Detailed presentation on atypical mycobacteria

1. ATYPICAL
MYCOBACTERIA
SPEAKER:DR.ABHINAV KUMAR
MEDICINE RESIDENT
M S RAMAIAH MEDICAL COLLEGE

2. INTRODUCTION
All mycobacterial species except those that cause
tuberculosis (TB)
Mycobacterium tuberculosis complex includes M.
tuberculosis
M.bovis
M. africanum
M. caprae
M. microti
M. pinnipedii
Leprosy (M. leprae).

4. Non-tuberculous
Mycobacteria
1954 Runyon first NTM classification
>100 NTM species
Other names
Mycobacteria other than tuberculosis (MOTT)
Atypical
Environmental
Opportunistic
Variable pathogenicity and geographic regions
40% cause diseases in human
Immunosuppressed host

5. Runyon Classification (1959)
Basis – Pigment production & Rate of growth
Group I –
Photochromogens
Form pigment after exposure
to light
Example – M. kansasii
Habitat – Water & animals
Causes Pulmonary, skin,
systemic, LN infections.
Group II –
Scotochromogens
Pigment produced in dark
Example – M. scrofulaceum
Habitat – Water, soil, fomites
Causes cervical lymphadenitis
in children
Group III-
Nonphotochromogens
No pigment production
Examples – M. intracellulare, M.
avium & M. xenopi
Habitat – Soil, Seawater, animals
Causes Pulmonary,
gastrointestinal, renal, systemic,
LN infections
Pulmonary, epididymis
Group IV –Rapid growers
Colonies appear within seven
days
Example –M. fortuitum,
Habitat- Water, soil & animals
Causes Pulmonary,
gastrointestinal, renal, systemic,
LN infections

6. Non-tuberculous
Mycobacteria
• Water, soil, food and animals
• Does not spread from person to another
• Relatively resistant to chlorination and ozonization
• Outbreak and Pseudo-outbreak in the hospital
• HIV and dialysis patients
• Improve laboratory methods  reporting

7. Laboratory Diagnosis
Rapid Growers
Days in broth and < 1
week in solid media
M.abscessus
M.chelonae
M.fortutum
Slow Growers
1-2 weeks in broth
and 2-4 weeks in
solid media
M.avium
M.kansasii
M.scrofulaceum
M.ulcerans
M.xenopi
M.gordonae

8. Special Diagnostic
Problems
M.marinum lower temperature required
M.haemophilum lower temperature required and iron
need to be added
M.ulcerans lower temperature required
M.genavense very slow growth in broth
DNA probes for MAC, M. kansasii and M. gordonae
available

9. Epidemiology
Precise frequency  unknown.
A nationwide survey of 32,000 mycobacterial isolates (not patients)
reported to CDC in 1979 to 1980 revealed that approximately one-
third were NTM
The most commonly 
MAC 61 %
M. fortuitum complex 19 %
M. kansasii 10 percent %
Most of the reported isolates  Respiratory specimens.

10. median age66 years,
59 %female.
M. avium complex was responsible for 88 percent of cases.
Burden of NTM disease  underestimated
Children Predominant disease Cervical lymphadenitis
MAC
M. scrofulaceum
cutaneous disease M. marinum
M. ulcerans
NTM strains cystic fibrosis and may be clinically significant.
In a study from 21 cystic fibrosis centers in the US, NTM were isolated from
the sputum of 13 percent of patients

11. Slow growers
M. avium complex (MAC)
M. kansasii
Rapid growers (RGM)
M. abscessus complex
M. chelonae
M. fortuitum
Common NTM species

12. M. avium complex (MAC)
M. avium
M. intracellulare
M. chimaera
M. abscessus complex
M. abscessus
M. massiliense
M. bolletii
Common NTM species

13. Risk factors
Immunosuppression ( HIV, Medications )
Aging
BCG vaccination
Cystic fibrosis
Fibronodular bronchiectasis

14. number of inherited and acquired defects in the host immune
response, particularly those that affect the Th1 cell and
macrophage pathway
increased susceptibility to NTM infections
Interferon gamma receptor deficiencies
Signal transducer and activator of transcription 1 (STAT1)
deficiency
Auto-antibodies to interferon gamma
CD4 lymphopenia due to HIV or other causes
Use of TNF-alpha inhibitors,
particularly infliximab and adalimumab

15. Common clinical syndromes:
1. Lymphadenopathy
2. Chronic pulmonary disease
3. Skin and soft tissue infections (often associated with
trauma or a foreign body) sometimes with extension to
bone and joint
4. Disseminated disease.

16. HOST PROTECTION
Epidemiologic studies from Sweden and Finland  childhood
immunization with BCG vaccine
reduced risk of childhood cervical lymphadenitis due to NTM

18. 1) MYCOBACTERIUM AVIUM COMPLEX
2) MYCOBACTERIUM KANSASII

19. MYCOBACTERIUM AVIUM COMPLEX
Ubiquitous
Natural reservoirs including soil and water, domestic and wild
animals, and foodstuffs
Environmental MAC isolates and clinical isolates belong to
different serovars
Identical to clinical isolates naturally occurring surface water,
hot tubs, and piped hot water systems
showerhead biofilms potential source of MAC infection in
humans
Prolonged exposure to soil  risk factor for MAC infection
no convincing data demonstrating human-to- human
transmission of infection

20. PULMONARY DISEASE
Not a reportable disease, precise prevalence and incidence
data are not available.
Two major clinical syndromes of MAC lung disease are
recognized:
Disease known underlying lung disease,
primarily white,
middle-aged or elderly men,
often alcoholics and/or smokers with underlying copd
MAC lung disease adolescents or adults with cystic fibrosis.
Disease without known underlying lung disease
nonsmoking women over age 50 who have interstitial patterns on

21. Two other less common forms of MAC lung disease have been
described:
A hypersensitivity pneumonitis syndrome most frequently
reported in association with hot tub use ("hot tub lung").
One report noted an unexpectedly high frequency (78 of 244
patients) of MAC pulmonary infections presenting as solitary
pulmonary nodules, which resembled lung cancer

22. MICROSCOPY
M. avium complex (MAC) includes
M. avium,
M. intracellulare,
M. chimaera,
M. colombiense.
M. scrofulaceum
Slowly growing organisms
Standard media such as BACTEC 12B broth and on Middlebrook 7H10 and
7H11 agar
In broth No clustering or "cording,”
Agar small, flat, translucent, smooth colonies that occasionally exhibit a
pale yellow color.

23. CDC/Dr. Edwin P. Ewing, Jr.
← MAC
infection of
lymph node.
Acid-fast bacilli
within plump
histiocytes.
Colon Biopsy
Mycobacterium
avium –
Acid Fast Stain → © Dr. Peter Anderson, University of Alabama at
Birmingham, Dept of Path.

24. Pathogenesis of NTM infections
PULMONARY INFECTION
poorly understood
acquired by inhalation, most likely aerosols from natural
surface water or from domestic and institutional hot water
systems.
In one study, a high rate of gerd was observed in patients with

25. Host response to MAC infection
host immune response is highly effective at containing or eliminating
the infecting microbes.
Cellular response
Inhaled, MAC encounters alveolar macrophages.
fibronectin receptors
MAC
Serum enhances phagocytosis
Bound mycobacteriaup in primary phagosomes
fuse with vacuoles in the phagocyte's cytoplasm
attempt to destroy its contents

26. Mycobacterial products induce apoptosis of macrophages
Macrophages also process mycobacterial antigens and present
them on their surface in conjunction with MHC class I and class II
molecules to T lymphocytes.
T lymphocyte clones
specifically recognize those antigens
Acquired immune responses and immunologic memory
Process is exemplified by the delayed hypersensitivity
response elicited by the tuberculin skin test

27. T helper (CD4) lymphocytes site of mycobacterial
infectionIL-2 + interferon gammaactivate
macrophagesenhance cytotoxic lymphocyte activity
If inhaled MAC survive
T helper lymphocytes are the basis of acquired (antigen-
specific) immunity,
natural killer (NK) cells are key components of the innate
immune response for these pathogens.
These events lead to two major forms of pulmonary MAC
disease in adults, the fibrocavitary and fibronodular forms

28. Mycobacterium avium complex lung
disease
Clinical Presentation
Variable presentation:
• Group 1 : Preexisting lung disease
• Group 2 : No previous lung disease
• Group 3 : Hot tub lung (HTL)
• Group 4 : HIV
• Group 5 : Interleukin-12 / -IFN defects

29. Mycobacterium avium complex lung
disease
Clinical Presentation
 Markedly abnormal pulmonary function tests
 Associated diseases: COPD, past granulomatous
lung disease (TB, fungal), radiation fibrosis,
bronchiectasis, silicosis
 CF: increased recognition of MAC as well as
other NTM
• Group 1 : Preexisting lung disease

30. Mycobacterium avium complex lung
disease
Clinical Presentation
• Group 1 : Preexisting lung disease
 Localized or diffuse fibrocavitary disease
 Male predominance: smokers
 Age: 6th to 8th decade

31. Mycobacterium avium complex lung
disease
Clinical Presentation
• Group 2 : No previous lung disease (Most common)
Mild abnormal pulmonary function tests: obst,
restrictive, mixed
• Associated findings: mitral valve prolapse, pectus
excavatum
• Functional IFN- defects not detected; increased
CFTR mutations noted

32. MYCOBACTERIUM KANSASII
southeastern and southern coastal states and the central plains
states
second most common respiratory NTM isolate in state laboratories
in the United States
Never been found in soil or natural water supplies, but has been
recovered consistently from tap water in cities
Incidence2.4 cases per 100,000 adults
270 cases identified, 187 were HIV positive, 33 HIV negative, and
50 with HIV status unknown.
Homelessness and lower socioeconomic status were also important

33. Risk factors
M. kansasii causes pulmonary disease resembling tuberculosis.
Major predisposing factor to lung infection is COPD (2/3)
malignancy,
immunosuppressive drugs,
alcohol abuse,
pneumoconiosis,
HIV infection
fifth decade or older,
3:1 male predominance.
occupational groups  miners, welders, sandblasters, and painters

34. MICROSCOPY
It grows readily in the BACTEC broth, as well as on
Middlebrook 7H10 agar and Lowenstein-Jensen agar.
rough large colonies that turn bright yellow with exposure to
light (photochromogen)
species- specific nucleic acid probe  Accuprobe, GenProbe,
Inc

36. Mycobacterium kansasii infection —closely resembles
typical TB in its clinical and radiographic features.
Older age,
male sex,
smoking,
underlying lung disease are common features.
M. kansasii is not an environmental contaminant or colonizer
only from municipal water supplieseven a single positive
culture may be considered diagnostic of disease

37. RAPIDLY GROWING MYCOBACTERIA
numerous species
clinically relevant species are
M. fortuitummost common
M. chelonae,
M. abscessus
Environmental saprophytes
Isolated from soil, dust, natural surface and municipal water, wild
and domestic animals,fish,hospital environments, and contaminated
reagents and pharmaceuticals
example of nosocomial transmissionoutbreak of surgical wound
infections caused by M jacuzzii, involving 15 women after insertion
of breast implants at a single medical center
A single surgeonsource for the organism.

38. Direct or indirect person-to-person transmission of certain
strains of M. abscessus has also been suggested.
Organisms grow readily on
Middlebrook 7H10 or 7H11 agar
BACTEC 12B broth,
5 percent sheep blood agar or chocolate agar,
Temperature requirements
M chelonae grow optimally at 30C rather than 35-37.
The laboratory impression is that these organisms do not
always stain well with the Ziehl-Neelsen or Kinyoun method
and may not be recognized readily with the fluorochrome

39. CLINICAL MANIFESTATIONS
• M. fortuitum causes human infection primarily by
• direct inoculation
primary skin
soft tissue infections
surgical wound infections
catheter-related sepsis
• Majority of M. fortuitum respiratory isolates are found in
individuals with other underlying pulmonary diseases, such as
bronchiectasis, and represent colonization or transient
infection
RGM infections in HIV-negative patients

40. M. chelonae
immunosuppressed patients,
surgical wound infections and keratitis
M. abscessus most pathogenic of the RGM group
pulmonary infection,
primarily in patients with underlying lung disease
cystic fibrosis related and non-cystic fibrosis related
bronchiectasis.

41. Pulmonary infection
Pulmonary diseaseM. abscessus (80%)
The median age at onset was 58 years (range 1 to 85 years).
Majority of these patients were Caucasian (83 percent) and
female (65 percent), while only 34 percent were current or
former smokers.
The diagnosis was usually not established until more than two
years after the onset of symptoms.
Cough (71%), but fever, weight loss, hemoptysis, and dyspnea
were also common.

42. CXR involvement of three or more lobes in more than one-half
of cases.
An interstitial pattern, mixed interstitial and alveolar infiltrates,
and a reticulonodular pattern were all seen with approximately
equal frequency (36 to 40 %)
cavitation was infrequent (16%).
findings are similar to findings in patients
with nodular/bronchiectatic (non-cavitary) M. avium complex
(MAC) lung disease.
Death was attributed directly to progressive RGM lung disease
with respiratory failure in 21 cases (14 percent).

43. Diagnosis of NTM of the lungs in HIV- negative
patients
Clinical manifestations underlying disease
cough,
fatigue,
malaise,
fever,
weight loss,
dyspnea,
hemoptysis,
chest discomfort
NTM are identified on sputum culture from a patient under
evaluation for tuberculosis

44. Mycobacterium avium complex lung
disease
Radiographic Findings
 Nodular infiltrates
 Cavity and fibrocavitary disease with or without
thickened walls
 Consolidation
 Solitary or multiple pulmonary nodules
 Cylindrical, cystic, or saccular bronchiectasis

45. Chest Radiography:
Chest X-rays typically reveal amorphous, lower zone
shadowing
Cavitary disease in the upper lung zones,
90 % M. kansasii infection
50 %  MAC infection.
Cavities
thinner walls
less surrounding parenchymal opacity

46. One study,evaluated 100 patients with bronchiectasis,
24 multiple pulmonary nodules
positive sputum culture for MAC
Bronchiectasis with pulmonary nodules53 %
Bronchiectasis without pulmonary nodules 4%
HRCT scans of the chest diagnosing this pattern of MAC
lung disease
nodular/bronchiectatic radiographic pattern can also be seen
with other NTM pathogens including M. abscessus, M. simiae,
and M. kansasii.

47. NTM Infection Presentation
Nontuberculous Mycobacterial Lung Disease
Common CXR findings:
A. Hazy opacity abutting the
heart border [#1]
1

48. CommonCXR findings:
B. Retrosternal shadowing
overlying the cardiac
silhouette [#2]
NTM Infection Presentation
2

49. NTM Infection Presentation
Nontuberculous Mycobacterial Lung Disease
Common HRCT scan findings:
A.Volume loss and variable
opacities of the right-middle
lobe (RML) and lingular
segment of the left-upper
lobe (LING)
B. Saccular or “honeycomb”
bronchiectasis in both the
RML & LING
C. Diffuse cylindrical and
varicoid bronchiectasis with
scattered nodular opacities
[RML] [LING]

50. SERODIAGNOSIS
In one study, an enzyme immunoassay that measured serum
IgA antibody to glycopeptidolipid core antigen specific for MAC
was useful for differentiating MAC lung disease from
tuberculosis.
MICROBIOLOGIC EVALUATION
smear and culture of at least three separate expectorated
sputum specimens obtained in the morning.
Etiology of symptoms remains uncertain+infiltrate persists,
bronchoscopy with bronchoalveolar lavage (BAL) and or

51. NUCLEIC ACID PROBES
Highly accurate nucleic acid probes (Accuprobe, GenProbe,
Inc)MAC isolates within one day after recognizable growth is
evident,
A similar nucleic acid probe is also available for the
identification of M. kansasii.

53. Treating Pulmonary NTM
Infection
Use multiple drugs to increase efficacy and to prevent acquired
resistance.
ATS guidelines usually suggest standard regimens based on
accurate identification of species, e.g. regimen “X” for M. kansasii.
Role of in vitro susceptibility (s) testing is debated
consistent agreement for in vitro (s) testing for macrolides in
MAC;
standard panel for rapidly-growing NTMs, such as M. abscessus
or M. chelonae;

54. ATS Guidelines for Treatment of MAC:
1. Initial Rx for nodular-bronchiectatic disease is TIW
a. Clarithromycin 1000 or azithromycin 500 mg
b. Ethambutol 25 mg/kg
c. Rifampin 600 mg
2. Initial Rx for fibrocavitary or severe nodular-
bronchiectatic disease is DAILY
a. Clarithromycin 500-1000 or azithromycin 250 mg
b. Ethambutol 15 mg/kg
c. Rifampin 10 mg/kg to maximum 600
3. Goal: 12 months of negative cultures while on therapy
4. Surgery may be useful in localized disease
Am J Respir Crit Care Med 175:367-416, 2007

55. Mycobacterium avium complex lung
disease
Treatment
• Observation
• Medical therapy : Triple drug therapy
Clarithromycin /azithromycin, rifampin/rifabutin , ethambutol
+/- streptomycin/amikacin first 2-3months
12 month culture negativity
Role of quinolones, clofazimine, others ?
• Adjunctive therapy:
Recent negative inhaled IFN- trial

56. Mycobacterium avium complex lung
disease
Treatment
• Surgery
• Other contributing factors:
Bronchiectasis, GERD, sinus disease
• Hot Tub Lung: Ag removal +/- steroids,
antimycobacterial Rx

57. Mycobacterium avium complex
lung disease
AJRCCM 175: 367-416, 2007
CONTROVERSIES:
 Is one macrolide, clarithromycin or azithromycin, superior to
another in the treatment of MAC lung disease?
 Does the inclusion of an injectable agent early in the treatment
of MAC lung disease improve long-term outcome?
 Is one rifamycin, rifabutin or rifampin, superior to another in the
treatment of MAC lung disease?

58. ATS Guidelines for Treatment of M. kansasii
Summary of ATS Recommendations for M. kansasii therapy
1. Daily regimen might include:
a. Rifampin 10 mg/kg/day to maximum 600 mg
b. Ethambutol 15 mg/kg/day
c. Isoniazid 5 mg/kg/day to maximum 300 mg*
2. Goal: 12 months of negative cultures while on therapy
* Recent data suggest that macrolides (clarithromycin or
azithromycin) may be substituted for INH; not part of ATS
Recommendations.
Am J Respir Crit Care Med 175:367-416, 2007

59. ATS Guidelines for Treatment of M. chelonae-
abscessus
Summary of ATS Recommendations for M. abscessus* Therapy
1. The only predictably curative therapy of limited (focal)
M. abscessus lung disease is surgical resection combined
with multidrug chemotherapy.
2. Periodic multidrug therapy (a macrolide and 1 or more
parenteral agents including amikacin, cefoxitin or
imipenem or a combination of the parenteral agents)
may help control symptoms and/or progression of
disease.
* Management of M. chelonae disease is analogous.
Am J Respir Crit Care Med 175:367-416, 2007

60. Complementary Elements of
Therapy
Patients with bronchiectasis often benefit from bronchial
hygiene:
Airway agitating devices (Acapella®, Flutter® or Pep valves)
Inhaled bronchodilating/anti-inflammatory agents, including
-agonists, anti-cholinergics and/or steroids
If patient has co-existing sinusitismanagement may improve
cough
GERD, if present, may provoke cough and periodically soil the
lungs. Acid-inhibition may not be sufficient; may need measures
to prevent reflux (posture in bed, meal patterns or, rarely, surgical
repair).

61. Management Strategies:
Duration:
Varies widely by patient, disease severity and
tolerance to medications
Average duration is 12-24 months
Rapidly growing NTM infections may require
intermittent treatment across lifetime
3/9/2015

62. Management Strategies:
Surgery:
Surgical resection may be an option for localized
disease.
Debulking of diseased tissue may significantly reduce
symptoms and the spread of disease in some patients.
Strongly consider referral to a specialty center when
considering surgery.
3/9/2015

63. Lymphadenitis
MAC
M. scrofulaceum

64. LYMPHADENITIS
Most common presentation of NTM lymphadenitis
Usually < 5 years of age
Unilateral, submandibular site most common
Onset of symptoms subacute
Skin induration and sinus tract formation may occur
R/O TB
MAC (80%) is the most common followed by M. scrofulaceum
Dx Fine needle or excisional Bx

65. Nontuberculous
Mycobacteria
Lymph node disease
Common etiological
agents
MAC
M. kansasii
M. malmoense
M. haemophilum
Uncommon
etiological agents
M. scrofulaceum
M.fortuitum/
peregrinum
M.abscessus/ chelonae

67. PPD tuberculin
Intermediate strength (5 tuberculin unit [TU] PPD tuberculin
weakly reactive skin test (5–9 mm) due to cross-reactivity with
NTM
some children may be negative,
one- third will have reactions with 10 mm or more induration
Distinguishing tuberculous from nontuberculous lymphadenitis
is key
Presumptive diagnosis of NTM
lymphadenitishistopathologic appearance of the lymph
node showing caseating granulomata with or without AFB and
a negative tuberculin skin test.
Failure of the node to yield M. tuberculosis provides

68. A definite diagnosis of NTM lymphadenitisrecovery of the
causative organism from lymph node cultures.
Simple diagnostic biopsy or incision avoided fistulae
formation with chronic drainage.
Even with excised nodes with compatible histopathology, only
about 50% will yield positive cultures although the recovery
rate may be as high as 82% in some centers.

69. TREATMENT
Excisional surgery  Success rate 95%
Children with recurrent diseasesecond surgical procedure is
usually performed.
Alternative for recurrent disease or high risk
surgeryClarithromycin multidrug regimen such as that used
for pulmonary disease
Child who has granulomatous disease with/without AFB on
examination of the excised lymph nodes, and whose PPD
tuberculin skin test is strongly positive (e.g., more than 15
mm).
course of antituberculosis therapy till node culture is available
Cultures NEGATIVE Discontinue antituberculosis unless

70. Skin/soft
tissue/bone/joint and
tendons
M. marinum
M. fortuitum/peregrinum
M. abscessus/chelonae
M. ulcerans

71. Skin/soft tissue/bone/joint
and tendons
History of trauma or superficial laceration
Presence of a foreign body

72. Nontuberculous
Mycobacteria
Skin/soft
tissue/bone/joint and
tendons
Common etiological
agents
M. marinum
M.
fortuitum/peregrinum
M.
abscessus/chelonae
 Uncommon etiological
agents
 MAC
 M. kansasii
 M. terrae
 M. haemophilum

73. M.marinum
Water ,fish
Lake, bay,ocean,pool,aquarium
1-2 month IP  granulomatous nodular – ulcerative
lesions (hands)
Bx for diagnosis

74. Fish tank granuloma/ M.marinum

75. Buruli ulcer /M.ulcerans
Chronic cutanous ulcer
Africa mostly
Debridment

76. Limited skin and soft tissue infection
Debridement plus combined drug therapy
Two agents for a minimum of four months to which the isolate is
susceptible for limited skin and soft tissue infection
Regimens include two of the following:
Trimethoprim-sulfamethoxazole (1 DS twice daily)
Doxycycline (100 to 200 mg daily)
Levofloxacin (500 mg daily)
Clarithromycin (500 mg twice daily) or azithromycin (250 to 500
mg daily)
Monotherapy with these agents should not be used because of
acquired resistance and treatment failures.

77. Disseminated disease

78. Disseminated Disease in
Patients without AIDS
Renal or cardiac transplantation, chronic corticosteroid use,
leukemia,
Mycobacterium avium complex fever of unknown origin
M. kansasii, M. chelonae, multiple subcutaneous
nodules or
abscesses that drain
spontaneously
M. scrofulaceum , M. abscessus
M. haemophilum

79. Disseminated Disease in
Patients with AIDS
Diagnosis is exceedingly rare in person with >100 CD4 cells
should usually be suspected only in persons with < 50 CD4
cells

80. Mycobacterium avium complex (MAC)
infections in HIV-infected patients
One international study found significantly higher rates of
disseminated MAC in developed compared to developing countries
(10 to 22 percent versus 2 to 3 percent) .
Risk factors for disseminated disease
Low CD4 count
Use of an indoor pool for swimming
Previous bronchoscopy
Repeated consumption of raw or partially cooked fish or shellfish
Therapy with granulocyte stimulating factor.

81. PATHOGENESIS
portals of entry respiratory and gastrointestinal tract with
bacteremia following dissemination via the lymphatics.
The mechanisms of interaction among MAC, HIV-1 virus
incompletely understood.
In one study TNF alpha levels were increased and the HIV
macrophage-tropic receptor, CCR5, was up regulated by
monocytes exposed in vitro to MAC organisms or antigens

82. The expression of the T cell-tropic receptor, CXCR4, was not
affected.
HIV-1 production was also increased in macrophage tissue culture
cells previously exposed to MAC antigens.
In lymph node tissue co-infected with MAC and HIV-1, increased
levels of CCR5 were demonstrated in comparison to lymph nodes
infected with HIV-1 alone.
Receipt of granulocyte stimulating factor was identified as a possible

83. CLINICAL MANIFESTATIONS
Disseminated infection — Era before the availability of
HAARTMAC most commonly presented as disseminated
disease.
The most common symptoms of disseminated MAC are non-
specific and include:
Fever,
Night sweats,
Abdominal pain,
Diarrhea,
weight loss
Lab Anemia and elevated ALP and lactate dehydrogenase.
Diagnosis is confirmed by the isolation of MAC from the blood.

84. DIAGNOSIS
Diagnosis of MAC isolation of the organism in culture usually of
the blood or lymph node.
BACTEC  Positive in 7 to 10 days.
Species identification using DNA probes distinguishes MAC from M.
tuberculosis.
Bone marrow culture often yields the organism before blood cultures
turn positive
In one retrospective studymean timepositive culture of MAC
from the bone marrow (22 days) was only marginally better than the
time for the results of a single lysis centrifugation blood culture (24
days)

85. PREVENTION OF MAC DISEASE
In placebo-controlled trials,
rifabutin,
Clarithromycin
Azithromycin
effective in reducing the incidence of MAC and reducing
mortality in patients with HIV infection

86. Clarithromycin versus placebo
In a clinical trial,
667 AIDS patients with a CD4 count <100 cells/mm3
randomly assigned to clarithromycin or placebo
After the interim analysis, the Data Safety Monitoring Board advised
that the trial be stopped due to the following results:
M. avium complex infections developed in significantly more patients
in the placebo arm (53 of 334 patients; 16 percent) compared with
the intervention arm (19 of 333; 6 percent).
Mortality rates were higher in the placebo than the intervention arm
(41 versus 32 percent).

87. Azithromycin comparative trial
The California Collaborative Treatment Group (CCTG) Study
574 was a randomized, placebo controlled, trial
once weekly azithromycin (1200 mg) to rifabutin (300 mg/day)
and to the combination of azithromycin (weekly) and rifabutin
(daily)
one-year cumulative incidence of disseminated MAC was
highest in the group receiving rifabutin alone (15.3 vs 7.6 and
2.8 percent, respectively for the azithromycin and the
combination therapy groups)

88. Recommended drug choice
Daily clarithromycin and once weekly azithromycin are superior to
rifabutin for MAC prophylaxis.
Combination therapy with rifabutin and clarithromycin
adds only toxicity and cost
does not improve efficacy
Rifabutin + azithromycinincrease efficacy but with added toxicity.
Many clinicians favor azithromycin based upon the once weekly
dosing and fewer drug interactions.

89. Timing of the initiation of prophylaxis
current CD4 count of less than 50 cells/mm3
Three to six months after starting antiretroviral therapy before
immune function is restored to a level that would reduce the
risk of MAC
Factors that may contribute to the future risk of MAC include:
The pre-therapy viral load
History of prior Ois
The magnitude of the CD4 increase on therapy

90. Discontinuation of
prophylaxis
first trialACTG
second studydouble-blind trial compared continuing or
stopping azithromycin prophylaxis in AIDS patients whose CD4
counts had risen to >100/microL on two consecutive
determinations in response to HAART therapy
These two clinical trials support the 2009 recommendations of
the USPHS/IDSA to discontinue MAC prophylaxis three
months after patients attain a CD4 cell count >100
cells/mm3

91. MORTALITY
shortened survival in AIDS.
threefold increased risk of death, independent of
CD4 count
Upregulation of HIV RNA or by direct effects of
MAC infectionincreased mortality

92. First-line agents
Clarithromycin (500 mg PO BID) and azithromycin (600 mg
once daily) are the cornerstones of therapy.
Clarithromycin is the preferred first agent due to more
extensive study in AIDS patients with MAC infection.
compared clarithromycin+ethambutol v/s azithromycin+
ethambutol
clarithromycin- containing regimen was superior
azithromycin can be substituted
difficulty with tolerance
drug interaction

93. Second-line agents
Ethambutol or rifabutin.
EthambutolLower rates of relapse in two studies and is the
preferred second agent
Addition of third agent
Additional medications (eg, amikacin or streptomycin)
Advanced immunosuppression (eg, CD4 cell count ≤50
cells/mm3),
high mycobacterial loads

94. NTM TREATMENT SUMMARY
MAC Clarithromycin or azithromycin +
ethambutol+Rifampin
M. xenopi Rifampin+Ethambutol +INH
M. kansasii Rifampin + Ethambutol
M. malmoense Rifampin or Ethambutol
M. marinum Rifampin or Clari + Ethambutol 2-3
months
Rapid growers doxycycline, amikacin, imipenem,
quinolones, sulfonamides, cefoxitin, clarithromycin

95. Antimycobacterium
M. haemophilum Clarithromycin, Rifampin Cipro or
Amikacin
M. genavense Clarithromycin, Rifabutin or
AmikacinEthambutol
M. ulcerans Clarithromycin, Rifampin,
Ethambutol or PAS ( Paraaminosalicylic acid)
MAC prophylaxis Azithromycin , Clarithromycin or
Rifabutin 300 if CD4 <50x 106/L

96. THANK YOU