Supportive Care in Cancer https://doi.org/10.1007/s00520-018-4090-8

REVIEW ARTICLE

Antimicrobial therapy in palliative care: an overview Filipa Macedo 1 & Catarina Nunes 2 & Katia Ladeira 2 & Filipa Pinho 2 & Nadine Saraiva 1 & Nuno Bonito 1 & Luísa Pinto 2 & Francisco Gonçalves 2 Received: 23 September 2017 / Accepted: 30 January 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract In the advanced stages of illness, patients often face challenging decisions regarding their treatment and overall medical care. Terminal ill patients are commonly affected by infections. However, in palliative care, the use of antimicrobials can be an ethical dilemma. Deciding whether to treat, withhold, or withdraw the antimicrobial treatment for an infection can be difficult. Antimicrobial administration can lead to adverse outcomes but the two main benefits, longer survival and symptom relief, are the main reasons why physicians prescribe antimicrobial when treating terminally ill patients. For the patient who has an irreversible advanced heart or lung disease, or an advanced dementia, or a metastatic cancer, it is easier the decision of withholding mechanical ventilation, tube feeding, and dialysis than antibiotherapy. To characterize infections, agents, and their treatments in palliative care, we conducted a review of the literature. We also included some tips to help health professionals to guide their clinical approach. Keywords Palliative care . End of life . Antimicrobians . Antibiotics . Infections . Survival

Introduction Palliative care has been defined by the World Health Organization (WHO) as Ban approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual^ [1]. Many cancer patients can now expect to recover from cancer, due to new advances in treatment. For some people, however, cancer either recurs or it is diagnosed as advanced or it does not respond to treatment [2]. In these cases, palliative care is offered. Palliative care utilization is expected to increase with the aging and increases in the prevalence of chronic and terminal diseases. The majority of the patients with cancer will need palliative care in some point of their lives. In developing countries, the proportion of patients requiring palliative care is no less than * Filipa Macedo [email protected] 1

Portuguese Oncology Institute of Coimbra, Coimbra, Portugal

2

Braga Hospital, Braga, Portugal

80%. In the world, most cancers are diagnosed when already advanced or incurable [1]. Nowadays, there is the intention of admitting patients in palliative care earlier, while still under treatment [3, 4]. The goal of palliative care is helping people die with dignity [5], but there comes a time when treatment may do more harm than good [6]. The most common complications experienced by terminal patients are infections and fever [7]. Almost 90% of patients hospitalized with advanced cancer are treated with antimicrobials during the week before their death [7]. Two retrospective reviews reported that it is common that incurably dying patients receive empirically systemic antibiotics in their last days or weeks of life, even in patients with Bdo not resuscitate^ or Bcomfort measures only^ orders [8, 9]. The frequency of infections among palliative cancer patients (non-neutropenic) being cared for in a palliative care unit is around 50–55% [10, 11]. Nagy-Agren reviewed eight reports with an overall rate of 41.6% [12]. Patients with advanced cancer have more susceptibility to infection caused by factors like asthenia, failure of host barriers, malnutrition, immunosuppression, immobility, lethargy, and the use of foreign bodies in the care of these patients (such as urinary catheters) [10, 13, 14]. Currently, there is no consensus among physicians regarding the use of antibiotics for patients in palliative care.

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Uncertainty remains regarding the ethical and legal issues such as withdrawal and withholding of antibiotic therapy. Adverse outcomes can arise from antimicrobial administration such as the following: use of invasive devices such as intravenous lines, acquisition of multidrug-resistant organisms, drug interactions, drugs reactions, additional suffering from side effects, clostridium difficile infection, and increased health care costs. The potential benefits of antimicrobials are the following: symptom relief and prolonged survival. Several studies evaluated the patients, families, and health care professionals’ attitudes about antibiotic therapy. For families and patients, antibiotics were a therapeutic option accepted and were more accepted than cardiopulmonary resuscitation or mechanical ventilation. On the other hand, physicians preferred to withdrawal of blood products than antibiotics, but they were more disposed to retire antibiotics than intravenous fluids or mechanical ventilation [15].

Useful vs non-useful Thompson A performed a retrospective study with 145 patients experiencing cancer-related death. From 145 patients, 86.9% received antimicrobials, from which only 69.8% had clinical findings suggestive of infection, and 51.6% were treated empirically [16]. Pereira J showed that 71.6% of diagnosed infections were treated with antibiotics. The remaining 28.4% were not treated due to either poor general condition or the patients’/families’ option [10]. Albrecht J, from 3884 patients who died in palliative care, concluded that 27% of the patients received at least one antibiotic during the final 7 days of life, and 1.3% received three or more antibiotics. It was also observed that from patients who received antibiotics, only 15% had an infectious disease diagnosed [17]. This practice has great impact in costs and in microbial resistance. Everes M, in a study performed with 303 patients from a chronic care facility, found that narcotic pain medications were prescribed only in 14% of the patients and systemic antibiotic use were 53%. During 15 years, we watched an increasing tendency to prescribe nonnarcotic and narcotic pain medications, but the antibiotic prescription did not modify significantly over the time. Therefore, although pain management information may have affected clinical practice during that time period, it would seem that the data on the use of antibiotics did not have a similar impact. [18] Yao C showed that from 201 patients with terminal cancer, 45.8% manifested the wish of use antibiotics even in the final stage of the disease, 27.8% were uncertain, and 26.4% whished not to have antimicrobials. Medical professionals were considered the most important advisors, which indicate

the responsibility of medical professionals in educating patients and families [19]. White P concluded that 79.2% of 255 terminal patients choose to get antimicrobial administration only for symptomatic use or no administration at all. However, the actual usage was significantly higher. This restricted choice for the use of antimicrobials was more common among older patients who had lower performance status [20]. Stiel S concluded that from 448 patients, 63.8% received antimicrobial treatment and physicians alone often decided the initiation of therapy, whereas pulling out treatment required more often the participation of other team members in the decision process. The most frequent reasons for withdrawal were the following: the wish of patient or family, therapy failure, worsening of the performance status, and adverse effects [21]. Clayton J monitored 41 patients that had received 43 courses of parental antibiotics. This use was considered helpful in 62% and unhelpful in 19% of cases [22]. Vitetta L, from 102 terminally patients, one-third developed infections during the last stage of care, and in 40%, the infection was not the direct cause of death. The patients with documented infection had longer median survival, possibly because the longer the survival, the greater the chance of infection [14]. On the other hand, in the study performed by White P, the survival rate was not significantly different between the group of infected patients and the uninfected ones. The use of antibiotics or the choice of the patient did not significantly affect the infection-related deaths and the patients’ overall survival [20] (Table 1). Albrecht J concluded that patients with longer stays in a hospice care institution had greater probability to receive antibiotics. Patients who reside in hospice care institutions may have developed infections as a result of a longer stay or because receiving antimicrobials may have prolonged their lives [17]. Brown N demonstrated that, during febrile episodes, the patients who received antibiotics had a significantly lower mortality rate when compared with expectant attitude (9 vs. 59%) [24]. Fabiszewski K studied a total of 104 institutionalized patients with Alzheimer’s disease and concluded that persons with severe dementia do not have a survival improvement when infections are aggressively treated, and it has been associated with a faster progression of the severity of dementia [25]. On the other hand, Chen L showed that patients without antimicrobial therapy had a smaller mean survival and a higher mortality rate than the patients with antimicrobial therapy [26]. Reinbolt R showed that the use of antibiotics or the existence of infection did not affect the survival, but the administration of antibiotics caused symptomatic relief in patients with urinary tract infections. The symptomatic control

Support Care Cancer Table 1

Distribution of studies’ conclusions about antimicrobial therapy in survival of patients

Longer survival with antibiotic therapy

Vitetta L. [14]

Albrecht J. [17]

✓

✓

White P. [20]

Reinbolt R. [23]

✓

✓

Fabiszewski K. [25]

✓

No difference between treated and not treated

was more difficult in blood, skin, and respiratory tract infections. This lack of symptom response was interpreted as due to co-morbid conditions or the existence of a cancer in the symptomatic organ [23]. In fact, there are other studies that conclude the same [14, 20, 22].

Patterns of antibiotics and infections In many studies, the urinary tract and lower respiratory tract were the most usual sites of infection (Table 2). The catheterrelated infections were less common with totally implanted ones [30], and the catheter removal rate varies between 3 and 28% [31–34]. The totally implanted access ports were associated with lower incidence of catheter-related infections than central venous catheters [30]. The causative agents of infections could be bacterial pathogens, viruses, and fungi. The bacteria account for more than 75% of nosocomial infections and fungus were isolated in nearly 3–10% of the infections. Viral microorganisms were responsible in only 2% of the cases and rare agents such Pneumocystis carinii accounted for the rest [27, 35]. The most frequent bacterial agents identified were Staphylococcus aureus (S. aureus) and Escherichia coli (E.coli) (Table 3). The most frequently antibiotic therapy prescribed was trimethoprim-sulfamethoxazole and fluoroquinolones (Table 4). Vitetta L concluded that antibiotic therapy had an overall success rate for symptom relief of 40%, and these 40% patients recovered from their diagnosed infections [14]. The study of White P included the anti-fungal therapy and fluconazole accounts for 7.8% of the prescriptions [20]. Table 2

Brown N. [24]

Chen L. [26] ✓

✓

The diagnosis The diagnosis of infections may be delayed due to the inability to express their complaints. The presence of multiple comorbidities becomes the findings on physical examination difficult to valorize, and the infection in elderly patients presents differently from younger adults. The clinical signs that an older person could be infected include fever, cough, yellow sputum, and purulence or skin injury; however, clinical manifestations could not be present or be too subtle to be recognized. Infection could more frequently be noticed as a change in mental or cognitive function or deterioration in functional status [36]. The Infectious Diseases Society established that infection should be suspected in patients with any of the following characteristics: decline in functional status, define as deteriorating mobility, failure to cooperate with staff, new or increasing confusion, reduced food intake, falling or incontinence; fever define as the following: (1) an increase in temperature of > 1.1 °C over the baseline temperature; (2) a single oral temperature > 37.8 °C; or (3) rectal temperatures > 37.5 °C or repeated oral temperatures > 37.2 °C [37]. As of yet, it has not been established the specific diagnostic tests to assess fever and infection in palliative patients and, when recommended, they have not been studied [38]. Diagnostic tests should only be made if they enhance the probability of diagnosis, if they improve patient management, have low risk, and are reasonable in cost. A test should not be ordered if its result would not produce an alteration in clinical conduct or treatment strategy [39]. The most used diagnosis tests are the following: –

Complete blood cell count with differential. The elevation of the total white blood cell count (with leukocytosis

Distribution of infection sites

Urinary tract infection Respiratory Infection Skin/subcutaneous infection Blood/bacteremia

Pereira J. [10]

Lagman R. [11]

Vitetta L. [14]

Albrecht J. [17]

Evers M. [18]

White P. [20]

Clayton J. [22]

Reinbolt R. [23]

Robinson G. [27]

Kuehn N. [28]

Homsi J. [29]

39.2% 36.5% 12.2%

– 22% –

42.5% 22.5% 12.5%

4% 7% 3%

30% 42% –

41.9% 34.9% 9.3%

37% 26% 16%

41.9% 34.9% 9.3%

2.6% 1.9% 1.9%

– 16% 22%

66% 21% –

5.4%

31%

12.5%

–

–

3.9%

–

3.9%

2.2%

2%

31%

Support Care Cancer Table 3 Distribution by main agents of infections

– –

–

– –

Pereira J. [10]

Vitetta L. [14]

White P. [20]

Reinbolt R. [23]

Staphilococcus aureus

20.0%

10.5%

14.9%

14.9%

Escherichia coli

22.9%

36.8%

22.9%

27%

Enterococcus Enterobacter Faecalis

11.4% –

– 15.8%

11% –

14.7% –

defined as ≥ 14000 cells/mm3) and a left shift (percent band neutrophils > 6% or total band count ≥ 1500/mm3) had the highest likelihood ratio for the detection of a bacterial infection [40]. Urinalysis and urine culture, however, the majority of elderly persons with bacteriuria are asymptomatic [41]. Blood cultures. The mortality rates correlated with bacteriemia range from 20 to 35%. In the first 24 h from the diagnosis of bacteriemia occur 50% of deaths, despite appropriate therapy [42]. Chest scans. Despite the more precise and accurate imaging methods that available nowadays, chest radiography continues to be the most reliable method of diagnosing a suspected pneumonia [43, 44]. Sputum examination, which is performed in only 5–10% of the patients with pneumonia [44]. Skin and soft tissue culture obtained from cellulitis and infected pressure ulcer.

Discussion Good practice guidelines in antimicrobial use in palliative care patients have not been established. Their frequency and determinants have not been well described. The prescription patterns need a better understanding to achieve a consensus for

Table 4 Distribution by antimicrobial therapy

structured guidelines about antimicromial use in this population [17]. Some physicians are anxious about suspension of antibiotic treatment since it may risk shortening the patient’s life. On the other hand, others are concerned that this therapy could prolong the dying process. It is not possible to calculate if antibiotics will increase the chance of a cure or whether withholding them will lead to death. Consequently, antibiotics do not fall into the category of life-sustaining treatments, as do mechanical ventilator support or tube feeding [12]. The diagnosis of infection in a palliative cancer patient is not always easy. Indicators that make physicians think about a possible infection such as fever or elevation of white blood cells are not always present. Palliative patients use frequently drugs such as acetaminophen, nonsteroidal anti-inflammatory drugs, and corticosteroids, which could potentially blur the febrile response. Corticosteroids can increase the peripheral white blood cells count, confusing the laboratory diagnosis of an infection. Patients having cognitive impairment may have difficulty in exposing their symptoms. A fever may not necessarily represent an infection; it could be neoplasm-induced. Moreover, acute phase proteins like reactive C protein and erythrocyte sedimentation rate are not good tools in differentiating between cancer and infection because cancer patients tend to have higher acute phase protein levels than individuals who do not have cancer [43]. However, there is a potential role for procalcitonin in the diagnosis of infection in cancer patients [44, 45].

Pereira J. [10] Levofloxacin Ciprofloxacin TMP/SMX Trimethoprim Cephalexin Macrolides Amoxicillin/clavulanate Fluconazole

– 23.6% 44.4% – – – – –

TMP/SMX trimethoprim-sulfamethoxazole *Fluoroquinolones

Vitteta L. [14]

Albrecht J. [17]

White P. [20]

Homsi J. [29]

26%*

18.2% 11.9% 28.6%

34.4%

20% 8.9%

19.1%

7.8% 49%

9% 7.8%

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In many cases, the existence of fever by itself led to a medical diagnosis of infection, thus the true rate of infection remains uncertain. In these cases, fever could have a potential non-infectious origin, like drug-induced fever and fever secondary to underlying malignancy, particularly in the setting of lymphoma, accelerated tumor growth or necrosis, or central nervous system or hepatic spread [12]. Another potential cause of fever is pulmonary embolism/deep venous thrombosis [46], for which cancer is one of the most relevant risk factor [47]. In the Urokinase Pulmonary Embolism Trial, 50% of the patients with pulmonary embolism presented temperature > 37.5 °C [48]. In the Prospective Investigation of Pulmonary Embolism Diagnosis Study, low-grade fever was presented in 14% of the patients with pulmonary embolism and no other source of fever [49]. For the diagnostic process, there are important components like history, physical examination, and clinical features (pain, tenderness, or swelling of the leg; shortness of breath, dyspnea, chest pain aggravated by inspiration (pleuritic-type pain), or hemoptysis. Antibiotic therapy may be beneficial in palliative symptom control [14]. Antimicrobial therapy produces a substantial and quick improvement in pain management. Green et al. reported two cases of cancer patients treated with antimicrobials with successful symptomatic control. One patient with the diagnosis of pneumonia had severe respiratory symptoms, and the second patients had a delirium due to sepsis [50]. MacKey et al. reported a patient with a large abscess in psoas muscle complaining of severe abdominal pain. A good symptomatic control was achieved with surgical drainage and antimicrobial treatment [51]. In other studies evoked in this review were reported an antibiotic-induced symptom control [14, 20, 22]. The decision-making process about the initiation of antibiotic therapy must have consideration in some aspects like the patient’s and family’s desires, the uncontrolled pain, the main diagnosis and its stage, and the level of multisystemic deterioration. Since it is not possible to say if an antimicrobial treatment will have a positive effect on symptomatic control, it seems wise to initiate a therapeutic trial. If the clinical status of the patient declines despite antimicrobial treatment, the physician may decide to stop the administration. The American Society of Clinical Oncology is against the use of palliative chemotherapy in patients who have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥ 3 since it was not associated with quality of life improvement and it was even associated with worse quality of life in patients with good performance status [52]. The authors think the same conclusion could be taken in concern to antimicrobial therapy; a patient with a lower ECOG performance status does not benefit from antimicrobial therapy. Antibiotic therapy is often prescribed, possibly since there are no guidelines about such a problem. Physicians have no formal training in conversations about end-of-life decisions

and are not sure about the clinical course of certain diseases [18]. Healthcare providers must be stimulated to actively discuss with patients and their families all the way through the course of illness [18]. The increasing trend of hospice care and the lack of clear guidelines regarding antibiotic use may lead to a growing number of patients receiving potentially unnecessary treatment for infections or not receiving the necessary palliative treatments. Consequently, further research is required to guide antibiotic use in hospice care [17]. Miller D presents two cases for which the suspension of antimicrobial therapy may be ethically accepted. The first situation is when antibiotics do not offer comfort or prolongation of life. The second situation is when the quality of life of the patient is getting worse, thus the patients himself do not consider prolongation to be valuable [53]. Some authors recommended an antimicrobial trial when in doubt about the treatment; an approach that comforts both the medical staff and family [54]. Another important concept is the palliative surgery, whose primary intention is to improve the patient’s quality of life and symptom relief, in particularly advanced diseases which cannot be treated in another way. The effectiveness of a palliative surgery is measured by the control and the durability of symptom control. To perform this kind of procedure, the symptom, the objectives of the patient, the impact of the procedure in the quality of life and in the function of the patient, the prognostic of the disease, the expected time of survival of the patient, the existence of non-surgical options, and experience of the surgeon and technical considerations like adherences, must all be considered. Some examples of procedures are the following: paracentesis, toracocentesis, pericardiocentesis, derivation of bile duct or choledochus, citorreduction, implantation of endoprosthesis to overcome an obstruction, pleurodesis, craniotomy, pathologic fracture fixation, amputation, tumor embolization, tracheostomy, and many others. The derivative procedures of the digestive tube have some contraindications, like ascites, peritoneal carcinomatosis, multiple sites of obstruction, very advanced disease, and low-performance status. No two patients are equal; therefore, the decision to perform a procedure or not must be made on a case-by-case basis and always taking into consideration the opinion of the patients, family, and physician. Suggestions for antibiotic use in palliative care & &

Patients and family should be heard and involved in the discussion regarding how to best treat their infections. Consider the symptomatic control as the main indication for the use of antimicrobials (antimicrobial treatment of urinary tract infections improves symptoms in a large majority of patients but is much less successful in respiratory and skin infections, and bacteremia is very poorly controlled) [14, 20, 22, 23].

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&

When the risk of danger and rare complications is irrelevant, consider the use of old-fashioned antibiotics, like chloramphenicol (it has good bioavailability, good cover range, and is inexpensive) [15]. When an infection do not contribute to debilitating symptoms, when multisystem affection is present or the patients can no longer swallow, antimicrobial therapy should not be considered palliative [12]. Discontinuing a medical therapy may be more difficult than initiating one. If a treatment is initiated and considered no longer helpful for the patient, it can be stopped. Although informed consent is not habitually required, the decision should be deliberated with the patient and family [55]. In all situations, the decision on starting an anitimicrobial therapy depends on the predictable prognosis of survival and the course of the illness, as the expected survival time of the patient should be long enough to finish and profit from the antibiotics [21].

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Compliance with ethical standards

20.

Conflict of interest The authors declare that they have no conflicts of interest.

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