Adrian Gardner MD, MPHAssistant Professor of Medicine (Research)

Warren Alpert Medical School of Brown UniversityJune, 2011

I have no relevant financial disclosures or conflicts of interest

Background of Drug Resistance◦ How does drug resistance develop?

MDR/XDR TB◦ Definitions and Epidemiology

Management: Clinical Case

Cross-resistance and Management of MDR Contacts

Multidrug resistance is a “man-made phenomenon”

◦ Primary (Initial):Drug resistance seen in the first isolate taken from the patient BEFORE the patient received any TB medications

◦ Acquired: Drug resistance seen in isolates that are taken after initiation of TB therapy (> 1 month)

Mechanisms:◦ Spontaneous genetic mutations Occur spontaneously at known rates for each drug Each of the drug mutation sites are independent

Unpaired drug use selects for drug resistance

Anti-TB drug Rate of mutation

INH 1 in 108

Rifampin 1 in 106

Ethambutol 1 in 107

Streptomycin 1 in 106

Fluoroquinolone 1 in 106-8

INH and Rifampin 1 in 1014

David HL. Applied Microbiology. 1970

Number of

organisms

present

Number of

drugs required

LTBI 10-100 1

Cavitary TB

Disease

100,000,000,000 2

Unique property◦ Works at an acidic pH◦ Works best on intracellular organisms (packaged in

lysosomes- acidic pockets within cytoplasm)◦ Reduces the length of therapy

Does not prevent emergence of resistance in a companion drug◦ Therefore, a patient who is on RZ is really on only one

effective drug = R

Drug A kills organisms susceptible to drug A and

those resistant to drug B

Drug B kills organisms susceptible to drug B and

those resistant to drug A

Any organisms that underwent both mutations

would not be killed by this combination◦ But the probability of one organism undergoing both

mutations is small

INHRIFPZA

INH

Drug-resistant

mutants in large

bacterial population

Multidrug therapy: No bacteria resistant to all 3 drugs

Monotherapy: INH-resistant

bacteria proliferate

Albino & Reichman. Respiration. 1998

INHRIF

INH

Spontaneous mutations

develop as bacilli

proliferate to >108

INH mono-resist.

mutants killed,

RIF-resist. mutants

proliferate MDR TB

INH resistant

bacteria multiply

to large numbers

Albino & Reichman. Respiration. 1998

Good TB control principles◦ PREVENT DRUG RESISTANCE

◦ ADHERENCE TO THERAPY

Identify cases

Treat with the correct regimen

Be attentive to and support adherence

In order to effect a cure, TB must be treated with at least two drugs to which the organism is susceptible.

◦ Two drugs – the uncoupling of drugs leads to drug resistance

◦ Susceptibility This is not know when the patient walks into the office

It can take weeks-months to obtain this information, so we usually start with 4 drug therapy

Development of drug-resistance is more complex◦ Model including: mutations occurring in the

absence of drug pressure, timing of mutations, death of organisms by immune system (ie many more replications have occurred), fitness costs.

◦ Calculated probability of emergence of resistance to R/H in the range of 10-5 to 10-4.

Colijn, et al. Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during therapy, PLoS One. March 30, 2011.

Other Mechanisms

◦ Exposure of Rifampin-resistant TB to Rifampin activates efflux pumps and transporter genes that reduce susceptibility to ofloxacin.

? Role for Efflux pump inhibitors (verapamil)

Thioridazine

Louw GE, et al. AJRCCM, April 21, 2011

MDR (Multidrug-resistant) TB:◦ Resistance to Isoniazid and Rifampin

XDR (Extensively drug resistant) TB:◦ Resistance to Isoniazid, Rifampin, Fluoroquinolone

and one of the 2nd line injectables

Estimated number of

annual cases (2008-

2009)

Estimated number of

annual deaths (2008-

2009)

All forms of TB (greatest

number of cases in Asia,

greatest rates per capita in

Africa)

9.4 million new cases

(137 per 100,000)

1.7 million

MDR-TB 440,000 150,000

XDR-TB ~ 50,000 ~ 30,000

Global TB Estimates

States Culture positive TB cases

INH resistance MDR

Maine 12 0 0

New Hampshire 29 4 (1.4%) 0

Vermont 7 - -

Massachusetts 380 37 (9.7%) 6 (1.6%)

Rhode Island 40 2 (5.0%) 0

Connecticut 162 20 (12.3%) 2 (1.2%)

TOTALS 630 63 (10%) 8 (1.3%)

CDC, Reported TB in the United States, 2008 and 2009 Annual Reports

Individuals with history of poor adherence◦ Alcohol/substance abuse

Individuals who develop TB disease again

after having completed therapy (recurrent)

Individuals from areas of world where DR-TB is common

Contacts of know DR-TB cases

Armenia

Azerbaijan

Bangladesh

Belarus

Bulgaria

China

Democratic Republic of Congo

Estonia

Ethiopia

Georgia

India

Indonesia

Kazakhstan

Kyrgyzstan

Latvia

Lithuania

Myanmar

Nigeria

Pakistan

Philippines

Republic of Moldova

Russian Federation

South Africa

Tajikistan

Ukraine

Uzbekistan

Vietnam

AP was a 26 year old female from India who had been living in US for 8 years◦ Presented to Emergency Department with cough

◦ Diagnosed with pneumonia and treated with FQ

◦ In follow-up, she continued to have cough and bronchoscopy was performed (BAL: AFB smear +)

◦ Started on R/H/Z/E

◦ 3 weeks later, her susceptibility results return with resistance to H/R/Z/E/S

Isoniazid

Rifampin

Ethambutol

Pyrazinamide

First-line

Other 2nd-line

Injectable

Quinolone

Ofloxacin

Levofloxacin

Moxifloxacin

Streptomycin

Kanamycin

Amikacin

CapreomycinEthionamide

Cycloserine

PAS

6. Never add single drug to failing regimen

1st line drugs◦ Better efficacy

◦ Less toxicity

2nd line drugs

Less efficacy◦ Substitute 2 for one 1st

line drug

More toxicity◦ All patients on second

line drugs WILL have side effects

◦ Just have to treat the side effects- cannot stop or the patient will die

Drug-Resistant Tuberculosis: A Survival Guide for Clinicians

Francis Curry International Tuberculosis Center

1st line drugs

◦ INH

◦ Rifampin

◦ Pyrazinamide

◦ Ethambutol

◦ Streptomycin

◦ Quinolones

2nd Line drugs◦ Ethionamide

◦ Para-aminosalicyclic

acid (PAS)

◦ Cycloserine

◦ Injectable

Capreomycin

Kanamycin

Amikacin

X

Started on levofloxacin, KM, ETA, PAS, Cycloserine◦ 2nd line DST did not reveal any other resistance

◦ Developed joint pains levo discontinued◦ Capreomycin decreased to 3x/wk after 3 months◦ Levofloxacin re-started◦ Cultures negative after 2 months

◦ Patient noted hair loss ETA discontinued◦ Capreomycin discontinued after 1 year◦ Levofloxacin, Cycloserine, PAS continued to

complete 24 months

Length of

treatment

Regimen/ # of

drugs

Cure rate

Pansusceptible 6 months H/R/Z x 2,

H/R x 4

99%

INH resistance 12 months 2 (R/E) 95% Z throughout

improves

outcome, ? FQ

Rifampin

resistance

18 months 2 (H/E) 95% ? FQ, ? inject

may allow 12

mo.

INH and

Rifampin

resistance

18-24 months 5 to include

injectable and

a quinolone

70% Consider

surgery

INH, Rifampin

plus

24 months

after sputum

culture

conversion

At least 5 to

include an

injectable

50-70% Consider

surgery

No evidence-based guidelines

Management of MDR contacts globally is inconsistent and ineffective

There is an urgent need to generate evidence to guide policy

“Consensus” Strategies◦ Periodic medical assessment/CXR at 6 month

intervals for 24 months

◦ Treatment with INH or Rif if source of infection is not entirely clear

◦ Use medications to which source case’s isolate is susceptible

FQ + Ethambutol/PZA for 6-12 months

Background of Drug Resistance◦ How does drug resistance develop?

MDR/XDR TB◦ Definitions and Epidemiology

Management: Clinical Case

Cross-resistance and Management of MDR Contacts

Dr. Jane Carter

Dr. Marie Turner

Funding: ◦ NIH Training Grant:5T32DA13911-09