MULTI DRUG RESISTANCE (MDR) TUBERCULOSIS : AN EMERGING GLOBAL PUBLIC HEALTH CRISIS…..... group members Mohan Giri Owais nabi Umesh bdr.bogatee Rahul Mishra Priyanka Shukla Ajay Vaishya Piyush Mishra

MDR TB is a manmade problem…..It is costly, deadly, debilitating, and the biggest threat to to our current TB control strategies.

“The greatest disaster that can happen to a patient with tuberculosis is that his organisms become resistant to two or more of the standard drugs… The development of drug resistance may be a tragedy not only for the patient himself but for others. F or he can infect other people with his drug-resistant organisms.” from C hemotherapy of pulmonary tuberculosis, by John Crofton (1912–2009), a pioneer in the use of combination drug therapy for the treatment of tuberculosis

What is MDR TB（什么是耐药结核菌） When we say that a strain of tubercle bacilli is drug resistant means that a patient yielding such organism would fail to respond to treatment with the drug concerned in normal dosage, i.e. a dosage that will cause response in patient infected with sensitive organisms. -Mitchison DA. What is drug resistance? Tubercle suppl 1969:50:44-47

Mono drug-resistant TB: disease caused by M Mono drug-resistant TB: disease caused by M. tuberculosis strains resistant to a single drug (most commonly isoniazid or streptomycin mono-resistant strains) Poly-resistant TB: disease caused by M. tuberculosis strains resistant to two or more drugs, except those which are simultaneously resistant to isoniazid and rifampicin (most commonly resistant to isoniazid and streptomycin)

Multidrug-resistant TB (MDR-TB): disease caused by M Multidrug-resistant TB (MDR-TB): disease caused by M. tuberculosis strains resistant to at least isoniazid and rifampicin Extensively drug-resistant TB (XDR-TB): disease caused by multidrug-resistant M.tuberculosis strains with additional resistance to at least one fluoroquinolone and one of the three injectable second line anti-TB drugs (kanamycin, amikacin and capreomycin)

TB Epidemiology Worldwide（结核病流行病学） 9.4 million new cases each year 440,000 MDR-TB cases 1.4 million HIV co-infected 1.8 million deaths each year 150,000 MDR-TB deaths 450,000 HIV co-infected One third of the world’s population (> 2 billion people) infected with TB One of the leading causes of death worldwide

Global TB Incidence Rates(世界各地结核发病率）

MDR - Resistance in TB Cases（耐多药结核情况）

XDR – Resistant In TB Cases(广泛耐多药结核情况）

Top 5 TB Burden Countries - 2011 （结核患病人数最多的5个国家） India 3.1 million cases China 1.4 million cases Indonesia 680,000 cases Bangladesh 620,000 cases Pakistan 620,000 cases Of estimated 1.37 million cases of HIV co-infected pt’s worldwide: 79% were in Africa 11% in Southeast Asia

Global Drug-Resistant TB: How Bad Is It ?（全球耐药结核情况） 2000 MDR TB estimates: 272,906 (1.1%) (estimate includes new cases only) 2004 MDR TB estimates: 424,203 (4.3%) (estimate includes new and previously treated cases) 2012 About 450 000 people developed MDR-TB in the world. More than half of these cases were in India, China and the Russian Federation. It is estimated that about 9.6% of MDR-TB cases had XDR-TB. WHO estimates that more than 2million people will develop MDR TB between 2011-2015.

MDR and XDR-TB: An Emerging Global Public H ealth Crisis （耐多药及广泛耐多药结核：全球公共卫生危机） Resistant to the 2 most effective 1st-line therapeutic drugs INH and rifampin. Tx requires use of more toxic, less effective, more expensive drugs Tx duration is thus significantly longer (increased from 6 months to 18-24 months post-culture conversion to neg.) Risk of relapse is higher No tx of proven efficacy for contacts Mortality rates among pt’s with XDR TB similar to TB pt’s in preantibiotic era. Some strains (esp. XDR-TB) may be virtually untreatable.

In 2013 funding for MDR-TB reached USD 1 billion in countries reporting data. Costs for second-line drugs alone amount to USD 0.4 billion in 2013. Countries with the greatest amount of funding available for MDR-TB in 2013 were India, Kazakhstan, the Russian Federation, South Africa, and Ukraine. The cost of just the drugs for treating the MDR-TB patient can be 50 to 200 times higher than that of drug susceptible TB patient. According to WHO, an estimated $8 billion will be required in 2015 for the diagnosis and treatment of TB, of which 2 billion are just for MDR-TB.

Types of Drug-resistant TB Cases （耐药结核病例类型） New Cases (Primary) Drug resistance in a patient who has never been treated for tuberculosis or received less than one month of therapy Previously Treated Cases (Secondary or Acquired) Drug resistance in a patient who has received at least one month of anti-TB therapy

MDR-TB in China（中国的耐多药结核） China reported its first ever nationwide drug resistance survey 5.7% of new TB cases are MDR-TB 25.6% of previously treated TB cases are MDR- TB 100,000 new MDR-TB cases annually in China.

Risk Factors for Drug Resistance（病菌耐药的危险因素） H igh numbers of organisms (e.g. cavitary pulmonary lesions, AIDS) Patient nonadherence to therapy (rationale for DOT, Rifamate/ Rifater)

Additional risk factors for drug resistance in developing countries（发展中国家病菌耐药的额外危险因素） > Irregular drug supply (shortages of drugs) Poor drug quality > Access to TB drugs without a prescription (eg., over – the - counter , black market) > Lack of a standardized drug regimen with the correct dosage > Poor program implementation > Lack of laboratory support (e.g., AF B cultures and drug susceptibility testing)

How does Mtb acquire drug resistance?（结核杆菌如何产生 耐药？）

Anti-TB Drugs classification（抗结核药分类） Group 1 - Isoniazid, Rifampin, Pyrazinamide,Ethambutol Group 2 - Amikacin, Kanamycin, Capreomycin Group 3 - F-Quinolones Group 4 - Ethionamide, Cycloserine. PAS,Prothionamide Group 5 - Clofazimine,Imipenem, Thioacetazone, Clavulin, Macrolides, Linezolid In December 2013, bedaquiline was approved by FOOD AND DRUGD (FDA) for the treatment of MDR.

Priorities for Tuberculosis Control &Prevention（结核病预防与治疗） Prompt identification and treatment of TB cases Prompt identification and treatment of contacts to infectious cases Targeted testing and treatment of latent TB infection (LTBI).

MDR TB Management（耐多药结核处理） Treatment should be individualized and based on drug susceptibility studies Patient to receive all the drugs to which the infecting M.TB is susceptible. When available drugs need to be given iv If there is past history of TB and drugs previously received are known, give at least 3 drugs (bactericidal) never used before If drug susceptibility still unknown give at least 3 bactericidal drugs, but no Rifampin or Isoniazid Treatment for 2 years following bacteriologic conversion DOT mandatory Well structured and strict follow-up Surgery in selected cases

conclusion Drug resistance is due to naturally occurring genetic mutations, but treatment errors select mutants which grow intio resistant strains. Amplification of resistance plays an important role in the creation of resistant strains,which then infect more people, completing the cycle.

Treatment errors are common in the treatment of drug resistant TB: Adding a single drug to a failing regimen(eg.prescribing category II for failures of category I) Failing to recognize and diagnose drug resistance in a timely manner(e.g. not recognizing the signs of treatment failure) Treatment with an inadequate regimen (e.g. prescribing standardized Ist line regimens for patients with undiagnosed MDR-TB

TB anywhere is TB everywhere THANKYOU