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Management of Drug-Resistant TuberculosisYour name Institution/organizationMeetingDate
International Standard 15
ISTC Training Modules 2008
Management of Drug-Resistant TB
Objectives: At the end of this presentation, participants will be able to: Describe the principles upon which treatment of
drug-resistant TB is based Understand the essential features of MDR-TB
case management Recognize the importance of patient-centered
DOT in MDR-TB treatment Become familiar with common side effects of
drugs used in the treatment of MDR-TB
International Standards 15
Management of Drug-Resistant TB
Overview: Definitions and predictors of
drug resistance Treatment principles Case-management principles Patient-centered directly
observed therapy Common side effects of
MDR-TB treatment
ISTC Training Modules 2008
Standard 15: Management of Drug-Resistant TB
Patients with tuberculosis caused by drug-resistant (especially MDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs.
At least four drugs to which the organisms are known or presumed to be susceptible should be used, and treatment should be given for at least 18 months.
Patient-centered measures are required to ensure adherence.
Consultation with a provider experienced in treatment of patients with MDR-tuberculosis should be obtained.
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
Recognizing Predictors of Drug-resistant TB
Assess drug resistance in any patient being started on treatment for tuberculosis
Nonadherence, default History of prior treatment Exposure to possible drug-resistant source case Community prevalence of drug resistance
If drug resistance is suspected based on any of the above factors, culture and susceptibility testing should be performed for INH, rifampicin, ethambutol, (and streptomycin).
ISTC Training Modules 2008Note: PZA does not prevent acquired resistance to companion drugs.
Predicted Resistance Pattern
Empiric Regimen (minimum duration)
INH RIF, EMB, PZA (6-9 mo)
INH, EMBRIF, PZA, Fluoroquinolone +
Injectable (9-12 mo)
RIF INH, EMB + PZA (18 mo minimum)
RIF, EMBINH, Fluoroquinolone,
PZA + Injectable (18-month minimum)
INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide
Empiric Regimens for Drug-resistant TB
ISTC Training Modules 2008
Multidrug-Resistant TB“I have been treated several times over the past five years
and I’m still coughing and can’t gain weight!”
ISTC Training Modules 2008
MDR/XDR Treatment Strategies: WHO
Three approaches to treatment: Standardized regimens Empiric regimens Individualized treatment regimens
(Ideal, but resources must be considered)
The choice among these should be based on: Availability of second-line drugs Local drug-resistance patterns, and the history of use
of second-line drugs Drug susceptibility testing of first- and second-line
drugs
ISTC Training Modules 2008
Drugs in parentheses = varies by country availability
Categories of Antituberculosis Drugs: WHO
Group 1 – First-line drugs: isoniazid, rifampicin, ethambutol, pyrazinamide
Group 2 - Injectable agents: streptomycin, kanamycin, amikacin, capreomycin, (viomycin)
Group 3 - Fluoroquinolones: ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, (gatifloxacin)
Group 4 - Oral bacteriostatic agents: ethionamide, cycloserine, para-aminosalicylic acid (prothionamide, thioacetazone, terizadone)
Group 5 - Unproven agents: clofazamine, amoxicillin/clavulanate, clarithromycin, linezolid
ISTC Training Modules 2008
Designing an MDR/XDR Treatment Regimen
General Principles, WHO Use of at least four drugs highly likely to be
effective. Do not use drugs for which there is
cross-resistance. Eliminate drugs that are unsafe for the patient. Include drugs from groups 1-5 in a hierarchical
order based on potency. Be prepared to prevent, monitor and manage
adverse effects from the drugs selected.
ISTC Training Modules 2008
Additional Important Principles: WHO
Use direct observation of treatment (DOT) Use daily, not intermittent, administration Treatment duration of a minimum of 18-24
months When possible, continue injectable for at
least six months post-culture conversion Continue at least three oral drugs for full
treatment duration
ISTC Training Modules 2008
Potential Effectiveness: WHO
Effectiveness is supported by a number of factors: Demonstrated susceptibility No history of treatment failure with the drug No contacts with resistance to the drug Resistance rare in similar patients (surveys) Drug is not commonly used in the area
If at least four drugs are not certain to be effective, use five to seven drugs, depending on specific drugs and degree of certainty.
ISTC Training Modules 2008
Cross-Resistance: WHO
All rifamycins: high level cross-resistance Fluoroquinolones: variable, but probably
should be assumed to be cross-resistant Amikacin and kanamycin: generally highly
cross-resistant, but both should be tested Capreomycin and aminoglycosides:
occasional cross-resistance, susceptibilities should be tested
ISTC Training Modules 2008
Drug Contraindications: WHO
Known severe drug allergy Unmanageable drug intolerance Risk of severe toxicity, with symptoms
such as renal failure, hepatitis, hearing loss, depression, and psychosis
Drugs of unknown quality (lack of quality assurance exposes patient to risks with unknown benefits)
ISTC Training Modules 2008
Determining Drugs to Use: WHO
Use any first-line drug likely to be effective (Group1)
Include aminoglycoside or capreomycin (Group 2)
A fluoroquinolone should always be used if deemed likely to be effective (Group 3)
Use remaining Group 4 drugs to make a regimen of at least four effective agents
Use Group 5 drugs as needed to make a regimen of at least four effective agents
ISTC Training Modules 2008
Predicted Resistance Pattern Empiric Regimen
INH, RIF Fluoroquinolone, PZA, EMB, Injectable
INH, RIF, EMB Fluoroquinolone, PZA, Injectable, CS, + PAS or ETH
INH, RIF, PZA Fluoroquinolone, EMB, Injectable, CS, + PAS or ETH
INH, RIF, PZA, EMB Fluoroquinolone, Injectable, CS, PAS or ETH, + one more drug
INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = PyrazinamideCS = Cycloserine, PAS = P-aminosalicylic acid, ETH = Ethionamide
Empiric Regimens for MDR-TB
ISTC Training Modules 2008
Use any available
One of these
One of these
First-line drugs Fluoroquinolones Injectable
agents
Pyrazinamide
Ethambutol
Levofloxacin
Moxifloxacin
Ofloxacin
Ciprofloxacin
Amikacin
Capreomycin
Streptomycin
Kanamycin
Building a Regimen for MDR-TB STEP 1
Begin with any first-line agents to which the isolate is susceptible
Add a fluoroquinolone and an injectable drug based on susceptibilities
PLUS PLUS
ISTC Training Modules 2008
Pick one or more of these
Oral second-line drugs
CycloserineEthionamidePAS
Building a Regimen for MDR-TB STEP 2
If 4 drugs are not identified in Step 1:Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)
ISTC Training Modules 2008
Consider use of these
Third-line drugs
Clofazimine
Linezolid
Amoxicillin/Clavulanate
Imipenem
Clarithromycin
STEP 3
Building a Regimen for MDR-TB
If there are not four to six drugs available in the abovecategories, consider third-line drugs in consultation with an expert.
ISTC Training Modules 2008
Building a Regimen for XDR-TB STEP 1
Begin with any first-line agents to which the isolate is susceptible
Add a fluoroquinolone and an injectable drug based on susceptibilities
Use any available
One of these
One of these
First-line drugs Fluoroquinolones Injectable
agents
Pyrazinamide
Ethambutol
Levofloxacin
Moxifloxacin
Ofloxacin
Ciprofloxacin
Amikacin ?
Capreomycin ?
Streptomycin ?
Kanamycin ?
Commonly not susceptible
By definition there is fluoroquinolone resistance
Select agent based on historyand susceptibility testing
PLUS PLUS
ISTC Training Modules 2008
STEP 2
Building a Regimen for XDR-TB
Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)
Pick one or more of these
Oral second-line drugs
CycloserineEthionamidePAS
With XDR-TB, often all three of these agents are necessary
ISTC Training Modules 2008
STEP 3
Building a Regimen for XDR-TB
If there are not four–six drugs available in the above categories, consider third-line drugs in consultation with an expert.
Consider use of these
Third-line drugs
Clofazimine
Linezolid
Amoxicillin/Clavulanate
Imipenem
Clarithromycin
ISTC Training Modules 2008
Ensure laboratory services for hematology, biochemistry and audiometry are available.
Establish a clinical and laboratory baseline before starting the regimen.
Initiate treatment gradually when using drugs that cause gastro-intestinal intolerance.
Ensure availability of ancillary drugs to manage adverse effects.
Use DOT for all doses.
Initiating Treatment: WHO
ISTC Training Modules 2008
Isolate until three consecutive sputum AFB smears are negative and there has been a good clinical response to treatment.
Initiate MDR-TB treatment under close supervision to provide patient education and monitoring and to treat drug toxicity.
Tailor toxicity monitoring to specific drugs employed.
Seek consultation with an expert as soon as drug resistance is known.
MDR/XDR-TB: Management Principles
ISTC Training Modules 2008
Use daily patient-centered DOT throughout entire treatment course.
Record drugs given, bacteriological results, chest radiographic findings, and the occurrence of toxicities.
Optimize management of underlying medical conditions and nutritional status.
MDR/XDR-TB: Management Principles
ISTC Training Modules 2008
MDR/XDR-TB: Monitoring
Collect sputum specimens for smear and culture periodically during treatment once culture negative
Obtain end-of-treatment sputum specimen for smear and culture
Perform chest radiograph periodically during treatment and at end of treatment
Resources permitting, monitor minimum of two years following treatment (quarterly during first year, every six months during second year)
ISTC Training Modules 2008
As soon as rifampicin resistance is known, order second-line drug susceptibility testing.
Repeat susceptibility testing on cultures that remain positive after two–three months of treatment.
MDR/XDR-TB: Laboratory Testing
ISTC Training Modules 2008
More Than Watching PatientsSwallow Their Pills DOT is a support system that enables
the completion of the long, difficult course of MDR-TB treatment.
A patient requires respect and dignity regardless of social class, educational level or unhealthy behaviors.
The whole patient, lifestyle and support system are assessed and routinely addressed in the delivery of care.
Goal: Inspire and empower patient via a relationship of trust and support.
Patient-centered DOT
ISTC Training Modules 2008
Weis SE, et al. NEJM 1994; 330(17): 1179-84* P < 0.001
Self-RX N=407 (pre 1987)
DOTN=581 (1987 +)
Primary R 13.0% 6.7%
Secondary R 10.3% 1.4%
Relapse 20.9% 5.5%
MDR relapse 6.1% 0.9%
Directly Observed TreatmentEffect on Resistance and Relapse
ISTC Training Modules 2008
Common Adverse Effects
G.I. complaints
Ethionamide CycloserinePAS Fluoroquinolones Clofazimine Rifabutin
Hepatotoxicity
(early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice)
INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones
ISTC Training Modules 2008
Common Adverse Effects
Peripheral neuropathy
INH Ethionamide Cycloserine LinezolidEthambutol
Rash All
Headache
Fluoroquinolones Isoniazid Cycloserine Ethionamide Ethambutol
Seizures Cycloserine
ISTC Training Modules 2008
Common Adverse Effects
Hypothyroidism Ethionamide, PAS
Hearing loss, Vestibular toxicity
Aminoglycosides, Capreomycin
Behavioral changes Cycloserine, Ethionamide, Isoniazid, Fluoroquinolones
Visual changes Ethambutol, Rifabutin, Isoniazid, Linezolid
Renal failureHypokalemia, Hypomagnesemia
Aminoglycosides, Capreomycin
ISTC Training Modules 2008
Management of Drug-Resistant TB
Summary:
Treatment of MDR-TB is complex and costly. It is much easier to prevent than to treat. XDR-TB is even more difficult!
Expert consultation should be obtained whenever possible when MDR- or XDR-TB is suspected.
ISTC Training Modules 2008
Management of Drug-Resistant TB
Summary (cont.):
Patients can be treated with a standardized or an empiric regimen. Ideally the regimen should be guided by drug-susceptibility tests.
There are sound principles that can be used to guide the design of a treatment regimen.
ISTC Training Modules 2008
Management of Drug-Resistant TB
Summary (cont.):
Considerable attention must be paid to treatment supervision and support.
A patient-centered approach to DOT is an important element of successful care
Adverse effects of second-line drugs are common and may be severe. Monitoring for these effects is essential.
ISTC Training Modules 2008
Standard 15: Patients with TB caused by drug-resistant
(especially MDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs.
At least four drugs to which the organisms are known or presumed to be susceptible should be used (treatment for at least 18 months).
Summary: ISTC Standard Covered*
*[Abbreviated version]
ISTC Training Modules 2008
Standard 15 (cont.):
Patient-centered measures are required to ensure adherence.
Consultation with a provider experienced in treatment of patients with MDR-TB should be obtained.
Summary: ISTC Standard Covered*
*[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
ISTC Training Modules 2008
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
Management of Drug-resistant TB
1. The 5 year-old son of a woman you are currently treating for known isoniazid and rifampicin resistant tuberculosis presents with cough and malaise for three weeks and an abnormal chest film. Of the following available regimens, choose the one best option:
A. Begin empiric treatment with at least four drugs that the mother’s organism is known to be susceptible to
B. Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide with the addition of a fluoroquinolone
C. Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide
D. Treat first for a potential community-acquired pneumonia with a fluoroquinolone
ISTC Training Modules 2008
Management of Drug-resistant TB
2. Reasonable steps for building a regimen for multidrug-resistant tuberculosis after drug-sensitivities results are known include all of the following except:
A. Always start by choosing any available first-line drug that the isolate remains susceptible to
B. Aim for a total of four to six drugs that the isolate is known to be sensitive to (preferably not drugs used previously by the patient)
C. Second-line agents (like cycloserine, ethionimide, and PAS) would be preferred over injectable agents to minimize healthcare resources used in association with injections and improve patient comfort
D. If there are not four to six drugs available among the first- and second-line agents, third-line agents could be considered, preferably in consultation with an expert
ISTC Training Modules 2008
Management of Drug-resistant TB
3. Clinical management and monitoring plans for the care of MDR/XDR-TB should include (as resources permit) all of the following except:
A. Daily patient-centered directly observed treatment (DOT) throughout the entire treatment course
B. Diligent recording of drugs given, bacteriological results, chest film findings and any occurrence of medication toxicity
C. Periodic sputum specimens for smear and culture, both to document culture conversion and monitor for signs of treatment failure
D. Monthly sputum for drug-sensitivity testing throughout the entire course of treatment