Current trends in antimicrobial use and the role of antimicrobial stewardship in palliative oncology: a narrative review

Abstract

Background

The overuse of antimicrobials is prevalent in palliative oncology care, with up to 86.9% of terminal cancer patients receiving these agents during end-of-life care. This overutilization stems from recurrent infections due to immunosuppression, malnutrition, and frequent hospitalizations, as well as difficulty differentiating infection-related symptoms from cancer-related complications.

Discussion

Antimicrobial use in palliative cancer care offers limited symptomatic relief while posing significant risks, including Clostridioides difficile infections, multidrug resistance, and patient dissatisfaction. The lack of clear survival benefit highlights the need for judicious antimicrobial use, particularly in terminally ill patients. Effective antimicrobial stewardship strategies, such as integrating infection management into goals-of-care discussions, early referrals to specialized palliative care teams, and implementing early intravenous-to-oral antimicrobial switches, are critical for balancing patient comfort and minimizing unnecessary antibiotic exposure.

Conclusion

Optimizing antimicrobial use in palliative oncology care requires a multidisciplinary approach that prioritizes patient-centered goals, minimizes harm, and addresses misconceptions about antibiotic efficacy in end-of-life care. Antimicrobial stewardship programs, when tailored to palliative settings, play a vital role in reducing overuse and improving care quality in this vulnerable patient population.

Graphical Abstract

Introduction

Palliative care (PC) is defined as a holistic approach that aims to enhance the quality of life (QOL) for patients and their families facing life-threatening or terminal illnesses by preventing and relieving suffering through early identification, comprehensive assessment, and management of pain as well as physical, psychosocial, and spiritual issues [1]. Oncology patients under PC are susceptible to infections due to several factors such as malnutrition, vulnerable immune systems, presence of catheters, and immunosuppression from chemotherapy [2]. Distinguishing between bacterial infections and disease-related symptoms can be challenging, often leading to overuse of antimicrobials without clear indications [2, 3].

Antimicrobial stewardship (ASP) aims to ensure that patients are receiving the right antimicrobial therapy, in the right indication, dose and duration. Applying ASP in oncology patients under PC is under looked but has great potential in achieving the goals of care; however, many challenges exist.

Understanding antimicrobial use, including its frequency, impact on patients’ survival and oncologists’ perceptions, is crucial for improving antimicrobial practices. This review aims to explore the current approach to antimicrobial use in palliative oncology settings, identify the associated challenges, and draw conclusions for best practices of ASP in oncology patients under PC.

Methods

This review was conducted by searching the Pubmed database for articles published between January 2000 and June 2024. The search strategy includes the following keyword (“palliative care” OR “end-of-life care” OR “comfort care”) AND (“antimicrobial” OR “antibiotic” OR “Antimicrobial stewardship”) AND (“oncology” OR “neoplasm” OR “malignancy” OR “cancer”). Articles were selected if they provided data on antimicrobial use in palliative setting, challenges and strategies for ASP.

Antimicrobial use in palliative oncology

Oncology patients receiving PC face an increased risk of infection due to factors such as a compromised immune system, the presence of invasive catheters, malnutrition, and recent chemotherapy [2, 3]. In fact, sepsis is an inevitable event in individuals nearing the end of life (EOL) [4]. Additionally, distinguishing between symptoms caused by cancer and those indicating a new infection can be difficult. For that reason, overuse of antimicrobials is not uncommon in patients with advanced cancer. Overprescription of antibiotics is a significant concern, contributing to the rise of multidrug-resistant organisms and other adverse effects, which can prolong hospital stays and reduce patient satisfaction.

Table 1 summarizes the characteristics of cohort studies on antimicrobial usage in cancer patients under PC. In two-thirds of the studies, antimicrobials were used in more than 50% of the patients and this frequency reached 97.5% in some studies [5, 6]. Even after shifting the patient to EOL and patients being taken in charge by PC doctors, a high percentage of patients were kept on antimicrobials. A study published in 2012 showed that 86.9% of hospitalized cancer patients were under antimicrobials during their last weeks of life with only 48.4% of them found to have a documented infection [7]. Furthermore, in the last few days of life, where comfort is the main goal of care, around 55% of those patients were still receiving antimicrobials [7]. This trend is not only limited to cancer patients but was also reported in other populations. Data from nursing homes caring for demented patients reported around 66.4% of residents receiving antimicrobials during the last weeks of their lifetime [8].

Table 1 Overview of study characteristics on antimicrobial usage in cancer patients under palliative care

However, this use is not without additional cost. Prescribing antibiotics is associated with emergence of multidrug resistance (MDR) in bacterial infections, drug-drug interactions (DDI), anaphylaxis and drug adverse effects [26]. MDR is considered one of the major threats to global public health due to limited treatment options and risk of transmission to other vulnerable patients (https://www.who.int/publications/i/item/9789241509763). In addition, antimicrobial use can lead to Clostridiodes difficile colitis, leading to an increased morbidity, hospital stay and cost (https://www.who.int/publications/i/item/9789241509763). Isolation precautions for patients colonized with MDR pathogens negatively impact both the patient and their caregivers, causing discomfort due to restricted visits and limited interaction. These measures also increase the workload for nursing staff [27]. This is crucial for this cohort of patients, as they require psychological support and continuous interaction with their loved ones and hospital staff.

In addition to that, these vulnerable cancer patients are on polypharmacy regimens including but not limited to opioids, which may have DDI with different antibiotic classes, which can ultimately affect the antibiotic’s pharmacokinetics [28]. Other adverse effects include injection site inflammation, phlebitis, local skin infections, and secondary bacteremia [26]. In fact, such risk is considered against the goals of palliation and symptom relief. Despite the previously mentioned risks, intravenous antibiotics were still used in up to 82% of patients as reported in some data [29]. In addition, increased use of antibiotics puts the patients at higher risk for fungal infections necessitating expensive and at times toxic antifungal agents [30].

Challenges leading to overuse of antibiotics

Optimizing antimicrobial use in palliative oncology is challenging. This is due to many reasons including patient-physician relationship, family preference, unrealistic hope, assumption that antibiotics are safe drugs with no harm, and misleading symptoms and laboratory results. These challenges with the assumption of beneficial impact of prescribing antibiotics can lead to antimicrobial misuse. Patients and their families are all at times reluctant not to prescribe antibiotics in the febrile patients despite the expectations for overall poor outcome. Regarding physician perceptions, Crispim et al. demonstrated in their online survey about antibiotic prescription at EOL that most physicians opted to initiate antibiotics in all hypothetical scenarios of patients with infections [30]. Physicians who had graduated since more than 13 years and those without formal education on PC were more likely to prescribe antibiotics.

While initiating antibiotics is challenging, withholding it carries a complex ethical challenge. Even for non-responders' patients, most doctors still chose to broaden or maintain antibiotic regimens 72-h after initiation rather than de-escalating [31]. Gaw et al. highlighted that half of the physicians chose to continue antibiotics for nearly all types of infections, even for patients under comfort care where death was imminent [32]. Many factors drive or even force physicians to continue antibiotics despite no response in EOL cancer patients, with family preference being a significant one. Larnard et al. demonstrated in a qualitative study that patient/family preference and the goal of providing palliation were the two major factors influencing physicians' decisions [33]. Similarly, Servid et al. concluded that 19.4% of antibiotic prescriptions were driven by the family's preference rather than by clinical signs of infection [34].

Apart from physicians' and family perspectives, obtaining a definite diagnosis in patients with advanced cancer is challenging because many symptoms can be attributed to disease progression. For instance, studies have shown that 7% to 19% of oncology patients with advanced cancer who presented with fever of unknown origin had paraneoplastic fever, and these patients usually respond well to non-steroidal anti-inflammatory drugs [35]. Additionally, in one study, leukemoid reaction was attributed to infection in only 15% of cases, compared to 10% resulting from a paraneoplastic reaction [36]. In both cases of paraneoplastic fever and leukemoid reaction, patients with advanced cancer will remain clinically stable but have a poor prognosis unless effective antineoplastic treatment is administered. Recognizing non-infectious causes of a patient's clinical presentation is crucial, as it can help optimize antibiotic use, especially when initial sepsis work-up is negative and the patient is clinically stable.

Antibiotic use and goals of care

The primary goal of palliative care (PC) is to preserve quality of life (QOL) and alleviate symptoms during a patient’s final days. While antibiotics are often used with the intention of prolonging survival, evidence shows that treating reversible infections does not significantly impact survival with limited effectiveness in palliating symptoms.

Several cohort studies examined the impact of antibiotics on survival in patients with advanced cancer. White et al., in their prospective cohort study, demonstrated that antibiotics use in suspected infections did not impact survival [21]. In the same line, Reibolt et al., and Mal et al., have shown no survival benefit of antibiotic use in EOL care of oncology patients [2, 22]. In contrast, Chen et al. et al. reported a positive impact of antibiotics on survival in advanced cancer patients (14.6 days vs. 8.7 days; p-value: 0.03) [23]. However, the extension of life in patients suffering from terminal illness is not a marker of a better outcome as it merely implies prolonging suffering in many cases.

The impact of antibiotics on controlling symptoms in terminal patients is also controversial. For instance, Vitetta et al. reported a 40% rate of symptom reduction with the use of antibiotics in patients with imminent death [37]. Similar results have been reported by Stiel et al., where 56% of the surveyed patients reported good or very good clinical effect after receiving antibiotics [38]. Despite the positive impact reported in some studies, the effect differs depending on the site of infection [5, 15, 17,18,19,20,21,22,23]. White et al. demonstrated that antibiotic use effectively resolved symptoms in most patients with urinary tract infections (UTIs) [21]. However, it was less effective in alleviating symptoms from infections at other sites, including respiratory infections, bacteremia, and skin and soft tissue infections [21]. Similarly, Fombuena et al. found that 64% of patients treated for possible infections experienced symptom resolution, with UTIs being the most responsive to antibiotic treatment [18]. Out of the 633 treated patients in an outpatient hospice care, symptomatic relief was reported in 79% of patients with UTI,43% with respiratory infections, 41% in skin and soft tissue infections and none with bacteremia [22]. In fact, the failure of palliating respiratory symptoms in patients with pneumonia was linked to high palliative prognostic index, indicating poorer prognosis [39].

Even in non-cancer terminally ill patients, the impact of antibiotics on symptomatic relief varied by the site of infection. Rosenberg et al., in a systematic review, showed that patients with UTI experienced the greatest improvement in symptoms following antibiotic therapy, with improvement rates ranging from 67 to 92% [40]. Therefore, it's essential to weigh the risks of treating potentially reversible infections against the limited evidence of benefit, ensuring that the diagnosis of infection is supported by clinical, laboratory, or microbiological evidence.

Approach of antibiotic use in palliative care

ASP aims to ensure that patients receive the appropriate antibiotic with the correct dose, indication and duration. While there are no definitive guidelines for management of infections in advanced cancer patients, the IDSA considered prescribing antibiotics in EOL care as an aggressive intervention [41]. In view of the previously mentioned challenges, several interventions can be applied to optimize the use of antimicrobials. A summary of potential ASP interventions is summarized in Table 2.

Table 2 Summary of specific AMS interventions in patients under palliative care

Infectious diseases (ID) specialist’s role is crucial for optimizing antimicrobials in palliative oncology setting. This should be done through different approaches including being actively involved in goals of care discussion for patients with recurrent infections. The integration of ID physicians in such discussions aims to set-up a plan for antimicrobial use based on realistic expectations rather than false hopes [42]. By being involved in goals of care discussion, the ID physician should emphasize to the patients and their families the inevitable consequences of the disease leading to possible infections, pros and cons of antimicrobials, and limited benefit of antimicrobials in later stages [26, 42].

Following the illustration of the realistic expectations, outlining the goals of care to either complete comfort, palliating symptoms or full treatment is needed. Even in the patients who decide to treat possible infections, a time-limited approach should be tried through setting-up objective markers for response to antibiotics followed by re-evaluation after 48-h and clear actions if antibiotics are ineffective [43]. Further discussions about care goals should occur when the patient's clinical situation deteriorates, acknowledging the emotional distress the patient is experiencing [42]. Besides, early referral to a specialized palliative team may help in effectively reducing antimicrobial use, as demonstrated by Jeong-Han Kim et al., in their retrospective cohort analysis [43]. Other ASP interventions that can be done to optimize antimicrobial use include institutional guidelines and educational interventions [44].

Conclusion

The use of antimicrobials in EOL care remains a challenge with no clear recommendations that can guide both the caregivers and the decision makers. Cultural factors, particularly from the family's perspective, and the views of physicians also play crucial roles. Optimizing antimicrobial use through setting up realistic expectations, outlining clear goals of care and balancing between treating possible infections and potential harms is needed. Further studies are necessary to develop guidelines and to evaluate their impact on the rational use of antibiotics in EOL patients.