Antibacterial Prophylaxis in Patients with Cancer and Neutropenia
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The recent studies by Bucaneve et al.1 and Cullen et al.2 (Sept. 8 issue) suggest that many patients with cancer and neutropenia may benefit from levofloxacin prophylaxis. Although the reports were published in tandem, their clinical implications differ fundamentally. Bucaneve et al. targeted "high-risk" patients (stem-cell transplant recipients or patients with leukemia) with anticipated neutropenia lasting more than seven days, a previously accepted approach.3
In contrast, most patients studied by Cullen et al. had solid tumors. Because patients with such tumors are unlikely to have prolonged or profound neutropenia, they are at lower risk for infectious complications.4 Although the authors do not report the average duration of neutropenia in the study patients, the outcomes for the 784 placebo recipients demonstrates their clinical stability. During neutropenia, 80 percent never had fever, and rates of severe infection or death were not significantly different between the two groups. Most levofloxacin recipients were therefore "treated" for problems that did not occur. These data do not support routine prophylaxis among "low-risk" patients, given drug costs and the hazards of antimicrobial resistance. Future efforts should define populations that will benefit from fluoroquinolone prophylaxis.
Alison G. Freifeld, M.D.
University of Nebraska Medical Center
Omaha, NE 68198-5400
Kent A. Sepkowitz, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
References
Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005;353:977-987.
Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988-998.
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-751.
To the Editor: Cullen et al. demonstrated that levofloxacin prophylaxis significantly reduced rates of neutropenic fever and hospitalization in patients with solid tumors or lymphoma who were receiving chemotherapy. Prophylaxis for 100 patients during each cycle of chemotherapy would be expected to prevent approximately six hospitalizations, without a significant effect on survival or the frequency of severe infections.
Quinolone-based regimens are the only orally administered, evidence-based option for outpatient management of neutropenic fever in lower-risk adults (adults at low risk for serious complications).1 The lack of an alternative oral antibiotic that is active against Pseudomonas aeruginosa and the concern about a breakthrough infection in patients receiving quinolone prophylaxis are factors that might prompt physicians to use an intravenous antibiotic regimen and to have a lower threshold for hospitalization as initial management of neutropenic fever. In addition, concern about the emergence of resistant pathogens associated with the widespread use of quinolone prophylaxis in lower-risk patients with cancer cannot be overstated. Given the options of early use of a quinolone for many patients (prophylaxis) and later, targeted use (empirical therapy for neutropenic fever), later may be better.
Nikolaos G. Almyroudis, M.D.
Brahm H. Segal, M.D.
Roswell Park Cancer Institute
Buffalo, NY 14263
brahm.segal@roswellpark.org
References
Freifeld AG, Brown AE, Elting L, et al. National Comprehensive Cancer Network practice guidelines in oncology: fever and neutropenia. (Accessed December 14, 2005, at http://www.nccn.org/physician_gls/f_guidelines.html.)
To the Editor: Cullen et al. reported that antibiotic prophylaxis with levofloxacin reduces the incidence of fever, probable infection, and hospitalization among patients whose solid tumors and lymphomas have been treated with standard-dose chemotherapy.
The study population included patients affected mainly by solid tumors; only 13 percent of patients had lymphoma. However, in our opinion, the number of patients with lymphoma is too limited to permit firm conclusions to be drawn regarding the benefit of levofloxacin prophylaxis in this subgroup. Furthermore, in the study by Cullen et al., patients who underwent randomization should be considered to have been at low risk for serious infective complications, according to the Multinational Association for Supportive Care in Cancer (MASCC) risk index,1 and would have been expected to have a short duration of neutropenia. Consequently, these patients could have been safely managed as outpatients with oral quinolone,2 reducing costs as well as the associated biologic consequences.3
Luca Castagna, M.D.
Armando Santoro, M.D.
Istituto Clinico Humanitas
20800 Rozzano, Italy
luca.castagna@humanitas.it
References
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;18:3038-3051.
Malik IA, Khan WA, Karim M, Aziz Z, Khan MA. Feasibility of outpatient management of fever in cancer patients with low-risk neutropenia: results of a prospective randomized trial. Am J Med 1995;98:224-231.
Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med 2005;353:1052-1054.
To the Editor: Fever was the main outcome analyzed in the two reports published in the September 8 issue.
Prophylaxis treatment given to between two and five patients prevented fever in one patient, with no effect on mortality or the severity of infection. This is a poor clinical outcome, and the problems associated with this strategy can be deleterious. Increasing resistance rates have been observed with increasing use of fluoroquinolones, a trend that was also shown by the authors. In addition, it is well known that prophylaxis might impair the isolation of organisms in culture, a problem common to both studies. At least three meta-analyses have shown a reduction in gram-negative bacteremia with quinolone-based regimens, but they have also shown that the reduction does not extend to infection-related mortality.1,2,3 We agree with Cullen et al. that their results alone "cannot be used to determine whether a policy of antibacterial prophylaxis should be applied systematically." The emergence of multidrug-resistant organisms is a serious danger that no longer belongs to the future.
Alessandro C. Pasqualotto, M.D., Ph.D.
University of Manchester
Manchester M13 9PT, United Kingdom
alessandro.pasqualotto@manchester.ac.uk
Daniela D. Rosa, M.D.
Christie Hospital NHS Trust
Manchester M20 4BX, United Kingdom
Adao L. Machado, M.D.
Hospital Independência
91430-000 Porto Alegre, Brazil
References
Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998;16:1179-1187.
van de Wetering MD, de Witte MA, Kremer LC, Offringa M, Scholten RJ, Caron HN. Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 2005;41:1372-1382.
Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996;23:795-805.
To the Editor: The prophetic editorial by Dr. Baden1 warns of the emergence of resistant organisms with the use of levofloxacin prophylaxis in patients with cancer who have neutropenia. Although no study has shown a survival benefit, we began using levofloxacin prophylaxis in similar patients in 1998. These patients included those receiving treatment for hematologic cancers and solid tumors and those undergoing hematopoietic-cell transplantation. Initially, we observed a decrease in bloodstream infection. However, in August 2004, the frequency of bloodstream infection started to increase along with a concurrent increase in levofloxacin resistance among blood isolates (to 61 percent). In April 2005, several interventions were implemented, including the discontinuation of levofloxacin prophylaxis. Subsequently, we have observed a decrease in bloodstream infection to levels seen before the increase (Figure 1). Levofloxacin resistance among blood isolates has also declined and is approaching the baseline rate (47 percent). Since it has been only eight months, we will continue to monitor the number and severity of cases of bloodstream infection. Although we cannot be certain, this may well be the very scenario that Dr. Baden feared.
Figure 1. Patients with Bloodstream Infection (BSI).
James I. Ito, M.D.
Bernard R. Tegtmeier, Ph.D.
Margaret R. O'Donnell, M.D.
City of Hope National Medical Center
Duarte, CA 91010
jito@coh.org
References
Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med 2005;353:1052-1054.
To the Editor: In their report on a randomized trial of prophylactic levofloxacin after chemotherapy, Cullen and coworkers report infection-related deaths. Overall mortality is not presented, in contrast to the companion article by Bucaneve et al. It would be helpful to know the rates for the Cullen et al. study, too.
Philipp Eller, M.D.
Christoph Pechlaner, M.D.
Innsbruck Medical University
A-6020 Innsbruck, Austria
christoph.pechlaner@uibk.ac.at
Dr. Bucaneve and colleagues reply: Dr. Pasqualotto and colleagues raise three problems in the interpretation of the results of our study. The first point is that the occurrence of fever is considered a "poor" outcome to use in evaluating the efficacy of prophylaxis. We disagree. The occurrence of fever in patients with cancer who have neutropenia is a clinically relevant and frequent finding, and it is mandatory to treat these patients empirically to prevent early deaths, even in the absence of clinical signs or symptoms or microbiologic isolates documenting infection.1
The second problem mentioned is that our study was unable to document a significant effect of prophylaxis in reducing mortality. Our trial did not have enough power to show an effect of prophylaxis on mortality. However, a significant survival advantage from prophylaxis has been shown in a recently published meta-analysis.2
Finally, Pasqualotto et al. state that the emergence of multidrug-resistant organisms could be a serious and dangerous result of prophylaxis. The fear of emerging resistance is not a reason to avoid the prophylactic use of fluoroquinolones in high-risk patients with neutropenia. In fact, there is some evidence that resistance to fluoroquinolones is a multiclonal and reversible phenomenon3,4 and does not adversely affect infection-related morbidity and mortality. Moreover, the selective pressure exerted by fluoroquinolones may be due mainly to their wide use in the community.
Albano Del Favero, M.D.
Università degli Studi di Perugia
06100 Perugia, Italy
delfa@unipg.it
Giampaolo Bucaneve, M.D.
Azienda Ospedaliera di Perugia
06100 Perugia, Italy
Pietro Martino, M.D.
Università La Sapienza Roma
00161 Rome, Italy
References
Reuter S, Kern WV, Sigge A, et al. Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis 2005;40:1087-1093.
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-751.
Tascini C, Menichetti F, Bozza S, et al. Molecular typing of fluoroquinolone-resistant and fluoroquinolone-susceptible Escherichia coli isolated from blood of neutropenic cancer patients in a single center. Clin Microbiol Infect 1999;5:457-461.
Dr. Cullen and colleagues reply: The correspondents repeat concerns about antimicrobial resistance that we have expressed. Previous work has concentrated primarily on inpatients with hematologic cancers, and we set out to test the efficacy of prophylactic antibiotics in outpatients with solid cancers and lymphomas. We demonstrated significant reductions in febrile episodes and in hospitalizations for the treatment of infections. To translate these findings into recommendations, more information will be required on mortality, high-risk groups, adverse consequences of prophylaxis, and adverse consequences of neutropenic fever.
As mentioned, we did not report mortality from all causes during the study period. This was lower in the levofloxacin group but not significantly so. Our numbers can be combined with those published in the large, recent meta-analysis that did show a significant reduction in mortality from all causes with fluoroquinolone prophylaxis.1
It is important not to confuse the risk of neutropenic fever with the risk of serious consequences, according to MASCC criteria — which can only be applied strictly once infection has occurred. In response to the editorial and the correspondents, we are now examining our data for pretreatment patient characteristics, disease type, and cycle number to identify those at high risk for neutropenic fever, with the goal of increasing the effect and efficiency of prophylaxis in future studies. Physicians might prefer to avoid prophylaxis in those at low risk and to treat uncomplicated neutropenic fever with oral fluoroquinolones, although the safety of this strategy in an outpatient context has yet to be shown.
Antimicrobial resistance as a result of prophylaxis is a potential problem, but the clinical impact is not easily predictable. For instance, a recent study has shown that resistance resulting from prophylaxis does not necessarily reduce the long-term prophylactic efficacy of the antibacterial agent within an inpatient, hematologic-cancer unit.2
Prevention of death and the sepsis syndrome are not the only reasons for preventing neutropenic fever. Delays and dose reductions in subsequent cycles of chemotherapy may have serious long-term consequences for patients with cancer.
At least in part, resistance to the concept of routine antibacterial prophylaxis after chemotherapy assumes an acceptance of the ethical propriety of depriving current patients of a proven therapy in order to benefit future patients. This requires open debate based on clear evidence, which should result from more work in the areas discussed above.
Neil Steven, M.B., B.S., Ph.D.
Lucinda Billingham, Ph.D.
Cancer Research UK Institute for Cancer Studies
Birmingham B15 2TH, United Kingdom
Michael Cullen, M.D.
University Hospital Birmingham Cancer Centre
Birmingham B15 2TH, United Kingdom
michael.cullen@uhb.nhs.uk
References
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Kern WV, Klose K, Jellen-Ritter AS, et al. Fluoroquinolone resistance of Escherichia coli at a cancer center: epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia. Eur J Clin Microbiol Infect Dis 2005;24:111-118.
Dr. Baden replies: Studies of novel antimicrobial prophylactic strategies are, by design, limited in their ability to detect the effects on the emergence of antimicrobial resistance. This limitation is due, in part, to the relatively short study duration and the delayed kinetics of this untoward consequence. Further challenges include both limited funding for this type of research and reporting biases, as these types of observations are less novel and exciting than the results of the initial prophylactic study. The challenge in natural experiments involving actual clinical practice is to quantify precisely the effect of increased antimicrobial use on the emergence of resistance in the setting of complex medical care. I encourage Dr. Ito and colleagues to study in detail what has occurred at their institution, for an improved understanding of the risk-to-benefit ratio.
Lindsey R. Baden, M.D.
In contrast, most patients studied by Cullen et al. had solid tumors. Because patients with such tumors are unlikely to have prolonged or profound neutropenia, they are at lower risk for infectious complications.4 Although the authors do not report the average duration of neutropenia in the study patients, the outcomes for the 784 placebo recipients demonstrates their clinical stability. During neutropenia, 80 percent never had fever, and rates of severe infection or death were not significantly different between the two groups. Most levofloxacin recipients were therefore "treated" for problems that did not occur. These data do not support routine prophylaxis among "low-risk" patients, given drug costs and the hazards of antimicrobial resistance. Future efforts should define populations that will benefit from fluoroquinolone prophylaxis.
Alison G. Freifeld, M.D.
University of Nebraska Medical Center
Omaha, NE 68198-5400
Kent A. Sepkowitz, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
References
Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005;353:977-987.
Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988-998.
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-751.
To the Editor: Cullen et al. demonstrated that levofloxacin prophylaxis significantly reduced rates of neutropenic fever and hospitalization in patients with solid tumors or lymphoma who were receiving chemotherapy. Prophylaxis for 100 patients during each cycle of chemotherapy would be expected to prevent approximately six hospitalizations, without a significant effect on survival or the frequency of severe infections.
Quinolone-based regimens are the only orally administered, evidence-based option for outpatient management of neutropenic fever in lower-risk adults (adults at low risk for serious complications).1 The lack of an alternative oral antibiotic that is active against Pseudomonas aeruginosa and the concern about a breakthrough infection in patients receiving quinolone prophylaxis are factors that might prompt physicians to use an intravenous antibiotic regimen and to have a lower threshold for hospitalization as initial management of neutropenic fever. In addition, concern about the emergence of resistant pathogens associated with the widespread use of quinolone prophylaxis in lower-risk patients with cancer cannot be overstated. Given the options of early use of a quinolone for many patients (prophylaxis) and later, targeted use (empirical therapy for neutropenic fever), later may be better.
Nikolaos G. Almyroudis, M.D.
Brahm H. Segal, M.D.
Roswell Park Cancer Institute
Buffalo, NY 14263
brahm.segal@roswellpark.org
References
Freifeld AG, Brown AE, Elting L, et al. National Comprehensive Cancer Network practice guidelines in oncology: fever and neutropenia. (Accessed December 14, 2005, at http://www.nccn.org/physician_gls/f_guidelines.html.)
To the Editor: Cullen et al. reported that antibiotic prophylaxis with levofloxacin reduces the incidence of fever, probable infection, and hospitalization among patients whose solid tumors and lymphomas have been treated with standard-dose chemotherapy.
The study population included patients affected mainly by solid tumors; only 13 percent of patients had lymphoma. However, in our opinion, the number of patients with lymphoma is too limited to permit firm conclusions to be drawn regarding the benefit of levofloxacin prophylaxis in this subgroup. Furthermore, in the study by Cullen et al., patients who underwent randomization should be considered to have been at low risk for serious infective complications, according to the Multinational Association for Supportive Care in Cancer (MASCC) risk index,1 and would have been expected to have a short duration of neutropenia. Consequently, these patients could have been safely managed as outpatients with oral quinolone,2 reducing costs as well as the associated biologic consequences.3
Luca Castagna, M.D.
Armando Santoro, M.D.
Istituto Clinico Humanitas
20800 Rozzano, Italy
luca.castagna@humanitas.it
References
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;18:3038-3051.
Malik IA, Khan WA, Karim M, Aziz Z, Khan MA. Feasibility of outpatient management of fever in cancer patients with low-risk neutropenia: results of a prospective randomized trial. Am J Med 1995;98:224-231.
Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med 2005;353:1052-1054.
To the Editor: Fever was the main outcome analyzed in the two reports published in the September 8 issue.
Prophylaxis treatment given to between two and five patients prevented fever in one patient, with no effect on mortality or the severity of infection. This is a poor clinical outcome, and the problems associated with this strategy can be deleterious. Increasing resistance rates have been observed with increasing use of fluoroquinolones, a trend that was also shown by the authors. In addition, it is well known that prophylaxis might impair the isolation of organisms in culture, a problem common to both studies. At least three meta-analyses have shown a reduction in gram-negative bacteremia with quinolone-based regimens, but they have also shown that the reduction does not extend to infection-related mortality.1,2,3 We agree with Cullen et al. that their results alone "cannot be used to determine whether a policy of antibacterial prophylaxis should be applied systematically." The emergence of multidrug-resistant organisms is a serious danger that no longer belongs to the future.
Alessandro C. Pasqualotto, M.D., Ph.D.
University of Manchester
Manchester M13 9PT, United Kingdom
alessandro.pasqualotto@manchester.ac.uk
Daniela D. Rosa, M.D.
Christie Hospital NHS Trust
Manchester M20 4BX, United Kingdom
Adao L. Machado, M.D.
Hospital Independência
91430-000 Porto Alegre, Brazil
References
Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998;16:1179-1187.
van de Wetering MD, de Witte MA, Kremer LC, Offringa M, Scholten RJ, Caron HN. Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 2005;41:1372-1382.
Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996;23:795-805.
To the Editor: The prophetic editorial by Dr. Baden1 warns of the emergence of resistant organisms with the use of levofloxacin prophylaxis in patients with cancer who have neutropenia. Although no study has shown a survival benefit, we began using levofloxacin prophylaxis in similar patients in 1998. These patients included those receiving treatment for hematologic cancers and solid tumors and those undergoing hematopoietic-cell transplantation. Initially, we observed a decrease in bloodstream infection. However, in August 2004, the frequency of bloodstream infection started to increase along with a concurrent increase in levofloxacin resistance among blood isolates (to 61 percent). In April 2005, several interventions were implemented, including the discontinuation of levofloxacin prophylaxis. Subsequently, we have observed a decrease in bloodstream infection to levels seen before the increase (Figure 1). Levofloxacin resistance among blood isolates has also declined and is approaching the baseline rate (47 percent). Since it has been only eight months, we will continue to monitor the number and severity of cases of bloodstream infection. Although we cannot be certain, this may well be the very scenario that Dr. Baden feared.
Figure 1. Patients with Bloodstream Infection (BSI).
James I. Ito, M.D.
Bernard R. Tegtmeier, Ph.D.
Margaret R. O'Donnell, M.D.
City of Hope National Medical Center
Duarte, CA 91010
jito@coh.org
References
Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med 2005;353:1052-1054.
To the Editor: In their report on a randomized trial of prophylactic levofloxacin after chemotherapy, Cullen and coworkers report infection-related deaths. Overall mortality is not presented, in contrast to the companion article by Bucaneve et al. It would be helpful to know the rates for the Cullen et al. study, too.
Philipp Eller, M.D.
Christoph Pechlaner, M.D.
Innsbruck Medical University
A-6020 Innsbruck, Austria
christoph.pechlaner@uibk.ac.at
Dr. Bucaneve and colleagues reply: Dr. Pasqualotto and colleagues raise three problems in the interpretation of the results of our study. The first point is that the occurrence of fever is considered a "poor" outcome to use in evaluating the efficacy of prophylaxis. We disagree. The occurrence of fever in patients with cancer who have neutropenia is a clinically relevant and frequent finding, and it is mandatory to treat these patients empirically to prevent early deaths, even in the absence of clinical signs or symptoms or microbiologic isolates documenting infection.1
The second problem mentioned is that our study was unable to document a significant effect of prophylaxis in reducing mortality. Our trial did not have enough power to show an effect of prophylaxis on mortality. However, a significant survival advantage from prophylaxis has been shown in a recently published meta-analysis.2
Finally, Pasqualotto et al. state that the emergence of multidrug-resistant organisms could be a serious and dangerous result of prophylaxis. The fear of emerging resistance is not a reason to avoid the prophylactic use of fluoroquinolones in high-risk patients with neutropenia. In fact, there is some evidence that resistance to fluoroquinolones is a multiclonal and reversible phenomenon3,4 and does not adversely affect infection-related morbidity and mortality. Moreover, the selective pressure exerted by fluoroquinolones may be due mainly to their wide use in the community.
Albano Del Favero, M.D.
Università degli Studi di Perugia
06100 Perugia, Italy
delfa@unipg.it
Giampaolo Bucaneve, M.D.
Azienda Ospedaliera di Perugia
06100 Perugia, Italy
Pietro Martino, M.D.
Università La Sapienza Roma
00161 Rome, Italy
References
Reuter S, Kern WV, Sigge A, et al. Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis 2005;40:1087-1093.
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-751.
Tascini C, Menichetti F, Bozza S, et al. Molecular typing of fluoroquinolone-resistant and fluoroquinolone-susceptible Escherichia coli isolated from blood of neutropenic cancer patients in a single center. Clin Microbiol Infect 1999;5:457-461.
Dr. Cullen and colleagues reply: The correspondents repeat concerns about antimicrobial resistance that we have expressed. Previous work has concentrated primarily on inpatients with hematologic cancers, and we set out to test the efficacy of prophylactic antibiotics in outpatients with solid cancers and lymphomas. We demonstrated significant reductions in febrile episodes and in hospitalizations for the treatment of infections. To translate these findings into recommendations, more information will be required on mortality, high-risk groups, adverse consequences of prophylaxis, and adverse consequences of neutropenic fever.
As mentioned, we did not report mortality from all causes during the study period. This was lower in the levofloxacin group but not significantly so. Our numbers can be combined with those published in the large, recent meta-analysis that did show a significant reduction in mortality from all causes with fluoroquinolone prophylaxis.1
It is important not to confuse the risk of neutropenic fever with the risk of serious consequences, according to MASCC criteria — which can only be applied strictly once infection has occurred. In response to the editorial and the correspondents, we are now examining our data for pretreatment patient characteristics, disease type, and cycle number to identify those at high risk for neutropenic fever, with the goal of increasing the effect and efficiency of prophylaxis in future studies. Physicians might prefer to avoid prophylaxis in those at low risk and to treat uncomplicated neutropenic fever with oral fluoroquinolones, although the safety of this strategy in an outpatient context has yet to be shown.
Antimicrobial resistance as a result of prophylaxis is a potential problem, but the clinical impact is not easily predictable. For instance, a recent study has shown that resistance resulting from prophylaxis does not necessarily reduce the long-term prophylactic efficacy of the antibacterial agent within an inpatient, hematologic-cancer unit.2
Prevention of death and the sepsis syndrome are not the only reasons for preventing neutropenic fever. Delays and dose reductions in subsequent cycles of chemotherapy may have serious long-term consequences for patients with cancer.
At least in part, resistance to the concept of routine antibacterial prophylaxis after chemotherapy assumes an acceptance of the ethical propriety of depriving current patients of a proven therapy in order to benefit future patients. This requires open debate based on clear evidence, which should result from more work in the areas discussed above.
Neil Steven, M.B., B.S., Ph.D.
Lucinda Billingham, Ph.D.
Cancer Research UK Institute for Cancer Studies
Birmingham B15 2TH, United Kingdom
Michael Cullen, M.D.
University Hospital Birmingham Cancer Centre
Birmingham B15 2TH, United Kingdom
michael.cullen@uhb.nhs.uk
References
Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142:979-995.
Kern WV, Klose K, Jellen-Ritter AS, et al. Fluoroquinolone resistance of Escherichia coli at a cancer center: epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia. Eur J Clin Microbiol Infect Dis 2005;24:111-118.
Dr. Baden replies: Studies of novel antimicrobial prophylactic strategies are, by design, limited in their ability to detect the effects on the emergence of antimicrobial resistance. This limitation is due, in part, to the relatively short study duration and the delayed kinetics of this untoward consequence. Further challenges include both limited funding for this type of research and reporting biases, as these types of observations are less novel and exciting than the results of the initial prophylactic study. The challenge in natural experiments involving actual clinical practice is to quantify precisely the effect of increased antimicrobial use on the emergence of resistance in the setting of complex medical care. I encourage Dr. Ito and colleagues to study in detail what has occurred at their institution, for an improved understanding of the risk-to-benefit ratio.
Lindsey R. Baden, M.D.