Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard...

Drug-Resistant Tuberculosis

Your name Institution/organizationMeetingDate

International Standard 11

ISTC TB Training Modules 2009


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/XDR and the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment.


Overview: Definitions Global burden and individual

impact Pathogenesis and

clinical/programmatic contributors to development

Early identification and risk factors

Recommendations for diagnosis

International Standard 11



MDR-TB is a manmade problem…It is costly, deadly, debilitating and is a major threat to our current control strategies.


Standard 11: Drug-Resistant TB(1 of 3)

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.


Standard 11: Drug-Resistant TB

Drug susceptibility testing should be performed at the start of therapy for all previously treated patients

Patients who remain sputum smear-positive at completion of 3 months of treatment and patients who have failed, defaulted from, or relapsed following one of more courses of treatment should always be assessed for drug resistance

(2 of 3)


Standard 11: Drug-Resistant TB

For patients in whom drug resistance is considered to be likely, culture and testing for susceptibility/resistance to at least isoniazid and rifampicin should be performed promptly

Patient counseling and education should begin immediately to minimize the potential for transmission

Infection control measures appropriate to the setting should be applied

(3 of 3)


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)


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


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%


Distribution of MDR: No Prior Treatment

Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR rates among new cases (previously untreated)


Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR: Prior Treatment

Distribution of MDR rates among previously treated cases


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


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


Adapted from Paul Nunn, StopTB/WHO 2009

Global TB estimates: XDR and MDR 2007

Estimated Global XDR

2007 Estimated number of cases

Estimated number of

deaths

All forms of TB 9.2 million(139 per 100,000)

1.77 million(27 per 100,000)

MDR 511,000 ~150,000

XDR ~50,000 ~30,000

ISTC TB Training Modules 2009WHO 2009

Distribution of XDR

Countries that had reported at least one XDR-TB caseby end of April 2009


Pathogenesis ofDrug Resistance


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


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



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


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


Weeks


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


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


Factors that Lead to Drug Resistance

Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors



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



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



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


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 Drug Resistance


Diagnosis of MDR-TB


Diagnosis of MDR

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)


Recognition of risk factors: History of prior therapy (most powerful

predictor)

• Failure of a retreatment regimen

• Failure of the initial treatment regimen

• Relapse after apparently successful treatment

• Return after default without recent treatment failure

Clinical Suspicion for MDR


Recognition of risk factors: Close contact to known or suspected

MDR-TB case (“incurable” TB or TB requiring multiple treatment courses)

Residence in an MDR-endemic area Exposure in institutions that have drug-

resistance outbreaks or high prevelance HIV infection (in some settings)



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



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


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.


Rapid Drug-Susceptibility Tests

Line-probe assays• Identifies M.tb and

genetic mutations associated with INH and RIF resistance

• Can be used directly on sputum specimens, results within 1-2 days

Endorsed for use on either direct smear positive sputum or culture specimens

*GenoType MTDBRplus strips (Hain Lifescience)


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


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


Predicting Risk for MDR

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


Predicting Risk for XDR

Two strongest risk factors for XDR are: Failure of a TB treatment which contains

second-line drugs including an injectable agent and a fluoroquinolone

Close contact with an individual with documented XDR or for whom treatment with second-line drugs is failing or has failed


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



Summary (cont.): Recognize when your patient is failing

standard treatment

Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR



Summary: ISTC Standard Covered*

Standard 11: Assessment for drug resistance should be obtained based on

a history of:• Prior treatment• Exposure to a possible drug-resistant source• High community prevalence

Drug-susceptibility testing should be performed at the start of therapy for all patients previously treated, or smear+ at three months of treatment, or if failed/defaulted/relapsed

If drug-resistance likely, do culture and DST for at least isoniazid and rifampicin

Patient counseling/education should begin immediately to minimize potential for transmission

Infection control measures should be applied*[Abbreviated version]


Alternate Slides


Resources WHO: Guidelines for the programmatic

management of drug-resistant tuberculosis, Emergency update 2008 www.who.int/tb

Drug-Resistant Tuberculosis, A Survival Guide for Clinicians 2nd edition, 2008 www.nationaltbcenter.ucsf.edu

The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org


Resource Availability

The following tests are available at _________: Smear microscopy

• Direct smear / light microscopy

• Fluorescence microscopy

• Concentration/chemical processing

Culture• Solid media

• Liquid media

Drug susceptibility testing Other


Resource Contact Information

Laboratory testing: Microscopy/culture/DST

[Name, addresses, e-mail, etc.]

Specimen transport:

[Name, addresses, e-mail, etc.]


Purpose of ISTC


ISTC: Key Points

21 Standards (revised/renumbered in 2009) 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


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


Questions


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



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)



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

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