DrugResistant Tuberculosis

1
Drug-Resistant Tuberculosis

• Pranee Sitaposa,M.D.
• ID Fellow1.
• Queen Sirikit National Institute of Child Health.
• 23/07/2007.

2
Genus Mycobacterium

• 3 groups
• M.tuberculosis complex M.tuberculosis
  M.bovis
  M.africanum
• Nontuberculous mycobacteria (NTM)
• M.leprae

3
DrugResistant M. tuberculosis

• Epidemiology
• Primary drug resistance
• initial drug resistance
• Secondary drug resistance
• acquire drug resistance
• Treatment of
  tuberculosis guidelines for national programmes,
  3rd ed. Geneva,
  World Health
  Organization, 2003(WHO/CDS/TB/2003.313).

4
DrugResistant M. tuberculosis

• Clinician
• Drug resistance
• Monodrug resistance
• Polydrug or Combined resistance (not INH and RIF)
• Multidrug resistance (MDR) (INH and RIF
  resistance)
• Extensively Multidrug resistance (XDR)
• MDR-TB and
• Resist to at least 3 classes of second line drugs
• 
  Treatment of tuberculosis guidelines for
  national programmes, 3rd ed. Geneva,
  
  World Health Organization, 2003(WHO/CDS/TB/2003.31
  3).

5
DrugResistant M. tuberculosis

• WHO
• Drug resistance among new cases
• Drug resistance among previously treated cases
• 
  Treatment of tuberculosis guidelines for
  national programmes, 3rd ed. Geneva,
  World
  Health Organization, 2003(WHO/CDS/TB/2003.313).

6
Gene location associated
Drug-Resistant M.tuberculosis

• Drug Gene
• Isoniazid Kat G, Inh A, Kas A
• Rifampicin rpo B
• Ethambutol emb B
• Streptomycin rps L
• Pyrazinamide pnc A
• Fluoroquinolones gyr A
• Dubaniewicz A, et al. Molecular
  sub-type of the HLA-DR antigens in pulmonary
  tuberculosis. Int J Infect Dis20004129-33.

7
??????????????????????????????????????????????

• ?????????
• ????????????????????? ?? ?.?. ????????????
  INH SM RMP EMB MDR
• ????????? 2530 650 10.2
  8.6 1.7 0.9 0.15
• ???.5 ?????????? 2535 1,697 15.2
  6.9 5.5 1.8 0.8
• ????????? 2539 316 -
  - - - 2.8
• ??.????????? 2541 347 4.9
  5.8 8.9 2.0 2.3
• ???.3 ?????? 2541 597
  12.4 11.4 4.0 2.0 2.7
• ???.6 ??????? 2541 211 7.1
  5.2 0.9 0.5 1.9
• ??.???????? 2541 487
  12.4 11.8 14.0 12.4 7.9
• ??.??????? 2543 -
  - 18.0 9.0 5.0 6.3
• ??.??????? 2545 -
  - 17.0 12.0 6.0 10.2

8
Drug resistance surveillance in Thailand
(Primary resistance)

• 1997-1998 2002
• Number 1015
  1505
• Any resistance () - 15.0
• Mono resistance ()
• Isoniazid 6.2 5.3
• Rifampicin 2.0 0.3
• Ethambutol 3.0 0.1
• Streptomycin 5.6 4.8
• MDR-TB 2.0 1.0
• 
  ?????????
  ????????????????????????????

9
Drug resistance surveillance in Thailand
(Secondary resistance)

• 1997-1998 2002
• Number -
  170
• Any resistance () - 39.4
• Mono resistance ()
• Isoniazid - 4.1
• Rifampicin - 1.8
• Ethambutol - 0.6
• Streptomycin - 5.3
• MDR-TB - 20.6
• 
  ?????????
  ????????????????????????????

10
Epidemiology information of MDR-TB

• Incidence varies according to reported sites.
• High incidence is located in some geographic area
  and not evenly distribution.
• Data of sensitivity can not be directly compared
  because of different methodology.
• No seperation of previously treated and untreated
  cases.
• High incidence is associated with poor compliance
  previous treatment history, HIV infection,
  contact with drug resistant case, inborn country.

11
Multidrug-Resistant Tuberculosis

• WHO and IUATLD
• The median prevalence of MDR-TB 1.1 in newly
  diagnosed patients.
• The median prevalence of MDR-TB 7.0 in patients
  who have previously received anti-TB treatment
• MDR-TB Threatening to destabilize global
  tuberculosis control
  (Chest2006130261-272)

12
XDR-TB a global threat

• Between 2000-2004, of 17,690 TB isolates in the
  world were MDR-TB 20 and XDR-TB 2
  (Lancet2006368964)
• Between 2003-2005, of 1,284 TB isolates in Iran
  were MDR-TB 9.3 and XDR-TB 1
  (CID2006316216)

13
Risk factors for infection with
Drug-Resistant Tuberculosis (1)

• Expose to person who has known drug-resistant
  tuberculosis
• Exposure to a person with active tuberculosis who
  has prior treatment for tuberculosis (treatment
  failure or relapse) and whose susceptibility test
  results are not known
• Expose to persons with active tuberculosis from
  areas in which there is a high prevalence of drug
  resistance
• 
  From Centers for Disease Control and Prevention.
  Treatment of tuberculosis. American Thoracic
  Society of America. MMWR Morb Mortal Wkly
  Rep.200352(RR-11)1-88.

14
Risk factors for infection with
Drug-Resistant Tuberculosis (2)

• Expose to persons who continue to have positive
  sputum smears after 2 months of combination
  chemotherapy
• Travel in an area of high prevalence of drug
  resistance
• From Centers for Disease Control and Prevention.
  Treatment of tuberculosis. American Thoracic
  Society of America. MMWR Morb Mortal Wkly
  Rep.200352(RR-11)1-88.

15
Sputum culture for TB and Susceptibility testing

• High-risk patient who has drug resistance TB
• Relapse case
• History of irregular treatment
• Treatment failure case
• Expose to person who has known Drug-Resistant
• Tuberculosis
• HIV co-infection
• Addictions
• Born in high prevalence country
• (Current
  Practice in Common Infectious Diseases2001.
  
  ?????????????????????????????2033
  9-353.)

16
Diagnosis DR-TB

• Monodrug or polydrug resistance
  but not MDR-TB
• Relaspe case
• History of irregular treatment
• Treatment failure case in standard drug 12 months

17
Standard Short course regimen of Anti-TB drugs
(WHO)

• Category I 2HRZE/4HR
• New case of pulmonary TB with sputum AFB
• Category II 2HRZES/HRZE/5HRE
• New case of pulmonary TB with sputum AFB
  Suspected Drug-Resistant TB
• Category III 2HRZ/4HR
• New case of pulmonary TB without sputum
  AFB , no extensive lesion
• Category IV Chronic case with MDR-TB
• 
  
  
• (
  Management of tuberculosis modified WHO modules
  of managing tuberculosis at district level
  1991)

18
Treatment DR-TB

• Category II 2HRZES/HRZE/5HRE
• Streptomycin resistance case 3HRZE/5HR
• Ethambutol resistance case 2HRZS/HRZ/5HR
• Pyrazinamide resistance case 2HRES/6HRE
• Isiniazid resistance case
  2RZES/RZE/5RE
• Rifampicin resistance case 2HSZE/HZE/5HE
• (Current
  Practice in Common Infectious Diseases2001.
  
  ?????????????????????????????20339-353.)

19
Diagnosis MDR-TB

• Isoniazid and Rifampicin resistance case
• Short course treatment failure sputum for AFB
  after 5 months of treatment
• fall and rise sputum for AFB
• Long course treatment failure sputum for AFB
  after complete 12 months
• Long duration of treatmont 18 24 months
• Susceptibility testing MDR-TB

20
Recommendations for MDR-TB Chemotherapy ATS
(2003)

• Do not limit the regimen to 3 agents
• Regimens employing 4 to 6 medications appear to
  be associated with better results
• Total treatment duration 18 24 months
  (24 months when EMB or PZA resistant)

21
Recommendations for MDR-TB Chemotherapy BTS
(1998)

• Treatment should start with 5 or more drugs to
  which the organism is susceptible and continue
  until sputum culture conversion.
• Drug treatment then has to be continued with
  at least 3 drugs for a minimum of nine
  further months and perhaps up to or beyond 24
  months.

22
Recommendations for MDR-TB Chemotherapy WHO
(2006)

• Regimen should consist of at least 4 drugs
  certain or highly to be effective.
• Treatment should last for at least 18 months
  after culture conversion (extension to 24 months
  in chronic cases with extensive pulmonary
  damage).

23
National MDR-TB Treatment Guideline 2005 (1)
(THAI)

• Failure of Category I, likely to be MDR-TB
• Recommended regimen
• 2 months Kanamycin (Streptomycin), Ofloxacin,
  PAS, Ethambutol and Pyrazinamide
• 16 months Ofloxacin, PAS, Ethambutol and
  Pyrazinamide
• 
  (??????????????? ???????
  2550 ?????????????????????????????)

24
National MDR-TB Treatment Guideline 2005 (2)
(THAI)

• Failure of Category II, likely to be MDR-TB plus
  EMB resistance
• Recommended regimen
• 2 months Kanamycin (Streptomycin), Ofloxacin,
  PAS, Pyrazinamide, Ethionamide
• 16 months Ofloxacin, PAS, Pyrazinamide,
  Ethionamide
• 
  
• 
  
  
  
  (??????????????? ??????? 2550
  ?????????????????????????????)

25
First Line drugs of anti-TB

• Pediatric Dosage in mg/kg/dose (max)
• Drugs QD
  2/wk
• INH 10 15 (300) 20 30
  (900)
• RMP 10 20 (600) 10 20
  (600)
• PZA 15 30 (2g) 50
  (2g)
• EMB 15 20 (1g) 50
  (2.5g)
• STM 20 40 (1g)
• (Rifabutin, Rifapentine)

26
Second Line Drugs (6 classes) (1)

• Aminoglycosides
• streptomycin (15 MKD)
• kanamycin,amikacin (15 MKD)
• -first 2-3 mo, at least 5 days/wk
• -after sputum for AFB negative 2-3 days/wk to
  6 mo or patient has adverse effects (ototoxic
  and nephrotoxic)
• Fluoroquinolones cross resistance
• oflxacin (10MKD)
• levofloxacin (10MKD) nausea vomiting,
  dizziness
• ciprofloxacin (30MKD)

no cross resistance
27
Second Line Drugs (6 classes) (2)

• Polypeptides Capreomycin
• Serine analog Cycloserine
• Ethionamide(10-20MKD)
  nausea vomiting, vertigo,
  postural hypotension
• Para-aminosalicylic acid (PAS) (200MKD) nausea
  vomiting, diarrhea, rash

28
Guidelines for Treatment of
Drug-Resistant Organism

• Never add one drug into the failing regimen
• Use gt 3 drug with in vitro susceptibility (1 drug
  should be injectable)
• Should not use intermittent therapy
• Need DOTS
• Amikin cross-R with Kana, SM not cross-R with
  other
• Two-inject-drug is not recommended
• Frequency of resistance mutation
• RIF 10?18 INH, SM 10?6 ETB 10?5

29
Empirical Treatment in Case of Failure/Relaspe/Res
istance

• Failure Add 3 new drugs
• -Quinolones
• -Aminoglycosides or Capreomycin
• -Ethionamide or PAS or Cycloserine
• Relaspe Suspect new infection ? IRZE
• Suspect resistance organism
• ? Empirical with Expanded Regimen
• INHRIFPZAEMBQuinolonesinject drug
• Then tailor regimen by susceptibility test

30
Surgical Intervention for MDR-TB

• Consider in every MDR-TB patients.
• Better outcome if adjunct to medication.
• Criteria for surgery
• Unilateral or single lesion that can be done in
  one operation.
• Still have 2 or more drugs which are sensitive.
• If it is possible smear should be negative at
  surgical time or 2 3 months after
  treatment.
• Unfavorable outcome in patient with preoperative
  comorbidity, aspergillosis, operation time,
  transfusion and male.
  
  
• 
  (Ann Thorac Surg200579959-963)

31
What do we need in MDR-TB

• Specialized and experienced institute.
• Correct identification of drug resistance case.
• Good laboratory support.
• Availability and adequate drugs.
• DOTS (directly observed therapy strategy).
• Strictly monitoring of treatment.
• Follow up patient to prevent relapse case.
• 
  
• (Current Practice in
  Common Infectious Diseases2001.
  ?????????????????????????????20339-353.)
  

32
New Drugs for Tuberculosis Treatment

• Fixed dose combination (FDC)-WHO formulation
• Fluoroquinolones ofloxacin, levofloxacin,
  gatimoxacin, moxifloxacin
• MPC below Cmax
• Sterilizing activity
• Oxazolidinones linezolid
• Imidazole derivatives PA824
• Diaryquinolone TMC207
• Ketolides telithromycin (no activities)
• Drug on latency stage Glyoxylate shunt
• (Mendell, et al.Principle and Practice of
  INFECTIOUS DISEASES20052852-2886.)

33
Conclusions (1)

• In any phase of MDR-TB chemotherapy, at least 3
  sensitive drugs other than PZA should be combined
  to prevent further drug resistance.
• In moderate cases, 3 sensitive drugs other than
  PZA are probably enough, even in initial phases
  of MDR-TB chemotherapy, for culture conversion
  and preventing further drug resistance.
• 
  
• 
  (??????????????? ???????
  2550 ?????????????????????????????)

34
Conclusions (2)

• In advanced cases, 4 or more sensitive drugs
  other than PZA may be necessary. But this is not
  yet concluded and controversial, and probably
  dependent partly on the indication of adjunctive
  surgery.
• If sensitive, PZA should be used in initial 2 to
  3 months, after that, when other sensitive drugs
  can be used, PZA should be replaced by other
  sensitive drugs.
• 
  
  (???????????????
  ??????? 2550 ?????????????????????????????)

35
Conclusions (3)

• Injectable drugs and fluoroquinolones should be
  use if possible.
• In case of INH low grade resistance, INH is
  probably not useful, and caution for TH cross
  resistance is necessary.
• 
  
  (??????????????? ??????? 2550 ????????????????????
  ?????????)

36
Thank you