In an effort to reduce antibiotic resistance, antimicrobial stewardship programs were established by acute care facilities as the standard of care based on The Joint Commission standard.1-3 These programs function as a coordinated effort to implement interventions focused on improving and measuring appropriate antibiotic use through optimizing antibiotic selection, dosing, route of administration, and total duration of therapy.2,4,5 The benefits of these interventions include reductions in the inappropriate use of antibiotics, antibiotic resistance, and patient harm as a result of antibiotic-related adverse events, toward the improvement of patient outcomes.4,6
Antimicrobial stewardship programs predominately focus on general patient populations, because there is less direct evidence and greater complexity when applying antimicrobial stewardship interventions specifically to immunocompromised populations.2
Although immunocompromised patients, including patients with cancer, present a challenging and complex population, such populations present a significant need and opportunity for antimicrobial stewardship programs to improve antibiotic use and patient outcomes.2 Patients with cancer who have infectious complications have an increased risk for poor outcomes, including life-threatening complications.2
Appropriate antibiotic selection is critical in patients with cancer, because immunocompromised patients often have previous antibiotic exposure and can potentially be colonized with resistant organisms.2,3 Delaying adequate antibiotic coverage can result in increased mortality.2 However, prescribing broad-spectrum antibiotics for Pseudomonas and methicillin-resistant Staphylococcus aureus (MRSA) coverage for prolonged durations increases the risk for adverse events, Clostridioides difficile infections, and infections resulting from multidrug-resistant organisms.2,7 Such events present a serious threat in the treatment and management of patients with cancer, which highlights the importance of providing a balanced approach to the use of appropriate antibiotic therapy, while minimizing the risk for adverse events and selecting resistant organisms.
The goals of this study were to describe the antibiotic prescribing patterns at our institution, to identify the potential for antibiotic stewardship opportunities in patients with cancer, and to identify areas of opportunity for improvement in antimicrobial agent use in hospitalized patients with cancer who have no febrile neutropenia.
This retrospective cross-sectional study included patients who were admitted to the oncology unit between August 1, 2018, and August 30, 2019, at Henry Ford Hospital, a large tertiary care academic medical center in southeastern Michigan. The study was approved by the Institutional Review Board of Henry Ford Health System. The study’s inclusion criteria required patients to be older than age 18 years, to have an active cancer diagnosis, and to have received a therapeutic antimicrobial agent during their hospital stay. Patients with febrile neutropenia were excluded from this study, because the hospital had recently implemented a febrile neutropenia process improvement, in accordance with national guidelines.8
The antimicrobial stewardship program within our institution is staffed by 1 full time–equivalent pharmacist and is supported by a faculty member and pharmacy trainees. The primary focus of the antimicrobial stewardship program is prospective audit and feedback for patients with positive sterile site microbiology rapid diagnostic and culture results (ie, blood, peritoneal fluid). In addition, education and guidelines are provided to unit-based pharmacists who are accountable for empiric antibiotic selection, duration of therapy, route of administration, and identifying candidates for allergy consultation.
Antibiotic prescribing patterns were assessed based on empiric antibiotic selection, opportunities for antibiotic de-escalation, unnecessary dual coverage, oral stepdown, and addressing antibiotic allergy history. Empiric antibiotic selection was assessed based on concordance with our institutional guidelines. The institutional guidelines were derived from national guidelines, such as the Infectious Diseases Society of America Guidelines,8 and encompass the immunocompromised and immunocompetent populations.
Empiric antibiotic therapy was defined as too broad, or excessive, if patients received broad-spectrum coverage without the presence of any of the following risk factors: a nosocomial infection (onset of ≥72 hours into hospitalization); systemic inflammatory response syndrome (SIRS) criteria9; and hospitalization for more than 2 days in the previous 90 days, parenteral antibiotic exposure, or a history of multidrug-resistant organisms.
The SIRS criteria were defined by meeting at least 2 of the following criteria: body temperature of <36°C or >38°C, heart rate of >90 beats per minute, respiratory rate of >20 per minute, and white blood cell count of <4 per µL or >12 per µL.9
Multidrug-resistant organism history was defined as previous colonization within the previous 12 months with resistance to ≥1 antibiotic classes used against the specified organism.10 Antibiotic coverage was classified as too narrow if the patient had any of the above risk factors and received antibiotics without spectrum of coverage against MRSA and Pseudomonas.
Antibiotic de-escalation was defined as a reduction in the antibiotic spectrum. For example, a patient started cefepime therapy empirically and was de-escalated to ceftriaxone treatment. Of note, de-escalation was not required to be the narrowest spectrum of coverage applicable to the identified pathogen. Unnecessary dual anaerobic antibiotic coverage was assessed when patients received metronidazole therapy concurrently with another antibiotic that provided anaerobic antibiotic coverage.
Patients who were discharged with outpatient parenteral antibiotic therapy were assessed for opportunities to receive oral therapy. This included assessing efficacy with an oral agent, any gastrointestinal absorption concerns, oral antibiotic with activity for pathogen, penetration to the site of infection, antibiotic adverse-event profile, and allergies. Antibiotic allergies were recorded based on patients reporting an allergy in the medical record.
Patients were identified through the institution’s electronic medical record (EMR; Epic Systems Corporation; Verona, WI) and were randomly selected. The data were manually collected using a standardized case report form on REDCap, including demographics, pertinent laboratory values, antimicrobial agent prescribing characteristics (eg, empiric therapy, indication), and patient outcomes (ie, temporally related antibiotic adverse events within 2 days of antibiotic exposure, 30-day readmissions, multidrug-resistant organisms within 90 days of antibiotic exposure).
All statistical analyses were performed using SPSS Software, version 27.0 (SPSS, Inc; Chicago, IL). Descriptive measures, including incidence, proportions, and measures of central tendency and dispersion, were used. Categorical variables were compared via a chi-square or Fisher’s exact test. A P value of ≤.05 was considered statistically significant for all comparisons.
Of the 375 patients screened, a total of 200 patients were included in the study. The most common reason for exclusion from the study was febrile neutropenia in 57 patients. The patients’ characteristics are shown in Table 1. Solid malignant tumors were the most common oncology diagnosis, in 141 of the 200 (70.5%) patients. A total of 91 (45.5%) patients received a chemotherapy agent or a targeted anticancer agent within the previous 30 days, and 189 (94.5%) patients had an absolute neutrophil count of >1000 cells/mm3. In all, 23 (11.5%) patients met ≥2 SIRS criteria, and 19 of the 23 (82.6%) patients had a bloodstream infection.
The most common antibiotic indications were pulmonary infections (ie, community-acquired pneumonia, hospital-acquired pneumonia, and chronic obstructive pulmonary disease exacerbation) in 77 (38.5%) patients, urinary tract infections (UTIs; ie, cystitis, complicated UTIs, and pyelonephritis) in 31 (15.5%) patients, and intra-abdominal infections in 34 (17%) patients.
Intravenous (IV) antibiotics were used in 187 (93.5%) patients. Empiric antibiotics included Pseudomonas coverage in 141 (70.5%) patients, MRSA coverage in 134 (67%) patients, ceftriaxone in 77 (38.5%) patients, and metronidazole in 64 (32%) patients.
Fluoroquinolones (ciprofloxacin and moxifloxacin) were used for treatment in 27 (13.5%) patients, and azithromycin was used in 26 (13%) patients. All other antibiotics were used in less than 10% of the patients. Pseudomonas and MRSA coverage were continued for a median of 4 days (interquartile range [IQR], 3-6 days) of therapy.
The 200 study patients received a median of 5 days (IQR, 4-7 days) of antibiotics during their hospitalization, and the 84 patients who were discharged with antibiotics received a median of 5 days (IQR, 3-10 days) of antibiotic therapy. When assessing the total antibiotic duration, the 200 patients received a median of 7 days (IQR, 5-11 days) of antibiotic therapy.
Table 2 outlines the opportunities for antibiotic stewardship interventions based on the infection site. Empiric antibiotic spectrum was inappropriate in 62 (31%) patients, for whom the coverage was too broad (ie, inappropriate) in 57 of the 62 (91.9%) patients, and 5 of the 62 (8.1%) patients had coverage that was too narrow per our institutional guidelines derived from different national guidelines for various disease states.
UTIs and intra-abdominal infections had the highest frequency of inappropriate coverage, with 41.9% (13 of 31) and 41.2% (14 of 34) of patients, respectively. Based on culture and susceptibility reports, 62 of the 200 (31.2%) patients were candidates for antibiotic de-escalation. Of the 62 patients eligible for de-escalation, 33 (53.2%) patients were de-escalated to a narrower spectrum of coverage, and 19 (57.6%) of them were de-escalated within 24 hours of culture finalization.
Of the 11 patients who received moxifloxacin, 4 (36.4%) concurrently received metronidazole for dual anaerobic antibiotic coverage. Of the 200 total patients, 116 (58%) were discharged without antibiotics, 66 (33%) were discharged with oral antibiotics, and 18 (9%) were discharged with plans for IV antibiotic therapy. Among the 18 patients discharged with IV therapy, 6 (33.3%) patients were able to receive oral antibiotics instead of requiring IV therapy. Of the 200 patients, 84 (42%) presented at least 1 opportunity to improve their antibiotic regimen. Of these 84 patients, the most common area for improvement was empiric coverage discordance, which occurred in 62 (73.8%) patients.
In total, 83 of the 200 (41.5%) patients had a potential antibiotic-related adverse event. Of these 83 potential antibiotic-related adverse events, 36 (42.9%) events were in patients who had at least 1 antibiotic stewardship opportunity identified. Patients receiving antibiotics with Pseudomonas coverage had 69 of the 83 (82.1%) adverse events compared with 14 of the 83 (16.9%) adverse events in patients without Pseudomonas coverage (odds ratio, 3.08; 95% confidence interval, 1.55-6.109; P <.001).
Gastrointestinal side effects were the most common adverse events in 68 of the 200 (34%) patients. In addition, 19 of the 200 (9.5%) patients had a new multidrug-resistant organism isolated within 90 days after receiving antibiotic therapy.
Readmission within 30 days occurred in 58 of 200 (29%) patients, with 82.8% of readmissions resulting from noninfectious reasons.
Our findings show that 42% of the patients presented an opportunity to improve at least 1 component of their antibiotic regimen. Opportunities for improvement include assessing the patient’s allergy history as an opportunity to de-label false allergies, optimizing empiric antibiotic coverage, avoiding dual anaerobic antibiotic coverage, de-escalating antibiotic treatment based on microbiology cultures and susceptibilities, and switching from IV to oral therapies. One potential approach to guide antibiotic decision-making is to use the framework by Tamma and colleagues to implement a structured approach for antibiotic stewardship interventions.11
This framework is broken down into 4 moments (or steps) of high likelihood for antibiotic optimization, which include (1) time the infection is suspected, (2) ordering cultures and empiric antibiotics, (3) monitoring for de-escalations (or switching from IV to oral administration, or treatment discontinuation), and (4) assessing treatment duration and discharge.11
The first moment focuses on pausing and considering if a noninfectious process (eg, pulmonary embolism) is involved that may explain an abnormal vital sign (eg, dyspnea or fever). Moment 2 focuses on identifying the correct cultures to be obtained, and on providing timely and appropriate empiric antibiotics, thereby assessing the source of infection and any patient-specific risk factors before selecting antibiotic coverage. Moment 3 reminds prescribers to perform daily antibiotic plans, based on cultures and response to therapy. Finally, moment 4 asks providers to assess clinical response and to use evidence-based medicine to avoid excessively long antibiotic courses.11
One antibiotic stewardship opportunity highlighted in our study is to optimize empiric antibiotic coverage to be guideline-concordant, which was the area that required the most attention within this study. Empiric MRSA and Pseudomonas coverage was used extensively, and for a median duration of 4 days. However, not every patient required this empiric broad coverage.
Identifying the potential pathogens based on the site of infection and the patients at high risk factors for multidrug-resistant organisms plays a critical role in tailoring empiric antibiotic selection and reducing unnecessary Pseudomonas and MRSA coverage.3 This continued broad coverage is associated with an increased risk in severe adverse events, C difficile infections, and antibiotic resistance.12-14
Assessing a patient’s allergy history and the potential opportunity to de-label false allergies can affect empiric and definitive antibiotic therapies. Our findings showed that 24% of patients had an antibiotic allergy, and 12.5% had a penicillin allergy. Penicillin allergies are reported by approximately 15% of hospitalized patients; however, approximately 1% to 4% of the US population have a true immunoglobulin (Ig)E-mediated penicillin allergy and other reported allergies may correlate with an adverse event or other medication reaction.15-18
In addition, studies show that 80% of patients with an IgE-mediated penicillin allergy lose their sensitivity 10 years after reaction.18,19 This can be assessed through penicillin skin testing. Penicillin skin testing is safe and effective in patients with cancer to rule out IgE-mediated penicillin allergies.6,20
Patients with penicillin allergies may receive an alternative antibiotic regimen. These alternative regimens tend to avoid penicillin and cephalosporins, which results in decreased efficacy, increased mortality, higher incidence of multidrug-resistant organisms, increased cost, and an increase in antibiotic-induced adverse events compared with regimens without a penicillin allergy label.16,17,21-23
Additional opportunities for antibiotic stewardship interventions include identifying opportunities to de-escalate treatment to the narrowest antibiotic spectrum and avoid dual anaerobic antibiotic coverage. With the site of infection, pathogen, and susceptibilities identified, antibiotics can be assessed for de-escalation to a reduced spectrum of coverage by selecting a more targeted antibiotic and avoiding unnecessary dual anaerobic antibiotic coverage.
Finally, there is an opportunity to assess patients for oral stepdown options, such as transitioning from IV ceftriaxone therapy to oral trimethoprim plus sulfamethoxazole to finish a UTI treatment course. This applies to patients who tolerate oral medications when oral antibiotics have activity and adequate penetration to the pathogen and site of infection. Conversion to oral therapy can play a significant role in reducing costs, hospital length of stay, and the need for a central line placement.3 Therefore, applying the framework by Tamma and colleagues to integrate antibiotic stewardship interventions opens up opportunities to optimize care in patients with cancer.11
This study has several limitations. As a single-center, retrospective study, the data collection was dependent on information documentation in the EMR. This has the potential for information and documentation bias, although all data points were collected using a standardized data collection instrument according to information in the center’s EMR system.
In addition, it is important to note that although pharmacists may provide antibiotic stewardship recommendations for the selection of empiric antibiotic regimen and to the discontinuation or de-escalation of antibiotic therapy, the final decision is up to the primary team physician. Thus, there might have been an attempt by a pharmacist during hospitalization to optimize the patient’s therapy, but the recommendation was not accepted.
Despite these limitations, the study findings demonstrate that there is significant room for improvement in optimizing antibiotic therapies and patient care.
The findings in our study suggest that antibiotic stewardship interventions can be challenging in patients with cancer, because the perceived risk for patient harm may be less than the potential benefits of broad-spectrum antibiotic coverage. However, in our study, harm was frequently observed, with antibiotic-related adverse events reported in 41.5% of the patients, as well as ample opportunity for antibiotic stewardship intervention. A potential method to optimize antibiotic therapy and patient outcomes is to incorporate antibiotic stewardship interventions by pharmacists into everyday patient care for patients with cancer.
Author Disclosure Statement
Dr Medler, Dr Kenney, and Dr Davis have no conflicts of interest to report.
- The Joint Commission. Approved: new antimicrobial stewardship standard. Jt Comm Perspect. 2016;36:1,3-4,8.
- Aitken SL, Nagel JL, Abbo L, et al; for the Antimicrobial Stewardship in Cancer Consortium (ASCC). Antimicrobial stewardship in patients with cancer: the time is now. J Natl Compr Canc Netw. 2019;17:772-775.
- Robilotti E, Holubar M, Seo SK, Deresinski S. Feasibility and applicability of antimicrobial stewardship in immunocompromised patients. Curr Opin Infect Dis. 2017;30:346-353.
- 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.
- Centers for Disease Control and Prevention. The core elements of hospital antibiotic stewardship programs: 2019. www.cdc.gov/antibiotic-use/core-elements/hospital.html. Accessed July 14, 2021.
- Pillinger KE, Bouchard J, Withers ST, et al; for the Southeastern Research Group Endeavor (SERGE-45). Inpatient antibiotic stewardship interventions in the adult oncology and hematopoietic stem cell transplant population: a review of the literature. Ann Pharmacother. 2020;54:594-610.
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- 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.
- Kaukonen KM, Bailey M, Pilcher D, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372:1629-1638.
- Siegel JD, Rhinehart E, Jackson M, et al. Management of multidrug-resistant organisms in healthcare settings, 2006. Updated February 15, 2017. www.cdc.gov/infectioncontrol/pdf/guidelines/mdro-guidelines.pdf. Accessed July 14, 2021.
- Tamma PD, Miller MA, Cosgrove SE. Rethinking how antibiotics are prescribed: incorporating the 4 moments of antibiotic decision making into clinical practice. JAMA. 2019;321:139-140.
- Chalmers JD, Akram AR, Singanayagam A, et al. Risk factors for Clostridium difficile infection in hospitalized patients with community-acquired pneumonia. J Infect. 2016;73:45-53.
- Teshome BF, Vouri SM, Hampton N, et al. Duration of exposure to antipseudomonal β-lactam antibiotics in the critically ill and development of new resistance. Pharmacother. 2019;39:261-270.
- Tamma PD, Avdic E, Li DX, et al. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern Med. 2017;177:1308-1315.
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- Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321:188-199.
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- Trubiano JA, Adkinson NF, Phillips EJ. Penicillin allergy is not necessarily forever. JAMA. 2017;318:82-83.
- Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol. 1981;68:171-180.
- Taremi M, Artau A, Foolad F, et al. Safety, efficacy, and clinical impact of penicillin skin testing in immunocompromised cancer patients. J Allergy Clin Immunol Pract. 2019;7:2185-2191.e1.
- Stone CA Jr, Trubiano J, Coleman DT, et al. The challenge of de-labeling penicillin allergy. Allergy. 2020;75:273-288.
- Owens RC Jr, Fraser GL, Stogsdill P. Antimicrobial stewardship programs as a means to optimize antimicrobial use: insights from the Society of Infectious Diseases pharmacists. Pharmacotherapy. 2004;24:896-908.
- Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin Immunol. 2016;137:1148-1153.