update on mycobacterial infections - confex starke... · 10/19/2011 idsa: vincent t. andriole id...

10/19/2011

IDSA: Vincent T. Andriole ID Board Review Course 1

Update on Mycobacterial Infections

Jeffrey R. Starke, M.D.Baylor College of Medicine

MYCOBACTERIOLOGY

non-motile, nonspore - forming, weakly Gram-positive rods; often appear slightly bent or beaded

obligate aerobes; simple growth requirements

cell wall: 20 to 60 percent lipids

generation time of 12 to 48 hours (except rapid growers)

acid-fastness: form stable mycolate complexes with arylmethane dyes (carbolfuchsin, crystal violet, auramine, rhodamine)

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GROWTH MEDIA FOR MYCOBACTERIA

Blood agar - “rapid” growers - M. fortuitum, M. chelonae, M. abscessus; 5-10 days

“Classic” - egg yolk and glycerin (Loewenstein - Jensen, Dorset); 3-6 weeks

“Synthetic” - glycerol and ammonium salts (Middlebrook, Tween - albumin); 2-6 weeks

Liquid-Radiometric (Middlebrook variant);

10-21 days

SPECIATION OF MYCOBACTERIA

Growth characteristics: colony shape and color, rate, temperature (33°- 40°)

Chemical tests: niacin (M. tuberculosis)

DNA probes

HPLC - unique patterns of mycolic acids

Drug susceptibility - eg. M. bovisresistant to pyrazinamide

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25 - 49

50 - 99

100 - 300

0 - 9

10 - 24

300 or more

No estimate

Rate per 100 000

Estimated TB incidence rates, 2009

www.who.int/tb/xdr

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10,000

12,000

14,000

16,000

18,000

20,000

22,000

24,000

26,000

28,000

1982 1985 1988 1991 1994 1997 2000 2003 2006 2009

Reported TB Cases* United States, 1982–2009

Year

No.

of C

ases

*

SOME REASONS WHY TUBERCULOSIS RESURGED IN THE

U.S. – 1984-92

HIV co-epidemic

Immigration and visitation

Transmission in congregate settings

Poor tuberculosis control

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Reported TB Cases by Age Group, United States, 2009

25–44 yrs (34%)

<15 yrs(6%)

15–24 yrs(11%)

45–64 yrs(30%)

>65 yrs(20%)

Number of TB Cases inU.S.-born vs. Foreign-born Persons

United States, 1993–2009*

No.

of C

ases

0

5000

10000

15000

20000

1993 1995 1997 1999 2001 2003 2005 2007 2009

U.S.-born Foreign-born

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Countries of Birth of Foreign-born Persons Reported with TB

United States, 2009

Mexico(23%)

Philippines(12%)

India(8%)

Vietnam(8%)

China(5%)

Guatemala(3%)

Haiti(3%)

OtherCountries(38%)

RISK FACTORS FOR TUBERCULOSIS

Increased risk of acquiring or having infection

Foreign born from high prevalence country

Intravenous drug or crack cocaine user

Family history of TB (2-3 generations)

Contact with HIV- infected individuals

Contact with inmates of prison or jail (past or present)

Some nursing homes, residential living

Some healthcare workers

Increased risk of developing disease after infection

HIV infected

Immune suppression - drugs or disease

Recent (<3 years) infection

Certain diseases: silicosis, diabetes mellitus

Extremes of ages: infants, elderly

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MONOCLONAL ANTIBODIES AND TUBERCULOSIS

Remicade (Infliximab)

monoclonal antibody against tnf – alpha black box warning for tuberculosis – 84 cases by 10/01 severe pulmonary, G-I and disseminated tuberculosis must do at least A TB risk assessment and TST prior

to use

Humira (adalimumab), Enbrel (etanercept)

less information known strong warning to assess for TB risk and place a TST

PathogenesisDroplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to the alveoli.

Tubercle bacilli multiply in the alveoli.

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Pathogenesis

A small number of tubercle bacilli enter the bloodstream and spread throughout the body. The tubercle bacilli may reach any part of the body, including areas where TB disease is more likely to develop (such as the brain, larynx, lymph node, lung, spine, bone, or kidney).

TRANSITIONS IN TUBERCULOSIS

Cured

Treated

Diagnosed

Susceptible

Exposed

Infected

Diseased

Sick

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STAGES OF TUBERCULOSIS

Exposure

Defined by contact investigation - recent (< 3 months) contact with an infectious case

Negative ST, physical exam and chest radiographs

Period during which the skin test may be negative in an infected person

Children < 5 years old should be treated (usually INH) because they may develop disease rapidly

Older children and adults often not treated, but repeat skin test 3 months after exposure over


Infection

Hallmark is a “positive” skin test

“Germs in the body”

Chest radiograph is normal or shows only one or more granulomas or fibrotic lesions

No symptoms, physical exam is normal

Anyone with infection should be treated when the risk of disease outweighs the risk of serious adverse reactions to the medication

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Risk of Developing DiseaseNormal Immune System

Untreated, 5% of infected persons with normal immunity develop TB in first 1–2 years post infection, another 5% later in life

Thus, about 10% of infected persons with normal immunity will develop TB at some point in life if not treated

Risk of Developing Disease (cont.)Weak Immune System

Persons with weak immunity at increased risk of progressing to TB disease

Untreated HIV infection highest risk factor: risk of developing TB disease is 7%–10% each year

Infants and toddlers have a 40% chance of developing TB disease with untreated TB infection

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Disease

Clinical and/or radiographic manifestations of progressive tuberculosis infection

Primary: complication of initial infection

Reactivation: disease occurs after period of dormancy of the infection

TST is negative in 10% of disease cases (50% of meningeal or miliary disease)

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Probability TB Will Be Transmitted

Susceptibility of the exposed person

Infectiousness of person with TB (i.e., number of bacilli TB patient expels into the air)

Environmental factors that affect the concentration of M. tb organisms

Proximity, frequency, and duration of exposure (e.g., close contacts)

Can be transmitted from children, though less likely

Infectiousness

Patient factors associated with infectiousness:

Coughing

Cavity in the lung

Sputum smears positive for acid-fast bacilli (AFB)

TB disease of the lungs, airway, or larynx

Undergoing cough-inducing or aerosol-generating procedures

Not receiving adequate therapy

Culture positive

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Environmental Factors that EnhanceRisk of Transmission

High concentration of droplet nuclei in the air

Exposure in small, enclosed spaces

Poor ventilation that inadequately dilutes or removes droplet nuclei

Recirculation of air containing droplets

Improper specimen handling procedures

Positive air pressure in patient’s room causing flow to other areas

Criteria to Be Considered Noninfectious

Patients no longer considered infectious if:

They have 3 consecutive negative sputum smears, AND

Their symptoms have improved, AND

They are adhering to an adequate treatment regimen for at least 2 weeks

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Most Common Systemic Symptoms of Tuberculosis

Fever

Chills

Night Sweats

Weight Loss

Loss of appetite

Fatigue

Malaise

Most Common Symptoms of Pulmonary Tuberculosis

Cough lasting 3 or more weeks

Coughing up sputum

Coughing up blood [late]

Chest pain [less common]

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Signs and Symptoms of Tuberculosis in Children Children have a relative paucity of

signs and symptoms

The chest xray is often “sicker” than the patient

Children are more likely to have extrapulmonary TB – a complete exam is important!

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TUBERCULOUS PLEURAL EFFUSION

Primarily in adolescents and young adults; uncommon before age 5, rare before age 2

Usually unilateral, but can be bilateral Almost never associated with a segmental

lesion; rare in miliary disease Usually abrupt onset: fever, chest pain, SOB Thoracentesis: several hundred WBC’s (M),

high protein, glucose < 30, AFB stain negative, culture positive in 30% to 60%

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LYMPHADENITIS CAUSED BY MYCOBACTERIUM TUBERCULOSIS

most often unilateral; may be bilateral chest xray usually normal usually indolent onset of enlarged, fixed,

matted nodes in anterior chains, submandibular

submental, occipital, axilliary, supraclavicular nodes less common

absence of systemic findings; minimal tenderness

often progress and “break down” -suppuration, sinus tracts

major differential dx: NTM, Bartonella, malignancy

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TUBERCULOUS MENINGITIS

most common in infants, young children, elderly

occurs soon after infection in children, years later in adults

pathogenesis: basilar infiltrate, hydrocephalus, vasculitis, infarct, tuberculoma

3 clinical stages: correlate with sequelae

I - non-specific signs and symptoms

II - focal neurologic findings, increased ICP

III - profound findings - coma, paralysis, death

CLASSIC FINDINGS IN CEREBROSPINAL FLUID

Viral Bacterial TB_______

Cells 0-500 5-10,000 10-500

Differential polys monos polys polys monos

Protein 20-60 20-400 50-5,000

(g/dl)

Glucose 30-80 <20 20-50

(mg/dl)

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CT SCAN/MRI FINDINGS IN TUBERCULOUS MENINGITIS

Basilar enhancement

Hydrocephalus (communicating)

Vasculitis

Infarct

“Paradoxical” tuberculomas - while on ultimately successful chemotherapy

DISSEMINATED (MILIARY) TUBERCULOSIS

most common in infants, recent after infection

Also occurs in the elderly, reactivation

protean manifestations at first - FUO common

usually insidious but may be explosive

chest radiograph usually normal early, then classic

other common features: hepatosplenomegaly, lymphadenopathy, cutaneous lesions, choroid tubercles

TST negative in up to 50% of cases

Dx: gastric aspirate, bronchoscopy, lung biopsy, liver biopsy, bone marrow, urine culture

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Evaluation of an Adult With Suspected Pulmonary Tuberculosis

Thorough history and physical exam

Risk factor/exposure history

Infection control precautions

Chest radiograph

Sputum for AFB smear and culture

+ TST or IGRA

Baseline AST/ALT, platelets

Notify the health department

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EVALUATION OF A CHILD WITH SUSPECTED TUBERCULOSIS DISEASE

Evaluate family members, other contacts

Tuberculin skin test

Appropriate radiographs

Sputum (if available) for AFB stain, culture

3 early a.m. gastric aspirates (pulmonary)

LP if < 1 year old

Bronchoscopy - if anatomy needs to be defined or diagnosis is in doubt

Report suspicion of disease to health department ASAP

MANTOUX TUBERCULIN SKIN TEST

uses 5 TU [2 TU if R23] of purified protein derivative

interpret in 48 – 72 hours

record size of induration in mm

if it makes a reaction at >72 hrs, it counts!

false negatives: 10% to 20% in disease

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INDURATION SIZE – POSITIVE TUBERCULIN SKIN TEST

> 5 mm

HIV co-infectionImmune compromiseRecent contact to TBSuspected disease

> 15 mm

No risk factorsPrevious BCG vaccination?

> 10 mm

Foreign-born from a HR countryDrug –usersLiving in HR congregate settingSpecific HR groupsChildren < 4 yrs old (AAP)

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Factors that May Affect the Skin Test Reaction

Type of Reaction Possible CauseFalse-positive • Nontuberculous mycobacteria

• BCG vaccination• Problems with TST administration

False-negative • Anergy• Viral, bacterial, fungal coinfection• Recent TB infection• Very young age; advanced age• Live-virus vaccination • Overwhelming TB disease• Renal failure/disease• Lymphoid disease• Low protein states• Immunosuppressive drugs• Problems with TST administration

Boosting of the TST Reaction

Some may have negative (waned) TST reaction when tested years after infection (e.g., older adults)

Initial skin test may stimulate (boost) ability to react to PPD

Subsequent positive boosted reaction may be misinterpreted as a new infection

May still be considered for treatment if currently at high risk for TB disease

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INTERACTION OF BCG VACCINES WITH THE TUBERCULIN SKIN TEST

50% of vaccinated infants do not react to a TST; most of the rest stop reacting within 5 years

Most older children and adults who get one or more BCG vaccinations will react to a TST (usually < 15 mm), but effect wanes over 5 –10 years

Current TST Dogma: outside infancy, “positive” TST more likely to indicate infection with M. tuberculosis than be residual from BCG

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INTERACTION OF BCG VACCINES WITH THE TUBERCULIN SKIN TEST

H1N1 influenza – Which makes you feel better?

• 99.9% get no serious complications

• If 1 million people in Houston get it, 1,000 will develop serious complications

BCG vaccination

• By 5 years post-vaccination, 90% will have a negative TST

• Millions of children get BCG

IGRAs - Interferon-γ Release Assays

detect host response to Mycobacterium tuberculosis-specific antigens

Two main tests currently available:

T-SPOT.TB

QuantiFERON Gold In-Tube

Offer several potential advantages over the tuberculin skin test (TST)

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Immune-based DiagnosticsCharacteristic TST IGRA

Antigens studied Many -PPD

ESAT-6, CFP-10, (TB-7.7)

Cross-reactivity with BCG Yes Unlikely

Cross-reactivity with NTM Yes Less Likely*

Estimated sensitivity, TB in immunocompetent adults

75-90% 75-95%

Estimated specificity, TB inimmunocompetent adults

70-95% 90-100%

Distinguish between TB infectionand TB disease

No No

Boosting Yes No

Patient visits required Two One

*Exceptions: M. kansasii, szulgai, marinum, gordonae

INTERFERON-GAMMA RELEASE ASSAYS - 2010

CDC expert panel recommends:

1. No preference for one test over the other2. Should replace the TST for most adults

and older children, except, perhaps, for immune compromised; less clear for children < 5 years of age

3. Can be used in contact investigations [even in contact investigations, many adults with a positive TST and history of BCG likely do not have LTBI]

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IGRAs AND THE 2009 AAP “RED BOOK”

Can use IGRAs in immunocompetent children > 4 years of age in all situations when a TST would be used

Particularly useful/preferred for children who have received a BCG vaccination: IGRA alone, or TST followed by IGRA [if TST +]

Use with caution in children < 5 years of age, immunocompromised children

Neither IGRAs nor the TST are perfect; always need clinical judgment!

NEJM 2011;364:1441

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Traditional Lab Methodology: a stepwise approach

Obtain culture

MODS

Speciate as TB vs. NTM: HPLC

Perform drug-susceptibility testing

Accelerated Diagnostics

Xpert

Traditional PCR

Sputum

6-8 wks

90 minutes

7-10 days

Medical Evaluation for TB Bacteriologic Examination of

Specimens Specimen collection, processing,

and review

All persons suspected of TB disease should have sputum cultured

Collect at least 3 sputum specimens at 8- to 24-hour intervals, at least 1 in the morning

Follow infection control precautions during specimen collection

Collection methods include coughing, sputum induction, bronchoscopy, gastric aspiration

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HOW IS TUBERCULOSIS DIAGNOSED?

Adults – Mycobacterial-based diagnosis positive sputum AFB smear - 60% - 75% positive sputum culture - 90% positive tuberculin skin test - 80% [HIV < 50%]

Children positive sputum or gastric AFB smear - 10% positive sputum or gastric culture - 10% - 40% positive tuberculin skin test - 50% - 80%

AFB SmearAFB (shown in red) are tubercle

bacilli

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ACID-FAST STAINS

Ziehl-Neelsen - Fuchsin (Red)

Kenyoun - Fuchsin (Red)

Crystal Violet - Purple

*Truant - auramine rhodamine

(yellow-green fluorescence)

Direct Detection Using Nucleic Acid Amplification (NAA)

NAA tests rapidly identify a specimen via DNA and RNA amplification

Benefits may include

Earlier lab confirmation of TB disease

Earlier respiratory isolation and treatment initiation

Improved patient outcomes; interruption of transmission

Perform at least 1 NAA test on each pulmonary TB suspect

A single negative NAA test does not exclude TB

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Conventional PCR for TB

Developed in the 1990s to distinguish TB from MAC in HIV-infected adults

Site Yield

Pleural biopsy 75%

Lymph node 95%

CSF 70%

Pericardial tissue 80%

Ascitic fluid 10%

Urine 50%

Xpert MTB/RIFCartridge-based NAAT & closed

sample preparation means

minimal biosafety requirements

WHO-endorsed December, 2010

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Xpert detected 90% of culture-confirmed cases

Versus 67% detected by smear microscopy (done 2-3 times)

Estimated sensitivity of smear microscopy: 30-80% in adults

99% specific

Sensitivity not affected by HIV status

Versus smear microscopy (69% v. 45% in HIV- v. HIV+)

Reduced time to treatment from 56 to 5 days and drop-out rates from 39% to 15% in smear-negative, culture-positive patients

Lancet 2011;377:1495

Lancet 2011;377:1495

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DRUG RESISTANCE IN TUBERCULOSIS

The development of drug resistance in M. tuberculosis is the result of a conspiracy among the organism, the patient, the doctor and the healthcare system!

DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

genetic loci for resistance on chromosome, unlinked

resistance of drugs independent

frequency of mutations at loci is known

more likely to have mutations when mycobacterial population is larger : infection vs. disease

primary - resistance present when infection acquired

secondary - resistance develops while ontherapy

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Primary Isoniazid Resistance in U.S.-born vs. Foreign-born Persons

United States, 1993–2009%

Res

ista

nt

Note: Based on initial isolates from persons with no prior history of TB.

0

2

4

6

8

10

12

14

1993 1995 1997 1999 2001 2003 2005 2007 2009

U.S.-born Foreign-born

Current Anti-TB Drugs

Isoniazid (INH)

Rifampin (RIF)

Pyrazinamide (PZA)

Ethambutol (EMB)

Rifapentine (RPT)

10 drugs FDA-approved for treatment of TB

Streptomycin (SM)

Cycloserine

Capreomycin

ρ-Aminosalicylic acid

Ethionamide

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Current Anti-TB Drugs

Four first-line drugs considered standard treatment:

Isoniazid (INH)

Rifampin (RIF)

Pyrazinamide (PZA)

Ethambutol (EMB)

Rifabutin and rifapentine also considered first-line drugs in some circumstances

Streptomycin (SM) formerly first-line drug, but now less useful owing to increased SM resistance

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Treatment Regimens for LTBI

Isoniazid for 9 months

Isoniazid for 6 months

Rifampin for 4 months [adults]

Rifampin for 6 months [children]

**Isoniazid and rifapentine once weekly for 12 weeks

LTBI Treatment Regimens

Isoniazid (INH)

9-month daily regimen is preferred: 270 doses within 12 months

Effective for HIV-infected as well as HIV-uninfected persons

Can be given twice weekly via DOT: 76 doses within 12 months

Children should always receive 9 months of therapy

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LTBI Treatment Regimens

Isoniazid (INH) (cont.)

6-month regimen also generally acceptable: 180 doses within 9 months

Can be given twice weekly via DOT: 52 doses within 9 months

Not recommended for children, HIV infected, persons whose x-rays suggest previous TB

Adverse Reactions to INH

Use of INH is associated with some adverse reactions

Peripheral neuropathy – give vitamin B6 if patient has risk factors, or if signs/symptoms develop

Elevation of liver enzymes – discontinue INH if adverse reactions develop, or if liver enzyme levels exceed 3X normal with symptoms, or 5X upper limit of normal with no symptoms

Fatal hepatitis – Rare! pregnant/postpartum women at increased risk; monitor closely

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Rifampin (RIF)

Alternative to INH is 4 months daily RIF:120 doses within 6 months

Use of RIF contraindicated with some combinations of antiretroviral therapy

In some instances where RIF cannot be used, rifabutin can be substituted

LTBI Treatment Regimens for Specific Situations

HIV-Infected Persons

Consult an expert in managing HIV and TB

INH daily for 9-mo, rather than 6-mo, is optimal: 270 doses within 12 months

RIF is generally contraindicated for persons taking protease inhibitors or delavirdine

Rifabutin with dose adjustments can sometimes be substituted for RIF

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Persons with Fibrotic Lesions Suggesting Previous TB

Should be treated for LTBI if they have

A positive TST reaction (at least 5 mm) or IGRA result

No symptoms of infectious TB disease

No history of treatment for TB disease

Treat only after active disease excluded with sputum testing

Acceptable regimens include

9 months of INH

4 months of RIF (with or without INH)

Persons with evidence of primary, healed TB not at increased risk for TB


Contacts of Persons with Multidrug-Resistant TB

Consider risk for progressing to MDR disease before recommending LTBI treatment

When prescribing treatment for these contacts, consult an MDR TB expert

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Pregnancy and Breast-Feeding

9 months of INH daily or twice weekly; give with vitamin B6

If cannot take INH, consult with TB expert

Women at high risk for progression to TB disease should not delay LTBI treatment; monitor carefully

Breast-feeding not contraindicated

Close Contacts with Negative IGRA or TST Result

Some contacts should be evaluated and treated for LTBI even with negative TB test results:

Children under 4 yrs of age

Immunosuppressed persons

Others at high risk for progressing to disease once infected

Always rule out TB disease with chest radiograph and medical evaluation before treating for LTBI

Give LTBI treatment (window prophylaxis) regardless of test result

Retest 8–10 weeks after last exposure to allow for delayed immune response

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Regimen 1 for Treatment of Pulmonary,Drug-Susceptible TB

6-Month Standard Regimen for Most Patients

Initial phase

INH, RIF, PZA, EMB daily (7 or 5 days/week) for 8 weeks

4-month continuation phase options

1) INH, RIF daily (7 or 5 days/week) for 18 weeks

2) INH, RIF intermittently (2 days/week or 1 day/week for INH, rifapentine) for 18 weeks


6-Month Daily + Intermittent Dosing Options

Initial phase

INH, RIF, PZA, EMB daily (7 or 5 days/week) for 2 weeks, then 2 days/week for 6 weeks


1) INH, RIF intermittently (2 days/week) for 18 weeks

2) INH, RPT intermittently (1 day/week) for 18 weeks

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6-Month Intermittent Dosing Options

Initial phase

INH, RIF, PZA, EMB intermittently (3 days/week) for 8 weeks

4-month continuation phase

INH, RIF intermittently (3 days/week) for 18 weeks


7-Month Regimen without Pyrazinamide

Initial phase

INH, RIF, EMB daily (7 or 5 days/week) for 8 weeks


1) INH, RIF daily (7 or 5 days/week) for 31 weeks

2) INH, RIF intermittently (2 days/week) for 31 weeks

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Adherence

Nonadherence results in inadequate treatment

Can lead to treatment failure, relapse, ongoing transmission, and drug resistance

Clinician responsible for completion of therapy

To ensure adherence, provide education, case management, DOT, incentives and enablers, and combination pills

If these fail, take more restrictive action

Directly Observed Therapy (DOT) Health care worker watches patient swallow each dose

DOT is preferred management strategy for all patients

Can reduce acquired drug resistance, treatment failure, and relapse

Nearly all regimens can be intermittent if given as DOT

DOT reduces total number of doses and encounters

For drug-resistant TB, use daily regimen and DOT

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Patient Monitoring

Baseline laboratory testing not routinely indicated for all patients

Baseline hepatic measurements are indicated for

Patients with a liver disorder or liver disease

Patients with HIV infection

Pregnant women and those in immediate postpartum period

Patients with abnormal baseline tests should be monitored regularly

Circumstances Increasing the Risk of Drug-Resistant TB

Risk of drug-resistant TB is increased with exposure to a person who

Has confirmed drug-resistant TB

Had prior unsuccessful treatment for TB, and drug susceptibility results not known

Originated in a drug-resistant TB prevalent country

Has positive smear and culture 2 months after treatment start

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CORTICOSTEROIDS IN TUBERCULOSIS

Useful when host inflammatory response is contributing to tissue damage or dysfunction

meningitis

endobronchial

miliary with alveolar block

pericardial with constriction

vertebral with spinal root irritation

Can use prednisone or dexamethasone

BCG VACCINES

Used in all but 2 countries

Negligible effect on TB epidemiology

do not prevent infection

little effect on reactivation disease

not instruments of TB control

Major use is preventing life-threatening forms

of tuberculosis in infants and children

(60% - 90%)

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Roles and Responsibilities of Specific Private Sector Providers

Role of Clinicians

Understand prevalent medical conditions of their patient populations

Be aware of local TB reporting laws

Know procedures for suspected TB: diagnose, hospitalize, report case, plan treatment

Follow current guidance for screening, diagnosis, treatment of TB and LTBI

Be able to administer TB tests, rule out TB disease, administer treatment

Roles and Responsibilities of Specific Private Sector Providers

Role of Hospitals

Develop infection control policies and plans to prevent transmission

Promptly report suspected/confirmed TB cases

Provide training to staff

Ensure TB patients are discharged on a standard regimen and with follow-up plan

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Hierarchy of Controls to Prevent transmission of M. tuberculosis

TB IC program should be based on three levels of controls:

Administrative controls to reduce risk of exposure

Engineering controls to prevent spread and reduce concentration of droplet nuclei

Personal respiratory protection to further reduce risk of exposure

NONTUBERCULOUS MYCOBACTERIA

INFECTIONSJeffrey R. Starke, M.D.Professor of Pediatrics

Baylor College of Medicine

10/19/2011


The “Bible” for Nontuberculous Mycobacterial Infections

Am J Respir Crit Care Med 2007; 175:367 – 416.

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NTM EPIDEMIOLOGY

No evidence for person-to-person transmission

Environmental sources – soil, dust, water, aerosols

Pathogenic strains of MAC preferentially aerosolized

MAC is common in animals – reservoir?

Poor statistics – no mandatory reporting, rarely a cause of death, incomplete identification

NTM EPIDEMIOLOGYNon-AIDS RELATED

Most common sites: Adults – lungsChildren – lymph

nodes, skin

Gender: Adults – maleChildren – female

Racial or Ethnic Predilection: None

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NTM - PATHOLOGY

Granulomas often absent

Acute and/or chronic inflammation

Often lymphocytic and/or histocytic infiltration

AFB stains usually negative (non-AIDS)

NTM AND THE TUBERCULIN SKIN TEST

No standardized NTM skin tests available

Reaction to PPD – TB variable

usually < 10 mm

can be > 15 mm, esp.

M. marinum, M. fortuitum

usually wanes over months

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NTM – LYMPH NODES

Most common site in children

MAC > M. kansasii > M. scrofulaceum > rapid growers

Most common in children < 5 years old

No predilection by race, gender

No risk factors (usually) for tuberculosis

NTM – LYMPH NODES Onset usually insidious, but may be

explosive Nodes usually non-tender, matted, firm

and fixed CT scan: more extensive involvement

than by exam Often progress to fluctuance, sinus

tract Overlying skin changes are common

and predict rupture Few systemic signs or symptoms

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NTM ADENITIS: MEDICAL THERAPY

45/55 patients underwent a trial of medical therapy (most clarithromycin +/-other antibiotic)

67% achieved resolution without surgery

13% responded well to antibiotic before surgery

20% poorly or non-responsive to antibiotics,needed surgery

Luong et al. Antibiotic therapy for NTM cervicofacial lymphadenitis.Laryngoscope 2005

NTM ADENITIS: SURGERY VS. ANTIMICROBIAL THERAPY

The Netherlands, OMFS

Prospective randomized multi-center trial

100 children NTMB

Microbiologically proven (FNA)

Purpose: to compare the effectiveness ofsurgical excision with that of antibiotictherapy (clarithromycin/rifabutin for atleast 12 weeks)

Lindeboom et al. Surgical excision vs. antibiotic treatment for NTM lymphadenitis in children. Clin Infect Dis 2007

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Lindeboom et al, 2007

96% cure rate with surgical excision

66% cure rate with antibiotic therapy95% confidence interval 16% - 44%

NTM ADENITIS: SURGERY VS. ANTIMICROBIAL THERAPY

Lindeboom et al. Surgical Excision vs. Antibiotic treatment for NTM lymphadenitis in children. Clin Infect Dis 2007

Surgical complications 28% (14/50 patients)

6 patients temporary facial nerve weakness

1 patient permanent facial nerve weakness

Medical complications 78% (39/50 patients)

4 patients had to discontinue treatment

1/3 needed > 12 weeks antibiotic therapy

Fever, fatigue, abdominal pain, tooth discoloration,headache, vomiting, abnormal stools, allergicrash

NTM ADENITIS: COMPLICATIONS OF TREATMENT

Lindeboom et al. Surgical excision vs. antibiotic treatment for NTM lymphadenitis in children. Clin Infect Dis 2007

10/19/2011


NTM ADENITIS : CURETTAGE

Retrospective case series Histologic diagnosis 25 children 11 children curettage

Conclusions Excision is treatment of choice For lesions proximal to facial nerve or with

extensive skin necrosis, initial curettage Preop counseling should include discussion of

revision surgery

Tunkel DE. Surgery for cervicofacial nontuberculous mycobacterial adenitis in children: an update. Arch OHNS 1999

NTM ADENITIS: SUMMARY

Surgical excision is still considered goldstandard

Surgical curettage is helpful for lesionsbeyond medical management, proximal tofacial nerve or with skin necrosis

Antimicrobial therapy is playing anincreasing role in treatment of atypical TB

“The Red Book” Therapy with clarithromycin OR azithromycin combined with ethambutol OR rifampin (or rifabutin) may be beneficial for children in whom surgical excision is incomplete or for children with recurrent disease

Diseases caused by nontuberculous mycobacteria. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book 2009: Report of the Committee on Infectious Diseases. 28th ed., p.701.

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NTM AND SKIN LESIONS

A bump you can feel!

A wart that won’t peel!

An ulcer that won’t heal!

Normal hosts: M marinum

Compromised hosts: rapid growers, MAC

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NTM - LUNGS

Most likely with a chronic underlying condition, esp. CF, smoking

M. kansasii causes a TB – like illness in a normal host

MAC in children may look like TB: hilar nodes, atelectasis, minor symptoms, no risk factors for TB, mild + TST

M. fortuitum, M. chelonae and M. abscessus mostly in adults

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NTM – DISTINGUISHING DISEASE FROM COLONIZATION

1. Quantity of growth2. Repeated isolation of same

organism3. Site of origin – more meaningful

with closed anatomic site4. Species of NTM isolated – usual

pathogen5. Host risk factors: immune

compromise, CF, smoking

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MAC LUNG INFECTIONS

Symptoms often similar to TB in adults and children

Cavities and nodular opacities common in adults

Adenopathy most common in children -< 5 years old

Pleural effusions are rare

Diagnosis usually requires an invasive procedure “Tuberculosis with no risk factors”

MYCOBACTERIAL INFECTION IN CYSTIC FIBROSIS

1984 – Brompton Hospital 7/223(3%)

1990 – Stockholm

6/54 (11%)

1992 – North Carolina17/87 (20%)

1993 – Seattle

8/64 (13%)

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MYCOBACTERIAL INFECTION IN CYSTIC FIBROSIS

Tuberculosis is rare in CF patients Incidence of NTM disease seems to be

increasing

? Age of CF patients ? Increased antibiotic use Environment

Colonization vs. Infection/Disease

POSSIBLE RISK FACTORS FOR NTM DISEASE IN CF PATIENTS

Severity of lung disease

Tenacious sputum

Diabetes mellitus

Use of corticosteroids

Antibiotic use – amount and/or pattern

Age

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CLUES TO NTM INFECTION IN CF PATIENTS

Decline in clinical status in association with appearance of the organism in sputum

Focal change in the chest radiograph

Species of NTM: M. kansasii, M. fortuitum, M. abscessus, M. chelonae, MAC

Response to specific antimicrobial therapy

MANAGEMENT OF NTM INFECTIONS

Remove foreign body if present Remove infected tissue, if focal and

“reachable” Drugs

anti – TB: M. kansasii, M. gordonae, M. marinum, M. xenopi, M. szulgai, M. haemophilumdoxycyline: M. marinumamikacin, cefoxitin: M. fortuitumclarithromycin: MAC, rapid growersfluoroquinolones: MAC, rapid growerslinezolid: many

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ATS/IDSA General Principles

ATS/IDSA Guidelines: Diagnosing NTM Lung Disease

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ATS/IDSA Guidelines: Treatment of MAC Lung

Disease

ATS/IDSA Guidelines: Treatment of MAC Disease

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ATS/IDSA Guidelines: Treatment of Disseminated MAC

ATS/IDSA Guidelines: Treatment of M. kansasii

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ATS/IDSA Guidelines: Treatment of M. chelonae and M. fortuitum

ATS/IDSA Guidelines: Treatment of M. abscessus

update on mycobacterial infections - confex starke... · 10/19/2011 idsa: vincent t. andriole id...

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