Extensively Drug-Resistant TB (XDR-TB) Extensively Drug-Resistant TB (XDR-TB) Lynelle Phillips, RN MPH Nurse Consultant Heartland National TB Center Adjunct.

Extensively Drug-Extensively Drug-Resistant TB (XDR-TB)Resistant TB (XDR-TB)

Lynelle Phillips, RN MPHLynelle Phillips, RN MPH

Nurse ConsultantNurse Consultant

Heartland National TB CenterHeartland National TB Center

Adjunct FacultyAdjunct Faculty

UM Masters of Public Health ProgramUM Masters of Public Health Program

Sinclair School of NursingSinclair School of Nursing

March 24, 1882 – “Do March 24, 1882 – “Do we know now, how to we know now, how to fight this enemy?”fight this enemy?” 1882 Robert Koch1882 Robert Koch

discovered the tubercle discovered the tubercle bacillus, Mycobacterium bacillus, Mycobacterium tuberculosis, the bacterium tuberculosis, the bacterium that causes tuberculosis.that causes tuberculosis.

In 1890 Koch announced that In 1890 Koch announced that he had discovered a he had discovered a substance that could protect substance that could protect against tuberculosis and even against tuberculosis and even cure it. He announced the cure it. He announced the following year, that it was a following year, that it was a glycerine extract of tubercle glycerine extract of tubercle bacille, now known as “Old bacille, now known as “Old Tuberculin”. Tuberculin”. (Nobel Prize – (Nobel Prize – 1905)1905) Smithsonian Jan 2002

TB disease treatment TB disease treatment regimenregimen

1944 – Streptomycin – IM if rifampin resistant1944 – Streptomycin – IM if rifampin resistant 1952 - Isoniazid – 6 months minimum1952 - Isoniazid – 6 months minimum

Also for treatment of infected contactsAlso for treatment of infected contacts

1952 – Pyrazinamide – 2 months1952 – Pyrazinamide – 2 months 1962 – Ethambutol – discontinue if 1962 – Ethambutol – discontinue if

pansensitivepansensitive 1966 – Rifampin – 6 months minimum1966 – Rifampin – 6 months minimum

Also for treatment of infected contactsAlso for treatment of infected contacts

A Silent Global EpidemicA Silent Global Epidemic

1/3 of the world’s population infected1/3 of the world’s population infected 8 million new cases of active disease per year8 million new cases of active disease per year 2-3 million deaths per year2-3 million deaths per year One person is newly infected every second One person is newly infected every second

and one person dies every 10 secondsand one person dies every 10 seconds Rising incidence of drug-resistant diseaseRising incidence of drug-resistant disease Billions of dollars in lost productivityBillions of dollars in lost productivity

0 - 24

25 - 49

50 - 99100 - 299

300 or more

No estimate

Rates per 100 000, all forms of TB

Estimated TB incidence rate, 2003

The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement.

© WHO 2004

Second-Line Drug Classes for MDR TB Treatment

Amikacin, Kanamycin

Ciprofloxacin, Ofloxacin

Ethionamide, Prothionamide

Thioamides

PAS

Polypeptides

Serine analogues

Capreomycin

WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006.

Aminoglycosides

Fluoroquinolones

Cycloserine

First line

drugs+

Primary MDR TB inPrimary MDR TB inU.S.-born vs. Foreign-born U.S.-born vs. Foreign-born Persons, United States, 1993–Persons, United States, 1993–2005*2005*

0

1

2

3

1993 1995 1997 1999 2001 2003 2005

U.S.-born Foreign-born

% R

esis

tan

t

*Updated as of March 29, 2006.

Note: Based on initial isolates from persons with no prior history of TB.MDR TB defined as resistance to at least isoniazid and rifampin.

Global WHO/IUATLD/CDC Global WHO/IUATLD/CDC SurveySurvey

Convenience sample (17,690 isolates) Convenience sample (17,690 isolates) submitted to participating international submitted to participating international SRL network, 2000-2004SRL network, 2000-2004 3520 (20%) of isolates MDR TB3520 (20%) of isolates MDR TB 347 ( 2%) of isolates XDR TB 347 ( 2%) of isolates XDR TB

XDRTB in all regions, more common XDRTB in all regions, more common FSU and Asia (Republic of Korea)FSU and Asia (Republic of Korea)

Denominator information unavailableDenominator information unavailable

Isolates contributed to survey

Number of MDR and XDR Cases, by Countries Submitting ≥ 1 M. tuberculosis Isolate to Participating SRLs, 2000–2004

Ind. NationsMDR 821

XDR 53 (6%)

Latin AmericaMDR 543

XDR 32 (6%)

E. EuropeMDR 406

XDR 55 (14%)

AsiaMDR 274

XDR 4 (1%)

Africa, Middle EastMDR 156

XDR 1 (< 1%)

Rep. KoreaMDR 1298XDR 200 (15%)

Total MDR= 3520; XDR= 347 (~ 10% of MDR)*

* Country unknown, MDR= 102; XDR= 2 (2%)

TB Treatment Outcomes, by TB Treatment Outcomes, by Selected Drug Resistance Selected Drug Resistance Patterns, Latvia, 2000-2003*Patterns, Latvia, 2000-2003*

0 10 20 30 40 50 60 70

MDR-TB All

HR+3SLD

HR+INJ+FQ

HR+AG+FQ

Cure Completion Death Default Failed Continue Tx HIV+

* Leimane V, et al. WHO XDR TB Task Force Meeting. Oct 9, 2006 (from N = 820 evaluated)

Percent

KZN Hospital KZN Hospital Background*Background* 119 patients in TB/ARV integration study119 patients in TB/ARV integration study

14 deaths14 deaths 10 (71%) of 14 with MDRTB10 (71%) of 14 with MDRTB 6/10 MDRTB resistant to all tested first and 6/10 MDRTB resistant to all tested first and

second line drugs (SLD) for TBsecond line drugs (SLD) for TB INH, RIF, EMB, STR, KANA, CIPROINH, RIF, EMB, STR, KANA, CIPRO

Suggestive of probable extensive drug Suggestive of probable extensive drug resistant TB in this hospitalresistant TB in this hospital

* Moll A, Gandhi NR, Pawinski R, Lalloo U, Sturm AW, Zeller K, Andrews J, Friedland G. HIV associated Extensively Drug-Resistant TB (XDR-TB) in Rural KwaZulu-Natal(South Africa MRC Expert Consultation Sept 8, 2006)

KZN Drug Resistant TB KZN Drug Resistant TB Survey* Survey*

Jan 2005 Jan 2005 − − Mar 2006 cross-sectional study of Mar 2006 cross-sectional study of patients suspected with active TB in rural patients suspected with active TB in rural district hospitaldistrict hospital

Isolates collected for mycobacterial culture Isolates collected for mycobacterial culture (MGIT) and DST on all (MGIT) and DST on all M. tuberculosisM. tuberculosis culturescultures INH, RIF, EMB, STR, KANA, CIPROINH, RIF, EMB, STR, KANA, CIPRO

Chart reviews of patients with strains resistant Chart reviews of patients with strains resistant to all tested drugs (“XDR TB” cases)to all tested drugs (“XDR TB” cases)

Molecular fingerprinting by spoligotyping on Molecular fingerprinting by spoligotyping on all “XDR TB” isolatesall “XDR TB” isolates

1539 isolates tested

544 (35%) Cx+M. tuberculosis

995 (65%) Cx Negative

221(41%) MDRTB 323 (59%) Susceptible

53 (10%) XDRTB(24% of MDRTB)

KZN Drug Resistant TB Survey Results*

* Moll A, Gandhi NR, Pawinski R, Lalloo U, Sturm AW, Zeller K, Andrews J, Friedland G.HIV associated Extensively Drug-Resistant TB (XDR-TB) in Rural KwaZulu-Natal (South Africa MRC Expert Consultation Sept 8, 2006)

Characteristics of KZN Characteristics of KZN XDRTB PatientsXDRTB Patients

CharacteristicsCharacteristics No. (%)No. (%) No prior TB TreatmentNo prior TB Treatment 26 (51) 26 (51) Prior TB treatmentPrior TB treatment

Cure or Completed treatment Cure or Completed treatment 14 (28)14 (28) Treatment Default or FailureTreatment Default or Failure 7 (14) 7 (14)

HIV-infected (44 tested)HIV-infected (44 tested) 44 44 (100)(100)

Dead (Includes 34% on ARV)Dead (Includes 34% on ARV) 52 (98)52 (98) Identical Identical M. tbM. tb spoligotype spoligotype 26/3026/30

Global 7-point Action Plan to Combat XDR Global 7-point Action Plan to Combat XDR TBTB

Emphasizes Essentials of Proper TB ControlEmphasizes Essentials of Proper TB Control 1.1. Conduct rapid surveys of XDR-TB (determine burden)Conduct rapid surveys of XDR-TB (determine burden)2.2. Enhance laboratory capacity (emphasis on rapid DST)Enhance laboratory capacity (emphasis on rapid DST)3.3. Improve technical capacity of clinical and public health Improve technical capacity of clinical and public health

practitioners to effectively respond to XDR-TB practitioners to effectively respond to XDR-TB outbreaks and manage patientsoutbreaks and manage patients

4.4. Implement infection control precautions (PLHA focus) Implement infection control precautions (PLHA focus) 5.5. Increase research support for anti-TB drug Increase research support for anti-TB drug

development development 6.6. Increase research support for rapid diagnostic test Increase research support for rapid diagnostic test

development development 7.7. Promote universal access to ARVs under joint TB/HIV Promote universal access to ARVs under joint TB/HIV

activitiesactivities

MRC Consultation, Johannesburg, South Africa. Sept 7, 2006

Reported Tuberculosis Cases in Reported Tuberculosis Cases in Foreign-Born PersonsForeign-Born PersonsMissouri 1985-2006Missouri 1985-2006

0

10

20

30

40

50

60percentnumber

Is there XDR TB in the U.S.?(MMWR: 4% of MDR Cases)

XDR Analysis, 2000 – 2004XDR Analysis, 2000 – 2004National TB Surveillance National TB Surveillance SystemSystem

Based on Revised WHO Based on Revised WHO

XDR TB DefinitionXDR TB Definition

Resistant: 13Resistant: 13

Tested:Tested: 509509

Number of Reported TB Number of Reported TB Cases with XDR TB, U.S., Cases with XDR TB, U.S., 2000-20042000-2004

MMWR DefinitionMMWR Definition Revised WHORevised WHO DefinitionDefinition

N= 18 (9 male)N= 18 (9 male) 13 (6 male) 13 (6 male)Age range 19-64Age range 19-64 19-7719-77HIV (+) HIV (+) 22 11HIV (HIV (−)−) 88 55HIV NA/unk HIV NA/unk 33 77CA CA 55 44FL FL 22 00NYC NYC 77 55NJ NJ 11 11IL, NV, TNIL, NV, TN 1 (ea)1 (ea) IL,NV, TX IL,NV, TX 1 (ea) 1 (ea)

ATS/CDC Recommends 4 Drug ATS/CDC Recommends 4 Drug Regimen if INH Resistance Over 4%Regimen if INH Resistance Over 4%ATS/CDC Recommends 4 Drug ATS/CDC Recommends 4 Drug Regimen if INH Resistance Over 4%Regimen if INH Resistance Over 4%

0

2

4

6

8

10

12

% c

ase

s IN

H r

esis

tan

t

INH resistantATS 4-drug guideline

Comparison of INH Comparison of INH resistance between all TB resistance between all TB cases and foreign-born TB cases and foreign-born TB cases - 2006cases - 2006

0

10

20

30

40

50

60

70

2000 2001 2002 2003 2004 2005 2006

% of total INH resistant

% of foreign born INHresistant

1989

1991

1993

1997

1998

1999

2000

2001

2002

RFLP testing

MDR TB outbreakMissouri001mo.H3514

Cx confirmedClinical caseConfirmed epi linkSuspect linkInside DOC Outside DOC

Corrections

Source: U.S. Department of Justice, 1998

Status adjusters in U.S.:~ 305,000

Immigrants andrefugees: ~ 435,000

Undocumented immigrants: ~ 275,000

Temporary visa holders: ~ 30,175,000

N= ~ 61,200,000

Visitors without visas:~ 30,000,000

Migrants Entering U.S.Migrants Entering U.S.

Opportunities for TB Opportunities for TB Prevention in Foreign-born Prevention in Foreign-born Persons in U.S.Persons in U.S.

Immigrants and Refugees

Status Adjusters Immigrants and Refugees

Panel Physicians

Civil Surgeons Health Departments

ICE

Quarantine Stations

Foreign-born Persons not Foreign-born Persons not Screened for TB before U.S. Screened for TB before U.S. "Entry”, 1998"Entry”, 1998

Visitors not requiring Visas: ~30, 000,000 Visitors not requiring Visas: ~30, 000,000 Non-Immigrant Visas: 30,174,627Non-Immigrant Visas: 30,174,627

Temporary Visitors: 27,766,580Temporary Visitors: 27,766,580 Temporary Workers/family: 458,519Temporary Workers/family: 458,519 Students/family: 598,520Students/family: 598,520 Transit Aliens: 365,607Transit Aliens: 365,607 Treaty traders/family: 144,572Treaty traders/family: 144,572 Foreign government officials: 126,543Foreign government officials: 126,543 Other 714,286Other 714,286 Undocumented visitors: ???Undocumented visitors: ???

Source: U.S. Department of Justice, 1998

DGMQ authorityDGMQ authority

……had not been tested since 1963 when had not been tested since 1963 when a traveler suspected of small pox was a traveler suspected of small pox was quarantined.quarantined.

Do Not Board ToolDo Not Board Tool Official request from CDC to DHS/OHA is required; Official request from CDC to DHS/OHA is required;

Upon DHS/OHA’s approval, DHS request TSA to Upon DHS/OHA’s approval, DHS request TSA to add the person to the Do Not Board list or requests add the person to the Do Not Board list or requests Customs and Border Protection to add the individual Customs and Border Protection to add the individual to the Lookout list. The travel restrictions will prevent to the Lookout list. The travel restrictions will prevent an individual from boarding a plane inbound, an individual from boarding a plane inbound, outbound, or within the U.S.outbound, or within the U.S. Applies to aliens and U.S. citizens Applies to aliens and U.S. citizens

Do Not Board is NOT the same as Do Not FlyDo Not Board is NOT the same as Do Not Fly Do Not Fly is aimed at protecting civil aviation and the Do Not Fly is aimed at protecting civil aviation and the

United States from acts of terrorismUnited States from acts of terrorism Persons on Do Not Board are not part of the Do Not FlyPersons on Do Not Board are not part of the Do Not Fly

Missouri Statute 199.210Missouri Statute 199.210

Missouri Rehabilitation Missouri Rehabilitation CenterCenter

July 1, 1996July 1, 1996 MRC becomes MRC becomes directly affiliated directly affiliated with the University with the University of Missouri at of Missouri at Columbia.Columbia.

Inpatient TB unit, Inpatient TB unit, approximately 9 approximately 9 negative pressure negative pressure isolation beds.isolation beds.

South Africa South Africa

Involuntary detentionInvoluntary detention WHO – patient assumes responsibility to WHO – patient assumes responsibility to

isolate themselves from general public – isolate themselves from general public – may be too permissive?may be too permissive?

Judiciaries often have the authority to issue Judiciaries often have the authority to issue orders compelling involuntary confinementorders compelling involuntary confinement Missouri court order systemMissouri court order system

““TB Patient Chafe Under TB Patient Chafe Under Lockdown in South Africa”Lockdown in South Africa”

By Celia W. Dugger, Port Elizabeth, SA, March By Celia W. Dugger, Port Elizabeth, SA, March 25, 200825, 2008

The Jose Pearson TB Hospital here is like a The Jose Pearson TB Hospital here is like a prison for the sick. It is encircled by three fences prison for the sick. It is encircled by three fences topped with coils of razor wire to keep patients topped with coils of razor wire to keep patients infected with lethal stains of TB from escaping. infected with lethal stains of TB from escaping. But at Christmastime and again around Easter, But at Christmastime and again around Easter, dozens of them cut holes in the fences, slipped dozens of them cut holes in the fences, slipped through electrified wires or pushed through the through electrified wires or pushed through the gates in a desperate bid to spend the holidays gates in a desperate bid to spend the holidays with their families.with their families.

Cont….Cont….

Patients have been tracked down and forced to Patients have been tracked down and forced to return; the hospital has quadrupled the number return; the hospital has quadrupled the number of guards. Many patients fear they will get out of guards. Many patients fear they will get out of here only in a coffin.of here only in a coffin.

““We’re being held here like prisoners, but we We’re being held here like prisoners, but we didn’t commit a crime,” Siyasanga Lukas, 20, didn’t commit a crime,” Siyasanga Lukas, 20, who has been here since 2006, said before who has been here since 2006, said before escaping last week. “I’ve seen people die and escaping last week. “I’ve seen people die and die and die. The only discharge you get from die and die. The only discharge you get from this place is to the mortuary.”this place is to the mortuary.”

In the United States…In the United States…

Arizona TB Patient Jailed as a Public Health Menaceby Richard KnoxListen Now add to playlist

Robert Daniels with his wife, Alla, and their son in Moscow, before he returned to the United States. Courtesy KJZZ 91.5 FM

Take Robert Daniels, the second most-famous TB patient these days. He has extensively drug-resistant TB and is being held in an Arizona hospital under court order. His case raises even sharper questions about how to provide complicated treatment, protect the public, and prevent the spread of a dangerous new strain of TB.

Since last summer, Daniels has been locked in a bare room on the fourth floor of the Maricopa County Hospital in Phoenix. It's a jail unit for criminals who need medical care. But Daniels has never been charged with a crime. He's there because he's been judged a menace to public health.

““There are no more borders. If There are no more borders. If one country suffers, every one country suffers, every country suffers. If one country country suffers. If one country has infectious disease, every has infectious disease, every country has infectious disease”country has infectious disease”

Dr. Juxel GarciaDr. Juxel Garcia

Deputy Director, PAHODeputy Director, PAHO