A survey of the antibiotic treatment of febrile neutropenia in haematology units in the United Kingdom

We performed a nationwide survey to define the different practices in managing febrile neutropenia in haematology units. A questionnaire was sent out to a named haematologist in each of 220 haematology units in the UK. Questions were asked regarding antibiotics of choice in managing febrile neutropenia and the use of antibiotic prophylaxis. Responses were received from 167 (76%) haematology units. Combination therapy with piperacillin-tazobactam and gentamicin is used first-line in febrile neutropenia by 72% of units. Piperacillin-tazobactam monotherapy is used first-line by 5% of units. When response to initial empirical therapy does not occur after 24-48 h, 32% of haematology units add a glycopeptide (vancomycin or teicoplanin) and 31% change to a carbapenem and a glycopeptide. Seventy-one percent of units use oral fluoroquinolone prophylaxis for all neutropenic patients. The antibiotic treatment of febrile neutropenia in haematology patients, and the use of antibiotic prophylaxis, vary significantly across the UK. This survey is the first to examine the prescribing of UK haematology units in this area, and could help in the formulation of practice guidelines.     

Retrospective review of febrile neutropenia in the Royal Darwin Hospital, 1994-99

Abstract Background : Febrile neutropenia is a life-threatening complication of cytotoxic chemotherapy. Empirical antibiotic treatment should be based on predominant pathogens and epidemiological characteristics of the treated community. The aim of the present study was to review cases of febrile neutropenia at the Royal Darwin Hospital (RDH) in order to assess the appropriateness of empirical antibiotic therapy.
Methods : A retrospective review of cases of febrile neutropenia secondary to malignancy or chemotherapy occurring at the RDH over the period 1994–99. In order to compare infections in this group with those in the wider hospital community, all positive blood cultures in the medical and intensive care units were reviewed for the same time period.
Results : Thirty-six episodes of febrile neutropenia were reviewed. Staphylococcus aureus (predominantly methicillin resistant), Pseudomonas aeruginosa and Escherichia coli were the most common organisms identified. Nine patients died of their infection, four with methicillin-resistant S. aureus bacteraemia. S. aureus , E. coli , Streptococcus pneumoniae and Burkholderia pseudomallei (melioid) were the most frequently isolated organisms from blood cultures taken in the medical and intensive care units.
Conclusions : Gram-positive organisms are the predominant pathogens in febrile neutropenic episodes at the RDH. Standard empirical therapy with an extended-spectrum penicillin and an aminoglycoside remains appropriate, with the addition of vancomycin when clinical status fails to improve. When practising in the Top End, particular consideration should be given to skin integrity and scabies and testing for Strongyloides in Aboriginal patients. (Intern Med J 2001; 31: 406–412)     

Using teicoplanin for empiric therapy of febrile neutropenic patients with haematological malignancies

S ummary The cumulative experience with teicoplanin in treating febrile neutropenic patients included in three different comparative clinical trials conducted at a single institution during a 3-year period, is presented. 1 52 febrile episodes in 129 neutropenic patients were treated with iv. teicoplanin (6 mg/kg/d) combined with amikacin (15 mg/kg/d) plus ceftazidime (90 mg/kg/d). The study population comprised 75 patients with acute leukaemia and 77 marrow recipients: 53(% (81/152) had a central venous catheter in place and 68%) (103/152) had severe neutropenia (< 100/mm³) at the beginning of the febrile episode.
The overall response rate of the evaluiable febrile episodes was excellent: 88% (107/122) improved. Bacteraemias due to Gram-positive cocci accounted for 75% of the total (42/56) and pathogens in the blood isolates were mostly staphylo-cocci (coagulase-negative 14, coagulase-positive 13) and streptococci (131. The response rate of Gram-positive bacteraemias was good: 88% (37/42) improved and 75% (9/12) of Gram-positive bacteraemias having teicoplanin as the only antibiotic with in vitro activity against the infective strains were cured. Death due to infection accounted for 7% of total febrile episodes (11/152). Side effects were documented in 14(%, of the episodes. In a setting of high prevalence of Grampositive infections caused by strains with a high rate of resistance to aminoglycoside and betalactam antibiotics, there may be an advantage in including teicoplanin in the initial empiric antibiotic regimen for febrile neutropenic cancer patients.     

Fever and neutropenia in cancer patients: the diagnostic role of cytokines in risk assessment strategies

Cancer patients treated with chemotherapy are susceptible to bacterial infections. Therefore, all neutropenic cancer patients with fever receive standard therapy consisting of broad-spectrum antibiotics and hospitalization. However, febrile neutropenia in cancer patients is often due to other causes than bacterial infections. Therefore, standard therapy should be re-evaluated and new treatment strategies for patients with variable risk for bacterial infection should be considered. This paper reviews the changing spectrum of microorganisms and resistance of microorganisms to antibiotics in infection during neutropenia and discusses new strategies for the selection of patients with low-risk for bacterial infection using clinical and biochemical parameters such as acute phase proteins and cytokines. These low-risk patients may be treated with alternative therapies such as oral antibiotics, early discharge from the hospital or outpatient treatment.     

Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer.

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.     

Short Courses of Intravenous Empirical Antibiotic Treatment in Selected Febrile Neutropenic Children with Cancer

Background: Since the optimal duration of antibiotic therapy in febrile neutropenic patients is not clear, we evaluated the safety and efficacy of short courses of intravenous antibiotic treatment in selected pediatric cancer patients admitted for fever and neutropenia. Patients and Methods: We retrospectively analyzed the clinical course of children with chemotherapy-induced neutropenia and fever. All patients were treated with empirical intravenous antibiotics. In episodes of fever of unknown origin (FUO), treatment regimen allowed discontinuation of antibiotics and early hospital discharge regardless of absolute neutrophil count (ANC) or evidence of bone marrow recovery as long as patients were afebrile for at least 24 h and had been treated for a minimum of 72 h. Results: 106 episodes of febrile neutropenia occurred in 56 patients. 84 episodes were classified as FUO and intravenous antibiotic therapy was discontinued regardless of ANC when patients met the criteria described above. No death or major complication occurred. None of the patients had to be rehospitalized for recurrent fever or infection. Conclusion: Discontinuation of intravenous antibiotics regardless of ANC or evidence of bone marrow recovery seems safe and effective in pediatric cancer patients with FUO when children are afebrile for at least 24 h and are treated for a minimum of 72 h. Received: June 28, 2001 · Revision accepted: October 29, 2001     

Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors

Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim–sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.     

Usefulness of G-CSF in pediatric high risk cancer patients with fever and neutropenia

Chemotherapy associated febrile neutropenia is an important cause of morbidity and mortality in pediatric patients with cancer. The use of granulocyte-colony stimulating factor (G-CSF) post chemotherapy decreases the risk of infectious complications but its efficacy during the febrile neutropenic episode remains controversial. Thirty five episodes of high-risk febrile neutropenia were randomized into two treatment arms, 18 received antibiotics and G-CSF (group A) and 17 received antibiotics only upon admission (group B). Both groups were comparable in terms of demographic and clinical characteristics. No significant differences between groups were found in duration of hospitalization (mean group A 7 vs group B 8 days), antibiotic treatment (mean 7 vs 8 days), fever (3 vs 2 days), nor of neutropenia (4 vs 3 days). One patient in group A died after RSV infection. Considering these results and a literature review, we propose that G-CSF should not be recommended in children during the course of their febrile neutropenic episode.     

Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies

The risk and outcome of infection in febrile neutropenic patients is mainly determined by the duration of neutropenia, the underlying disease or the treatment. This study was undertaken to compare infections and the outcome after conventional chemotherapy (CCT), allogeneic PBSC transplantation (alloPBSCT) or autologous PBSC transplantation (autoPBSCT), during the period of neutropenia, in a single center. A total of 145 patients (50 in CCT group, 50 in alloPBSCT and 45 in autoPBSCT) were evaluated. In the alloPBSCT group, 86% of the patients (43/50), in the autoPBSCT group 93% of the patients (42/45) and in the CCT group 92% (46/50) of the patients had at least one febrile episode during their neutropenic period (P > 0.05). Microbiologically and/or clinically documented infection rates were 50% (25/50), 42% (19/45) and 48% (24/50) respectively. Gram-positive pathogens, mostly coagulase-negative staphylococci were the most frequent cause of bacteremias in all groups. The frequency of CNS infections was significantly higher in the alloPBSCT and autoPBSCT groups compared to the CCT group (P < 0. 008 and P < 0.04, respectively). Catheter infections were frequent in the PBSCT groups and pulmonary infections were more frequent in the CCT group (P < 0.05). The CCT group needed longer antibiotic usage compared to the alloPBSCT group (P < 0.006). The duration of neutropenia and the type of treatment given, does not affect the rate of febrile episodes, but affects the type of infections in febrile neutropenic patients.     

Prophylactic antibiotics for the prevention of neutropenic fever in patients undergoing autologous stem-cell transplantation: results of a single institution, randomized phase 2 trial

One hundred and fifty-seven patients undergoing high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) for hematopoietic malignancies and solid tumors were randomly assigned to receive (Group A) or not (Group B) prophylaxis with ciprofloxacin, orally, and vancomycin, intravenously. Prophylactic antibiotics were given from day 0 until resolution of neutropenia or the appearance of a febrile event. Furthermore, patients in both groups received once a day fluconazole, orally. The primary end-point of our study was the incidence of neutropenic febrile episodes attributed to infection. One hundred and twelve (71.3%) patients developed neutropenic fever, 50 (56.2%) in Group A and 62 (91.2%) in Group B (P < 0.001) with the majority (82%) of patients developing fever of unknown origin. Patients on prophylactic antibiotics had a significantly lower rate of bacteremias (5.6%) than did those randomized to no prophylaxis (29.4%) (P = 0.005) and, when developing neutropenic fever, they had a lower probability of response to first-line empirical antibiotics (P = 0.025). Prophylactic administration of ciprofloxacin and vancomycin reduced the incidence of neutropenic fever in patients receiving HDT with ASCT, however, without affecting the total interval of hospitalization, time to engraftment, or all-cause mortality. Therefore, our results do not support the use of antibiotic prophylaxis for patients undergoing HDT and ASCT.     

After empiric therapy: what to do until the granulocyte comes back

The prompt initiation of empiric broad-spectrum antibiotic therapy when a granulocytopenic patient becomes febrile has become standard practice and has resulted in a significant reduction in the early morbidity and mortality associated with infection. Granulocytopenic patients, however, are at risk for multiple infectious episodes, particularly when the duration of neutropenia is prolonged. Accordingly, the addition of one or more antimicrobial agents to the initial empiric antibiotic regimen is often necessary to deal effectively with these second infections and to help maximize the patient's chance for survival. An organized plan that incorporates modifications of the primary antibiotic regimen (e.g., the addition of another antibiotic or an antifungal agent) into the overall management of the febrile neutropenic patient is important, especially when neutropenia lasts for more than a week.     

Antibiotics and growth factors in the management of fever and neutropenia in cancer patients

The association of neutropenia and infection continues to be a major cause of morbidity and mortality in cancer patients receiving myelosuppressive chemotherapy. Prompt hospitalization and initiation of empirical intravenous broad-spectrum antibiotics has been the standard of care during the past three decades. Recently, risk-assessment models have been developed that allow the identification of febrile neutropenic patients that are at low risk for medical complications and mortality. New treatment strategies are being evaluated in this low-risk patient population to safely reduce toxicity, decrease costs, and improve quality of life. These include early shift from intravenous therapy to oral antibiotics, immediate initiation of oral empiric treatment, early hospital discharge, or outpatient care. A risk-based approach should also be applied to the use of colony-stimulating factors in this setting. Growth factors should not be routinely administered to neutropenic patients with uncomplicated febrile episodes. However, recent data support their use in populations with high-risk neutropenic fever.     

Vancomycin as part of initial empirical antibiotic therapy for febrile neutropenia in patients with cancer: pros and cons.

Gram-positive organisms predominate as the bacterial pathogens identified in episodes of febrile neutropenia. This has led to increased use of antibiotics with efficacy against gram-positive organisms (often vancomycin) as part of empirical antibiotic regimens for treating febrile neutropenia. Among 101 children randomized to receive amikacin, ticarcillin, and vancomycin or ticarcillin/clavulanate and amikacin along with vancomycin placebo, treatment success in those treated with vancomycin was higher (85% vs. 62%). In 1990, the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada Clinical Trials Group compared amikacin and ceftazidime with and without vancomycin and concluded that there was no need to include vancomycin in initial empirical antibiotic therapy. Results from another study and a retrospective review of a large clinical trial also support the previous conclusion. In 1999, most experts in the field recommend vancomycin not be part of the initial empirical therapy regimen for treating febrile neutropenia in patients with cancer.     

Stopping antibiotic therapy in neutropenic patients

Infection is the major cause of death in neutropenic patients. Because of the lack of acute inflammatory cells, the usual signs of infection are often absent in these patients. Therefore, unexplained fever in a neutropenic patient requires prompt initiation of antibiotic therapy. Many physicians advocate continuing antibiotic therapy until neutropenia resolves. However, prolonged treatment with broad-spectrum antibiotics increases the risks of drug toxicity and superinfection with resistant bacteria and fungi. Based on a critical review of the literature and a large personal clinical experience, I offer tentative guidelines for withdrawing antibiotic therapy in persistently neutropenic patients. When antibiotic therapy is discontinued, frequent and careful monitoring of these patients and a low threshold for reinstituting antibiotic therapy are essential.     

A pilot study of antibiotic cycling for the treatment of febrile neutropenia patients with hematological diseases

Two antibiotics recommended by the guideline of Infectious Diseases Society of America (IDSA) were selected for treatment of febrile neutropenia, and these paired antibiotics were changed periodically three times. The clinical efficacy of each antibiotic was retrospectively evaluated at the end of the final period. There was no significant difference about efficacy rate between two kinds of antibiotics in the same sequential period. However, the efficacy rate has been rising and febrile duration has been shortening by degrees. Only a few drug resistant bacteria were recognized by the surveillance culture during antibiotic cycling. Recently, antibiotic cycling therapy has attracted attention especially in the ICU. However, a clinical study of treatment for febrile neutropenia has not been reported. Our trial suggests that cycling therapy may be useful for febrile neutropenia. However, Some deviation in the patients characteristics of each period may affect the result. It seems that further examination is necessary about usefullness of the cycling therapy for febrile neutropenia.     

Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia

We review experimental and clinical data on the pharmacokinetics and pharmacodynamics of antibacterial drugs in febrile neutropenic hosts. Since major pharmacokinetic changes have been reported for various classes of antibiotics in these patients, we advocate the need for adequate initial dosing regimens in all cases. Monitoring drug serum concentrations is mandatory for aminoglycosides and glycopeptides, and special attention should be paid to the dosing frequency of the short half-life beta-lactams to optimise the management of febrile neutropenia, especially in patients with severe sepsis.     

Novel Antifungal Drugs Against Fungal Pathogens: Do They Provide Promising Results for Treatment?

The febrile neutropenia episodes of hematological patients and their outcomes were evaluated with respect to fungal pathogens and antifungal therapy in this retrospective study. All patients, who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy due to hematological cancer from November 2010 to November 2012, were included into the study. We retrospectively collected demographic, treatment, and survival data of 126 patients with neutropenia and their 282 febrile episodes. The mean Multinational Association for Supportive Care in Cancer score was 17.18 ± 8.27. Systemic antifungal drugs were initiated in 22 patients with 30 culture-proven invasive fungal infections (IFIs), 25 attacks of 19 patients with probable invasive pulmonary aspergillosis (IPA), 42 attacks of 38 patients with possible IPA, and 31 attacks of 30 patients with suspected IFI. Voriconazole (VOR), caspofungin and liposomal amphotericin B were used to treat 72 episodes of 65 patients, 45 episodes of 37 patients and 34 episodes of 32 patients as a first-line therapy, respectively. Unfavorable conditions of our hematology ward are thought to increase the number of cases with invasive pulmonary aspergillosis and VOR use. It should be taken into consideration that increased systemic and per oral VOR usage predisposes patients to colonization and infection with azole-resistant fungal strains. Catheters should be removed in cases where patients’ conditions are convenient to remove it. Acute myeloblastic leukemia cases that are more likely to develop invasive fungal infections should be monitored closely for early diagnosis and timely initiation of antifungal drugs which directly correlates with survival rates.     

Beta-lactam-resistant Enterobacter bacteremia in febrile neutropenic patients receiving monotherapy

Bacteremia with resistant Enterobacter species has been reported in febrile, neutropenic cancer patients receiving beta-lactam antibiotics. To assess the relationship between enterobacter bacteremia and ceftazidime monotherapy, medical records were reviewed and isolates were tested from 16 neutropenic and 35 nonneutropenic patients with Enterobacter bacteremia. Fifteen isolates from the neutropenic patients were resistant to extended spectrum cephalosporins; only 12 of 35 isolates from the nonneutropenic patients were resistant to Enterobacter species. The neutropenic patients also had more beta-lactam therapy, both immediately before bacteremia and in the preceding year, than did nonneutropenic patients. Prior beta-lactam antibiotic exposure may predispose neutropenic patients to develop resistant Enterobacter bacteremia.     

The clinical impact of antibacterial prophylaxis and cycling antibiotics for febrile neutropenia in a hematological malignancy and transplantation unit

Febrile neutropenia is an expected complication during treatment of aggressive hematological malignancies and hematopoietic cell transplantation. We conducted a prospective cohort trial to determine the effects and safety of prophylactic fluoroquinolone administration, and rotation of empiric antibiotics for neutropenic fever in this patient population. From March 2002 through 2004, patients were treated with prophylactic levofloxacin during prolonged neutropenia, and a cycling schedule of empiric antibiotic therapy for neutropenic fever was initiated. The rates of bacteremia, resistance and complications were compared to a retrospective cohort of previously treated patients. The rate of gram-negative bacteremia decreased after the initiation of prophylactic levofloxacin (4.7 vs 1.8 episodes/1000 patient days, P<0.05). Gram-positive bacteremia rates remained unchanged, but more isolates of Enterococcus faecium were resistant to vancomycin after the intervention began. Resistance to the antibiotic agents used in the rotation did not emerge. There was no change in mortality during the intervention period. A prophylactic and cycling antibiotic schedule was successfully implemented on a hematological malignancy and hematopoietic cell transplant unit. gram-negative bacteremia was significantly decreased, without emergence of resistance. Concerns with Gram-positive resistance will require further observation.     

Appropriateness of diagnosis of unstable angina pectoris in patients referred for coronary arteriography

BACKGROUND

A diagnosis of unstable angina pectoris (UAP) often carries with it a decision to catheterize the patient promptly. However, UAP remains a clinical diagnosis, based mostly on a patient’s clinical history and electrocardiogram (ECG) findings.

OBJECTIVE

To evaluate whether the diagnosis of UAP is overused in patients referred for coronary arteriography.

METHODS

Ninety-six patients with a diagnosis of UAP who were referred for invasive studies were re-examined clinically before catheterization. Coronarography was independently reviewed for correlation with clinical findings.

RESULTS

Based on the patient’s history and ECG changes, UAP was classified by two independent cardiologists as ‘very likely’ in 58% and 49%, ‘possible’ in 19% and 30%, and of ‘low probability’ in 23% and 21%, respectively. Patients with ‘very likely’ UAP had a high incidence of significant coronary lesions (87% and 96% for each cardiologist) and complex lesions by angiography (41% and 49%, respectively). Patients with a diagnosis of ‘low probability’ UAP had a low incidence of significant coronary lesions (55% for each cardiologist) and a very low incidence of complex angiographic lesions (5% for each cardiologist). Patients with ‘possible’ UAP had intermediate results.

CONCLUSION

Because of a presumptive diagnosis of UAP, approximately 22% of all patients referred for coronarography have no clinical and/or ECG evidence for this diagnosis. The incidence of complex coronary lesions in this group is very low.