Although the widespread use of antimicrobials has made modern cancer care possible, the increase in the number of infections due to multidrug–resistant organisms and the dearth of effective agents to combat them has created a serious and pressing issue facing healthcare providers who care for patients with cancer.
In 2017, the Joint Commission mandated that every hospital establish an antimicrobial stewardship program (ASP) to optimize anti-infective utilization and improve patient care.1 This standard applies not only to general patient populations but also to immunocompromised patients, including those with cancer and undergoing transplantation. This commentary describes the rationale for antimicrobial stewardship in patients with cancer, the current state of antimicrobial stewardship in hematology/oncology, and how we as healthcare providers caring for patients with cancer can collectively improve antimicrobial use.
The Benefits of Antibiotics and Their Adverse Consequences
The history of cancer therapy is closely entwined with antimicrobial use. Patients with cancer receive prolonged and varied courses of antimicrobial agents either to prevent or treat infection, but such exposure increases the likelihood of bacterial resistance emergence. Infections caused by antibiotic-resistant pathogens, such as FQ-resistant streptococci, vancomycin-resistant Enterococcus, and multidrug-resistant gram-negative bacteria (including extended-spectrum beta-lactamase–producing and carbapenem-resistant (CR) strains) in patients with cancer are increasingly common. This is of particular importance in patients with cancer in whom delays in adequate therapy are associated with significantly increased mortality.2 The problem of antimicrobial overuse extends beyond antibiotic resistance and encompasses fungal and viral resistance as well as Clostridium difficile infections.
The role of the microbiome is just beginning to be understood as it relates to clinical outcomes for patients with cancer. A loss of microbiome diversity is linked to increased infections in patients with hematologic malignancy, increased risk of gastrointestinal graft-versus-host-disease, and poor response to immune checkpoint inhibitors.3 Although there is still much to learn about the human microbiome and its interplay with antibiotics in patients with cancer, mounting evidence suggests that how we use antimicrobials may have effects that extend far beyond the immediate problems of infections, antimicrobial resistance, and directly observable toxicities.
The Current State of Antimicrobial Stewardship in Patients With Cancer
The Society for Healthcare Epidemiology of America (SHEA), the Infectious Disease Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) advocate for formalizing antimicrobial stewardship in all patient populations.4 A practical way to approach this is through the creation of a formal institutional ASP that is generally comprised of an infectious disease–trained physician or clinical pharmacist who works with and educates staff involved in antimicrobial ordering, dispensing, administering, and monitoring.1,5 The goals of an ASP are to optimize clinical outcomes, minimize adverse consequences of antimicrobial use, and reduce antimicrobial overuse.5
Antimicrobial stewardship efforts in immunocompromised patients are challenging because of the complexity of cases, difficulty with accurate and timely diagnoses, and high mortality related to invasive infections.6 Although more data for patients with cancer are needed, available studies indicate that the benefits of ASPs seen in general populations are applicable to them. In several studies that have included patients with cancer and/or those undergoing hematopoietic stem cell transplant (HSCT), antibiotic approvals and/or review and feedback to prescribers on existing antibiotic orders (ie, prospective audit and feedback) have been associated with decreased antimicrobial use and cost reduction without resulting in harm.6
How Antimicrobial Stewardship Can Be Implemented in Patients With Cancer
The Centers for Disease Control and Prevention (CDC) has outlined core elements for ASPs, which describe essential components for their structure and day-to-day function (Table 1). All hospitals accredited by the Centers for Medicare and Medicaid Services (CMS) are now required to adhere to these core elements.1 The updated 2016 IDSA and SHEA guideline also provides evidence-based recommendations for implementation and measurement of antimicrobial stewardship interventions in inpatient populations including hematology-oncology patients (Table 2).5 We highlight several stewardship strategies that have been successfully applied to patients with cancer.
Centers for Disease Control and Prevention Stewardship Core Elements
Recommended Activities that Promote Appropriate Antimicrobial Prescribing
Clinical Guidelines
Collaboration between the ASP and hematology/oncology or HSCT teams to develop institution-specific, evidence-based guidelines and clinical pathways to standardize prescribing is not only feasible but necessary. Examples of highly used pathways in patients with cancer include the management of fever and neutropenia, antifungal prophylaxis and treatment, and cytomegalovirus prophylaxis and treatment. Combining infectious diseases, hematology/oncology, transplant, and pharmacy expertise is crucial to address the unique aspects of cancer care, such as diverse patient subgroups (eg, solid tumor vs hematologic malignancy), novel cancer therapies, immune dysfunction related to cancer therapies, types of infections (common and opportunistic), and emerging antibiotic resistance. Such efforts should be coupled with an implementation plan and education to ensure uptake of the guidelines.5
To date, few studies assessing the impact of stewardship-focused clinical guidelines on antibiotic use in patients with cancer have been published, but existing data suggest that they can optimize antimicrobial use. For example, improved survival in adult and pediatric patients with neutropenia has been shown after implementation of local fever and neutropenia practice protocols, and higher response rates have been shown for invasive aspergillosis when first-line antifungal treatment was prescribed in accordance with consensus guidelines.6 Although deviations from guideline-based recommendations do occur, improved patient outcomes have been shown even with partial adherence.6 In this rapidly changing field, ASPs must also be prepared to organize efforts to modify clinical guidelines to address drug shortages, new diagnostics, shifting resistance patterns, and novel treatment approaches for patients with cancer (eg, chimeric antigen receptor T-cell therapy, immunotherapy).
Safety of Antimicrobial De-escalation in Patients With Febrile Neutropenia
Retrospective studies suggest that antibiotic de-escalation to fluoroquinolone prophylaxis in patients with febrile neutropenia who have defervesced and remain clinically stable is feasible without adverse consequences, specifically in regards to the requirement to reinitiate broad-spectrum antibiotics.7 Previous studies are limited by small sample sizes and single-center natures; however, they set the stage for prospective evaluations of early antibiotic de-escalation in high-risk patients with cancer. An alternative approach to de-escalation is to simply stop antibiotics after 72 hours of defervescence and clinical recovery, regardless of neutrophil recovery. This strategy was evaluated in a recent open-label, randomized, controlled, multicenter study conducted in Spain.7 Short-course antibiotic therapy was associated with less overall antibiotic exposure. The overall incidence of adverse effects was higher in the experimental (ie, short course) group, but most adverse effects were considered nonsevere. Conversely, the incidence of severe adverse effects was higher in the control (ie, prolonged therapy) group with most of these being secondary infections and safety events related to antimicrobial toxicity. The results of this and other studies suggest that shorter courses of antimicrobial therapy are not only safe, but may be preferred to prolonged therapy and should encourage further investigation.
Antifungal Stewardship
Although antibiotics and the optimization of care for bacterial infections are the cornerstone of most ASPs, patients with cancer and who have undergone HSCT are at uniquely high risk for IFIs. Given the high frequency and devastating consequences of IFIs, antifungal prophylaxis is nearly universal among the highest-risk cancer patients.8 However, antifungal prophylaxis is frequently continued beyond the high-risk period for these patients and may increase the risk of toxicities or predispose patients to resistant fungal infections during subsequent courses of chemotherapy. Additionally, therapeutic endpoints for patients receiving antifungal therapy for proven or suspected fungal infections remain unclear, and practice is largely heterogeneous.
Rapid diagnostics (eg, T2Candida), biomarkers (eg, galactomannan, 1-3-beta-d-glucan), and improved imaging may increase the ability to rapidly diagnose and treat true fungal infections, provide targeted therapy while minimizing empirical therapy, and stop therapy in patients without infection.8 ASPs are a key component in the systematic standardized implementation of these diagnostic techniques and corresponding antifungal use guidelines. Single-center studies have shown that ASPs can establish antifungal stewardship programs with subsequent improvements in patient care and appropriate minimization of antifungal use when possible.9,10
Conclusions
Although antimicrobials can be life saving in patients with cancer, their inappropriate use has shown adverse consequences. These include increasing rates of multidrug–resistant organisms, Clostridium difficile infections, and disruptions of the healthy microbiome. These complications are not unique to patients with cancer, but those patients may have the most to gain from the continued effectiveness of anti-infective agents. Nearly all aspects of modern cancer therapy, including high-dose combination chemotherapy, HSCT, complex surgical procedures, and implanted devices, are in part made possible by these drugs. Without them, further advances in cancer care may not be possible. Although infectious disease physicians and pharmacists have traditionally been the leaders of antimicrobial stewardship efforts, hematologists, oncologists, and all others caring for patients with cancer are important partners. Additional data are needed to help this diverse group of clinicians better understand the risk/benefit profile of antimicrobial stewardship at the individual patient level, but successful collaborations between cancer clinicians and the institutional ASP can ensure the long-term success of antimicrobial stewardship in patients with cancer and lead to significant improvements in cancer care.
References
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The Joint Commission. New Antimicrobial Stewardship Standard. Available at: https://www.jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf; Accessed: September 9, 2018.
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Baker TM, Satlin MJ. The growing threat of multidrug-resistant Gram-negative infections in patients with hematologic malignancies. Leuk Lymphoma 2016;57:2245–2258.
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Routy B, Le Chatelier E, Derosa L, et al.. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91–97.
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Society for Healthcare Epidemiology of AmericaInfectious Diseases Society of AmericaPediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012;33:322–327.
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Barlam TF, Cosgrove SE, Abbo LM, et al.. Implementing an antibiotic stewardship program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016;62:e51–e77.
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Robilotti E, Holubar M, Seo SK, et al.. Feasibility and applicability of antimicrobial stewardship in immunocompromised patients. Curr Opin Infect Dis 2017;30:346–353.
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Aguilar-Guisado M, Espigado I, Martín-Peña A, et al.. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol 2017;4:e573–e583.
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Hamdy RF, Zaoutis TE, Seo SK. Antifungal stewardship considerations for adults and pediatrics. Virulence 2017;8:658–672.
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Micallef C, Aliyu SH, Santos R, et al.. Introduction of an antifungal stewardship programme targeting high-cost antifungals at a tertiary hospital in Cambridge, England. J Antimicrob Chemother 2015;70:1908–1911.
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Mondain V, Lieutier F, Hasseine L, et al.. A 6-year antifungal stewardship programme in a teaching hospital. Infection 2013;41:621–628.
Samuel L. Aitken, PharmD
Samuel L. Aitken, PharmD, is at The University of Texas MD Anderson Cancer Center and the Center for Antimicrobial Resistance and Microbial Genomics, UT Health McGovern Medical School, Houston, Texas.
Jerod L. Nagel, PharmD
Jerod L. Nagel, PharmD, is at the University of Michigan Health System and University of Michigan College of Pharmacy, Ann Arbor, Michigan.
Lillian Abbo, MD
Lillian Abbo, MD, is at the Jackson Health System, in Miami, Florida.
William Alegria, PharmD
William Alegria, PharmD, is at the University of Michigan Health System, Ann Arbor, Michigan.
Jason N. Barreto, PharmD
Jason N. Barreto, PharmD, is at Mayo Clinic, Rochester, Minnesota, and Hematology/Oncology Pharmacy Association, Chicago, IL
Sanjeet Dadwal, MD
Sanjeet Dadwal, MD, is at City of Hope National Medical Center, Duarte, California.
Alison G. Freifeld, MD
Alison G. Freifeld, MD is at the University of Nebraska Medical Center, Omaha, Nebraska.
Rupali Jain, PharmD
Rupali Jain, PharmD, is at the University of Washington, Seattle, Washington.
Steven A. Pergam, MD, MPH
Steven A. Pergam, MD, MPH, is at the University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, Washington.
Frank P. Tverdek, PharmD
Frank P. Tverdek, PharmD, is at The University of Texas MD Anderson Cancer Center, Houston, Texas.
Susan K. Seo, MD
Susan K. Seo, MD, is at Memorial Sloan Kettering Cancer Center, New York, New York.
