12. TREATMENT IN SPECIAL SITUATIONS

12.1. Introduction

Co-existing or co-morbid conditions often render MDR-TB treatment even more problematic. The following situations require special attention in MDR-TB patients considered for treatment:

12.2. Oral Contraception Use

Birth control is strongly recommended for all women receiving DR-TB treatment because of the potential negative consequences for both mother and foetus of frequent and/or severe ADRs.

There is no contraindication to taking oral contraceptives with second-line anti-TB drugs. However, since oral contraceptives may have decreased efficacy due to potential drug interactions, other methods such as the use of medroxy-progesterone or barrier methods (e.g., diaphragm or condom) should be considered for use throughout the period of treatment.

If the patient opts for oral contraception, she should be made aware of the fact vomiting results in decreased absorption of the pill, and possible decreased efficacy. She should be advised not to take the pill at the same time with anti-tuberculosis treatment and that if vomiting occurs within the first two hours of taking the pill, she should use a barrier method of contraception.

12.3. Pregnancy

Female patients of childbearing age should be tested for pregnancy during initial evaluation. Second-line drugs are not contra-indicated in pregnancy but some of the drugs have teratogenic effects and the risk of not treating DR-TB may have serious consequences to both mother and foetus.

Pregnant patients should be carefully evaluated, taking into consideration the gestational age and the severity of the disease. The risks and benefits of treatment should be carefully considered. Apply the following principles:

Discuss condition and treatment plan with the patient

A discussion of risks and benefits need to take place. The benefits of initiating treatment upon diagnosis outweigh the risks of not starting treatment. Any concerns a patient may have in starting therapy or in using medicines while pregnant need to be addressed. If the patient agrees to start therapy, use three or four oral drugs with demonstrated efficacy and then reinforce the regimen with an injectable agent after the second trimester of pregnancy or immediately postpartum.

Avoid injectable agents

Aminoglycosides should not be used in the treatment of pregnant patients as they are particularly toxic to the developing foetal ear. Capreomycin may carry the same risk of ototoxicity, but it is a drug of choice if an injectable agent cannot be avoided.

Use of ethionamide

Ethionamide should be given with caution because it may increase the risk of nausea and vomiting associated with pregnancy and teratogenic effects have been observed in animal studies.

Table XXV shows the safety profile of the second-line drugs in pregnancy.

12.4. Breastfeeding

Lactating Mothers

A woman who is breastfeeding and has active DR-TB should receive a full course of treatment, as timely and properly applied chemotherapy is the best way to prevent transmission of DR-TB to the baby.

Nursing Infants

In lactating mothers on treatment, most anti-tuberculosis drugs are found in the breast milk in minute concentrations compared to the therapeutic doses used in treating infants. However, the effects on infants of such exposure during the full course of treatment have not been established. Therefore, the use of infant formula is the only reasonable way to avoid any unknown adverse effects. However, the use of infant formula will depend on multiple factors, including the patient’s resources, safety of water supply, and bacteriological status of the mother. If the setting is not appropriate for infant formula, then breast-feeding may be considered.

The mother and baby should not be forced to stay apart. If the mother is smear-positive, she should consider using a mask when in close contact with the infant or leaving the care of the infant to family members until she is negative.

12.5. Children

Children with MDR- or XDR-TB generally have primary disease transmitted from a source adult case. Since children often have paucibacillary disease, they are seldom culture-positive. Nevertheless, every effort should be made to confirm MDR- or XDR-TB bacteriologically in children.

In culture-negative children who have clinical evidence of active TB and close contact with a person who has confirmed MDR- or XDR-TB, the child’s treatment should be guided by the DST results and history of TB drug exposure of the source case. There is limited reported experience on the use of the second-line medications for extended periods in children. Careful consideration of the risks and benefits of each drug should be made, but the child should be started on an effective regimen. Education and counselling of the patient and family is critical at the initiation of treatment. Given that MDR- and XDR-TB are life-threatening diseases, no drugs are absolutely contraindicated in children.

It should be noted that while fluoroquinolones have been shown to retard cartilage development in beagle puppies, experience in the treatment of children with cystic fibrosis and many MDR- TB cases over prolonged periods has failed to demonstrate similar effects in humans. It is now considered that the benefit of fluoroquinolones in treating MDR-TB in children outweighs the risks. Additionally, ethionamide, PAS, cycloserine and terizidone have been used effectively in children and are well tolerated.

In general, drug dosages should be based on the weight of the child. Monitoring monthly weight is therefore important in children with adjustment of the dosages as the child gains weight. All drugs, including the fluoroquinolones, should be dosed at the higher end of recommended ranges whenever possible.

In children who are not culture-positive at the start of treatment, failure is difficult to assess. Children, as is the case in adults, should get monthly cultures of either gastric aspirates or (induced) sputum until they become culture-negative. Thereafter two-monthly specimens for culture should be obtained until completion of treatment if they had severe lung disease (same as in adults). Persistent abnormalities on chest radiograph do not necessarily signify a lack of improvement. Failure to gain weight or weight loss (less common) is of particular concern, and often one of the first (or only) signs of treatment failure. Monitoring weight gain would therefore assist in the early detection of treatment failure.

Anecdotal evidence suggests that adolescents are at high risk for poor adherence and poor treatment outcomes, perhaps due to biologic reasons (more advanced disease due to late diagnosis) and social factors (more problems with adherence due to peer pressure, behaviour, drug use, pregnancy, denial poor acceptance of illness). Early diagnosis, strong social support, individual and family counselling, and a close relationship with the medical provider may help improve outcomes.

12.6. Diabetes

The prognosis of treatment in a diabetic patient with uncontrolled glucose levels is poor. Therefore the responsibility falls on the physician and patient to ensure proper diabetic care and control. In addition, diabetes may potentiate ADRs, especially renal failure and peripheral neuropathy. Oral hypoglycemic drugs can be safely given with second-line drugs, but ethionamide and prothionamide may make it more difficult to control insulin dependent diabetes.

In the management of the diabetic patient with DR-TB, the following is recommended:

• Medical follow-up: Diabetes must be managed closely throughout treatment.
• Patient education: The basics on the diet, treatment compliance, weight control, exercise, and foot care should be communicated to the patients, together with the symptoms of hypo- and hyper-glycaemia and what to do when they occur.
• Glucose monitoring

        - Goals for capillary blood testing: 80-120 mg/dl before meals; 100-140 mg/dl before bedtime; the range should be higher if patient has a history           of hypoglycaemia.

        - Patients may need a period of intensive glucose monitoring until these targets are attained. Once a patient is on a stable dose of insulin, blood             sugar may be monitored four times weekly to ensure that targets are being maintained.

        - If a patient is on oral anti-diabetic agents, sugar may be monitored twice weekly.

• Regular monitoring

        - Creatinine and potassium should be monitored weekly for the first month and then at least monthly thereafter.

        - If the creatinine rises, creatinine clearance should be checked and the second-line anti-TB drugs should be adjusted accordingly. Once the dose             is adjusted, the creatinine should be checked weekly until it has stabilised.

        - HbA1C every three months if treatment changes or patient is not meeting target; every six months if stable. Target: HbA1C<7.

        - Retinal examination annually.

• Screening and treatment for hypertension

        - Blood pressure measurements should be conducted monthly.

        - Hypertensive patients with diabetes should be started on an ACE-inhibitor.

• Prevention of diabetic nephropathy

        - Adjust the dose of the injectable drug based on the creatinine clearance.

        - Consider using an ACE inhibitor in patients with albuminuria >300 mg/24 hours

12.7. Renal Insufficiency

Renal insufficiency due to longstanding tuberculosis infection itself or previous use of aminoglycosides is not uncommon. Great care should be taken in the administration of second- line drugs in the patient with renal insufficiency, and the dose and/or the interval between dosing should be adjusted based on creatinine clearance.

The formula to calculate the creatinine clearance (CrCI) or the glomerular filtration rate (GFR) is as

follows:

Estimated Glomerular Filtration Rate (GFR): Men: (140 – age) x (ideal body weight in kg)

72 x (serum creatinine, mg/dl)

Women: (140 – age) x (ideal body weight in kg) x 0.85

72 x (serum creatinine, mg/dl)

Normal values for creatinine clearance are:

Men: 97 to 137ml/min

Women: 88 to 128ml/min

An example of adjusting the dose of a medication in renal insufficiency:

A male patient has a serum creatinine = 2.4, age = 59, ideal body weight = 53 kg. What should the dose of Kanamycin be?

Step 1: Calculate the Glomerular Filtration Rate (GFR)

= (140 – age) x (ideal body weight in kg)

72 x (serum creatinine, mg/dl)

= (140 – 59) x (53)

72 x 2.4

= 24.8 ml/min

Step 2: Refer to Table XXV and make the appropriate dose adjustment.

In this case the 24.8 ml/min falls below 30 ml/min. The dose of kanamycin given in Table XXV is 12-15 mg/kg. The dose to prescribe would be between 12 x 53 = 636 mg and 15 x 53 = 795 mg. It is reasonable to choose a dose between these two that is relatively easy to draw up from the vial. In this case, 750 mg three times a week is the logical choice.

Note:

• For this patient, every drug in the regimen should be examined and adjusted if necessary.

• The creatinine will need to be monitored periodically (often weekly or more frequently in the

patient with severe renal insufficiency) and doses readjusted for any change.

If this were a woman, the GFR = 24.8 x 0.85 = 21.1 ml/min.

Kanamycin dose: 12-15 mg/kg which works out to 636-795 mg, therefore 750 mg three times a week

(Adapted from:  World Health Organization. Guidelines for the Programmatic Management of Drug-resistant Tuberculosis (WHO/HTM/TB/2005.361), World Health

Organization: Geneva, Switzerland, 2006).

12.8. Liver Disorders

Pyrazinamide is the most hepatotoxic of the first-line anti-tuberculosis drugs. Of the second- line drugs, ethionamide, prothionamide and PAS are hepatotoxic, although less so than any of the first-line drugs. Hepatitis is quite rare with the fluoroquinolones, but may occur. In general, patients with chronic liver disease should not receive pyrazinamide. All second-line drugs can be used, however close monitoring of liver enzymes is advised, and if significant worsening of liver inflammation is seen, responsible drugs may need to be stopped.

Patients who are hepatitis virus carriers and those with a past history of acute hepatitis or excessive alcohol consumption can be started on second-line drugs provided there is no clinical evidence of chronic liver disease; however, hepatotoxic reactions may be more common in these patients and should be anticipated.

Uncommonly, a patient may have DR-TB and unrelated concurrent acute hepatitis. Clinical judgement is necessary in this instance - in some cases it will be possible to defer treatment until the acute hepatitis has resolved. In other cases, it will be necessary to start the treatment during the acute hepatitis phase in which case a combination of four non-hepatotoxic drugs will be the safest option.

12.9. Seizure Disorders

Some patients requiring DR-TB treatment may have past or present medical history of seizures. The first step is to determine whether the seizures are under control and if the patient is on any treatment. If the seizures are not under control, initiation or adjustment of treatment that the patient is taking will be needed prior to the start of DR-TB treatment. In addition, if other underlying conditions or causes of the seizures exist, they should be corrected.

Cycloserine and terizidone should be avoided in patients with uncontrolled seizures.  However, in cases where there is no option, cycloserine/ terizidone may be given and the treatment for seizures adjusted to control them. The risks and benefits of using cycloserine/ terizidone should be considered and discussed with the patient. When seizures present for the first time whilst patient is on DR-TB treatment, there is a good chance that they are related to one of the second- line drugs.

12.10. Substance Dependency

Patients who abuse alcohol and drugs should be started on a rehabilitation programme and if necessary adjuvant therapy given. Although complete abstinence from alcohol or drugs should be strongly encouraged, treatment is not contraindicated in people who abuse alcohol or drugs. If the treatment is repeatedly interrupted due to the patient’s addiction, then it should be suspended until successful rehabilitation or other measures to ensure adherence are established.

Cycloserine and terizidone will have a higher incidence of adverse reactions in the alcohol or drug- dependent patients, including seizures. However, if any of these drugs is considered important to the regimen, it should be used and the patient closely monitored for side effects, and adequately treated when necessary.

12.11. Psychiatric Disorders

It is prudent to have a psychiatrist conduct a psychiatric evaluation on all patients before the start of MDR-TB treatment, or at least on all patients with a history of psychiatric illness. The initial evaluation will document any pre-existing psychiatric condition and establish a baseline for comparison if new psychiatric symptoms develop while the patient is on MDR-TB treatment. Any identified psychiatric illness at the start or during treatment should be managed appropriately.

There is a high baseline incidence of depression and anxiety in patients with DR-TB, often related to the chronicity of the disease, confinement in hospital and other socioeconomic stressors. If a psychiatrist is not available, the treating physician should document any psychiatric conditions the patient may have at the initial evaluation.

Treatment of the psychiatric condition with the appropriate drugs, individual counselling, and/or group therapy may be necessary to manage the patients. Group therapy has been very successful in providing a supportive environment for DR-TB patients and may be helpful for patients with or without psychiatric conditions. The use of cycloserine or terizidone is not absolutely contraindicated for the psychiatric patient.  Adverse effects from these drugs may be more prevalent in the psychiatric patient, but the benefits often outweigh the potential higher risk of adverse reactions. Close monitoring is recommended if cycloserine or terizidone is used in patients with psychiatric disorders.

The hospital should have an organised system for management of psychiatric emergencies which include psychosis, suicidal ideation, and any situation involving the patient being a danger to him/ her or others. Referral mechanisms to deal with psychiatric emergencies (often to psychiatric hospitals with isolation facilities for infectious diseases) should be available twenty-four hours a day.