- Email: [email protected]
Management of the febrile neutropenic patient
International Journal of Antimicrobial Agents 26S (2005) S120–S122
Management of the febrile neutropenic patient Juan J. Picazo ∗ Department of Clinical Microbiology, Hospital Universitario de San Carlos, Universidad Complutense de Madrid, Spain
Abstract Fever of unknown origin in oncological patients is a frequent problem throughout the world. The microbiology of infections in these patients can vary widely. Gram-negative bacteria were more prevalent in early trials, but Gram-positive organisms have become increasingly common since the mid 1980s. However, Gram-negative microorganisms appear to be resurging. Equally important changes have occurred in the antimicrobial susceptibility of infective pathogens, most importantly methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, vancomycin-resistant enterococci, viridans group streptococci, ciprofloxacin-resistant Escherichia coli and Pseudomonas aeruginosa. Current management strategies for febrile neutropenic patients emphasize risk assessment and the suitability of individual patients for outpatient versus hospital treatment and for oral versus parenteral therapy. Among the new determinants of infection risk, the most important are the severity and duration of neutropenia. Additional significant issues include: the selection of monotherapy versus combination therapy; and prophylaxis, which involves, among other strategies, quinolone use, prevention of fungal and viral infections, surveillance cultures, prevention of catheter-related infections, and vaccines. With relation to the consensus document, it should clearly define fever and neutropenia, and rank the strength of recommendations and the quality of the evidence on which they are based. Finally, the document should provide a detailed, stepwise management algorithm, addressing the initial empirical antimicrobial therapy and the antimicrobial therapy on days 3–5 and days 5–7 of therapy. © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Antimicrobial susceptibility; Febrile neutropenia; Antimicrobial therapy
1. Introductory remarks Fever of unknown origin in patients with malignancies is a frequent problem throughout the world. This has been the driving force behind efforts, such as those that have led to the present meeting, aimed at developing guidelines designed to optimize the management of these patients. There are a growing number of regional and national guidelines, such as those issued by the Infectious Diseases Society of America (IDSA) in the United States, those issued in Latin America, Germany, Spain, Japan [1,2] and in many other countries and regions. The task of establishing guidelines for the management of febrile neutropenia is particularly challenging in the Asia–Pacific region because of the size of the involved territory and the significant differences that exist between the participating countries in terms of microbiological epidemiology, resistance patterns and medical practices. For the ∗
Fax: +34 91 330 3478. E-mail address: [email protected].
proposed guidelines to be credible and to gain general acceptance, representatives from each participating country have been asked to provide evidence-based guidance on common issues and to identify particular situations that apply to individual countries or subgroups of countries. 1.1. The microorganisms When attempting to develop anti-infective treatment guidelines, the causative pathogen and the patient him/herself should be the focus of the discussion. The microbiology of infections affecting neutropenic subjects with unexplained fever can vary widely. Successive trials that the International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer (EORTC) have been conducting for more than three decades have reflected the changes in the epidemiology of bacteremias in these patients. Whereas Gram-negative bacteria were considerably more prevalent in the early trials, this tendency changed by the mid 1980s with
0924-8579/$ – see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2005.07.010
J.J. Picazo / International Journal of Antimicrobial Agents 26S (2005) S120–S122
a growing incidence of Gram-positive organisms. However, a resurgence of Gram-negative microorganisms appears to be occurring, perhaps at a rate of 3% or 4% per year [3]. Equally important as the identification of the causative pathogen is the changing antimicrobial susceptibility of these pathogens. Special attention should be paid to specific pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, vancomycin-resistant enterococci, viridans group streptococci, ciprofloxacin-resistant Escherichia coli and Pseudomonas aeruginosa. 1.2. The patient In the past, the management of febrile neutropenia involved a standard approach, similar for all patients without consideration of their individual risk level. However, current strategies evaluate the risk and the suitability of individual patients for outpatient versus hospital treatment and for oral versus parenteral therapy. The current approach can be reasonably expected to evolve further towards improved models of risk prediction and improved risk-based treatment strategies. Several efforts have been undertaken to develop appropriate tools for risk assessment. In 1992, Talcott et al. [4] tried to identify clinical characteristics in the first 24 h following hospital admission that would predict subsequent serious medical complications during the hospital stay of cancer patients with fever and neutropenia. Serious medical complications occurred in 34% of patients with identified risk factors such as prior inpatient status, serious independent comorbidities and/or progressive neoplasia. Complications did not occur in patients without the risk factors mentioned above. In 2000, the Infectious Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC), chaired by Jean Klastersky, conducted a trial that led to the development of a risk predictive model based on a scoring system (Table 1) [5]. The trial was based on a large population of Table 1 Score derived from the logistic equation of the Multinational Association of Supportive Care in Cancer (MASCC) predictive model (1386 patients with febrile neutropenia)a Characteristic Burden of illness No or mild symptoms Moderate symptoms No hypotension No chronic obstructive pulmonary disease Solid tumor or no previous fungal infection in hematological tumor Outpatient status No dehydration Age <60 years
Points 5 3 5 4 4 3 3 2
a The purpose of scoring (maximum score, 26) is to select low-risk patients having a high probability of favorable outcome, with a score of 21 or more predicting <5% risk of severe complications.
S121
cancer patients with fever and neutropenia. According to the proposed system, a score of 21 or more was predictive of a <5% risk for severe complications. When compared with Talcott’s model, the MASCC risk score proved more effective in identifying low-risk febrile neutropenic patients. The MASCC score had a 91% positive predictive value for severe complications and death in a subgroup of 663 high-risk patients. A statistically significant difference was found in the MASCC-predicted bacteremias between high-risk (30%) and low-risk (13%) patients. Bacteremias were uncomplicated in 67% and 32% of low-risk and high-risk patients, respectively, and had a fatal outcome in 19% of high-risk patients compared with only 2% among those stratified as low risk. The MASCC score has been used in the 2002 IDSA guidelines for antimicrobial therapy of neutropenic cancer patients [6]. Patient characteristics that identify low-risk febrile neutropenic patients include the degree of symptoms (ranging from absent or mild to moderate, as opposed to severe), absence of hypotension, absence of chronic obstructive pulmonary disease, presence of a solid tumor, absence of fungal infection, absence of dehydration, outpatient status at the onset of fever, and age below 60 years. A score equal to or greater than 21 indicates a low risk for infection. In Spain, Garc´ıa Rodr´ıguez et al. [7] have pointed out a number of patient characteristics that help to identify febrile neutropenic patients at a low risk for infections. These characteristics include: • an expected duration of neutropenia of less than 10 days at age below 60 years; • no criteria for severe sepsis; • absence of an apparent clinical focus and of co-morbidities such as diabetes mellitus, renal failure or chronic hepatitis; • no history of documented infection during a previous episode of neutropenia; and • absence of uncontrolled neoplasia, and a favorable social and economic background. Among the many factors that have been added to the previously mentioned infection risk assessment models for febrile neutropenic patients, the most important ones are the severity and duration of neutropenia. Fig. 1 shows an initially marked difference in the risk for infection between patients with an absolute neutrophil count (ANC) of fewer than 1000 cells/ mm3 and those with an ANC below 100 cells/mm3 . However, this difference in infection risk diminishes as the duration of neutropenia increases, and virtually vanishes when patients have been neutropenic for 14 weeks [8,9]. 1.3. Additional considerations Besides clinical and microbiological characteristics, other issues need to be considered when trying to determine the optimal treatment for febrile neutropenic patients. These include the selection of monotherapy as opposed to combination therapy. In principle, combination treatment is indicated for:
S122
J.J. Picazo / International Journal of Antimicrobial Agents 26S (2005) S120–S122
Fig. 1. Risk of infection by severity (granulocytes/L) and duration (weeks) of neutropenia (adapted from [8,9]).
• patients with signs of infection at the catheter insertion site; • colonization with MRSA; • severe mucositis; • signs of a focal infection; • colonization with non-fermenter Gram-negative bacilli such as P. aeruginosa and Acinetobacter spp.; • recent history of treatment with a -lactam agent; • severe sepsis, septic shock or respiratory distress; or • an allergy to -lactam antibiotics. Another crucial issue is prophylaxis, which involves a series of strategies such as quinolone use, prevention of fungal, viral (specifically cytomegalovirus) and Pneumocystis carinii infections, surveillance cultures, prevention of catheter-related infections, and vaccines. In 2002, the US Healthcare Infection Control Practices Advisory Committee issued specific guidelines for the prevention of infections related to intravascular catheters [10]. Other issues to be addressed include costs, duration of antimicrobial therapy, and outpatient or home treatment as opposed to inpatient treatment. High-risk patients need to be treated in a hospital setting with parenteral antibiotics. However, those who defervesce promptly can be discharged and continue treatment in an outpatient setting with parenteral or oral antibiotics. This approach can be used with low-risk patients and can lower costs, reduce the risk for superinfections and improve the patient’s quality of life. On the other hand, however, it can be associated with a risk of severe complications, an increased likelihood of non-adherence, a false feeling of safety, and the need to develop a complex infrastructure at home [11].
2. The consensus document It may be useful to summarize the salient characteristics desirable in a set of practice guidelines. The document
should include clear definitions of fever and neutropenia, perhaps with different cut-off points for patients with different types of malignancies, i.e. leukemic and non-leukemic patients. It is particularly important to rank the power of recommendations and the quality of the evidence on which they are based. The IDSA guidelines [6] provide a good example of this. The document should also indicate the studies to be performed as part of the initial evaluation, such as two blood cultures, urine culture, complete blood count, chest radiograph and C-reactive protein, as well as those that will help to evaluate subsequently febrile neutropenic patients, including general biochemistry testing, hematological testing and microbiological studies such as blood culture taken from a peripheral vein and a catheter, urine culture, and sputum Gram stain and culture. Finally, the core of the document should be a detailed, stepwise management algorithm, addressing the initial empirical antimicrobial therapy and the antimicrobial therapy on days 3–5 and days 5–7 of therapy.
References [1] Masaoka T. Management of fever of unknown origin in the neutropenic patient: the Japanese experience. Int J Hematol 1998;68(Suppl. 1):S9–11. [2] Proceedings of the consensus meeting: Evidence-Based Recommendations on the Management of Febrile Neutropenia in Japan. Honolulu, Hawaii, 8–9 March 2003. Clin Infect Dis 2004;39(Suppl. 1):S1–69. [3] Glauser MP, Pizzo PA. Management of infections in immunocompromised patients. London, New York: WB Saunders; 2000. [4] Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, twocenter validation of a prediction rule. J Clin Oncol 1992;10:316– 22. [5] Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–51. [6] Hughes WT, Armstrong D, Bodey GP. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51. [7] Garc´ıa Rodr´ıguez JA, Gobernado M, Gomis M, et al. Clinical guide for the evaluation and treatment of patients with neutropenia and fever. Rev Esp Quimioter 2001;14:75–83 [in Spanish]. [8] Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulation leukocytes and infection in patients with acute leukaemia. Ann Intern Med 1966;61:328–40. [9] Glauser MP, Calandra T. Infections in patients with hematologic malignancies. Ontario, Canada: WB Saunders Company; 2000. p. 41–88. [10] O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2002;30:476–89. [11] Rolston KV. New trends in patient management: risk-based therapy for febrile patients with neutropenia. Clin Infect Dis 1999;29:515–52.
Management of the febrile neutropenic patient Juan J. Picazo ∗ Department of Clinical Microbiology, Hospital Universitario de San Carlos, Universidad Complutense de Madrid, Spain
Abstract Fever of unknown origin in oncological patients is a frequent problem throughout the world. The microbiology of infections in these patients can vary widely. Gram-negative bacteria were more prevalent in early trials, but Gram-positive organisms have become increasingly common since the mid 1980s. However, Gram-negative microorganisms appear to be resurging. Equally important changes have occurred in the antimicrobial susceptibility of infective pathogens, most importantly methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, vancomycin-resistant enterococci, viridans group streptococci, ciprofloxacin-resistant Escherichia coli and Pseudomonas aeruginosa. Current management strategies for febrile neutropenic patients emphasize risk assessment and the suitability of individual patients for outpatient versus hospital treatment and for oral versus parenteral therapy. Among the new determinants of infection risk, the most important are the severity and duration of neutropenia. Additional significant issues include: the selection of monotherapy versus combination therapy; and prophylaxis, which involves, among other strategies, quinolone use, prevention of fungal and viral infections, surveillance cultures, prevention of catheter-related infections, and vaccines. With relation to the consensus document, it should clearly define fever and neutropenia, and rank the strength of recommendations and the quality of the evidence on which they are based. Finally, the document should provide a detailed, stepwise management algorithm, addressing the initial empirical antimicrobial therapy and the antimicrobial therapy on days 3–5 and days 5–7 of therapy. © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Antimicrobial susceptibility; Febrile neutropenia; Antimicrobial therapy
1. Introductory remarks Fever of unknown origin in patients with malignancies is a frequent problem throughout the world. This has been the driving force behind efforts, such as those that have led to the present meeting, aimed at developing guidelines designed to optimize the management of these patients. There are a growing number of regional and national guidelines, such as those issued by the Infectious Diseases Society of America (IDSA) in the United States, those issued in Latin America, Germany, Spain, Japan [1,2] and in many other countries and regions. The task of establishing guidelines for the management of febrile neutropenia is particularly challenging in the Asia–Pacific region because of the size of the involved territory and the significant differences that exist between the participating countries in terms of microbiological epidemiology, resistance patterns and medical practices. For the ∗
Fax: +34 91 330 3478. E-mail address: [email protected].
proposed guidelines to be credible and to gain general acceptance, representatives from each participating country have been asked to provide evidence-based guidance on common issues and to identify particular situations that apply to individual countries or subgroups of countries. 1.1. The microorganisms When attempting to develop anti-infective treatment guidelines, the causative pathogen and the patient him/herself should be the focus of the discussion. The microbiology of infections affecting neutropenic subjects with unexplained fever can vary widely. Successive trials that the International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer (EORTC) have been conducting for more than three decades have reflected the changes in the epidemiology of bacteremias in these patients. Whereas Gram-negative bacteria were considerably more prevalent in the early trials, this tendency changed by the mid 1980s with
0924-8579/$ – see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2005.07.010
J.J. Picazo / International Journal of Antimicrobial Agents 26S (2005) S120–S122
a growing incidence of Gram-positive organisms. However, a resurgence of Gram-negative microorganisms appears to be occurring, perhaps at a rate of 3% or 4% per year [3]. Equally important as the identification of the causative pathogen is the changing antimicrobial susceptibility of these pathogens. Special attention should be paid to specific pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, vancomycin-resistant enterococci, viridans group streptococci, ciprofloxacin-resistant Escherichia coli and Pseudomonas aeruginosa. 1.2. The patient In the past, the management of febrile neutropenia involved a standard approach, similar for all patients without consideration of their individual risk level. However, current strategies evaluate the risk and the suitability of individual patients for outpatient versus hospital treatment and for oral versus parenteral therapy. The current approach can be reasonably expected to evolve further towards improved models of risk prediction and improved risk-based treatment strategies. Several efforts have been undertaken to develop appropriate tools for risk assessment. In 1992, Talcott et al. [4] tried to identify clinical characteristics in the first 24 h following hospital admission that would predict subsequent serious medical complications during the hospital stay of cancer patients with fever and neutropenia. Serious medical complications occurred in 34% of patients with identified risk factors such as prior inpatient status, serious independent comorbidities and/or progressive neoplasia. Complications did not occur in patients without the risk factors mentioned above. In 2000, the Infectious Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC), chaired by Jean Klastersky, conducted a trial that led to the development of a risk predictive model based on a scoring system (Table 1) [5]. The trial was based on a large population of Table 1 Score derived from the logistic equation of the Multinational Association of Supportive Care in Cancer (MASCC) predictive model (1386 patients with febrile neutropenia)a Characteristic Burden of illness No or mild symptoms Moderate symptoms No hypotension No chronic obstructive pulmonary disease Solid tumor or no previous fungal infection in hematological tumor Outpatient status No dehydration Age <60 years
Points 5 3 5 4 4 3 3 2
a The purpose of scoring (maximum score, 26) is to select low-risk patients having a high probability of favorable outcome, with a score of 21 or more predicting <5% risk of severe complications.
S121
cancer patients with fever and neutropenia. According to the proposed system, a score of 21 or more was predictive of a <5% risk for severe complications. When compared with Talcott’s model, the MASCC risk score proved more effective in identifying low-risk febrile neutropenic patients. The MASCC score had a 91% positive predictive value for severe complications and death in a subgroup of 663 high-risk patients. A statistically significant difference was found in the MASCC-predicted bacteremias between high-risk (30%) and low-risk (13%) patients. Bacteremias were uncomplicated in 67% and 32% of low-risk and high-risk patients, respectively, and had a fatal outcome in 19% of high-risk patients compared with only 2% among those stratified as low risk. The MASCC score has been used in the 2002 IDSA guidelines for antimicrobial therapy of neutropenic cancer patients [6]. Patient characteristics that identify low-risk febrile neutropenic patients include the degree of symptoms (ranging from absent or mild to moderate, as opposed to severe), absence of hypotension, absence of chronic obstructive pulmonary disease, presence of a solid tumor, absence of fungal infection, absence of dehydration, outpatient status at the onset of fever, and age below 60 years. A score equal to or greater than 21 indicates a low risk for infection. In Spain, Garc´ıa Rodr´ıguez et al. [7] have pointed out a number of patient characteristics that help to identify febrile neutropenic patients at a low risk for infections. These characteristics include: • an expected duration of neutropenia of less than 10 days at age below 60 years; • no criteria for severe sepsis; • absence of an apparent clinical focus and of co-morbidities such as diabetes mellitus, renal failure or chronic hepatitis; • no history of documented infection during a previous episode of neutropenia; and • absence of uncontrolled neoplasia, and a favorable social and economic background. Among the many factors that have been added to the previously mentioned infection risk assessment models for febrile neutropenic patients, the most important ones are the severity and duration of neutropenia. Fig. 1 shows an initially marked difference in the risk for infection between patients with an absolute neutrophil count (ANC) of fewer than 1000 cells/ mm3 and those with an ANC below 100 cells/mm3 . However, this difference in infection risk diminishes as the duration of neutropenia increases, and virtually vanishes when patients have been neutropenic for 14 weeks [8,9]. 1.3. Additional considerations Besides clinical and microbiological characteristics, other issues need to be considered when trying to determine the optimal treatment for febrile neutropenic patients. These include the selection of monotherapy as opposed to combination therapy. In principle, combination treatment is indicated for:
S122
J.J. Picazo / International Journal of Antimicrobial Agents 26S (2005) S120–S122
Fig. 1. Risk of infection by severity (granulocytes/L) and duration (weeks) of neutropenia (adapted from [8,9]).
• patients with signs of infection at the catheter insertion site; • colonization with MRSA; • severe mucositis; • signs of a focal infection; • colonization with non-fermenter Gram-negative bacilli such as P. aeruginosa and Acinetobacter spp.; • recent history of treatment with a -lactam agent; • severe sepsis, septic shock or respiratory distress; or • an allergy to -lactam antibiotics. Another crucial issue is prophylaxis, which involves a series of strategies such as quinolone use, prevention of fungal, viral (specifically cytomegalovirus) and Pneumocystis carinii infections, surveillance cultures, prevention of catheter-related infections, and vaccines. In 2002, the US Healthcare Infection Control Practices Advisory Committee issued specific guidelines for the prevention of infections related to intravascular catheters [10]. Other issues to be addressed include costs, duration of antimicrobial therapy, and outpatient or home treatment as opposed to inpatient treatment. High-risk patients need to be treated in a hospital setting with parenteral antibiotics. However, those who defervesce promptly can be discharged and continue treatment in an outpatient setting with parenteral or oral antibiotics. This approach can be used with low-risk patients and can lower costs, reduce the risk for superinfections and improve the patient’s quality of life. On the other hand, however, it can be associated with a risk of severe complications, an increased likelihood of non-adherence, a false feeling of safety, and the need to develop a complex infrastructure at home [11].
2. The consensus document It may be useful to summarize the salient characteristics desirable in a set of practice guidelines. The document
should include clear definitions of fever and neutropenia, perhaps with different cut-off points for patients with different types of malignancies, i.e. leukemic and non-leukemic patients. It is particularly important to rank the power of recommendations and the quality of the evidence on which they are based. The IDSA guidelines [6] provide a good example of this. The document should also indicate the studies to be performed as part of the initial evaluation, such as two blood cultures, urine culture, complete blood count, chest radiograph and C-reactive protein, as well as those that will help to evaluate subsequently febrile neutropenic patients, including general biochemistry testing, hematological testing and microbiological studies such as blood culture taken from a peripheral vein and a catheter, urine culture, and sputum Gram stain and culture. Finally, the core of the document should be a detailed, stepwise management algorithm, addressing the initial empirical antimicrobial therapy and the antimicrobial therapy on days 3–5 and days 5–7 of therapy.
References [1] Masaoka T. Management of fever of unknown origin in the neutropenic patient: the Japanese experience. Int J Hematol 1998;68(Suppl. 1):S9–11. [2] Proceedings of the consensus meeting: Evidence-Based Recommendations on the Management of Febrile Neutropenia in Japan. Honolulu, Hawaii, 8–9 March 2003. Clin Infect Dis 2004;39(Suppl. 1):S1–69. [3] Glauser MP, Pizzo PA. Management of infections in immunocompromised patients. London, New York: WB Saunders; 2000. [4] Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, twocenter validation of a prediction rule. J Clin Oncol 1992;10:316– 22. [5] Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–51. [6] Hughes WT, Armstrong D, Bodey GP. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51. [7] Garc´ıa Rodr´ıguez JA, Gobernado M, Gomis M, et al. Clinical guide for the evaluation and treatment of patients with neutropenia and fever. Rev Esp Quimioter 2001;14:75–83 [in Spanish]. [8] Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulation leukocytes and infection in patients with acute leukaemia. Ann Intern Med 1966;61:328–40. [9] Glauser MP, Calandra T. Infections in patients with hematologic malignancies. Ontario, Canada: WB Saunders Company; 2000. p. 41–88. [10] O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2002;30:476–89. [11] Rolston KV. New trends in patient management: risk-based therapy for febrile patients with neutropenia. Clin Infect Dis 1999;29:515–52.