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Drug-Resistant Tuberculosis
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International Standard 14
ISTC Training Modules 2008
Drug-Resistant Tuberculosis
Objectives: At the end of this presentation,participants will be able to: Define the areas with the highest global burden of
MDR. Understand the microbiological basis for the
development of drug resistance. Recognize the clinical errors and programmatic
factors that can lead to the development of drug resistance.
Recognize the risk factors for MDR and the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment.
Drug-Resistant Tuberculosis
Overview: Definitions Global burden and individual impact Pathogenesis and clinical/programmatic
contributors to development Early identification and risk factors Recommendations for diagnosis
International Standard 14
ISTC Training Modules 2008
Drug-Resistant Tuberculosis
MDR-TB is a manmade problem…It is costly, deadly, debilitating and is a major threat to our current control strategies.
ISTC Training Modules 2008
Standard 14: Drug-Resistant TB
An assessment of the likelihood of drug resistance, based on
• history of prior treatment,
• exposure to a possible source case having drug-resistant organisms,
• and the community prevalence of drug resistance,
should be obtained for all patients. Patients who fail treatment and chronic cases should
always be assessed for possible drug resistance. For patients in whom drug resistance is considered to be
likely, culture and drug-susceptibility testing for isoniazid, rifampicin, and ethambutol should be performed promptly.
ISTC Training Modules 2008
Drug-Resistant TB: Definitions
Mono-resistant: Resistance to a single drug Poly-resistant: Resistance to more than one
drug, but not the combination of isoniazid and rifampicin
Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin
Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)
ISTC Training Modules 2008
Drug-Resistant TB: Definitions
Primary drug-resistance: “New Cases”Drug resistance in a patient who has never been treated for tuberculosis or received less than one month of therapy
Secondary (acquired) drug-resistance:“Previously Treated Cases”
Drug resistance in a patient who has received at least one month of anti-TB therapy
ISTC Training Modules 2008
WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008
Estimated global incidence and proportionof MDR among TB cases, 2006
Estimated Global MDR Cases
2006 TB cases MDR cases %
New Cases* 9,123,922 285,718 3.8
Previously treated cases* 1,052,145 203,230 19.3
Total cases** 10,192,986 489,139 4.8
*175 countries reporting; **185 countries reporting*175 countries reporting; **185 countries reporting
WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008
Estimated Global MDR Cases
Estimated global prevalence of MDR (based on 2-3 year duration as an active case): 1,000,000 –1,500,000 cases
Estimated 42% of global MDR cases have had prior treatment
China and India carry 50% of the global MDR burden, with the Russian Federation carrying a further 7%
ISTC Training Modules 2008
Distribution of MDR: No prior treatment
Zignol M, et al. JID 2006; 194: 479-85
Distribution of MDR rates among new cases (previously untreated)
ISTC Training Modules 2008
Zignol M, et al. JID 2006; 194: 479-85
Distribution of MDR: Prior Treatment
Distribution of MDR rates among previously treated cases
ISTC Training Modules 2008
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 mos.), often difficult and toxic
Long periods of isolation may be necessary
Depression is common Disease may be incurable (chronic) Higher rate of death
ISTC Training Modules 2008
Impact of Resistance on Outcome
Resistance pattern New Cases (%) Retreatment (%)
Pan-susceptible 4 10
Any Resistance 5 21
MDR 30 45
INH (not MDR) 6 23
RIF (not MDR) 13 29
Other 4 15
% of cases with failure or death, standard 4-drug regimen
Espinal MA, et al. JAMA. 2000;283(19):2537-45
ISTC Training Modules 2008
Pathogenesis ofDrug Resistance
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INH = 1 in 106
RIF = 1 in 108
EMB = 1 in 106
Strep = 1 in 106
INH + RIF = 1 in 1014
Frequency of Resistance Mutations
ISTC Training Modules 2008
Development of Drug Resistance
1 2
3
Multiple Drugs vs. Monotherapy
I = INH resistant, R = RIF resistant, P = PZA resistant, E = EMB resistant
INH
IR
EP
RIFPZAEMB
INH II
I I
I
I
ISTC Training Modules 2008
Development of Drug Resistance
I = INH resistant, R = RIF resistant, P = PZA resistant
Further acquired resistance after single drug added
II
I I
I
I
IR IRIR
IRIR
IR
IR
IR
IRIR IR
IRIR
IRP
III
I
II
I
II
I II
IIP
IRI
INHRIFINH
ISTC Training Modules 2008
Mixed population (susceptible and resistant)
INH-resistant bacilli
0 2 4 6 8 10 12 14 16 18 20 22 24
Emergence of INH-resistant strain because of ineffective treatment (INH monotherapy)
Effective multi-drug therapy
Development of Drug Resistance
Weeks
ISTC Training Modules 2008
Months of Rx 0 5 7 9
INH
RIF
EMB
Smear + + + +
Culture + + + +
Susceptibility
INH R* R R R
RIF S* R R R
EMB S* S S R* Results not known to clinician
Resistance: Unintended Monotherapy
ISTC Training Modules 2008
Resistance: Unintended Acquired
Months of Rx 0 2 4 8
INH/RIF/EMB/PZA
Capreo/Moxi
Smear + + + -
Culture + + + -
Susceptibility
INH R* R R R
RIF S* R R R
EMB R* R R R
* Results not known to clinician
ISTC Training Modules 2008
Factors that Lead to Drug Resistance
Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors
ISTC Training Modules 2008
Factors that Lead to Drug Resistance
Patient-related factors: Non-adherence, default Malabsorption of drugs Adverse drug reactions Lack of information, transportation, money Social barriers to treatment adherence Substance dependency disorders
ISTC Training Modules 2008
Factors that Lead to Drug Resistance
Healthcare provider-related factors: Inadequate initial treatment regimen: Wrong
combination or doses, guideline noncompliance Treatment “in the dark” for retreatment cases:
no drug susceptibility testing available, or results delayed
Clinical errors: Adding a single drug to a failing regimen
Lack of proper monitoring Lack of proper provider awareness
ISTC Training Modules 2008
Factors that Lead to Drug Resistance
Healthcare program-related factors: Inconsistent access to care Unavailability of drugs (stock-outs or delivery
disruptions) Poor drug quality, poor storage conditions Poorly organized or under-funded TB-control
programs Inappropriate or no guidelines Lack of appropriate or timely laboratory testing
ISTC Training Modules 2008
Common Causes Interventions
Nonadherence, default
Patient-centered DOT, education, support, incentives
Management errors, lack of expertise
Consultation with experts, vigilant patient monitoring for treatment failure, provider training
Inadequate regimen in presence of drug resistance
Improved access to drugs and susceptibility testing
Strategies to Prevent MDR
ISTC Training Modules 2008
Diagnosis of MDR-TB
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Diagnosis of MDR-TB
Appropriate diagnosis and timely treatmentintervention for MDR-TB is facilitated by:
Recognition of risk factors for MDR-TB Early recognition of treatment failure Drug-susceptibility testing (if available)
ISTC Training Modules 2008
Recognition of risk factors: History of prior therapy (most powerful predictor) History of non-adherence, default Residence in an MDR-endemic area Exposure to known or suspected MDR-TB case
(“incurable” TB or TB requiring multiple treatment courses)
HIV infection (in some settings)
Clinical Suspicion for MDR-TB
ISTC Training Modules 2008
Early recognition of treatment failure:
Cough should improve within the first two weeks of effective treatment
Signs of failure: lack of sputum conversion, persistent or recurrent cough, continued fever, night sweats and failure to gain weight
Clinical Suspicion for MDR-TB
ISTC Training Modules 2008
Laboratory Diagnosis of MDR
Drug-susceptibility testing, if available,should be ordered when: Risk factors for MDR are present There is evidence of treatment failure
Results can both: Confirm diagnosis of drug resistance Guide treatment choices
ISTC Training Modules 2008
Drug-Susceptibility Results: Problems
Identification of MDR may take 4 – 8 weeks, andsecond-line drug testing 6 – 12 weeks for results:
• 2 – 4 weeks for initial culture to become positive
• Additional 2 – 4 weeks to get 1st-line DST
• Additional 2 – 4 weeks to get 2nd-line DST
In view of this inherent delay, don’t wait to treat with an augmented regimen if MDR suspicion is high and resistance pattern can be predicted.
ISTC Training Modules 2008
Drug-Susceptibility Results: Problems
Drug-susceptibility testing requires training and experience
Quality assurance is difficult Testing is unreliable for some drugs,
especially ethambutol and pyrazinamide Results will sometimes differ in different
laboratories
ISTC Training Modules 2008
Predicting Patterns of Resistance
Examine prior treatment regimen:
Consider all drugs used previously as potentially ineffective
Example: A symptomatic patient with 2 prior treatment courses using red capsules, white pills and shotsPredict: Resistance to INH, RIF, and streptomycin
ISTC Training Modules 2008
Predicting Patterns of Resistance
If there has been contact to a known MDR case, use pattern of drug resistance in index case
Use epidemiologic information determined from surveys to identify patterns and rates of resistance
Presence of RIF resistance predicts MDR
ISTC Training Modules 2008
Summary: Early suspicion, diagnosis and appropriate
treatment is critical in preventing further progression and transmission of drug-resistant disease
Prior treatment is the most significant predictor for drug resistance, but learn to recognize all risk factors
Drug-Resistant Tuberculosis
ISTC Training Modules 2008
Summary (cont.): Recognize when your patient is failing
standard treatment
Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR
Drug-Resistant Tuberculosis
ISTC Training Modules 2008
Summary: ISTC Standard Covered*
Standard 14:
Assessment for drug resistance should be obtained based on a history of:
• Prior treatment• Exposure to a possible drug-resistant source• High community prevalence• Treatment failure or chronic disease
If suspicion for drug-resistance, obtain culture and drug-susceptibility testing promptly.
*[Abbreviated version]
ISTC Training Modules 2008
Alternate Slides
ISTC Training Modules 2008
Resources WHO: Guidelines for the programmatic
management of drug-resistant tuberculosis www.who.int/tb
Drug-Resistant Tuberculosis, A Survival Guide for Clinicians www.nationaltbcenter.edu
The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org
ISTC Training Modules 2008
Purpose of ISTC
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ISTC: Key Points
17 Standards Differ from existing guidelines: standards
present what should be done, whereas, guidelines describe how the action is to be accomplished
Evidence-based, living document Developed in tandem with Patients’ Charter
for Tuberculosis Care Handbook for using the International
Standards for Tuberculosis Care
ISTC Training Modules 2008
Audience: all health care practitioners, public and private
Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines
Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs
ISTC: Key Points
ISTC Training Modules 2008
Questions
ISTC Training Modules 2008
Drug-resistant Tuberculosis
1. A 68 year-old man presents with cough and weight loss for 2 months. He recalls treatment for TB eight years ago, but believes it only lasted a few months. A chest film reveals a cavitary infiltrate in the right apex of the lung. Factors that predict or are associated with a risk for the development of drug-resistance would include all of the following except:
A. Prior inadequate TB treatment
B. Development of chronic diarrhea with possible malabsorption of drugs
C. New diagnosis of diabetes
D. Persistent cough and weight loss after two months of standard therapy
ISTC Training Modules 2008
Drug-resistant Tuberculosis
2. Extensively-drug resistant (XDR) TB is defined as TB that is resistant to:
A. At least six anti-tuberculosis drugs
B. At least isoniazid and rifampicin
C. Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, and a fluoroquinolone
D. Isoniazid, rifampicin, a fluoroquinolone, and at least one of these three injectable agents (amikacin, kanamycin, capreomycin)
ISTC Training Modules 2008
Drug-resistant Tuberculosis
3. Which of the following statements regarding the microbiologic pathogenesis of drug-resistant tuberculosis is most correct?A. Patients with cavitary tuberculosis have a low bacillary load and
therefore are unlikely to harbor any naturally occurring drug-resistant organisms
B. Mono-therapy with a single anti-tuberculosis drug can lead to selective proliferation of naturally occurring drug-resistant organisms
C. Acquired resistance to anti-tuberculosis drugs only occurs for isoniazid and rifampicin
D. In a patient on a standard initial four-drug treatment regimen with evidence for clinical failure in whom there is a high suspicion for drug resistance, the addition of a fluoroquinolone alone will reduce the risk for further development of drug resistance