When to Use Prophylactic Antibiotics in Neutropenic Patients

September 15, 2016

Current guidelines recommend antimicrobial prophylaxis with fluoroquinolones in patients at high risk for infection-related morbidity and mortality, but this practice provides a short-term benefit to individual patients.

The Rationale for Use of Antibiotic Prophylaxis in Patients With Neutropenia

Patients receiving cytotoxic chemotherapy for malignancy are at high risk for infection-related complications. Factors that may precipitate an infection include immunologic compromise; multiple comorbidities; malnutrition; and breaches in natural barriers, caused by medical procedures, radiation therapy, mucositis, and central venous catheter placement. Notably, the degree of severity and the duration of neutropenia associated with cytotoxic chemotherapy are critical determinants of the development of invasive bacterial infections-a relationship initially described by Bodey and colleagues in 1966 in patients with acute leukemia.[1] Many chemotherapy agents injure the mucosal linings of the body, particularly in the gastrointestinal tract (from oral cavity to anus), conferring a high risk for enteric bacterial translocation and subsequent systemic infection. In the setting of neutropenia, even common enteric bacterial bloodstream infections (BSIs) may become quickly fatal when unopposed by effector white cells (neutrophils). Febrile neutropenia is often the only clinical hallmark of serious infections, primarily bacteremia. Febrile neutropenia is defined as a one-time oral temperature of > 38.3°C (approximately 100.9°F) or a sustained temperature of > 38°C (100.4°F) for ≥ 1 hour in a patient who has an absolute neutrophil count (ANC) of < 500 cells/mm3 or an ANC expected to decrease to < 500 cells/mm3 within a 48-hour period.[2] Therefore, patients with febrile neutropenia require urgent evaluation and initiation of empiric therapy with broad-spectrum antibiotics.

More than 80% of patients receiving chemotherapy for leukemia or undergoing allogeneic hematopoietic stem cell transplantation (HSCT) will experience at least 1 episode of febrile neutropenia.[2-5] Conversely, only 5% to 30% of patients receiving chemotherapy for a solid tumor will have febrile neutropenia, with the highest rates occurring during the first cycle of treatment.[2,5,6] Febrile neutropenia is associated with an overall mortality rate of approximately 8% in patients with solid tumors and rates ranging from 14% to 34% in patients with leukemia.[7] Up to 40% to 60% of episodes are due to a clinically or microbiologically documented infection, with approximately 20% to 30% of patients having a BSI.[3,7,8] Gram-negative rods (GNRs), particularly Enterobacteriaceae (including Escherichia coli, Klebsiella species, and Enterobacter species) and Pseudomonas aeruginosa, are historically the most common pathogens in this population, and if not treated promptly and aggressively, infections with these microorganisms are rapidly fatal.[9] Even with adequate early empiric antibiotic treatment, bacteremia due to GNRs in the setting of neutropenia is associated with crude mortality rates as high as 34% to 50%.[7,10] Therefore, antibacterial prophylaxis for neutropenic patients has been proposed in an effort to reduce febrile neutropenia, infection (particularly with gram-negative pathogens), and mortality in high-risk populations. Initial studies evaluating nonabsorbable antibiotics vs the combination trimethoprim-sulfamethoxazole revealed no consistent benefits.[11,12]

In the 1990s, antibiotic prophylaxis with fluoroquinolones showed excellent activity against gram-negative pathogens, with good tolerability and high oral bioavailability. In 2005, a large randomized controlled trial published by Bucaneve et al demonstrated significant reductions in febrile neutropenia and in documented bacteremias in patients whose hematologic malignancies were treated with levofloxacin, compared with placebo.[4] Several meta-analyses of the numerous published studies of fluoroquinolone prophylaxis have also shown it to be associated with reductions in both febrile neutropenia and infections due to GNRs, with one study providing evidence for decreased mortality among patients receiving prophylaxis.[13-15] However, these studies were not able to characterize the impact of fluoroquinolone prophylaxis on colonizing flora and the risk for development of resistance to fluoroquinolones.

Antibiotic Prophylaxis in an Era of Increasing Antimicrobial Resistance

The use of fluoroquinolones for antibacterial prophylaxis and treatment is associated with increased rates of infection due to fluoroquinolone-resistant organisms, in particular with fluoroquinolone-resistant E coli.[16] In fact, centers that routinely used fluoroquinolone prophylaxis have reported resistance in E coli isolates exceeding 30% to 50%, and rates are significantly higher in the oncology patient population, compared with the general population.[17,18] Accordingly, it is plausible that these drugs could eventually cease to be effective infection prophylaxis for patients at centers where the incidence of resistance is particularly high. However, the threshold level of fluoroquinolone resistance within a given population or center at which this could occur is unknown. Our ability to gauge this landscape is limited by many factors, including the lack of national data on BSIs in patients with neutropenia and the ever-changing epidemiology of infections in patients with neutropenia, since even at the time of publication the data are already antiquated. As a result, it is difficult to make an enduring recommendation regarding prophylaxis, with some centers moving toward omitting antibiotic prophylaxis altogether in selected high-risk populations, in order to mitigate the problem of rising antibiotic resistance. In these settings, patients are simply closely monitored for signs and symptoms of developing infection. In the absence of routine prophylaxis, these centers have uncovered increased rates of GNR bacteremia, but no change in mortality.[19,20]

In addition to its association with the emergence of fluoroquinolone-resistant E coli, use of fluoroquinolone prophylaxis is also linked to an increased risk of colonization and infection with other multidrug-resistant organisms, including other Enterobacteriaceae, Pseudomonas, and even methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.[21-23] BSIs caused by these multidrug-resistant organisms can present a clinical dilemma, since treatment options are often limited (fluoroquinolones eliminated as potential therapeutic agents) and initial empiric antibiotic choices may not be effective.[21,22,24] Infections due to these organisms are associated with higher rates of mortality,[9,25] and the use of fluoroquinolones is linked to increased rates of colonization and infection with Clostridium difficile.[26] In addition, in 2015 a US Food and Drug Administration advisory panel evaluated risks of fluoroquinolones and called for limiting their use in patients with sinusitis, bronchitis, and urinary tract infection, due to concerns about the risk of adverse drug reactions, including tendonitis/tendon rupture, peripheral neuropathy, and cardiac arrhythmias.[27] Therefore, it is important for centers to continue to evaluate their practice based on local antibiograms and patient outcomes.

Who Should Receive Antibiotic Prophylaxis?

Current National Comprehensive Cancer Network (NCCN) guidelines define patients at low risk for febrile neutropenia as those with neutropenia lasting less than 7 days or those receiving chemotherapy for solid tumors, and so do not recommend antibiotic prophylaxis for these populations. Patients undergoing autologous HSCT or receiving chemotherapy for a hematologic malignancy who have an anticipated 7- to 10-day duration of neutropenia are considered to be at intermediate risk. Patients categorized as high risk are those expected to have neutropenia lasting more than 10 days, including patients undergoing allogeneic HSCT. The NCCN guidelines recommend consideration of bacterial prophylaxis with a fluoroquinolone in intermediate-risk and high-risk patients.[28,29] The Infectious Diseases Society of America and the American Society of Clinical Oncology both recommend antibacterial prophylaxis with a fluoroquinolone in patients who are expected to remain profoundly neutropenic (with an ANC < 100 cells/mm3) for more than 7 days.[2,5] Interestingly, the guidelines developed by the Australian Consensus Guidelines 2011 Steering Committee do not recommend the use of fluoroquinolone prophylaxis for neutropenic patients in general.[30]

Our institution follows NCCN recommendations and provides antimicrobial prophylaxis with levofloxacin at an oral dosage of 500 mg daily during neutropenic periods to patients with hematologic malignancies who are either receiving induction and consolidation chemotherapy for leukemia or undergoing HSCT. After 10 years of performing autologous stem cell transplants without the use of fluoroquinolone prophylaxis, and after encountering several cases of severe sepsis due to fluoroquinolone-susceptible organisms, we recently revised our practice to now include fluoroquinolone prophylaxis. As suggested by current NCCN guidelines, we will monitor the incidence of fluoroquinolone-resistant pathogens in this population and reassess this practice periodically.

If patients develop febrile neutropenia, our practice is to stop levofloxacin while they are receiving empiric treatment with cefepime, piperacillin-tazobactam, or meropenem. If no infectious etiology is identified, we recommend switching back to levofloxacin prophylaxis for the duration of the neutropenia if the patient defervesces and remains afebrile for 48 hours. We stop the prophylaxis as soon as the ANC is > 500 cells/mm3, as long as the ANC is increasing. We do not recommend prophylaxis in patients receiving chemotherapy for solid tumors or for any other neutropenia events anticipated to be classified as “low risk.”

Conclusion

Despite more than 50 years of clinical experience and research, the prevention of febrile neutropenia and bacterial infections in oncology patients remains a challenge. Current guidelines recommend antimicrobial prophylaxis with fluoroquinolones in patients at high risk for infection-related morbidity and mortality, but this practice provides a short-term benefit to individual patients. While fluoroquinolone prophylaxis has reduced some of the collateral damage of intensive chemotherapy, the direct and indirect adverse effects of these agents may limit their utility. It is imperative that we consider the long-term implications of this practice on our population as a whole. We have reservations about the durability of success with fluoroquinolone prophylaxis and advocate for continuous reevaluation of this practice, using information from ongoing studies and national data.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64:328-40.

2. Freifeld AG, Bow EJ, Sepkowitz KA, et al. 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:e56-e93.

3. Celebi H, Akan H, Akcaglayan E, et al. Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies. Bone Marrow Transplant. 2000;26:211-4.

4. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977-87.

5. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794-810.

6. Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005; 353:988-98.

7. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258-66.

8. Feld R. Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents. 2008;32(suppl 1):S30-S33.

9. Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005;49:760-6.

10. Elting LS, Rubenstein EB, Rolston KV, Bodey GP. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis. 1997;25:247-59.

11. Weiser B, Lange M, Fialk MA, et al. Prophylactic trimethoprim-sulfamethoxazole during consolidation chemotherapy for acute leukemia: a controlled trial. Ann Intern Med. 1981;95:436-8.

12. Gualtieri RJ, Donowitz GR, Kaiser DL, et al. Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies. Am J Med. 1983;74:934-40.

13. Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol. 1998;16:1179-87.

14. Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142:979-95.

15. Leibovici L, Paul M, Cullen M, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer. 2006;107:1743-51.

16. Cometta A, Calandra T, Bille J, Glauser MP. Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia. N Engl J Med. 1994;330:1240-1.

17. Freifeld AG, Zinner S, Bow EJ. Antibiotic resistance: impact on managing cancer patients with fever and infection. In: DeVita VT, Lawrence TS, Rosenberg SA; Ovid Technologies Inc. Devita, Hellman, and Rosenberg’s cancer principles & practice of oncology. Philadelphia: Wolters Kluwer; 2015.

18. See I, Freifeld AG, Magill SS. Causative organisms and associated antimicrobial resistance in healthcare-associated, central line-associated bloodstream infections from oncology settings, 2009-2012. Clin Infect Dis. 2016;62:1203-9.

19. Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2013;19:474-9.

20. Heidenreich D, Kreil S, Nolte F, et al. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis. Ann Hematol. 2016;95:287-93.

21. Ford CD, Lopansri BK, Haydoura S, et al. Frequency, risk factors, and outcomes of vancomycin-resistant Enterococcus colonization and infection in patients with newly diagnosed acute leukemia: different patterns in patients with acute myelogenous and acute lymphoblastic leukemia. Infect Control Hosp Epidemiol. 2015;36:47-53.

22. Garnica M, Nouer SA, Pellegrino FL, et al. Ciprofloxacin prophylaxis in high risk neutropenic patients: effects on outcomes, antimicrobial therapy and resistance. BMC Infect Dis. 2013;13:356.

23. Rangaraj G, Granwehr BP, Jiang Y, et al. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer. 2010;116:967-73.

24. Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis. 2011;24:545-53.

25. Macesic N, Morrissey CO, Cheng AC, et al. Changing microbial epidemiology in hematopoietic stem cell transplant recipients: increasing resistance over a 9-year period. Transpl Infect Dis. 2014;16:887-96.

26. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005;353:2442-9.

27. US Food and Drug Administration. Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The benefits and risks of systemic fluoroquinolone antibacterial drugs for the treatment of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease (ABECB-COPD), and uncomplicated urinary tract infections (uUTI). November 5, 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf. Accessed August 10, 2016.

28. van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol. 2014;167:441-52.

29. Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw. 2012;10:1412-45.

30. Slavin MA, Lingaratnam S, Mileshkin L, et al. Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee. Intern Med J. 2011;41:102-9.