Several studies report contrasting data about a poorer tolerance of TB drugs in elderly patients. Among an Indian cohort of TB, reported side effects were higher in elderly patients (63%) vs. younger patients (54%) [59]. Similarly, the elderly had a higher frequency of adverse drug reactions (18.5% vs. 40.7%) in a Korean cohort [34]. These results are inconsistent with some studies in high-income countries showing that adverse TB drug reactions were similar or higher in younger adult patients than in the elderly. For example, among nursing home residents in Arkansas, isoniazid-related liver toxicity occurred in only 4.5% of those over 80 years of age compared to 3.5% of those aged 50 to 64 years. Digestive intolerance was reported in 6.9% and 4.1% of the same population [60]. Moreover, the overall rate of side effects leading to discontinuation or change of TB treatment was lower in older patients (21%) compared to younger ones (24%) [61].

The influence of aging in the risk of hepatotoxicity during TB treatment is also unclear, and involves, besides age-related physiological changes, potential other comorbidities and treatments [61,62,63]. The risk of drug-induced hepatitis and other serious adverse events could increase with age due to less efficient elimination of drugs as a result of reduced renal and hepatic clearance [64].

Because pyrazinamide is most frequently responsible for liver damage [62,65,66], the American Thoracic Society, the Centers for Disease Control and Prevention and the Infectious Diseases Society of America assess that in the elderly with a moderate TB disease with low risk of drug resistance, the benefits of pyrazinamide use in the initial dosing regimen is less than the risk of serious adverse events [62,67]. Therefore, American guidelines do not recommend the use of pyrazinamide during the intensive phase in patients aged >75 years for moderate disease and low resistance risk [68,69]. In this setting, the initial regimen consists of isoniazid, rifampicin and ethambutol.

The total duration of treatment for tuberculosis without pyrazinamide during the intensive phase should be extended to at least 9 months. When an elderly patient has active TB with a high bacillary load (cavitary forms), the addition of a fourth antibiotic is necessary to prevent the development of resistance, and the use of pyrazinamide or a fluoroquinolone (levofloxacin, moxifloxacin) may be considered [69]. Nevertheless, a recent study shows that in very elderly patients (>80 years) the use of pyrazinamide with careful monitoring can be safe and well tolerated [70].

Frequent impairment of renal function complicates the use of TB drugs and warrants dose adjustment. For clearances between 30 and 50 no dose adjustment is necessary but regular dosing is warranted. For creatinine clearances <30 mL/min, it is recommended to reduce the daily dosage or space out the doses according to each molecule. The 2016 IDSA guidelines offer a dose adjustment chart [69]. Rifampicin and isoniazid are metabolized by the liver and conventional dosing can be used in renal failure. Pyrazinamide is metabolized by the liver, but its metabolites may accumulate in patients with renal impairment warranting a 48 h interval or three intakes per week for pyrazinamid and ethambutol [71,72].

Drug-drug interactions can alter the concentrations of the drugs involved. This problem should be considered in the elderly, who are often exposed to polymedication.

Few interactions significantly modify the concentrations of anti-tuberculosis drugs other than fluoroquinolones. The concomitant use of vitamin supplements containing calcium, iron and zinc and antacids reduces the absorption of fluoroquinolones. It is necessary to space out the intake of these drugs by at least two hours from that of the fluoroquinolones.

On the other hand, TB treatments modify the concentrations of other drugs. Rifampicin is an enzyme inducer. By inducing the activity of metabolic enzymes, rifampicin decreases the serum concentrations of many drugs, sometimes to subtherapeutic levels.

The drugs frequently used in the elderly, and justifying monitoring with adaptation of doses or search for alternative drugs, includes in a nonexhaustive list: Benzodiazepines, Simvastatin, luvastatin, Verapamil, Nifedipine, diltiazem, Enalapril, Losartan, Glimepiride, Repaglinide, Propranolol, Metoprolol, Corticosteroids, Warfarin, and Levothyroxine.

Isoniazid is a relatively potent inhibitor of several isozymes. Isoniazid increases the concentrations of some neurotropic drugs used in the elderly such as carbamazepine and certain benzodiazepines and serotonergic antidepressants. This effect is offset by the inducing effect of rifampicin. This should be taken into account when discontinuing either drug [71].

Measuring plasma TB drugs concentrations has not been shown to be of therapeutic benefit but may be performed in cases of suspected noncompliance and suspected drug interactions to guide dosage adjustment [69].

The elderly population is schematically divided into three types of subjects according to their health status [73]: vigorous elderly people in good health who are independent and autonomous; frail elderly people who are distinguished by a lessening of their ability to deal with stress, no matter how small, and dependent elderly people in poor health due to chronic polypathology causing handicaps. Frail or dependent elderly people are not only at greater risk of contracting an infection than vigorous elderly people, but are also at greater risk of presenting serious complications in the case of infection. Recognising frailty to prevent loss of independence is a major challenge in dealing with the therapeutic aspects of elderly patients. The most relevant clinical markers of a state of frailty are malnourishment, falls, incontinence, cognitive disorders (Alzheimer’s disease or similar, and delirium).

The management of an elderly TB patient is, therefore, ideally based on an adaptation of the treatment based on a standardized gerontological assessment [74]. Frailty screening tools exist, allowing clinicians to refer the patient for geriatric evaluation or not, as cancerologists do with the G8 tool. These tests, for example the Edmonton Scale, most often assess cognition, general condition, functional addictions, social support, multiple medication, and risk for falls [75].

The treatment of TB in the elderly requires adaptations linked to the specific nature of aging. Regardless of the role of ethambutol, which is questionable in the elderly, tolerance of the treatment is often poor and requires therapeutic adaptations, which are sometimes difficult. In addition, the elderly are often cognitively impaired, socially isolated, polypathological and fragile. They are therefore exposed to a major risk of poor compliance, drug interaction and intolerance to treatments, in particular linked to renal failure and hypoalbuminemia.

Adherence and tolerance of TB treatment involve education and training of both caregivers and patients and, if necessary, the attention of the health professional on a daily basis to ensure the dispensing of drugs. Adherence to TB treatment is a fundamental issue in the outcome if lack of strict adherence to treatment exposes the patient to the risk of therapeutic failure and the emergence of anti-tuberculosis drug resistant strains. The actual intake is easy to control, due to the expected side effects of the treatment such as red urine (due to rifampicin) or hyperuricemia (due to pyrazinamide). Nevertheless, taking the daily treatment on an empty stomach, to improve oral bioavailability of anti-TB drugs (rifampicin, isoniazid), can pose nutritional problems, since breakfast is important for the elderly. Older patients with active TB are frequently undernourished because of the infection, so physicians need to be particularly attentive to obtain good nutritional status for patients with the support of a dietician, use of food supplements and vitamin supplementation. Although there is little evidence for routine nutritional and vitamin supplementation [76], daily administration of pyridoxine (vitamin B6) during isoniazid treatment is recommended, including in elderly patients [69,77]. Adherence support aimed at ensuring successful tuberculosis treatment has historically relied on the use of directly observed therapy (DOT) [78]. The use of DOT has shown mixed results in multiple studies and metaanalyses, largely because the term appears to be a catchall phrase for different treatment support approaches [79]. When coupled with emotional support, nutritional supplementation, and other types of enablers, DOT can be a way to ensure daily contact with vulnerable individuals and close monitoring for the development of adverse events. DOT is, therefore, particularly well suited to frail elderly subjects. DOT performed by the family is, nevertheless, inferior to DOT performed by a provider [77,78,79].

Recently studies have been shown the superiority of innovative strategies based on new technology, such as virtually observed therapy using smartphones [80]. However, these strategies were conducted in young people, and are probably not enforceable with older people who have little access to new technologies such as smartphones.

In addition, it is recommended that fixed combinations be used in preference, as they simplify the taking of medication and compliance [2].

Many other infectious diseases with local and systemic symptoms of TB are caused by the growth of M. tuberculosis and the host’s inflammatory response to the presence of the bacteria in the tissue [81]. TB infection initiates an inflammatory immune response that causes tissue damage. In addition, active TB infection by itself appears to be an immunosuppression factor, via the modification of the immune response, which favors the long-term persistence of the bacteria in the tissue [82,83]. Hence, during adequate sterilizing antimycobacterial treatment, immunopathological reactions, due to gradual restoration of pathogen-specific immune responses, may occur with paradoxical worsening and upgrading clinical reactions [84]. However, these paradoxical reactions during TB treatment occurred less frequently, and with less exaggeration, than immune reconstitution inflammatory syndrome with dynamics of rapid immune restoration in immunocompromised individuals [85], such as HIV-infected subjects on antiretroviral therapy [15]. These paradoxical clinical worsening in non-HIV-patients, generally self-limited, are more common in lymph node TB, consistent with exacerbation of pain and swelling following the initiation of chemotherapy [85]. In addition, age was not found to predict the occurrence of paradoxical upgrading reactions in a retrospective analysis [86]. Adjunctive transient corticosteroid therapy may be used to treat paradoxical upgrading reactions. Frequent complications associated with corticosteroid therapy among the elderly (osteoporosis with osteoporotic fractures, falls or osteoarticular problems, protein-energy malnutrition, amyotrophy, and psychiatric complications) should be prevented and treated because they may have serious consequences in this frail population [87]. Attention should be paid to the prescription of preventive measures through comprehensive care.