Page 1

Extreme Drug Resistant TB and the Work Place

Dr Jennifer Coetzee

Ampath

Page 2

Outline

• The “ABC” of TB drug resistance–Current anti-TB drugs available

–What is MDR?

–What is XDR?

–How does TB drug resistance develop?

• Epidemiology of XDR TB

• XDR TB in the work place?

• Prevention and management of TB transmission

in the occupational setting

Page 3

Anti TB Drugs Currently Available

• 1st Line Drugs:

• INH

• Rifampicin

• PZA

• Ethambutol

• Streptomycin

• 2nd Line Drugs

• Capreomycin

• Kanamycin

• Ethionamide

• PAS

• Cycloserine

• Quinolones

• Thiacetazone

Page 4

The ABC of TB Drug Resistance

• MDR TB: Resistance to INH and Rifampicin

• XDR TB: MDR TB that is also resistant to quinolones

(e.g. ciprofloxacin) and one other of 2nd line injectable drug

• Thus Extreme Drug resistance

• Laboratory diagnosis based on susceptibility testing

• Cure rate for MDR TB +/- 50%

• XDR TB 64% more likely to die than if MDR TB

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How does TB drug resistance develop?

• Spontaneous and random mutations in the bacterial

• chromosome:

–INH - 1 X 106 organisms

–Rif - 1 x 108

–EMB - 1 x 106

–Strep - 1 x 105

• Probability of spontaneous mutants being simulta-

neously resistant to 2 or more drugs is product of

individual frequencies…

• INH + Rif = 106 + 108 = 1014

Page 6

MDR: Global Perspective

• 50 million people infected worldwide

• Low prevalence of MDR:–well functioning TBCP with DOTS, low prevalence

of TB, resource rich

• High prevalence of MDR TB:–high TB rates, poor countries, limited medication

available

• MDR rates estimated to be 3 - 4%

• Primary MDR: 1 - 3%

• Acquired: 7 - 17%

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Implications of MDR TB

• 100 X more expensive to treat

• Duration of Rx up to 24 months–Patient hospitalised for 4 - 6 months

• Extensive laboratory monitoring required

• Side effects of 2nd line drugs significant

• Inconvenient routes of administration

• >30% default rate

• Treatment failure > 10% if optimally Mx

• Mortality rate:–30 - 40% if HIV uninfected

–70 - 80% if HIV infected

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XDR TB

• Hot off the press

• Term coined in March 2006

• Report published in MMWR 24/03/06

• 350 cases worldwide between 2000 and 2004

• Primarily in South Korea, Eastern Europe and

western Asia

• 74 cases in USA

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Current Situation XDR

• USA: 4% of MDR cases meet criteria for XDR

• Latvia: 19% of MDR cases considered XDR

• Australia, Belgium, Canada, France, Germany,

Ireland, Portugal, Spain, Britain:–XDR TB increased from 3% of drug resistant

cases to 11% (2000 to 2004)

• Pandemic threat!

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RSA: The Tugela Ferry Event

• In Tugela Ferry HIV/TB co-infected patients, respon-

ding to ARV but not to ATT, were identified early

2005

• This prompted culture and susceptibility testing

• Infection with highly resistant M.tuberculosis

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South African Situation (Tugela Ferry)

1428 Patients with sputum sent

475 (34%)Culture-Positive for M.tb

921 Culture-Negative

Lancet 2006, 368:1575-1580

Surveillance at District Hospital:

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475 patientsCulture-Positive for M.tb

185 (39%)Resistant to Isoniazid & Rifampin

(MDR TB)

290 Susceptible or Resistant

but not MDR

30 (6%) Resistant to all tested drugs

(XDR TB) Prof. W. Sturm

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Overall Data for the Area

• 52 of 53 people with XDR TB died

• 44 were co-infected with HIV

• Average survival was 16 days after sputum collection

• 55% of the patients were primary XDR!

• At least 2 HCWs were infected, died. A further 4

were suspected to have contracted XDR TB

• Strain resistant to all 7 anti-TB drugs available in SA

• Impact of 5.5 million people infected with HIV/AIDS

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Susceptibility Pattern

• Isoniazide R• Rifampicin R• Pyrazinamide R• Ethambutol R• Streptomycin R

• Kanamycin/amikacin R• Ciprofloxacin/ofloxacin R• Ethionamide S• Cycloserine ?• Capreomycin S• PAS ?

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XDR TB and the Work Place

• Health care workers from KZN only published

proven transmission of XDR TB to have occurred

to date

• Recent case of patient with XDR TB on aero-

plane in US

• Outbreaks of MDR TB has been well described

• No evidence to suggest that MDR or XDR TB

is more easily transmitted than drug susceptible

TB

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Principles of TB Transmission

• Inhalation of microscopic, aerosolised particles containing

TB bacilli

• Vast majority: particles elaborated by coughing, sneezing

or singing

• Alveolar deposition thought to be essential– Tiny enough to drift with inspired air rather than impact on

mucous membranes

• Droplet nuclei of 0.5-5 µm usually vectors of infection

• Patients with extensive pulmonary TB pose greatest risk

• Study form Alabama, gradient of skin-test reactivity of

contacts:– HHCs to smear (+) cases: 46%

– Non-HHCs to smear (+) cases: 34%

– HHCs to smear (-), culture (+) cases: 28%

– Non-HHCs to smear (-), culture (+) cases: 24%

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Environmental Factors That Increase the Risk of Transmission of TB

• Exposure to TB in small, enclosed spaces

• Inadequate local or general ventilation that results

in insufficient dilution or removal of infectious

nuclei

• Recirculation of air containing infectious droplet

nuclei

• Inadequate cleaning and disinfection of medical equipment

• Improper procedure for handling specimens

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Risk for Health-Care Associated Transmission of TB

• Transmission and outbreaks well described

• Magnitude of risk varies by:–Setting

–Occupational group

–Prevalence of TB in the community

–Patient population

–Effectiveness of TB infection-control measures

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Outbreaks in Health-Care Settings

• Multiple outbreaks involved transmission of MDR

TB strains to both patients and HCWs–Majority of patients and HCWs were HIV infected

• Also outbreaks described in outpatient settings

• Factors contributing to outbreaks:–Delayed diagnosis of TB disease

–Delayed initiation and inadequate airborne precautions

– Inadequate precautions for cough-inducing and aerosol-generating procedures

–Lack of adequate respiratory protection

Page 20

Principles of Management of TB Contacts

• Earliest possible identification of index cases–Rapid laboratory detection of MDR TB if indicated

• Duration / time-line of exposure often unknown• Baseline CXR, symptom screening• Diagnosis of latent TB infection

–Role of blood assays, incl. TB Spot, Quantiferon Gold–Skin testing?

• Counseling, HIV testing imperative–Risk of reactivation disease

• Treatment of latent TB infection• If exposed to MDR/XDR TB, to be referred to infectious disease specialist. Optimal therapy unknown.

Page 21

Conclusion

“After 25 years working in TB treatment, I’m extremely concerned - we see very little

progress, and there seems to be complacency in general about TB”

Dr Karin Weyer, August 2006