Common causes of treatment mismanagement

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• 2008 by the author

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Common causes of treatment mismanagement

• Jean-Pierre Zellweger
• Swiss Lung Association

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What is mismanagement of TB?
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The  ideal  TB management

• Symptoms
• Suspicion of TB
• Bacteriological confirmation
• Treatment
• Cure (Thank you, doctor!)

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The real-life TB management

• Symptoms
• Suspicion of TB
• Bacteriological confirmation
• Treatment
• Cure (Thank you, doctor!)

Wrong diagnosis Delay
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The real-life TB management

• Symptoms
• Suspicion of TB
• Bacteriological confirmation
• Treatment
• Cure (Thank you, doctor!)

Incorrect assessment
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The real-life TB management

• Symptoms
• Suspicion of TB
• Bacteriological confirmation
• Treatment
• Cure (Thank you, doctor!)

Missing drug sensitivity testing
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The real-life TB management

• Symptoms
• Suspicion of TB
• Bacteriological confirmation
• Treatment
• Failure, relapse, MDR/XDR-TB

Inappropriate drug treatment
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Delayed diagnosis
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Mean patients and HCWs delay (days) in 42
studies
Mean total diagnostic delay 21 136 days
Patients delay
Storla DG, BMC Public Health 2008815
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Patients delay

• Frequency of symptoms before diagnosis
• Cough 85
• Sputum 67
• Fever 65
• Weight loss 62
• Fatigue 55
• Haemoptysis 25
• Sweating 35

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Factors associated with delayed health-seeking
behaviour

• Socioeconomic factors
• Low access to health care
• Rural residence
• Low income, poverty
• Low education
• Sociopsychological factors
• Low-level health care facility
• Traditional or unqualified practicioner
• Private practicioner
• Beliefs about TB
• Sociodemographic factors
• Old age
• Female gender
• Immigration
• Illegal residency

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Doctors delay

• Factors influencing delay
• HIV
• Chronic cough
• Negative sputum
• Substance or alcohol abuse
• Smoking
• Poor health
• Coexistent disease
• Mild symptoms
• No haemoptysis

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Delay associated with health-care providers

• Repeated consultations with incompetent
  healthcare providers
• Governmental primary health posts
• Private practicioners with low awareness
• Unqualified traditional practicioners
• Overcentralization of govermental TB programme
• Repeated courses of inappropriate antibiotics

Storla DG, BMC Public Health 2008815
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Diagnostic deficiencies

• Misinterpretation of clinical presentation
• Other diagnosis cancer, pneumonia, smoking, COPD
• Misinterpretation of chest X-ray
•  inactive TB 
• Incorrect interpretation  cancer, abscess
• TB diagnosis without evidence
• No bacteriological examination (lymph node
  biopsies, surgical samples!)
• Diagnosis based on chest X-ray only
• Culture not available or not requested

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Inappropriate treatment

• Single drug treatment of active TB
• Standard treatment (cat 1) of undetected MDR-TB
• Ovelooking risk factors for MDR-TB
• Prior treatment
• Origin from region with high rate of MDR-TB
• Addition of a single drug to a failing regimen
• Insufficient doses
• Missing doses in intermittent treatment
  (1-weekly)

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Case 13

• Woman born in Portugal, 28 years
• Coughs since 3 weeks
• CXR
• Receives moxifloxacine

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Case 13

• Woman born in Portugal, 28 years
• Coughs since 3 weeks
• CXR
• Rx moxifloxacine
• Feels better
• 2nd CXR after 2 weeks

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Case 13

• Woman born in Portugal, 28 years
• Coughs since 3 weeks
• CXR
• Rx moxifloxacine
• Feels better
• 2nd CXR after 2 weeks
• Recurrent symptoms 3 weeks later
• Smear positive

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Message 3 errors1. wrong interpretation of
chest X-ray (it was TB, not cavitating
pneumonia!)2. incorrect choice of the
antibiotic (no quinolone for possible TB!)3.
wrong interpretation of the improvement(bacterici
dal effect of moxifloxacin on M.tb)
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Who has primary MDR-TB?

• Patients with prior TB treatment (10 times)
• Foreign-born patients
• Young patients
• Males
• HIV positives

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Risk factors for MDR-TB in Europea) patients
with previous treatment
Faustini A, Thorax 200661158-63
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Risk factors for MDR-TB in Europeb) previous
treatment in E and W Europe
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MDR-TB in immigrants arriving in UK risk factors
ORiordan Ph, PLoS One 2008,3(9)e3173
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Insufficient follow-up

• Irregular controls
• Undetected adverse effects of treatment
• Erratic changes in treatment schedule due to
  adverse events (replacement of H or R by
  second-line drugs)
• Undetected negative evolution

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Uncertain cure

• End of treatment without documentation of cure

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Mismanagement and creation of MDR/XDR-TB
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Mismanagement and creation of MDR/XDR-TB

• Errors inducing MDR-TB
• Inappropriate choice of drugs
• Inappropriate regimen (twice-weekly without
  supervision)
• Too low doses
• Malabsorption of drug (low blood levels)

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Creation of drug resistance effect of drugs on
mycobacteria with different growth speed
Mitchison DA , IJTLD 19982(1)10-15
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Creation of drug resistance growth speed of
sensitive and resistant mycobacteria
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Creation of drug resistance regrowth of of
sensitive and resistant mycobacteria
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Creation of drug resistance impact of lag phase
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Mismanagement and creation of MDR/XDR-TB

• Errors inducing MDR-TB
• Induction of MDR-TB without error under standard
  DOTS strategy
• Initiation of standard therapy in new patients
  with undetected drug resistance
• No culture available or requested
• No DST
• DST inappropriate
• DST arriving too late (3-4 months)
• DST never transmitted to clinician

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Situation at initiation of treatment
Caminero JA, IJTLD 200812(8)869-77
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Possible course of treatment
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Initial resistance to H
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Initial MDR-TB
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Outcome of treatment and retreatment in sites
with low MDR-TB prevalence
Gninafon M, IJTLD 20048(19)1242-7
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Outcome under correct DOTS in sites with high
prevalence of MDR/XDR-TB

• 1999 (Bakou prisons, Azerbaïjan) all prisoners
  under correct treatment (cat 1, DOT)
• Mortality during treatment 11
• Sputum conversion obtained in 42
• Cure rate 54 (71 in completers)
• 55 had strains resistant to 2 or more drugs

Coninx R, Lancet 1999353969-73
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Creation of new MDR/XDR-TB under correct DOTS

• 2901 new smear pulmonary TB under DOTS in
  Vietnam
• 125 failures
• 2nd DST in 40 failure with two positive cultures
  and identical RFLP pattern
• 17 had MDR-TB at beginning of treatment
• 15 without MDR at beginning developed MDR under
  DOTS
• 39 relapses
• No primary MDR-TB
• 3 had MDR-TB at relapse

Quy HTW, IJTLD 2003,7(7)631-36
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Outcome and acquired drug resistance in 1681 new
TB patients in cat 1 DOTS (Tomsk)
Seung KJ, Clin Infect Dis 2004391321-8
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Acquired drug resistance under DOTS

• Among 382 new pulmonary TB patients treated by a
  standard DOTS regimen
• 62 were still smear positive at 2 months (with
  identical strains)
• 24 had MDR-TB
• 19/62 identical strains developed new or
  additional drug resistance during treatment
• 3.5 of patients with DST other than MDR
  developed MDR-TB during treatment

Cox HS, Clin Inf Dis 2007441421-7
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Amplification of drug resistance in patients
under retreatment

• 410 patients in Uganda received retreatment for
  TB according to WHO 2HRZES/1HRZE/5HRE
• 12.5 had MDR-TB at the beginning of retreatment
• 5.2 developed additional drug resistance during
  retreatment (half of them developed new MDR-TB)
• Risk of acquired drug resistance was
• 10.4 for patients with H or R resistance
• 46.1 for patients with MDR-TB
• 42.4 for patients still C after 5 months of
  treatment

Temple B, Clin Inf Dis 2008471126-34
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Outcome by rate of resistance and MDR in 6 sites
in FSU
Bonnet M, IJTLD 20059(10)1147-54
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Initial drug resistance and treatment failurea)
fully sensitive strains
Lew W, Ann Int Med 2008149123-34
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Initial drug resistance and treatment failureb)
initial single drug resistance
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Initial drug resistance and treatment failurec)
polyresistant strains
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Initial drug resistance and treatment failure
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Initial drug resistance and treatment
outcome.Duration of R treatment and outcome, by
resistance
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Initial drug resistance and treatment
failure.Acquired drug resistance
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Rate of failure in new and retreatment cases, by
local rate of initial MDR-TB (source WHO data)
Mak A, Am J Respir Crit Care Med 2008178306-12
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Speed of detection of MDR-TB (in immigrants) and
outcome of treatment
ORiordan Ph, PLoS One 2008,3(9)e3173
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How to treat failure and relapse cases?

• Low MDR-TB prevalence 2HRZES/1HRZE/5HRE (?)
• Beware of any risk factor for drug resistance
• Strict DOT
• Obtain DST
• High MDR-TB prevalence
• Obtain rapid DST
• Avoid using only first-line drugs as retreatment
  schedule
• Consider using second-line drugs (injectables and
  quinolones)

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Conclusions how to avoid creating MDR/XDR-TB?

• Obtain a bacteriological confirmation whenever
  possible, at least in retreatment cases
• Obtain DST as soon as possible (consider using
  rapid amplification technology)
• Search for all possible risk factors for drug
  resistance
• Initiate appropriate drug treatment
• Supervise drug intake

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The curse of MDR/XDR-TB

•  A mycobacterium for a mycobacterium 
• Your mycobacterium is my mycobacterium
• You and your children will be cursed to the
  seventh generation!