Matthew Burns, MDDivision of Infectious DiseasesNovember 17, 2014

Aerobic, non-spore forming, non-motile bacilli.

Their cell walls include mycolic acid, long chain glycolipids that protect the organism.

Characteristically acid-alcohol-fast.

Do not contain capsules and are weakly Gram-positive.

Smooth or rough colony forming.

Pigmented or non-pigmented.

Have a single, large, circular DNA.

1. outer lipids2. mycolic acid3. polysaccharides (arabinogalactan)4. peptidoglycan5. plasma membrane6. lipoarabinomannan (LAM)7. phosphatidylinositol mannoside8. cell wall skeleton

Mycobacterium tuberculosis complex• Mycobacterium tuberculosis • Mycobacterium africanum• Mycobacterium bovis• Mycobacterium leprae

Atypical or non-tuberculous mycobacteria• more than 120 species• one-half are considered to be potential sources of disease• 28 of these isolates have been described in the past 5

years

59 year old man 40 lb weight loss, malaise, night

sweats, fever and cough No incarceration or EtOH or HIV Temp 100.1 CBC: 8.7/8.0/24.6/427 Albumin 1.5; SGOT 107, SGPT 116 BMP OK; CRP 140

BacterialPneumococcus, Staph aureus, GNR,

Legionella, Tularemia InfluenzaPCPHistoplasmosisMTB

Contact precautions Droplet precautions Airborne precautions No isolation necessary

Neisseria meningitidis, pertussis, influenza, adenovirus, H. influenzae type b, Mycoplasma pneumoniae, rubella, Varicella/Zoster

Droplet precautions Particles of respiratory secretions < 5 micron Private room preferred; cohorting allowed if necessary Mask when within 3 feet of the patient Mask the patient during transport

Suspected or confirmed tuberculosis (TB), measles, smallpox, and SARS

AIIR (airborne infection isolation room) Monitored negative pressure room with at least 6-12 air exchanges

per hour Room exhaust appropriately discharged outdoors or passed through a

HEPA filter Certified respirator worn by anyone entering the room of a patient with

diagnosed or suspected tuberculosis. Transport of the patient should be minimized;

Masked if transport within the hospital is unavoidable

Ziehl-Neelsen or Kinyoun stain At least 104 colony

forming units (CFU)/mL to yield a positive smear.

Culture on Löwenstein-Jensen or Middlebrook requires 4 to 8 weeks.

Empiric treatmentAwait the culture resultsTB PCRGene Xpert

Treatment of Active Tuberculosis

Agent Side Effects Notes

Isoniazid Rash; liver enzyme elevation; hepatitis; peripheral neuropathy; lupus-like syndrome

Hepatitis risk increases with age and alcohol consumption. Pyridoxine may prevent peripheral neuropathy. Adjust for kidney injury.

Pyrazinamide Hepatitis; rash; GI upset; hyperuricemia

May make glucose control more difficult in diabetic patients. Adjust for kidney injury.

Rifampin Hepatitis; rash; GI upset Care with PIs and NNRTIs. Colors bodily fluids orange.

Rifabutin Rash; hepatitis; thrombocytopenia; severe arthralgia; uveitis; leukopenia

Adjust with PIs and NNRTIs. Monitor for toxicity and effectiveness of HAART drugs.

Rifapentine Similar to Rifampin Contraindicated in HIV positive patients. (High rate of failure/relapse).

Ethambutol Optic neuritis; rash Baseline and periodic color vision and acuity testing. Adjust for kidney injury.

Agent Side Effects Notes

Streptomycin Auditory, vestibular, and kidney toxicity

Avoid or reduce dose in age >59. Monitor kidney and hearing function.

Cycloserine Psychosis; convulsions; depression; headaches; rash; drug interactions

Pyridoxine may decrease CNS side effects. Measure serum drug levels.

Capreomycin Auditory, vestibular, and kidney toxicity

Monitor kidney and hearing function.

Ethionamide GI upset; hepatotoxicity; hypersensitivity

May case hypothyroidism.

Kanamycin and Amikacin Auditory, vestibular, and kidney toxicity

Not FDA approved. Monitor kidney and hearing function.

Levofloxacin, Moxifloxacin, Gatifloxacin

GI upset; dizziness; hypersensitivity; drug interactions

Not FDA approved. Don’t use in children.

Para-aminosalicylic acid GI upset; hypersensitivity; hepatotoxicity

May cause hypothyroidism,especially if used with Ethionamide. Measure LFTs.

What about steroids? Only in 2 cases (Hint: Extra-pulmonary)

Risk factors: Previously treated for TB, especially if initial treatment was

inadequate due to adherence or poor drug choice. Infected in countries with high rates of resistance. Adherent patients who are not responding to empiric

therapy. Close contact with a person with known resistant TB.

Multidrug Resistant (MDR): strains that are resistant to at least Isoniazid and Rifampin.

Extensively Drug Resistant (XDR): strains that are resistant to Isoniazid and Rifampin plus the flouroquinolones and at least one of the following three second-line injectable agents: Kanamycin Capreomycin Amikacin

28 y/o Internal Medicine resident who took care of Patient 1

3 months after hospitalization of Patient 1 sees Employee Health for routine screening

PPD positive Seroconverter

What’s next?

CXR Treatment for latent tuberculosis: Daily INH (300 mg) for 9 months or Weekly Rifapentine (900 mg) plus

Isoniazid (900 mg) for 12 weeks As effective as INH group with

better completion rate

NEJM 365;23 December 8, 2011

In general, about 4-5% of infected individuals acquire active disease during the first year after tuberculin conversion.

An additional 5% do thereafter. This increases dramatically with immunosuppression.

ELISA that detects the release of IFN-γ in whole blood from sensitized persons

Available in < 24 hours No reader bias Not affected by previous BCG or

non-tuberculous infection

A 33 year-old man is evaluated after learning that a person living in his home was recently found to have active tuberculosis. The patient has no acute symptoms. He was recently diagnosed with HIV infection, and his CD4 count is 250. He is a U.S. citizen and has no history of incarceration, homelessness, or travel to areas with an increased prevalence of tuberculosis. He takes no medications but had been planning to begin HAART at his next office visit. On physical exam, vital signs are normal. The remainder of the examination, including cardiopulmonary findings, are normal.A tuberculin skin test induces 0 mm or induration. A CXR is normal.

Which of the following is the most appropriate next step in the management of this patient?

A. Begin Isoniazid and PyridoxineB. Begin Isoniazid, Rifampin, Pyrazinamide, Pyridoxine, and EthambutolC. Begin Rifampin and PyrazinamideD. No additional evaluation or therapy is needed

A 63 year-old man undergoes annual screening for tuberculosis. The patient is a physician, and this screening is required for maintaining his hospital appointment. His medical history is significant for bladder cancer diagnosed 1 year ago that was treated with bacillus Calmette-Guérin. There is no current evidence of active bladder cancer on follow-up cystoscopy, and he has no respiratory or systemic symptoms.On physical examination, vital signs are normal. The remaining physical examination findings, including cardiopulmonary examination, are normal.

Which of the following is the most appropriate next step in management?

A. Chest X-rayB. Interferon-gamma release assayC. Tuberculin skin testD. Two-step tuberculin skin testing

• Estimated: 9.0 million (8.6–9.4 million) new TB cases.

• Estimated: 1.1 million(0.98–1.3 million) HIV-negative people died from TB and 0.36 million (0.31–0.41 million) HIV-positive people died from TB

*Updated as of June 11, 2014.

No

. of C

ases

0

5,000

10,000

15,000

20,000

U.S.-born Foreign-born

Only moderately infectious as compared to measles (infects 80% of people who have casual contact).

Contact with and infectiousness of the source.

Pattern of cough and sputum production.

Having HIV does not increase infectious nature.

A cough can produce 3,000 infectious droplets, talking for 5 minutes and equal number, and sneezing many more than that.

The room air may remain infectious for up to 30 minutes after a person with active pulmonary TB vacates the room.

Once patients are on effective therapy, it generally takes about 2 weeks before they are no longer infectious to others.

Rapidly Growing Mycobacteria• Produce mature growth on media plates

within 7 days. Slowly-Growing Mycobacteria

• Require more than 7 days to reach mature growth.

Intermediately Growing Mycobacteria• Require 7 to 10 days to reach mature growth.

M. tuberculosis M. bovis M. africanum M. canetti M. caprae M. microti M. pinnipedii M. avium M. avium paratuberculosis M. avium silvaticum M. avium hominissuis M. colombiense M. indicus pranii M. asiaticum M. gordonae M. gastri M. kansasii M. hiberniae M. nonchromogenicum M. terrae M. triviale

M. ulcerans M. pseudoshottsii M. shottsii M. triplex M. genavense M. florentinum M. lentiflavum M. palustre M. kubicae M. parascrofulaceum M. heidelbergense M. interjectum M. simiae M. branderi M. cookii M. celatum M. bohemicum M. haemophilum M. malmoense M. szulgai M. leprae

M. lepraemurium M. lepromatosis M. botniense M. chimaera M. conspicuum M. doricum M. farcinogenes M. heckeshornense M. intracellulare M. lacus M. marinum M. monacense M. montefiorense M. murale M. nebraskense M. saskatchewanense M. scrofulaceum M. shimoidei M. tusciae M. xenopi

A 59 year-old woman is evaluated for a dry cough with moderate exertional dyspnea, which has remained stable in intensity over the past 7 months. The onset of her respiratory symptoms does not correlate with any unusual exposures. She has intermittently been treated with oral antibiotics for outpatient pneumonia without a change in her symptoms. She has no systemic signs or symptoms and otherwise feels well. Medical history is unremarkable. She does not smoke. She has lived most of her adult life in the south-eastern United States. She currently takes no medications. On physical examination, vital signs are normal. Pulmonary auscultation reveals scattered rhonchi. The remainder of the examination, including cardiac examination, is normal.A CT scan of the lungs demonstrates scattered nodular infiltrates, mostly confined to the right middle and bilateral upper lobes. Normal respiratory flora grows from as sputum culture, and although the smear for AFB is negative, the culture eventually grows Mycobacteria avium complex by DNA gene-probe testing.

Which of the following is the most appropriate next step in management?

A. Bronchoalveolar lavageB. Clarithromycin, Ethambutol, and RifampinC. Repeat sputum AFB smear and cultureD. VATS lung biopsyE. Observation

Comprises two closely related organisms: Mycobacterium intracellulare Mycobacterium avium

Four major disease syndromes in humans: Pulmonary disease: usually adults with intact immune system Disseminated disease: usually in advanced HIV patients Hypersensitivity pneumonitis: an allergic type related to

exposure of hot tubs, pigeons, and exotic birds. Cervical lymphadenitis: largely a disease of children.

Can rarely be cutaneous. Frequency of pulmonary disease and lymph node disease is rising. Frequency of disseminated disease rose precipitously with HIV

pandemic, but has declined due to HAART and effective prophylaxis.

Organisms are common in the environment and are acquired by inhalation or ingestion.

Colonizes natural water sources, indoor water systems, pools, and hot tubs.

Ubiquitous Prolonged exposure to soil is a risk factor for MAC

infection in the US Detected by acid fast smear and culture techniques Nucleic acid probes accurate after one day growth Can become aerosolized from aqueous sources

M. Avium complex

Lung disease is by far the most common presentation of NTM infection.

Clinical presentation: Months or years of throat clearing Nagging cough Slowly progressive fatigue

Patients will likely have seen physicians multiple times.

The typical lag between onset of symptoms to diagnosis is 5 years.

Predisposing factors: bronchiectasis, pneumoconiosis, COPD, primary ciliary dyskinesia, CF, alpha-1 antitrypsin deficiency.

Patients must be symptomatic

Must have abnormal CXR or high-resolution CT of the chest

Must have one of the following:1. Two positive MAC sputum cultures2. A BAL with a positive culture for MAC3. AFB or granulomas, or a positive culture for MAC

on a histopathologic specimen

Disease in those with known underlying lung disease

Resembles typical tuberculosis clinically and radiographically but less severe

Indolent but extensive lung damage by time of diagnosis

Areas of prior bronchiectasis

MAC Lung Disease

Lady Windermere syndrome Oscar Wilde play “Lady

Windermere’s Fan” Proper ladies will not cough

RML or lingular infiltrates Elderly women

MAC Lung Disease

In the 1980s and early 1990s nearly half of all people dying from AIDS complications has disseminated mycobacterial infections.

Were always due to MAC.

The use of HAART has greatly decreased this rate.

The portal of entry was the bowel with spread into the bloodstream and bone marrow.

CD4 < 50 cells uL Prophylaxis with Azithromycin

Lung infection unusual Disseminated:

Positive blood cultures and bone marrow Fever, wasting GI tract Lymph nodes, CNS, peritoneum Treatment: Macrolide + Ethambutol with

or without a Rifamycin

The most common form of NTM infection among children.

Most common in children <5 years of age.

Swelling is usually firm, painless, and lacks systemic symptoms.

Can create fistulas to the skin or surrounding structures that get better with treatment.

31 y/o physician presented with flu-like illness followed by cough and progressive dyspnea of 4 week duration.

pO2 45, afebrile.

4 friends with similar symptoms.

All went hunting 5 weeks earlier. Killed turkeys. Enjoyed hot-tub and beer.

Biopsy and culture-Mycobacterium avium complex.

Hypersensitivity pneumonitis MAC exposure in immunocompetent hosts

without underlying lung disease “Hot tub lung“ Treatment:

No hot tub or Better hot-tub cleaning Role of antibiotics limited Steroids

Multi-drug therapy.

Clarithromycin or Azithromycin + Ethambutol + a rifamycin (Rifampin or Rifabutin).

Pulmonary MAC: thrice weekly macrolide + ethambutol + a rifamycin . A course lasts for at least 18 months.

We generally treat for 1 year beyond negative cultures.

Other drugs against MAC: IV or aerosolized aminoglycosides, flouoroquinolones, or clofazimine.

M. abscessus M. chelonae M. bolletii M. fortuitum M. fortuitum subsp. acetamidolyticum M. boenickei M. peregrinum M. porcinum M. senegalense M. septicum M. neworleansense M. houstonense M. mucogenicum M. mageritense M. brisbanense M. cosmeticum M. parafortuitum M. austroafricanum M. diernhoferi M. hodleri M. neoaurum M. frederiksbergense M. aurum M. vaccae M. chitae

M. fallax M. confluentis M. flavescens M. madagascariense M. phlei M. smegmatis M. goodii M. wolinskyi M. thermoresistibile M. gadium M. komossense M. obuense M. sphagni M. agri M. aichiense M. alvei M. arupense M. brumae M. canariasense M. chubuense M. conceptionense M. duvalii M. elephantis M. gilvum

M. hassiacum M. holsaticum M. immunogenum M. massiliense M. moriokaense M. psychrotolerans M. pyrenivorans M. vanbaalenii M. pulveris M. arosiense M. aubagnense M. caprae M. chlorophenolicum M. fluoroanthenivorans M. kumamotonense M. novocastrense M. parmense M. phocaicum M. poriferae M. rhodesiae M. seoulense M. tokaiense

M. fortuitum Infection primarily by direct inoculation

Skin and soft tissue infections, surgical wound infections, and catheter-related sepsis, breast implant

Rarely: keratitis, prosthetic valve endocarditis, cervical lymphadenitis

Most respiratory isolates represent colonization or transient infection

M. chelonae Primarily immunosuppressed patients Keratitis with foreign body Multiple erythematous nodules with draining

fistulas

Local injection of homologous fat obtained from the submandibular region

Liposuction

Liposuction

Severe disease requires IV treatment 6-12 months 2 drugs Amikacin, Tobramycin, Cefoxitin, Imipenem,

Levofloxacin Oral after IV treatment

Bactrim, Doxycycline, Levofloxacin, Azithromycin or Clarithromycin

Most common rapid grower to cause lung infection M. abscessus 80%

Usually Caucasian women in mid 50’s Cough (71 percent), fever, weight loss,

hemoptysis, and dyspnea were also common Cystic fibrosis (increased lung function decline) Multilobar Cavitation infrequent

Treatment (difficult) For severe infections including pulmonary disease

for 4-8 weeks with: Amikacin (15 mg/kg per day divided in two

doses) plus either: Cefoxitin (2 g intravenously every four hours) or Imipenem (1 g intravenously every six hours) plus Clarithromycin (500 mg twice daily) or

Azithromycin (250 to 500 mg daily)

Questions?