever.     

Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer

BACKGROUND: Children with cancer who develop an episode of chemotherapy-induced febrile neutropenia usually are admitted to the hospital for intravenous empiric antibiotic therapy. In the current study, the authors examined the use of ciprofloxacin as outpatient management in selected patients with fever during an episode of neutropenia. METHODS: Febrile neutropenic patients with a diagnosis of cancer were eligible for outpatient management with oral ciprofloxacin if they appeared well and demonstrated the following characteristics: age 1-21 years, malignancy in remission, absolute phagocyte count > 100/mm(3), > 7 days since the initiation of the last course of chemotherapy, and reliable parents. Eligible children received a single dose of ceftazidime and were observed for 2-23 hours. Patients were discharged receiving oral ciprofloxacin (20/mg/kg/day divided in 2 doses) until the patient was afebrile for 24 hours, had sterile blood cultures, and had evidence of bone marrow recovery. Patients were admitted if they appeared toxic, had positive blood cultures, or were febrile for >/= 5 days. RESULTS: Forty-five evaluable episodes occurred in 32 children. Forty of the 45 patients (89%) were treated successfully in the outpatient setting. The 95% lower confidence bound on the proportion of successful outcomes was 70%. Five children required hospitalization: 2 due to noncompliance, 1 to receive intravenous acyclovir for herpes zoster, and 2 (4%) whose blood cultures were positive for Streptococcus viridans and S. pneumoniae. All had uncomplicated hospitalizations. CONCLUSIONS: The current study demonstrates that very carefully selected, low risk patients with febrile neutropenia may be treated successfully without hospitalization using oral ciprofloxacin. Additional research is required to refine further the optimal criteria for the selection of appropriate patients for outpatient management.     

Outcome of febrile neutropenic patients on granulocyte colony stimulating factor in a tertiary care hospital

Introduction: Febrile neutropenia is a relatively frequent event in cancer patients treated with chemotherapyand improvement in absolute neutrophil count (ANC) has been linked directly to improved outcome. Evaluationof granulocyte colony stimulating factors (GCSFs) for treatment has shown reduced incidences of episodes ofprolonged neutropenia and protracted hospitalization. To determine absolute neutrophil counts with GCSF infebrile neutropenic cancer patients admitted to a tertiary care centre and to co-relate the improvement in ANCwith mortality and hospital discharge. Methods: A prospective cross sectional study was carried at an oncologyward at Aga Khan University hospital from January 2010 to June 2011. All adult patients who were admittedand treated with GCSF for chemotherapy induced febrile neutropenia were included. Multivariable regressionwas conducted to identify the factors related with poor outcomes. Results: A total of 131 patients with febrileneutropenia were identified with mean age of 43.2 (18-85) years, 79 (60%) being ≤50. Seventy-five (57%) hadsolid tumors and 56 (43%) hematological malignancies, including lymphoma. Fifty seven (43.5%) had an ANCless 100 cells/mm3, 34 (26%) one between100-300 cells/mm3 and 40 (31%) an ANC greater than 300 cells/mm3.Thirty (23%) patients showed ANC recovery in 1-3 days, and 74(56%) within 4-7 days. Thirteen (10%) patientsshowed no recovery. The overall mortality was 18 (13.7%) patients. The mean time for ANC recovery seen inhematological malignancies was 6.34 days whereas for solid tumors it was 4.88 days. Patients with ANC <100cells/mm3 were more likely to die than patients with ANC >300 cells/mm3 by a factor of 4.3. Similarly patients>50 years of age were 2.7 times more likely to die than younger patients. Conclusion: Our study demonstratedthat use of GCSF, in addition to intravenous antibiotics, in treatment of patients with chemotherapy inducedfebrile neutropenia accelerates neutrophil recovery, and shortens antibiotic therapy and hospitalization. Wepropose to risk classify the patients at the time of admission to evaluate the cost effectiveness of this approachin a resource constrained setup.     

Bone marrow suppression--including guidelines for the appropriate use of G-CSF

For previously untreated patients receiving most chemotherapy regimens, primary prophylactic administration of granulocyte colony-stimulating factor (G-CSF) cannot be recommended. Secondary prophylactic G-CSF administration can lessen incidence of febrile neutropenia (FN) in subsequent cycles of chemotherapy in patients with a prior episode of FN. Physicians should consider chemotherapy dose reduction after neutropenic fever or severe or prolonged neutropenia after the previous cycle of treatment. Intervention with G-CSF in afebrile neutropenic patients is not recommended. For the majority of patients with FN, the available data do not clearly support the routine initiation of G-CSF as an adjunct to antibiotic therapy. However, certain FN patients may have prognostic factors that are predictive of clinical deterioration, such as pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The therapeutic use of G-CSF together with antibiotics may be reasonable in such high-risk patients. Empirical antifungal therapy is effective, especially for patients with neutropenia who were treated for seven days with empirical antibiotic therapy but remained febrile, or became afebrile but then had recurrent fever. The patient's overall clinical status and laboratory parameters are both considered when deciding to transfuse a patient. Epoetin may be available for use in the future as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dl. Giving prophylactic platelets at a threshold of 10,000/microliter compared with 20,000/microliter can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.     

Risk-adapted approach for fever and neutropenia in paediatric cancer patients – A national multicentre study

BackgroundIn this national multicentre study, we examined the safety of reducing antibiotics in selected paediatric cancer patients with febrile neutropenia.MethodsPatients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk and received antibiotic therapy. Remaining patients were allocated to low- or medium risk, depending on their interleukin-8 level. Low-risk patients did not receive any antibiotics and were discharged from the hospital after having been afebrile for 12 h. Medium-risk patients were re-evaluated after 72 h of antibiotic treatment and, in selected patients, antibiotics were stopped.ResultsTwo hundred thirty-three febrile neutropenic episodes in 141 paediatric cancer patients were included in the study. Sixty-four episodes were classified high risk (28%), 122 medium risk (52%), and 47 (20%) low risk. In the medium-risk group, antibiotics were stopped after 72 h in 50 in 122 episodes (41%). Median duration of antibiotic treatment and hospital admission was significantly lower in low- and medium-risk episodes with early discharge. No failures were observed in the medium-risk group with early discharge. In the low-risk group, six failures were observed (12.8%), due to coagulase-negative staphylococci-positive blood cultures and recurrent fever.ConclusionWe showed that it is safe to shorten antibiotic treatment to 72 h in selected medium-risk patients with febrile neutropenia, regardless of the neutrophil count. The safety of withholding antibiotics in selected low-risk paediatric cancer patients with febrile neutropenia requires further investigation, using more suitable definitions for safety. Reduction in hospital admissions allows children with cancer more time at home and consequently improves their quality of life.     

Duration of intravenous antibiotics for patients with neutropenic fever

BACKGROUND:: Standard therapy for febrile neutropenia after chemotherapyhas consisted of intravenous antibiotic until resolution ofboth fever and neutropenia. We attempted to shorten the hospitalstay by discontinuing intravenous antibiotics in blood culturenegative patients who remained clinically stable and afebrilefor 48 hours. PATIENTS AND METHODS:: Febrile neutropenic admissions of non-leukemic patients werereviewed. They were divided by three consecutive six month intervalsinto Group 1 (prior to initiation of the policy), Group 2 (afterthe policy was instituted), and Group 3 (to monitor the implementationof the policy after the initial six months). RESULTS:: There were 134 admissions for neutropenic fever. Median durationof intravenous antibiotic for Group 1 was 7 days (95% ConfidenceInterval 6–9). It was significantly decreased to 5 days(4–6) and 4 days (3–5) for Groups 2 and 3 respectively(p – 0.004 and p < 0.001). Median duration of hospitalstay for Group 1 was 10 days (7–13). It was also significantlydecreased to 7 (5–8) and 6 days (5–7) for Groups2 and 3 respectively (p = 0.04 and p = 0.002). CONCLUSION:: Early discontinuation of intravenous antibiotics in patientswith negative blood culture who remain afebrile and clinicallystable for 48 hours results in shorter duration of hospitalstay with potential for reduction in hospital costs. antibiotics, fever, neutropenia     

Feasibility of withholding antibiotics in selected febrile neutropenic cancer patients.

PURPOSE: To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model. PATIENTS AND METHODS: Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol. RESULTS: Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P < .0001). The incremental costs of the experimental treatment protocol amounted to a saving of 471 (US $572) for every potentially low-risk patient. CONCLUSION: This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.     

Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Carefully selected low risk children with fever and neutropenia can be treated safely as outpatients. Close daily medical scrutiny is required.     

Empirical oral antibiotic therapy for low risk febrile cancer patients with neutropenia

For over 30 years, fever and neutropenia in cancer patients has been treated with the utmost urgency, necessitating inpatient evaluation and immediate initiation of empirical broad-spectrum parenteral (IV) antibiotics. This practice is based on the recognition that delays in starting antibiotic therapy in febrile neutropenic patients have been associated with life-threatening infections and sometimes fatal consequences. Over the past decade, it has become evident that neutropenic cancer patients are not a homogeneous group and that practice guidelines may vary on their risk status. In fact, attempts have been made to stratify patients into high-risk and low-risk groups and differentiate treatment options respectively. Recent studies suggest that those neutropenic cancer patients who are at low risk may even be successfully treated with oral therapy, thus opening the possibility for ambulatory or home-based management. Oral antibiotic therapy, especially if safely delivered at home, offers a number of advantages including lower cost, improved quality of life (although the impact of shifting the burden of care from the hospital to the home setting on the patient, parent or care provider needs careful assessment) and a decreased risk for nosocomial infection.     

Outpatient treatment of neutropenic fever with oral antibiotics and granulocyte colony-stimulating factor.

In recent years, several cancer patients who developed neutropenic fever were effectively treated on an outpatient basis with either intravenous or oral antibiotics. This approach is associated with reduced cost and improved patient convenience. However, the appropriate antibiotic regimen and the role of growth factors have not been established yet. In order to address these issues we performed a nonrandomized phase II study to assess the feasibility and efficacy of an oral antibiotic regimen in combination with granulocyte colony-stimulating factor (G-CSF) for the outpatient treatment of cancer patients with low-risk neutropenic fever. In 50 patients with solid tumors or lymphoma, 60 episodes of neutropenic fever were treated with the combination of oral ofloxacin 400 mg twice a day, oral amoxicillin 1 g 3 times a day and G-CSF 5 microgram/kg/day subcutaneously. Patients receiving G-CSF prophylaxis were eligible for our study. Oral antibiotics were administered for at least 5 days and G-CSF was continued until resolution of neutropenia. Our patients were ambulatory, hemodynamically stable, and without significant comorbidity. Our combination was successful in 57 episodes (95%) with a median time for fever resolution of 3 days (range: 1-5 days). There was no significant toxicity associated with the antibiotic regimen with the exception of one case of reversible renal impairment. The role of G-CSF in the success of our antibiotic treatment is highly questionable since one half of our patients developed fever while on G-CSF prophylaxis. The combination of oral ofloxacin and amoxicillin with G-CSF is highly effective for the outpatient treatment of cancer patients who develop uncomplicated febrile neutropenia. The relative contribution of G-CSF needs clarification with a prospective randomized study.     

Phase II study of combination therapy with high-dose cisplatin, etoposide, and mitomycin in patients with advanced non-small-cell lung cancer.

Forty-six patients with metastatic non-small-cell lung cancer (NSCLC) were treated with a combination of high-dose cisplatin, etoposide, and mitomycin. Thirty-four patients (74%) had a performance status of 1, and 39 patients (85%) had adenocarcinoma. Of the 42 patients evaluable for response and toxicity, four achieved a partial response (10%); no patient achieved a complete response. Seven patients who had received prior chemotherapy showed no major response. The median survival of all 42 patients was 23 weeks. Myelosuppression was the major dose-limiting toxicity for this regimen, and 12 of 46 patients (26%) developed neutropenic fever requiring hospitalization and parenteral antibiotics. Of the 12 patients with severe neutropenic fever, one patient died because of toxicity. Nonhematologic toxicities, including azotemia, peripheral neuropathy, nausea, vomiting, and hearing loss were transient and modest. We conclude that high-dose cisplatin combined with etoposide and mitomycin is a relatively toxic regimen with a low response rate. Further evaluation of the combination as given in this trial is not warranted.     

Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia

BACKGROUND: Traditionally, children with malignant disease who present with fever and neutropenia are hospitalized for parenteral antibiotics. More recently, outpatient strategies have been proposed for lower risk cohorts of such patients. The authors sought to identify clinical and laboratory parameters that are associated with a low risk of bacteremia in children with malignant disease who presented with febrile neutropenia. METHODS: A multicenter, retrospective cohort of children with malignant disease and fever with neutropenia was established in three pediatric oncology centers over a 5-year period. A total of 1171 episodes of febrile neutropenia (absolute neutrophil count [ANC] < 500 cells per mm(3)) were identified in children with malignant disease age > 1 year. The endpoints examined were 1) bacteremia and 2) intensive care unit admission or death related to bacteremia. The odds ratio was used to determine which of the following admission parameters and cut-off values were associated with the lowest risk for bacteremia: ANC, absolute phagocyte count (APC), absolute monocyte count (AMC), platelet count, and admission temperature. RESULTS: A total of 189 episodes of bacteremia were identified among the 1171 episodes of febrile neutropenia (14% bacteremia). Only 11 of 1171 episodes (0.9%) resulted in intensive care unit admission, and 3 of these patients died. All 11 patients had an AMC < 30 cells per mm(3). The lowest frequency of bacteremia (6.1%) occurred in the children with an admission AMC of > or = 155 cells per mm(3). None of the patients identified as low risk by AMC required an intensive care unit admission or died. No level of ANC, APC, temperature, or platelet count was associated with a statistically significant decrease in the risk for bacteremia in the patient population. CONCLUSIONS: Adverse outcomes due to bacteremia are infrequent in pediatric oncology patients who present with fever and neutropenia are treated with parental antibiotics. Patients with fever and neutropenia and an AMC value of > or = 155 cells per mm(3) have the lowest risk for bacteremia and may be potential candidates for outpatient management.     

Empirical Amphotericin B therapy on Day 4 or Day 8 of Febrile Neutropenia

Febrile neutropenic patients are at greater risk of getting bacterial and fungal infections. Empirical antifungal therapy is considered if the fever persists despite broad‐spectrum antibiotics including vancomycin. However, the timing of initiating empirical antifungal therapy can vary from 3 to 8 days of non‐response to antibiotics. We choose to determine the response of empirical amphotericin B deoxycholate (dAMB) starting either on day 4 or day 8 in febrile neutropenic patients not responding to broad‐spectrum antibiotics and without localisation of fever. Fifty‐six patients with persistent neutropenic fever despite 72 h of antibiotic therapy were randomly assigned to receive dAMB either starting on day 4 (group A, n = 27, median age 23 years) or starting on day 8 (group B, n = 29, median age 25 years). Satisfactory response (patient remaining afebrile for 48 h and maintaining absolute neutrophil count >500 μl^?1) occurred in 85.2% of patients in group A vs. 69.5% in group B (P = 0.209). Patients in group A took significantly fewer days to become afebrile than group B (5.4 ± 3.9 days vs. 11.3 ± 4.0 days, P = 0.0001). The adverse side effects of dAMB (nephrotoxicity, hypokalemia and hypomagnesemia) occurred at similar rates in both groups. Early addition of empirical dAMB in febrile neutropenic patients leads to their early defervescence and decreased dose requirement.     

Infectious emergencies in oncology patients

The development of neutropenia in a patient undergoing therapy for cancer represents a serious medical problem that rapidly escalates if fever develops. A diligent history and physical examination cannot be overemphasized, since this maneuver may direct the medical person to quickly identify the source of the infection and initiate appropriate therapy. No time should be wasted, but every attempt should be made to quickly obtain body fluids or tissue for microbiologic culture purposes. Appropriate therapy should then be instituted in an empiric manner. The antibacterial agents that are chosen as initial therapy should be selected based on a knowledge of the current local ecology and the antibiotic resistances of endemic strains of bacteria. The empiric therapy should continue until the patient has evidence of recovery of bone marrow function. In those patients who have developed obvious tissue infection, such as pneumonia or bloodstream infection, the therapy should be continued until the infection is eradicated. In patients who have persistent fever despite broad-spectrum antibacterial agents, a painstaking search for the source and type of infection should continue, including repeated blood cultures and other tests. Additional antibiotic or fungal agents should be administered as the need arises. Such an approach to this group of patients has resulted in a significantly better outcome for cancer patients. With the advent of recombinant hematopoietic growth factors, which may allow for a more rapid marrow and immunologic recovery, the therapy for the neutropenic patient should continue to improve.     

Oral administration of cefixime to lower risk febrile neutropenic children with cancer

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study

Neutropenic sepsis remains a potentially life-threatening complication of anticancer chemotherapy. However, it is possible to identify patients who are at low risk for serious complications and for whom less-intensive, more-convenient treatment may be appropriate. The aim of this study was to assess the efficacy and safety of oral antibiotics in conjunction with early hospital discharge in comparison with standard in-patient intravenous antibiotics in patients with low-risk neutropenic fever. In all, 126 episodes of low-risk neutropenic fever occurred in 102 patients. Patients were randomised to receive either: an oral regimen of ciprofloxacin (750 mg 12 hourly) plus amoxicillin-clavulanate (675 mg 8 hourly) for a total of 5 days, or a standard intravenous regimen of gentamicin and tazocin (piperacillin/tazobactam) until hospital discharge. Patients randomised to oral antibiotics were eligible for discharge following 24 h of hospitalisation, if clinically stable and symptomatically improved. The efficacy of the two arms was similar: initial treatment was successful without antibiotic modification in 90% of episodes in the intravenous arm and 84.8% of episodes in the oral arm, P=0.55, absolute difference between the groups 5.2%; 95% confidence interval (CI) for the difference -7 to 17.3%. Only one episode in the oral arm was associated with significant clinical deterioration: this occurred within the initial in-patient assessment period. The median in-patient stay was 4 days in the intravenous arm (range 2-8) and 2 days in the oral arm (range 1-16 days), P&<0.0005. The reduction in hospital stay led to significant cost-savings in the oral arm. In conclusion, this study suggests that oral antibiotics in conjunction with early hospital discharge for patients who remain stable after a 24 h period of in-patient monitoring offers a feasible and cost-effective alternative to conventional management of low-risk neutropenic fever.     

Antibiotic prophylaxis in chemotherapy-induced neutropenia: time to reconsider

The use of antibiotic prophylaxis in neutropenic patients remains controversial. The main arguments against prophylaxis are the lack of survival benefit and the risk of inducing antibiotic resistance. At present, clinical guidelines advise against routine use of antibiotic prophylaxis and current practice is to commence broad-spectrum antibiotics at the onset of fever in the neutropenic patient. However hospitalization, investigations and treatment all impact on resources as well as affecting patient quality of life, often resulting in chemotherapy delays and dose reductions. The benefits of prophylactic antibiotics have been emphasized by two major double-blind, placebo controlled trials with levofloxacin with very significant reductions in all infection-related events. Furthermore, the meta-analysis confirms a survival advantage and this is greatest with the use of fluoroquinolones. These benefits must be weighed against the problem of emerging antibiotic resistance. It has been shown that antibiotic prophylaxis does induce resistant organisms, but some studies have shown that the impact on clinical outcomes may not be as great as expected. Current evidence supports antibiotic prophylaxis with fluoroquinolones in acute leukaemia and high-dose chemotherapy patients, commencing at the same time as chemotherapy. Febrile episodes are much commoner with the first cycle in patients with solid tumours or lymphoma having moderately myelosuppressive chemotherapy, and these patients should be offered prophylaxis for at least the first cycle of chemotherapy. Further work is ongoing to facilitate the selection of patients with the greatest chance of benefit so that prophylaxis can be used efficiently.     

Antibiotic Management of Febrile Neutropenia: Current Developments and Future Directions

Abstract

Mortality due to febrile neutropenia has decreased since the concept of empiric therapy became standard care. However, infections complications remain the most common adverse events of chemotherapy. Bacterial epidemiology has changed during the past decades. There is currently an increasing trend in infections due to Gramnegative bacteria which have higher rates of resistance for a variety of reasons.

The use of biomarkers for diagnosis remains a domain of further investigation. Since the patient population with febrile neutropenia is very heterogeneous, models of risk assessment have been developed with the most commonly used today being the MASCC score.

Oral antibiotic treatment seems to be appropriate in low-risk patients. In moderate or high-risk patients monotheraphy is the most common option. However, due to emerging resistance this could change by next year, Some new antibiotics have been developed, but experiences in the treatment of neutropenic fever is limited. The use of antibiotics for prophylaxis remains controversial, although recent studies suggest a reduction in death from all causes.     

Efficacy of intravenous ciprofloxacin in patients with febrile neutropenia refractory to initial therapy

We previously reported that monotherapy with carbapenem or cefepime exhibited efficacy equivalent to cefepime plus an aminoglycoside as initial therapy for febrile neutropenia (FN), achieving an adequate response in two-thirds of the patients. However, only one-third of the remaining poor responders to monotherapy became afebrile after an aminoglycoside was added to the initial carbapenem or cefepime. The present study was designed to evaluate the benefit of intravenous ciprofloxacin for neutropenic patients with fever who were refractory to initial therapy given for the first 3 days. Patients with FN--as defined by an axillary temperature >or=37.5 degrees C and a neutrophil count <1,000/microL-who had no response to initial therapy with carbapenem or cefepime for 72 hours were to receive additional ciprofloxacin 600 mg/day. They were otherwise managed according to the Japanese guidelines for FN. An adequate response was defined as a decline of temperature to <37.5 degrees C within 7 days after initiation of ciprofloxacin treatment. Thirty-one patients with FN (seventeen male and fourteen female; mean age 53.1 +/- 14.8 years) were entered in the study. The initial antibiotics were cefepime (2 - 4 g/day) in twenty and carbapenem (1 - 2 g/day) in eleven. Three patients were excluded from analysis, leaving 28 patients for evaluation of efficacy. The response rate was 16/31 patients (51.6%),with four patients judged non-assessable due to adverse effects, protocol violation or early change to other agents. Adverse events occurred in seventeen patients, but all were mild and reversible. Only three patients had adverse events (skin rash, hepatic dysfunction and elevation of alkaline phosphatase in one patient, respectively) considered related to ciprofloxacin. These findings indicate that addition of intravenous ciprofloxacin is effective against FN refractory to initial antibiotic therapy and has acceptable toxicity.     

Fatal anerobic bacteremia after hematopoietic stem cell transplant

We describe 3 cases of fatal but clinically unsuspected anerobic bacteremia amongst hematopoietic stem cell transplant (HSCT) recipients treated empirically for fever and neutropenia with third or fourth generation cephalosporins. All patients had diarrhea but none had classical findings of neutropenic enterocolitis. HSCT recipients with fever, neutropenia and gastrointestinal tract symptoms such as abdominal pain or diarrhea or with septic shock despite broad spectrum antibiotics should receive an antimicrobial agent with anerobic activity.