Richard Kohler, MD TB Consultant, Indiana State Department of Health Division of Infectious Diseases Indiana University School of Medicine

 Definitions  Epidemiology  Diagnosis  Treatment  Prevention

Drug-resistant TB: Resistance to isoniazid (INH) or rifampin (RIF) or pyrazinamide (PZA) or ethambutol (ETH) Multidrug-resistant (MDR) TB: Resistance to INH and RIF (and possibly others) Extensively drug-resistant (XDR)TB: Resistance to INH, RIF, fluoroquinolones, and amikacin/kanamycin and/or capreomycin

 Indiana  United States  World

cdc.gov/tb

*Updated as of May 20, Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

 Primary multi-drug-resistant TB is not often seen in Indiana and occurs in roughly 1/200 cases in the U.S.A.

 WHO estimates 440,000 MDR-TB cases emerge every year, with more than 110,000 deaths (2008).

Nationwide%Sub-National% Moldova19.4Murmansk Ob. (Russia)28.3 Estonia15.4Pskov Ob. (Russia)27.3 Kazakhstan14.2Arkhangelsk Ob. (Russia)23.8 Latvia12.1Baku City (Azerbaijan)22.3 Armenia9.4Ivanovo Ob. (Russia)20.0 Lithuania9.0Kaliningrad Ob. (Russia)19.3 Georgia6.8Belgorod Ob. (Russia)19.2 China5.7Dushanbe/Rudaki (Tajikistan)16.5 Jordan5.4Mary El Republic (Russia)16.1 Peru5.3Donetsk Ob. (Russia)16.0

 MDR-TB Survey Findings:  MDR-TB, on average, in 3.6% of all TB cases  Highest ever incidence in parts of northwest Russia (Murmansk, Archangelsk, Pskov) (24-28%)  50% of all cases in China and India  Downward trends Estonia and Latvia  Sustained declines in Hong Kong and USA, stable low levels in western Europe  Only 22 or 46 countries in Africa have data.  Estimated only 7% of patients identified and notified.

 MDR and XDR TB are not common in Indiana, the USA, western Europe, or Japan.  MDR TB accounts for a high percentage of TB in countries that were formerly a part of the USSR.  Half the world’s cases exist in China and India.  MDR TB incidence/prevalence is unknown for much of Africa.  XDR TB exists in at least 58 countries and accounts for about 5% of cases of MDR TB.

 Where does drug resistant TB come from?

 Number of mycobacteria in a pulmonary cavity: 1,000,000,000 (10 9 )  Frequency of mutants that are resistant to any single drug: ~ 1 in 1,000,000. (10 6 )  Number of bacilli in cavity already resistant to each drug: ~ 1,000.  Most (all?) patients with pulmonary TB have organisms in their bodies resistant to all single TB drugs at the outset of therapy.

 Mono-resistant organisms are there from the start.  Inadequate multi-drug therapy can select out the mono-resistant organisms.  Mono-resistant organisms, particularly if transmitted to a new human, can then grow up to achieve large numbers, with new mutants now resistant to both the original drug and with additional mutations to other drugs. If that person is inadequately treated …

 Suspect it based on epidemiologic grounds or on clinical course.  Ultimately requires laboratory confirmation

 History of prior treatment for TB  Especially if poor compliance (psychosocial barriers, addictions, side effects), no DOT.  Drug selection errors (including erroneously treating active TB with treatment for latent TB)  Contact with patients with MDR-TB.  Patients who fail to convert sputum cultures by 4 months

 Traditional drug susceptibility testing.  Liquid medium: takes 4-5 weeks  Solid medium: takes 6-8 weeks  Detection of gene mutations that confer drug resistance  Nucleic acid amplification tests (PCR: polymerase chain reaction + hybridation) ▪ Hours to run

 Because of the low prevalence of MDR TB in the USA and the standard use of RIPE therapy for the initiation phase, reliance on slow susceptibility testing methods is acceptable.  In a high MDR prevalence setting, standard susceptibility test methods are too slow.

 ~95% of rifampin-resistant TB strains carry mutations along an 81 base pair region of a particular TB gene (rpoB)  ~85% of INH-resistance is readily detected by genetic testing.  Because most rifampin-resistant isolates in many locales (including US) are also INH- resistant, rapid genetic testing for rifampin resistance should identify mostly MDR strains. “Report of Expert Consultations on Rapid Molecular Testing to Detect Drug-Resistant Tuberculosis in the United States”

Boehme CC et al.; NEJM 2010;363:

CATEGORYMTB/RIF (+)MTB/RIF (-) All culture positive2821/2955 (95.5%) (92.7 – 97.8%)* Culture (+)/Smear (+)2244/2262 (99.2%) (98.2 – 99.8%)* Culture (+)/Smear (-)577/693 (83.2%) (72.5 – 90.2%)* Culture (-)/Clinical (+)31/105 (29.3%) No TB (Culture/Smear/Clinical)2423/2457 (98.6%) (98.1 – 99.2%)* Rifampin Resistant209/211 (99.1%) Rifampin Susceptible506/506 (100%) MDR195/200 (97.5%) * Depending on whether test done once on unprocessed specimen or thrice (two processed, one unprocessed) specimens Boehme CC et al.; NEJM 2010;363:

 Very rapid combined diagnosis of TB and confirmation of rifampin susceptibilty is technologically possible.  Technology remains too expensive for most areas of the world in which it is needed.  Machine purchase cost.  Maintenance ▪ Otherwise less costly than standard drug susceptibility testing.

 Mono Resistant  MDR  XDR

 INH monoresistance  RPE for 6-9 months, or 4 months after sputum conversion.  95% success in 107 patients in 1987 trial (Hong Kong)  Rifampin monoresistance  IPS for 9 months.  IPE for at least 12 months. Some recommend 18 months after sputum conversion  Role of supplemental quinolone unclear Schluger, N.; UpToDate 2010 (last update 5/3/10)

 Fluoroquinolone + PZA + ethambutol + injectable agent + additional drug. Treat months.  Fluoroquinolone + (PZA or ethambutol) + injectable agent + two additional drugs. Treat 24 months.  Additional drugs: Pick from:  Ethionamide, cycloserine, PAS, linezolid  Clarithromycin, amoxicillin-clavulanate

 HIV patients excluded  Clinical response: 24/25 (96%)  Microbiologic response: 17/17  Time to culture conversion (69 days; range 2 to 705)  Side effects requiring medication stoppage: 4/23 (17%)  Median follow up: 91 weeks (41 – 225)  Relapses: 0 Telzak EE et al; NEJM 1995;333:

 Use at least three effective drugs. All patients (25) were treated with a fluoroquinolone.  Other drugs used: ethionamide (13), PZA (12), aminoglycoside (11), cycloserine (11), capreomycin (8), PAS (4), clofazimine (2).  Mean duration of oral drugs: 568 days.  Mean duration of injectable drugs: 252 days.  Surgery used for 3/25. Telzak EE et al; NEJM 1995;333:

GROUPCURES MDR400/603 (66%) XDR29/48 (60%) Mitnick et al., NEJM 2008;359:563 (Partners in Health)

 Cases mostly recognized as standard regimen failures.  Drug susceptibility testing at or near MDR/XDR regimen initiation.  Five effective drugs (Susceptible, or not used within 30 days, including FQ + injectable)*  18+ months rx (at least 8 for injectable)  Supervised daily therapy  Adverse event management algorithms

 If five effective drugs not possible:  Treat longer than 18 months (and longer than 8 months for injectables.  Add other drugs ▪ Previously susceptible but clinically failed drugs. ▪ Clarithromycin, amoxicillin-clavulanate, clofazimine, rifabutin.  Surgery

 Number of drugs: XDR  Frequency of drug use in regimens:  Cycloserine: 100%  Amoxicillin-clavulanate: 100%  Clofazimine: 98%  PAS: 96%  Moxifloxacin: 72%  Ethionamide: 66%  Capreomycin: 53%  Clarithromycin: 45%

 months of treatment.  Four drugs that are active.  If possible use aminoglycoside (at least 6 months) + fluoroquinolone (e.g., moxifloxacin) - ~85% cure rates.  Plus two other drugs  DOT

 TB drug in development.  Works very well in animal models.  Studied in randomized control comparison with placebo.  All patients had MDR-TB.  All patients treated with additional five drugs, typically ofloxacin + injectable + ethionamide + PZA + cycloserine or terizodone

Impact on Sputum Cultures and Time to Conversion Diacon AH et al.; NEJM 2009;360:

Impact on Quantity of Remaining Living Bacilli Diacon AH et al.; NEJM 2009;360:

 Optimal approach unknown.  Expert opinion:  Select two drugs to which the index case isolate is known. ▪ E.g., pyrazinamide + [ethambutol or fluoroquinolone]  Duration: 6-12 months Horsburgh, CR. UpToDate (last update 5/20/10

 Big problem worldwide. Not yet in USA. We remain vulnerable.  Technology for rapid detection of MDR-TB needed in high prevalence areas. Seems to be available. Not affordable most places that need it.  Treatment not as successful for MDR/XDR cases but still 60% or better. Expensive. Difficult.

Nathanson et al.; NEJM 2010;363:

 Highest rates ever recorded of MDR-TB.  Severely limited laboratory capacity has meant limited data availability in Africa (only 22 of 46 countries have data).  Insufficient efforts in many areas of the world to treat and control MDR-TB  Equipment to rapidly diagnose MDR-TB in 1 week instead of 3 months exists but most patients cannot access such services  Extraordinary measures are needed in Eastern Europe: rapid detection, effective care, access to drugs

 Recurrence after prior treatment, especially if DOT was not used.  Failure to convert sputum culture.  Known contact with MDR patient.