7.1. Introduction

This chapter outlines the management of drug-resistant TB in selected special conditions and situations. HIV infection is addressed separately in Chapter 8.

7.2. 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 fetus (1,2). Pregnant patients should be carefully evaluated, taking into consideration the gestational age and severity of drug-resistant TB. The risks and benefits of treatment should be carefully considered, with the primary goal of smear conversion to protect the health of the mother and child, both before and after birth. The following are some general principles to consider when treating pregnant women.

• Benefits and risks of treatment. Most pregnant patients should be started on treatment as soon as the diagnosis is made. However, since the majority of teratogenic effects occur in the first trimester, treatment may be delayed until the second trimester when the patient is very stable with minimum disease. Delaying treatment carries a risk as TB can advance quickly in a pregnant patient. A decision to start treatment in the first trimester or to postpone until after the first trimester should be agreed to by at least the patient and the doctor, after analysis of the risks and benefits. Other family members, especially the father-to-be, may need to be consulted depending on the relevant family, religious, cultural and social dynamics. The decision is based primarily on clinical judgment established on the basis of signs/symptoms and severity/aggressiveness of the disease.
• Treat with three or four second-line anti-TB drugs plus pyrazinamide. Treat with three or four oral second-line anti-TB drugs which are likely to be highly effective (see Chapter 5) against the infecting strain plus pyrazinamide. The regimen should be reinforced with an injectable agent and other drugs as needed immediately postpartum (3).
• Avoid injectable agents. Aminoglycosides can be particularly toxic to the developing fetal ear. Because there is little experience or evidence of the use of capreomycin in pregnancy, the risks/benefits of its use should be discussed with the mother. Capreomycin may also carry a risk of ototoxicity but is the injectable drug of choice if an injectable agent cannot be avoided because of an immediate life-threatening situation resulting from multidrug-resistant TB (MDR-TB). The option of using capreomycin thrice weekly from the start can be considered to decrease drug exposure to the fetus.
• Avoid ethionamide. Ethionamide can increase the risk of nausea and vomiting associated with pregnancy, and teratogenic effects have been observed in animal studies.
• Consider termination of pregnancy if the mother's life is compromised. When the condition of the mother is so poor that a pregnancy would carry a significant risk to her life, a medical abortion may be indicated. The decision is based primarily on clinical judgment of the severity of the disease, the effective treatment and care options available, and assessment of the risk/benefits with the mother. Whenever this decision is made, the TB programme, in coordination with other relevant health care providers, must facilitate access to safe abortion care in the context of the existing country legislation for abortion (For further information see Safe abortion: technical and policy guidance for health systems. 2nd edition. Geneva: World Health Organization; 2012. [PubMed: 23700650]).

Despite limited data on safety and long-term use of fluoroquinolones (cycloserine, para-aminosalicylic acid (PAS) and amoxicillin/clavulanate) in pregnancy, they are considered the drug of choice for MDR-TB treatment during pregnancy.

If the injectable agents, ethionamide/prothionamide, or other drugs were withheld because of the pregnancy, they can be added back postpartum to make a more complete regimen. There may not be a clear transition between the intensive phase and continuation phase, and the injectable agent can be given for three to six months postpartum even in the middle of treatment. Alternatively, if the patient is doing well and past the normal eight-month period for the injectable agent, it need not be added. Any addition of drugs should be mindful of the principle of never adding a single drug to a failing regimen.

The total treatment duration is the same as for MDR-TB treatment (see Chapter 5).

National TB control programmes should provide clear instructions on the management of MDR-TB in pregnancy and standardized regimens need adjustments in almost all cases.

The child should receive Bacillus Calmette–Guérin (BCG) vaccination at birth as per WHO policy.

7.3. Breastfeeding

In lactating mothers on treatment, most anti-TB drugs will be found in the breast milk in concentrations that would equal only a small fraction of the therapeutic dose used in an infant. However, any effects on infants of such exposure during the full course of drug-resistant TB treatment have not been established. Therefore, it is preferable to provide infant formula options as an alternative to breastfeeding. The infant formula should be available free of charge for the patient, especially in resource-poor settings, and the drug-resistant TB control programme must budget in advance for the estimated number of patients who may need this support. Clinicians and parents may agree to breastfeeding when the formula is not a feasible option. A woman who is breastfeeding and has active drug-resistant TB should receive a full course of anti-TB treatment. Timely and properly applied chemotherapy is the best way to prevent transmission of tubercle bacilli to the baby.

The mother and her baby should not be completely separated. However, if the mother is sputum smear positive, the care of the infant should be left to family members until she becomes sputum smear negative, if this is feasible. When the mother and infant are together, this common time should be spent in well-ventilated areas or outdoors. The mother should use a surgical mask (see Chapter 13) until she becomes sputum smear negative.

7.4. Contraception

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 fetus resulting from drug-resistant TB treatment during pregnancy.

There is no contraindication to the use of oral contraceptives with non rifamycin containing regimens. Patients who vomit directly after taking an oral contraceptive can be at risk of decreased absorption of the drug and therefore of decreased efficacy. These patients should be advised to take their contraceptives apart from times when they may experience vomiting caused by the anti-TB treatment medications. Patients who vomit at any time directly after, or within the first two hours after taking the contraceptive tablet, should use a barrier method of contraception until a full month of the contraceptive tablets being tolerated.

For patients with mono- and poly-resistant TB but who are susceptible to rifampicin, the use of rifampicin interacts with the contraceptive drugs resulting in decreased efficacy of protection against pregnancy. A woman on oral contraception while receiving rifampicin treatment may choose between two options following consultation with a physician: (i) the use of an oral contraceptive pill containing a higher dose of estrogen (50 µg); or (ii) the use of another form of contraception.

Condoms are a reasonable solution for patients who do not want to take additional pills and/or when protection against sexually transmitted diseases is also needed. Patients should be aware that condom use is not as effective as contraceptive pills, especially when not used correctly. Medroxyprogesterone intramuscular injections and other methods of contraception can also be considered (For further information on contraception see Medical eligibility criteria for contraceptive use. 4th edition. Geneva: World Health Organization; 2010. ).

7.5. Children

Children with drug-resistant TB generally have initial resistance transmitted from a primary case with drug-resistant TB. Evaluation of children who are contacts of drug-resistant TB patients is discussed in Chapter 13. When DST is available it should be used to guide therapy. Detection of drug-resistant TB in children is discussed in Chapter 4, Section 4.8.

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 (also see Chapter 13) (4).

There is limited reported experience on the use of second-line drugs for extended periods in children (5). The risks and benefits of each drug should be carefully considered while designing a regimen. Frank discussions with family members is critical, especially at the outset of therapy. Drug-resistant TB is life-threatening, and no anti-TB drugs are contraindicated in children (although new anti-TB drugs that have recently been introduced into the market have no safety data on children and should be considered for use in any extreme life threatening cases, with risk/benefits fully disclosed, and intense safety monitoring). Children who have received treatment for drug-resistant TB have generally tolerated the second-line drugs well (4–6).

Although fluoroquinolones have been shown to retard cartilage development in beagle puppies (7), similar effects in humans have not been demonstrated (8,9). The benefit of fluoroquinolones in treating drug-resistant TB in children have shown to outweigh any risk. Additionally, ethionamide, para-aminosalicylic acid (PAS) and cycloserine have been used effectively in children and are well tolerated.

In general, anti-TB drugs should be dosed according to body weight (See Annex 3 for weight-based dosing). Monthly monitoring of body weight is therefore especially important in paediatric cases, with adjustment of doses as children gain weight.

Expert opinion is that all drugs, including fluoroquinolones, should be dosed at the higher end of the recommended ranges whenever possible, except ethambutol. Ethambutol should be dosed at 15 mg/kg, and not at 25 mg/kg as sometimes used in adults with drug-resistant TB, as it is more difficult to monitor optic neuritis in children.

Dosing of anti-TB drugs in children is weight-based and presented in Annex 3.

In children, microbiological monitoring of the response to treatment is often difficult (for the same reasons it is difficult to obtain a microbiological diagnosis). This makes it difficult to diagnose treatment failure in children. Persistent abnormalities on chest radiographs do not necessarily signify a lack of improvement. In children, weight loss or, more commonly, failure to gain weight adequately in the presence of proper nutritional intake, is of particular concern and often one of the first (or only) signs of treatment failure. This is another key reason to monitor weight carefully in children.

Early diagnosis, strong social support, parental and family counselling and a close relationship with the health care providers may help to improve outcomes in children.

More information on the management of MDR-TB in children can be found in other sources (5, 10).

BOX 7.1

EXAMPLE OF REGIMEN DESIGN FOR PAEDIATRIC CASES. A mother on treatment for MDR-TB for nine months has been smear-negative and culture-negative for six months. She brings her child to the health centre for evaluation. The child is 11 months old and weighs (more...)

7.6. Diabetes mellitus

Diabetic patients with MDR-TB are at risk for poor treatment outcomes (11). In addition, the presence of diabetes mellitus may potentiate the adverse effects of anti-TB drugs, especially renal dysfunction and peripheral neuropathy. Diabetes must be managed closely throughout the treatment of drug-resistant TB. The health care provider should be in close communication with the physician who manages the patient's diabetes. Oral hypoglycaemic agents are not contraindicated during the treatment of drug-resistant TB but may require the patient to increase the dosage as the use of ethionamide or prothionamide may make it more difficult to control insulin levels. However, none of the anti-TB drugs are contraindicated. Creatinine and potassium levels should be monitored more frequently, often weekly for the first month and then at least monthly thereafter in view of the renal effects of aminoglycosides.

7.7. Renal insufficiency

Renal insufficiency caused by longstanding TB infection itself or previous use of aminoglycosides is not uncommon. Great care should be taken in the administration of second-line drugs in patients with renal insufficiency, and the dose and/or the interval between dosing should be adjusted according to Table 7.1. The dosing is based on the patient's creatinine clearance, which is an estimate of the glomerular filtration rate or renal function.

TABLE 7.1

Adjustment of anti-TB drugs in renal insufficiency.

An example of how to estimate a patient's creatinine clearance is provided in Box 7.2.

BOX 7.2

CALCULATING CREATININE CLEARANCE. The creatinine is measured in the serum. The constant in the formula is = 1.23 for men and 1.04 for women

7.8. Liver disorders

All first-line drugs – isoniazid, rifampicin and pyrazinamide – are associated with hepatotoxicity. Of the three, rifampicin is least likely to cause hepatocellular damage, although it is associated with cholestatic jaundice. Pyrazinamide is the most hepatotoxic of the three first-line drugs. Among the second-line drugs, ethionamide, prothionamide and PAS can also be hepatotoxic, although less so than any of the first-line drugs. Hepatitis occurs rarely with fluoroquinolones.

Patients with history of liver disease can receive the usual anti-TB drug regimens provided there is no clinical evidence of severe chronic liver disease, hepatitis virus carriage, recent history of acute hepatitis or excessive alcohol consumption. However, hepatotoxic reactions to anti-TB drugs may be more common in these patients and should be anticipated.

In general, patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised. If significant aggravation of liver inflammation occurs, the drugs responsible may have to be stopped.

Uncommonly, a patient with TB may have concurrent acute hepatitis that is unrelated to TB or anti-TB treatment; and here clinical judgment becomes necessary. In some cases, it is possible to defer anti-TB treatment until the acute hepatitis has been resolved. In other cases when it is necessary to treat drug-resistant TB during acute hepatitis, the combination of four non-hepatotoxic drugs is the safest option. Viral hepatitis should be treated if medically indicated and treatment can occur during drug-resistant TB treatment.

7.9. Seizure disorders

Some patients requiring treatment for drug-resistant TB will have a previous or current medical history of a seizure disorder. The first step in evaluating such patients is to determine whether the seizure disorder is under control and whether the patient is taking antiseizure medication. If the seizures are not under control, initiation or adjustment of antiseizure medication will be needed before the start of drug-resistant TB therapy. In addition, any other underlying conditions or causes of seizures should be corrected.

Cycloserine should be avoided in patients with active seizure disorders that are not well controlled with medication. However, in cases where cycloserine is a crucial component of the treatment regimen, it can be given and the antiseizure medication adjusted as needed to control the seizure disorder. The risks and benefits of using cycloserine should be discussed with the patient and the decision on whether to use cycloserine should be made together with the patient.

High dose isoniazid also carries a high risk of seizure and should be avoided in patients with active seizure disorders.

The prophylactic use of oral pyridoxine (vitamin B6) can be used in patients with seizure disorders to protect against the neurological adverse effects of isoniazid or cycloserine. The suggested prophylactic dose for at-risk patients on isoniazid is 10 to 25 mg/day and for patients on cycloserine is 25 mg of pyridoxine for every 250 mg of cycloserine daily. The optimal prophylactic dose of pyridoxine for children has not been established, nonetheless 1–2 mg/kg/day has been recommended in some reports (14) with a usual range of 10–50 mg/day for paediatric patients at risk for neurological sequella.

In mono- and poly-resistant cases, the use of isoniazid and rifampicin may interfere with many of the antiseizure medications. Drug 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 drugs. More information on the specific strategies and protocols to address a seizure when it is an adverse effect is provided in Chapter 9.

7.10. Psychiatric disorders

It is advisable for psychiatric patients to be evaluated by a health care worker with psychiatric training before the start of treatment for drug-resistant TB. The initial evaluation documents and any existing psychiatric condition establish a baseline for comparison if new psychiatric symptoms develop while the patient is on treatment. Any psychiatric illness identified at the start of or during treatment should be fully addressed. There is a high baseline incidence of depression and anxiety in patients with drug-resistant TB, often connected with the chronicity and socioeconomic stress factors related to the disease (13).

Treatment with psychiatric medication, individual counselling and/or group therapy may be necessary to manage the patient suffering from a psychiatric condition or an adverse psychiatric effect caused by medication. Group therapy has been very successful in providing a supportive environment for drug-resistant TB patients and may be helpful for patients with or without psychiatric conditions (15,16). (Adequate measures to prevent infection risk should be in place for the group therapy; see Chapter 14.)

The use of cycloserine is not absolutely contraindicated for the psychiatric patient. Adverse effects from cycloserine may be more prevalent in the psychiatric patient, but the benefits of using this drug may outweigh the potentially higher risk of adverse effects. Close monitoring is recommended if cycloserine is used in patients with psychiatric disorders.

All health care workers treating drug-resistant TB should work closely with a mental health specialist and have an organized system for psychiatric emergencies. Psychiatric emergencies include psychosis, suicidal ideation and any situation involving the patient being a danger to oneself or others. (Additional information on psychiatric adverse effects is provided in Chapter 11, Table 11.3.)

7.11. Substance dependence

Patients with substance dependence disorders should be offered treatment for their addiction, although active consumption is not a contraindication for anti-TB treatment. Complete abstinence from alcohol or other substances should be strongly encouraged but should not be pursued at the expense of compromising adherence to drug-resistant TB treatment. If the treatment is repeatedly interrupted because of the patient's dependence, therapy should be suspended until measures to ensure adherence have been established. Patient-centred directly observed therapy gives the patient contact with and support from health care providers, which often allows complete treatment even in patients with substance dependence.

Cycloserine will have a higher incidence of adverse effects (as in the psychiatric patient) in patients dependent on alcohol or other substances, including a higher incidence of seizures; the drug is contraindicated in severe central nervous system disease (12). However, if central nervous system disease is not severe and cycloserine is considered important to the regimen, it can be used in these patients under close observation for adverse effects and prompt treatment if any develop.

7.12. HIV-infected patients

Given the important interactions between HIV infection and drug-susceptible and drug-resistant TB, a full chapter (Chapter 8) is devoted to this subject.

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