This study charted incidence trends of hospital-acquired (HA) pneumonia, bacteraemia and urinary tract infections (UTI) in a haematology department.
Prospective surveillance of hospital-acquired infections (HAI) was undertaken in a 42-bed haematology department of a university hospital. All patients hospitalized ≥48 hours between 1st January 2004 and 31st December 2010 were included. Definitions of HAI were based on a standardized protocol. The incidence was the number of events per 1000 patient-days at risk; only the first HAI was counted. Multivariate Poisson regression was fitted to assess temporal trends.
Among 3 355 patients (58 063 patient-days at risk) included, 1 055 (31%) had HAI. The incidence of HA pneumonia, HA bacteraemia and HA UTI was respectively 3.3, 12.0 and 2.9 per 1000 patient-days at risk. HA bacteraemia incidence increased by 11% (95% confidence interval: +6%, +15%, P<0.001) per year, independently of neutropenia, central venous catheterization (CVC) and haematological disease. The incidences of HA pneumonia and HA UTI were stable. The most frequently isolated pathogens were Aspergillus spp. (59.2%) for pneumonia, coagulase-negative Staphylococcus (44.2%) for bacteraemia and enterobacteria (60%) for UTI.
Citation: Huoi C, Vanhems P, Nicolle M-C, Michallet M, Bénet T (2013) Incidence of Hospital-Acquired Pneumonia, Bacteraemia and Urinary Tract Infections in Patients with Haematological Malignancies, 2004–2010: A Surveillance-Based Study. PLoS ONE 8(3): e58121. https://doi.org/10.1371/journal.pone.0058121
Editor: Vishnu Chaturvedi, California Department of Public Health, United States of America
Received: September 12, 2012; Accepted: January 30, 2013; Published: March 5, 2013
Copyright: © 2013 Huoi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Patients with haematological malignancies are at high risk of hospital-acquired infections (HAI) because the severity of their underlying illness often requires aggressive treatment: chemotherapy, bone marrow or peripheral blood stem cell transplantation. This could lead to severe and prolonged immunosuppression, increasing the risk of infection and possibly worsening the prognosis , . Mortality attributable to hospital-acquired (HA) bacteraemia in patients with cancer ranges between 10 and 20% –, whereas mortality from HA pneumonia is much higher, between 40 and 60% –. Over the past few decades, major progress has been made in the curative treatment of haematological malignancies which has resulted in reduced overall mortality –, but also longer neutropenia and higher risk of infectious complications , .
HAI are important adverse events in the disease history of patients with haematological malignancies, sometimes culminating in death; they are also responsible for longer hospital stay and increased healthcare costs , . However, few studies have examined the incidence of HAI in this adult patient population as most surveillance have focused only on bone marrow transplant patients or children , –. For example, Engelhart et al. noted an incidence of 25.3 HAI per 1000 patient-days at risk , and Urrea et al. reported 17.7 HAI per 1000 patient-days among paediatric haematology/oncology patients . To the best of our knowledge, trends in HAI incidence in the general population of adult patients with haematological malignancies have been poorly investigated. The objectives of this prospective surveillance were: 1) to track trends in the incidence of HA pneumonia, bacteraemia and urinary tract infections (UTI) in patients with haematological malignancies; 2) to identify the common etiological pathogens for these infections.
Prospective surveillance of HA pneumonia, bacteraemia and UTI was implemented at the 42-bed haematology department of Edouard Herriot University Hospital in Lyon, France, between 1st January 2004 and 31st December 2010. This 1000-bed hospital is composed of 3 haematology adult acute care units. Each of these units can accommodate 14 patients in single rooms. In total, 16 rooms are equipped with laminar airflow (LAF), 14 rooms with positive pressure isolation and high-efficiency particulate air (HEPA) filtration, and 12 have no specific air system. Patients with acute myeloid leukaemia (AML) or acute lymphoid leukaemia (ALL) were selectively admitted in the department, whereas patients with lymphoma were more often admitted to another hospital.
All patients hospitalized ≥48 hours in the haematology department between 1st January 2004 and 31st December 2010 were included in the surveillance. A standardized data sheet was filled for each patient, based on clinical observation and microbiological results. It recorded demographic and medical data: patient age, gender, dates of admission and discharge, diagnosis of the haematological disease, reason for admission. The main risk factors of infection were also recorded: neutropenia (<500 neutrophils/mm3) and its length, exposure to central venous catheterization (CVC), length of stay, hospitalization in non protected room. Surveillance was based on a local, standardized protocol derived from the French national protocol for HAI surveillance .
The case definition of HA pneumonia was: 1) chest X-rays or chest computed tomography-scans exhibiting lung infiltrates; and 2) temperature >38°C or leukocyte count >12 000/mm3 or <4 000/mm3; and 3) at least 1 of the following: (a) sputum change, (b) suggestive auscultation, (c) low oxyhaemoglobin saturation, or (d) increased pulmonary oxygen consumption; and 4) confirmation of pneumonia diagnosis by: (a) the practitioner in charge of the patient; and/or (b) microbial identification of the potential causal microorganism. The etiological agents were isolated from sputum, or directed bronchoalveolar lavage, or protected specimen by telescopic brush or protected distal tracheal specimen by catheter, or histological sample .
The case definition of HA bacteraemia was: 1) at least 1 positive blood culture justified by clinical signs for most microorganisms; or 2) at least 2 positive blood cultures justified by clinical signs, at 2 different times, separated by less than 48 hours from each other, when the microorganism was 1 of the following: coagulase-negative Staphylococci, Bacillus spp. (except Bacillus anthracis), Corynebacterium spp., Propionibacterium spp., Micrococcus spp. .
The case definition of HA UTI was: 1) at least 1 of the following clinical signs/symptoms: fever (>38°C), urgency, increased urinary frequency, dysuria, burning on urination or pain in the lower abdomen, with no other recognized cause; and 2) a positive urine culture (≥105 microorganisms/mm3) with 1 or 2 different pathogens isolated in case of urinary catheter exposure in the previous 7 days, or leukocyturia (≥104 leukocytes/mm3) and positive urine culture (≥103 microorganisms/mm3) with 1 or 2 different pathogens isolated if any urinary catheter was in place in the previous 7 days .
The causative microorganism for each infection was recorded. Only the first HAI per hospital stay that occurred ≥48 hours after patient admission was considered. Also, patient-days at risk were censored at first HAI, if it occurred.
Discrete variables were described as number and percentage, and continuous variables, as mean and standard deviation (SD). The HAI attack rate was the number of HAI per 100 patients, HAI incidence was the number of HAI per 1000 patients-days of hospitalization at risk. Poisson regression was fitted to assess temporal trends of HA pneumonia, bacteraemia and UTI incidence. The number of HAI was the dependent variable and the number of patient-days at risk was the offset. The independent variable of interest was the year of hospitalization. Potential confounders were: patient age, gender, neutropenia during hospital stay, CVC during hospital stay, diagnosis at admission, and main treatment received during hospitalization. Variables with P<0.15 after univariate analysis were entered in the initial multivariate model; then, a backward step-wise process was initiated, the models were compared with the likelihood ratio test. The significance level was P<0.05; all tests were 2-tailed. Statistical analysis was performed with Stata 10.0 (Stata Corp.). Data were recorded with EpiInfo, version 6.0. All data were analyzed anonymously.
From 2004 to 2010, 3 355 patients, accounting for 58 063 patient-days at risk, were included. The mean duration of hospital stay was 26 days (SD: 21.1 days). Overall, 1 873 (55.8%) were men and 1 482 (44.2%) were women (men/women gender ratio = 1.26). Mean age was 48.8 years (SD: 15.7 years). Patient characteristics are reported in Table 1. In total, 51.3% (n = 1704) had AML, 22.2% (n = 739) had ALL, and 9.5% (n = 315) had multiple myeloma. During their hospitalization, 66.7% of patients (n = 2 063) had neutropenia for a mean duration of 20.9 days (SD: 12.9 days). Most patients (89.7%, n = 2 574) had CVC and 56.9% (n = 1 909) were hospitalized in a protected room. In-hospital mortality was 5% (n = 159).
Between 2004 and 2010, variations in age (P<0.001), diagnosis of haematological disease (P<0.001), and reason for hospitalization (P<0.001) were observed but without linear trends. The proportions of patients with neutropenia or CVC exposure during hospital stay increased during the study period: from 66.9% of patients with neutropenia in 2004 to 74.9% in 2010 (P<0.001), and from 88.9% of patients with CVC in 2004 to 97.6% in 2010 (P<0.001).
In total, 1 055 (31.4%) patients had HAI: 191 (5.7%) had pneumonia, 694 (20.7%) had bacteraemia and 170 (5.1%) had UTI. Table 2 describes the incidence by site of infection, year and haematological disease. Figure 1 depicts trends of incidence over the years. The overall HAI attack rate was 31.4 per 100 patients and its incidence was 18.2 per 1000 patient-days at risk (95% confidence interval (95% CI): 17.1–19.3). The HA pneumonia attack rate was 5.7 per 100 patients and its incidence was 3.3 per 1000 patient-days at risk (95% CI: 2.8–3.8). The HA bacteraemia attack rate was 20.7 per 100 patients and its incidence was 12.0 per 1000 patient-days at risk (95% CI: 11.1–12.9). The HA UTI attack rate was 5.1 per 100 patients and its incidence was 2.9 per 1000 patient-days at risk (95% CI: 2.5–3.4). HA pneumonia incidence was higher among AML patients (incidence: 4.2‰ patient-days, 95% CI 3.5–4.9) compared to ALL patients (incidence: 1.8‰ patient-days, 95% CI 1.1–2.7). HA bacteremia incidence and UTI incidence were similar according to patient haematological diagnosis.
Univariate Poisson regression indicated that the incidence of HA pneumonia was stable between 2004 and 2010: −4% per year (95% CI: −11%, +3%, P = 0.23). HA bacteraemia increased by 12% per year (95% CI: +8%, +16%, P<0.001). A trend for increased HA UTI was observed: +7% per year (95% CI: 0%, +16%, P = 0.08).
Multivariate Poisson regression models after controlling for neutropenia and medical treatment showed a stable incidence rate for HA pneumonia over years: +5% per year (95% CI: −12%, +2%, P = 0.17). Multivariate Poisson regression models after controlling for neutropenia, CVC and diagnosis of haematological disease showed an increase by 11% per year (95% CI: +6%, +15%, P<0.001). Multivariate Poisson regression models after controlling for patient gender showed a stable incidence rate for HA UTI: +6% per year (95% CI: −1%, +15%, P = 0.11).
Figure 2 reports the distribution of microorganisms by infection site. The causative pathogens isolated most frequently in HA pneumonia were Aspergillus spp. (59.2%, n = 113) and Candida (7.8%, n = 15). Viral HA pneumonia affected 8 patients overall (4.2%). The causative pathogens isolated most frequently in HA bacteraemia were coagulase-negative Staphylococcus (44.2%, n = 307) and Candida (4.6%, n = 32). Hospital-acquired blood infection by a virus concerned 7 patients (1.0%). The causative pathogens isolated most frequently in HA UTI were enterobacteria (60%, n = 102). Viral HA UTI affected 5 patients (2.9%).
B. Distribution of the isolated pathogens in hospital-acquired bacteraemia, Haematology Department, Edouard Herriot Hospital, Lyon (France) 2004–2010. C. Distribution of the isolated pathogens in hospital-acquired urinary tract infections, Haematology Department, Edouard Herriot Hospital, Lyon (France) 2004–2010.
The study’s objective was to describe trends in HA pneumonia, bacteraemia and UTI incidence between 2004 and 2010 as they were the most frequent and lethal sites of infection in patients with haematological malignancies , , , . No significant trend was found in HA pneumonia and UTI incidence. HA bacteraemia incidence increased by 11% per year independently of neutropenia, CVC and patient’s haematological disease. Table 3 compares our results with 3 previous surveillance studies about neutropenic cancer patients  and patients with haematological malignancies , .
Engelhart et al. reported data on HAI and fever of unknown origin among adult haematology and oncology patients . They discerned a higher pneumonia incidence (9.7 per 1000 patient-days), while most rooms in their department were not equipped with LAF or positive pressure isolation and HEPA filtration. Consequently, protection against Aspergillus, the most common pathogen in HA pneumonia in this patient group, would be less efficient , . In our study, the globally-stable incidence of HA pneumonia could be balanced by decreased invasive aspergillosis during the same period . Consequently, it is not clear whether pneumonia of other origins was truly stable. However, we found a high rate of Aspergillus pneumonia (59.2% of the causative agents in pneumonia) although 56.9% of the patients were hospitalized in a protected room. Aspergillosis remained a large concern among our patients and Aspergillus pneumonia occurred mainly in immunosuppressed patients like AML or ALL patients , . Moreover, in our survey, incidence of HA-pneumonia appeared higher among AML patient compared with ALL patients or other patients.
The incidence of bacteraemia rose during the study period. Bacteraemia are mostly of endogenous origin, caused by pathogens or saprophytic cutaneous flora, such as Staphyloccocus spp. . Over the years, we noted a higher proportion of patients with CVC, well-known to be a major risk factor for HA bloodstream infection . The length and depth of the neutropenic phase, especially during chemotherapy, could also be related to incidence of bacteraemia. Nevertheless, the increased HA bacteraemia incidence was independent of CVC-exposure or neutropenia. Other factors could explain this increase, like more intense chemotherapy over the years, changes in antibiotic prophylaxis or hygiene practices. However, a previous study reported a protective impact of hygiene measures . Then, the increase of incidence might be mostly related to the severity of patients or to their underlying diseases. Carlisle et al. recorded a lower HA bacteraemia rate than what we observed in our department . They implemented 42-month surveillance and detected 13.5 bacteraemia per 100 neutropenic days. However, their study focused on neutropenic cancer patients and not on a specific population hospitalized with haematologic malignancies, the last population could have more severe immune system dysfunction related to their disease and not only chemotherapy. On the other hand, we found a similar incidence of bacteraemia as Engelhart et al. (11.2 per 1000 patient-days at risk) who investigated patients with haematological-oncologic diseases .
UTI incidence was stable. We encountered a similar incidence as Carlisle et al. (5.7 per 100 neutropenic patients)  and Engelhart et al. (6.0 per 100 patients) . Dettenkofer et al. reported a much lower UTI rate (3.0 per 100 patients, 0.8 per 1,000 patient-days) in transplant patients , but all of them received antimicrobial prophylaxis, which could have reduced the risk of infection in prolonged neutropenia cases –.
Our study had some limitations. First, the study population was mainly composed of AML and ALL patients. Our findings cannot be generalized to all haematological populations. Secondly, no post-discharge surveillance was undertaken, which could have led to underestimation of the incidence because infections with long incubation periods could have been missed. However, it did not affect trends because possible underestimation could be constant over the years. Furthermore, some potential risk factors for infection were not collected in our surveillance database, like length of CVC exposure, mechanical ventilation, type of stem-cell transplant (autologous or allogenous).
Its main strength was prospective data collection, with standardized case definitions. Ours was a single-centre study, which permitted us to compare trends and reinforced internal validity. Moreover, the true incidence was assessed because all patients were followed until their discharge. Few investigations have analyzed data over such a long time period and in such a large population, which increased the study’s power calculation. Finally, major confounding factors were taken into account with multivariate analysis.
In summary, we observed that the incidence of HA pneumonia and HA UTI remained stable. This could be explained by improvement of infection control measures, and took account of patient exposure to more aggressive chemotherapies. The incidence of bacteraemia increased independently of CVC exposure or neutropenia, which are known risk factors of bacteraemia. Further etiological studies are needed to explore in depth the factors that could explain this trend.
We thank Ovid Da Silva for editing the manuscript. We thank all residents of the infection control unit who took part in case surveillance: Caroline Landelle, Silène Cronenberger, Maud Mandy-Bertin, Pauline Pluviaud, Guilaine Boursier, Valérie Paix, Pierre Cassier and Guillaume Debeurne. We acknowledge the nursing staff of the Infection Control Unit: Christine Chémorin, Monique Hulin, Sylvie Monier and Léone Monrandat. We are also indebted to the Microbiology and Virology Departments of Centre de biologie et pathologie Est (Bron, France) as well as the Parasitology and Mycology Laboratory of Groupement hospitalier Nord (Lyon, France). Finally, we appreciate the efforts of the nursing and medical staff of the Haematology Department at Edouard Herriot Hospital.
Conceived and designed the experiments: PV M-CN MM TB. Analyzed the data: CH PV TB. Contributed reagents/materials/analysis tools: CH PV TB. Wrote the paper: CH PV M-CN MM TB.
- 1. Thirumala R, Ramaswamy M, Chawla S (2010) Diagnosis and management of infectious complications in critically ill patients with cancer. Crit Care Clin 26: 59–91.
- 2. Bailey LC, Reilly AF, Rheingold SR (2009) Infections in pediatric patients with hematologic malignancies. Semin Hematol 46: 313–24.
- 3. Wisplinghoff H, Cornely OA, Moser S, Bethe U, Stützer H, et al. (2003) Outcomes of nosocomial bloodstream infections in adult neutropenic patients: a prospective cohort and matched case-control study. Infect Control Hosp Epidemiol 24: 905–11.
- 4. Velasco E, Soares M, Byington R, Martins CA, Schirmer M, et al. (2004) Prospective evaluation of the epidemiology, microbiology, and outcome of bloodstream infections in adult surgical cancer patients. Eur J Clin Microbiol Infect Dis 23: 596–602.
- 5. Gonzales-Barca E, Fernandez-Sevilla A, Carratala J, Salar A, Peris J, et al. (1999) Prognostic factors influencing mortality in cancer patients with neutropenia and bacteremia. Eur J Clin Microbiol Infect Dis 18: 539–44.
- 6. Pannuti C, Gingrich R, Pfaller MA, Kao C, Wenzel RP (1992) Nosocomial pneumonia in patients having bone marrow transplant. Attributable mortality and risk factors. Cancer 69: 2653–62.
- 7. Pannuti C, Gingrich R, Pfaller MA, Wenzel RP (1991) Nosocomial pneumonia in adult patients undergoing bone marrow transplantation: a 9-year study. J Clin Oncol 9: 77–84.
- 8. Ewig S, Glasmacher A, Ulrich B, Wilhelm K, Schäfer H, et al. (1998) Pulmonary infiltrates in neutropenic patients with acute leukemia during chemotherapy: outcomes and prognostic factors. Chest 114: 444–51.
- 9. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, et al. (2010) Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363: 2091–101.
- 10. Pulte D, Gondos A, Brenner H (2008) Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990–2004. J Natl Cancer Inst 100: 1301–9.
- 11. Wayne AS, Reaman GH, Helman LJ (2008) Progress in the curative treatment of childhood hematologic malignancies. J Natl Cancer Inst 100: 1271–3.
- 12. Socié G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, et al. (1999) Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 341: 14–21.
- 13. Carlisle PS, Gucalp R, Wiernik PH (1993) Nosocomial infections in neutropenic cancer patients. Infect Control Hosp Epidemiol 14: 320–4.
- 14. Crawford J, Dale DC, Lyman GH (2004) Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 100: 228–37.
- 15. De Angelis G, Murthy A, Beyersmann J, Harbarth S (2010) Estimating the impact of healthcare-associated infections on length of stay and costs. Clin Microbiol Infect 16: 1729–35.
- 16. Roberts RR, Scott RD 2nd, Hota B, Kampe LM, Abbasi F, et al (2010) Cost attributable to healthcare-acquired infection in hospitalized adults and a comparison of economic methods. Med Care 48: 1026–35.
- 17. Dettenkofer M, Wenzler-Röttele S, Babikir R, Bertz H, Ebner W, et al. (2005) Surveillance of nosocomial sepsis and pneumonia in patients with a bone marrow or peripheral blood stem cell transplant: a multicenter project. Clin Infect Dis 40: 926–31.
- 18. Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, et al. (2001) Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control Hosp Epidemiol 22: 510–7.
- 19. Dettenkofer M, Ebner W, Bertz H, Babikir R, Finke J, et al. (2003) Surveillance of nosocomial infections in adult recipients of allogeneic and autologous bone marrow and peripheral blood stem-cell transplantation. Bone Marrow Transplant 31: 795–801.
- 20. Engelhart S, Glasmacher A, Exner M, Kramer MH (2002) Surveillance for nosocomial infections and fever of unknown origin among adult hematology-oncology patients. Infect Control Hosp Epidemiol 23: 244–8.
- 21. Urrea M, Rives S, Cruz O, Navarro A, García JJ, et al. (2004) Nosocomial infections among pediatric hematology/oncology patients: results of a prospective incidence study. Am J Infect Control 32: 205–8.
- 22. Al-Tonbary YA, Soliman OE, Sarhan MM, Hegazi MA, El-Ashry RA, et al. (2011) Nosocomial infections and fever of unknown origin in pediatric hematology/oncology unit: a retrospective annual study. World J Pediatr 7: 60–4.
- 23. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB (2003) Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 36: 1103–10.
- 24. Saavedra S, Jargue I, Sanz GF, Moscardó F, Jiménez C, et al. (2002) Infectious complications in patients undergoing unrelated donor bone marrow transplantation: experience from a single institution. Clin Microbiol Infect 8: 725–33.
- 25. Saavedra S, Sanz GF, Jargue I, Moscardó F, Jiménez C, et al. (2002) Early infections in adult patients undergoing unrelated donor cord blood transplantation. Bone Marrow Transplant 30: 937–43.
- 26. Pottecher B, Herbrecht R, Blanc-Vincent MP, Bussy Malgrange V, Escande MC, et al. (2000) Standards, Options and Recommendations (SOR) for the surveillance and the prevention of cross infections in oncology. Fédération Nationale des Centres de Lutte Contre le Cancer. Bull Cancer 87 557–91.
- 27. Comité technique des infections nosocomiales (1999) 100 recommandations pour la surveillance et la prévention des infections nosocomiales. 2e éd. Ministère de l’Emploi et de la Solidarité, Secrétariat d’Etat à la Santé et à l’action sociale, Paris, France.
- 28. Velasco E, Thuler LC, Martins CA, Dias LM, Gonçalves VM (1997) Nosocomial infections in an oncology intensive care unit. Am J Infect Control 25: 458–62.
- 29. Bénet T, Nicolle MC, Thiebaut A, Piens MA, Nicolini FE, et al. (2007) Reduction of invasive aspergillosis incidence among immunocompromised patients after control of environmental exposure. Clin Infect Dis 45: 682–6.
- 30. Hahn T, Cummings KM, Michalek AM, Lipman BJ, Segal BH, et al. (2002) Efficacy of high-efficiency particulate air filtration in preventing aspergillosis in immunocompromised patients with hematologic malignancies. Infect Control Hosp Epidemiol 23: 525–31.
- 31. Nicolle MC, Bénet T, Thiebaut A, Bienvenu AL, Voirin N, et al. (2011) Invasive aspergillosis in patients with hematological malignancies: incidence and description of 127 cases enrolled in a single institution prospective survey from 2004 to 2009. Haematologica 96: 1685–91.
- 32. Cornet M, Fleury L, Maslo C, Bernard JF, Brücker G, et al. (2002) Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect 51: 288–96.
- 33. Rupp ME (2004) Nosocomial bloodstream infections. In: Glen Mayhall C, editor. Hospital Epidemiology and Infection Control, 3rd edition. Lippincott Williams and Wilkins. 253–65.
- 34. Bénet T, Vanhems P (2009) Correlation of nosocomial bloodstream infection incidences: an ecological study. J Hosp Infect 73: 217–24.
- 35. Segal BH, Freifeld AG (2007) Antibacterial prophylaxis in patients with neutropenia. J Natl Compr Canc Netw 5: 235–42.
- 36. Leibovici L, Paul M, Cullen M, Bucaneve G, Gafter-Gvili A, et al. (2006) Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer 107: 1743–51.
- 37. Cullen M, Baijal S (2009) Prevention of febrile neutropenia: use of prophylactic antibiotics. Br J Cancer 101: S11–4.