LA CONSULTA SEMANAL

 

MAYO 2000

 

 

CONSULTA:

Neutropenia febril

 

N Engl J Med 2000 Jan 6;342(1):56; discussion 56-8 [Texto completo] 
Oral antibiotics for febrile patients with neutropenia due to cancer chemotherapy. 
Rubenstein EB, Rolston KV, Kim YJ 

Clin Infect Dis 1999 Sep;29(3):515-21 
New trends in patient management: risk-based therapy for febrile patients with neutropenia. 
Rolston KV 
Section of Infectious Diseases, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.  krolston@notes.mdacc.tmc.edu 
Standard management of febrile neutropenia includes the prompt administration of empirical, broad-spectrum, parenteral antibiotic therapy. This is generally done in a hospital-based setting. Although effective (overall survival of >90%), such therapy leads to prolonged hospitalization, excessive resource utilization, and increased costs. Recently, risk-assessment models have been developed that reliably differentiate febrile patients with neutropenia that are at low risk for morbidity and/or mortality. This has enabled clinicians to administer risk-based treatment to such patients. High-risk patients still receive standard, hospital-based, parenteral treatment. Many patients, however, defervesce promptly and can be discharged home with parenteral or oral antibiotics. Low-risk patients need not be hospitalized at all and can be safely treated with parenteral or oral antibiotics in the outpatient or home setting. Careful risk assessment and patient selection, appropriate antimicrobial regimen(s), and meticulous monitoring for response or the development of complications or toxicity are essential for the success of risk-based therapy. 

Clin Infect Dis 1999 Sep;29(3):508-14 
Is monotherapy for febrile neutropenia still a viable alternative? 
Ramphal R 
Department of Medicine, University of Florida, Gainesville, 32610, USA. ramphr@medmac.ufl.edu 
Monotherapy for empirical treatment of febrile neutropenia is effective and often less costly than combination therapy but remains controversial. The controversy results from observations that combination therapy for Pseudomonas aeruginosa improved outcomes, and this approach became a standard. Many subsequent publications, including the Infectious Diseases Society of America guidelines for febrile neutropenia, now support monotherapy. However, changes in the pathogens involved in febrile neutropenia and in their resistance prompt a reevaluation. In the evaluation of new antibiotics, recent trials comparing either cefepime or meropenem with combination therapy or with ceftazidime confirm that monotherapy remains a viable therapeutic approach, with infectious mortality in the 5% range in all arms. The choice of monotherapy should, however, be made on the basis of resistance patterns seen in an institution. The agent selected should be very active against the organisms that are likely to cause rapidly fatal infections, and clinicians must be prepared to modify monotherapy as appropriate.  

Clin Infect Dis 1999 Sep;29(3):495-502 
Contemporary antimicrobial susceptibility patterns of bacterial pathogens commonly associated with febrile patients with neutropenia. 
Jones RN 
Department of Pathology, University of Iowa College of Medicine, Iowa City 52242, USA. ronald-jones@uiowa.edu 
One of the most challenging problems in antimicrobial chemotherapy is the effective empirical treatment of infection in patients with neutropenia. The rates of occurrence for pathogens have significantly changed (from predominance of gram-negative to gram-positive organisms) under selective pressure of broad-spectrum antimicrobial therapy or prophylaxis, and novel resistance mechanisms have emerged. To address the need for appropriate monotherapy or combination regimens for patients with neutropenia, physicians must prescribe agents with a spectrum of antimicrobial activity to inhibit the major, prevalent pathogens encountered in bloodstream infection and pneumonia; in addition, these selected agents must be active against recently described resistant organisms. Data from the SENTRY Antimicrobial Surveillance Program indicate that several broad-spectrum agents remain highly active and can be used alone or in combinations. In most cases, the newer compounds with increased activity and spectrum against gram-positive cocci (i.e., carbapenems, cefepime, levofloxacin, and trovafloxacin) offer a greater inhibitory potential for empirical therapy among patients with neutropenia and severe infections. 

N Engl J Med. 1999 Jul 29;341(5):362-3   [Texto completo] 
Fever and Neutropenia -- How to Use a New Treatment Strategy 
Robert W. Finberg, M.D. James A. Talcott, M.D. 

N Engl J Med 1999 Jul 29;341(5):305-11 
A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. 
Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, Hiemenz J, Hiemenz S, Hicks JE, Gill V, Steinberg SM, Pizzo PA 
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. 
Comments: 
Comment in: N Engl J Med 1999 Jul 29;341(5):362-3 

Curr Clin Top Infect Dis 1999;19:160-80 
Current considerations in the management of fever and neutropenia. 
Alexander SW, Pizzo PA 
Harvard Medical School, Boston, Massachusetts, USA. 

Infection 1999 Jan-Feb;27(1):23-7 
Cost-effectiveness of ceftazidime or imipenem/cilastatin versus ceftriaxone + aminoglycoside in the treatment of febrile episodes in neutropenic cancer patients in Germany. 
Dietrich ES, Patz E, Frank U, Daschner FD 
Institut fur Umweltmedizin und Krankenhaushygiene, Universitatskliniken Freiburg, Germany. 
A three-pronged cost-effectiveness analysis of the treatment of febrile episodes in neutropenic cancer patients was conducted. It included a review of 37 randomized, controlled studies in the MEDLINE and EMBASE databases (1980-1996). Clinical outcomes as well as costs of treatment with imipenem/cilastatin, ceftazidime and ceftriaxone + aminoglycoside were compared. Primary therapy and modification, respectively, were successful in 62 and 27% of patients treated with imipenem/cilastatin, in 56 and 31% with ceftazidime and in 41 and 13% with ceftriaxone + aminoglycoside. From the perspective of a 1,800-bed teaching hospital, the average overall cost per successfully treated patient was DM 7,475 with imipenem/cilastatin, DM 7,810 with ceftazidime and DM 8,963 with ceftriaxone + netilmicin (DM 1 = USD 0.56; 7/97). The costs for the German national economy were imipenem/cilastatin DM 23,828, ceftazidime DM 24,985 and ceftriaxone + netilmicin DM 29,838. 
Comments: 
Comment in: Infection 1999 Nov-Dec;27(6):372-5 

Infect Dis Clin North Am 1998 Dec;12(4):963-77, viii 
Outpatient parenteral antibiotic therapy for fever and neutropenia. 
Tice AD 
Department of Medicine, University of Washington School of Medicine, Seattle, USA. 
The treatment of fever and neutropenia following chemotherapy lends itself well to outpatient parenteral antimicrobial therapy (OPAT). Patients prefer to be at home rather than hospitalized again. There is a clear cost advantage of outpatient therapy. With a quality program and careful patient selection, OPAT can be provided effectively and safely. The chances of an infection due to resistant bacteria also appear to be reduced. There are an increasing number of studies that support the use of empiric antibiotic therapy for the first fever in neutropenic patients. The choice of antimicrobial, dose, as well as vascular access and infusion devices must be tailored to the individual patient needs and circumstances. 

Presse Med 1998 Sep 5;27(25):1306-8 
[Management of febrile episodes in neutropenic patients]. 
Herbrecht R 
Service d'Onco-Hematologie, Hopital de Hautepierre, Strasbourg. 

Oncology 1998 Sep-Oct;55(5):489-500 
Italian guidelines for the management of infectious complications in pediatric oncology: empirical antimicrobial therapy of febrile neutropenia. 
Viscoli C, Castagnola E, Caniggia M, De Sio L, Garaventa A, Giacchino M, Indolfi P, Izzi GC, Manzoni P, Rossi MR, Santoro N, Zanazzo GA, Masera G 
Italian Association for Paediatric Haematology and Oncology (Associazione Italiana Ematologia e Oncologia Pediatrica - AIEOP) Supportive Therapy Group - Infectious Disease Section, Genoa, Italy. 
The Italian Association for Paediatric Haematology and Oncology prepared a guideline document aimed at unifying and rationalising as much as possible the management of febrile neutropenia in children with cancer, because of the potential impact of these procedures on hospital costs and on the development of antibiotic resistance. Before starting anti-infective therapy, at least 2 blood cultures, a throat swab, urine-culture, and cultures from any suspected infected site, should be performed. Routine chest X-rays at onset of febrile neutropenia are probably not necessary, in absence of respiratory signs. At the present time, the safer option probably remains the combination of a beta-lactam and an aminoglycoside, and treating febrile neutropenia outside of hospital should be considered an investigational approach. The choice of the most appropriated regimen for each institution should be based also on the local bacteriological statistics and patterns of bacterial resistance. Antibiotic toxicity and cost should be other important factors. Every subsequent addition or substitution of antibiotics should be based on objective signs of clinical deterioration. The only accepted empirical modification is empirical antifungal therapy, while the empirical addition of a glycopeptide antibiotic cannot be recommended. 

J Antimicrob Chemother 1998 Jun;41 Suppl D:65-80 
The evolution of the empirical management of fever and neutropenia in cancer patients. 
Viscoli C 
University of Genoa, National Institute for Cancer Research, Italy. viscolic@igecuniv.cisi.unige.it 
Infectious complications are an important cause of morbidity and mortality in cancer patients, especially those receiving chemotherapy. Furthermore, neutropenia, fever and infection limit the dose-intensity of antineoplastic chemotherapy in cancer patients. Fever without clinical signs of a localized infection is the commonest clinical presentation in neutropenic patients. Early empirical administration of broad-spectrum antibiotics at the onset of fever has become common practice, but the specific empirical regimen remains controversial. Guidance from therapeutic clinical trials is not straightforward, since it is difficult to compare trials, due to major differences and deficiencies in their design and analysis. Clinical trials fall into two categories: (i) explanatory trials which assess the hypothesis under ideal conditions, and (ii) pragmatic trials, which assess the regimen under the conditions of clinical practice. Methodological issues that are of crucial importance in the recognition of limits and value of the results of clinical trials in this field are discussed. The EORTC-IATCG has performed nine large therapeutic trials of empirical antibacterial and antifungal therapy in febrile, neutropenic patients with cancer. The results of trials, V, VIII, IX and
XI are reviewed, and issues to be resolved in future trials are also considered. 

J Antimicrob Chemother 1998 Jun;41 Suppl D:57-64 
Neutropenic infections: a review of the French Febrile Aplasia Study Group trials in 608 febrile neutropenic patients. 
Marie JP, Vekhoff A, Pico JL, Guy H, Andremont A, Richet H 
Service d'Hematologie Biologique, Hotel-Dieu, Paris, France. jean-pierre.marie@htd.ap-hop-paris.fr 
From 1986 to 1992, the Febrile Aplasia Study Group conducted a series of studies involving severely neutropenic patients. The average duration of neutropenia was 21 days, following chemotherapy for leukaemia, or chemotherapy/radiotherapy as part of a conditioning regimen for autologous or allogeneic bone marrow transplantation. A total of 591 evaluable febrile episodes were randomized to treatment with either ceftazidime 3 g daily + amikacin (the reference regimen; n=246), ceftazidime alone (n=98), ceftazidime + vancomycin (n=77), ceftazidime + ciprofloxacin (n=64) or piperacillin/tazobactam + amikacin (n=106). Only three patients treated with the reference dose of ceftazidime died or suffered serious morbidity from infections caused by Gram-negative bacteria. Piperacillin/tazobactam + amikacin was the only antibiotic regimen to have an effect significantly different from the reference regimen. Piperacillin/tazobactam + amikacin produced a higher rate of defervescence at 72 h (P=0.003), fewer days of fever (P < 0.001), fewer superinfections (P=0.018), a less frequent requirement for addition of vancomycin (P=0.01) and a higher incidence of treatment judged to be a 'complete success' (enduring defervescence without a change in antibiotics) (P=0.04). Despite the improved control of Gram-positive microorganisms, the infection-related death rate remained unchanged from 1987 to 1992. An increase in disseminated aspergillosis compensated for the reduction in lethal Gram-positive septicaemia. 

Clin Infect Dis 1997 Sep;25(3):551-73 [Texto completo en formato PDF]
1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. 
Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards JE, Feld R, Pizzo P, Rolston KV, Shenep JL, Young LS 
Fever and Neutropenia Guideline Panel, Infectious Diseases Society of America, Alexandria, Virginia, USA. 
This is the first in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are internists, pediatricians, and family practitioners. The targeted patients and setting for the fever and neutropenia guideline are hospitalized individuals with neutropenia secondary to cancer chemotherapy. Panel members represented experts in adult and pediatric infectious diseases and oncology. The guidelines are evidence-based. A standard ranking system was used for the strength of the
recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. The guideline will be listed on the IDSA home page at http://www.idsociety.org


Clin Infect Dis 1997 Feb;24 Suppl 2:S256-65 
Empirical treatment of febrile neutropenia: evolution of current therapeutic approaches. 
Hathorn JW, Lyke K 
Duke University Medical Center, Durham, North Carolina 27710, USA. 
Administration of empirical antibiotic therapy is now standard practice in the management of febrile neutropenia, but there has been considerable debate about the selection of an efficacious empirical antimicrobial regimen over the past 2 decades. A variety of approaches, including both monotherapeutic and multidrug regimens, have been demonstrated to be effective, although no one regimen has been proven to be superior to another. Changes in the epidemiology of infectious organisms and the growing emergence of highly drug-resistant strains make it necessary to continually reevaluate the therapeutic options. Fortunately, the number of therapeutic options has also been broadening as new antimicrobial agents, including third-generation cephalosporins and carbapenem antibiotics such as imipenem and meropenem, become available. Optimal management is directed by the findings of a clinical evaluation of the patient as well as an awareness of institutional patterns of infection and susceptibility of likely infecting organisms. 

Infect Dis Clin North Am 1996 Dec;10(4):777-96 
Fever in the neutropenic host. 
Chanock SJ, Pizzo PA 
Infectious Disease Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 
Fever in the neutropenic patient following myelosuppressive chemotherapy is a medical emergency. Appropriate antimicrobial therapy can dramatically reduce infection-related morbidity and mortality. This article reviews the rationale and methodology of treatment as well as its applicability to other neutropenic states. The utility of adjunct therapy with granulocyte- stimulating compounds is also discussed. 

Infect Dis Clin North Am 1996 Jun;10(2):223-37 
Early empiric antibiotic therapy for febrile neutropenia patients at low risk. 
Rolston KV, Rubenstein EB, Freifeld A 
Ambulatory and Supportive Care Oncology Research Program, University of Texas M.D. Anderson Cancer Center, Houston, USA. 
Although it is apparent that certain patients with febrile neutropenic episodes can benefit from outpatient antibiotic therapy, not all low-risk patients are treated in this fashion. There are barriers, real and perceived, to implementing this approach for patients, health care providers, and caregivers. Table 3 summarizes the advantages and disadvantages of ambulatory management of febrile neutropenic patients. For many patients and physicians, outpatient oral antibiotics may be preferred, whereas for others a more conservative approach might be needed in order to feel comfortable with treating this population on an outpatient basis. In this situation, patients can be treated in a stepwise fashion as shown in Table 4. These alternatives allow physicians and patients options to discuss when planning treatment strategies for febrile neutropenia. 

Med Clin North Am 1995 May;79(3):559-80 
Empiric therapy for infections in the febrile, neutropenic, compromised host. 
Giamarellou H 
Department of Internal Medicine, Athens University School of Medicine, Laiko, General Hospital, Greece. 
In the years to come, it is likely that with the advent of cytokines and even more with possibility to insert drug-resistant genes into hematopoietic stem cells, the risk of infection will be decreased because the severity and duration of neutropenia will be minimized. It is true that the ideal empiric antimicrobial regimen--a single antibiotic with a low incidence of superinfection and a low toxicity, without need for subsequent additions and readjustments--is still a wish. In the meantime and while living in the neutropenic area, physicians, for the benefit of patients, have to follow guidelines and create algorithms (see Fig. 1). Recommendations, however, should be always adjustable to the individual characteristics of the patient and the institution and to progress in antimicrobial chemotherapy. It is inevitable that research and clinical practice should go "hand in hand" in these "difficult-to-manage" and "difficult-to-treat" patients. After all, it should never be forgotten that the ultimate goal of empiric antimicrobial regimens in febrile neutropenia is to ensure patients' survival. 

Clin Infect Dis 1995 Feb;20(2):363-71 
Outcome for hospitalized patients with fever and neutropenia who are infected with the human immunodeficiency virus. 
Hambleton J, Aragon T, Modin G, Northfelt DW, Sande MA 
Department of Medicine, University of California, San Francisco 94143, USA. 
We conducted a retrospective cohort study to evaluate the occurrence of bacteremia and associated mortality among hospitalized patients who were seropositive for the human immunodeficiency virus (HIV) and who developed fever and neutropenia following antineoplastic chemotherapy or for other reasons. Review of medical records revealed 224 episodes in 142 patients. Of these episodes, 57% occurred following antineoplastic chemotherapy, and 43% occurred under other circumstances. Members of the chemotherapy group had significantly less-advanced HIV disease, a lower mean absolute-neutrophil-count nadir, and a shorter duration of hospitalization. There was no difference between the two groups in the frequency of bacteremia or mortality due to all causes when they were compared by multivariate analysis. Statistically significant univariate and multivariate predictors of bacteremia included sepsis syndrome and concurrent infection. Predictors of mortality included sepsis syndrome, concurrent infection, bacteremia, and antimicrobial therapy. This study suggests that the cause of neutropenia in HIV-seropositive patients is not a predictor of the outcome of fever and neutropenic episodes. Instead, clinical presentation and concomitant illnesses have a greater impact on outcome for a patient. 

American Society of Clinical Oncology. [Texto completo]

Recommendations for the use of hematopoietic colony-stimulating factors:evidence-based, clinical practice guidelines. 
PURPOSE: Standard practice in protecting against chemotherapy-associated infection has been chemotherapy dose modification or dose delay, administration of progenitor-cell support, or selective use of prophylactic antibiotics. Therapy of chemotherapy-associated neutropenic fever or infection has customarily involved treatment with intravenous antibiotics, usually accompanied by hospitalization. The hematopoietic colony-stimulating factors (CSFs) have been introduced into clinical practice as additional supportive measures that can reduce the likelihood of neutropenic complications due to chemotherapy. Clinical benefit has been shown, but the high cost of CSFs has led to concern about their appropriate use. The American Society of Clinical Oncology (ASCO) wishes to establish evidence-based, clinical practice guidelines for the use of CSFs in patients who are not enrolled on clinical trials. METHODS: An expert multidisciplinary panel reviewed the clinical data documenting the activity of CSFs. For each common clinical situation, the Panel formulated a guideline to encourage reasonable use of CSFs to preserve effectiveness but discourage excess use when little marginal benefit is anticipated. Consensus was reached after critically appraising the available evidence. Guidelines were validated by comparing them with recommendations for CSF use developed in other countries and by several academic institutions. Outcomes considered in evaluating CSF benefit included duration of neutropenia, incidence of febrile neutropenia, incidence and duration of antibiotic use, frequency and duration of hospitalization, infectious mortality, chemotherapy dose-intensity, chemotherapy efficacy, quality of life, CSF toxicity, and economic impact. To the extent that these data were available, the Panel placed greatest value on survival benefit, reduction in rates of febrile neutropenia, decreased hospitalization, and reduced costs. Lesser value was placed on alterations in absolute neutrophil counts (ANC). CONCLUSIONS: CSFs are recommended in some situations, eg, to reduce the likelihood of febrile neutropenia when the expected incidence is > or = 40%; after documented febrile neutropenia in a prior chemotherapy cycle to avoid infectious complications and maintain dose-intensity in subsequent treatment cycles when chemotherapy dose-reduction is not appropriate; and after high-dose chemotherapy with autologous progenitor-cell transplantation. CSFs are also effective in the mobilization of peripheral-blood progenitor cells. Therapeutic initiation of CSFs in addition to antibiotics at the onset of febrile neutropenia should be reserved for patients at high risk for septic complications. CSF use in patients with myelodysplastic syndromes may be reasonable if they are experiencing neutropenic infections. Administration of CSFs after initial chemotherapy for acute myeloid leukemia does not appear to be detrimental, but clinical benefit has been variable and caution is advised. Available data support use of CSFs in pediatric cancer patients similar to that recommended for adult patients. Outside of clinical trials, CSFs should not be used concurrently with chemotherapy and radiation, or to support increasing chemotherapy dose-intensity. Further research is warranted as a means to improve the cost-effective administration of the CSFs and identify clinical predictors of infectious complications that may direct their use.

 

 

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