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New England TB Intensive
Ronald J. Karpick, M.D.
F.A.C.P., F.C.C.P.
Fairfax County Health Department
9-15-08
Drug Resistant Tuberculosis
Goals for today
• Learn how to treat drug resistant TB before
all of the susceptibilities are known
• Learn about the consultation services of the
RTMCCs
• Recognize that we are at a point in time to
diagnose and treat TB disease better
• Become aware of the future in TB care
2008 TB Statistics
Fairfax County 98 people 9.3/100,000
Virginia 292 3.8
USA 12,898 4.2
TB in Fairfax County
2008
Number of
cases
98 9.3/
100,000
US born 10 10.2%
Foreign
born
88 89.8%
Drug
Resistant
INH-9
MDR-1
12.9%
1.4%
HIV 2 2.0%
Case
• 21 yo woman from India, in USA one year.
• History of a positive TST, negative HIV
• 10 days of a progressively severe headache
associated with low grade fever of 101.2,
chills, stiff neck, photophobia and a 3 lb.
weight loss over the past 3 months.
• PE: Stiff neck
Lab Data 7-10-08
• WBC 8.2, HGB 11.7, platelets 273
• BUN 10, Cr 0.8, Glucose 93
• Liver associated enzymes-normal
• Lumber Puncture Cerebral Spinal Fluid
Total protein 90 mg% ( nl.=18-58)
Glucose 93 mg%
WBC: 32: ( nl <6)
14 polys, 72 lymphs,
8 monos
Tuberculoma
MRI
Chest X-ray
Miliary Tuberculosis
High Resolution CAT scan of the lung
Clinical Course
• Increased Hydrocephalus
• ALT up to 443, stopped INH, Rif and PZA
• Started on Amikacin, Moxifloxin, EMB
• Eventually got back on INH, Rifampin,
EMB and PZA
• Placed a Ventricular Shunt
Clinical Course
• Patient actually doing better, ready to be discharged
from the hospital, admitted 7/10/08
• 9/09/08 Bronchial biopsy from 7/22 positive for M. tb
• 9/18/08 CSF grew M. tb
• 9/22/08 Resistant to all first line drugs:
INH, RMP, PZA, EMB
(2 months after culture submitted!)
• Revise Treatment program! How?
• Review Francis Curry Center “Clinician’s Guide to
Drug Resistant TB”
MDR TB in the World
Totally Drug Resistant TB
• 15 isolates
• Beijing and Haarlem I
superfamilies
• Pts. from Afghan,
Azerbaijan, Iraq and
Iran
• Resistant to all first
and second line anti-
TB drugs
Chest 2009; 136: 420-425
Regional Training and Medical
Consultation Centers
Empirical Drug Regimen
1) Moxifloxacin 400 mg./day
2) Amikacin 15 mg./Kg. Daily
3) Cycloserine 250 mg. plus Vit. B6 100 mg./d
4) Linezolid 600 mg. po daily
5) Isoniazid 900 mg. twice a week
Southeast National Tuberculosis Center
1-800-4TB-INFO or 1-800-482-4636
Second line drug susceptibilities
10/28/08
(3 months after specimen
collected)
INH 0.4---------Resistant
Ofloxacin-------Resistant
Ethionamide----Borderline
Capreomycin---Susceptible
Second line drug susceptibilities
10/28/08
(3 months after specimen
collected)
INH 0.4---------Resistant
Ofloxacin-------Resistant
Ethionamide----Borderline
Capreomycin---Susceptible
Pre-XDR TB
What do we suggest now?
• Stop Isoniazid ?
• Continue Moxifloxin ?
• Continue Amikacin ?
• Continue Cycloserine ?
• Continue Linezolid ?
• Consider add Paser (PAS) ?
• Consider add Augmentin ?
• Wait for CDC report? When
will it come?
What I did
• Stopped INH
• Continued Moxifloxin
• Continued Amikacin
• Continued Cycloserine/ Vitamin B6 100 mg
• Continued Linezolid
• Added PAS 4 gram twice a day
Wanted to have at least 5 drugs
CDC Results
5 months later
Susceptible
• Isoniazid 5.0 ug/ml
• Kanamycin
• Capreomycin
• Amikacin
• PAS
Resistant
• Isoniazid 0.2 and 1.0
• Rifampin/Rifabutin
• Ethambutol
• Streptomycin
• Ciprofloxacin
• Ofloxacin
• Ethionamide
Still pre- XDR!
New Suggestions for the Treating
Physicians
• Discontinue Moxifloxcin (???)
• Continue Amikacin 15 mg./d three days/week
• Continue Cycloserine 250-500 mg./day (check serum level)
• Continue Linezolid 600 mg./day
• Continue PAS 4 grams twice a day
• Continue Vitamin B6 100 mg./day
Is this the way that TB should be
treated?
• NO!!!!
• We need more rapid turn around times for
the detection of the TB organism
• We need more rapid turn around time for
the drug susceptibility tests, first line and
second line
How could this course be
avoided?
• Are there more rapid diagnostic tests for TB?
• AFB stains do not distinguish between the various species of Mycobacteria
• Nucleic Acid Amplification Tests-(Gen-Probe and Amplicor) used on AFB smear positive sputa. If positive, MTC is presumed.
Performance of Gen-Probe MTD and
Roche Amplicor M. tb Test Direct
Smear +
(%)
Smear –
(%)
Sensitivity 95-96 48-53
Specificity 100 96-99
PPV 100 24-58
NPV 86-90 99
AJRCCM 1997;155:1804-1814
Barnard, M et al., AJRCCM 2008; 177: 787-792
South Africa-536 specimens
Statistics !
• Sensitivity= No. true positives divided by
no. true positives plus no. false negatives
• Specificity= No. true negatives divided by
no. true negatives plus no. false positives
• Positive Predictive Value (PPV)=No. true
positives divided by no. true positives plus
no. false positives
• Negative Predictive Value (NPV)=No. true
negatives divided by the number of true
negatives plus the no. of false negatives
Causse,M et al., IJTLD 2008; 12(12): 1456-1460
Spain-54 Specimens
GenoTypeMTBDRplus
Smear Negative specimens
• If culture was negative, MTBDR was neg.
• Three cultures were contaminated and MTBDR gave results
• Twenty-five cultures were positive and drug susceptibility testing was done on 20.
– 80% gave interpretable MTBDR results for RIF
– 74% gave MTBDR results for INH!
Value with HIV patients-usually with low bacillary loads
Barnard et al., AJRCCM 2008;177:787-792
Holtz T et al., Ann Int Med 2006; 144: 650-659
Latvia 2000
Leimane V, et al., Lancet 2005; 365: 318-326
Latvia 2000
GenoType MTBDRsl
106 clinical isolates, 64 sputa
Sensitivity Specificity
FLQ 90.2% 100%
AMIKACIN 83.3 100
CAPREOM 86.8 99.1
EMB 59 100
J. Clin. Micro 2009;47: 1767-1772
Why don’t we use these tests?
• MMWR 1/16/09; 58(1):7-10 CDC
recommends NAA testing of one AFB
smear positive sputum on all clients, but no
money given to the labs
• The CDC has put money into Genotyping
which has a certain value
• However, in this time when it still takes at
least 30 days to get drug susceptibilities and
usually longer if drug resistance is
appearing, this time lag is not acceptable!
If Nucleic Acid Amplification
was more available
• If M. tb was ruled out, patients would not be exposed to potentially toxic medications
• Respiratory Isolation would not be imposed
• Contact investigation would not be initiated
• If drug resistance was known within 48 hours, more appropriate medications would be prescribed for the patient
• This would decrease length of illness, infectiousness and thus spread of disease
What More is Needed?
Need additional rapid molecular tests to check for the other drugs.
EMB embB ETHI ethR, ethA,
inhA, katG
PZA pncA CSN air, ddl
SM rpsL/
rrs
PAS
KANA necK IMIP
AMIK rrs LINE
CAPR cac, cph
tlyA
FQ GyrA/B,
IfrA
Need More Therapies
• Linezold
– PNU 100480
• Fluoroquinolones-Moxifloxcin
• SQ109 (Diamine)
• TMC-207 (“J” drug, Diarylquinoline)
• OPC 67,683 ( a Nitro-Dihydro-Imidazooxazole
• PA-824 (Nitroimidazopyran)
• BTZ 043 (Benzothiazone)
• Adjunctive Immunotherapy (M. vaccae)
• Micro-Nutrients ?
Still Need Surgery
Perform surgery before the client gets to
XDR status so that there are medications
available to treat the client after the surgery
to ensure the patient is cured.
Summary
• Need to collect specimens for culture and
drug susceptibilities
• Do rapid screening for drug resistance
• Tailor the patients medications depending
on the drug susceptibilities as defined by
rapid testing and confirmed by liquid and
agar susceptibilities
Summary (2)
• Select drugs from the first line and then the
second line and finally from the third line
classes until you have at least 5 drugs
including one injectable drug to which the
organism is susceptible
• Monitor the culture conversion and if this is
extended beyond 3-4 months, consider
surgery if the patient has sufficient
pulmonary reserve and there are drugs
available to treat after surgery
Summary (3)
• Never add one drug to a failing regimen,
you will only promote drug resistance!
What we did today
• Learned how to treat drug resistant TB
before all of the susceptibilities are known
• Learned about the consultation services of
the RTMCCs
• Recognize that we are at a point in time to
diagnose and treat TB disease better
• Became aware of the future in TB care
Thank you !!