1. Nocardia & Actinomycosis
Infect topic
Nocardia & Actinomycosis
Nattaya Mangkalapiwat
28 April 2008

2. Nocardia :History Edmond Nocard, 1888
Aerobic actinomycete from cattle with bovine farcy

3. Nocardia Genus : aerobic actinomycetes
G+ branching filamentous bacteria
Subgroup: aerobic nocardiform actinomycetes
-Mycobacterium
-Corynebacterium
-Nocardia
-Rhodococcus
-Gordona
-Tsukamurella

4. Nocardia At least 13 species : cause human infection 7most important
1. Nocardia asteroides complex
:80% of noncutaneous dz.
:most systemic & CNS nocardiosis ***
2. Nocardia farcinica :less common,more virulent
:more antibiotic-resistant member
3.Nocardia nova
4.Nocardia brasiliensis: skin,cutaneous,lymphocutaneous
5.Nocardia pseudobrasiliensis:systemic infections, CNS
6.Nocardia otitidiscaviarum
7.Nocardia transvalensis .

5. Nocardia :ECOLOGY& EPIDEMIOLOGY
Ubiquitous environmental saphrophyte
Soil, organic matter,water
Tropical and subtropical regions
:Mexico, Central and South America,Africa and India

6. Nocardia :ECOLOGY& EPIDEMIOLOGY
Nearly all cases :sporadic
Human-to-human
Animal-to-human not documented
Outbreaks : Contamination of the hospital environment, solutions,drug injection equipment.

7. Nocardia :ECOLOGY& EPIDEMIOLOGY
The risk of pulmonary or disseminated disease
*deficient cell-mediated *
-Alcoholism
-Diabetes
-Lymphoma
-Transplantation
-Glucocorticoid therapy
-AIDS CD4+ < 250
Transmission
Inhalation
Skin

8. Nocardia : PATHOLOGY
Acute pyogenic inflammatory reaction. Branching, beaded, filamentous bacteria
G/S from a nocardial lung abscess
G/S from nocardial pneumonia

9. Nocardia :PATHOGENESIS
Neutralization of oxidants
Prevention of phagosome-lysosome fusion
Prevention of phagosome acidification.
Mycolic acid polymers:ass.with virulence

10. CLINICAL MANIFESTATIONS : 4 main form
Lymphocutaneous syndrome
Pulmonary :Pneumonia
CNS : Brain abscess
Disseminated disease
CNS
Eyes (particularly the retinaKeratitis),
Skin& subcutaneous
Kidneys,
Joints, bone
Heart

11. Lymphocutaneous syndrome
-Cellulitis
-Lymphocutaneous syndrome
-Actinomycetoma
Ubiquitous in soil inoculation injuries,
Insect and animal bites contaminated abrasions
N. brasiliensis : most common
N. asteroides : self-limited
Because initial response Rx as staphylococcus
underdiagnosed Mycetoma
Days to months ,typical:distal limb

12. Nocardial actinomycetoma swelling, multiple sinus tracts,

13. Pulmonary disease Pneumonia Endobronchial inflammatory mass
Subacute(more acute in immunosuppressed)
Cough**
Small amounts of thick, purulent sputum
Fever, anorexia, weight loss, malaise
Endobronchial inflammatory mass
Lung abscess
Cavitary disease
Inadequate therapy Progressive fibrotic diseaseฆ
Cerebral imaging,should be performed in all cases of pulmonary and disseminated nocardiosis

14. Nocardial pneumonia. Discrete nodular in midlung on both sides

15. CT scan (A),CXR (B) from : multiple abscesses : Nocardia farcinica

16. CNS : Brain abscess
Insidious presentations : mistaken for neoplasia !!!
Granulomatous , abscesses
Cerebral cortex, basal ganglia and midbrain***
Less commonly: spinal cord or meninges.
Brain tissue diagnosis in pulmonary nocardiosis
: not necessary
However,
cerebral biopsy:considered early in immunocompromised

17. brain abscess ; Nocardia farcinica
Nocardial abscess :rt. occipital lobe

18. LABORATORY DIAGNOSIS Gram-positive, beaded, branching filaments
usually weak acid fast+ve .
Standard blood culture :48 hrs to several wks, but
typical = 3 to 5 days
Colonization of sputum
:underlying pulmonary dz +
not receiving steroid therapy no specific therapy
Susceptibility testing
-Deep-seated /disseminated dz. fail initial therapy
-Relapse after therapy
-Alternatives to sulfonamides are being considered

19. MANAGEMENT :Medication
Sulfonamides : the mainstay of therapy
treatment of choice :N. brasiliensis
N. asteroides complex
N. transvalensis.
severely ill patients, CNS /disseminated/ immunosuppressed patients =/> 2 drugs
Amikacin and Carbapenem or
3rd generation cephalosporin.

20. MANAGEMENT :Medication
TMP-SMX :currently preferred
:drugs in serum:CSF = 1:20
:high MICs  good therapeutic responses
-General:5-10 mg/kgTMP & mg/kgSMX divide2- 4times
-Cerebral abscesses,severe,disseminated,AIDS
:15 mg/kg TMP and 75 mg/kg SMX)
-Cutaneous infection: 5 mg/kg/day (TMP) + DB
Hypersensitivity reactions :Desensitization

21. MANAGEMENT Medication:alternative therapeutic drugs
Failed sulfonamide Rx: N. otitidiscaviarum
Intolerant : hypersensitivity,GI toxicity, myelotoxicity)
Parenteral : Imipenem & amikacin
: Meropenem
: 3rd-gen cephalosporins Ceftriaxone, cefotaxime
Oral:Amoxicillin clavulanate
:Minocycline(100–200 mg twice daily)
:Linezolid :new oxazolidinone ;effective orally
(bioavailability~100%), good CSF penetration

22. MANAGEMENT Surgical drainage: depend on site
Extraneural aspirate,drainage, excision
Brain abscesses
1) Accessible and relatively large AND
2.1) Lesions progress within 2 wks or
2.2) No reduction in abscess size within a month.

23. Duration of Therapy : at least 12 mo. +
Clinical improvement: most days
Parenteral 3 to 6 wks oral regimen
Primary cutaneous infection :1-3 mo.
Nonimmunosuppressed
-Pulmonary /systemic nocardiosis: at least 6 mo
-CNS involvement : for 12 months
Immunocompromised
HIV-negative immunosuppressed
:12 mo or longer if there are intercurrent increases in immunosuppression
AIDS
: at least 12 mo. +
low-dose maintenance
(long life)

26. Outcome of therapy Cure rates -skin or soft tissue : almost 100%
-pleuropulmonary disease : 90%
-disseminated infection : 63%
-brain abscess : 50%
Mortality
-brain abscesses :31%
-multiple abscesses :41%
-immunocompromised patients :55%

27. Actinomycosis

28. Genus : Actinomyces 3 clinical presentations
Slowly progressive infection
Colonize : mouth, colon, vagina
Infection : mucosal disruption
In vivo : Grains / Sulfur granules
The most misdiagnosed disease
3 clinical presentations
1.chronicity, progress across tissue boundaries, masslike
2. develop sinus tract, resolve and recur
3. refractory/relapsing after a short course therapy

29. Etiologic Agents A. israelii*** A. naeslundii/viscosus
A. odontolyticus
A. viscosus
A. meyeri
A. gerencseriae
pelvic disease ass. IUCDs & “lumpy jaw”
16S rRNA gene sequencing led to identification of an ever-expanding list of Actinomyces spp

30. Concomitant bacteria Staphylococcus / Streptococcus Enterobacteriaceae
Actinobacillus comitans
Eikenella corrodens HACEK
Fusobacterium
Bacteroides
Capnocytophaga (Dog bite)

31. Epidemiology Members of oral, GI, and genital flora
Never been cultured from nature
No document of person-to-person transmission
The peak incidence : mid-decades
Male > Female
(poorer dental hygiene & oral trauma )

32. Pathogenesis & Pathology
Disruption of the mucosal barrier.
Spreads : slow progressive manner, ignoring tissue planes.
Hallmark : chronic, indolent phase (single /multiple indurations)
Wooden – fibrotic wall
As mature lesion : soft , fluctuant and suppurates centrally.
The fibrous walls :wooden
 absence of suppuration: neoplasm???
 Sinus tracts : spontaneously close and re-form
skin  adjacent organs(bone)
Pathology :Central necrosis consisting of neutrophils + sulfur granules.

33. Actinomycosis
G/S :Variable cellular morphology, ranging from diphtheroidal to coccoid filaments มักพบ sulfur granule จากการย้อม gram ได้ และย้อมไม่ติด mAFB

34. Actinomycosis
Sulfur granules
G/S :sulfur granule

35. Risk Factors Foreign bodies : IUCDs Abnormal host defense : HIV
Post transplantation
Radio-Chemotherapy
Ulcerative mucosal infection: HSV/CMV

36. Clinical Manifestations
Oral-Cervicofacial Disease
Thoracic Disease
Abdominal Disease
Pelvic Disease
Central Nervous System Disease
Musculoskeletal & Soft tissue infection
Disseminated Disease

37. Oral-Cervicofacial Disease
Most frequently site
Soft tissue swelling / mass/ abscess : mistaken for a neoplasm
Most common site : Angle of jaws
Dx: mass lesion/relapsing infection in head &neck
Complication :-Otitis, sinusitis, and canaliculitis
:-extend to cranium,c- spine, thorax

38. Most common site : Angle of jaws

39. Thoracic Disease Chest pain, fever, and weight loss ***.
Cavitary disease / hilar adenopathy
>50% pleural thickening / effusion / empyema
pulmonary nodules or endobronchial lesions : Rare
CT scan:central low attenuation + ringlike rim enhancement
Complication:
- Mediastinal infection***
: uncommon, usually from thoracic extension
- Breast disease
- Primary Endocarditis

40. A:Chest wall mass
D:Purulent pleural fluid (aspiration)
B and C: Chest x-ray + CTscan :pulmonary infiltrate, pleural effusion,
pleural and chest wall extension (arrow).

41. Abdominal Disease(1) Usually pass from inciting event
Appendicitis
Diverticulitis
PUD
Foreign bodies
Bowel surgery
ascension from IUCD-associated pelvic disease
Abscess, mass, mixed lesion : mistaken—tumor???
CT: heterogeneous enhance+ thick adjacent bowel.
Sinus tracts  abd. wall / perianal/ between bowel
(Mimic inflammatory bowel disease)
Clue : Recurrent dz /wound or fistula : fails to heal
Imaging and percutaneous techniques
:Therapeutic diagnosis

42. A.CTscan:multiple hepatic abscesses and small splenic lesion extend out side liver. Inset: Gram's stain of abscess
B.Subsequent formation of a sinus tract.

43. Abdominal Disease(2) KUB Disease All levels: can be infected
- pyelonephritis
- renal and perinephric abscess
Bladder involvement:usually due to pelvic disease
urine : stains and cultures

44. Pelvic Disease Risk:IUD in place >1yr-months after removed
S&S: Typically indolent
fever, wt loss, abd pain,
abnormal vaginal bleeding or discharge
Endometritis  masses/tuboovarian abscess
delayed Rxfrozen pelvis
Removed as early as possible :but not removal of the IUCD unless a suitable contraceptive

45. An IUCD encased by endometrial fibrosis (solid arrowhead)
paraendometrial fibrosis (open arrow)

46. Single/multiple abscess** Irregular nodular Rim-enhancing thick wall
CNS Disease
Rare
Single/multiple abscess**
Irregular nodular Rim-enhancing thick wall
Meningitis / Epidural / Subdural space infection
Cavernous sinus syndrome
MS & Soft tissue
Associated trauma:Fx
Adjacent soft tissue  Bone
Periostitis / Osteomyelitis/
Cutaneous sinus tracts** .
Disseminated Disease
:Lung* / Liver*
:multiple nodules ~ CA metas
but, indolent

47. MS & Soft tissue: Cutaneous sinus tracts

48. Diagnosis 16S rRNA gene amplification and sequencing
Avoid unnecessary surgery
Aspirations & Biopsy
Material for C/S + microscopic identification
Sulfur granules : In vivo matrix of bacterial + CaPO4 + host debris
Grossly identified from sinus tract
DDx : Mycetoma / Botryomycosis
C/S isolated in 5-7 d but 2-4 wk. if previous ATB
16S rRNA gene amplification and sequencing
: not routinely used

49. Treatment Combined medical-surgical therapy
Can cure with medical Rx alone even in extensive dz
Medical Management
High doses and prolonged period
1. serious infections and bulky disease
Intravenous PGS mU /day : 2-6 wk.
then Oral Penicillin / Amoxycillin : 6-12 mo.
2.Less extensive disease, e.g. oral-cervicofacial
: cured with shorter course.
Combined medical-surgical therapy
initial attempt cure with medical Rx alone, CT and MRI : monitor
Critical organs : Reproductive /CNS e.g. epidural space
Fails suitable medical therapy

51. Thank you for your attention
Reference
-Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases,6TH Edition
-Harrison's PRINCIPLES OF INTERNAL MEDICINE,17th Edition -CLINICAL MICROBIOLOGY REVIEWS, Apr. 2006, p. 259–282