Objectives
Treatment of Drug Resistant TB Diana M. Nilsen, RN, MD Bureau of TB Control New York City Department of Health & Mental Hygiene
¾ Definition of other drug resistant (ODR),
multiple drug resistant (MDR TB) and extensive drug resistant TB (XDR TB) ¾ Discussion of the drugs and therapies used for treatment of drug resistant TB ¾ Discussion of isolation issues related to MDR TB ¾ Case discussion of MDR TB
Revised Definition XDR TB (10/06)
Definition of DR TB ¾
MDR TB A specimen of M. tuberculosis isolate that is resistant to at least INH and RIF Can be resistant to other drugs as well
¾
ODR TB Resistant to INH, sensitive to RIF, with or without resistance to other first or secondsecond-line drugs Resistant to RIF, sensitive to INH, with or without resistance to other drugs Resistance to any (1 or more) firstfirst-line drugs (EMB, PZA, SMN) other than INH or RIF
¾ Resistance to at least INH and RIF from
among the 1st -line antianti-TB drugs (MDR TB) ¾ Plus resistance to any fluoroquinolone, fluoroquinolone, ¾ And to at least one of 3 injectable 2nd-line antianti-TB drugs used in TB treatment
Capreomycin Kanamycin Amikacin
Tuberculosis Cases and Rates New York City, 1980 – 2009*
MultiMulti-drug Resistant TB* New York City, 19921992-2009
760 Cases in 2009 Number of Cases 4,000
Rate/100,000 60 51.1
Case Rate # Cases
3,500
441
50
400
3,000 40
2,500 2,000
Number of Cases 500
296
300 30
21.4
1,500
9.1
20
176
200
109
1,000 10
500
*Rates since 2000 are based on population estimates.
% of MDR Cases
% of all Cx+ cases with susceptibility results who had drug resistance
18
10 8 6 4
11
MDRTB
100
18
ODRTB 13
15
13 13
12
4
12
16
15
1414
13 13 12 12 11 11 11 11
16
18
21
19
20
43
67
40
40
4
3
3
2
3
3
2
2
3
2
3 1
2
2
20
57
57
33
56
55
Unknown
62
61 54
75
57
51 39
40 30
26
21 8
0
19
22
29
33
36
24 13
92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
Year
Year MDR-TB: resistance to at least INH & RIF ODR-TB: resistance to other first-line drugs but not multi-drug resistant
13
64
0 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
9
35
18
72 63
11
20 9
55
5
14
17
37
25
60
24
25
33
80
11 10
14
25
8 6
8
Multidrug Resistant Tuberculosis* by HIV Status New York City, 19921992-2009
20
12
9
*Multi-drug resistant TB or MDRTB: organism resistant to at least INH & RIF
Tuberculosis Drug Resistance New York City, 19921992-2009
14
53 38 31 25 24 27 21 18 24 21
92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 Year
Year
16
84
0
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
0
100
*Defined as resistant to at least INH & RIF
HIVHIV+
Characteristics of MDR Cases (N=8) New York City, 2009 ¾ 100% are nonnon-US born ¾ 13% are
HIVHIV-positive ¾ 100% had pulmonary TB only ¾ 75% reside in Queens ¾ 86% of those eligible are on DOT
DrugDrug-Resistant TB • DrugDrug-resistant TB transmitted same way as drugdrug-susceptible TB • Drug resistance is divided into two types
Primary resistance develops in persons initially infected with resistant organisms − HealthHealth-care associated transmission − Community transmission
Secondary resistance (acquired resistance) develops during TB therapy − Nonadherence to therapy − Inappropriate therapy
Rates of Natural Resistance in M. tuberculosis ¾ Isoniazid ¾ Rifampin ¾ Ethambutol ¾ Streptomycin ¾ INH & RIF
1 in 106 1 in 108 1 in 106 1 in 105 1 in 1014
Number of organisms in a TB cavity = 109-1011
Pathogenesis of Drug Resistance I
R
I II I I I i I I I
INH RIF PZA
INH
I
I I
I I I
Pathogenesis of Drug Resistance II I
I i I
I
I I
I
I
I
I
I
IR
I
I
INH RIF
IR I
I I
IR I
I
IR
I
IR
IR
(Inappropriate Therapy) Treatment Isoniazid Rifampin Ethambutol
6/08
Smear Culture
+ +
9/08
2/09
+ +
+ +
R R S
R R R
IR
IR
IR IR
IR
IR
IR
Emergence of Resistance
Susceptibility Isoniazid Rifampin Ethambutol
IR
IR
R S S
14
MDR/ODR TB
Emergence of Resistance (Nonadherence and Inappropriate Therapy) Treatment Isoniazid Rifampin Ethambutol
6/08
Smear Culture
+ +
9/08
12/08 3/09
6/09
Accurate and prompt identification Notification to the field staff and provider(s) provider(s) Appropriate case management
? DOT
Susceptibility Isoniazid Rifampin Ethambutol
S S S
+ +
+ +
+
R S S
R S R
R R R
¾ Patients with DR TB need to have
+ +
15
Antituberculosis Drugs First-Line Drugs
Second-Line Drugs Streptomycin
•
Isoniazid
•
•
Rifampin
•
Cycloserine
•
p-Aminosalicylic acid
•
Ethionamide
•
Amikacin or kanamycin* kanamycin*
•
Capreomycin
•
Levofloxacin* Levofloxacin*
•
Moxifloxacin*
•
Pyrazinamide
•
Ethambutol
•
Rifabutin* Rifabutin*
•
Rifapentine
Third-Line Drugs Used in MDR TB Treatment ¾
Linezolid Used since 2000 in selected cases Adverse effects of pancytopenia and peripheral/optic neuritis • may or may not be reversible • may or may not be ameliorated by vitamin B6 • consider using 600 mg daily Use with caution with selective serotonin reuptake inhibitors (SSRIs (SSRIs))
* Not approved by the U.S. Food and Drug Administration for use in the treatment of TB
Third-Line Drugs Used in MDR TB Treatment-II ¾
¾
Clofazimine More commonly used in patients with leprosy Used in selected cases Needs IND γ-Interferon Research medication Inhaled Used only with pulmonary disease AFB smear + Expensive
Step 1 Use any available Begin with any 1st-line agents to which the isolate is susceptible
First-line drugs
Add a fluoroquinolone and an injectable drug based on susceptibilities
Adapted from Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, available from Francis J. Curry National Tuberculosis Center
Pyrazinamide Ethambutol
PLUS
One of these
PLUS
One of these
Fluoroquinolones
Injectable agents
Levofloxacin Moxifloxacin
Amikacin Capreomycin Streptomycin Kanamycin
Step 1
Step 1 Use any available
Begin with any 1st-line agents to which the isolate is susceptible
PLUS
First-line drugs
Add a fluoroquinolone and an injectable drug based on susceptibilities
Pyrazinamide Ethambutol
Step 2 Add 2nd-line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)
One of these
PLUS
One of these
Fluoroquinolones
Injectable agents
Levofloxacin Moxifloxacin
Amikacin Capreomycin Streptomycin Kanamycin
Use any available Begin with any 1st-line agents to which the isolate is susceptible
First-line drugs
Add a fluoroquinolone and an injectable drug based on susceptibilities
Pick one or more of these
Pyrazinamide Ethambutol
Add 2nd-line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)
Cycloserine Ethionamide PAS
Principles for Managing MDR TB ¾
MDR TB should never be treated without expert consultation of a specialist in MDR TB treatment ¾ Patients must be treated with a regimen of at least 33-5 antianti-TB medications to which the strain is likely to be susceptible (4(4-6 or better)
Adapted from Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, available from Francis J. Curry National Tuberculosis Center
One of these
PLUS
Fluoroquinolones
Injectable agents
Levofloxacin Moxifloxacin
Amikacin Capreomycin Streptomycin Kanamycin
Oral second-line drugs
Step 3 Adapted from Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, available from Francis J. Curry National Tuberculosis Center
One of these
Pick one or more of these
Step 2
Oral second-line drugs
PLUS
If there are not 4-6 drugs available consider 3rd-line in consult with MDRTB experts
Cycloserine Ethionamide PAS
Consider use of these Third-line drugs Imipenem Linezolid Macrolides Amoxicillin/Clavulanate Clofazimine High-dose isoniazid
Principles for Managing MDR TB - 2 ¾ A single new drug should never be added to a failing regimen ¾ When initiating or revising therapy, always attempt to use at least 3 previously unused drugs to which there is in vitro susceptibility
One agent should be an injectable agent A good response does not justify continuation of an inadequate regimen
Principles for Managing MDR TB - 3 ¾
Patients with DR TB should be treated under a program of DOT Intermittent regimens should not be used. All 2nd-line agents must be administered daily Twice/day DOT should be used when feasible, and more frequent dosing than twice daily should be avoided All doses must be observed for the patient to get credit
Principles for Managing MDR TB - 5 ¾
Resistance to RIF is generally associated with crosscross-resistance to rifabutin and rifapentine When RIF resistance is present but in vitro sensitivity to rifabutin is reported, treatment should be the same as if RIFRIF-resistant
¾ ¾
There is crosscross-resistance between amikacin and kanamycin Determination of resistance to PZA is problematic, but is uncommon in the absence of resistance to other 1st-line drugs If monoresistance to PZA is found, consider the specimen may be M. bovis, bovis, not M. tb
Principles for Managing MDR TB – 4 ¾
¾
¾
Injectable agents can be given 5 days/wk initially. After culture conversion, dosing for injectable can be 22-3 times/wk With extensive disease or slow conversion of sputum cultures, the injectable should be used for longer periods after culture conversion Fluoroquinolones: Fluoroquinolones: Levofloxacin is the preferred agent of choice in adults Moxifloxacin is used w/ the approval of the BTBC Bureau Director
Principles for Managing MDR TB - 6 ¾ ¾
Serum drug level monitoring may be used Most medications used to treat MDR TB are known to cause fetal abnormalities or have not been studied adequately regarding their safety in pregnancy In pregnant MDR TB patients, patients, PZA can be used as a main agent, and is recommended by WHO & ATS WHO recommends its use in pregnancy even for drugdrug-susceptible TB patients In the U.S., it is considered a category C agent
Principles for Managing MDR TB - 7 ¾
¾
¾
Some experts use EMB at a dose of 25 mg/kg daily when used as treatment of patients with MDR TB If this higher dose is used, monthly visual monitoring is recommended If isolates show resistance to INH only at a low concentration, concentration, INH 900 BIW (high intermittent dose) can be used. Do not rely on its effectiveness as a main agent. This may be applicable to the W strain Surgery should be considered if a patient’ patient’s cultures fail to convert to negative after 4 months of appropriate treatment
Drug Intolerance
Principles for Managing MDR TB - 8 For all with RIFRIF-resistance (mono(mono-RIF or MDR TB), consider extended therapy if:
¾
¾
There is cavitary or extensive disease The patient is HIVHIV-positive or has risk factors for HIV infection The patient is immunosuppressed Time to culture conversion is prolonged
All patients with RIFRIF-resistant TB should be followed for at least 1212-24 months after treatment completion
INH Resistant TB Initial Phase
¾ In
general, length of treatment for drug intolerance is the same as for drug resistance.
Continuation Phase
Total length
RIF/PZA/EMB 2 months
6-9 months
RIF/PZA/EMB
2 RIF/EMB months
9 months
RIF/EMB + FQ or IA
2 RIF/EMB + FQ months or IA
12 months
RIF/PZA/EMB If extensive disease consider adding a 4th agent (FQ or IA)
Extend to 9 months if culture positive at 2 months • Preferred regimen, even in pregnancy •
Rifampin Resistant TB Initial Phase
PZA+ Strep Resistance
Continuation Phase Total length
INH/PZA/ EMB 2-3 months INH/PZA/ EMB 18 months Injectable+FQ after culture + FQ (preferred conversion regimen)
Initial Phase
INH/RIF/EMB 2 months
Continuation Phase
INH/RIF
Total length
9 months
INH/PZA/ SMN 2-3 months INH/PZA/ SMN 9 months + EMB after culture + EMB conversion
INH/EMB + SMN Resistant TB Initial Phase
RIF/PZA/FQ + injectable
2-3 months after culture conversion
Continuation Phase Total length
RIF/PZA/FQ
9-12 months 6 months after culture conversion, whichever longer
•
MDR TB
Initial Phase INH/RIF + SMN
PZA/EMB/FQ & IA, 5 days a week
INH/RIF/EMB PZA/FQ/IA + SMN 5 days a week plus at least 11-2 secondsecond-line agents* INH/RIF/PZA + SMN
EMB/FQ/ IA, IA, 5 days a week plus at least 11-2 secondsecond-line agents *
INH/RIF/PZA/ FQ/IA, FQ/IA, 5 days a EMB + SMN week plus at least 22-3 secondsecond-line agents*
Continuation
6 months after culture conversion
PZA/EMB/FQ
PZA/FQ plus at least 112 secondsecond-line agents
Total length
1818-24 months after culture conversion
Extend therapy: • Cavitary EMB/FQ, EMB/FQ, plus disease at least 11-2 secondsecond-line • HIV positive agents or risk factors • ImmunoImmunoFQ plus at least suppressed 2-3 secondsecond-line • Prolonged agents time to culture conversion
MDR TB Initial Phase
General Side Effects of Medications
Continuation Total length
INH/RIF/EMB/ SMN/KAN/ ETH/RBT + PZA (strain W and W variants)
FQ/IA plus at least 22-3 other agents to which the organism is susceptible
6 months after culture conversion
FQ plus at least 22-3 second line agents to which organism susceptible
1818-24 months after culture conversion
INH/RIF/EMB/ SMN/FQ/ + 2nd-line IA +PZA (i.e. XDR TB)
Any 33-4 drugs to which organism is susceptible. Consider Linezolid, Linezolid, Clofazamine & γ-interferon
Until culture conversion
Any 33-4 drugs to which organism is susceptible. Consider Linezolid, Linezolid, γ-interferon & Clofazamine
•
¾ All medications can cause skin rash ¾ Allergic reactions/hypersensitivity ¾ Diarrhea
At least 24 months after culture conversion • Ideal therapy duration unknown • Evaluate for early surgery
Drug Activity Against TB Bactericidal vs. Bacteriostatic Bactericidal ¾ INH ¾ Rifampin ¾ Streptomycin ¾ Capreomycin ¾ Kanamycin/Amikacin ¾ Moxifloxacin
Bacteriostatic ¾ PZA ¾ Ethambutol ¾ Levofloxacin (may be bactericidal) ¾ Ethionamide ¾ PAS ¾ Cycloserine
Treatment of Contacts to Drug Resistant TB ¾
Persons exposed to INHINH-resistant TB: - Rifampin: Rifampin: − 4 months adults − 6 months children
¾
Persons likely infected with MDR TB: - 6-12 months PZA and EMB, or PZA and FQ (i.e., ≥ 2 drugs to which organism is susceptible) - Usually 12 months for immunocompromised and children - Option to follow for 2 years if no treatment given
Indications for Surgery ¾
¾ ¾ ¾ ¾ ¾
Adequate 1st and 2nd -line regimens of antianti-TB medications have failed to cure or cause M. tb cultures to convert to negative within 4 to 6 months Sufficient medications are available to treat the patient postoperatively Localized disease Remaining lung tissue is relatively free of disease Acceptable surgical risk, with sufficient pulmonary reserve to tolerate the resection Additional possible indications for surgery: 9 Major bronchial obstruction 9 Severe hemoptysis, hemoptysis, or 9 Bronchopleural fistula (BPF)
Infection Control Issues Related to Multidrug Resistant TB Patients ¾ MDR TB patients should remain hospitalized or on home isolation if an outpatient until:
3 sputum smears are AFBAFB- negative Clinically improved and near resolution of cough Tolerating an appropriate treatment regimen Patient agrees to DOT and it has been arranged Proper arrangements have been made for followfollow-up A home assessment should be done with evaluation for insertion of a HEPA filter in the residence
Surgery for MDR TB Patients ¾ Even after lung resection, the patient
must complete a full course of treatment (i.e., 1818-24 months after culture conversion) with medications to which the M.tb strain is susceptible ¾ If patient is culture negative after surgery, then surgery is considered the conversion episode
Situations Where Culture Conversion Should Be Confirmed Prior to Return to Work ¾ Work sites where individuals with drug susceptible TB and MDR TB should be excluded until culture conversion is confirmed:
Work sites where persons with HIV or other immunocompromised patients are cared for Neonatal intensive care units Patient care areas Nursing homes Congregate settings such as daycare and schools
Follow-up of MDR TB Patients after Treatment Completion
Returning MDR TB Patients to Work or SchoolSchool-Culture Conversion ¾ MDR TB patients should be kept from returning to work or school, or transferring to another congregate setting such as a shelter or nursing home until culture conversion is confirmed 2 consecutive negative cultures at least 2 weeks apart ¾ Culture conversion is necessary unless the patient will be transferred to a airborne infection isolation room in the congregate setting
¾ Patients with TB resistant to INH and RIF or treated without RIF/RBT Medical evaluation every 4 months during the 1st year after treatment completion Then every 6 months during the 2nd year ¾ Months: 4, 8, 12, 18, 24 post treatment ¾ Educate about relapse and to return if
they develop symptoms
¾ Exceptions can be made for certain types of work settings, if all the conditions in previous slide are met Decided in consultation w/ Office of Medical Affairs
Case #2
Case #1 ¾
The DR Coordinator informs you that your patient at the private doctor’ doctor’s office has INH resistant tuberculosis. The patient has a cavity in the RUL, and still has positive cultures into the 2nd month of therapy 1. What are the different options for treatment, and the length of therapy? 2. Who should be informed? 3. How should the patient’ patient’s 4 year old and 10 year old children be treated for LTBI?
¾
Patient in the clinic is still infectious after 1 ½ months of INH/RIF/PZA/EMB. The report comes back from the lab that the patient is resistant to INH/RIF/PZA and sensitive to EMB 1. How should this patient be treated initially and for how long? 2. When can the patient return to work/school? 3. What should be discussed in the case management meeting about this patient? 4. How long should the patient be followed after completing therapy 18 months later?
