Global TB: The TB world
is flat too!
Drug Resistant TB: A world tour
Juzar Ali M.D., FRCP(C), FCCP
Russell C. Klein M.D. LSU ALUMNI Professor of Medicine
Vice Chair (Clinical) Department of Medicine
Director: LSU Chest & LSU-Wetmore TB Clinics
Section of Pulmonary & Critical Care Medicine
Louisiana State University Health Sciences Center, New Orleans
JUNE 6 2008
At the end of the presentation, the audience will have
• Reviewed the global epidemiology of
Drug-resistant TB including MDRTB and
XDRTB
• Identified risk factors in Drug – resistant
Tuberculosis
• Been given an overview of and emphasis
on the focal points of management of Drug
resistant TB.
References
1 Farmer P, Furin J, Shin S. The clinical management of multidrug-resistant tuberculosis. J Respir Dis
2000; 21:53-56.
2 Iseman M, Madsen L. Drug resistant tuberculosis. Clin Chest Med 1989; 10:341-353.
3 Iseman M. Management of multidrug-resistant tuberculosis.Chemotherapy 1999; 45(supl 2):3-4••
Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with
extensive resistance to second-line drugs-worldwide, 2000-2004.
4. MMWR Morb Mortal Wkly Rep 2006; 55:301-305.
5 Pablos-Mendez A, Raviglione M, Laszlo A, et al. Global surveillance for antituberculosis drug
resistance, 1994-1997. World Health Organization-International Union Against Tuberculosis and
Luna Disease Working group on Antituberculosis Drug Resistance Surveillance. N Engl J Med
1998; 338:1641-1649.
6 Blumberg, HM, Burman, WJ, Chaisson, RE, et al. American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J
Respir Crit Care Med 2003; 167:603.
7 Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus
isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30
months. Am Rev Respir Dis 1977; 115:727
8. Mitchison DA, Nunn Aj. Influence of initial drug resistance on the response to short-course
chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423-430.
9. Hong Kong Chest Service, British Medical Research Council. Five-year follow-up of a controlled trial
of five, 6 month regimens of chemotherapy for tuberculosis. Am Rev Respir Dis 1987;136:13391342.
10. Hong Kong Chest Service, British Medical Research Council. Controlled trial of 6-monthand 9month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for
pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115:727-735.
Am J Respir CritCare Med 2003; 167:603
Types
• Primary drug resistance “ or in new cases”
is said to occur in a patient who has never
received anti- tuberculosis therapy.
• Secondary drug resistance i.e. “acquired”
refers to the development of resistance
during or following chemotherapy, for what
had previously been drug-susceptible
tuberculosis.
Definition
The term "drug-resistant tuberculosis" refers to cases of tuberculosis caused
by an isolate of Mycobacterium tuberculosis, which is resistant to one of the
first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, ethambutol,
or streptomycin
• Multidrug-resistant tuberculosis (MDR-TB)
is caused by an isolate of M. tuberculosis,
which is resistant to at least isoniazid and
rifampin, and possibly additional
chemotherapeutic agents.
• Extensively drug-resistant tuberculosis
(XDR-TB) is caused by an isolate of M.
tuberculosis, which is resistant to at least
isoniazid, rifampin, fluoroquinolones, and
either aminoglycosides (amikacin,
kanamycin) or capreomycin, or both.
WHO. Laboratory XDR-TB definitions. Geneva: Meeting of the global XDR TB task force 2006
The Story of DR- MDRTB ; not a
new tale
• Exists and ongoing throughout the world over
the years.. Russia, Far East, South Asia;
Globally 400K cases “reported”
• 1990s Several outbreaks in hospitals and
correctional facilities in NY and Florida; Mostly
HIV, 80% mortality; Dx-Death time 4-16 weeks
• Nosocomial transmission; not more contagious
but more difficult to treat
• Lower cure rate and increased cost
The story started….
• Late 1940’s
• Streptomycin; its success and its
limitations
Concept of Multi drug regimens
• In a survey of resistance in 58 sites on six continents conducted by
the World Health Organization (WHO) and the International Union
against Tuberculosis and Lung Disease from 1996 through 1999,
primary resistance to at least one drug ranged from a low of 1.7
percent in Uruguay to a high of 36.9 percent in Estonia (median
value 10.7 percent.
• Multi-drug resistance was present was 14.1, 10.8, 9.0, 9.0, and 5.0
percent in Estonia, Henan Province (China), Latvia, Russian
Ivanovo, and Iran, respectively.
• A mathematical model estimated that 3.2 percent of all cases of
tuberculosis in the world in 2000 were caused by multidrug resistant
strains.
References available
Nearer home
A survey of drug resistance among M. tuberculosis
isolates in Mexico in 1997, showed a rate of primary
resistance of 12.9 and 2.4 percent to one drug and
multiple drugs, respectively, which rose to 50.5 and 22.4
percent, respectively, for re- treatment cases. Patients in
this study were all smear positive and usually treated
with three- as opposed to four-drug regimens; directly
observed therapy was inconsistently applied.
References available
• Population-based data on drug
susceptibility of TB isolates were obtained
from the United States (for 1993--2004),
Latvia (for 2000--2002), and South
Korea (for 2004), where 4%, 19%, and
15% of MDR TB cases, respectively, were
XDR.
MMWR 3/2006. 55(11); 301-305
In the US
• The emergence of drug resistance in the United States occurred
unevenly. In New York state, 12.9 percent of isolates were resistant
to isoniazid and rifampin in 1991, and New York City alone
accounted for nearly 60 percent of all cases of MDR-TB in the entire
United States] .
• The rate of resistance in New York City in 1991 was 52.4 times
higher than that in the rest of the country
• Single drug resistance to isoniazid occurred in 8 percent of cases in
the United States in 1995 and 1996, although it varied from less
than 4 percent in North Carolina, West Virginia, and Wisconsin to
greater than 10 percent in Delaware, Hawaii, New York, and Rhode
Island.
.
Focus
Infection
Control
DOT
Initial 4 drug Rx
The three P’s
•
•
•
•
•
People
Refugees
Migrants
Displaced
Homeless
Transitional
Protocols
& Policies
PHS ; Private ; Academia
MDs , HCWs,
Infrastructure
Support
$$$$
Politics
International National NGOs
TB: Refugees & Transients
% of populations infected with TB
4
6
25
50
50
NA Europe Homeless (UK) LA Refugees
Ref: UNHCR 1995 Crises study and LA 1997 stats
In the US!!
A “revolving door” Health system
The “Bermuda Triangle” of TB
ED
Lack of
Accountabiliy
Mobile
Population
RESISTANCE PATTERNS
• Initial resistance to I> E> S> R
• Prognostic factors:
Nutritional status
Diabetic
Renal Disease
• Resistance to isoniazid (INH) was most common,
occurring in 8 percent of all isolates, and this rate has
remained steady through 2001. Resistance to rifampin,
streptomycin, and ethambutol was detected in 1.7, 5.9,
and 1.6 percent of isolates, respectively. Resistance to
both INH and rifampin (ie, multidrug-resistance) was
detected in 2.5 percent of the isolates in 1997; by 2001,
fewer than two percent of cases of tuberculosis in the
United States were caused by multidrug resistant strains
•
CDC. Reported tuberculosis in the United States, 2002. Center for Disease Control, 2003
Factors
•
•
•
•
•
A multivariate analysis identified the following factors as
associated with MDR-TB :
Previous TB diagnosis
Positive acid-fast bacilli sputum smear
Asian/Pacific Islander ethnicity
Time in the United States <5 years at diagnosis
An outcome of "died" or "moved” or “cold case” or “case
closed” ( my terms )
Granich, RM, Oh, P, Lewis, B, et al. Multidrug resistance among persons with tuberculosis in California, 1994-2003. JAMA 2005; 293:2732.
The Perfect Storm
•
Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global
epidemic, with ~425,000 new cases estimated to occur annually.
•
Institutional outbreaks of MDR-TB have primarily affected HIV-infected
persons.
•
Delayed diagnosis
inadequate initial treatment,
prolonged infectiousness
HIV infection may lead to malabsorption of anti-TB drugs and acquired
rifamycin resistance.
AUWells CD; Cegielski JP; Nelson LJ; Laserson KF; Holtz TH; Finlay A; Castro KG; Weyer K SOJ Infect Dis. 2007 Aug 15;196 Suppl
1:S86-107.
XDRTB
During the time period 1993 to 2006, 49 XDR-TB
isolates were identified in the United States.
These 49 cases were reported from nine states,
with the largest numbers occurring in New York
and California. Among 41 persons with XDR-TB
and known clinical outcomes, 12 (29%) died; 10
of those had HIV infection and the other two did
not undergo HIV testing.
WHO. Laboratory XDR-TB definitions. Geneva: Meeting of the global XDR TB task force 2006.
D2D period : 16 days
Gandhi et al
South Africa 2006
Lancet
•INH inhibits the synthesis of mycolic acids
•PZA inhibits the synthesis of short-chain, fatty-acid precursors
•RMP inhibits transcription by binding to the β-subunit of RNA polymerase].
Previously demonstrated and proposed sites of action of isoniazid (INH), pyrazinamide
(PZA), and rifampin (RMP) on the M tuberculosis cell. This figure is adapted in
part from Parsons et al.
Somoskovi et al. Respiratory Research 2001 2:164 doi:10.1186/rr54
The Molecular Basis
• Virtually all isolates resistant to rifampin and related rifamycins have
a mutation that alters the sequence of a 27-amino-acid region of the
beta subunit of ribonucleic acid (RNA) polymerase.
• Resistance to isoniazid (INH) is more complex. Many resistant
organisms have mutations in the katG gene encoding catalaseperoxidase that result in altered enzyme structure. These structural
changes apparently result in decreased conversion of INH to a
biologically active form.
• Some INH-resistant organisms also have mutations in the inhA
locus or a recently characterized gene (kasA) encoding a betaketoacyl-acyl carrier protein synthase.
• Streptomycin resistance is due mainly to mutations in the 16S rRNA
gene or the rpsL gene encoding ribosomal protein S12.
• Resistance to pyrazinamide in the great majority of organisms is
caused by mutations in the gene (pncA) encoding pyrazinamidase
that result in diminished enzyme activity.
• Ethambutol resistance in approximately 60% of organisms is due to
amino acid replacements at position 306 of an arabinosyltransferase
encoded by the embB gene.
• Amino acid changes in the A subunit of
deoxyribonucleic acid gyrase cause
fluoroquinolone resistance in most organisms.
• Kanamycin resistance is due to nucleotide
substitutions in the rrs gene encoding 16S rRNA.
• Multidrug resistant strains arise by sequential
accumulation of resistance mutations for
individual drugs.
•
AURamaswamy S; Musser JM SOTuber Lung Dis 1998;79(1):3-29.
What to do
at a patient level ?
• A careful history / “mycobacteriogram” must be obtained from
every patient with tuberculosis before treatment begins, and while
drug susceptibility data are pending. Clinical and radiographic
features on presentation are not altered in comparison with drugsusceptible disease, but several demographic and historical
features should raise the suspicion of drug-resistant tuberculosis.
These include:
• Previous treatment for active tuberculosis, particularly if therapy
was self-administered or non documented
• Tuberculosis treatment failure or relapse in a patient with
advanced HIV infection treated with a highly intermittent anti-TB
regimen
• Acquisition of tuberculosis in a region with known high rates of drug
resistance
• Contact with a case of drug-resistant tuberculosis
• Failure to respond to empiric therapy, particularly if adherence to
therapy has been documented
Mono resistance
Not much clinical significance
And /or management issues
PZA
SM
Q
E
?synergy
RI
Remove the R
QEI or SPI
*Longer duration
But with issues
* Use of Rb?
Remove the I ( “low level , high level )
REZ, REQ, RES
Longer duration
• Isoniazid monoresistance — Tuberculosis resistant to isoniazid
(INH) should be treated with a rifamycin (rifampin or rifabutin),
pyrazinamide, and ethambutol for six to nine months, or four months
after culture conversion
• Success rates of 95 to 98 percent with this type of regimen among
• Some experts consider continuing isoniazid in the setting of "lowlevel" INH resistance, ie, resistant to a concentration of 0.2 µg/mL
but sensitive to 2.0 µg/mL.
• Some experts (Cat C evidence) recommend that a quinolone be
added to this regimen for the duration of therapy in HIV and high
burden cases] .
•
Rifampin monoresistance — Rifampin monoresistance most often occurs in HIVpositive patients and represents an uncommon but increasingly frequent clinical
problem
•
Rifampin monoresistance may be more likely to develop in HIV-infected with
advanced immunosuppression (eg, CD4 cell counts <100/µL) patients treated with
highly intermittent (i.e., once or twice weekly) regimens.
Streptomycin, isoniazid, and pyrazinamide given together for nine months. This is the
shortest duration regimen with good efficacy for use in rifampin monoresistance, and
although it is our preferred regimen, as it has been evaluated in well-conducted
clinical trials (in HIV-negative patients), many patients often object to the nine months
of injections with their attendant side effects. Some experts recommend extending
treatment to 12 months for HIV-infected patients who do not convert their sputum
cultures and clinically improve during the first two months of treatment [8,16] .
Isoniazid, pyrazinamide, and ethambutol. The duration of this regimen should be at
least 12 months, and some would treat for 18 months after culture conversion. Some
recommend adding streptomycin for the first two to three months of treatment, or the
addition of a quinolone such as levofloxacin or moxifloxacin throughout.
").
•
•
•
• Of the 14 mutant RNA polymerase alleles, which
confer resistance to rifampin, 9 also confer highlevel resistance to rifabutin] . Approximately 25
percent of rifampin-resistant clinical isolates are
sensitive to rifabutin, which appears as effective
clinically as rifampin in short-course regimens
for patients with drug-sensitive disease] .
• However, no data are available regarding shortcourse, rifabutin-containing regimens in patients
with rifabutin-sensitive, but rifampin-resistant
disease. Therefore, its use in this setting cannot
be recommended at the present time.
MDR
PSQE
RI
Duration, tolerance, Cost
Compliance, ADR’s
Resection Surgery
XDRTB
RESECTIONAL Surgery
Tailored chemotherapy
2-3 de novo / new drugs at
least
Prolonged Rx
• Pyrazinamide monoresistance — Single
drug-resistance to pyrazinamide requires a
nine month regimen of isoniazid and
rifampin. This combination is well studied,
and has a greater than 96 percent success
rate in large trials
• Monoresistance to other agents —
Single drug resistance to ethambutol,
streptomycin, or second-line agents is of
little clinical significance. Patients can still
be treated with the standard short course
regimen of two months of isoniazid,
rifampin, and pyrazinamide followed by
four months of isoniazid and rifampin,
which yields success rates of around 97
percent
• Isoniazid, pyrazinamide, and ethambutol.
The duration of this regimen should be at
least 12 months, and some would treat for
18 months after culture conversion. Some
recommend adding streptomycin for the
first two to three months of treatment, or
the addition of a quinolone such as
levofloxacin or moxifloxacin throughout.
• Pyrazinamide monoresistance — Single
drug-resistance to pyrazinamide requires a
nine month regimen of isoniazid and
rifampin. This combination is well studied,
and has a greater than 96 percent success
rate in large trials.
Outcome of MDRTB
• Patients presenting with MDR-TB had been previously
treated with a median of five to six drugs
• The overall success rate of patients treated after 1990
was similar in reports from the United States, Turkey,
Latvia, and other resource-limited countries (52 to 77
percent)
• Predictors of successful therapy included surgical
intervention, fluoroquinolone use and younger age
• The outcome of patients with MDR-TB appears to vary
with HIV status.
XDRTB
•
•
XDR-TB infection is also a particular problem in HIV-infected patients.
Time to sputum culture conversion is a useful interim indicator of treatment
outcome in patients with MDR-TB
•
In one study conversion to negative cultures at a median time of 60 days
(range 4 to 462 days) occurred in 129 (77 percent) of patients. Thirty-eight
patients (23 percent) did not convert.
•
Predictors of a longer conversion time were:
Previous treatment of MDR-TB
High colony count on initial sputum culture
Bilateral cavitation on chest radiography
The number of drugs the initial isolate was resistant to at the time of treatment
initiation
The mortality rate varies depending on whether the individual has been
previously treated for compared to newly diagnosed with tuberculosis
Treatment Regimens for TB
Resistant Only to INH
HIV-Negative Persons
•
Carefully supervise and manage treatment to avoid
development of MDR TB
•
Discontinue INH and continue RIF, PZA, and EMB
or SM for the entire 6 months
•
Or, treat with RIF and EMB for 12 months
HIV-Positive Persons
•
Regimen should consist of a rifamycin, PZA, and EMB
Multidrug-Resistant TB (MDR TB)
•
Presents difficult treatment problems
•
Treatment must be individualized
•
Clinicians unfamiliar with treatment of MDR TB
should seek expert consultation
•
Always use DOT to ensure adherence
TB Control: Tackle head-on
Elicit International support
Get National commitment
Shun Skepticism
Develop database and identify priorities
Develop pilot programs
Structure control mechanisms
Provide Incentives
Evaluate and establish accountability
Continued supervision
But , then …...
Governmental
malaise
and corruption
Family and social
dynamics
The “leeches” of
the system; the
profiteers and
pilferers
HCWs apathy
and incompetence
Overall
Non-commitment,
and cynicism
A story of a country
1/5 new cases ever diagnosed
1/7 Rx correctly
no effective guidelines
no standardized protocols
HCW individual idiosyncrasies
1% budget on health care
DOT costs $ 50 for full Rx; It costs $ 5 per year to save a life
But, how ?
And will we ?
Current Issues in Global TB Control:
Heard these before?
•
•
•
•
Definition of Compliance
Public & Private Sector Partnership
What is “political will” ?
Will “Surrogate DOT” succeed? Is it
reliable?
Treatment of TB
• IDEAL
•
•
•
•
•
•
WHAT WE HAVE
1. Single combination multiple meds
2. Uninterrupted supply Erratic
3. Affordable
Prohibitive cost
4. Controlled environ
“Open season”
5. Topical solutions
“one size fits all”
“The blame game”

B ureaucracy
 L op-sided national and local priorities
 A ffordability and availability of medications
 M alaise and mediocrity of Medical and
Public Health leadership
 E xpenses of programs
Let us face it…we are not getting anywhere
International Scenario
Fragmented and disjointed system
Hosp with in patient services
TB
Regional
Centers
Community
Clinics
TB Clinics
In Hospital
STIGMA OF THE DISEASE
STIGMA OF BEING A “TB DOCTOR”
Case # 5 MDRTB
Success Stories
*A breakthrough in Peru: 22% drop in case rates from 1992-96
*97% of public health facilities offered access free of charge
*Completion of Rx rates increased to 90 %
*132 % increase in lab facilities and personnel
Nepal * Increased cure rates
Bangladesh* Incentive driven ““tailor” –made”” rural program
increased cure rates to 85 %
Successful national TB
programs
Tanzania; Malawi; Kenya ; China; Vietnam; Indonesia
Increased Notification rates
Rx Success rate 70-80 %
“Ten get it, nine die” replaced by “ ten detected
nine cured” …Chinese proverb
Summary 1: Priniciples
• Empiric choice based on history and
“mycobacteriogram”
• Revaluated regimen based on fresh data
• Close liaison with lab; “synergistic” sensitivities
• 7 day DOT ; zero tolerance
• Drug levels and GI absorption factors
• Monitor of side effects and tolerance
• D-D Interactions; D-F interactions; Customized
Rx / step ladder approach
• Co-morbid conditions
• Surgical options
Summary
Prevention of DRTB is the key
Front end resources to avoid back end costs
•Accountability
•Accessibility
•Affordability
The *“AAA” approach
Thank you
JA