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Actinomycetes are a group of aerobic and anaerobic bacteria in the order

Actinomycetales. These organisms are phylogenetically diverse but


morphologically similar, exhibiting characteristic filamentous branching with
fragmentation into bacillary or coccoid forms [6]. Aerobic actinomyces that
cause human and veterinary disease include Nocardia, Gordona,
Tsukamurella, Streptomyces, Rhodococcus, Mycobacteria, and
Corynebacteria.

Nocardia typically appear as delicate filamentous gram-positive branching


rods (picture 1) that appear similar to Actinomyces species. Nocardia can
usually be differentiated from Actinomyces by acid-fast staining, as Nocardia
typically exhibit varying degrees of acid fastness due to the mycolic acid
content of the cell wall

Thus,thecoccoidcelscharacteristicforthe
 stationaryphaseofgrowth
wereconsistentlylessvirulentand
 lestoxicthanwerethefilamentous,lo
garithmicallygrowing
 celsfrom thesame organism

Classification -

ECOLOGY EPIDEMIOLOGY
Ubiqiotous environmental saprophytes, occurring in soil, organic matter, water

N asteroides species complex now changed to individual species names with advent of
molecular characterization

CLINICAL EPIDEMIOLOGY
Most cases are in those with immunocompromised. Very strong risk factor

more common and generally more serious in severely immunocompromised and


debilitated patients.

Beaman et al. 1994  review of 1050 randomly selected cases


from the literature showed that more than 60% of all reported
nocardiosis cases are associated with preexisting immune
compromise

Also, Kim et al. 2016  Of a total of 54 patients with culture-proven


nocardiosis diagnosed over 13 years, 18 (33%) were immunocompetent. Half
of immunocompetent patients had chronic lung disease and were not
receiving systemic corticosteroid
Most significant risk factors  Primarily involving impaired
cell mediated immunity
alcoholism, diabetes, chronic granulomatous disease, organ
transplantation, and acquired immunodeficiency syndrome
(AIDS)

⬇CMI - Transplant, lymphoid neoplasia, HIV, malignancy

Presentation
1994 literature review of 1050 cases of nocardiosis
• Pulmonary (only) – 39 percent
• Systemic (≥2 sites involved) – 32 percent;
• 44% CNS involvement
• Single-site extrapulmonary (eg, eyes, bone) – 12
percent
• CNS (only) – 9 percent
• Cutaneous or lymphocutaneous – 8 percent

CLINICAL MANIFESTATIONS

Ubiquitous in soil, nocardiae can establish superficial infection


after relatively trivial inoculation injuries ( Fig. 255-2 ), which
may vary from insect and animal bites to puncture wounds and
contaminated abrasions.

Can get isolated cutaneous infection, causing a mycetoma

Lymphocutaneous infection can result in sporotrichoid spread


along lymph vessels

Outer layer lipids induce production of the proinflammatory


cytokines in macrophages and result in the powerful
granulomatous reaction which characterizes the initial
pathogenesis of the disease.
As such, can initially be mistaken for staph or strep in origin in
early stages, but generally much more indolent
In more advanced disease, the acute infection can follow an
indolent and progressive course and lead to the development of
a mycetoma with sinus tract formation.
Mycetomas are a chronically progressive, destructive disease,
occurring days to months after inoculation, and are typically
located distally on the limbs.
Suppurative granulomas, progressive fibrosis and necrosis,
sinus formation with destruction of adjacent structures, and
macroscopically visible infective granules are regular features of
nocardial mycetoma.
The granules represent small colonies of the infecting agent surrounded by masses of
inflammatory cells(439,599,600). Usually the mycetoma remains localized but enlarges
by extension of the organisms through the tissues. With time, the infection involves
both the muscle and bone, wherein a destructive osteomyelitis occurs.

PULMONARY

Pulmonary disease is the predominant clinical presentation


because inhalation is the primary route of exposure (>40% of
reported cases). 12 17 Any species may cause lung infection,
although the most common are N. cyriacigeorgica , N. nova,
and N. farcinica .

It can present as either an acute or chronic lung disease or


somewhere in between, and the clinicopathologic features are
highly variable, with no pathopneumonic clinical feature or
radiological finding.

productive or nonproductive cough, dyspnea, hemoptysis, and


fever and other systemic symptoms

The mainfestations within the lungs may vary from a mild,


diffuse infiltration to a a lobar or multilobar consolidation.
There may also be solitary endobronchial masses,
reticulonodular infiltrates, irregular cavitating lesions, and
pleural effusions.
A granulomatous response with central necrosis similar to TB
has been described, but lacking the epitheloid cells that are
characteristic of TB granuloma.

50 percent of all pulmonary cases disseminate to sites outside the lungs, most
commonly the brain

CNS INVOLVEMENT

CNS involvement was recognized in more than 44% of cases of


all systemic nocardiosis in one large survey. 17 Cerebral
nocardiosis often accompanies pulmonary disease, but isolated
CNS disease is not uncommon. Indeed, up to one quarter of
cases of nocardial disease (excluding mycetoma) involve the
CNS. Nearly half of these affect the CNS exclusively. 11 61 62 63

NEOPLASIA mimic:
Infections of the brain by Nocardia spp are often insidious in
onset and difficult to diagnose and treat successfully.

Can invade brain silently and persist as inapparent infection


Thus signs and symptoms expressed following brain infection
are variable and there may not be any outward neurological
manifestations.
When symptoms are present, most often result in a broad range
of neurological deficits over a period of several months to years.

As such, because of the paucity of clinical and laboratory signs


of bacterial inflammation, and silent invasion and persistence -
insidious presentations are often mistaken for neoplasia or CVA
make diagnosis and management more difficult. 11 17
Highlighted very well by Ms EM’s case and also by a very similar cause described by
Bauman et al. about a nonimmunocompromised patient with a nocardia brain
abscess: “Because of the absence of signs of infection and the age of the patient, a
presumptive diagnosis of brain tumour was made, and therapy was instituted with
dexamethasone. As the lesion was accessible to surgery, a biopsy was performed,
which isolated Nocardia spp with no evidence of malignancy on histology.

Clinical manifestations of CNS nocardiosis usually result from


local effects of granulomas or abscesses in the brain.
Case reports of culture proven nocardia brain abscesses
demonstrate that can be single large focal abscess, or multifocal
distant or clustered together, and, less commonly can involve
the spinal cord or meninges

Often localized to the frontal, parietal and occipital cerebral


cortex, midbrain and pons, but can occur essentially anywhere
within the brain.

Also, have been reports of meningitis without discrete brain


abscess

On MRI, typical appearance includes ring-enhancing lesions,


with a large surrounding area of vasogenic oedema. Can be
mistaken for fast growing metastasis or neoplasm such as GBM

Systemic Nocardiosis

When lesions are found at two or more locations within the


body, the disease is classified as systemic nocardiosis

Pathogenesis:

site:
any anatomic location can be involved, but most common sites
to be infected during dissemination are CNS, cutaneous and
subcutaneous tissues, eyes (esp retina), kidneys, bones, joints,
and heart.

morphology:
hallmark of disseminated nocardial lesions is abscess
formation, with polymorphs representing dominant cell type in
early stages of infection.
In advanced stages, host cell reponse becomes mixed.

Abscesses enlarge by direct extension of nocardial filaments


through the skin.

Becomes relentlessly progressive.

Laboratory Diagnosis

Growth of Nocardia may take 48h to 7-14 days, but typical


colonies seen after 3-5 days.

On culture media, colonies demonstrate either waxy,


cerebriform colonies, but if aerial hyphae are produced, as can
be visualized with stereoscopic microscopy, the colonies may
demonstrate a chalky-white appearance.
Gene sequencing has been used for species identification (rapid
and reliable). Sequencing of the first 500-600 base pairs of the
5’ end of the 16s rRNA gene is currently the leading approach –
sufficient sequence variability for species identification.

TREATMENT

No prospective randomized trials have determined the most effective therapy


for nocardiosis. In addition, it is unlikely that such trials will ever be performed,
since a large number of patients with similar clinical manifestations would be
required. Two hallmarks of nocardiosis are its relative rarity and the diversity
of the clinical presentation in different patients. Thus, the choice of
antimicrobials is based upon cumulative retrospective experience [23],
investigations in animal models, and in vitro antimicrobial activity profiles.

Susecptibility testing:
Antimicrobial susceptibilities should be performed on all Nocardia isolates as
a guide to therapy.

Choice of drug
Sulfonamides have been considered the standard of therapy for more than 50
years, despite the lack of controlled comparative data. This consensus is
based in part upon the results of a few retrospective reviews in which there
was a trend toward increased survival in nocardiosis with the use of
sulfonamide-containing regimens

Although all sulfonamides appear to be equally efficacious, trimethoprim-


sulfamethoxazole (TMP-SMX) is considered by most clinicians to be the drug
of choice
TMP-SMX has demonstrated synergy against Nocardia in several in vitro
studies; the optimal ratio of TMP to SMX in vitro ranges from 1 to ≤5 to a ratio
of 1 to 10

Other agents

Despite the success of TMP-SMX in the treatment of nocardiosis, combination


therapy with other agents is warranted in patients with severe infections.
These drugs are also indicated in patients with sulfonamide intolerance or
allergy and documented clinical treatment failures. The choice of agent varies
with susceptibility testing and with known patterns of response with different
Nocardia spp. (See 'Antibiotic susceptibility' above.)
In vitro susceptibilities and animal models of disease have demonstrated
activity against Nocardia with a variety of antibiotics, including amikacin,
imipenem, meropenem, third-generation cephalosporins (ceftriaxone and
cefotaxime), minocycline, extended spectrum fluoroquinolones (eg,
moxifloxacin), linezolid, tigecycline, and dapsone [19,30-32]. Several
anecdotal reports indicate that these agents are successful in treating patients
with nocardiosis [33-35]. There are few reports of successful treatment of N.
nova infections using clarithromycin, either as a single agent [36], or as part of
a combination regimen [37].
Although limited clinical experience suggests efficacy with linezolid, even as
monotherapy [35], the use of linezolid for more than two weeks is associated
with substantial risk of hematologic toxicity, particularly thrombocytopenia, as
well as neurotoxicity (eg, peripheral neuropathy, serotonin syndrome) [38,39].
Given the length of treatment recommended for nocardiosis (usually 6 to 12
months), linezolid seems unlikely to become a widely used in this setting.

Severe infection
Severe nocardiosis includes some cases of pulmonary disease, and all cases
of disseminated disease or central nervous system disease, as well as all
infections involving more than one site in immunocompromised patients.

Despite the lack of data to support the superiority of combination therapy over
single drug regimens, most infectious diseases specialists initially treat severe
nocardial infection with two intravenous drugs prior to the availability of
susceptibility results (table 1) [1,2]. However, in cases of life-threatening
infection, we suggest using three intravenous drugs

severe infection that does not involve the CNS


be treated initially with TMP-SMX (15 mg/kg IV of the trimethoprim component
per day in two to four divided doses) plus amikacin (7.5 mg/kg IV every 12
hours).

Initial Treatment
Initial treatment (ie, induction therapy) should be administered intravenously
for at least three to six weeks and/or until clinical improvement is documented.
We favor at least two intravenous agents during this phase of therapy for all
patients with severe disease. Patients initially on three intravenous drugs who
both improve on initial intravenous combination therapy and are proven to
have susceptible isolates may be switched to two intravenous drugs to
complete the induction phase of therapy. The results of susceptibility testing
should be used to tailor the regimen. As an example, if the isolate is
susceptible to the third-generation cephalosporins (ceftriaxone, cefotaxime),
imipenem can be switched to one of these agents.

Duration

The optimal duration of antimicrobial treatment for severe disease has not
been determined, but most recommend a prolonged course because of the
relapsing nature of Nocardia infection. We usually treat for a duration of three
to six months for isolated cutaneous infection in immunocompetent patients,
but for 6 to 12 months in immunocompromised patients. Serious pulmonary
infection is treated for 6 to 12 months or longer. All immunocompromised
patients (except those with isolated cutaneous infection) as well as patients
with CNS involvement should be treated for at least one year [2], and some
suggest indefinite suppressive therapy in immunocompromised patients.
Within these ranges, the total duration of therapy (IV followed by oral) is based
upon the severity and extent of disease and the clinical and radiographic
response to treatment.

Resistance

Uhde et al. reported that of 765 isolates of Nocardia submitted to the


Centers for Disease Control and Prevention (CDC) in Atlanta, GA,
from 1995 to 2004, 61% were resistant to SMX and 42% were
resistant to TMP-SMX (20).

In a 2011 study of 186 Nocardia species isolated from patients in


Spain, Larruskain et al. described 16.1% resistance to TMP-SMX
(11).

Another 2011 report from Canada described 43% of 157 Nocardia


isolates recovered from Quebec from 1988 to 2008 as resistant to
TMP-SMX (19).
We reviewed 552 recent susceptibilities of clinical isolates of
Nocardia from six major laboratories in the United States, and only
2% of the isolates were found to have resistant MICs of trimethoprim-
sulfamethoxazole and/or sulfamethoxazole. We hypothesize that the
discrepancies in the apparent sulfonamide resistance between our
study and the previous findings may be associated with difficulty in
the laboratory interpretation of in vitro MICs for trimethoprim-
sulfamethoxazole and sulfamethoxazole and the lack of quality
controls for Nocardia for these agents.

Five of the six laboratories identified Nocardia isolates to the species


or complex level by 16S rRNA or secA gene sequencing, PCR
restriction fragment enzyme analysis (PRA), and/or drug
susceptibility patterns

Broth microdilution of TMP-SMX and/or SMX was performed in all


six laboratories according to the current recommendations of the
Clinical and Laboratory Standards Institute (CLSI) on 552 isolates

Despite these reports of in vitro sulfonamide resistance, there have


been only rare recent clinical reports describing treatment failure of
Nocardia with TMP/SMX

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