PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

Infections in cancer patients are a very common complication making the routine use of antibiotics lifesaving in the treatment of these patients. As many as 1 in 5 cancer patients undergoing treatment will need antibiotics during their treatment¹. Infections in cancer patients may be related to an immunosuppressed state due to alteration of the underlying immune system caused by the primary cancer, as is the case in some hematologic malignancies. However, more commonly cancer patients are at a high risk of infections due to the lowering of immune defences by different methods of treatment, in particular cytotoxic chemotherapy and hematopoietic stem-cell transplantation (HSCT). Specifically, a common side effect of these treatment modalities is neutropenia, the depletion of neutrophils (a type of white blood cell), which compromises the ability of cancer patients to mount an immune response against infectious microbes, in particular bacterial and fungal infections. Furthermore, catheters and other devices used in treatment often increase the risk of infections². Pneumonia and sepsis are among the most frequent causes for admission to intensive care units for cancer patients. In fact, it is estimated that 8.5% of cancer deaths are due to severe sepsis (extreme response to infection)³.

Use of antimicrobials in cancer patients

The morbidity (disease giving symptoms) and mortality (death) associated with infections from different pathogens among cancer patients has necessitated the formulation of guidelines for prescribing antimicrobial agents prophylactically to prevent infections in patients that are high risk for infectious complications and therapeutically for patients with fever and neutropenia⁴. An example is the prescription of antimicrobial prophylaxis, including prophylaxis for invasive fungal infections, for patients undergoing HSCT or induction chemotherapy for acute leukaemia. These patients experience prolonged periods of neutropenia as a side effect of treatment. Antibiotics are also empirically prescribed in patients with febrile (fever) neutropenia. Given the high rate of mortality associated with cases of febrile neutropenia and septic shock, which can be up to 50% for patients admitted to hospital, the guidelines recommend prompt initiation of broad-spectrum antibiotics within an hour for cancer patients with febrile neutropenia to mitigate the impact of serious and possible fatal complications⁵. In some cases, patients may subsequently be switched to more specific antimicrobial agents once a causative agent is identified. Often, fever is the only sign of infection and microbiology results do not indicate a specific focus or foci of infection.

Integral to the issue of AMR in cancer patients is the need for sustained access to affordable and high quality-assured medicines and microbial diagnostics globally, especially in low-resource settings.

Unfortunately, global disparities in access to diagnostic microbiology and antimicrobial agents have led to several challenges with antibiotic use in cancer patients. In lower-resource settings, although diagnostic capacity for HIV, tuberculosis and malaria have been integrated into the respective control programs for these disease groups, anecdotal data suggests that these diagnostics are not consistently available in the management of cancer patients to either identify sources of infection or the infecting microbe. Patients are often treated empirically with antibiotics, which may or may not be adequate in the absence of microbial surveillance and this can contribute to antimicrobial resistance (AMR). In high-resource settings, practices may vary, but in immunocompromised patients, repeat and prolonged use of very broad-spectrum antibiotics in the setting of multiple infectious complications may also give rise to drug-resistant organisms. Such is the case with invasive fungal infections where drug-resistant organisms in patients with hematologic malignancies have been driven in part by the prevalent use of prophylactic and empirical antifungal treatment⁶. Several institutions have employed antimicrobial stewardship programs to promote appropriate use of antibiotics to improve treatment outcomes and minimize inappropriate and overuse that promotes the selection of multi-drug resistant organisms.

Antimicrobial resistance: a huge concern for cancer patients

The emergence of resistance to antimicrobial agents used to treat infections is a public health problem worldwide, especially as antimicrobial treatment options are becoming limited. This is a huge concern for cancer patients who are more likely to be infected by multidrug-resistant bacteria⁷. While there is a lack of comparable data on a global scale, several in-country hospital microbial surveillance studies suggest an increase in antibiotic-resistant organisms in cancer patients. In India, for instance, about 73% of patients with blood cancers were colonized with carbapenem-resistant bacteria in the gut⁸. In Ethiopia, a 2017 study showed that bacterial infections in cancer patients was 19.4%, and multidrug resistance was common⁹. Data from the SENTRY Antimicrobial surveillance program with sites in the United States, Europe, Latin America, parts of Asia, and the Western Pacific have shown an emerging trend of antifungal drug resistance in Candida bloodstream infections¹⁰. These emerging data suggest that key advances in medicines, including the newer immunotherapies for cancer patients, may be undermined by the increasing threat of antibiotic resistance globally.

Addressing AMR in care for cancer patients

The Union for International Cancer Control (UICC) is the oldest and largest cancer-fighting organization globally. Its mission is to unite and support the cancer community in addressing the global cancer burden, promoting equity, and ensuring cancer control remains a global priority. UICC is committed to addressing the threat of AMR in cancer patients and improving cancer care outcomes. In this regard, UICC has convened a task force¹¹ that includes infectious diseases and cancer experts. The task force will showcase current evidence, identify research gaps in knowledge of cancer and AMR, share best practices, and ultimately engage the cancer community to collaborate and bring about policy change on addressing the threat of AMR.

Ongoing review of the current evidence shows a lack of data on how AMR affects treatment outcomes for cancer patients¹². This data is important for quantifying the contribution of AMR to preventable deaths among cancer patients and for increasing awareness, supporting advocacy and guiding policy actions to address AMR on a national level. Cancer organizations in concert with infectious disease societies can play an important role by working with national cancer registries to guide data collection on variables pertinent to AMR and work with healthcare professionals and hospitals to develop rigorous policies and data collection mechanisms for antibiotic surveillance and stewardship. In North America, the American Society for Clinical Oncology and the Infectious Disease Society of America have developed joint guidelines to guide the appropriate use of antibiotics in cancer patients prophylactically and empirically.

While there is a lack of comparable data on a global scale, several in-country hospital microbial surveillance studies suggest an increase in antibiotic-resistant organisms in cancer patients.

Integral to the issue of AMR in cancer patients is the need for sustained access to affordable and high quality-assured medicines and microbial diagnostics globally, especially in low-resource settings¹³. This also includes R&D for new medicines and diagnostics to tackle the changing landscape of AMR. Furthermore, R&D should be focused on developing Rapid Diagnostic Tests to identify pathogens that are likely to cause hospital-acquired infections in cancer patients. With regard to access to medicines, ensuring access to the medicines listed on the WHO Model List of Essential Medicines should be a national priority and adhering to the rational use of medicines based on the WHO AWaRe classification (the Access, Watch, Reserve classification of antibiotics)¹⁴ is key, so these medicines are available and used in a timely and appropriate way in order to ensure treatment for the cancer continues.

Recent years have seen huge advances in cancer care, including the new targeted therapies and immunotherapy for cancer treatment, and similar R&D of newer therapies are needed to address infectious pathogens, which undermine the effectiveness of cancer treatments. The Netflix model and the PASTEUR act¹⁵ (both subscription models that pay a company to develop medicines and commit to procurement of these medicines) are both novel models set to provide incentives for pharmaceutical manufacturers to develop novel antibiotics. Furthermore, the DISARM act¹⁶ in the US aims to reimburse hospitals and consequently encourage procurement of the newer but expensive medicines, this way also incentivizing R&D for new therapies. Both of these novel models are a step in the right direction to ensure cancer patients have access to the appropriate antimicrobial treatment while undergoing treatment for cancer. Similar models and novel collaborative mechanisms should be expanded to include ensuring access in low-resource settings in order to provide equitable access to medicines and diagnostics to address AMR in cancer patients and improve cancer outcomes due to AMR globally.

Cancer advocacy and infection control advocacy are linked, as the control of infection prevents relapse in addition to preventing death due to infection. Therefore, the cancer community and infectious diseases communities should come together and ensure equitable access to treatments for cancer patients.

References

1. Norwegian Cancer Society (2020) What are the consequences of antibiotic resistance for cancer patients?
2. Rolston KV (2017) Infections in Cancer Patients with Solid Tumors: A Review. Infectious Diseases Therapy. 6(1):69-83.
3. Williams MD, Braun LA, Cooper LM, Johnston J, Weiss R, Qualy R et al. (2004) Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Critical Care. 8(5):R291-8 
4. Taplitz RA, Kennedy EB, Flowers CR (2018) Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update Summary 14(11) 692-695.
5. Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK et al. (2018) Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. Journal of Clinical Oncology. 36: 1443-1453
6. Sanguinetti M, Posteraro B, Fiori B, Ranno S, Torelli R, Fadda G (2005) Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrobial Agents and Chemotherapy. 49(2):668-79
7. ReAct Group (2020) Successful cancer treatment relies on effective antibiotics
8. Kumar A, Mohapatra S, Bakhshi S, Mahapatra M, Sreenivas V, Das BK (2018) Rectal Carriage of Carbapenem-Resistant Enterobacteriaceae: A Menace to Highly Vulnerable Patients. Journal of Global Infectious Diseases. 10(4):218-221
9. Fentie A, Wondimeneh Y, Balcha A, Amsalu A, Adankie BT (2018) Bacterial profile, antibiotic resistance pattern and associated factors among cancer patients at University of Gondar Hospital, Northwest Ethiopia. Infection and Drug Resistance 11:2169-2178
10. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M (2011) Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009). Journal of Clinical Microbiology. 49(1):396-9.
11. The Union for International Cancer Control (UICC) (2021) The role of UICC and its members on Antimicrobial resistance 
12. Wellcome Trust (2021) How drug-resistant infections are undermining modern medicine and why more research is needed now
13. International Federation of Pharmaceutical Manufacturers and Associations (2020) 5 questions to… Cary Adams, CEO of the Union for International Cancer Control (UICC)
14. World Health Organization (2019) WHO AWaRe Classification Database of Antibiotics for evaluation and monitoring of use
15. BIOCOM (2021) US Senate re-introduces PASTEUR Act.
16. MacDonald JV (2019) The DISARM Act Proposes New Strategies to Fight The Growing Threat Of Antibiotic Resistance. Infection Control Today