8. MANAGEMENT OF PATIENTS WITH XDR-TB

8.1. Introduction

By definition, two key classes of second-line anti-TB drugs are compromised in XDR-TB. Individualised treatment regimens are therefore essential and must be designed according to DST results and history of previous drug use.

A detailed clinical history can help suggest which drugs are likely to be ineffective; therefore you may need to obtain records from previous health care providers. The probability of acquired drug resistance increases with the duration of drug administration. In particular, evidence of clinical or bacteriological treatment failure during treatment is highly suggestive of drug resistance. If a patient has used a drug for more than a month with persistent positive smears or cultures, that drug should be considered as ‘probably resistant’, even if DST is reported as susceptible.

DST results should complement rather than invalidate other sources of data about the likely effectiveness of a specific drug. For example, if a history of prior anti-tuberculosis drug use suggests that a drug is likely to be ineffective due to resistance, this drug should not be relied on as one of the four core drugs in the regimen, even if the strain is susceptible in the laboratory. Alternatively, if the strain is resistant to a drug in the laboratory, but the patient has never taken it and resistance to it is extremely uncommon in the community, this may be a case of a laboratory error or a result of the limited specificity of DST of some second-line drugs.

Another important pitfall is that due to the delays in confirming the diagnosis, the patient may have already been started on a standard or empiric treatment by the time DST results become available from the laboratory. The possibility of further acquired resistance during this time must be considered. If there is a high probability of acquired resistance to a drug after the specimen for culture and DST was collected, this drug should not be counted as one of the four drugs in the core regimen.

XDR-TB patients have a much-reduced chance for cure and a very high risk of premature death; therefore, management of these cases should be prioritised using the same principles as those for MDR-TB. XDR-TB patients must be hospitalised, preferably at the MDR-TB hospitals.

8.2. Basic Principles of Treatment

There is currently no international consensus on the optimum duration of XDR-TB treatment; therefore, the same principles as for MDR-TB treatment apply, but clinical assessment of individual patients is required to decide on the termination of XDR-TB treatment.

The following principles must be applied when designing XDR-TB regimens:

• At least four drugs expected or known to be effective or patient has not been exposed to should be included.
• All patients should receive an injectable drug if susceptibility is documented or expected.
• Other medications are added based on estimated susceptibility, drug history, efficacy, side- effect profile. Drugs to be considered are: PAS, ethionamide and terizidone.
• A recent South African study undertaken in four provinces from South Africa, and confirmed in a recent meta-analysis, found that moxifloxacin improved outcomes in the face of ofloxacin resistance. The use of moxifloxacin is therefore recommended.
• The use of thioacetazone is not recommended because of the high risk of skin rashes that
• are more prevalent in HIV-positive individuals and can result in Stevens-Johnson syndrome and death. In addition, thioacetazone has cross-resistance with the thiomides (ethionamide and prothionamide) and is considered a relatively weak anti-TB agent. While thioacetazone is included among Group 5 drugs, it is the least used agent for the treatment of DR-TB and is not available in South Africa.
• Newer rifamycins (e.g. rifabutin, rifapentine) have almost complete cross-resistance with rifampicin.
• Group 5 drugs should be considered where in cases where adequate regimens are impossible to construct with available drugs from the other groups and you need to strengthen the regimen. The total dosage will depend on the degree of uncertainty and regimen will often contain five or more drugs. Clofazimine is the drug of choice among the group 5 drugs.

The rationale for individualised regimens in the treatment of patients with XDR-TB is that they have to receive drugs that the strain is susceptible to and exclude those that they are resistant to. This is simple, but in practice the DST results for second-line drugs is too complex and the tests are not as sensitive as we would like them to be. As previously discussed the margin between the minimum inhibitory concentration and the critical concentration is narrow hence it is easy to misinterpret the results. The only accurate second-line DST tests are for kanamycin or amikacin and the fluoroquinolones.

Based on the above, the recommended standardised regimen for XDR-TB is as follows

but may be modified based on DST results:

6 Cm-Mfx-Eto-Trd -Z-PAS-Clofazimine/ 18 Mfx-Eto-Trd or Cs-Z –PAS/Clofazimine

8.3. Standardised Regimen for Adult XDR-TB Treatment

The other reinforcing agents or agents with unclear efficacy (Group 5) may only be considered if the patient has a considerable resistance pattern which makes it difficult to construct an effective regimen using the first- and second-line drugs.

XDR-TB treatment for children is essentially like adults. Same drugs used in adults are to be administered to children with one exception: levofloxacin should be used in children younger than 8 years.