MDR/XDR TB “The growing menace” NE TB Controllers Conference October 12 th , 2011 C. Scott Mahan, MD Director, Cuyahoga County TB Program TB Consultant, ODH
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MDR/XDR TB “The growing menace”
NE TB Controllers Conference October 12th, 2011 C. Scott Mahan, MD Director, Cuyahoga County TB Program TB Consultant, ODH
Overview
• Define MDR/XDR TB
• Epidemiology
• How does resistance emerge?
• MDR/XDR in developing world
• MDR/XDR in the U.S.
TB drug resistance-definitions-WHO, 2010 Drug resistant TB- resistant to one of the 1st line tb
drugs: H,R,E,or Z MDR TB: resistant to H and R XDR TB : resistant to H,R, FQ, and to at least one
second line injectable agent (kanamycin, amikacin or capreomycin).
Primary resistance- patient has never received TB therapy previously
Secondary- resistance during therapy or after prior treatment for drug susceptible TB
Prevalence of MDR among new TB cases. (WHO, 2006)
2010 WHO estimates: 440,000 cases MDR in 2008
150,000 deaths
3.6% of overall TB cases
Presenter
Presentation Notes
In 2008: 29,423 reported MDR cases in 127 countries. Felt to represent only about 7% of the ~450,000 cases of mdr tb globally, 150,000 deaths. 3.6% of all cases globally are MDR IN the 27 high burden MDR-TB cases only 1% of new TB cases and 3% of previously treated cases underwent DST 50% of MDR cases are in China, and India with high rates in Russia and the Russian block countries. Latest data WHO: : 2001-2009: Moldova #1 on list with 19.4% of new case of TB with MDR, and 50.8% of retreatment
MDR-TB Among Previously Treated TB Cases, 2006- WHO
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*2010: 58 countries with at least one case of XDR *5 4% of MDR are XDR
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2010 WHO report: estimated 25,000 XDR-TB cases emerging every year
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Reported MDR-TB in 2008 in US 94 cases 1.2% of TB cases 88% of MDR cases in foreign born 7% of TB in foreign born with prior hx of TB is MDR
From 1993-2007: Primary XDR=48 cases, acquired XDR=33. No confirmed cases in 2009.
How does resistance emerge? 1. Spontaneous mutations
2. Selective pressure- inappropriate tx (within weeks)
3. Primary transmission of resistant TB to contacts
Adapted from Iseman, 2000
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Spontaneous mutations develop as bacilli proliferate to >108
Drug Mutation Rate Rifampin 10-8
Isoniazid 10-6 Pyrazinamide 10-6
Presenter
Presentation Notes
M. tuberculosis bacteria become resistant to anti-TB drugs by acquiring mutations that confer resistance. Such mutations develop spontaneously as the bacteria proliferaet in the host. Rif-R mutants arise at a frequency of 1 in 10exp-8 INH-R and PZA-R mutants arise at a frequency of 10exp-6 So, prior to treatment, the population of bacteria in a TB pateint already contains drug-resistant bacteria.
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INH RIF PZA
INH
Drug-resistant mutants in large bacterial population
Multidrug therapy: No bacteria resistant to all 3 drugs
Monotherapy: INH-resistant bacteria proliferate
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If one treats this population with three effective drugs, all bacteria are killed. However, if one treats with only one drug, say INH, one selects for INH resistant bacteria. --
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INH RIF
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
Presenter
Presentation Notes
These bacteria then can multiply to large numbers and once again spontaneous mutations can arise. In this case acquisition of a second drug resistance. Treatment with two drugs then leads to selection of the MDR strain and its proliferation can lead to the acquisition of additional resistance. This sort of amplification of drug resistance can occur one drug at a time to ultimately lead to XDR TB. -
KwaZulu-Natal Province, SA, 2005
What were are trying to avoid: KwaZulu-Natal Province, South Africa
• Outbreak of XDR TB in 2005 in HIV infected persons
• 544 culture confirmed cases of TB: (221) 40% MDR, 53 (10%) XDR.
• Of those with XDR TB 44 were tested for HIV and all were positive.
• 52 of 53 with XDR died within a median of 16 days from presentation. 16 of these received HAART.
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This rural area with a traditional Zulu population has an extraordinarily high incidence of TB—more than 1,000 per 100,000 population. The incidence of MDR TB, by Friedland’s calculation, is 100 per 100,000 population, much higher even than nonresistant TB in most parts of the world.
KwaZula-Natal in the interim • Moodley et al, PloS ONE, 2011 • Cross-sectional study using KZN TB
laboratory databases. Sputum cx + from 1/2006- 7/2007.
• 20,858 patients from 1 of 73 hospitals had +cx for MTB.
• 4170 (20%) had MDR, 443 (2%) had XDR • Only 1429 of MDR- TB were seen at
referral hospital
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More than 65% of all diagnosed MDR-TB cases including XDR-TB patients were left untreated and likely remain in the community as a source of infection!
A representation of the limited knowledge of the extent of MDR TB in KwaZulu-Natal Province, 2006
Friedland, 2008
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demonstrates the limited knowledge of the extent of MDR TB in KwaZulu-Natal. At the beginning of the epidemic, the one facility in the province that had access to second-line drugs treated 686 patients for MDR TB, a mere 28 percent of the nearly 2,500 cases of MDR TB that were diagnosed. Behind these numbers, however, are an unknown number of patients who were seen and not diagnosed because of both the paucity of laboratory facilities and a policy of not doing cultures for individuals when they first present with TB, but only when they have failed treatment with first-line drugs. Finally, according to Friedland, the largest group is likely those who have never been diagnosed or treated because they have not visited a health care facility. Left untreated each person with active tb will infect 10-15 persons/year (WHO, 2010 fact sheet)
High mortality due to MDR and XDR TB in Tugela Ferry (2005–2007)
The top curve represents MDR TB mortality (67 percent), and the bottom curve represents XDR TB mortality (82 percent). Gandhi et al., 2009.
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WHO: 2010 world report: Treatment success in MDR TB is around 60% overall worldwide.
Factors influencing drug resistance
• Poor public health programs. • Poor adherence to DOT. • Wide availability of TB drugs-OTC in many
countries. -highest drug resistance in
intermediate countries. • HIV- no proof of increased risk for TB drug
resistance…but some associations with resistance epidemiologically (in KZN province 90% of MDR/XDR cases have HIV)
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? impact of rifampin and rifabutin for the treatment of disseminated MAC. -monocytic cells chronically infected with HIV have been shown to express higher levels of a drug efflux pump leading to less uptake of INH. (Gallapudi, 1994)
What is needed to combat MDR/XDR TB epidemic from growing? • Rapid methods for diagnosis of drug
resistant TB- particularly in areas with a high incidence of MDR TB .
• New treatment options.
• Will need to provide high burden countries with adequate funding.
Rapid diagnosis • Liquid culture- BACTEC/ MGIT • MODS- inverted microscopy- looks for cording- results,
including initial susceptibilities within 7 days vs. 22 days for liquid, and 68 days for solid, (Moore et al., NEJM, 2006)
• Molecular methods: Line probe assays- on smear positive specimens. High sensitivity and specificity for detection of
rifampin (+/- INH) resistance. Requires DNA extraction and amplification facilities or self contained system-$$$.
• NAAT- Gen-Probe (determine MTB complex on smear positive)-labor intensive.
• Strip based ( detects TB specific antigens in positive cultures- Capila TB- inexpensive
• *serologic method(-( JID,2009- Abs to cell wall protein- ptrp) • *Urine assay- antigen detection for LAM
Presenter
Presentation Notes
Often still just sputum smear (70% sensitive- lower in HIV), solid cx- long time. PTRP- gene encoding proline-threonine repetitive protein – cell wall protein-without known function- specific to mtb in all clinical isolates- Able to detect abs to ptrp in human blood in >80% of smear positive, and >50% of smear negative persons. MODS- microscopic observational drug susceptibility
What are some really excited about?
• Gene Xpert MTB/RIF
• Automated molecular test for MTB and rifampin resistance
• Heminested real-time PCR (DNA amplification)
Presenter
Presentation Notes
Isolated rifampin resistance is uncommon. Therefore if rifampin resistance must assume MDR (hence both INH and rifampin resistance at least).
NEJM, 2010 • Tested on 1730 patients in Peru, Azerbaijan, South Africa
and India • compared solid and liquid culture versus Xpert MTB/RIF
test • Identified 98.2% with smear + TB and 72.5 with smear
negative TB. • If 3 sputums for analyzed by Xpert test sensitivity
increased to 90.2% on smear negative. • Identified 97.6% with rifampin resistant bacteria. • Results in < 2 hours
Funded by FIND
Cepheid Gene Xpert MTB/RIF test • • sputum smear +, or smear - • • simple 1-step external sample prep. procedure • • time-to-result < 2 h • • throughput: > 16 tests / day / module • • no need for biosafety cabinet • • integrated controls- easy to use • Performance • • specific for MTB • • sensitivity better than smear, similar to culture • • detection of rif-resistance via rpoB gene • Obstacles in resource poor settings: initial start up cost for device,
reliable power supply, operating temps <30 Celsius.
Dr. Leonid Heifets- “Will still need micro lab”…(other DST, second line agents… will need culture growth)
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Dr. Heifets- director Nat. Jewish Health Micro Lab
New drugs in the pipeline • High dose rifampin or rifapentin • Fluoroquinolones- Levo and Moxi. (good early and late eba,
moxi substitution for INH in intensive phase –some evidence of increased 2 month culture conversion)
• Diarylquinolone (TMC-207) –inhibits mycobacterial ATP synthetase- very effective in mouse models- phase IIb human studies- (48% vs 9% cx conversion)-(NEJM,2009)
• Nitrofuranylamides: PA-824-and OPC-67683- inhibit cell wall synthesis- both effective in mouse models with evidence for tx shortening- now in phase II studies
• SQ109- congener of ethambutol- but effective in ethambutol resistant strains- Phase 1 studies
• PNU-100480- oxazolidinones (like linezolid)- much greater activity than linezolid in mouse model. In phase 1.
• AZD5847- oxazolidinone
Presenter
Presentation Notes
No new drugs since 1980;s. Linezolid early eba was less than INH or FQs. Poor extended (2-7d) activity. TMC 207- phase 2 study in 47 patients with MDR TB – placed on optimized 5 drug regimen +/- TMC 207. had significantly shorter time to culture conversion and increased proportion of patients with 2 week culture conversion (48% vs. 9%)- only 47 patients.
Need for Financial Support • WHO: medications 50-200x greater than for drug
susceptible TB
• All cost total 10X the cost. (very variable)
- Peru: standardized MDR regimen cost
$2381 (Suarez, Lancet, 2002)
- In U.S. –estimates range up to $250,000
- According to Stop TB Partnership’s Global Plan to Stop TB: 1.3 million cases will need to be treated in 27 high burden countries between 2010-2015 at a cost of $16.2 billion, current funding in 2010 in these countries is <$0.5 billion.
What about here in the U.S.A? • 34 yo male from Moldova.
• >8 months of NS, intermittently productive cough, 15 lb wt loss, anorexia and fatigue.
• Seen in FL –felt to have copd/bronchitis- tx with antibiotics without improvement. CT chest 6/09 with LLL cavitary lesion. Failed 3rd round of antibiotics in Ohio before TB considered. TST placed- read as 25 mm.
• SH: neighbor with TB in Moldova 2 years prior, married, 5 year old daughter
• Sputum smears + 7/1 -7/3/09 x 3. amplified DNA probe positive for MTB complex. HIV negative
• Referred to TB clinic 7/15/09. .
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88% of MDR cases in US are in Foreign born, Moldova with >19% rate of MDR at baseline
X-Ray at initial visit to TB clinic
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IMPRESSION:�Bilateral pulmonary infiltrates, left greater than the right with�possible cavity in the left upper lobe.�
Case continued • Started HREZ. (7/15/09). • Seen 8/14/09. little change in symptoms.
Still smear positive. No change in meds made.
• 8/20/09: Susceptibilities from 7/1/09 specimen: INH resistant (0.2 ug/ml and 1.0 ug/ml), rifampin – R , ethambutol – susceptible.
• What to change to?
Changes made 8/25/09 • Changed to: ethambutol, pza, moxifloxacin, amikacin,
ethionamide. • Asked ODH to do second-line susceptibilities on 7/1/09
specimen: • 9/17/09: result from ODH: resistant to ethambutol,
rifampin, INH, streptomycin, ethionamide. • Susceptible to ; cipro, capreomycin, PAS, ofloxacin,
amikacin, and pza. • 10/1/09: changed to PZA, moxi, amikacin, PAS, linezolid. (we asked ODH to do linezolid, clofazamine, clarithro, and
PZA susceptibilities from 8/15/09 specimen) • 10/24/09: ODH report: susceptible to linezolid,
clofazimine, clarithromycin, PZA. ( no change made to regimen)
11/2, 11/5, 11/6- afb smear negative x 3. tolerating meds
Treatment principles • Never add a single drug to a failing regimen-
preferably add 3 or more potentially active agents.
• DOT, adherence is key. Consider monitoring drug levels.
• MDR/XDR TB – consider surgery. (resistance to all 1st line agents, less than 4 second-line agents are available, localized disease)
• Treatment of 18-24 months after culture conversion with at least 4 effective drugs if possible.
Presenter
Presentation Notes
Great review for tx of mdr and xdr TB by Caminero in Lancet/infection september 2010
Surgery for MDR/XDR TB • Indications- (Iseman)- 1)persistence of cx + MDR-TB
despite extended drug tx, 2)extensive pattern of resistance, 3) evidence of local disease amenable to resection.
• Pomerantz et al.- Denver- 1983-2000: 172 patients with MDR TB had pulmonary resections. All had minimum of 3 months of antecedent medical therapy: 3.3% operative mortality, 6.8% late mortality, 12% significant morbidity. Only 2% remained sputum positive after operation.
• Dravniece et al., Latvia 1999-2005- 17 persons with XDR TB – 47% cured with adjunctive surgery
Conclusions • MDR/XDR TB is a real threat.
• Globally: resources needed to improve public health delivery (DOT, DOTS+), need for new diagnostics, need for new treatment options.
• Management is uniquely challenging both abroad and at home.
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