The Conundrum Of Antibacterial Use in Neutropenic Patients Undergoing Chemotherapy for Hematologic Malignancy or HSCT

April 15, 2019

Patients with hematologic malignancy who are undergoing chemotherapy or a conditioning regimen for hematopoietic stem cell transplant (HSCT) are at high risk of infection because of the severity and duration of neutropenia. Fever with neutropenia is a common presentation that suggests an infection leading to empiric antibacterial therapy. To prevent infection and thus the neutropenic fever, antibacterial prophylaxis, especially with fluoroquinolones, emerged as a common practice based on results of 2 randomized controlled trials published in 2005 that showed reduced incidence of fever and bacteremia despite lack of a mortality benefit.

Patients with hematologic malignancy (HM) who are undergoing chemotherapy or a conditioning regimen for hematopoietic stem cell transplant (HSCT) are at high risk of infection because of the severity and duration of neutropenia. Fever with neutropenia is a common presentation that suggests an infection leading to empiric antibacterial therapy. To prevent infection and thus the neutropenic fever, antibacterial prophylaxis, especially with fluoroquinolones, emerged as a common practice based on results of 2 randomized controlled

trials published in 2005 that showed reduced incidence of fever and bacteremia despite lack of a mortality benefit.1,2

However, results from 2 systematic reviews by Gafter-Gvili et al, first in 2005 and later in 2012, demonstrated that antibiotic prophylaxis was associated with a mortality benefit, based on pooling data, along with reduction in the incidence of fever and bacteremia.3,4 Based on these results, many clinicians have adopted universal prophylaxis to prevent infection in patients who develop neutropenia from chemotherapy for HM or HSCT. Furthermore, in those who develop fever while neutropenic, empiric broad-spectrum antibacterial treatment with activity against gram-negative bacteria, especially Pseudomonas aeruginosa, and coverage for gram-positive infection per clinical indication is suggested. Clinical guidelines suggest continuation of empiric antibacterial agents until the resolution of neutropenia, even when no organism or source is identified.5

Inconsistency in Guidelines

US clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Clinical Oncology recommend use of fluoroquinolones in high-risk patients, defined as those with an absolute neutrophil count <100/mm3 and neutropenia with an expected duration of >7 days.6 Infection prevention guidelines from the National Comprehensive Cancer Network also recommend fluoroquinolones as first-line prophylaxis in highrisk neutropenic patients.7 Meanwhile, Australian and European guidelines recommend against routine prophylaxis because of a lack of mortality benefit and concern about emerging resistance in gram-negative organisms.8,9

In a meta-analysis of literature published between 2006 and 2014, Mikulska et al concluded that there was no “mortality benefit” from antibacterial prophylaxis.10 Although extensive literature on the management of neutropenic fever exists, discussions with colleagues across cancer centers reveals a lack of consensus on the practice of prophylaxis, and de-escalation after initiation of empiric therapy varies despite the guidelines.

Concern About Antimicrobial Resistance

The emergence of antimicrobial resistance and toxicity with prophylaxis and prolonged courses of broad-spectrum antibiotic use in neutropenic patients represents a serious issue. Potential burden of antibiotic resistance was assessed in a 2015 modeling study.11 Infection with multidrug resistant organisms (MDROs) such as the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) is now a major management challenge.12,13 The concerns with fluoroquinolone prophylaxis center on an increase in infections from coagulase-negative staphylococci, fluoroquinolone-resistant viridans streptococcal infections, emergence of extended-spectrum β-lactamase enzyme producing Enterobacteriaceae, and induction of resistance to carbapenems in Pseudomonas species and Clostridium difficile infection. In a study from a major cancer center using routine fluoroquinolone prophylaxis, the rate of fluoroquinolone-resistant

Escherichia coli infections increased from 28% to 60% over 9 years.14 Beyond concerns about MDROs, fluoroquinolones carry a risk of various adverse effects, with the FDA having expanded the black box warnings on their use. These include risks for aortic aneurysm, retinal detachment, and tendinitis.15

Research on the damaging impact of antimicrobials on the gut microbiome is also emerging. Investigators have demonstrated the harmful effect of antibiotics, specifically loss of microbial diversity, which has led to a higher risk of acute graft-versus-host disease (aGVHD) and an independent risk factor for mortality in allogeneic HSCT recipients.16-18 An increased rate of bacteremia has also been associated with alteration of the gut microbiome. This information is very important in assessing the approach to universal antibacterial prophylaxis and continuation of empiric therapy until resolution of neutropenia.

The morbidity and mortality associated with MDRO infections are substantial, as is the cost of care compared with that of a non-MDRO infection.19 Efforts to reduce the burden of MDRO infection would entail minimization of inappropriate prescribing, effective infection control, and, in the context of HM/HSCT, the use of caution with prophylactic approaches and prolonged empiric treatment. Results from recent studies suggest that not using antibacterial prophylaxis for chemotherapy-induced neutropenia is safe.20 In addition, in reporting results from a cohort of allogeneic HSCT recipients, a European group suggested the safety of de-escalation/stopping of empiric antibiotics in patients who had no identifiable source and had become afebrile.21 In our own personal experience, during the era of routine fluoroquinolone prophylaxis (since 1998), the rate of fluoroquinolone

resistance in bloodstream bacterial isolates increased from 47% over a period of 6 years to 61% in 2004.22 In 2005, we restricted its use, and since then, the rate of fluoroquinolone-resistant bacterial isolates has declined for patients in our institution to 40% in 2018 (S.S.D. et al; unpublished data).


It is critical that we as healthcare providers seriously consider the benefits and harms of antimicrobial prophylaxis and empiric therapy for neutropenic fever. Because the mortality benefit from prophylaxis is in question, efficacy of fluoroquinolone prophylaxis in the context of MDRO colonization may be ineffective. There is emerging data on loss of gut microbiome diversity and increase mortality/aGVHD in allogeneic HSCT patients, even though IDSA guidelines suggest continuing empiric therapy until neutropenia resolution and mention that de-escalation should be considered. It is imperative that we revisit the dogma surrounding the antibacterial prophylaxis and unfettered empiric antibacterial therapy.AUTHOR INFORMATION:

Sanjeet Singh Dadwal, MD, is a clinical professor in the Department of Medical Specialties, Division of Infectious Disease at City of Hope in Duarte, Division of Infectious Disease, California. There are no disclosures to report.REFERENCES:

  1. Bucaneve G, Micozzi A, Menichetti G, et al; Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Infection Program. Levofloxacin to prevent bacterial infection in patients with cancer in neutropenia. N Engl J Med. 2005;353(10):977-987. doi: 10.1056/NEJMoa044097.
  2. Cullen M, Steven N, Billingham L, et al; Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/- Antibiotic in a Number of Tumours (SIGNIFICANT) Trial Group. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005:353(10):988-998. doi: 10.1056/NEJMoa050078.
  3. Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142(12 pt 1):979-995.
  4. Gafter-Gvili A, Fraser A, Paul M, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochran Database Sys Rev. 2012;1:CD004386. doi: 10.1002/14651858.CD004386.pub3.
  5. Freifeld AG, Bow EJ, Sepkowitz KA, et al; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-93. doi:10.1093/cid/cir0732011;52(4):e56-93.
  6. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36(30):3034-3054. doi: 10.1200/JCO.18.00374.
  7. Baden LR, Swaminathan S, Angarone M, et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(7):882-913.
  8. Slavin MA, Lingaratnam S, Mileshkin L, et al; Australian Consensus Guidelines 2011 Steering Committee. Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee. Intern Med J. 2011;41(1b):102-109. doi: 10.1111/j.1445-5994.2010.02341.x.
  9. Neumann S, Krause SW, Maschmeyer G, Schiel X, von Lilienfeld-Toal M; Infectious Diseases Working Party (AGIHO), German Society of Hematology and Oncology (DGHO). Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol. 2013;92(4):433-442. doi: 10.1007/s00277-013-1698-0.
  10. Mikulska M, Averbuch D, Tissot F, et al; European Conference on Infections in Leukemia (ECIL). Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines. J Infect. 2018;76(1):20-37. doi: 10.1016/j.jinf.2017.10.009.
  11. Teillant A, Gandra S, Barter D, Morgan DJ, Laxminarayan R. Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study. Lancet Infect Dis. 2015;15(12):1429-1437. doi: 10.1016/S1473-3099(15)00270-4.
  12. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12. doi: 10.1086/595011.
  13. Bow EJ. There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy. J Antimicrob Chemother. 2013;68(3):492-495. doi: 10.1093/jac/dks512.
  14. Mihu CN, Rhomberg PR, Jones RN, Coyle E, Prince RA, Rolston KV. Escherichia coli resistance to quinolones at a comprehensive cancer center. Diagn Microbiol Infect Dis. 2010;67(3):266-269. doi: 10.1016/j.diagmicrobio.2010.02.014.
  15. FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions [news release]. Silver Spring, MD: FDA; July 10, 2018. Accessed April 8, 2019.
  16. Weber D, Jenq RR, Peled JU, et al. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(5):845-852. doi: 10.1016/j.bbmt.2017.02.006.
  17. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra371. doi: 10.1126/scitranslmed.aaf2311.
  18. Taur Y. Intestinal microbiome changes and stem cell transplantation: lessons learned. Virulence. 2016;7(8):930-938. doi: 10.1080/21505594.2016.1250982.
  19. Morales E, Cots F, Sala M, et al. Hospital costs of nosocomial multi-drug Resistant Pseudomonas aeruginosa acquisition. BMC Health Serv Res. 2012;12:122.
  20. Heidenreich D, Kreil S, Nolte F, Reinwald M, Hofmann WK, Klein SA. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis. Ann Hematol. 2016;95(2):287-293. doi:10.1007/s00277-015-2535-4.
  21. de Wyngaert ZV, Berthon C, Debarri H, et al. Discontinuation of antimicrobial therapy in adult neutropaenic haematology patients: a prospective cohort [published online March 1, 2019]. Int J Antimicrob Agents. doi: 10.1016/j.ijantimicag.2019.02.020.
  22. Ito JI, Tegtmeier BR, O’Donnell MR. Antibacterial prophylaxis in patients with cancer and neutropenia. N Engl J Med. 2006;354(1):90-94.