Clinical Overview of Drug-Resistant Tuberculosis Disease

Primary drug resistance is caused by person-to-person transmission of drug-resistant TB bacteria.

Secondary drug resistance (also called acquired resistance) develops during TB treatment. Secondary resistance can develop when:

• A patient is not treated with the appropriate treatment regimen,
• A patient does not follow the prescribed treatment regimen (taking the drugs incorrectly or irregularly),
• A patient's body does not absorb the drugs, or
• Drug-drug interactions cause low serum levels

Risk factors for primary drug resistance include:

• Exposure to a person who
  • Has known drug-resistant TB disease
  • Received prior treatment for TB disease and experienced treatment failure or relapse and whose susceptibility test results are unknown
  • Was born in or frequently travels to an area with a high prevalence of drug-resistant TB disease
  • Continues to have positive smears and cultures after two months of treatment
• Travel to areas with high prevalence of drug-resistant TB disease

If patients do not take all of their medications, or do not take their medications as often as prescribed, the TB may develop secondary (acquired) drug resistance.

People who will be working or living in setting where people with drug-resistant TB disease are likely to be should consult infection control or occupational health experts.

• Ask about administrative and environmental procedures to prevent exposure to TB bacteria
• Consider using personal respiratory protective devices.

The most important way to prevent secondary (acquired) drug-resistant TB disease from developing is to ensure patients take all TB drugs exactly as prescribed by the health care provider. No doses should be missed, and treatment should not be stopped early.

Health care providers can help prevent secondary drug-resistant TB disease by:

• Quickly diagnosing cases,
• Following recommended treatment guidelines,
• Ordering drug susceptibility tests to confirm an effective treatment regimen is being given to the patient, and drug-resistant TB disease is not becoming more drug resistant,
• Monitoring patients' response to treatment, and
• Making sure patients complete their treatment.

There are different laboratory tests that can detect mutations of the bacterial genome that are associated with drug resistance in TB. Some of these assays can be performed directly on patient specimens prior to cultures turning positive; others require an isolate cultured from patient specimens. Some molecular tests can provide results within 24 to 48 hours.

When to use molecular detection of drug resistance

Send respiratory specimens for molecular detection of drug resistance testing immediately when patients have risk factors for drug-resistant TB disease and

• Acid-fast bacilli (AFB) results are smear positive and/or
• Nucleic acid amplification (NAA) test result is positive

Consider molecular detection of drug resistance for patients with the following characteristics:

• High risk of rifampin resistance (e.g., previously treated TB disease, contacts with someone with MDR TB, or being born in or frequently traveling to a country with a high rate of rifampin resistance)
• First-line drug susceptibility results are available and show resistance to rifampin
• Infectiousness poses a risk to vulnerable populations (e.g., daycare employee, nurse)
• Contraindications to essential first-line medications (e.g., rifampin allergy)
• Contamination, no growth in subculture, or other challenges encountered in the laboratory while performing growth-based drug susceptibility testing.

Limitations of molecular detection of drug resistance

• Although many high confidence mutations have been identified for both first- and second-line drugs, the clinical relevance of some mutations remains unknown.
• The absence of mutations cannot always completely rule out resistance.
• Limitations and knowledge base differ by drug, the particular assay, and the specific genetic regions evaluated.

Molecular results can be used in conjunction with results from conventional growth-based drug-susceptibility tests when both are available.

Growth-based drug susceptibility testing can be done using a liquid (broth-based) medium or solid (agar proportion) medium method. Organisms that grow in media containing a specific drug are considered resistant to that drug.

Liquid medium methods are faster (results within 7 to 14 days) than solid media methods (results can take up to 21 days) for determining susceptibility to first-line TB medications.

Second-line drug susceptibility testing should be performed only in reference laboratories and should generally be limited to specimens from patients who have the following characteristics:

• Prior TB disease treatment
• Difficulty with tolerating first-line treatment
• Contact with a patient with known anti-TB drug resistance
• Demonstrated resistance to first-line anti-TB drugs
• Positive cultures after more than three months of treatment

Patients with TB disease that is resistant to INH only (sometimes referred to as INH monoresistance) should be treated with a 6-month daily regimen of rifampin (RIF), ethambutol (EMB), pyrazinamide (PZA), and a later-generation fluoroquinolone. In certain situations, the duration of PZA can be shortened to two months. Expert consultation (from your state TB program or TB Center of Excellence for Training, Education, and Medical Consultation) should be sought for the treatment of patients with INH-resistant TB disease.

Patients with MDR TB disease must be referred immediately to an expert (from your state TB program or TB Center of Excellence for Training, Education, and Medical Consultation) in the management of drug-resistant TB disease.

A MDR TB treatment regimen should only include drugs to which the patient’s M. tuberculosis isolate is susceptible.

A patient's treatment regimen may depend on factors including:

• Patient preferences,
• Harms and benefits associated with the drugs,
• Ability to appropriately monitor for adverse effects,
• Drug-drug interactions,
• Comorbitities, and
• Drug availability.