Patient-centered care principles should be applied when treating individuals for MDR or extensively drug-resistant TB. Patients should be educated about the disease and treatment, and engaged in their care through shared decision making with their health care providers. Multidisciplinary support (physiotherapy, occupational therapy, nutritionists, social workers, TB nurses and medical specialist services) should be easily accessible to address patients’ physical, psychosocial, material and legal (eg, immigration-related) needs. At minimum, patients should be followed by a dedicated team consisting of 1 or more physicians with expertise in TB, as well as 1 or more nurses with such expertise.
Treatment should be directly observed at the initiation of MDR and extensively drug-resistant TB treatment. DOT, including virtual DOT, for 5 days per week with self-medication on weekends is acceptable if there are no problems with adherence. A switch to fully self-administered treatment can be considered once patients are no longer contagious, and there is confidence on the part of patients as well as the treating team that the risk of missing doses is sufficiently low.
To the extent that it is possible, outpatient (ambulatory) care is encouraged.93 The role of hospitalization should be limited to situations where there is a need for: 1) close medical monitoring due to acute illness or unstable condition, and/or while introducing treatment in a patient with significant prior or anticipated drug adverse events; and/or 2) preventing transmission to household members when a person with MDR or extensively drug-resistant TB is contagious. Ideally, patients who require hospitalization should be admitted to specialized centers able to provide the suggested multidisciplinary support.
It is recommended that the monitoring of patients with MDR-TB include a systematic, organized approach, such as that outlined in detail by the Francis J. Curry National Tuberculosis Center56 and the WHO companion handbook.111 The specific elements necessary to monitor for treatment response and drug toxicity will be dependent upon the patient’s TB disease manifestations and treatment regimen.
With respect to treatment response, monitoring includes regular evaluation of symptoms, weight, radiography and mycobacteriology. Early in therapy, clinicians should assess inpatients daily, and outpatients weekly, until treatment is well tolerated, and then monthly thereafter, asking about symptoms of TB disease, drug toxicity and adherence. Treatment adherence should also be assessed more often by the DOT worker. Weight should be measured at least monthly. Patients with pulmonary MDR-TB should have chest x-rays done at baseline, every 3-to-6 months during treatment, and at end of treatment. Radiographs (x-rays, CT scans, or MRIs) are useful in monitoring response to treatment for patients with extra-pulmonary TB.
Regarding mycobacteriology, the use of sputum smear and culture results, rather than sputum smear alone, is recommended for the monitoring of patients with MDR-TB during treatment. Patients with smear- and/or culture-positive pulmonary disease should have 3 sputum samples submitted at baseline, 2-to-3 sputum samples submitted at least every 1-to-2 weeks until smear conversion, and then at least monthly until culture conversion. If cultures remain positive after 3-to-4 months of treatment, drug-susceptibility tests should be repeated. Even after culture conversion, at least one sputum specimen should be submitted at least monthly to document the stability of the mycobacteriologic response.
Patients with infectious pulmonary MDR-TB should remain in airborne isolation until drug-susceptibility testing results for second line drugs are available, and until the patient is established on an effective regimen consisting of at least 3 drugs for which the isolate is susceptible (or expected to be susceptible). (For further details see Appendix B – De-isolation Review and Recommendations).
Monitoring for drug toxicity will vary depending upon the regimen composition. See the section later in this chapter on adverse drug events, and Table 6 for a summary of common drug adverse events and suggested monitoring for each drug used to treat MDR-TB.
Although the exact role of therapeutic drug monitoring in the management of MDR-TB has not been extensively studied, there are a few situations in which drug concentrations are routinely measured: aminoglycoside concentrations, especially in patients who have known renal dysfunction; cycloserine concentrations to help predict and minimize central nervous system adverse reactions and prevent seizure activity; and EMB concentrations in patient with reduced renal function.56 Monitoring of linezolid to minimize toxicity and maintain efficacy has been utilized by some specialized American centers112 but this approach has not been systematically evaluated. Other reasons to consider therapeutic drug monitoring include known or suspected malabsorption; patients who are not responding to treatment or failing treatment; patients with few effective drugs in their regimen; and patients with potentially significant drug-drug interactions.
Patients who have completed treatment of MDR-TB or XDR-TB should undergo clinical, radiologic and mycobacteriologic follow-up at 6-month intervals for a minimum of 2 years.56
Table 6. Adverse events and monitoring recommendations for anti-TB drugs used for the treatment of MDR-TB.
|Medicine||Incidence of adverse events resulting in drug discontinuation (95%CI) a||Common adverse eventsb||Recommended routine monitoring|
|Levofloxacin||1.3% (0.3–5.0)||MSK (64%), peripheral neuropathy (14%), rash (14%), hypoglycemia (7%), GI disturbance, headache, anxiety, tremulousness, prolonged QT interval||EKG when used in combination with other QT-prolonging drugs|
|Moxifloxacin||2.9% (1.6–5.0)||Cardiovasculard (21%), hepatotoxicity (17%), GI disturbance (13%), peripheral neuropathy (11%), MSK (8%), headache, anxiety, tremulousness||EKG when used in combination with other QT-prolonging drugs|
|Bedaquiline||1.3% (0.3–5.0)||Cardiovasculard (56%), hepatoxicity (22%), CNS toxicity (11%), MSK (11%), GI disturbance||EKG at baseline and weeks 2, 12, 24. Baseline potassium, magnesium, calcium. Baseline and monthly liver tests|
|Linezolid||14.1% (9.9–19.6)||Peripheral neuropathy (64%), myelosuppression (22%), optic neuropathy (5%), GI disturbance (2%), rash (2%)||Regular (initially weekly, then at least monthly) complete blood counts
Clinical assessment for peripheral neuropathy
Visual acuity and color vision monthly
|Clofazimine||1.3% (0.3–5.0)||Skin hyperpigmentation (42%), cardiovasculard (33%), rash (17%), GI disturbance (8%), discoloration of conjunctiva, cornea and body fluids, photosensitivity||EKG when used in combination with other QT-prolonging drugs|
|Cycloserine, Terizidone||5.7% (4.1–7.8)||Psychiatric (66%) (depression, psychosis, suicidal ideation), CNS toxicity (25%) (seizures, lethargy), GI disturbance (4%), peripheral neuropathy (1%), rash (1%), optic neuritis||Peak concentrations after 1-2 weeks of starting, then intermittently throughout treatment;
Screen for psychiatric symptoms
|Ethambutol||1.8% (1.0–3.3)||Visual impairment (including optic neuritis) (70%), GI disturbance (17%), MSK (3%), rash (3%), hepatotoxicity (2%)||Baseline and monthly visual acuity and color discrimination|
|Pyrazinamide||5.1% (3.1–8.4)||MSK (33%), GI disturbance (23%), hepatotoxicity (20%), rash (13%), hyperuricemia (6%)||Monthly liver tests|
|Delamanidc||N/A||GI disturbance, dizziness, insomnia, QT prolongation||EKG at baseline and monthly. Baseline potassium, magnesium, calcium, albumin; monthly if risk factors for electrolyte disturbance or QT prolongation|
|Amikacin||10.2% (6.3–16.0)||Ototoxicity (87%), nephrotoxicity (10%), GI disturbance (1%), MSK (1%), vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia||Baseline and monthly assessment of hearing and vestibular system (symptoms, physical exam, audiology)
Baseline and regular (at least monthly)
|Streptomycin||2.9% (1.3–6.2)||Ototoxicity (83%), peripheral neuropathy (17%), vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia||Renal function and electrolytes.
Peak and trough concentration at least at baseline if impaired renal function; some monitor routinely
|Imipenem-cilastatin, Meropenem||5.1% (3.1–8.4)||Hepatotoxicity (50%), rash (17%), fatigue (17%), pneumonia (7%), GI disturbance, seizure (in CNS infection)|
|Ethionamide||6.5% (4.1–10.1)||GI disturbance (48%), hepatotoxicity (22%), psychiatric (6%), gynecomastia (5%), MSK (5%), hypothyroidism, neurotoxicity||Monthly liver tests
TSH at least every 3 months
|p-aminosalicylic acid||11.6% (7.1–18.3)||GI disturbance (79%), hypothyroidism (5%), hepatic dysfunction (4%), rash (4%), nephrotoxicity (3%). Avoid if allergic to aspirin.||CBC, electrolytes
Monthly liver tests
TSH at least every 3 months
Abbreviations: MDR-TB, multidrug-resistant tuberculosis; MSK, musculoskeletal; EKG, electrocardiogram; GI, gastrointestinal; CNS, central nervous sytem; TSH, thyroid stimulating hormone; CBC, complete blood count.
Note: The complete list of possible adverse events and monitoring parameters is not provided. Please refer to The Curry International TB Center Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, 3rd Edition. 56
a Incidence of adverse events taken from an Individual Patient Data Meta-analysis (IPD-MA) including 9178 patients from 35 studies; adverse events as defined here were those that resulted in permanent discontinuation of the drug. 115
b Estimates of frequencies of adverse events taken from an IPD-MA 115 and include only those that resulted in permanent discontinuation of the drug, therefore the frequency of occurrence of adverse events that can be managed without drug discontinuation may differ from those reported here. Adverse events shown in the table without associated frequencies are from, 56 , 93 not the IPD-MA.
c Adverse events associated with delamanid were not reported in the IPD-MA.
d Further details regarding the type of cardiovascular adverse event were not provided in the IPD-MA;115however these drugs are known to cause QT prolongation.
Table 7. Drug-drug interactions with second-line anti-TB drugs.
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