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12.0 Management of relapse, treatment failure and drug resistance

12.1 Relapse

TB relapse is defined as a patient who has become (and remained) culture negative while receiving therapy but after completion of therapy becomes:

  1. Culture positive again or
  2. Has clinical or radiographic deterioration that is consistent with active tuberculosis.

Every effort should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance.

Most relapses occur within the first 6–12 months after completion of therapy.

Patients whose initial tuberculosis was drug susceptible and who were treated with rifamycin containing regimens using DOT, relapse with susceptible organisms in nearly all cases.  In patients who received self-administered therapy or a non-rifamycin regimen and who relapse, the risk of acquired drug resistance is substantial.

The selection of any empirical TB treatment for patients with relapse should be based on the prior treatment regimen and severity of disease.

  1. For patients with tuberculosis caused by drug susceptible organisms and who received DOT, initiation of the standard four-drug regimen is appropriate until the results of drug susceptibility tests are available. [AII]
  2. For patients who have life threatening forms of tuberculosis, at least three additional agents to which the organisms are likely to be susceptible should be included even if the criteria in 1) are fulfilled. [AIII]
  3. For patients with relapse who did not receive DOT, and/or who were not treated with a rifamycin based regimen, or who are known or presumed to have had irregular treatment, or poor adherence then it should be assumed that drug resistance is present and to treat with isoniazid, rifampicin, and pyrazinamide plus an additional two or three agents.  Such agents would include a fluoroquinolone, an injectable agent such as streptomycin or amikacin,,with or without additional oral drugs such as para-aminosalicylic acid (PAS), cycloserine, prothionamide and clarithromycin. [AIII]

12.2 Treatment failure

Treatment failure is the presence of continued or recurrently positive cultures during the course of antituberculosis therapy. After 3 months of multi-drug therapy for pulmonary tuberculosis caused by drug susceptible organisms, 90–95% of patients will have negative cultures and show clinical improvement.  All patients with positive cultures after 3 months of appropriate treatment must be evaluated carefully to identify the cause of the delayed conversion. Patients whose sputum cultures remain positive after 4 months of treatment should be classified treatment failures. 

There are many reasons for treatment failure in patients receiving appropriate regimens.  These include:

  1. Non-adherence
  2. Drug resistance
  3. Malabsorption of drugs
  4. Laboratory error and
  5. A few patients take a long time to respond as part of extreme biological variation.

If treatment failure occurs the case should be referred to a regional centre116. M. tuberculosis isolates should be sent to a reference laboratory for drug susceptibility testing to both first and second line agents.

One of the fundamental principles in managing patients with treatment failure is never to add a single drug to a failing regimen, as this leads to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs to which the patient has not been exposed and susceptibility thought likely should be added.

Empirical regimens usually include a fluoroquinolone and an injectable agent such as streptomycin and an oral agent such as para-aminosalicylic acid (PAS), cycloserine, prothionamide or clarithromycin. Once drug susceptibility test results are available, the regimen should be adjusted according to the results.

12.3 MDR-TB

TB resistant to at least isoniazid and rifampicin (multi-drug resistant [MDR]) are at high risk of further acquired drug resistance. All such patients whatever their HIV status should be referred to regional treatment centres.

Although patients with strains resistant to rifampicin alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert.

There are no definitive randomized or controlled studies to establish the best regimens for treating patients with various patterns of drug resistant tuberculosis.  Such treatment recommendations are based on expert opinion. Surgical resection in the management of patients with pulmonary MDR tuberculosis has had mixed results and its role has not been established in randomized studies.