Mycobacterial Infections

Robert F. Nash D.O.

2007

Mycobacterial Infections

M. tuberculosisM. avium complexM. kansasiiM. fortuitumM. chelonae/abscessusM. 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 1882Mycobacterium 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

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 infectiousActive 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-xrayPulmonary 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

DOT

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 nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Frequent Drug Reactions

Pyrazinamide Hepatotoxicity Thrombocytopenia Interstitial Nephritis

Ethambutol Hepatotoxicity Optic Neuritis

Resolution

3 negative sputum culturesResponse to AB therapyImprovement 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

References

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Crit Care Med 1999 Jan;159(1):15-21. 5. Comstock GW, Palmer CE. (1966). "Long-term results of BCG in the southern United States". Am Rev Resp

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Licensed to Lake Erie College SupportTag: [WEB006-208.12.102.170-0DDE3B1234-2347.2330] 8. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med

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