reducing nosocomial drug resistant tb...

Turning Off the SpigotReducing Nosocomial Drug Resistant TB

TransmissionTransmission

Edward A. Nardell, MD

Harvard Medical School/PIH

Brigham & Women’s Hospital

TB is an airborne infection

• Every case of MDR/XDR TB prevented is one fewer patient who will require 18-24 months of difficult and expensive treatmentexpensive treatment

• Effective treatment for TB = prevention

– but treatment alone is not

enough

Reconsidering TB Transmission Control Priorities

• Institutional Institutional Institutional Institutional transmissiontransmissiontransmissiontransmission is fueling M/XDR epidemic spreadis fueling M/XDR epidemic spreadis fueling M/XDR epidemic spreadis fueling M/XDR epidemic spread

– Reinfection Reinfection Reinfection Reinfection is an essential propagation component is an essential propagation component is an essential propagation component is an essential propagation component

– Implications for: Implications for: Implications for: Implications for: • importance of institutional transmission controlimportance of institutional transmission controlimportance of institutional transmission controlimportance of institutional transmission control

• the potential for INH preventionthe potential for INH preventionthe potential for INH preventionthe potential for INH prevention

• the potential for a new TB vaccinethe potential for a new TB vaccinethe potential for a new TB vaccinethe potential for a new TB vaccine• the potential for a new TB vaccinethe potential for a new TB vaccinethe potential for a new TB vaccinethe potential for a new TB vaccine

• the importance of communitythe importance of communitythe importance of communitythe importance of community----based MDR treatmentbased MDR treatmentbased MDR treatmentbased MDR treatment

• Prompt, effective Prompt, effective Prompt, effective Prompt, effective treatmenttreatmenttreatmenttreatment stops transmissionstops transmissionstops transmissionstops transmission

– Persons withPersons withPersons withPersons with unsuspected or inadequately treated drug resistant unsuspected or inadequately treated drug resistant unsuspected or inadequately treated drug resistant unsuspected or inadequately treated drug resistant TBTBTBTB cause most transmissioncause most transmissioncause most transmissioncause most transmission

– Implications for:Implications for:Implications for:Implications for:• rapid diagnosticsrapid diagnosticsrapid diagnosticsrapid diagnostics

• traditional transmission control prioritiestraditional transmission control prioritiestraditional transmission control prioritiestraditional transmission control priorities


• Institutional transmission is fueling M/XDR epidemic spread

– Reinfection is an essential propagation component

– Implications for:

• importance of institutional transmission control

• the potential for INH prevention

• the potential for a new TB vaccine

• the importance of community-based MDR treatment

• Prompt, effective treatment stops transmission

– Persons with unsuspected or inadequately treated drug resistant TBcause most transmission

– Implications for:

• rapid diagnostics

• traditional transmission control priorities

How is MDR acquired?

• 2008 WHO data:

– more than 50% of MDR occurs in patients NOT

previously treated

• primary, transmitted TB• primary, transmitted TB

• not acquired through poor therapy

– Many previously treated cases are re-infected

• also transmitted, but misclassified as “acquired”, as if poor treatment was the cause

Trends: Peru 1996-2005

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

1995 1997 1999 2001 2003 2005 2007

% MDR-TB among new cases

0

50

100

150

200

1995 1997 1999 2001 2003 2005 2007

TB notification rate

1995 1997 1999 2001 2003 2005 2007

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

1995 1997 1999 2001 2003 2005 2007

% Any INH resistanceamong new cases

Peru 1996-2005

1995 1997 1999 2001 2003 2005 2007

Not listed in 2010 report as a country with decreasing MDR cases

MDR Trends in Tomsk and Orel1994-2008

Importance of Transmission in TomskGlemanova, et al., Bull WHO, 2007; 85:703-711.

• Retrospective study– role of non-adherence and default and the acquisition of

multidrug resistance

• Substance abuse– strong predictor of non-adherence (OR 7.3 (2.89-18.46)– strong predictor of non-adherence (OR 7.3 (2.89-18.46)– but non-adherence NOT associated with MDR-TB

• MDR-TB occurred – among adherent patients who had been hospitalized in the

course of therapy compared to those treated as out-patients• OR 6.34 (1.34 – 29.72) – began treatment in hospital• OR 6.26 (1.02 – 38.35) – hospitalized later during treatment

53 XDR Patients in Kwazulu Natal, South Africa55% had no previous TB treatment – i.e., transmitted

- most had the same “KZN” strain67% had been hospitalized100% had HIV co-infection100% mortality – avg 16 days from TB diagnosis

Samara Oblast 9-yr StudyDimitrova B. Int J Tuberc Lung Dis. 2005 Jan;9(1):43-8

• TB among health workers:

– TB risk: 742/100K person-years at risk

• 10X that of general population.• 10X that of general population.

– In-patient TB facilities

• incidence ratio of 17.7 compared general health

workers

– Implications for global TB work force









– Persons with unsuspected or inadequately treated drug resistant TB cause most transmission

– Implications for:• rapid diagnostics


Reinfection Drug Resistant TBin a Boston Homeless Shelter

Nardell, et al. NEJM 1986; 315:1570-5

• Proved

exogenous

reinfection as reinfection as

common in a

1983 drug

resistant TB

outbreak




– Implications for: • importance of institutional transmission control


• the potential for a new TB vaccine• the potential for a new TB vaccine






Treatment

delivered in

homes by

trained, paid,

community

health workers

PIH introduced community-based treatment of MDR TB in Peru in 1996. Now in PIH-Lesotho, Karachi, Cambodia, and other sites

- only about 10% of patients hospitalized in Lima

Highly effective, with less opportunity for institutional transmission








• Prompt, effective Prompt, effective Prompt, effective Prompt, effective treatmenttreatmenttreatmenttreatment stops transmissionstops transmissionstops transmissionstops transmission– Persons with unsuspected or inadequately treated drug resistant

TB cause most transmission

– Implications for:• rapid diagnostics


Riley Experimental TB Ward, 1956-60Am J Hyg 1959; 70:185-196.

(reprinted as “classic” Am J Epidemiol 1995; 142:3-14)

Hundreds of sentinel guinea pigs sampled the air from a 6-bed TB ward in Baltimoreward in Baltimore

TB transmission only from

untreated patients - 1• Patients selected:

– strongly smear positive

– cavitary TB

• 3 of 77 patients produced 35 of 48 (73%) of GP infections that were culturedwere cultured

– all drug resistant M.

tuberculosis on inadequate therapy

– 4 month period* of no

infections when drug

susceptible patients were

admitted to the ward.

Riley Ward – 2nd 2-year study- included untreated patients

Relative infectivity of patients*:

– Susceptible TB• 61 Untreated (29 GPs) 100%

• 29 Treated (1 GP) 2%

– Drug-resistant TB• 6 Untreated (14 GPs) 28%

• 11 Treated (6 GPs) 5%

*all smear positive patients, relative to the amount of time on the ward

TB transmission only from untreated patients – Peru

Escombe 2008 Plos Medicine; 5:e188

– 97 HIV+ pulmonary TB patients exposed 292 guinea pigs over 505 days

• 66 cult +, 35 smear +• 66 cult +, 35 smear +

– 122/125 GP infections due to 9 MDR patients• all inadequately or delayed treatment

» 108/125 infections due to 1 MDR patient

• 3 drug susceptible patients infected 1 guinea pig each

» 2 had delayed treatment

» 1 had treatment stopped

The AIR FacilityWitbank, Mpumalanga Provence, RSA

TB transmission only from untreated patients – South AfricaAirborne Infections Research (AIR) Facility – unpublished data

• All MDR patients - selected for:– strongly smear + – cavitary TB – recently started on therapy

• Experiment 1: 26 MDR-TB patients exposed 360 guinea pigs over 4 months

– 75% guinea pig infected – 11 spoligotype patterns from GP isolates – All due to 3 patients later found to have had XDR-TB not on effective

treatment.

• Experiment 2: 10% guinea pigs infected over 3 months– no XDR patients identified so far

• Experiment 3: 53% guinea pigs infected over 2 months– 3 XDR patients identified

Transient TB Infections

observed1. Many guinea pigs reverted their skin test back to 0 mm.

2. Guinea pigs did not show signs of TB or have histological findings at autopsy

20 20

0

20

40

60

80

100

TST1 2 3 4 5

0

5

10

15

0 4 8 12 18

GP 8

0

5

10

15

20

0 4 8 12 18

GP 33

Timing of TST (weeks) Timing of TST

(weeks)

TST size in mm

TST size in mm

Reinfection is an essential pathway to cavitary disease under endemic conditionsSmith DW, et al. Rev Infect Dis 11: S385-S393 (1989)

Stead Theory









– Persons withPersons withPersons withPersons with unsuspected or inadequately treated drug unsuspected or inadequately treated drug unsuspected or inadequately treated drug unsuspected or inadequately treated drug resistant TBresistant TBresistant TBresistant TB cause most transmissioncause most transmissioncause most transmissioncause most transmission

– Implications for:Implications for:Implications for:Implications for:

• rapid diagnosticsrapid diagnosticsrapid diagnosticsrapid diagnostics


Unsuspected, untreated TB

TBDR

General Medical WardOrthopedic WardObstetrics WardPsychiatric Ward

TBDS

How common is unsuspected TB?(Emerg Inf Dis 2001; 7:123-7)

• 250 of 349 pts admitted to on female ward in Lima were screened for TB over 1 year:

- sputum

- CXR

- history-- physical exam

• 40 pts (16%) had positive cultures

- 26/40 (65%) smear positive

- 13/40 (33%) unsuspected

- 8/40 (20%) had MDR

• Incl. 6/8 MDR unsuspected

- 3/6 were smear positive

Unsuspected, untreated

MDR/XDR TBAll other patients on effective treatment

TBTBTB TB TBDR

TB

TB HospitalPotential for re-infection

TB

TBTBTB

TBDR

TBTB

TB

Unsuspected, untreated

XDR TBAll other patients on effective treatment

TBTBTB TB TBXDR

TB

MDR TB WardPotential for re-infection

TB

TBTBTB

TBXDR

TBTB

TB








• Prompt, effective treatment stops transmission– Persons withPersons withPersons withPersons with unsuspected or inadequately treated drug resistant TBunsuspected or inadequately treated drug resistant TBunsuspected or inadequately treated drug resistant TBunsuspected or inadequately treated drug resistant TB cause cause cause cause

most transmissionmost transmissionmost transmissionmost transmission



TB Triage – PIH-HaitiCommunity based TB treatment

Hospitalized patients on treatment

General ward TB Pavilion 6 isolation rmsGeneral ward

Sm -, HIV +/-

TB Pavilion

Sm+, HIV-

6 isolation rms

SM+ and HIV+

Poor Hospital and Clinic Design- need to build local capacity

One million dollar renovation of old TB hospital in BotswanaPoor design - multiple small isolation rooms off common entries

PIH Lesotho, 2007

Botsabelo MDR Hospital

Building Global Capacity

• “Building Design and Engineering for

Airborne Infection Control – an International

Perspective”

– Harvard School of Public Health, Boston– Harvard School of Public Health, Boston

• August 2-13, 2010

• Co-sponsored by CDC, NIH, WHO

• https://ccpe.sph.harvard.edu/request.cfm

General Air Disinfection: Upper Room Ultraviolet Fixtures

• 75% effective in recent studies

• Better locally produced fixtures neededfixtures needed

• Expertise needed

Room Disinfection:Open bulb Ultraviolet Lamps

Common in Russia and E. EuropeUsed in empty roomsNot likely to be effective

-> false assurance.

Room Air Cleaners – filter or UV

- generally ineffective - false assurance


• Institutional Institutional Institutional Institutional transmissiontransmissiontransmissiontransmission is fueling M/XDR epidemic spreadis fueling M/XDR epidemic spreadis fueling M/XDR epidemic spreadis fueling M/XDR epidemic spread










Global Health Delivery – on line

• GHDonline.org

– Free MDR and TB transmission control resource

– Discussion on topics of interest– Discussion on topics of interest

– Monitored by international experts

– Resource for guidelines, documents, and

consultants around the world

reducing nosocomial drug resistant tb...

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