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PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
This coronal section gross photograph demonstrates
Pseudomonas aeruginosa necrotizing hemorrhagic
pneumonia . (Courtesy Franz von Lichtenberg
Infectious Disease Collection, BWH.)
TERMINOLOGY
Definitions
Pseudomonas: Greek: "Pseudes" (false) + "monas" (a
nonflagellated protist)
Burkholderia: Walter H. Burkholder (a plant pathologist
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
at Cornell University)
Haemophilus: Greek: "Haima" (blood) +
"philos" (loving)
Legionella: Named for 1st documented outbreak at
a hotel among members of the American Legion in
1976
INFECTIOUS AGENTS
Pseudomonas
Epidemiology
Pseudomonas aeruginosa is the most significant cause
of human disease, but other species (e.g., P. putida)
may be isolated
Widely present in environment
Most common in immunocompromised, those at
extremes of life, with cystic fibrosis (accounts for
60-70% of respiratory infections in this group), on
ventilators, or with burns or other wounds
Clinical manifestations
Hospital/healthcare-associated pneumonia
(ventilated and nonventilated patients),
community-acquired pneumonia, and chronic
colonization in patients with respiratory tract
diseases
Bloodstream and urinary tract infections
Infective endocarditis
Ecthyma gangrenosum: In gluteal region or
extremities that progress from macules to vesicles
II
and bullous lesions
Characteristically with dark, central eschar
Gram stain highlights sparse, short, gram-negative rods
in pseudomonal pneumonia in a cystic fibrosis patient.
The organisms may be panresistent to antibiotics.
Often in setting of bacteremia in
immunocompromised patients
Can be caused by organisms other than
pseudomonads
Osteomyelitis and septic arthritis of any site
Particularly associated with sternoclavicular
septic arthritis, vertebral osteomyelitis, temporal
bone and skull base osteomyelitis, septic arthritis
and osteomyelitis of pubic symphysis, and
osteomyelitis caused by nail puncture or combat
wounds
Immunocompetent hosts: Skin and soft tissue
infections (folliculitis, paronychia) and otitis
externa (Swimmer’s ear): Keratitis with malignant
otitis externa and endophthalmitis are 2 severe,
aggressive manifestations
Burkholderia
Epidemiology
Burkholderia cepacia complex, composed of 10 distinct
species designated genomovars
Widely distributed environmental saprophyte in soil
and water
Have been described as contaminants of
disinfectants such as chlorhexidine, IV solutions,
medical devices used in urologic and obstetric
procedures, and cosmetics
Transmission is thought to occur from environment
given its ubiquitous nature, nosocomially via
exposure to contaminated medicines and devices
and person-to-person contact
Can be difficult to discern between colonizer vs.
pathogen
Predisposed include patients with cystic fibrosis
(impaired mucociliary clearance and reduced
antimicrobial production), chronic granulomatous
disease (defective oxidative killing), burns, sickle cell
anemia, and the immunocompromised
2
40
PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
B. cepacia complex species have been isolated in
approximately 3% of positive respiratory cultures
isolated from cystic fibrosis patients
Clinical manifestations
Pneumonia, catheter-associated infections,
abscesses, bone and joint infections, varied skin
and soft tissue involvement (ulcers to ecthyma
gangrenosum), endocarditis, genitourinary
infections
Burkholderia mallei
Causative agent of Glanders disease
Endemic in Africa, Asia, Middle East, Central and
South America
Transmission mainly through broken skin via direct
contact with horses, donkeys, mules, and other
animals, but also may be inhaled
Laboratory infections reported
Clinical manifestations
Dependent on route of exposure; e.g., with
skin ulcerations or abscesses, increased mucus
production in eyes, nose, and respiratory tract or
signs and symptoms of pneumonia
If untreated, dissemination can occur within 1-4
weeks of initial infection, leading to abscesses in
liver and spleen
Burkholderia pseudomallei
Causative agent of melioidosis, a.k.a. Whitmore
disease
Endemic in tropical climates, in particular Southeast
Asia and Australia but also in Middle East, India,
and China
In endemic geographic regions, annual incidence of
melioidosis up to 50 cases per 100,000
Transmission via percutaneous inoculation and
inhalation in wet seasons
Rarely, mother-infant transmission (in setting
of mastitis), laboratory acquired, and iatrogenic
infections
Most infections are subclinical
Clinical manifestations
Usually presents in patients in 5th-6th decade
with underlying conditions (diabetes, alcoholism,
renal insufficiency, chronic lung disease,
immunosuppression, thalassemia, and kava
consumption)
Incubation is usually 1-21 days but can be up to
months or years
Acute form defined as < 2 months of symptoms
Presents with skin and soft tissue infections,
pulmonary involvement, disseminated disease
involving abscesses of spleen, kidney, prostate,
and liver, and encephalomyelitis
Parenchymal abscesses and suppurative parotitis
and, more rarely, mycotic aneurysms, mediastinal
masses, pericardial collections and adrenal
abscesses have also been described
Chronic form defined as > 2 months of
symptoms
Presentation usually involves skin and soft tissue
as well as pulmonary infections mimicking
tuberculosis (a.k.a. Vietnamese tuberculosis)
Reactivity can occur many years after primary
infection with latency lasting as long as 62 years
Relapse is reported in up to 20% of cases
Haemophilus
Epidemiology
"Chancroid" refers to genital ulcerations caused by
Haemophilus ducreyi
Clinically relevant species: Haemophilus influenzae
and Haemophilus ducreyi
H. influenzae subdivided into typeable (serotypes
A-F) and nontypeable strains (lacking an
antigenic, polysaccharide capsule)
Vaccine against H. influenzae type B has caused more
frequent isolation of nontypeable strains
Natural reservoirs of both H. influenzae and H.
ducreyi are human beings
H. influenzae: Spread by droplets or contact with
infected secretions
Disease generally preceded by colonization
(most often in children and adults with chronic
obstructive pulmonary disease [COPD])
H. ducreyi: Spread by sexual contact
Clinical manifestations
Nontypeable strains
Otitis media (25-35% of all cases), sinusitis, and
bacterial conjunctivitis (most common agent in
children)
Exacerbations of COPD, community-acquired
pneumonia, sinusitis
Neonatal and maternal sepsis (mortality rates:
50-90%)
Typeable H. influenzae (particularly type B)
More likely to cause invasive disease
Meningitis
Epiglottitis
Pneumonia
Cellulitis (facial)
Bacteremia
Septic arthritis
H. ducreyi
Causes chancroid, an ulceration of genitals
Lesion begins as a papule and progresses into an
painful ulcer with an irregular border
Region surrounding ulcer is characteristically
uninflamed; inguinal lymphadenopathy often
present
Legionella
Epidemiology
Legionnaire’s disease and Pontiac fever are both
manifestations of Legionella infection
Legionella pneumophila is most commonly isolated
species
Group consists of 16 serogroups, with serogroup I
being most frequently isolated
Widespread in warm aqueous environments
Growth is fostered by replication within freeliving amebas
Infection occurs via inhalation of an infectious dose
in contaminated air droplets from a man-made
water source (e.g., air conditioning)
II
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41
PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
Clinical manifestations
Legionnaire’s disease
Consolidating pneumonia characterized by pulsetemperature dissociation (Faget sign, also seen
with Salmonella typhi infection), myalgia, diarrhea,
elevated hepatic enzymes, and electrolyte
imbalances
Headache and confusion, may be severe
Metastatic infection is rare and mainly confined
to immunocompromised
Pulmonary symptoms not prominent, though a
cough and pleuritic chest pain may occur
Pontiac fever, a self-limited syndrome marked
by fever, headache, and myalgias is other main
manifestation
CLINICAL IMPLICATIONS
Laboratory Tests
Cultures of affected site (sputum, wound, blood etc.)
except for nontypeable H. influenzae (as a normal
member of oropharynx diagnosis is almost exclusively
based on clinical findings)
Cultures for H. influenzae type B are useful, since
this organism causes invasive disease into normally
sterile sites
For B. pseudomallei encephalomyelitis, cerebral spinal
fluid parameters usually have elevated white blood
cell counts with mononuclear predominance, normal
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
or slightly decreased glucose, and intermittently
elevated protein levels
An immunoassay for Legionella urinary antigen
can be used for a rapid result, though limited to L.
pneumophila serogroup I
Serologies not generally used for diagnosis or
monitoring
Treatment
P. aeruginosa: Usually a later generation cephalosporin
with an aminoglycoside (resistance is a significant
problem)
Vaccination against H. influenza type B is used to
prevent disease
Many antibiotic options for nontypeable H. influenzae
outside of narrow-spectrum -lactams
L. pneumophila: Macrolides and quinolones
Prognosis
Morbidity and mortality range widely from mild and
self-limited to extremely virulent (i.e., H. influenzae
neonatal sepsis, P. aeruginosa sepsis)
MICROBIOLOGY
Morphologic and Biochemical
Characteristics
Aerobic or facultatively aerobic, gram-negative, nonspore-forming rods
II
P. aeruginosa can be differentiated from other
pseudomonads by the production of oxidase
Culture
Pseudomonas grows on most laboratory media
Mueller-Hinton agar often used to highlight the
production of blue-green pigments (pyocyanin and
pyoverdin)
B. pseudomallei is selected by Ashdown agar
(containing gentamicin) or liquid transport broth
(containing colistin) when used to culture samples
from nonsterile sites
Culture propagation is extremely dangerous and
laboratory staff should take precautions when
working with potential or suspect samples
H. influenzae is fastidious and needs 2 erythrocytederived growth factors: X (hemin) and V (NAD)
Differentiates from other species of Haemophilus
except closely related Haemophilus hemolyticus
(distinguished by its ability to lyse horse or rabbit
erythrocytes)
Colonies are large, smooth, and light gray
Encapsulated strains may appear mucoid
Legionella cannot be grown on standard laboratory
media due to its requirement for cysteine and soluble
iron
Optimal growth is on BCYE- agar (iron, ketoglutarate, charcoal yeast extract)
Opalescent colonies may take several days to appear
Microbiologic Identification
B. pseudomallei and B. mallei require an enhanced
biosafety environment and will not be worked-up in a
standard clinical laboratory
A large part of the laboratory identification of these
organisms is by culture characteristics
Automated platforms and identification strips (Vitek,
API strips, etc.) are used in clinical laboratory to
identify most of these species
Antisera may be used to determine the serotype of H.
influenzae
B. cepacia complex requires sequencing of multiple
targets to be identified past "complex" level
DISEASES BY ORGAN SYSTEM
Central Nervous System
H. influenzae: (Usually type B) can cause a purulent
meningitis in unvaccinated patients
P. aeruginosa: Less common cause of meningitis, often
associated with neurosurgical procedures
B. pseudomallei: Abscess and encephalitis
Pulmonic
Pneumonia
Pseudomonas and Burkholderia species
Virulent pneumonia characterized by hemorrhage
and necrosis
Often involves microvasculature, resulting in
bacteremia and sepsis
In Legionella infection, alveolar spaces are
characteristically filled with fibrin and necrotic
macrophages (fibrinohistiocytic response)
2
42
PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
Silver stains are generally required to see
organisms
H. influenzae type B can cause a consolidative
pneumonia (most typically in younger patients)
Nontypeable H. influenzae infection can less
commonly develop into pneumonia
Cardiac
Endocarditis
P. aeruginosa is a rare cause of suppurative gramnegative endocarditis
Hepatic
B. mallei or B. pseudomallei: Liver abscess
Reticuloendothelial
B. mallei or B. pseudomallei: Splenic abscess
Genitourinary
H. ducreyi
Causes chancroid
Ulcers with a necrotic base and a ragged,
nonindurated edge (in contrast to syphilitic
ulcerations)
Organisms may be seen with Gram stain in
superficial portion of lesion
A mixed inflammatory infiltrate may be present,
along with proliferating endothelial cells in dermis
Bone
H. influenzae (usually type B)
May cause a suppurative, monomicrobial
osteomyelitis via hematogenous spread in
unvaccinated individuals
P. aeruginosa
Osteomyelitis via hematogenous spread or direct
inoculation
Contiguous spread is often from chronic, decubitus,
or diabetic foot ulcers
Will likely be polymicrobial and demonstrate
chronic infection
Skin
P. aeruginosa
Ecthyma gangrenosum: Characterized by epidermal
and dermal necrosis, necrotizing vasculitis, and a
mixed inflammatory infiltrate
Bacteria can be isolated from lesion
Malacoplakia (nodules characterized by von
Hanseman cells, macrophages with eosinophilic
granules, and occasionally basophilic MichaelisGutmann bodies)
Botryomycosis (a purulent abscess filled with
basophilic granules of varying size, corresponding to
colonies of bacteria, embedded in a hyaline matrix)
B. pseudomallei: Reported to cause nodules and ulcers
with microabscesses, though range of reported
findings varies widely
Soft Tissue
Typeable Haemophilus influenzae has rarely been
reported as causative agent of necrotizing fasciitis
SELECTED REFERENCES
1. D’Agata E: Pseudomonas aeruginosa and other Pseudomonas
species. In Bennett JE et al: Mandell, Douglas, and
Bennett’s Principles and Practice of Infectious Diseases. 8th
Edition. Philadelphia: Elsevier. 2518-31, 2015
2. Edelstein PH et al: Legionnaire’s disease and Pontiac
fever. In Bennett JE et al: Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases. 8th Edition.
Philadelphia: Elsevier. 2633-44, 2015
3. Murphy TF: Haemophilus species, including H. influenzae
and H. ducreyi (chancroid). In Bennett JE et al: Mandell,
Douglas, and Bennett’s Principles and Practice of Infectious
Diseases. 8th Edition. Philadelphia: Elsevier. 2575-83, 2015
4. Jalalvand F et al: Haemophilus influenzae: recent
advances in the understanding of molecular pathogenesis
and polymicrobial infections. Curr Opin Infect Dis.
27(3):268-74, 2014
5. Prasad SC et al: Osteomyelitis of the temporal bone:
terminology, diagnosis, and management. J Neurol Surg B
Skull Base. 75(5):324-31, 2014
6. Van Eldere J et al: Non-typeable Haemophilus influenzae,
an under-recognised pathogen. Lancet Infect Dis.
14(12):1281-1292, 2014
7. Ganesan S et al: Host evasion by Burkholderia cenocepacia.
Front Cell Infect Microbiol. 1:25, 2012
8. Torres AG et al: Recent progress in melioidosis and
glanders. Front Microbiol. 3:149, 2012
9. Wiersinga WJ et al: Melioidosis. N Engl J Med.
367(11):1035-44, 2012
10. Currie BJ et al: The epidemiology and clinical spectrum of
melioidosis: 540 cases from the 20 year Darwin prospective
study. PLoS Negl Trop Dis. 4(11):e900, 2010
11. Mahenthiralingam E et al: Burkholderia cepacia complex
bacteria: opportunistic pathogens with important natural
biology. J Appl Microbiol. 104(6):1539-51, 2008
12. Brent AJ et al: Misdiagnosing melioidosis. Emerg Infect Dis.
13(2):349-51, 2007
13. Ezzedine K et al: Imported cutaneous melioidosis in
traveler, Belgium. Emerg Infect Dis. 13(6):946-7, 2007
14. Vonberg RP et al: Hospital-acquired infections related to
contaminated substances. J Hosp Infect. 65(1):15-23, 2007
15. Aaron SD et al: Combination antibiotic susceptibility
testing to treat exacerbations of cystic fibrosis associated
with multiresistant bacteria: a randomised, double-blind,
controlled clinical trial. Lancet. 366(9484):463-71, 2005
16. Srinivasan A et al: Glanders in a military research
microbiologist. N Engl J Med. 345(4):256-8, 2001
17. Belchis DA et al: Histopathologic features of Burkholderia
cepacia pneumonia in patients without cystic fibrosis. Mod
Pathol. 13(4):369-72, 2000
18. Biological and chemical terrorism: strategic plan for
preparedness and response: Recommendations of the CDC
Strategic Planning Workgroup. MMWR Recomm Rep.
49(RR-4):1-14, 2000
19. Winkelstein JA et al: Chronic granulomatous disease.
Report on a national registry of 368 patients. Medicine
(Baltimore). 79(3):155-69, 2000
20. Berry MD et al: Pseudomonas cepacia bacteremia in
children with sickle cell hemoglobinopathies. Pediatr
Infect Dis J. 10(9):696-9, 1991
21. Tablan OC et al: Pseudomonas cepacia colonization
in patients with cystic fibrosis: risk factors and clinical
outcome. J Pediatr. 107(3):382-7, 1985
22. Noriega ER et al: Subacute and acute endocarditis due
to Pseudomonas cepacia in heroin addicts. Am J Med.
59(1):29-36, 1975
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
II
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43
PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
p
p
p
A
p
Gross and Microscopic Features
(Left) This gross photograph
demonstrates necrosis of
terminal airways
atient with Pseudomonas
aeruginosa pneumonia.
(Courtesy Franz von
Lichtenberg Infectious Disease
Collection, BWH.) (Right)
Fibrinoid necrosis of
lung parenchyma is one of
the key findings of gramnegative pneumonia (in
this case the culprit is P.
aeruginosa). Despite the
debris and necrosis, one can
still appreciate the alveolar
architecture of the tissue in this
image.
(Left) Acute inflammatory
exudate rims expansile
hemorrhage in necrotic
lung in this case of P.
aeruginosa. In severe
cases such as this, both
necrotizing pneumonia and
eventually diffuse alveolar
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
damage result in high
mortality. (Right) This image
shows acute P. aeruginosa
neumonia associated
with ectatic bronchiole
(35-year-old patient with
advanced cystic fibrosis).
The chronic inflammation
is a consistent feature of
cystic fibrosis regardless of
colonization.
in a
(Left) This section shows acute
P. aeruginosa pneumonia
centered on airways
with sparing of the adjacent
ulmonary parenchyma in
a patient with cystic fibrosis.
s the disease progresses, the
organisms may break through
bronchial walls and cause
spill-over pneumonia in the
II
alveoli. (Right) This gross
hotograph demonstrates
Pseudomonas aeruginosa
vegetative endocarditis
. (Courtesy Franz von
Lichtenberg Infectious Disease
Collection, BWH.)
2
44
PRIMARY GRAM-NEGATIVE RESPIRATORY PATHOGEN INFECTIONS
p
p
p
p
p
g
p
p
g
Microscopic Features
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
(Left) Acute consolidative
neumonia caused by
Burkholderia cepacia is seen
in this section of lung. Note
the space consistent with
a liquified area of abscess.
(Right) Necrosis with
fibrin extravasation is
shown, likely due to the
ropensity of Burkholderia
cepacia to grow along
ulmonary capillaries
and cause infarction of
distal tissues. Note the
atchy distribution of the
destruction.
(Left) Bronchiolar rupture
with reactive fibroblastic
roliferation , which
might have formed an
abscess cavity, is shown.
This patient’s cultures
rew Burkholderia cepacia
but could have also been
Pseudomonas. (Right)
Miliary lung lesions rich
in macrophages are
demonstrated in this patient
with melioidosis sepsis
caused by Burkholderia
seudomallei.
(Left) Gram stain elucidates
dense growth of B.
seudomallei in lung
lesions in a patient with
melioidosis. (Right) Skin
biopsy from a patient with
chancroid (H. ducreyi
infection) demonstrates
a nonulcerated lesion
with edema and
deep lymphoplasmacytic
inflammation . Classic
lesions are ulcerated with
3 layers, including an
upper layer of neutrophils,
fibrin, and debris (not seen
here) overlying central
ranulation tissue, with
chronic inflammation below.
II
2
45
NEISSERIA AND MORAXELLA SPECIES INFECTIONS
A brain from a patient who died of meningococcemia,
with DIC and purpura but without meningitis,
shows petechiae. (Courtesy Franz von Lichtenberg
Collection of Infectious Disease Pathology, BWH.)
TERMINOLOGY
Synonyms
Meningococcus (Neisseria meningitidis)
Gonococcus (Neisseria gonorrhoeae)
Definitions
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
Neisseria from Albert Neisser who discovered
etiological agent of gonorrhea
Greek: "Gonorrhoeae" (a seminal flux)
ETIOLOGY/PATHOGENESIS
Environmental Exposure
Humans are only known host: N. meningitidis, N.
gonorrhoeae, and Moraxella catarrhalis
Infectious Agents
Clinically relevant species of Neisseria: N. meningitidis
and N. gonorrhoeae
N. meningitidis
Major site of colonization is nasopharynx
Invasive disease almost exclusively caused by
encapsulated strains
Transmitted by inhalation of infected droplets or
other contact with respiratory secretions
N. gonorrhoeae
Primarily infects urogenital epithelia, though
disseminated disease is possible
Pathogenicity differs between male and female hosts
Spread is by sexual contact in both sexes or
maternal-fetal transmission at time of birth
Most clinically relevant species of Moraxella: M.
catarrhalis
Historically described as a commensal organism of
nasopharynx, now considered a pathogen
II
Colonizes respiratory epithelia and induces uptake
Predilection for damaged epithelium (e.g., in COPD
patients)
2
This patient demonstrated fulminant meningococcemia
with purpuric hemorrhage. (Courtesy Franz von
Lichtenberg Collection of Infectious Disease Pathology,
BWH.)
Spread by inhalation of droplets or other contact
with respiratory secretions
Disease often caused by spread of colonizing
organisms to other sites (e.g., middle ear, lower
respiratory tract)
CLINICAL ISSUES
Epidemiology
N. meningitidis is carried asymptomatically in
nasopharynx in 5-25% of population (highest in
adolescents and those in crowded living conditions)
Hosts with particular immune deficiencies (e.g.,
defects in terminal complement pathway) are
susceptible
Large burden of disease in sub-Saharan Africa with
high attack rate (ranging from 100 per 100,000 to 1
per 100)
N. gonorrhoeae is far more common in United States
than in other industrialized countries
Highest attack rates in 15- to 19-year-old African
American females
Men who have sex with men (MSM) are also at
increased risk
M. catarrhalis colonizes a large percentage of infants
and 1-5% of healthy adults
Patients with COPD at particularly high risk
Presentation
N. meningitidis
Invasive disease usually consists of bacteremia
shock and meningitis
Less common manifestations: Pneumonia, septic
arthritis, purulent pericarditis, conjunctivitis,
epiglottitis, sinusitis, otitis, urethritis, and proctitis
Onset is usually abrupt and signs and symptoms
progress rapidly (fever, weakness, cold and pallor
of extremities, organ failure, and disseminated
intravascular coagulation (DIC)
46
NEISSERIA AND MORAXELLA SPECIES INFECTIONS
Etiology
Humans are only known host for Neisseria
meningitidis, Neisseria gonorrhoeae, and Moraxella
catarrhalis
Clinical Issues
N. meningitidis invasive disease is bacteremia shock
and meningitis
N. gonorrhoeae
Presents in males as acute urethritis
In females, predominant site is endocervix, often
with minor symptoms
~ 10-20% of women develop infection of upper
genital tract (pelvic inflammatory disease [PID])
Disseminated gonococcal infection (DGI)
commonly presents as an arthritis-dermatitis
syndrome
Key Facts
M. catarrhalis is a common cause of otitis media,
sinusitis, and COPD exacerbation
N. meningitidis is carried asymptomatically in
nasopharynx in 5-25% of population (highest in
adolescents and those in crowded living conditions)
M. catarrhalis colonizes a large percentage of infants
and 1-5% of healthy adults (COPD at high risk)
N. gonorrhoeae is more common in USA than other
industrialized countries, with highest attack rates in
15- to 19-year-old African American females
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
Carriage rates in a population correlate with attack
rates
Additional symptoms of meningitis include
headache, photophobia, altered mental status,
irritability, and neck stiffness
Often a characteristic purpuric or petechial rash
Complications can include WaterhouseFriderichsen
syndrome (adrenal hemorrhage) and myocarditis
(seen in < 1/2 of patients at autopsy)
N. gonorrhoeae
Males
Acute urethritis with purulent discharge and
dysuria
Epididymitis and rectal involvement prostatitis
may be present
Females
Predominant site is endocervix, though urethra
and anus may also be involved
Symptoms include vaginal discharge, dysuria, and
vaginal bleeding (often low grade)
~ 10-20% of women develop infection of upper
genital tract (pelvic inflammatory disease [PID])
Signs and symptoms of PID include abdominal
tenderness, fever, nausea, and vomiting; exam
findings include adnexal tenderness and pain with
cervical movement
Complications of PID include infertility, ovarian
abscess, and perihepatitis (Fitz-Hugh-Curtis
syndrome)
Other manifestations in both men and women
include pharyngitis, conjunctivitis, and
disseminated gonococcal infection (DGI)
DGI commonly presents as an arthritis-dermatitis
syndrome
Arthritis is usually an asymmetric polyarthritis
and can progress to a septic arthritis
Dermatitis is usually confined to extremities and
consists of multiple papules and pustules, some
with evidence of hemorrhage or necrosis
Infection in pregnancy can result in spontaneous
abortion or premature labor with increased infant
mortality
M. catarrhalis
Most common manifestations are otitis media in
children and sinusitis in children and adults
Very commonly a cause of COPD exacerbations
Can cause pneumonia in elderly, particularly if there
are underlying conditions
Laboratory Tests
N. meningitidis
Blood and CSF Gram stain and culture can reveal
organisms
Direct PCR may be useful
N. gonorrhoeae
Urethral/rectal/endocervical specimens can be
tested by culture or (more commonly) nucleic acid
amplification tests (NAATs)
Direct Gram staining of specimens is most useful in
male urethritis
In DGI
Blood culture often positive, synovial culture
often negative
Skin biopsies can demonstrate bacteria with
immunohistochemistry, but are usually culture
negative
M. catarrhalis
Most often diagnosed in context of COPD
exacerbation by sputum culture
Cultures of middle ear and sinus aspirates can grow
organisms, but are rarely done
Treatment
Surgical approaches
Surgical treatment may be required for survivors of
fulminant meningococcemia (e.g., limb and digit
amputations)
Drugs
N. meningitidis: Preferred treatment is a 3rdgeneration cephalosporin
Vaccines are routinely given to young adults and
other groups deemed high risk
N. gonorrhoeae: Ceftriaxone is mainstay of treatment
II
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NEISSERIA AND MORAXELLA SPECIES INFECTIONS
M. catarrhalis: Several drugs are routinely used
(cephalosporins, tetracycline, trimethoprimsulfamethoxazole, etc.)
MICROBIOLOGY
Morphologic and Biochemical
Characteristics
Gram-negative diplococci ("coffee beans")
Oxidase positive
N. meningitidis may be encapsulated
Culture
Both N. meningitidis and N. gonorrhoeae are commonly
isolated on modified Thayer-Martin media (though
other agars may be used)
Moraxella are less fastidious
Colonies can be differentiated from Neisseria on
chocolate agar by their appearance (larger and
pinker) and the "hockey puck" sign (can be easily
pushed along agar surface)
Microbiologic Identification
N. meningitidis and N. gonorrhoeae are differentiated by
patterns of carbohydrate utilization: Meningococcus
utilizes both glucose and maltose, while gonococcus
utilizes only glucose
Memory pearl: Meningoccus (has M & G, using
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
maltose and glucose); Gonococcus (has only G, uses
only glucose)
Platforms that can identify these species and
differentiate them from each other include the NH
ID card for the Vitek 2 and the API-NH strips by
Biomerieux
N. gonorrhoeae
Infection in males may produce epididymitis, which
histologically would demonstrate suppurative
inflammation
A common cause of purulent cervicitis, though
rarely examined by biopsy
PID
Gonococcal endometritis is generally a chronic
state: Numerous plasma cells in a mixed
inflammatory cell infiltrate
Acute salpingitis is marked by edematous fallopian
tubes
Plicae may be adherent and are edematous and
inflamed
Can progress to tubo-ovarian abscess, which is
marked by purulent inflammation and adhesions
Can form cystic structures upon healing
DGI: Dermatitis-arthritis
May cause a suppurative, septic arthritis or a
"sterile" arthritis
Characteristic skin lesion is a pustule surrounded
by erythema
Histopathology demonstrates a pustular vasculitis
with intra- or subepidermal abscesses
Organisms may be revealed by Gram stain
M. catarrhalis
Specimens from acute sinusitis, otitis media,
and COPD exacerbations are rarely evaluated by
pathologists
DIFFERENTIAL DIAGNOSIS
Other Bacterial Meningitides
Differentiate by Gram stain, culture, and direct PCR
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MICROSCOPIC PATHOLOGY
Histologic Features
N. meningitidis
Sheets of neutrophils in leptomeninges; bacteria are
often observable (usually within neutrophils)
Cytologic analysis of CSF will demonstrate large
number of neutrophils
Bacteria (gram-negative diplococci) can be seen
(usually within neutrophils)
Death from meningitis is associated with cerebral
edema and impingement of midbrain
Histopathological findings of meningococcemia in
skin include microthrombi in dermal vessels and, in
some instances, necrotizing vasculitis
Other common findings: Interstitial pneumonitis
(mononuclear inflammation mainly confined to
alveolar septa), adrenal hemorrhage and necrosis,
myocarditis, and glomerular fibrin thrombi
Gram staining will often reveal clumps of gramnegative cocci
Joint findings in meningococcal arthritis are
usually those of a sterile arthritis, though it can
demonstrate either suppurative inflammation or a
mixed inflammatory cell infiltrate
Infectious and Noninfectious Arthritis
Must differentiate between gonococcus and
meningococcus and other organisms (by clinical
picture, culture, etc.) and from noninfectious arthritis
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
Finding of gram-negative diplococci on a tissue Gram
stain should prompt pathologist to consider Neisseria
species
SELECTED REFERENCES
1. Marrazzo JM et al: Neisseria gonorrhoeae (gonorrhea).
In Bennett JE et al: Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases. 8th Edition.
Philadelphia: Elsevier/Saunders. 2446-62, 2015
2. Murphy TF. Moraxella catarrhalis, Kingella, and other gramnegative cocci. In Bennett JE et al: Mandell, Douglas, and
Bennett’s Principles and Practice of Infectious Diseases. 8th
Edition. Philadelphia: Elsevier/Saunders. 2463-70, 2015
3. Lichtenberg, F: Pathology of Infectious Diseases. New York:
Raven Press, 1991
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NEISSERIA AND MORAXELLA SPECIES INFECTIONS
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p
Microscopic Features
Bacterial Infections: Bacterial Infections Requiring Culture/Ancillary Confirmation
(Left) This H&E section
of heart tissue from a
atient with fulminant
meningococcemia
demonstrates widespread
intravascular meningococcal
colony growth . Note
the absence of a cellular
reaction. (Right) Heart
tissue (Gram stain) from
a patient with fulminant
meningococcemia
demonstrates thick colonies
in the intravascular
space. (Courtesy Franz von
Lichtenberg Collection of
Infectious Disease Pathology,
BWH.)
(Left) In meningococcal
meningitis, a diffuse
olymorphonuclear infiltrate
of the leptomeninges
can be seen. In the absence
of neutrophils, petechial
hemorrhages may be seen
due to fibrin thrombi in
meningococcemia. (Right)
This image demonstrates
a neutrophil from the
cerebrospinal fluid of an
infected patient, packed
with Neisseria diplococci
. (Courtesy Franz von
Lichtenberg Collection of
Infectious Disease Pathology,
BWH.)
(Left) In meningococcemia
with DIC, fibrin
microthrombi can be
seen plugging glomerular
capillaries. These same
thrombi are responsible
for skin petechiae. (Right)
In meningococcemia with
DIC, microthrombi can
be observed plugging the
skin venules of a patient
with purpuric rash. The
microthrombi are not
restricted to skin, and they
cause damage throughout
the body. (Courtesy Franz
von Lichtenberg Collection
of Infectious Disease
Pathology, BWH.)
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