Mycobacterial Infections
Robert F. Nash D.O.
2007
Mycobacterial Infections
M. tuberculosis
M. avium complex
M. kansasii
M. fortuitum
M. chelonae/abscessus
M. smegmatis
History
 “The Consumption”
 Found in Skeletal remains from 4000 BC
 Hippocrates states this is the most wide spread
disease of the time
 First sanitarium opened in 1859 in Poland
 BCG vaccine first used in 1921
60-80% effective in UK study
14% in Georgia and Alabama
 Pneumothorax technique
 Streptomycin 1946
M. tuberculosis
Robert Koch in 1882
Mycobacterium tuberculosis, the etiologic
agent of tuberculosis (TB)
He was awarded the Nobel Prize in
Physiology or Medicine, for his
tuberculosis findings in 1905.
He is considered one of the founders of
bacteriology.
1/7 of all deaths in Europe
Cellular Biology
There is no true outer membrane in
Mycobacterium
Acid fast bacillus (AFB)
Stains used in evaluation of tissue
specimens or microbiological specimens
include Fite's stain, Ziehl-Neelsen stain,
and Kinyoun stain
Generation time is about 20 to 24 hours.
20 minutes for e-coli
Schematic diagram of Mycobacterial cell wall.
1. outer lipids
2. mycolic acid
3. polysaccharides (arabinogalactan)
4. peptideglycan
5. plasma membrane
6. lipoarabinomannan (LAM)
7. phosphatidylinositol mannoside
8. cell wall skeleton
M. tuberculosis
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Reportable disease
8 million new cases a year worldwide
3 million infected patients die a year
1953 - 84,304 cases
1985 - 22,201
1992 - 26,673
2005 - 14,093
Why ?
Schneider E; Moore M; Castro KG (2005); Deterioration
of tuberculosis program infrastructure, the HIV/AIDS
epidemic, drug-resistant tuberculosis, and tuberculosis
among foreign-born persons contributed to the
resurgence.
Epidemiology
 HIV
 Foreign born
 Prisoners
 Low socioeconomic class
 Cancer patients
 Celiac Disease
 Tumor necrosis factor-alpha antagonists
 >15 mg of prednisone
 Children
Pathophysiology
Tiny aerosolized droplets inhaled from
Patients with infectious TB.
Infection either becomes:
Latent
Active
Latent is not infectious
Active IS INFECTIOUS
Pathophysiology
Possible outcomes
Clearance
5-10%, lifetime risk, of exposed immunocompetent
become infected
10% risk per year in immunocompromised patients
Primary infection
Chronic or latent infection
Active disease many years after the infection
(reactivation disease)
Clinical manifestations
 Pulmonary infection
 Classic
 Constitutional symptoms
 Cough
 Blood tinged sputum
 Other symptoms
 Pleuritic chest pain
 Retrosternal and
interscapular dull pain
 Extrapulmonary
Infections
 Constitutional symptoms
 Site specific complaints
 Pleura
 Skeletal
 CNS
 Peritonium
 Kidneys and Adrenals
 Genitals
 GI
 Miliary
 Hematologic
 CV
Diagnostic Testing
 Tuberculin skin test
Intradermal placement
Read 48-72 hours after placing
25% newly diagnosed TB will be negative
Anergy
 Single step or two step testing (Core
Curriculum on Tuberculosis (2000) from
CDC)
Two-step testing should be used for the
initial skin testing of adults who will be
retested periodically, such as health care
workers
Booster effect
Guidelines for determining a positive tuberculin skin test
reaction
 Induration >5 mm: HIV-positive persons Recent contacts of TB case Fibrotic
changes on chest radiograph consistent with old TB, Patients with organ transplants
and other immunosuppressed patients (receiving the equivalent of >15 mg/d
Prednisone for >1 mo)
 Induration >10 mm: Recent arrivals (<5 yr) from high-prevalence countries Injection
drug users, Residents and employees* of high-risk congregate settings: prisons and
jails nursing homes and other health care facilities, residential facilities for AIDS
patients, and homeless shelters, Mycobacteriology laboratory personnel, Persons
with clinical conditions that make them high-risk: silicosis diabetes mellitus, chronic
renal failure, some hematologic disorders (eg, leukemias and lymphomas), other
specific malignancies (eg, carcinoma of the head or neck and lung), weight loss of
>10 percent of ideal body weight, gastrectomy, jejunoileal bypassChildren <4 yr of
age of infants, children, and adolescents exposed to adults in high-risk categories
 Induration >15 mm: Persons with no risk factors for TB
 * For persons who are otherwise at low risk and are tested at entry into employment,
a reaction of >15 mm induration is considered positive.
Potential causes of falsely negative
tuberculin skin tests
 Factors related to the person being tested Infections Viral (HIV, measles,
mumps, chickenpox) Bacterial (typhoid fever, brucellosis, typhus, leprosy
pertussis, overwhelming tuberculosis, tuberculous pleurisy) Fungal (South
American blastomycosis) Live virus vaccinations (measles, mumps, polio)
Metabolic derangements (chronic renal failure) Low protein states (severe
protein depletion, afibrinogenemia) Diseases affecting lymphoid organs
(Hodgkin's disease, lymphoma, chronic lymphocytic leukemia, sarcoidosis)
Drugs (corticosteroids and many other immunosuppressive agents) Age
(newborns, elderly patients with "waned" sensitivity) Recent (within the past
10 weeks) or overwhelming infection with M. tuberculosis Stress (surgery,
burns, mental illness, graft versus host reactions) Factors related to the
tuberculin used Improper storage (exposure to light and heat) Improper
dilutions Chemical denaturation Contamination Adsorption (partially
controlled by adding Tween 80)Factors related to the method of
administration Injection of too little antigen Subcutaneous injection Delayed
administration after drawing into syringe Injection too close to other skin
tests Factors related to reading the test and recording results:
Inexperienced reader, Conscious or unconscious biasError in recording
Diagnostic Testing
 QuantiFERON®-TB Gold Test
Test was approved by the U.S. Food and Drug
Administration (FDA) in 2005
Blood test
No booster effect
Limited data available for use on children
 NAA
Used if AFS is positive to rule out TB
C-xray
Pulmonary TB
Classic
Cavitary and/or infiltrative lesions in either
upper lobe
Granuloma’s
Fibrosis
Traction or enlargement of hilar or mediastinal
lymph nodes
1/3 cases do not present typically
Circ. 1935
Gold Standard
Sputum/ Tissue culture
Self induced
BAL
Induced
Conde MB, Am J Respir Crit Care Med 2000
Dec;162(6):2238-40. Showed both BAL and
Induced to have 100% specificity and 38% and
34% sensitivity, respectively.
Treatment
 Latent:
9 months of Isoniazid
4 months of Rifampin
 Active:
4 drug Regiment for 2 months
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
2 drug Regiment for 4 or seven months
Isoniazid
Rifampin
Labs
 Baseline and routine laboratory monitoring
during treatment of LTBI are indicated
only when there is a history of liver
disease, HIV infection, pregnancy (or
within 3 months post delivery), or regular
alcohol use. Baseline hepatic
measurements of serum AST, ALT, and
bilirubin are used in the situations
mentioned above and to evaluate
symptoms of hepatotoxicity.
Frequent Drug Reactions
 Isoniazid
Hepatotoxicity
B6 depletion
INH increases blood levels of phenytoin (Dilantin)
and disulfiram (Antabuse)
 Rifampin
Hepatotoxicity
Orange/red body fluids
Decreases blood levels of many drugs including
oral contraceptives, warfarin, sulfonureas, and
methadone
Contraindicated in HIV-infected individuals being
treated with protease inhibitors (PIs) and most
Frequent Drug Reactions
Pyrazinamide
Hepatotoxicity
Thrombocytopenia
Interstitial Nephritis
Ethambutol
Hepatotoxicity
Optic Neuritis
Resolution
3 negative sputum cultures
Response to AB therapy
Improvement in Chest radiograph (Pt with
pulmonary TB)
Infection control
Negative Pressure Isolation Room (NPIR)
Protective mask (N95)
Patient instructed to cover mouth and
nose when coughing, with tissue
M. avium complex
 MAC
 Several different syndromes are caused by Mycobacterium avium complex
(MAC). Disseminated infections are usually associated with HIV infection.
Less commonly, pulmonary disease in nonimmunocompromised persons is
a result of infection with MAC. In children, the most common syndrome is
cervical lymphadenitis. Hot tub associated hypersensitivity pneumonitis.
 In HIV infected persons, manifestations include night sweats, weight loss,
abdominal pain, fatigue, diarrhea, and anemia.
 American Thoracic Society (ATS) Guidelines
 Treatment: A regimen of daily clarithromycin (500 mg twice a day) or
azithromycin (250 mg), rifampin (600 mg) or rifabutin (300 mg), and ethambutol
(25 mg/kg for two months, then 15 mg/kg) is recommended for therapy of adults
not infected with the HIV virus. Streptomycin two to three times per week should
be considered for the first eight weeks as tolerated. Patients should be treated
until culture-negative on therapy for one year.
 Prophylaxis: CD4 counts < 50 cells, especially with a history of a prior
opportunistic infection. Rifabutin 300 mg/d, clarithromycin 500 mg twice daily,
azithromycin 1,200 mg once weekly and azithromycin 1,200 mg once weekly
plus rifabutin 300 mg daily are all proven effective regimens.
M. kansasii
 The most common presentation of M kansasii is a chronic
pulmonary infection that resembles pulmonary tuberculosis. It may
also infect other organs. Incidence of infection has increased
because of the HIV/AIDS epidemic. It is the second most common
nontuberculous, opportunistic mycobacterial infection associated
with AIDS, surpassed only by Mycobacterium avium complex
(MAC).
 ATS Guideline: Regimen of daily isoniazid (300 mg), rifampin (600
mg), and ethambutol (25 mg/kg for 2 months, then 15 mg/kg) for 18
months with a minimum of 12 months' culture negativity is
recommended for pulmonary disease in adults caused by M
kansasii. Clarithromycin or rifabutin will need to be substituted for
rifampin in HIV-positive patients who take protease inhibitors.
M. fortuitum
Local cutaneous disease, osteomyelitis,
joint infections, and ocular disease (eg,
keratitis, corneal ulcers) may occur after
trauma. M fortuitum is a rare cause of
isolated lymphadenitis. Disseminated
disease, usually with disseminated skin
lesions and soft tissue lesions, occurs
almost exclusively in the setting of severe
immunosuppression, especially AIDS.
Endocarditis has been documented.
M. chelonae/abscessus
 M abscessus is increasingly recognized as a persistent
pathogen in patients with cystic fibrosis.
 Disseminated disease, usually with disseminated skin
and soft tissue lesions, occurs almost exclusively in the
setting of immunosuppression, especially AIDS
 lung disease
 Surgical site infections due to M chelonae
 ATS Guideline: Therapy of nonpulmonary disease
caused by M fortuitum, M abscessus, and M chelonae
should include drugs such as amikacin and
clarithromycin, based on in vitro susceptibility tests.
What medication(s) do you use to initiate
treatment of active pulmonary
Tuberculosis?
 Isoniazid
 Rifampin
 Pyrazinamide
 Ethambutol
 All the above
Negative Tuberculin test rules out TB.
a) True
b) False
TB is considered non-infectious when,
Patient has:
a) 3 negative sputum cultures
b) Response to AB therapy
c) Improvement in Chest radiograph (Pt
with pulmonary TB)
d) All the above
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