Treatment of drug-resistant TB in special conditions and situations

Clinical description

Pregnancy

• All female patients of childbearing age should be tested for pregnancy upon initial

evaluation.

• Pregnancy is not a contraindication for treatment of active drug-resistant TB but

poses great risk to the lives of both the mother and foetus.

• Pregnant patients should be carefully evaluated, taking into consideration the

gestational age and severity of drug-resistant TB.

• Pregnant patients should be started on DR-TB treatment as soon as the diagnosis is

made, and not delayed until after the first trimester of pregnancy.

92 National Tuberculosis Control Programme

• Treat with three or four oral second-line anti-TB drugs which are likely to be highly

effective against the infecting strain plus pyrazinamide.

• The injectable agents and ethionamide are contraindicated during pregnancy, thus the

use of Delamanid or Bedaquilline to construct an effective DR-TB treatment regimen should be strongly considered for the benefit of the pregnant woman. Aminoglycosides can be toxic to the developing foetal ear, and Eto can increase the risk of nausea and vomiting associated with pregnancy (teratogenic effects have also been observed in animal studies).

• If a woman falls pregnant while on the shorter DR-TB regimen, the decision about

continuing the shorter regimen will depend on whether the patient has culture converted, the number of months the patient has been on treatment, and whether the patient is receiving the injectable and ethionamide. If cultured converted and completed at least four months of intensive phase, the patient can be switched to continuation phase of the shorter regimen; if neither of these criteria are met, the patient should be switched to an individualized regimen with new drugs (in consultation with the National DR-TB committee).

In lactating mothers,

• Second line DR-TB drugs are not contraindicated in breastfeeding patients. The general

recommendation is that women can breastfeed while they are on DR-TB treatment, although formula feeding is an option if safe and feasible (AFASS criteria for the choice of formula feeding are affordable, feasible, accessible, sustainable, and safe).

• Most DR-TB drugs are passed to the infant through breastmilk, but the concentrations

are sub-therapeutic (very low).

• The notable exceptions are clofazimine and Bedaquilline, both of which accumulate in

the fatty tissues of the breast and are excreted in the milk (the baby can have coloration of the skin due to clofazimine).

• If the mother has bacteriologically confirmed DR-TB, either of the following

precautionary measures can be taken:

o Recommend that the infant be placed under the care of a family member;

o The mother uses a surgical mask, especially while breastfeeding, until culture conversion.

Each breast-feeding patient should be considered individually, with a multidisciplinary approach that includes social workers, treatment supporters, nursing staff, and the management team.

What will work for one mother-child pair will not work for another.

• It is essential to closely monitor the infant, as well as other children in the household,

for signs and symptoms of TB while managing DR-TB in the mother Contraception Ideally pregnancy should be avoided during DR-TB treatment. A baseline pregnancy test at the start of DR-TB treatment is mandatory, and effective use of contraceptives (preferably an injectable contraceptive or intrauterine device) throughout DR-TB treatment should be considered an essential component of patient education.

National Tuberculosis Control Programme 93 Birth control is strongly recommended for all non-pregnant sexually active women receiving therapy for drug-resistant TB because of the potential consequences for both the mother and foetus resulting from drug-resistant TB treatment during pregnancy. There is no contraindication to the use of oral contraceptives with non-rifamycin containing regimens.

Treatment of DR-TB in children Children with drug-resistant TB generally have initial resistance transmitted from a primary case with drug-resistant TB. The treatment of culture-negative children with clinical evidence of active TB disease and a contact with a documented case of drug-resistant TB should be guided by the results of DST and the history of the contact’s exposure to anti-TB drugs.

• Treatment should be based on contact DST or DST of a sample from the child when it

is available.

• The same inclusion criteria for adults should be applied for children being considered

for the shorter regimen or individualized regimen, though the documentation of fluoroquinolone or injectable resistance, as well as history of prior treatment with 2nd line medication may be taken from the adult index case.

• It is important to monitor the weight monthly and to adjust the dosages accordingly.
• All drugs should be dosed at the higher end of the recommended range when it is

possible (with the exception of Ethambutol which should be dosed at the lower range:

15 mg/Kg)

• Ideally the dose of the injectable is between 15-20 mg/kg/day. Consider using the

injectable five times per week.

• New second-line anti-TB drugs paediatric formulations will be available soon. In the

meantime, it may be necessary to split the adult pills in order to approximate the correct dose.

• To achieve the average dose, clofazimine may be given every other day, or even every

third day. If clofazimine 50 mg capsules are not available, the 100 mg capsule can be diluted in 10 ml of sunflower oil (using gloves to avoid colour the hands).

• Delamanid is recommended by WHO for children above the age of 6 (weighing more

than 20 kg) and adolescents who are not eligible for the shorter regimen.

• For infants and children under 6 years of age that need a regimen with new drugs,

consult the national DR-TB committee.

• Provide adequate nutritional support for all malnourished children (ready to use

therapeutic food, therapeutic milk when necessary).

• Co-morbidities should be adequately managed.
• Monitoring children for visual changes should be done monthly on the shorter DR-TB

regimen to assess for visual changes with EMB use.

• Monthly weights should be taken, and dosage adjustment of medications should

take place based on weight. Unfortunately, there are no dispersible DR TB treatment formulations.

94 National Tuberculosis Control Programme

• There should be special attention to adherence and psychosocial support for

adolescents on DR-TB treatment regardless of regimen selection.

• Decisions on treatment duration in children, if unable to be determined from

bacteriologic results, should be based on clinical improvement or standard durations.

Table 10.4-7: Paediatric dosing of second-line anti TB drugs23 Medicine name Daily paediatric dose in mg/kg (max dose in mg)

Bedaquilline23 400mg daily for 2 weeks, then 200mg 3 times a week 20 – 34kg 50mg twice daily, for 24 weeks Delamanid >35kg 100mg twice daily, for 24 weeks Fluoroquinolones Levofloxacin 15 – 20 (1000)

Moxifloxacin 7.5 – 10 (800)

Second-Line Injectable Kanamycin 15 – 20 (1000)

Amikacin 15 – 20 (1000)

Capreomycin 15 – 20 (1000)

Other core second-line agents Ethionamide/protionamide 15 – 20 (1000) 2x daily Cycloserine/terizidone 10 – 20 (1000) 1x/2x daily Renal insuff iciency

• Renal insufficiency can be caused by longstanding TB or previous aminoglycoside use

(e.g. patients that received streptomycin as part of category II re-treatment).

• The frequency and dosage of first and second line TB drugs should be adjusted if the

creatinine clearance is below 30 mL/min; patients with renal insufficiency should be monitored carefully on DR-TB treatment.

• Bdq or Dlm can be used to substitute second-line injectable drugs in patients with

significant pre-existing or aminoglycoside-related renal dysfunction.

23 There is no recommendation for general use of Bedaquilline in children under the age of 12, but there is limited experience with adolescents for whom it may be used if options are severely limited.

National Tuberculosis Control Programme 95

• No dose adjustment of Bdq or Dlm is required in patients with mild or moderate renal

impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, Bdq can be used but with caution (Bdq should be taken after hemodialysis). There are no data on the use of Dlm in patients with severe renal impairment and its use is not recommended.

Liver disorders

• Many of the first and second line drugs for TB are associated with liver toxicity

(Pyrazinamide, Isoniazid, Ethionamide/Prothionamide, PAS, Bedaquilline, Fluoroquinolones).

• DR-TB patients can be treated with SLDs provided there is no clinical evidence of

chronic liver disease, hepatitis, or excess consumption of alcohol. The clinician should anticipate hepatotoxic adverse effects

• Pyrazinamide should not be given to patients with chronic liver disease.
• Eto, HHD, PAS, and Bdq might be hepatotoxic; use with caution in chronic stable liver

disease with close monitoring.

• Check the ALT (SGPT) at baseline; if the ALT is less than 5 times the upper limit of

normal, commence DR-TB treatment; if the ALT is greater than 5 times the upper limit of normal, consult the DR-TB Committee, investigate the cause, and re-check the ALT in one week.

• Screen for Hepatitis B at baseline by performing a HBsAg; if HBsAg is positive,

investigate for active Hepatitis B by consulting the DR-TB Committee for additional investigations.

• Monitor ALT monthly if the ALT (SGPT) is elevated at baseline. Stop all drugs if the ALT

(SGPT) is more than five times the upper limit and investigate accordingly.

• Avoid other potentially hepatotoxic drugs in patients with underlying chronic liver

disease.

• No formal studies of drug–drug interactions between the hepatitis C protease

inhibitors and the second-line tuberculosis drugs have been done; if a patient has stable liver function, treatment of DR-TB should be initiated first.

• Alcohol use might substantially exacerbate liver disease in some settings, although

studies have found that no increased risk of hepatic adverse events in DR-TB patients.

Psychiatric disorders

• There is a high baseline incidence of depression and anxiety in patients with DR-TB,

often related to the chronicity of the condition and socioeconomic stress factors associated with the disease.

• Medical treatment, individual counselling and/or group therapy may be necessary to

manage the patient suffering from a psychiatric condition or an adverse psychiatric event caused by DR-TB medication. Group therapy provides a supportive environment for DR-TB patients and should be provided for all patients, including those without psychiatric conditions. Every facility that treats DR-TB patients is encouraged to 96 National Tuberculosis Control Programme conduct regular support group sessions for patients.

• Psychiatric adverse events from Cycloserine or high dose isoniazid may be more

prevalent in the psychiatric patient; close monitoring is recommended if either drug is used in patients with psychiatric disorders.

• All facilities treating DR-TB should have an organized system for psychiatric emergencies

(e.g. psychosis or suicidal tendencies); atypical antipsychotics should be used for DR- TB patients on multiple QT prolonging DR-TB drugs since haloperidol significantly prolongs the QTc interval and has been associated with torsades de pointes a rare type of ventricular tachycardia.

• Avoid serotonin reuptake inhibitors and tricyclic antidepressants with linezolid, as

there is a risk of serotonin syndrome. (The degree of symptoms can range from mild to severe. Symptoms include high body temperature, agitation, confusion, increased reflexes, tremor, sweating, dilated pupils, and diarrhea).

Seizure disorders

• Cycloserine (Cs) should be avoided in patients with poorly controlled seizure disorders.

However, in cases where Cs is a crucial component of the treatment regimen, it can be given and the anti-seizure medication can be adjusted as needed to control the seizure disorder.

• If the patient is on Cs or isoniazid, provide pyridoxine prophylaxis (50 mg of vitamin

B6 for every 250 mg of Cs).

• Caution must also be exercised when giving isoniazid or imipenem as it may trigger

seizures.

• The use of isoniazid and rifampicin may interfere with some commonly used anti-

seizure medications. Interactions should be checked before their use.

• Seizures that present for the first time during anti-TB therapy are likely to be the

result of an adverse effect of one of the anti-TB medicines, particularly Cycloserine or isoniazid.

• Other causes of seizure should be considered especially in HIV positive patients

(cryptococcal meningitis, cerebral toxoplasmosis, tuberculoma, malignancies etc).