Gisela Schecter, M'D', M'P'H'

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Practical Management of MDR-TB California Style

• Gisela Schecter, M.D., M.P.H.
• CTCA
• May 17, 2007

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MDR-TB

• Recognition
• Treatment
• Prevention
• California Resources

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Recognition Who is at higher risk of MDR-TB

• History of previous TB treatment, particularly if
  recent
• Foreign born patients from countries or
  ethnicities with high prevalence of MDR
• Poor response to standard 4 drug rx
• Known exposure to MDR-TB case
• HIV positive

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Recognition - Examples

• Previous rx
• Particularly if after 1980, when Rifampin became
  widely used
• Foreign born
• Hmong refugees
• Tibetan ancestry
• Cases from former USSR, China, Korea, Peru,
  Honduras disproportionately MDR
• (Largest number MDR from Mexico, but rate of MDR
  no higher than state wide rate)

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Recognition - Examples

• Poor response to rx
• Culture remains after 2 months rx
• HIV
• Higher incidence of Rifampin monoresistance
• Known exposure
• Named contact to MDR case but did not take MDR
  LTBI rx due to pregnancy

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High Risk MDR Action Steps

• Obtain Molecular Beacons
• Consider initiation of expanded regimen
• Contact of MDR TB case with active TB
• Immigrant with history of extensive treatment for
  TB in the past and again has active TB

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Molecular Beacon Testing

• Using realtime PCR technology combined with
  Molecular Beacons, provides
• Identification of M.tb complex
• Screening for INH and Rif resistance

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Genes Associated with INH and RIF Resistance

• RIF resistance
• rpoB core region (gt95)
• INH resistance
• katG, inhA, ahpC, ndh (85)
• unknown (10-15)

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Molecular Beacon TestingSpecimens

• Sputum sediments (at least 0.5 ml) with () AFB
  smear
• Growth on solid media or MGIT tube
• Call MDL lab for instructions on how to send
  specimens

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Molecular Beacon TestingPerformance

• Prevalence of INH resistance 23.8
• Prevalence of Rif resistance 21.8

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Molecular Beacon Testing
Treat with Rif, EMB, and PZA For 6-9 months
Resistance Mutation Detected to
Expanded regimen For MDR-TB With INH
Resistance Mutation Detected to
Expanded regimen For MDR-TB Without INH
Resistance Mutation Detected to
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Limitations

• Limited genes sites are targeted.
• Some mutations are not detected.
• Emerging resistance in mixed populations may not
  be detected.
• Silent mutations do not confer resistance.
• Rare occurrence leads to wrong interpretation.
• Available for INH and RIF only
• Phenotypic drug susceptibility testing is still
  needed for other drugs for confirmation of MB
  results.

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MDR-TB Treatment Principles

• Perform extensive patient evaluation prior to
  starting treatment
• Try to use at least 3 previously unused drugs
  with in vitro sensitivity
• Initially, one drug should be bactericidal
  injectable agent
• A fluoroquinolone should be used whenever possible

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MDR-TB Treatment Principles (2)

• When possible continue injectable for at least 6
  months post culture conversion
• Continue at least 3 oral drugs for full treatment
  duration
• When possible do not limit regimen to 3 drugs,
  especially if extensive resistance
• Never add a single drug to a failing regimen

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MDR-TB Treatment DrugsSecond Line Third
Line

• Augmentin
• Imipenem
• Clarithromycin
• Linezolid
• Clofazimine

• Aminoglycosides
• (Streptomycin)
• Amikacin/ Kanamycin
• Capreomycin
• Fluoroquinolones
• Cycloserine
• Ethionamide
• PAS

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Linezolid (Zyvox)

• One case series found linezolid to be well
  tolerated and a good adjunctive medication when
  no other drugs are available
• Excellent activity against M.tb in vitro
• Dose 600 mg po qd
• Cost of therapy high
• Main side effects myelosuppression, peripheral
  neuropathy
• Avoid tyramine containing foods, soy products and
  OTC meds containing pseudoephedrine and
  phenylpropanolamine while on linezolid

Linezolid A Promising New Agent for Multi-Drug
Resistant Tuberculosis TreatmentP. Hadjiangelis,
E. Leibert, T.J. Harkin, W.N. Rom, R. Condos.
Division of Pulmonary and Critical Care Medicine,
NYU School of Medicine/Bellevue Chest Service,
New York, NY
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Building a Treatment Regimen for MDR-TB
Step 1
Use any available
One of these
One of these
Begin with any first-line agents to which the
isolate is susceptible Add a fluoroquinolone and
an injectable drug based on susceptibilities
Injectable agents
Amikacin Capreomycin Streptomycin Kanamycin
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Building a Treatment Regimen for MDR-TB
Step 2
Pick one or more of these
Add second-line drugs until you have 4-6 drugs to
which the isolate is susceptible (and preferably
which have not been used to treat the patient
previously)
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Building a Treatment Regimen for MDR-TB
Step 3
Consider use of these
If there are not 4-6 drugs available in the above
categories, consider third-line drugs in
consultation with an MDR-TB expert
Third-line drugs
Clofazimine Linezolid Amoxicillin/ clavulanate
Imipenem Macrolides High-dose Isoniazid
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Regimens for MDR-TB
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Cross-resistance for First-line Agents
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Cross-resistance for Second-line Agents
50 of strains may not be true cross-resistance
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MDR-TB ClinicalCase Management Principles

• Seek consultation with MDR-TB expert as soon as
  multidrug resistance known
• Use daily DOT throughout entire treatment course
• Use case management tools (drug-o-gram) to follow
  serial changes in drugs, bacteriology, CXR,
  toxicities
• Optimize management of underlying medical
  conditions and nutritional status

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MDR-TB ClinicalCase Management Principles (2)

• Isolate until 3 consecutive sputa AFB smears are
  negative and there has been a good response to
  treatment
• Consider isolation until culture negative in
  certain situations
• Hospitalization is often helpful when initiating
  MDR-TB treatment, including placement of PIC
  line, if used
• Tailor toxicity monitoring to specific drugs
  employed

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MDR-TB Monitoring Principles

• Collect sputa smears and cultures periodically
  during treatment once culture negative
• Obtain end of treatment sputum for smear and
  culture
• Perform CXR periodically during treatment and at
  end of treatment
• Monitor minimum of 2 years following treatment
  (quarterly during first year, every 6 months
  during second year)

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MDR-TB Laboratory Principles

• As soon as isolate known resistant to INH and
  RIF, order second-line drug susceptibilities
• Repeat susceptibilities on cultures that remain
  positive after 2-3 months
• Laboratory required by law to submit MDR isolates
  to state lab via the local PHL for surveillance

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Directly Observed Therapy for MDR-TB

• Essential
• Improved overall cure rates, including multiple
  drug resistance cases
• Reduction in community prevalence of multiple
  drug resistance

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Directly Observed Therapy Effect on Resistance
and Relapse
P lt 0.001
Weis, NEJM 1994 330, 1179
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Common Side Effects

• G.I. complaints
• Hepatotoxicity (early symptoms are anorexia and
  malaise, then abd pain, vomiting, jaundice)

• Ethionamide, Cycloserine,PAS,
• Quinolones, Clofazimine,
• Rifabutin
• INH, Rifampin/rifabutin, Ethionamide, PZA, PAS,
  quinolones

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Common Side Effects

• Hypothyroidism
• Hearing loss, vestibular toxicity
• Behavioral changes
• Visual changes
• Hypokalemia, hypomagnesemia

• Ethionamide, PAS
• Aminoglycoside, Capreomycin
• Cycloserine, Ethionamide, INH, quinolones
• EMB, Rifabutin, INH, Linezolid
• Aminoglycosides, Capreomycin

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Common Side Effects

• Peripheral neuropathy
• Rash
• Headache

• INH, ethionamide, cycloserine, linezolid
• All
• Quinolones, INH, cycloserine, ethionamide, EMB

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Surgery ?

• No hard and fast rules
• Consider
• if very extensive resistance
• residual large cavity
• predominantly one sided disease
• previous MDR treatment failure

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Prevention

• Preventing Acquired Drug Resistance
• Preventing Transmission of MDR-TB to Contacts
• Preventing Progression to Active Disease in
  infected MDR-TB Contacts

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Preventing Acquired Drug ResistanceCase 07-004

• 48 yo US born , recent onset NIDDM
• Dx 1/5/06 with cough, sputum, 40 lb. wt loss in
  another state
• 4 AFB sputum, extensive bilateral disease with
  cavitation
• RX 2 weeks daily IRZE given DOT M-F
• No weekend doses

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Case 07-004
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Preventing Acquired Drug ResistanceCase 07-004

• Thus, after 10 doses, at beginning of week 3,
  changed to t.i.w. DOT
• At the end of week 3, DST INH resis
• INH d/ced, but t.i.w. rx continued
• Moved to CA
• Culture still June, 2006, now resis to INH
  and Rifampin

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Preventing Acquired Drug ResistanceCase 07-004

• Why did this patient acquire MDR-TB?
• Patient factors
• Extensive cavitary disease
• 4 AFB on smear
• DM, with resultant immunecomp.
• Debilitated state at diagnosis

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Preventing Acquired Drug ResistanceCase 07-004

• Why did this patient acquire MDR-TB?
• Programmatic factors
• Policy to give only 2 weeks daily rx consisting
  of 10 doses (no option for patient to take
  weekend doses)
• Continuing intermittent induction phase despite
  INH resis

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Preventing Acquired Drug ResistanceCalifornia
Style

• DOT for all smear () and/or cavitary TB
• Daily therapy throughout induction phase if
  initial isolate is INH resistant, or if patient
  is HIV
• Reminder CDC and ATS recommend intermittent
  therapy for drug susceptible TB, there is no
  recommendation to use intermittent therapy when
  resistance present

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Preventing Transmission of MDR-TB

• High index of suspicion
• Get MBs if at increased risk of MDR-TB so
  effective rx can begin earlier
• If very high risk of MDR, begin an expanded
  regimen
• Ensure that all contacts are fully evaluated to
  rule out active disease

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Isolation (CTCA/CDHS Guidelines)

• Patients with pulmonary MDR-TB should be
  considered infectious until
• An appropriate MDR regimen has been initiated and
  tolerated for 2 weeks AND
• A favorable clinical response has occurred AND
• 3 consecutive sputum smears are documented AFB
  negative

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Isolation

• More stringent criteria of culture negativity
  apply if case will live or work in site
• With HIV or other immunocompromised persons
• Where children lt 5 visit, live, or receive care
• Congregate living (prison, jail, group home,
  homeless shelter)

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Preventing Progression to Active TB

• Very little published data on LTBI rx for MDR-TB
  contacts
• No randomized trials
• One article showed no significant effect of INH
  vs no rx
• One case series showed protection

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Preventing Progression to Active TB

• Pediatrics Vol. 109 May, 2002
• South African study of children lt5, contacts to
  adults with MDR TB
• 125 children, median age 27.5 months
• 14 (12) had disease at initial eval.
• 105 had follow up thru 30 months

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Preventing Progression
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Preventing Progression

• Regimens used
• Hi-dose INH, PZA, Ethionamide (Eth), Ethambutol
  (E) in various combinations
• 37/41 used a 3 drug regimen
• 20/41 INH, PZA, Eth
• 9/41 INH, PZA, E

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Possible Treatment Regimens for MDR-TB Contacts

• LEVO PZA
• LEVO EMB
• PZA EMB
• Other combinations? Duration?
• LEVO alone?
• Any aminoglycoside?
• Follow only?

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(Non) Consensus Recommendations for MDR LTBI rx

• Assess degree of exposure
• Assess infection
• Assess likelihood of infection with MDR
• Assess risk of progression to active TB
• Offer MDR LTBI rx to those with significant
  exposure, likely inf. with MDR, and increased
  risk of progression
• 2 best drugs for 9-12 months

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California Resources

• State
• MDR-TB Service
• Provides clinical consultation, case management,
  CI assistance
• Microbial Diseases Lab
• Provides MBs for drug resistance, phenotypic DST
  for first line drugs and Amikacin, Levofloxacin,
  Capreomycin, and Ethionamide genotyping
• State Outbreak Response Team for outbreaks or
  extended CIs
• Patient Locating Service

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T.E.A.M.
MDR Service
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California Resources

• F.J.Curry National Tuberculosis Center, CDC
  funded/based in San Francisco
• Warmline phone consultation with MDR-TB expert
• MDR Clinician survival guide
• MDR-TB Expert Network meetings
• Cure TB
• Care continuity during moves to Mexico
• (TB-Net)

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California Resources

• San Francisco General Hospital
• Experienced thoracic surgeon for consultation and
  MDR surgery
• Phil Hopewell