Slide 44 -
Dr biplob Nath Departmrnt of pulomonary medicine silchar medical college & hospital DRUG REISTANT TUBERCULOSIS (DRTB) Background
How drug resistance develops
DRUG RESISTANT TB DRUG RESISTANT TB A person with active TB disease has drug resistant TB if the TB bacteria that the person is infected with, will not respond to, and are therefore resistant to, at least one of the main TB drugs.
Anti-TB Drugs (H)Isoniazid
Cpreomycin First-Line Second-Line Types of DRTB Mono-resistance(MR): A TB patient whose biological specimen is resistant to one first line ATD only
poly-resistance(PDR): A TB patient whose biological specimen is resistant to more than one first-line anti TB drug other than both INH and rifampicin
Multi Drug Resistant( MDR-TB): A TB patient whose biological specimen is resistant to both INH and rifampicin with or without resistant to other first line drugs based on the results from a quality laboratory Types of DRTB Rifampicin resistant(RR): resistance to rifampicin detected using phenotypic or genotypic methods with or without resistance to other anti_TB drugs excluding INH.Patien,who have any rifampicin reisstance should also be managed as if they are an MDR TB case
Extensively Drug resistant(XDR):A MDR TB case whose biological specimen is additionaly resistant to a flouroquilonone and a secomd line injectable anti TB drugfrom a quality assured laboratory
The Universe of TB 4/25/2014 7 Drug-Resistant TB Drug-resistant TB is transmitted the same way as drug-susceptible TB
Drug resistance is divided into two types:
Primary resistance refers to cases initially
infected with resistant organisms
Acquired resistance develops during TB therapy Drug Resistant TB is Man-Made It is the result of interrupted, erratic, or inadequate TB therapy, and its spread is undermining efforts to control the global TB epidemic.
It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies.
4/25/2014 9 10 Spontaneous mutations
develop as bacilli
proliferate to >108 4/25/2014 11 INH RIF PZA INH Drug-resistant mutants in large bacterial population Multidrug therapy:
No bacteria resistant to all 3 drugs Monotherapy: INH-resistant bacteria proliferate 4/25/2014 12 INH RIF INH Spontaneous mutations
develop as bacilli
proliferate to >108 INH mono-resist.
RIF-resist. mutants proliferate MDR TB INH resistant bacteria multiply
to large numbers 4/25/2014 Drug-resistant TB can occur when drugs are misused or mismanaged Examples include:
When people do not complete the full course of treatment;
When health care providers prescribe the wrong treatment, the wrong dose, or wrong length of time for taking the drugs;
When the supply of drugs is not always available;
When the drugs are of poor quality. 4/25/2014 13 Drug-Resistant TB Is More Common In People Who: Do not take their TB drugs regularly
Do not take all of their TB drugs
Develop TB disease again, after being treated for TB disease in the past
Come from areas of the world where drug-resistant TB is common
Have spent time with someone known to have drug-resistant TB disease 4/25/2014 14 BURDEN of DRTB Drug-Resistance Among TB Cases About 3.6% of new tuberculosis (TB) patients in the world have multidrug-resistant strains.
Levels are much higher – about 20% - in those previously treated for TB.
The frequency of MDR-TB varies substantially between countries.
About 10% of MDR-TB cases are also resistant to the two most important second-line drug classes, or XDR-TB. 4/25/2014 16 Estimated Global MDR Cases; 23% detected 20%started treatment Global TB Report 2016 Estimated Indian MDR Cases; 36% diagnosed.34% started treatment Global TB Report 2016 The global TB situation Estimated incidence, 2012 Estimated number of deaths, 2012 940,000*
(0.8–1.1 million) 8.6 million
(8.3–9.0 million) 450,000 (300,000–600,000) All forms of TB Multidrug-resistant TB HIV-associated TB 1.1 million
(1.0–1.2 million) 320,000
(300,000–340,000) Source: WHO Global Tuberculosis Report 2013 * Excluding deaths attributed to HIV/TB 170,000 (100,000–240,000) Diagnosis of MDR-TB
Diagnosis based on –
bacteriological evidence;serve as the gold standard PRESUMPTIVE DR TB Who failed treatment with first line dugs
Pediatric TB non responders
Contacts of persons with drug-resistant TB
TB patient who are found positive on any follow up smear examination during treatment with first line drugs
Previously treated TB case
Tb patient with HIV co-infevtion
Drug-Susceptibility Test Limitations; Identification of MDR may take 4–8 weeks, and second-line drug sensitivity testing 6–12 weeks for results
2–4 weeks for initial culture to become positive
Additional 2–4+ weeks to get 1st-line susceptibilities
Additional 2–4+ weeks (sent to reference laboratory) to get 2nd-line susceptibilities
Molecular techniques –have been used for identification of resistance associated mutation.
WHO with stop TB partnership endorsed LPA in low resource countries in 2008.LPA can do rapid screening of patient with DR TB risk within 2days
The CB NAAT endorsed by WHO 2010 enables simultaneous detection of TB and rifampicin resistance (reliable proxy for MDRTB)in < 2 hrs as a surrogate marker for the diagnosis of MDR-TB
Treating drug-resistant and MDR-TB Individual Impact of MDR Average direct medical costs per case in the US: $27,752 [Burgos, et al. CID 2005; 40: 968-75]
Long treatment duration (18-24 months), often difficult and toxic
Long periods of isolation may be necessary
Depression is common
Disease may be incurable (chronic)
Higher rate of death Principles for Managing MDR TB Directly observed treatment (DOT, also known as fully supervised treatment) for MDR-TB patients is necessary throughout the entire period of treatment.
4/25/2014 28 29 Principles for Managing MDR TB A single drug should never be added to a failing regimen
When initiating or revising therapy, always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility
Sufficient numbers of oral drugs should be started at onset of therapy to make sure there is an adequate regimen once the injectable agent is discontinued
American Thoracic Society, Centers for Disease Control & Prevention, & Infectious Diseases Society of America, 2003 4/25/2014 Principles for Managing MDR TB Do not limit the regimen to 3 agents if other previously unused drugs that are likely to be active are available
Intermittent therapy should not be used in treating MDR TB
The use of drugs to which there is demonstrated in vitro resistance is not encouraged
American Thoracic Society, Centers for Disease Control & Prevention, & Infectious Diseases Society of America, 2003
4/25/2014 30 31 Principles for Managing MDR TB A good response does not justify continuation of an inadequate regimen
Serum therapeutic drug level monitoring should generally be utilized, especially for the bactericidal drugs and those most toxic
Resistance to RIF is associated in most cases with cross resistance to rifabutin and in all cases to rifapentine
American Thoracic Society, Centers for Disease Control & Prevention, & Infectious Diseases Society of America, 2003 4/25/2014
For treatment of MDRTB/RRTB standardised, empirical and individualised approaches have been laid down. Table 6. Medicines recommended for the treatment of RR-TB and MDR-TB WHO reclassified in 2016 in four groups
Group A. Fluoroquinolones: Levofloxacin Moxifloxacin Gatifloxacin
Group B. Second-line injectable agents
Amikacin ,Capreomycin Kanamycin Streptomycin
Group C. Other core second-line agents
Ethionamide / prothionamide Cycloserine terizidone Linezolid Clofazimine
Group D. Add-on agents (not part of the core MDR- TB regimen)
D1 Pyrazinamide Ethambutol High-dose isoniazid
D2 Bed aquiline Delamanid
D3 p-aminosalicylic acid Imipenem–Cilastatin
Ideally an appropriate treatment regimen should consist of pyrazinamide and at least four new drugs selected from four groups of anti Tb drugs in hierarchical order which the patient has not taken previously or to which bacilli is considered to be sensitive
DOTS PLUS/PMDRT: Modified Regime—if resistant to ofloxacin then substitute Lfx withMfx+PAS.If resistant to Km then substitute Km with Cm. BEDAQUILINE- Bedaquiline (also known as TMC207) is the first new anti-TB drug to be introduced into the market in almost 50 years. The drug belongs to the diarylquioline family and has a novel mechanism of action against M. tuberculosis . The drug is given daily for two weeks and then thrice weekly for a total of six months . It has a long half-life of almost five-and-a-half months.
Bedaquiline should be reserved for patients with MDR TB when effective regimen with Pyrazinamide and four second line drugs as recommended by WHO cannot otherwise be designed. It is also recommended for the treatment of MDRTB with documented resistance to any flouroquilones.It is decided by DR committee. Newer shorter and economical regimen recommended by WHO recently-2016
Uncomplicated MDR-TB-1200 pt-cure rate 82% and success rate 84.5%
Bangladesh regimen,PaMZ(9-12month) Common Adverse Effects Common Adverse Effects (2) Common Adverse Effects (3) PREVENTION Strategies to Prevent MDR Summary Treatment of MDR-TB is complex and costly. It is much easier to prevent than to treat
Expert consultation should be obtained when MDR-TB is suspected
Patients can be treated with a standardized,individulised and empirically
Ideally the regimen should be guided by drug-susceptibilities Summary Considerable attention must be paid to treatment supervision and support
A patient-centered approach to DOT is an important element of successful care
Adverse effects of second-line drugs are common and may be severe. Monitoring for these effects is essential!