A survey on hematology-oncology pediatric AIEOP centers: prophylaxis, empirical therapy and nursing prevention procedures of infectious complications

A nationwide questionnaire-based survey was designed to evaluate the management and prophylaxis of febrile neutropenia in pediatric patients admitted to hematology-oncology and hematopoietic stem cell transplant units. Of the 34 participating centers, 40 and 63%, respectively, continue to prescribe antibacterial and antimycotic prophylaxis in low-risk subjects and 78 and 94% in transplant patients. Approximately half of the centers prescribe a combination antibiotic regimen as first-line therapy in low-risk patients and up to 81% in high-risk patients. When initial empirical therapy fails after seven days, 63% of the centers add empirical antimycotic therapy in low-and 81% in high-risk patients. Overall management varies significantly across centers. Preventive nursing procedures are in accordance with international guidelines. This survey is the first to focus on prescribing practices in children with cancer and could help to implement practice guidelines.     

High-risk febrile neutropenia in Auckland 2003-2004: the influence of the microbiology laboratory on patient treatment and the use of pathogen-specific therapy

Background: International guidelines recommend routine microbiological assessment of patients with febrile neutropenia, but do not recommend a change from broad-spectrum antibiotic therapy to pathogen-specific therapy when a clinically relevant organism has been isolated. The aim of the study was to determine the aetiology of febrile neutropenia in adult haematology patients at Auckland City Hospital, to document the changes in treatment made following isolation of a clinically relevant organism and to assess adverse outcomes in any patient who received pathogen-specific therapy after a positive culture result. Methods: The results of all microbiological tests together with antibiotic therapy were recorded from consecutive patients with fever and a neutrophil count <0.5 × 10⁹/L over 1 year beginning in May 2003. Results: One thousand one hundred and ninety-six specimens were collected from 81 patients during 116 episodes of febrile neutropenia. A pathogen was isolated from blood cultures in 40 episodes: Gram-positive cocci accounted for 46% of isolates and Gram-negative bacilli for 35%. Isolation of a pathogen from blood cultures resulted in a change of treatment in 25 of 40 (62.5%, 95%CI 46–77%) episodes. In 12 of these episodes, antibiotic therapy was optimized to a single pathogen-specific agent. No adverse events or subsequent changes in antibiotic therapy occurred in any of these 12 patients. Isolation of a pathogen from specimens other than blood seldom led to a change in therapy. Conclusion: Isolation of a pathogen from blood cultures often allows antibiotic therapy to be simplified to a pathogen-specific regimen. Further study of this approach is warranted.     

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.     

Treatment of febrile neutropenia: what is new?

PURPOSE OF THE REVIEW: To identify the more recent challenges in the treatment of patients with febrile neutropenia following antineoplastic chemotherapy or bone marrow transplant published in the English language in the period late 2000-early 2002 regarding: changes in etiology of bacteremia in neutropenic patients; new options for initial empirical antibacterial therapy; factors associated with the risk of developing infection in cancer patients; prediction of prognosis in febrile neutropenia; oral therapy; need for a specific anti-Gram-positive coverage in persistently febrile and neutropenic patients. RECENT FINDINGS: Findings may be summarized according with the identified topics as follows: many centers are reporting an increase in the incidence of Gram-negative bacteremias; piperacillin-tazobactam could be safely administered as monotherapy of febrile neutropenia; congenital factors and intensity of chemotherapy and other medical interventions, such as antifungal prophylaxis, are recognized as of increasing importance in the determination of infectious risk; it is now possible to identify patients with a good prognosis (low risk) by means of validated scoring systems; oral therapy is feasible in low risk patients; the empirical addition of a glycopeptide in persistently febrile neutropenic patients is not indicated. SUMMARY: Many of the identified points may have a great impact in the daily management of febrile granulocytopenic patients. However, all recent epidemiological and therapeutical studies underline the absoloute need for the knowledge of the pattern of infecting organisms in each center.     

Management of infection in patients with acute leukemia during chemotherapy in Japan: questionnaire analysis by the Japan Adult Leukemia Study Group

Guidelines for the management of febrile neutropenia (FN), deep fungal infection or use of granulocyte colony-stimulating factor (G-CSF) published in the US and Europe cannot be directly applied in other countries. In this study, we undertook a questionnaire survey of member institutions of the Japan Adult Leukemia Study Group to investigate the status of, and problems with, the management of infectious complications in patients with acute leukemia. The questionnaire consisted of 52 multiple-choice questions covering therapeutic environment, antibacterial, and antifungal prophylaxis, empirical therapy (ET) for FN, and use of G-CSF. The results were compared to a previous survey performed in 2001. Usable responses were received from 134 of 184 (71.7%) institutions. With regard to antibacterial prophylaxis, fluoroquinolones and sulfamethoxazole-trimethoprim were most commonly used. Regarding antifungal prophylaxis, the most frequently used agent was fluconazole, followed by itraconazole. In ET for FN, monotherapy with cephems or carbapenems accounted for almost all of the responses. Most respondents indicated that they used micafungin (MCFG) in ET. Prophylactic use of G-CSF during remission induction therapy in acute myeloid leukemia was reported by only 4% of respondents. Strategies for antibacterial and antifungal prophylaxis or treatment of FN should be reviewed and updated as needed.     

Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial

We report on 232 patients undergoing autologous haematopoietic stem cell transplantation (ASCT) entered into a multicentre, randomised trial comparing the efficacy and tolerability of meropenem (MPM) with that of piperacillin/tazobactam (P/T) as empirical antimicrobial first-line therapy for febrile neutropenia. In 27.6% of patients in the MPM group and 22.4% in the P/T group, therapy was initially supplemented with a glycopeptide for venous catheter infection or bacteraemia because of coagulase-negative staphylococci. Complete response rate after 72 h was 63.8% in the MPM group and 49.6% in the P/T group (P = 0.034). Overall complete response rate after treatment modification was 94.0% in the MPM group and 93.1% in the P/T group. Median time to defervescence was 2 d in the MPM group and 3 d in the P/T group. The most frequently isolated pathogens were Gram-positive cocci. Treatment was well tolerated in both groups. One patient (0.4%) died from infection. Empirical first-line therapy with MPM as well as with P/T is safe and effective in febrile episodes emerging after ASCT. Higher response rates to primary treatment can be achieved with MPM.     

Shifting guidelines for myeloid growth factors: applications in cancer chemotherapy

Neutropenia is a frequent dose-limiting complication of chemotherapy. Although myeloid growth factors decrease the risk of febrile neutropenia and the resulting complications of hospitalizations, dose delays, and dose reductions, not all patients need or benefit from the prophylactic administration of myeloid growth factors. A recent risk model showed that the predictors of febrile neutropenia include anthracycline use, poor performance status, and low pretreatment blood counts. These predictors may be used in addition to the intensity of the chosen chemotherapy regimen to determine whether a patient warrants primary prophylaxis with myeloid growth factors. The 2005 guidelines of the National Comprehensive Cancer Network call for primary prophylactic use in all patients with a risk of febrile neutropenia above 20%. Other recent studies show that pegylated filgrastim is also effective at preventing febrile neutropenia in patients receiving intermediate- risk chemotherapy.     

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.     

Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate?

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.     

Antibiotic prophylaxis with teicoplanin on alternate days reduces rate of viridans sepsis and febrile neutropenia in pediatric patients with acute myeloid leukemia

Intensive chemotherapy directed against acute myeloid leukemia of childhood is followed by profound neutropenia and high risk for bacterial and fungal infections, including viridans group streptococci as a common cause for gram-positive septicemia. Few retrospective studies have shown the efficacy of various antibiotic prophylactic regimens in children. We retrospectively studied 50 pediatric patients treated on the AML-BFM 2004 protocol between 2005 and 2015 at St. Anna Children’s Hospital and assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia and bacterial sepsis. Fifty pediatric patients underwent 199 evaluable chemotherapy cycles. Viridans sepsis occurred after none of 98 cycles with prophylactic administration of teicoplanin/vancomycin in comparison to 12 cases of viridans sepsis among 79 cycles without systemic antibacterial prophylaxis (0 vs. 15 %, p?<?0.0001). In addition, there were significantly fewer episodes of febrile neutropenia in the teicoplanin/vancomycin group (44 % vs. no prophylaxis 82 %, p?<?0.0001). Severity of infection seemed to be worse when no antibiotic prophylaxis had been administered with a higher rate of intensive care unit treatment (0/98, 0 %, vs. 4/79, 5 %, p?=?0.038). So far, no increase of vancomycin-resistant enterococcus isolates in surveillance cultures was noticed. Antibiotic prophylaxis with teicoplanin (or vancomycin) appears safe and feasible and resulted in eradication of viridans sepsis and decreased incidence of febrile neutropenia in pediatric AML patients. The possibility to administer teicoplanin on alternate days on an outpatient basis or at home could contribute to patient’s quality of life and decrease health care costs.     

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)     

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.     

Fever associated with chemotherapy-induced neutropenia: a review of current therapeutic approaches

The numbers of cancer patients subjected to chemotherapy-induced neutropenia steadily grows as the new indications for systemic treatment expand. When these patients develop fever, or other signs of infection, they must receive immediate medical attention. This paper discusses the current therapeutic strategy for febrile neutropenia in cancer patients and reviews some of the newer approaches, which include empirical monotherapy, outpatient protocols, antibiotic prophylaxis and the use of haematopoietic growth factors.     

Cost effective approaches to antimicrobial use in oncology patients

PURPOSE OF REVIEW: In the current era of cost containment, the management of the oncology patient who presents with neutropenia and fever remains a challenge. This article will review which measures of cost are helpful in determining cost effective antibiotic use in patients with febrile neutropenia. RECENT FINDINGS: The majority of direct medical costs associated with treating febrile neutropenic patients are room and board costs. The most recent cost analysis reports a mean cost/day of US$1598. SUMMARY: Over the past two decades, infection-related mortality rates have decreased from 50% to rates as low as 10%. In contrast to the numerous studies comparing clinical outcomes of patients receiving different antimicrobial regimens for febrile neutropenia, the recent literature revealed limited studies that evaluate economic data. Typically, new antibiotic regimens show equal efficacy to the standard regimens but are often more expensive. If efficacy rates and safety are the same for an antibiotic, the cost is often used to select the product.     

Continuous infusion of ceftazidime for patients with breast cancer and multiple myeloma receiving high-dose chemotherapy and peripheral blood stem cell transplantation

This prospective study was performed to examine the safety and efficacy of a continuous infusion of ceftazidime in patients who developed febrile neutropenia after high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT) and to determine if the underlying disease represents a risk factor for infectious complications. From September 1995 to May 2000, 55 patients with breast cancer (BC, group I, 54 females, one male) and 32 patients with multiple myeloma (MM, group II, 10 female, 22 male) were included in this study. The febrile patients received a 2 g intravenous bolus of ceftazidime, followed by a 4 g continuous infusion over 24 h using a portable infusion pump. If the fever persisted for 72 h a glycopeptide antibiotic was added. The median age was 42 years (range 22-59) in group I and 52 years (range 35-63) in group II. Thirty-five BC patients (64%) and 20 MM patients (63%) responded to the monotherapy with ceftazidime. After addition of a glycopeptide antibiotic, an additional 11 BC patients vs 10 MM patients became afebrile. The causes of fever in group I were fever of unknown origin (FUO) in 49 patients, microbiologically documented infection (MDI) in five patients, and clinically documented infection (CDI) in one patient. The causes of fever in group II were FUO in 22 patients, MDI in eight patients and CDI in two patients. Forty-one febrile episodes in BC patients (75%) and 22 episodes in the MM patients (69%) were successfully managed by out-patient treatment, resulting in a saving of an average of 20 days of inpatient care. Significantly more episodes of MDI and CDI occurred in patients with MM (P = 0.05). The results indicate that BC and MM patients with febrile neutropenia after HDCT and PBSCT can be treated as outpatients with close monitoring to ensure safety. This approach represents a better use of health care resources.     

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.     

Infections in hematogical cancer patients: the contribution of systematic reviews and meta-analyses

Systematic reviews and meta-analyses have made a major contribution to the evidence-based management of infections in cancer patients. We review the contribution of systematic reviews with regard to antibiotic, antifungal, antiviral and Pneumocystis pneumonia prophylaxis; antibiotic and antifungal treatment of febrile neutropenia; use of intravenous immunoglobulins, and infection control strategies during neutropenia. We focus on limitations of randomized controlled trials and the way systematic reviews have addressed and resolved some of these limitations. Systematic reviews allow us to ask the right clinical question; consider the most relevant clinical outcome; address the problem of small trials and rare outcomes; address external validity and bias in randomized controlled trials, and point at gaps in evidence.     

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.     

Changing pattern of bacterial susceptibility to antibiotics in hematopoietic stem cell transplant recipients

Adequate infection prophylaxis and empirical antibiotic therapy are of critical importance after hematopoietic stem cell transplantation (HSCT). We examined the evolution of bacterial susceptibility to antibiotics in 492 patients (198 allografts and 294 autografts) transplanted between 1982 and 1999 and evaluated whether ciprofloxacin prophylaxis and an empirical antibiotic regimen (glycopeptide + third-generation cephalosporin) were still valid. We collected all susceptibility tests performed during the initial hospitalization on blood cultures as well as routine surveillance cultures and analyzed susceptibility to ciprofloxacin and to major antibiotics used in our unit. Gram-positive cocci rapidly became resistant to ciprofloxacin (susceptibility around 70% in 1990 to less than 20% in 1998) but sensitivity to glycopeptides remained unaltered. There was a rapid decline in the number of patients colonized with Gram-negative bacilli in the early years of ciprofloxacin prophylaxis. However, susceptibility to ciprofloxacin fell sharply from around 90% in 1990 to around 30% in 1999. In parallel, susceptibility to ceftazidime also decreased to less than 80% in recent years. Piperacillin (+/- tazobactam) did not show any variation over time and its efficacy remained too low (about 60%). Imipenem as well as recently introduced cefepim and meropenem showed stable and excellent profiles (>90% susceptibility). In conclusion: (1) quinolone prophylaxis has now lost most of its value; (2) the choice of a third-generation cephalosporin for empirical antibiotic therapy may no longer be the best because of the emergence of Gram-negative strains resistant to beta-lactamases, such as Enterobacter sp. More appropriate regimens of empirical antibiotic therapy in HSCT recipients may be based on the use of a carbapenem or fourth-generation cephalosporin.     

Bacteraemia in hospitalised patients with malignant blood disorders: a retrospective study of causative agents and their resistance profiles during a 14-year period without antibacterial prophylaxis

Bacteraemia is a major cause of morbidity and mortality in patients with haematological disorders during chemotherapy-induced neutropenia. The generally reported trend during the last two decades has been a gradual replacement of Gram-negative bacilli by Gram-positive cocci as the major causes of bacteraemia in neutropenic hosts. However, data that are unaffected by the use of antibacterial prophylaxis are scarce. Our objective therefore was to study the incidence of bacteraemia with different microorganisms in a haematology centre where antibacterial prophylaxis has not been used during the years 1988-2001. A total of 1402 episodes of clinically significant bacteraemia in 927 patients were identified. All patients were treated in the haematology wards and had an underlying haematological disorder, with lymphoma, leukaemia, and myeloma dominating. There were 536 (58%) male, and 391 (42%) female patients, with a median age of 58 years. The dominating pathogens were coagulase-negative staphylococci (CNS) 17%, Escherichia coli 16%, alpha-haemolytic streptococci 12%, Staphylococcus aureus 9%, Klebsiella spp 9%, Enterococcus spp 7%, and Pseudomonas spp 5%. The only significant incidence change was an increase of E. faecium bacteraemia. The balance between Gram-negative and Gram-positive microorganisms was essentially stable over the 14-year period. The rates of antibiotic resistance were generally low and stable. Gram-negative bacteria exhibited resistance to fluoroquinolones after 1998. The 7- and 30-day mortality rates were 6.3 and 15.6%, respectively, being significantly higher in patients with bacteraemia caused by Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or E. faecium.