Drug Resistant Tuberculosis

In its Global Tuberculosis Report for 2013, the World Health Organization (WHO) estimated a total of 8.6 million tuberculosis (TB) incident cases and 1.3 million deaths from the disease during the previous year. Most of the drug resistant TB (DRTB) cases were not even detected due to a variety of weaknesses of national TB programs. Only 28% of the 300,000 pulmonary TB patients expected to have MDR-TB in the world were reported; the WHO estimates that globally 3.6% of new TB cases and 20.2% of previously treated cases have MDR-TB, and of those, approximately 9.6% will have XDR-TB. In 2012 only 5% of the strains from new bacteriologicallyconfirmed TB cases and 9% of those previously treated for TB were cultured and tested for drug susceptibility. Outcome of treatment for patients with extensively drug resistance TB (XDR-TB) in a cohort from 26 countries was dismal with an overall cure rate of 20% and a 44% death rate.

The Mycobacteria genus, member of the Mycobacteriacea family and Actinomycetales order, are nonmotile, nonsporulating, acid-fast bacilli, 2-4 μ in length and 0.2-0.5 μ in width. Their waxy cell wall, rich in mycolic acid plays an important role in its resistance to many antibiotics. The Mycobacterium genus can be separated into two major groups. One group includes the Mycobacterium tuberculosis complex and the other includes non-tuberculous (also known as environmental) mycobacteria. The Mycobacterium tuberculosis complex includes M. tuberculosis (Mtb), M. canettii, M. africanum, M. microti, M. bovis, M.caprae and M. pinnipedii. Mycobacteria are facultative intracellular bacteria that multiply within phagocytic cells. In addition to the ability to acquire new resistance through the acquisition of chromosomal mutations, Mtb has a variety of intrinsic resistance mechanisms that allow active neutralization of antibiotic actions. Mtb intrinsic drug resistance can be divided into two categories: passive resistance and specialized resistance mechanisms; besides the cell wall barrier that helps slow down the penetration of antibiotics, Mtb operates multiple specialized resistance mechanisms that allow active detoxification of drugs once they reach the cytoplasmic space. Mtb, acquired drug resistance is caused by spontaneous random mutations in chromosomal genes, facilitating the selection of resistant strains during sub-optimal drug therapy. Clinically, drug resistance in Mtb represents the selection of random genetic mutations, not a change caused by exposure to the medication.

This chapter deals with the classification and mechanisms of drug resistance in tuberculosis, from mono-resistant to extensive drug resistance (XDR) strains. Resistance can be classified as “new cases” for patients never treated before (or treated for less than a month) with antituberculosis drugs and infected by an already drug resistant strain, and “previously treated cases”. There are multiple factors associated to drug resistance but they can be grouped in three basic categories: clinical, biological and social factors. Clinical factors include, among others, inadequate treatment regimens (wrong drugs, wrong doses), using drugs of unproven quality, drug shortages, and treatment with weak regimens by private physicians. Biological factors can include factors both the host and from the mycobacteria: being infected with an already resistant strain or host immunosuppression. Social factors include residing in areas with high rates of DR-TB, extreme poverty and lack of social support, illiteracy, poorly structured and supported TB control programs and lack of political compromise.

This chapter deals with the clinical diagnosis of drug resistant tuberculosis. Clinical detection of drug resistant tuberculosis requires a high index of suspicion by the clinician based in the information obtained from clinical records and the patient’s medical history. Underlying drug resistance must be considered in patients who have been previously treated for TB, especially if there is a history of inadequate treatment regimen, in patients who are not showing significant clinical improvement or lack of bacteriological conversion, in contacts of a known drug resistant case and in chronic cases with a history of multiple treatment regimens. Required information includes a detailed clinical history of past tuberculosis episodes, name, dose and time a particular drug was taken by the patient, adverse reactions while under treatment, previous image studies for comparison purposes and all previous bacteriological studies available from clinical or laboratory records. The initial evaluation must include a thorough physical examination and basic laboratory tests (hemogram, blood chemistry, viral panel for hepatitis and HIV), audiometry, new chest x-rays and obtaining appropriate samples for complete bacteriological studies.

This chapter covers the available techniques for the diagnosis of tuberculosis (TB) and drug resistant tuberculosis. Definite diagnosis of tuberculosis requires the isolation on culture or the identification by molecular biology methods of M. tuberculosis (Mtb). Resistance to antituberculosis drugs, once Mtb has been identified can be carried through conventional culture methods (phenotypic methods) or molecular biology (genotypic methods). Ideally, susceptibility to at least isoniazid and rifampin should be carried in every case, especially in regions with high burden of drug resistant TB. The World Health Organization (WHO) recommends that at least 20% of all new cases and 100% of previously treated patients should be tested for drug resistance. Although the isolation of Mtb in cultures is still considered as the gold standard, advances in the field of molecular biology allows for a much rapid identification of Mtb, with excellent sensitivity and specificity. Drug susceptibility testing by phenotypic methods can be carried out in both solid and liquid media, but this process is slow, especially with the time-honored proportions method; we now have available molecular biology methods with excellent reliability for isoniazid and rifampin with results in a matter of hours.

This chapter includes a comprehensive review of all drugs to treat tuberculosis. The WHO has classified these drugs in five groups, with drugs in Group 1 being the most effective, and less toxic and drugs in Group 5 being drugs with unproven efficacy or frequent side effects and/or toxicity. Each drug is discussed in detail, including its mechanisms of action, suggested doses and side and adverse effects, as well as the required clinical and laboratory monitoring for each drug. Recently added drugs bedaquiine and delamanid are also included in this review.

This chapter covers the strategies recommended to build an effective regimen for drug resistant tuberculosis. Treatment outcomes for multidrug resistant tuberculosis (MDR-TB) and beyond show a progressively lower cure rate as the resistance pattern became more complex. Basically all treatment recommendations for drug-resistant tuberculosis are based on expert opinion, with just a few available clinical trials. Rifampin is the most important drug in the first line regimen; if the strain is resistant is considered as pre-MDR TB and the patient must be treated for at least 18 months. There are two types of MDR-TB patients: patients who have never been treated for tuberculosis in the past and that were infected with an already resistant strain and patients previously treated for tuberculosis. The latter are much more frequent and more difficult to treat. To design a regimen for MDR-TB the following order is recommended: include ethambutol and/or pyrazinamide (WHO recommends the use of pyrazinamide regardless of the results of the drug susceptibility testing); however this drugs should not be counted as effective drugs. As a second step, a second line injectable (amikacin, kanamycin or capreomycin) will be included. Then add a fluoroquinolone (levofloxacin or moxifloxacin). Finally to complete the regimen add as many drugs from Group 4 (ethionamide, cycloserine and PAS) as needed. If necessary, include drugs from group 5. The first choice will be linezolid.

This chapter covers side and adverse effects associated to antituberculosis treatment. Gastrointestinal side effects are usually the first to appear after the start of treatment, with nausea and vomiting being the most common. Drug regimens for multidrug resistant tuberculosis include drugs that very frequently produce side effects and/or toxicity that sometimes require the definitive suspension of the drug. Almost all patients undergoing drug treatment for MDR-TB experience some type of side effects and/or toxicity that involve a modification of the drug regimen in up to 50% of the cases. A problem associated to second-line drugs is that several of these drugs share side effects and toxicities, which makes it difficult sometimes to determine which drug is the culprit. It is extremely important to avoid as much as possible interruptions in treatment due to side effects because this decreases the effectiveness of the regimen and increases the risk of amplifying drug resistance. Peripheral neuropathy is more common in patients that are already prone to it such as diabetics, alcoholics, pregnant and malnourished patients. All antituberculosis injectable drugs are toxic to the eight cranial nerve and can cause both vestibular (equilibrium) and cochlear (auditory) damage. Hepatic toxicity is the most common adverse effect of antituberculosis treatment and its severity can range from asymptomatic elevation of liver enzymes to fulminant liver insufficiency with encephalopathy and high mortality. Although any patient under treatment with antituberculosis drugs can develop hepatic toxicity, patients with previous liver damage are at higher risk of this complication.

This chapter describes the recommended routine for follow-up of drug resistant cases during treatment. Directly observed treatment is absolutely indispensable in patients with drug resistant tuberculosis to avoid the development of further resistance due to inadequate adherence. Monthly evaluation should include active search of side effects and adverse reactions through clinical and laboratory studies. Bacteriological follow-up will consist of monthly sputum smears and cultures, and after culture conversion, monthly sputum smears and bimonthly cultures.

There are three special situations in drug resistant tuberculosis that merit a more detail description: HIV co-infection, pregnancy and drug resistant TB in children. HIV co-infection: The risk of reactivation of latent tuberculosis infection is 50-100 times higher for subject living with HIV and up to 170 times higher for those with AIDS. Every patient diagnosed with TB must be tested for HIV infection and vice versa. The WHO recommends that ARV treatment in patients recently diagnosed as co-infected with HIV and tuberculosis should start within 8 weeks from the start on antituberculosis drugs.

Pregnancy: The best way to deal with MDR-TB during pregnancy is to prevent it. All females of child-bearing age being treated for MDR-TB should be encouraged to adopt an effective contraceptive method or even a combination of them. Most of the drugs used to treat MDR-TB are classified as unsafe during pregnancy or their safety is unknown.

Pediatric tuberculosis: Unlike the adults, most MDR-TB pediatric cases are the result of infection with an already resistant strain, frequently from contact with a household adult. Children with signs and symptoms compatible with active tuberculosis and risk factors for MDR-TB should be started on MDR-TB treatment even if the diagnosis has not been confirmed bacteriologically.

This chapter covers the management of actual MDR/XDR patients with a concise discussion of the importance of previous episodes of TB, the diagnostic algorithm and treatment regimen. Cases with adverse reactions to drugs are also discussed as well as patients with co-morbidities.