1 .3 Determine whether there are other special circumstances affected by the regimen

GROUPING DRUGS (ABBREVIATION) Principles

Group 5 –

Agents with unclear efficacy

(not recommended by WHO for routine use in MDR-TB patients) Clofazimine (Cfz)*; Amoxicillin/ Clavulanate (Amx/ Clv); Clarithromycin (Clr); Linezolid* (Lzd) These are not recommended by WHO for routine use in MDR-TB treatment because their contribution to the efficacy of multidrug regimens is unclear. However, they can be used in cases where adequate regimens are impossible to form with the drugs from Groups 1–4.

* Not being used in the PMDT country program **Used in patients who are susceptible to H and/or R (DR-TB only)

Vitamin B6 (pyridoxine) should be given to all patients receiving cycloserine to prevent adverse neurological side effects at 50 mg for every 250 mg of cycloserine.

There are a number of conditions that should be investigated by the health care worker to ensure that additional measures should be taken before treatment. These conditions or circumstances should have been noted in the MDR-TB Screening Form. Be sure to check the form as you decide how to design each patient’s proposed regimen. Each patient’s situation should be handled differently and must be taken into account before treatment begins to ensure the most effective management. Below is a list of some common conditions of patients and some general guidelines.

1. HIV-infection – HIV prevalence in the Philippines is 0.01 -0.03 per cent in the general population and < 1% in the most at risk populations. Among HIV patients in general, however, TB is the most prevalent co-infection (50%) and occurs as TB disease in 40%. TB/HIV particularly MDR-TB/HIV coinfected patients present a challenge for treatment strategies. The patient with DR-TB disease and HIV will require intensive medical care to decrease the high level of mortality. Coordination between the team treating DR-TB and the HIV control program for training, care and treatment is an essential component. MDR-TB/HIV coinfection rate has the potential to increase rapidly in any country where infection control and TB/HIV management activities are not fully implemented.

2. Substance dependence - Patients with substance dependence disorders should be offered treatment for their addiction. Complete abstinence from alcohol or other substances should be strongly encouraged, although active consumption is not a contraindication for anti-TB treatment. If the treatment is repeatedly interrupted because of the patient’s addiction, therapy should be suspended until successful addiction treatment or measures to ensure adherence have been established.

3. Psychiatric disorder - Adverse effects from cycloserine may be more prevalent in the psychiatric patient, but the benefits of using this drug may outweigh the potential higher risk of adverse effects. Hence, the use of cycloserine is not absolutely contraindicated. However, close monitoring is recommended if this is used in patients with psychiatric disorders.

4. Liver disorder - Patients with a history of liver disease can receive the usual DR-TB chemotherapy regimens provided there is no clinical evidence of chronic active liver disease, hepatitis virus carriage, acute viral hepatitis, or excessive alcohol consumption. Otherwise, pyrazinamide should be avoided and other drugs known to cause hepatotoxicity should be used with caution, such as isoniazid and rifampicin which may be used in DR-TB, ethionamide, prothionamide and PAS. Close monitoring of liver enzymes is necessary.

5. Seizure disorder - 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 with the anti-seizure medication adjusted as needed to control the seizures. Active 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 antiTB drugs which should be suspended either temporarily or permanently depending on the level of control of the seizure.

6. Renal insufficiency - These patients require very close supervision and dose modification of certain drugs. Monitor the creatinine and BUN level at least once every 3 months while on the injectable until noted to be stable. Refer to the table on dosage adjustment for renal insufficiency in Annex A Recommended dosages of anti-TB drugs.

7. Diabetes mellitus – These patients require very close supervision and under co-management with a specialist. Fasting blood sugar, creatinine and potassium levels should be monitored monthly until stable then quarterly thereafter. Oral hypoglycemics may require patients to increase the dosage. The use of ethionamide/prothionamide may make it more difficult to control insulin levels.

8. Children –Refer to the recommended pediatric doses for SLDs in Annex A Recommended dosages of anti-TB drugs. Although children are presumed to have the same DST pattern as the index case, this may not necessarily happen and every effort must be done to confirm drug-resistance and avoid unnecessary exposure to toxic drugs. However, many times a pediatric patient will have a negative culture; and regimens can only be designed based on the DST data of the contact. Although no long-term studies have proven the safety of drugs given for prolonged periods in children, MDR-TB is life-threatening and the risks and benefits of treatment should be discussed with the family. There is no anti-TB drug that is absolutely contraindicated in children including the fluoroquinolones whose benefit outweighs the risk.

9. Breastfeeding mothers – Babies of MDR-TB mothers may be placed on formula due to the secretion of drugs in the breast milk particularly since there is limited experience in prolonged exposure of infants to MDR-TB drugs. The option on whether to breastfeed or not is best discussed with the mother. Should she decide to breastfeed, she should wear an N95 mask while breastfeeding. While she is smear-positive, it is best for other family members to take care of the baby to prevent transmission.

10. Use of oral contraception – Patients generally have no problems unless there is frequent vomiting caused by anti-TB drugs which can lead to poor absorption of the oral contraceptive. Contraceptive drugs can also interact with rifampicin used in rifampicin-susceptible DR-TB cases leading to decreased contraceptive efficiency. In this case, other forms of contraception should be advised.

11. Pregnancy – Treatment for MDR-TB is not contraindicated but injectables are not allowed. Ethionamide should also be avoided because of teratogenic effects noted in animal studies. Since there have been limited studies on the effects of SLDs on the pregnant patient, particularly to the fetus, treatment may be postponed till the second trimester since most teratogenic effects happen on the first trimester. However, if the condition of the mother is severe or life-threatening, treatment using 3 to 4 oral drugs deemed effective should be started sooner but excluding injectable agents and ethionamide. Immediately post-partum, as necessary, therapy should be reinforced with an injectable or other drugs.