New England TB Intensivenewenglandtb.pbworks.com/f/TB Intensive Drug... · 1) Moxifloxacin 400 mg./day 2) Amikacin 15 mg./Kg. Daily 3) Cycloserine 250 mg. plus Vit. B6 100 mg./d 4)

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 !!