7. MANAGEMENT OF PATIENTS WITH MDR-TB

7.1. Introduction

Treatment of patients with MDR-TB involves second-line drugs. They are much more expensive, less effective and have more side effects than first-line TB drugs. The design of treatment regimens for patients with MDR-TB poses several challenges, complicated by a limited choice of second- line drugs, with greater toxicity and less efficacy.  As with drug-susceptible TB, the use of multiple drugs is imperative to prevent the development of additional resistance. Consideration of cross- resistance is also important when designing treatment regimens for MDR-TB.

Before the patient is referred to the MDR-TB hospital the following must be done at the diagnosing clinic:

• Ensure that all details regarding the treatment are communicated to the patient; this will enable the patient to take an informed decision on consent to treatment.
• Counsel and educate the patient and family member. This should include information on what MDR- or XDR-TB is, how one is infected, why one needs to be admitted to hospital, length of hospitalisation and the treatment, what is going to happen in hospital and what happens after discharge.
• Address any patient concerns.
• Verify patient’s physical and work address.
• Enquire about close contacts at home or work.
• Arrange for screening of and testing of all contacts.
• Provide a checklist of things the patient will need to take with to hospital.
• Make the necessary transport arrangements for the patient and a family member where necessary to the MDR-TB hospital.

7.2. Definitions of Terms used to Describe Treatment Strategies

Common treatment strategies include:

Standardised Treatment Regimen

Drug-Resistance Survey (DRS) data from representative patient population are used to base regimen design in the absence of individual DST. All patients in a defined group or category receive the same regimen. Not confirmed MDR-TB patients should be confirmed by DST whenever possible. In South Africa, we have a standardised regimen. All newly diagnosed MDR-TB patients receive a standardised regimen.

Standardised Treatment Regimen followed by Individualised Treatment Regimen

Patients on standardised regimen may be switched to an individualised regimen when other DST results become available. Each regimen is individually designed based on the patient’s previous history of anti-tuberculosis treatment and individual DST results.

Empiric Treatment followed by Individualised Treatment

Empirical treatment regimen is given to MDR-TB patients diagnosed on clinical grounds. DST of the presumed MDR-TB contact is considered as well as DRS data from the representative patient population. Commonly, an empirical regimen is adjusted when DST results on the individual patient become available

7.3 Standardised MDR-TB Regimen

The limited number of available second-line drugs imposes obvious limitations on the design of adequate MDR-TB treatment regimens. The most successful treatment regimens are those that include multiple drugs, which the patient had not previously received. A standardised MDR-TB regimen is recommended and this is based on the country-specific profiles of drug resistance and previous drug use of second-line drugs.

The design of the standardised regimen is based on first-line DST at diagnosis. DST of ethambutol and pyrazinamide do not have high reproducibility and reliability.

The standardised regimen consists of at least six months intensive phase treatment with five drugs:

Kanamycin/amikacin, moxifloxacin, ethionamide, terizidone and pyrazinamide taken at least six times per week during the injectable phase followed by a continuation phase treatment with four drugs moxifloxacin, ethionamide, terizidone and pyrazinamide) taken at least six times per week.

Levofloxacin will be used in patients who may not tolerate moxifloxacin.

Administration of the standardised regimen has been simplified across four weight bands to accommodate the formulations available in the country while complying with the international requirements for minimum, maximum and average dose per kg.

Ethambutol may be used as an additional item (sixth item in the standardised regimen) in areas with confirmed low prevalence to ethambutol resistance or in patients who have not received ethambutol for more than one month before DR-TB treatment.

The standardised treatment regimen described above applies only to MDR-TB patients previously treated with regime 1 or regime 2 of our TB programme, these are patients who have not been previously exposed to second-line anti-tuberculosis agents.

Patients who were previously exposed to second-line anti-tuberculosis drugs will require an individualised regimen based on two factors: firstly history of anti-TB drugs received and secondly DST results.

• In principle, any agent not previously received by the patient is likely to be susceptible and any agent used for more than a month before is likely to be resistant.
• Most MDR-TB patients who were exposed to first- and second-line anti-TB drugs and patients with resistance to an injectable or a fluoroquinolone will require drugs such as capreomycin, para-amino salicydic acid granules, moxifloxacin or levofloxacin, high dose INH and clofazimine among other drugs in their regimens.

7.4. Second-Line Drugs

The following first- and second-line drugs are available locally for the treatment of DR-TB.

Pyrazinamide and/or ethambutolare used in second-line treatment, given the limited number of second-line drugs available. Resistance to pyrazinamide is neither easy to acquire nor easy to prove by DST. Pyrazinamide has a bactericidal effect in an acid medium (bacilli inside macrophages), it should initially be used in combination with an aminoglycoside (active against multiplying bacilli outside macrophages) to obtain maximum effect.

Ethambutol is a valuable agent for preventing the emergence of resistance to other drugs. Ethambutol is no longer part of the standardised regimen due to lack of high reproducibility, reliability and high level resistance to MDR-TB strains.

Aminoglycocides: Kanamycin and amikacin are parenteral drugs that are structurally similar. Strains resistant to streptomycin are usually susceptible to kanamycin and amikacin. Resistance to kanamycin induces almost complete cross-resistance with amikacin and they should be considered as the same drug. Amikacin is as active as kanamycin and better tolerated, but much more expensive.

Polypeptide: Capreomycin is a cyclic polypeptide that differs structurally from kanamycin, amikacin and does not exhibit uniform cross-resistance with the aminoglycosides.

Thioamides: Ethionamide and prothionamide are two different presentations of the same active substance, with bacteriostatic activity against M. tuberculosis at therapeutic concentrations; they are bactericidal at higher concentrations. The pharmacokinetics of the two preparations is very similar, but prothionamide may be better tolerated. They induce complete cross-resistance and should therefore be regarded as the same drug.

Fluoroquinolones: Moxifloxacin is a preferred drug in the management of MDR- and XDR-TB. There is limited evidence that shows that strains resistant to ofloxacin may still be susceptible to moxifloxacin (i.e., there is not complete cross-resistance between these fluoroquinolones). Ofloxacin and levofloxacin will be used in patients younger than 8 years and adults who may not tolerate moxifloxacin.

Ciprofloxacin must not be used as an anti-tuberculosis agent in the management of DR-TB because of its weak efficacy compared with other fluoroquinolones.

Terizidone and Cycloserine: Terizidone is a combination of two molecules of cycloserine and they should therefore be regarded as the same drug. Terizidone and cycloserine are bacteriostatic at the recommended dosage. Both drugs have a high incidence of side effects, specifically related to central nervous system toxicity, and can precipitate focal or grand mal seizures with high serum concentrations. Psychotic disturbances and suicidal thoughts have been reported in patients with appropriate serum concentrations. Pyridoxine (150 mg) should be given together with terizidone or cycloserine to prevent neurological side effects. Both are valuable companion drugs in the prevention of resistance to other second-line drugs, since they do not have cross-resistance with other active TB drugs.

Para-aminosalicylic acid (PAS): PAS is a bacteriostatic agent, valuable in preventing resistance to other drugs. It is bulky, unpleasant to take and causes gastrointestinal disturbances; however, enteric-coated formulas are better tolerated.

7.5. Other Drugs

Oral medications sometimes referred to as “third-line drugs” that have been used for the treatment of MDR-TB include thioacetazone, clofazimine, amoxicillin-clavulanate, macrolides (clarithromycin and azithromycin) and other rifamycins (rifabutin and rifapentine), imipenem and linezolid.

• Thioacetazone is associated with the development of Stevens-Johnson syndrome in HIV- infected patients. In addition, it shows cross-resistance with ethionamide, prothionamide and isoniazid. It is therefore not recommended for use in this country.
• Clofazimine, an antileprosy drug, which has been known to have in vitro activity against M. tuberculosis with unproven clinical efficacy. But a recent study from Bangladesh has shown that clofazimine is an important MDR-TB drug. This is the drug of choice among the others in this group.
• Amoxycillin-clavulanate, clarithromycin and azithromycin have high minimal inhibitory concentrations (MIC) for most strains of M. tuberculosis relative to achievable serum concentrations, but clinical efficacy has again not been proven.
• Rifabutin exhibits cross-resistance with rifampicin in up to 80% of patients, while rifapentine has complete cross-resistance with rifampicin.
• Imipenem is a carbapenem. Carbapenems are very broad-spectrum antibiotics. A recent study showed activity against M. tuberculosis when given in combination with clavulanic acid. It is however an intravenous drug.
• Linezolid is an oxazolidinone antibacterial. It showed good activity against M. tuberculosis in vitro and has been used with success in MDR/XDR-TB patients in several case reports. Linezolid should be considered if cost permits.

Therefore, none of these drugs are recommended for routine MDR-TB treatment. They can be used when it is difficult to design treatment regimen with drugs in Groups 1-4.  XDR-TB patients will require drugs in Group 5 to be part of their treatment regimen.

7.6. Second-Line Drug Groups

Second-line drugs are grouped according to efficacy, experience of use, and drug class, the different groups are described in table below:

7.7. Standard Codes for Drugs and Regimens

Standard codes are used for MDR-TB treatment regimens. An MDR-TB regimen consists of two phases:

Phase 1: The intensive/injectable phase where a combination of injectable and oral drugs is used.

Phase 2: The continuation phase during which only oral drugs are used.

The number shown at the beginning stands for the phase duration in months, and is the minimum duration that phase should last. The number in subscript (i.e., ) is the number of drug doses per week. If there is no number in subscript, treatment is daily (a minimum of six times a week). The alternative drug(s) is indicated in brackets. The drugs in the higher groups are written first, followed by others in descending order.

Example of drug standard codes used to describe drug regimens

Regimen: 6Z-Km(Am)-Mfx-Eto-Trd/ 18Z-Mfx-Eto-Trd

The above regimen is 6 months intensive phase treatment with five drugs. The injectable drug is kanamycin, but there is an option for amikacin. The continuation phase is for at least 18 months with oral agents. Treatment is taken daily throughout the treatment period, which is twenty-four months in total.

7.8. Standardised Regimen for Adults (including children 8 years and older) MDR-TB Treatment

Intensive phase: at least 6 months, guided by TB Culture Conversion (treatment taken at least six times per week)

Continuation phase: at least 18 months after TB culture conversion (treatment taken at least six times per week)

7.9. Basic Principles of Treatment

• Use five drugs in intensive or injectable phase and four drugs in continuation phase as per standard regimen. Drugs are administered at least six days per week.
• Of the five drugs used in intensive phase: Give at least four drugs with either certain, or almost certain effectiveness. Drugs previously used for a month or more may not be included among drugs with certain effectiveness.
• Each dose should be given under strict supervision throughout the treatment period.
• Sputum specimens are taken every month for TB smear microscopy and culture
• The duration of the injectable phase is guided by TB culture conversion.
• TB culture conversion occurs when a patient obtains two consecutive negative TB culture results on sputum taken 30 days apart; the culture conversion date is the collection date of the first specimen that turned TB culture negative.
• The injectable phase is determined by adding four months to the culture conversion date if
• the total duration is less than six months then the patient should receive a total of six months injection because the injectable phase must be at least six months.
• Capreomycin should be considered for use in patients with renal insufficiency, hearing loss, or peripheral neuropathy.
• Pyrazinamide and fluoroquinolones should preferably be given once a day as the high peaks attained in once daily dosing may be more efficacious. Once daily dosing is also recommended for other second-line drugs; however, ethionamide, cycloserine, terizidone and para-amino salicylic acid are often given in divided doses during the day to facilitate patient tolerance.
• Pyrazinamide may be used for the entire treatment period if the strain is thought to be susceptible to the drug.  Many MDR-TB patients have chronically  inflamed  lungs,  which theoretically produce an acidic environment in which pyrazinamide is active.
• If patient’s organism is resistant to kanamycin or amikacin but susceptible to ofloxacin: add capreomycin, clofazimine and PAS.
• It is further recommended that culture results, chest X-ray findings and the patient’s clinical status be taken into account in deciding whether or not to continue with the injectable drug for a longer period, particularly in patients for whom the susceptibility pattern is unknown, the effectiveness of the drug is questionable and those with extensive or bilateral pulmonary disease.
• Intermittent therapy with the injectable drug - three times a week after an initial period of two to three months of daily therapy can be considered in patients who have been on the injectable for a prolonged period of time. Beyond six months and when toxicity becomes a greater risk to the patient.

7.10. Duration of Treatment

The recommended duration of treatment is guided by culture conversion and is determined by adding 18 months to the culture conversion date. Extension for up to 24 months may be indicated in chronic cases with extensive pulmonary damage.

7.11. Extrapulmonary MDR-TB Treatment

Extrapulmonary MDR-TB is treated using the same strategies and treatment duration as pulmonary MDR-TB. If the patient has symptoms suggestive of central nervous system involvement and is infected with MDR-TB, the drugs used should have adequate penetration into the central nervous system. Pyrazinamide, ethionamide, cycloserine and terizidone have good penetration; kanamycin, amikacin and capreomycin only show penetration in the presence of meningeal inflammation; and PAS has poor or no penetration.

7.12. Terminal Illnesses

Terminally ill patients, where circumstances permit, may be discharged for care by family members, with the consent of the family. Conditions, under which the patient may be discharged, include:

• The patient will remain within the confines of his/her home.
• There are no young children or persons with known HIV infection in the household who will be placed at risk.
• All necessary measures would be taken to prevent spread of infection.
• Access to the patient by other people will be restricted or controlled.