OpiniãoOlder patients
TB-related morbidity and mortality tends to be higher among older people than in the younger population. Patients aged 65 years and older with MDR/RR-TB are more vulnerable to the adverse effects of TB medications owing to physiological changes of ageing (e.g. increase in QT interval and decrease in estimated glomerular filtration rate [eGFR]), other comorbidities and overlapping, additive drug toxicities (owing to a higher likelihood of polypharmacy in older people). Advanced age has also been reported as a risk factor for linezolid-induced anaemia (54). Whereas the 9-month all-oral regimen may be offered to eligible patients of any age, older people may require closer monitoring for drug-related adverse events as well as closer adherence support and assistance to administer treatment daily or as prescribed.
Patients with diabetes mellitus
The 9-month all-oral regimen may be used to treat MDR/RR-TB in patients with diabetes; however, there are currently no data on safety and outcomes of this regimen in this specific group. Type 2 diabetes is associated with several liver disorders; therefore, it is prudent to monitor closely for hepatotoxicity among these patients. Blood sugar levels may be difficult to control in patients with MDR/RR-TB and diabetes, and insulin may be required to gain adequate blood sugar control during treatment. Patients with diabetes are also at increased risk of peripheral neuropathies, which may be further exacerbated following exposure to linezolid and high doses of isoniazid. These patients must be counselled to report symptoms of peripheral neuropathies early because such symptoms may necessitate a change in regimen – either to the ethionamide-containing 9-month regimen (bearing in mind this will still include high doses of isoniazid in the initial phase), or a longer individualized regimen without linezolid.
Patients with hepatic dysfunction
The 9-month all-oral regimen may not be the most appropriate option for people with chronic liver disease because this regimen contains several potentially hepatotoxic drugs (e.g. pyrazinamide, isoniazid and ethionamide). Although this regimen may still be offered with close monitoring of liver enzymes in people with chronic stable liver dysfunction, a longer regimen with fewer hepatotoxic drugs may be preferable in some settings where closer monitoring is not feasible.
Patients with renal failure
The 9-month all-oral regimen may be used to treat MDR/RR-TB in patients with renal failure provided the dose or dosing interval of renally excreted drugs are adjusted for the patient’s creatinine clearance. Levofloxacin (but not moxifloxacin), ethambutol and pyrazinamide require dose or frequency adjustment for adults with creatinine clearance of less than 30 mL/min. Treatment does not have to be extended unless indicated by lack of smear conversion at month 4 of treatment, as for patients with normal renal function.
Patients with anaemia
Patients with TB commonly have anaemia of chronic disease (55), and treatment with an effective drug regimen (even one that includes linezolid) may lead to improvement or resolution of the anaemia once the disease is properly treated. Many patients with TB also suffer with nutritional deficiencies, and low haemoglobin may also be a result of iron deficiency and low iron stores (56). This deficiency may resolve naturally once effective TB treatment (even including linezolid) leads to resolution of TB symptoms and improvement in the patient’s diet and appetite. Extended use (≥2 weeks) of linezolid has been associated with reversible myelosuppression (57). Therefore, the linezolid-containing 9-month regimen must not be offered to patients with a pretreatment serum haemoglobin below 8 g/dL that cannot be rapidly corrected (i.e. with blood transfusions) before starting MDR/RR-TB treatment. Similarly, owing to the morbidity associated with severe neutropenia and thrombocytopenia, the linezolid-containing 9-month regimen is not suitable in patients with neutrophils below 0.75 × 109/L (or 750/mm3) or platelets below 150 × 109/L (or 50 000/mm3) before starting treatment. Some patients respond well to an initial blood transfusion that raises their haemoglobin above 8 g/ dL and allows them to at least start a linezolid-containing regimen – linezolid will not necessarily cause myelosuppression in patients with baseline anaemia, although a baseline haemoglobin below 10.5 g/dL has been reported as a risk factor for linezolid-induced anaemia (54). It is not uncommon for haemoglobin to drop again shortly after blood transfusion in a person with untreated chronic TB disease, but the temporary increase in haemoglobin may allow enough time for a linezolid-containing regimen to be effective in treating the TB disease, and the patient’s haemoglobin is likely to improve as the disease is brought under control.
Blood transfusions may not be a lasting solution in situations where haemoglobin drops significantly from baseline because of linezolid toxicity when linezolid is continued. Although blood transfusions may help to reverse anaemia following withdrawal of linezolid, they may not resolve linezolid-induced myelosuppression with ongoing exposure to the drug. Therefore, if linezolid toxicity leads to a drop in haemoglobin below 8 g/dL during the first 2 months of treatment, linezolid should be withdrawn and the regimen switched appropriately. More research is needed on the role of iron supplementation to treat anaemia during MDR/RR-TB treatment; however, oral supplementation of iron is often not well tolerated and is not immediately effective at the start of treatment, at a time when the pill burden can be overwhelming and the risk of multiple drug side-effects is high.