1335CHAPTER 174 Nocardiosis

condition is important, as are the administration of antibiotics and

the monitoring of patients for an adequate interval (see below).

Epidemiologic treatment of sexual partners and advice about how

to improve genital hygiene are recommended.

The recommended drug regimens for donovanosis are shown

in Table 173-1. Gentamicin can be added if the response is slow.

Ceftriaxone, chloramphenicol, and norfloxacin also are effective.

Patients treated for 14 days should be monitored until lesions have

healed completely. Those treated with azithromycin probably do

not need such rigorous follow-up.

Surgery may be indicated for very advanced lesions.

■ CONTROL AND PREVENTION

Donovanosis is probably the cause of genital ulceration that is most

readily recognizable clinically. Donovanosis is now limited to a few

specific locations, and its global eradication is a distinct possibility.

■ FURTHER READING

Muller EE, Kularatne R: The changing epidemiology of genital

ulcer disease in South Africa: Has donovanosis been eliminated? Sex

Transm Infect 96:596, 2020.

O’Farrell N: Donovanosis, in Sexually Transmitted Diseases, 4th ed.

KK Holmes et al (eds). McGraw-Hill, 2008, pp 701–708.

Rajam RV, Rangiah PN: Donovanosis (granuloma inguinale, granuloma venereum). Monogr Ser World Health Organ 24:1, 1954.

Sehgal VN, Prasad AL: Donovanosis. Current concepts. Int J Dermatol 5:8, 1986.

FIGURE 173-2 Pund cell stained by rapid Giemsa (RapiDiff) technique. Numerous

Donovan bodies are visible.

■ DIAGNOSIS

A clinical diagnosis of donovanosis made by an experienced practitioner on the basis of the lesion’s appearance usually has a high positive

predictive value. The diagnosis is confirmed by microscopic identification of Donovan bodies (Fig. 173-2) in tissue smears. Preparation

of a good-quality smear is important. If donovanosis is suspected on

clinical grounds, the smear for Donovan bodies should be taken before

swab samples are collected to be tested for other causes of genital ulceration so that enough material can be collected from the ulcer. A swab

should be rolled firmly over an ulcer previously cleaned with a dry

swab to remove debris. Smears can be examined in a clinical setting by

direct microscopy with a rapid Giemsa or Wright’s stain. Alternatively,

a piece of granulation tissue crushed and spread between two slides can

be used. Donovan bodies can be seen in large, mononuclear (Pund)

cells as gram-negative intracytoplasmic cysts filled with deeply staining

bodies that may have a safety-pin appearance. These cysts eventually

rupture and release the infective organisms. Histologic changes include

chronic inflammation with infiltration of plasma cells and neutrophils.

Epithelial changes include ulceration, microabscesses, and elongation

of rete ridges.

A diagnostic polymerase chain reaction (PCR) test was based on the

observation that two unique base changes in the phoE gene eliminate

Hae111 restriction sites, enabling differentiation of K. granulomatis

comb nov from related Klebsiella species. PCR analysis with a colorimetric detection system can now be used in routine diagnostic laboratories. A genital ulcer multiplex PCR that includes K. granulomatis

has been developed. Serologic tests are only poorly specific and are not

currently used.

The differential diagnosis of donovanosis includes primary syphilitic chancres, secondary syphilis (condylomata lata), chancroid,

lymphogranuloma venereum, genital herpes, neoplasm, and amebiasis. Mixed infections are common. Histologic appearances should

be distinguished from those of rhinoscleroma, leishmaniasis, and

histoplasmosis.

TREATMENT

Donovanosis

Many patients with donovanosis present quite late with extensive

ulceration. They may be embarrassed and have low self-esteem

related to their disease. Reassurance that they have a treatable

TABLE 173-1 Effective Antibiotics for the Treatment of Donovanosis

ANTIBIOTIC ORAL DOSE

Azithromycin 1 g on day 1, then 500 mg daily for 7 days or 1 g

weekly for 4 weeks

Trimethoprimsulfamethoxazole

960 mg bid for 14 days

Doxycycline 100 mg bid for 14 days

Erythromycin 500 mg qid for 14 days (in pregnant women)

Tetracycline 500 mg qid for 14 days

Section 7 Miscellaneous Bacterial

Infections

174

Nocardiosis can occur after infection with bacteria in the genus

Nocardia, saprophytic aerobic actinomycetes that commonly reside in

soil worldwide and contribute to the decay of organic matter. Nocardiae

are relatively inactive in standard biochemical tests, and speciation with

traditional biochemical methods is difficult. In the last 20 years, molecular phylogenetic techniques have identified more than 100 Nocardia

species, more than 50 of which are implicated in human disease.

In the past, the majority of isolates associated with pneumonia and

systemic disease were identified biochemically as Nocardia asteroides,

but the lineage of the type strain was muddled, and most human isolates in fact belong to other species. Nine species or species complexes

are commonly associated with human disease (Table 174-1). Most

systemic disease involves N. cyriacigeorgica, N. farcinica, N. pseudobrasiliensis, and species in the N. transvalensis and N. nova complexes.

Nocardiosis

Gregory A. Filice

1336 PART 5 Infectious Diseases

more commonly involved in cases from eastern Asia. However, exact

species prevalences are difficult to determine precisely since nocardial

infections are not reportable and most publications consist of case

reports or case series.

Mycetoma is an indolent, slowly progressive disease of skin and

underlying tissues with nodular swellings and draining sinuses. Actinomycetoma refers to cases of mycetoma associated with actinomycetes

as opposed to fungi or other bacterial orders, and nocardia strains

commonly associated with actinomycetoma include N. brasiliensis,

N. otitidiscaviarum, and N. transvalensis complex. Mycetoma occurs

mainly in tropical and subtropical regions. Most cases are reported

from Sudan, Mexico, and India. The most important risk factors are

lower socioeconomic status and frequent contact with soil or vegetable

matter; accordingly, many patients are laborers or women who perform

outdoor chores like gathering wood.

Pulmonary and/or systemic nocardiosis is more common among

adults than among children and more common among males than

among females. Nearly all cases are sporadic, but outbreaks have been

associated with contamination of the hospital environment, cosmetic

procedures, and parenteral illicit drug use. Person-to-person spread

is not well documented. There is no known seasonality. In regions

of the world where tuberculosis is relatively common, nocardiosis is

diagnosed in 1–5% of patients in whom pulmonary tuberculosis is suspected, and tuberculosis and nocardiosis can occur in the same patient.

The majority of cases of pulmonary or disseminated disease occur

in people with a host defense defect. Most have deficient cell-mediated

immunity, especially that associated with lymphoma, transplantation,

glucocorticoid therapy, or AIDS. In transplant recipients, nocardiosis

has been associated with high-dose prednisone, elevated calcineurin

inhibitor concentrations, and cytomegalovirus disease. The incidence is ~140-fold greater among patients with AIDS and ~340-fold

greater among bone marrow transplant recipients than in general

populations. In AIDS, nocardiosis usually affects persons with <250

CD4+ T lymphocytes/μL. Nocardiosis has also been associated with

pulmonary alveolar proteinosis, tuberculosis and other mycobacterial

diseases, chronic granulomatous disease, interleukin 12 deficiency, and

autoantibodies to granulocyte-macrophage colony-stimulating factor

(GM-CSF). Any child with nocardiosis and no known cause of immunosuppression should undergo tests to determine the adequacy of the

phagocytic respiratory burst. Cases have been associated with newer

immunomodulating drugs, especially with tumor necrosis factor and

calcineurin inhibitors. Nocardia is frequently isolated from and may

persist in respiratory secretions of patients with cystic fibrosis and may

be associated with deterioration of lung function, but this association

has not been convincingly established.

■ PATHOLOGY AND PATHOGENESIS

Pneumonia and disseminated disease are both thought to follow inhalation of fragmented bacterial mycelia. The characteristic histologic

feature of nocardiosis is an abscess with extensive neutrophil infiltration and prominent necrosis. Granulation tissue usually surrounds the

lesions, but extensive fibrosis or encapsulation is uncommon.

Actinomycetoma is characterized by suppurative inflammation with

sinus tract formation. Granules—microcolonies composed of dense

masses of bacterial filaments extending radially from a central core—

are occasionally observed in histologic preparations. The granules are

frequently found in discharges from lesions of actinomycetoma but

almost never in discharges from lesions in other forms of nocardiosis.

Nocardiae have evolved a number of properties that enable them to

survive within phagocytes, including neutralization of oxidants, prevention of phagosome–lysosome fusion, and prevention of phagosome

acidification. Neutrophils phagocytose the organisms and limit their

growth but do not kill them efficiently. Cell-mediated immunity is

important for definitive control and elimination of nocardiae. Antibodies to GM-CSF have been found in the majority of patients with

alveolar proteinosis and appear to be central to the pathogenesis of

this disease. Nocardiae stimulate the production of GM-CSF in phagocytes in vitro, and nocardial infection has been observed in several

patients with autoantibodies to GM-CSF, most of whom had not had

TABLE 174-1 Nocardia Species Most Commonly Associated with

Human Disease and Their In Vitro Susceptibility Patterns

SPECIES SUSCEPTIBLE TOa RESISTANT TOb

N. abscessus Amikacin, amoxicillin/

clavulanate, ampicillin,

ceftriaxone, gentamicin,

linezolid, minocycline,

tigecycline, tobramycin,

TMP-SMX

Ciprofloxacin,

clarithromycin

(v), imipenem (v),

moxifloxacin

N. brevicatena/

paucivorans

complex

(N. brevicatena,

N. paucivorans,

N. carnea, others)

Amikacin, ampicillin,

ceftriaxone, ciprofloxacin (v),

clarithromycin (v), gentamicin,

imipenem, linezolid,

minocycline (v), moxifloxacin,

tigecycline, tobramycin,

TMP-SMX

Amoxicillin/clavulanate

(v)

N. nova complex

(N. nova,

N. veterana,

N. africana,

N. kruczakiae,

N. elegans, others)

Amikacin, ampicillin (v),

ceftriaxone (v), clarithromycin,

gentamicin (v), imipenem,

linezolid, tigecycline (v),

TMP-SMX

Amoxicillin/clavulanate,

ciprofloxacin,

minocycline,

moxifloxacin,

tobramycin

N. transvalensis

complex

(N. blacklockiae,

N. wallacei, others)

Ceftriaxone (v), ciprofloxacin

(v), linezolid, moxifloxacin,

TMP-SMX (v)

Amikacin (v),

amoxicillin/clavulanate

(v), ampicillin,

clarithromycin,

gentamicin, imipenem,

minocycline (v),

tobramycin

N. farcinica Amikacin, amoxicillin/

clavulanate (v), linezolid,

moxifloxacin (v), TMP-SMX

Ampicillin, ceftriaxone,

ciprofloxacin (v),

clarithromycin,

gentamicin, imipenem

(v), minocycline,

tigecycline (v),

tobramycin

N. cyriacigeorgica Amikacin, ceftriaxone,

gentamicin, linezolid,

tigecycline, tobramycin,

TMP-SMX

Amoxicillin/clavulanate,

ampicillin, ciprofloxacin,

clarithromycin,

imipenem (v),

minocycline,

moxifloxacin

N. brasiliensis Amikacin, amoxicillin/

clavulanate, linezolid,

tigecycline, tobramycin,

TMP-SMX

Ampicillin, ceftriaxone

(v), ciprofloxacin,

clarithromycin,

imipenem, minocycline

(v), moxifloxacin

N.

pseudobrasiliensis

Amikacin (v), ciprofloxacin,

clarithromycin, linezolid,

tobramycin, TMP-SMX (v)

Amoxicillin/clavulanate,

ampicillin, ceftriaxone,

imipenem, minocycline

N. otitidiscaviarum

complex

Amikacin, gentamicin (v),

linezolid, tobramycin (v),

TMP-SMX

Amoxicillin/clavulanate,

ampicillin, ceftriaxone,

ciprofloxacin,

clarithromycin,

imipenem, minocycline

(v), moxifloxacin (v)

a

From 85 to 100% of isolates are susceptible unless the drug name is followed by (v),

in which case 50–84% are susceptible. b

From 0 to 15% of isolates are susceptible

unless the drug name is followed by (v), in which case 16–49% are susceptible.

Abbreviations: TMP-SMX, trimethoprim-sulfamethoxazole; v, variable.

Source: Adapted from multiple sources.

N. brasiliensis is usually associated with disease limited to the skin. N.

asteroides sensu stricto is rarely associated with human disease. However, most clinical laboratories cannot speciate isolates accurately and

may identify them simply as N. asteroides or Nocardia species.

■ EPIDEMIOLOGY

Pulmonary and/or systemic nocardiosis occurs worldwide. The annual

incidence, estimated on three continents (North America, Europe, and

Australia), is ~0.375 case per 100,000 persons and may be increasing.

There is some geographic variation in species frequencies; for example,

N. asiatica, N. beijingensis, and N. terpenica infections appear to be

1337CHAPTER 174 Nocardiosis

pulmonary alveolar proteinosis. The relationships between pulmonary

alveolar proteinosis, nocardiosis, and antibodies to GM-CSF remain

incompletely defined.

■ CLINICAL MANIFESTATIONS

Respiratory Tract Disease Pneumonia, the most common form

of nocardial disease in the respiratory tract, is typically subacute; symptoms have usually been present for days or weeks at presentation. The

onset is occasionally more acute in immunosuppressed patients. Cough

is prominent and produces small amounts of thick, purulent sputum

that is not malodorous. Fever, anorexia, weight loss, and malaise are

common; dyspnea, pleuritic pain, and hemoptysis are less common.

Remissions and exacerbations over several weeks are frequent. Roentgenographic patterns vary, but some are highly suggestive of nocardial

pneumonia. Infiltrates vary in size and are typically dense. Single or

multiple nodules are common (Figs. 174-1 and 174-2), sometimes

suggesting tumors or metastases. Infiltrates and nodules tend to cavitate (Fig. 174-2). Empyema is present in one-quarter of cases.

Nocardiosis may spread directly from the lungs to adjacent tissues.

Pericarditis, mediastinitis, and superior vena cava syndrome have all

been reported. Nocardial laryngitis, tracheitis, bronchitis, and sinusitis

are much less common than pneumonia. In the major airways, disease

often presents as a nodular or granulomatous mass. Nocardiae are

sometimes isolated from respiratory secretions of persons without

apparent nocardial disease, usually individuals who have underlying

lung or airway abnormalities.

Extrapulmonary Disease In half of all cases of pulmonary nocardiosis, disease appears outside the lungs. In one-fifth of cases of disseminated disease, lung disease is not apparent. The most common site

of dissemination is the brain. Other common sites include the skin and

supporting structures, kidneys, bones, muscles, and eyes, but almost

any organ can be involved. Peritonitis has been reported in patients

undergoing peritoneal dialysis. Nocardiae have been recovered from

blood in a few cases of pneumonia, disseminated disease, or central

venous catheter infection. Nocardial endocarditis occurs rarely and can

affect either native or prosthetic valves.

The typical manifestation of extrapulmonary dissemination is a

subacute abscess. A minority of abscesses outside the lungs or central

nervous system (CNS) form fistulas and discharge small amounts of

pus. In CNS infections, brain abscesses are usually supratentorial, are

often multiloculated, and may be single or multiple (Fig. 174-3). Cases

in the posterior fossa and spinal cord have been reported, but they are

less common. Brain abscesses tend to burrow into the ventricles or

extend out into the subarachnoid space. The symptoms and signs are

somewhat more indolent than those of other types of bacterial brain

abscess. Meningitis is uncommon and is usually due to spread from

a nearby brain abscess. Nocardiae are not easily recovered from cerebrospinal fluid (CSF).

Disease following Transcutaneous Inoculation Disease that

follows transcutaneous nocardial inoculation usually takes one of three

forms: cellulitis, lymphocutaneous syndrome, or actinomycetoma.

Cellulitis generally begins 1–3 weeks after a recognized breach of

the skin, often with soil contamination. Subacute cellulitis, with pain,

swelling, erythema, and warmth, develops over days to weeks. The

lesions are usually firm and not fluctuant. Disease may progress to

involve underlying muscles, tendons, bones, or joints. Dissemination is

FIGURE 174-1 Nocardial pneumonia. A dense infiltrate with a possible cavity and

several nodules are apparent in the right lung.

FIGURE 174-2 Nocardial pneumonia. A computed tomography scan shows bilateral

nodules, with cavitation in the nodule in the left lung. FIGURE 174-3 Nocardial abscesses in the right occipital lobe.

1338 PART 5 Infectious Diseases

rare. N. brasiliensis and species in the N. otitidiscaviarum complex are

most common in cellulitis cases.

Lymphocutaneous disease usually begins as a pyodermatous nodule at the site of inoculation, with central ulceration and purulent or

honey-colored drainage. Subcutaneous nodules often appear along

lymphatics that drain the primary lesion. Most cases of nocardial

lymphocutaneous syndrome are associated with N. brasiliensis. Similar

disease occurs with other pathogens, most notably Sporothrix schenckii

(Chap. 219) and Mycobacterium marinum (Chap. 180).

Actinomycetoma usually begins with a nodular swelling, sometimes

at a site of local trauma. Lesions (Fig. 174-4A) typically develop on the

feet or hands but may involve the posterior part of the neck, the upper

back, the head, and other sites. The nodule eventually breaks down,

and a fistula appears, typically followed by others. The fistulas tend to

come and go, with new ones forming as old ones disappear. The discharge is serous or purulent, may be bloody, and often contains 0.1- to

2-mm white granules consisting of masses of mycelia (Figs. 174-4C

and 174-4D). The lesions spread slowly along fascial planes to involve

adjacent areas of skin, subcutaneous tissue, and bone. Over months or

years, there may be extensive deformation of the affected part. Lesions

involving soft tissues are only mildly painful; those affecting bones

or joints are more so (Fig. 174-4B). Systemic symptoms are absent

or minimal, but mycetoma cases are often associated with prolonged,

severe disability. Infection rarely disseminates from actinomycetoma,

but lesions on the head, neck, and trunk can invade locally to involve

deep organs.

Eye Infections Nocardia species are uncommon causes of subacute

keratitis, usually following eye trauma. Nocardial endophthalmitis can

develop after eye surgery. In one series, nocardiae accounted for more

than half of culture-proved cases of endophthalmitis after cataract

surgery. Endophthalmitis can also occur during disseminated disease.

Nocardial infection of lachrymal glands has been reported.

■ DIAGNOSIS

The first step in diagnosis is examination of sputum or pus for crooked,

branching, beaded, gram-positive filaments 1 μm wide and up to

50 μm long (Fig. 174-5). Most nocardiae are acid-fast in direct smears

if a weak acid is used for decolorization (e.g., in the modified Kinyoun,

Ziehl-Neelsen, and Fite-Faraco methods). The organisms often take

up silver stains. Recovery from specimens containing a mixed flora

can be improved with selective media (colistin–nalidixic acid agar,

modified Thayer-Martin agar, or buffered charcoal–yeast extract agar).

A B

C D

FIGURE 174-4 Nocardia brasiliensis mycetoma. A. Draining sinuses and giant white grains with a seropurulent discharge. B. Radiography of the foot showing marked soft

tissue enlargement and bony lytic lesions. C. Direct microscopy of grains stained with Lugol’s iodine (×40). D. Periodic acid–Schiff stain of skin biopsy (×40). (Images provided

by Roberto Arenas and Mahreen Ameen, St. John’s Institute of Dermatology, Guy’s & St Thomas’ NHS Trust, London, UK. Reprinted from R Arenas, M Ameen: Lancet Infect

Dis 10:66, 2010, with permission from Elsevier.)

FIGURE 174-5 Gram-stained sputum from a patient with nocardial pneumonia.

(Image provided by Charles Cartwright and Susan Nelson, Hennepin County

Medical Center, Minneapolis, MN.)

1339CHAPTER 174 Nocardiosis

TABLE 174-2 Treatment Duration for Nocardiosis

DISEASE DURATION

Pulmonary or systemic

Intact host defenses 6–12 months

Deficient host defenses 12 monthsa

CNS disease 12 monthsb

Cellulitis, lymphocutaneous

syndrome

2 months

Osteomyelitis, arthritis, laryngitis,

sinusitis

4 months

Actinomycetoma 6–12 months after clinical cure

Keratitis Topical: until apparent cure

Systemic: until 2–4 months after apparent

cure

a

In some patients with AIDS and CD4+ T lymphocyte counts of <200/μL or with

chronic granulomatous disease, therapy for pulmonary or systemic disease must

be continued indefinitely. b

If all apparent central nervous system (CNS) disease has

been excised, the duration of therapy may be reduced to 6 months.

Nocardiae grow well on most fungal and mycobacterial media, but

procedures used for decontamination of specimens for mycobacterial

culture can kill nocardiae and should not be used when nocardiae are

suspected.

Nocardiae grow relatively slowly; colonies may take up to 2 weeks

to appear and may not develop their characteristic appearance—white,

yellow, or orange, with aerial mycelia and delicate, dichotomously

branched substrate mycelia—for up to 4 weeks. Several blood culture

systems support nocardial growth, although nocardiae may not be

detected for up to 2 weeks. The growth of nocardiae is so different from

that of more common pathogens that the laboratory should be alerted

when nocardiosis is suspected in order to maximize the likelihood of

isolation.

In nocardial pneumonia, sputum smears are often negative. Unless

the diagnosis can be made in smear-negative cases by sampling lesions

in more accessible sites, bronchoscopy or lung aspiration is usually

necessary. To evaluate the possibility of dissemination in patients

with nocardial pneumonia, a careful history should be obtained and

a thorough physical examination performed. Suggestive symptoms or

signs should be pursued with further diagnostic tests. MRI or CT with

contrast of the brain should be done when feasible in cases of pulmonary or disseminated disease. When clinically indicated, CSF or urine

should be concentrated and then cultured. Actinomycetoma, eumycetoma (cases involving fungi; Chap. 219), and botryomycosis (cases

involving cocci or bacilli, often Staphylococcus aureus) are difficult to

distinguish clinically but are readily distinguished with microbiologic

testing or biopsy. Granules should be sought in any discharge. Suspect

particles should be washed in saline, examined microscopically, and

cultured. Granules in actinomycetoma cases are usually white, pale yellow, pink, or red. Viewed microscopically, they consist of tight masses

of fine filaments (0.5–1 μm wide) radiating outward from a central

core (Fig. 174-5). Granules from eumycetoma cases are white, yellow,

brown, black, or green; under the microscope, they appear as masses

of broader filaments (2–5 μm wide) encased in a matrix. Granules of

botryomycosis consist of loose masses of cocci or bacilli. Organisms

can also be seen in wound discharge or histologic specimens. The most

reliable way to differentiate among the various organisms associated

with mycetoma is by culture.

Isolation of nocardiae from sputum or blood occasionally represents

colonization, transient infection, or contamination. In typical cases of

respiratory tract colonization, Gram-stained specimens are negative

and cultures are only intermittently positive. A positive sputum culture in an immunosuppressed patient usually reflects disease. When

nocardiae are isolated from sputum of an immunocompetent patient

without apparent nocardial disease, the patient should be observed

carefully without treatment. A patient with a host-defense defect that

increases the risk of nocardiosis should usually receive antimicrobial

treatment.

Nocardia DNA has been detected in respiratory tract samples

from patients with proven or suspected pulmonary nocardiosis, other

chronic lung diseases, and healthy controls. The sensitivity and specificity of DNA testing has not been well defined.

Species are definitively determined by molecular techniques. Matrixassisted laser desorption/ionization/time-of-flight (MALDI-TOF)

mass spectrometry is accurate in 75% or more cases when compared

with genetic testing. MALDI-TOF is much more practical for clinical

laboratories and is becoming common in laboratories in high-resource

countries.

Because nocardiosis is uncommon, data on the relation between susceptibility test results for specific drugs and clinical outcomes in patients

treated with these drugs are meager. Careful clinical monitoring is

essential, and consultation with clinicians who have experience with

nocardiosis is often needed. Susceptibility to antimicrobial agents in

vitro is best determined with a Clinical Laboratory Standards Institute

(CLSI)–approved broth dilution test. Susceptibility testing with E-test

or BACTEC radiometric methods is less definitive. Nocardial growth

is slower than the growth of most clinically important bacteria, and

nocardiae tend to clump in suspension so that susceptibility-test end

points are difficult to read; thus experience is necessary for reliable

reading of results. If an isolate can be accurately speciated, its susceptibility to antimicrobial drugs can be predicted with reasonable accuracy.

Speciation by molecular methods or MALDI-TOF is not practical

in many resource-poor countries. As a result, therapy for nocardiosis is

often initiated without definitive speciation or knowledge of susceptibility results. For mild or moderate cases, therapy with drugs known to

be effective against most isolates is usually adequate. For severe cases

or cases that do not respond promptly to antimicrobial therapy, isolates

should be sent to a laboratory experienced with Nocardia for identification and susceptibility testing whenever possible.

TREATMENT

Nocardiosis

Trimethoprim-sulfamethoxazole (TMZ-SMX) is the drug of choice

for most cases (Tables 174-1 and 174-2). Reported rates of TMPSMX susceptibility have varied widely, and controversy has ensued

about the reliability of sulfonamides for therapy. However, clinical

responses to appropriate sulfonamide treatment around the world

are usually satisfactory. At the outset, 10–20 mg/kg of TMP and

50–100 mg/kg of SMX are given each day in two divided doses.

Later, daily doses can be decreased to as little as 5 mg/kg and

25 mg/kg, respectively. In persons with sulfonamide allergies,

desensitization usually allows continuation of therapy with these

effective and inexpensive drugs.

Clinical experience with other oral drugs is limited. Minocycline

(100–200 mg twice a day) is often effective; other tetracyclines are

usually less effective. Linezolid is the most consistently active antimicrobial agent, but adverse effects become common and limiting

in many patients after 2–3 weeks. Amoxicillin (875 mg) combined

with clavulanate (125 mg), given twice a day, has been effective in

N. brasiliensis cases and some N. farcinica cases. Among the quinolones, moxifloxacin and gemifloxacin appear to be most active.

Amikacin, the best-established parenteral drug except in

cases involving the N. transvalensis complex, is given in doses of

5–7.5 mg/kg every 12 h or 15 mg/kg every 24 h. Serum drug levels

should be monitored during prolonged therapy in patients with

diminished renal function and in the elderly. Ceftriaxone and

imipenem are usually effective except as indicated in Table 174-1.

Tigecycline appears to be active in vitro against some species, but

little clinical experience has been reported.

Patients with severe disease are initially treated with a combination including TMP-SMX, amikacin, and ceftriaxone or imipenem.

Clinical improvement is usually noticeable after 1–2 weeks of therapy but may take longer, especially with CNS disease. After definite

1340 PART 5 Infectious Diseases

Actinomycosis is uncommon, and most physicians’ personal experience with its clinical presentations is limited. Laboratory identification

of the etiologic agents from the order Actinomycetales is not routine.

Thus, actinomycosis remains a diagnostic challenge, even for a skilled

clinician. However, this infection is usually curable with medical

therapy alone. Therefore, an awareness of the full spectrum of clinical

syndromes can expedite diagnosis and treatment and minimize unnecessary surgical interventions, morbidity, and mortality.

Classical actinomycosis is an indolent, slowly progressive infection

caused by anaerobic or microaerophilic bacteria, primarily of the genus

Actinomyces, that colonize the mouth, colon, and vagina. Mucosal disruption may lead to infection at virtually any site in the body. In vivo

growth of actinomycetes usually results in the formation of characteristic clumps called grains or sulfur granules. The clinical presentations of

actinomycosis are myriad. Common in the preantibiotic era, actinomycosis has diminished in incidence, as has its timely recognition. Actinomycosis has been called the most misdiagnosed disease, and it has been

said that no disease is so often missed by experienced diagnosticians.

Three “classic” clinical presentations that should prompt consideration of this unique infection are (1) the combination of chronicity,

progression across tissue boundaries, and mass-like features (mimicking malignancy, with which it is often confused); (2) the development

of a sinus tract, which may spontaneously resolve and recur; and (3) a

refractory or relapsing infection after a short course of therapy, since

cure of established actinomycosis requires prolonged treatment.

■ ETIOLOGIC AGENTS

Actinomycosis is most commonly caused by A. israelii, A. naeslundii,

A. odontolyticus, A. viscosus, A. meyeri, A. graevenitzii, and A. gerencseriae.

Infections due to A. neuii have been increasingly recognized. Most

if not all actinomycotic infections are polymicrobial. Aggregatibacter (Actinobacillus) actinomycetemcomitans, Eikenella corrodens,

Enterobacteriaceae, and species of Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, and Streptococcus are commonly isolated

with actinomycetes in various combinations, depending on the site of

infection. Their contribution to the pathogenesis of actinomycosis is

uncertain.

Comparative 16S rRNA gene sequencing has led to the identification of an ever-expanding list of Actinomyces species and a reclassification of some species to other genera. At present, 53 species and

2 subspecies have been recognized (https://www.bacterio.net/genus/

actinomyces), with at least 25 species implicated as causes of human

disease. A. europaeus, A. neuii, A. radingae, A. turicensis, A. cardiffensis, A. urogenitalis, A. hongkongensis, A. georgiae, A. massiliensis, A.

timonensis, and A. funkei as well as two former Actinomyces species—

Trueperella (Arcanobacterium) pyogenes and Trueperella (Arcanobacterium) bernardiae—and Propionibacterium propionicum are additional

causes of human actinomycosis, albeit not always with a “classic”

presentation.

■ EPIDEMIOLOGY

Actinomycosis has no geographic boundaries and occurs throughout

life, with a peak incidence in the middle decades. Males have a threefold higher incidence than females, possibly because of poorer dental

hygiene and/or more frequent trauma. Improved dental hygiene and the

initiation of antimicrobial treatment before actinomycosis fully develops

have probably contributed to a decrease in incidence since the advent of

antibiotics. Individuals who do not seek or have access to health care,

those who have an intrauterine contraceptive device (IUCD) in place for

a prolonged period (see “Pelvic Disease,” below), and those who receive

bisphosphonate treatment (see “Oral–Cervicofacial Disease,” below) are

probably at higher risk.

175 Actinomycosis

Thomas A. Russo

clinical improvement, therapy can be continued with a single oral

drug, usually TMP-SMX. Some experts use two or more drugs for

the entire course of therapy, but whether multiple drugs are better

than a single agent is not known, and additional drugs increase the

risk of toxicity. In patients with nocardiosis who need immunosuppressive therapy for an underlying disease or prevention of transplant rejection, immunosuppressive therapy should be continued.

Use of SMX and TMP in high-risk populations to prevent Pneumocystis disease or urinary tract infections appears to reduce but

not eliminate the risk of nocardiosis. The incidence of nocardiosis

is low enough that prophylaxis solely to prevent this disease is not

recommended.

Surgical management of nocardial disease is similar to that

of other bacterial diseases. Brain abscesses should be aspirated,

drained, or excised if the diagnosis is unclear, if an abscess is large

and accessible, or if an abscess fails to respond to chemotherapy.

Small or inaccessible brain abscesses should be treated medically; clinical improvement should be noticeable within 1–2 weeks.

Brain imaging should be repeated to document the resolution of

lesions, although abatement on images often lags behind clinical

improvement.

Antimicrobial therapy usually suffices for nocardial actinomycetoma. In deep or extensive cases, drainage or excision of heavily

involved tissue may facilitate healing, but structure and function

should be preserved whenever possible. Keratitis is treated with a

topical sulfonamide or amikacin drops plus a sulfonamide or an

alternative drug given by mouth.

Nocardial infections tend to relapse (particularly in patients with

chronic granulomatous disease), and long courses of antimicrobial

therapy are necessary (Table 174-2). If disease is unusually extensive or if the response to therapy is slow, the recommendations in

Table 174-2 should be exceeded.

With appropriate treatment, the mortality rate for pulmonary

or disseminated nocardiosis outside the CNS should be <5%. CNS

disease carries a higher mortality rate. Patients should be followed

carefully for at least 6 months after therapy has ended. Actinomycetoma often responds better to therapy than mycetoma associated

with fungi, but relapses occur in a minority of patients, and disability often persists.

■ FURTHER READING

Abbas M et al: The disabling consequences of mycetoma. PLoS Negl

Trop Dis 12:e0007019, 2018.

Body B et al: Evaluation of the Vitek MS v3.0 Matrix-Assisted Laser

Desorption Ionization–Time of Flight Mass Spectrometry System

for identification of mycobacterium and nocardia. J Clin Microbiol

56:e00237, 2018.

Coussement J et al: Nocardia infection in solid organ transplant

recipients: A multicenter European case-control study. Clin Infect

Dis 63:338, 2016.

Haussaire D et al: Nocardiosis in the south of France over a 10-years

period, 2004–2014. Int J Infect Dis 57:13, 2017.

Huang L et al: Clinical features, identification, antimicrobial resistance

patterns of Nocardia species in China: 2009–2017. Diagn Microbiol

Infect Dis 94:165, 2019.

Mei-Zahav M et al: The spectrum of nocardia lung disease in cystic

fibrosis. Pediatr Infect Dis J 34:909, 2015.

Paige EK, Spelman D: Nocardiosis: 7-year experience at an Australian

tertiary hospital. Intern Med J 49:373, 2019.

Rosen LB et al: Nocardia-induced granulocyte macrophage colonystimulating factor is neutralized by autoantibodies in disseminated/

extrapulmonary nocardiosis. Clin Infect Dis 60:1017, 2015.

Schlaberg R et al: Susceptibility profiles of nocardia isolates based

on current taxonomy. Antimicrob Agents Chemother 58:795,

2014.

Viscuse PV, Mohabbat AB: 69-year-old woman with fatigue, dyspnea, and lower extremity pain. Mayo Clin Proc. 94:149, 2019.

1341CHAPTER 175 Actinomycosis

■ PATHOGENESIS AND PATHOLOGY

The etiologic agents of actinomycosis are members of the normal oral

flora and are often cultured from the bronchi, the gastrointestinal

tract, and the female genital tract. The critical step in the development

of actinomycosis is disruption of the mucosal barrier. Local infection

may ensue. Once established, actinomycosis spreads contiguously in

a slow, progressive manner, ignoring tissue planes. Although acute

inflammation may initially develop at the infection site, the hallmark

of actinomycosis is the characteristic chronic, indolent phase manifested by lesions that usually appear as single or multiple indurations.

Central necrosis consisting of neutrophils and sulfur granules develops

and is virtually diagnostic. The fibrotic walls of the mass are typically

described as “wooden.” The responsible bacterial and/or host factors

have not been identified. Over time, sinus tracts to the skin, adjacent

organs, or bone may develop. In rare instances, distant hematogenous

seeding may occur; lymphatic spread and associated lymphadenopathy

are uncommon. As mentioned above, these unique features of actinomycosis mimic malignancy, with which it is often confused.

Foreign bodies appear to facilitate infection. This association most

frequently involves IUCDs. Reports have described an association of

actinomycosis with HIV infection; transplantation; common variable

immunodeficiency; chronic granulomatous disease; treatment with

anti–tumor necrosis factor α agents, glucocorticoids, or bisphosphonates; and radio- or chemotherapy. Ulcerative mucosal infections

(e.g., by herpes simplex virus or cytomegalovirus) may facilitate disease

development.

■ CLINICAL MANIFESTATIONS

Oral–Cervicofacial Disease Actinomycosis occurs most frequently at an oral, cervical, or facial site, usually as a soft tissue swelling,

abscess, mass, or ulcerative lesion that is often mistaken for a neoplasm.

Dental diseases or procedures are common precipitating factors. The

angle of the jaw is generally involved, but a diagnosis of actinomycosis

should be considered with any mass lesion or relapsing infection in the

head and neck. Radiation therapy and especially bisphosphonate treatment have been recognized as contributing to an increasing incidence

of actinomycotic infection of the mandible and maxilla (Fig. 175-1).

Canaliculitis (commonly due to P. propionicum), otitis, sinusitis, and

laryngeal disease also can develop. Pain, fever, and leukocytosis are

variably reported. Contiguous extension to the cranium, cervical spine,

or thorax is a potential sequela.

Thoracic Disease Thoracic actinomycosis, which may be facilitated by aspirated foreign material, usually follows an indolent

FIGURE 175-1 Bisphosphonate-associated maxillary osteomyelitis due to

Actinomyces viscosus. A sulfur granule is seen within the bone. (Reprinted with

permission from NH Naik, TA Russo: Bisphosphonate related osteonecrosis of the

jaw: The role of Actinomyces. Clin Infect Dis 49:1729, 2009. © 2009 Oxford University

Press.)

FIGURE 175-2 Thoracic actinomycosis. A. A chest wall mass from extension of

pulmonary infection. B. Pulmonary infection is complicated by empyema (open

arrow) and extension to the chest wall (closed arrow). (Courtesy of Dr. C. B. Hsiao,

Division of Infectious Diseases, Department of Medicine, State University of New

York at Buffalo.)

A

B

progressive course, with involvement of the pulmonary parenchyma

and/or the pleural space. Chest pain, fever, and weight loss are common. A cough, when present, is variably productive. The usual radiographic finding is either a mass lesion or pneumonia. On CT, central

areas of low attenuation and ring-like rim enhancement may be seen;

cavitary disease may develop. More than 50% of cases include pleural

thickening, effusion, or empyema (Fig. 175-2). Rarely, pulmonary

nodules or endobronchial lesions occur. Lesions suggestive of actinomycosis include those that cross fissures or pleura; extend into the

mediastinum, contiguous bone, or chest wall (empyema necessitatis); or

are associated with a sinus tract. In the absence of these findings, thoracic actinomycosis is usually mistaken for a neoplasm or pneumonia

due to more usual causes.

Mediastinal infection is uncommon, usually arising from thoracic

extension but rarely from perforation of the esophagus, trauma, or

extension of head and neck or abdominal disease. The structures

within the mediastinum and the heart can be involved in various

combinations; consequently, the possible presentations are diverse. Primary endocarditis (in which A. neuii has been increasingly described),

esophageal infection, and isolated disease of the breast occur.

Abdominal Disease Abdominal actinomycosis poses a great

diagnostic challenge. Months or years usually pass from the inciting

event (e.g., appendicitis, diverticulitis, peptic ulcer disease, spillage of

gallstones or bile during cholecystectomy, foreign-body perforation,

bowel surgery, or ascension from IUCD-associated pelvic disease)

to clinical recognition. Because of the flow of peritoneal fluid and/

or the direct extension of primary disease, virtually any abdominal

1342 PART 5 Infectious Diseases

organ, region, or space can be involved. The disease usually presents

as an abscess, a mass, or a mixed lesion that is often fixed to underlying tissue and mistaken for a tumor. On CT, enhancement is most

often heterogeneous and adjacent bowel is thickened. Sinus tracts to

the abdominal wall, to the perianal region, or between the bowel and

other organs may develop and mimic inflammatory bowel disease

(Chap. 326). Recurrent disease or a wound or fistula that fails to heal

suggests actinomycosis.

Hepatic infection usually presents as one or more abscesses or

masses (Fig. 175-3). Isolated disease presumably develops via hematogenous seeding from cryptic foci. Imaging and percutaneous techniques have resulted in improved diagnosis and treatment.

All levels of the urogenital tract can be infected. Renal disease usually

presents as pyelonephritis and/or renal and perinephric abscess. Bladder involvement, usually due to extension of pelvic disease, may result

in ureteral obstruction or fistulas to bowel, skin, or uterus. Actinomyces

can be detected in urine with appropriate stains and cultures.

Pelvic Disease Actinomycotic involvement of the pelvis occurs

most commonly in association with an IUCD but can also be associated with other foreign bodies, such as surgical mesh. When an IUCD

is in place or has been used but removed, pelvic symptoms should

prompt consideration of actinomycosis. The risk, although not quantified, appears small. The disease rarely develops when the IUCD has

been in place for <1 year, but the risk increases with time. Symptoms

are typically indolent; fever, weight loss, abdominal pain, and abnormal vaginal bleeding or discharge are the most common. The earliest

stage of disease—often endometritis—commonly progresses to pelvic

masses or a tuboovarian abscess (Fig. 175-4). Unfortunately, because

the diagnosis is often delayed, a “frozen pelvis” mimicking malignancy

or endometriosis can develop by the time of recognition, which may

lead to unnecessary surgery. Cancer antigen 125 levels may be elevated,

further contributing to misdiagnosis. In contrast to malignancy and

tuberculosis, pelvic actinomycosis only uncommonly includes ascites

and lymphadenopathy. An endometrial biopsy may enable diagnosis

in a minimally invasive fashion.

Actinomyces-like organisms (ALOs), which are identified in Papanicolaou-stained specimens in (on average) 7% of women using an

IUCD, have a low positive predictive value for diagnosis. The detection

of ALOs in an asymptomatic patient warrants education and close

follow-up but not removal of the IUCD unless a suitable contraceptive

alternative is agreed on. In the presence of symptoms that cannot be

accounted for, it seems prudent to remove the IUCD and—if advanced

disease is excluded—to initiate a 14-day course of empirical treatment

for possible early endometritis.

Central Nervous System Disease Actinomycosis of the central

nervous system (CNS) is rare. Single or multiple brain abscesses are

FIGURE 175-3 Hepatic–splenic actinomycosis. A. Computed tomogram showing multiple hepatic abscesses and a small splenic lesion due to Actinomyces israelii. Arrow

indicates extension outside the liver. Inset: Gram’s stain of abscess fluid demonstrating beaded filamentous gram-positive rods. B. Subsequent formation of a sinus tract.

(Reprinted with permission from Saad M: Actinomyces hepatic abscess with cutaneous fistula. N Engl J Med 353:e16, 2005. © 2005 Massachusetts Medical Society. All

rights reserved.)

FIGURE 175-4 Computed tomogram showing pelvic actinomycosis associated with

an intrauterine contraceptive device. The device is encased by endometrial fibrosis

(solid arrow); also visible are paraendometrial fibrosis (open triangular arrowhead)

and an area of suppuration (open arrow).

most common. Individuals with hereditary hemorrhagic telangiectasia

are at increased risk for brain abscess with Actinomyces as the potential

etiologic agent. An abscess usually appears on CT as a ring-enhancing

lesion with a thick wall that may be irregular or nodular. Magnetic resonance perfusion and spectroscopy findings have also been described,

as have primary meningitis, epidural or subdural space infection, and

cavernous sinus syndrome.

Musculoskeletal and Soft Tissue Infection Actinomycotic

infection of bones and joints is usually due to adjacent soft tissue infection but may be associated with trauma, injections, surgery (e.g., prostheses), osteoradionecrosis and bisphosphonate osteonecrosis (limited

to mandibular and maxillary bones), or hematogenous spread. Because

of slow disease progression, new bone formation and bone destruction

can be seen concomitantly. Infection of soft tissue is uncommon and

is usually a result of trauma. Actinomycetoma is a slowly progressive

infection of the skin and subcutaneous tissue that is usually seen in

warm climates. Despite the name being suggestive of Actinomyces as a

causative agent, it is most commonly caused by Nocardia or Actinomadura species (Chap. 174).

Disseminated Disease Hematogenous dissemination of disease from any location rarely results in multiple-organ involvement.

1343CHAPTER 175 Actinomycosis

A. meyeri is most commonly involved. The lungs and liver are most

often affected, with the presentation of multiple nodules mimicking

disseminated malignancy. The clinical presentation may be surprisingly indolent given the extent of disease.

■ DIAGNOSIS

The diagnosis of actinomycosis is rarely considered. All too often,

actinomycosis is first mentioned by the pathologist after extensive

surgery. Since medical therapy alone is frequently sufficient for cure,

the challenge for the clinician is to consider the possibility of actinomycosis, to diagnose it in the least invasive fashion, and to avoid

unnecessary surgery. The clinical and radiographic presentations that

suggest actinomycosis are discussed above. Of note, hypermetabolism

has been demonstrated by 18F-fluorodeoxyglucose positron emission

tomography (FDG-PET) in actinomycotic disease. Aspirations and

biopsies (with or without CT or ultrasound guidance) are being used

successfully to obtain clinical material for diagnosis, although surgery

may be required. The microscopic identification of sulfur granules

(an in vivo matrix of bacteria, calcium phosphate, and host material)

in pus or tissues, which increases with the examination of additional

histopathologic sections and the use of positively charged slides to optimize adhesion, is the most common means of diagnosis. Occasionally,

these granules are identified grossly from draining sinus tracts or pus.

Although sulfur granules are a defining characteristic of actinomycosis,

granules also are found in mycetoma (Chaps. 174 and 219) and botryomycosis (a chronic suppurative bacterial infection of soft tissue or, in

rare cases, visceral tissue that produces clumps of bacteria resembling

granules). These entities can easily be differentiated from actinomycosis with appropriate histopathologic and microbiologic studies.

Microbiologic identification of actinomycetes is often precluded by

prior antimicrobial therapy or failure to perform appropriate microbiologic cultures. For optimal yield, the avoidance of even a single dose of

antibiotics is mandatory. Although some species can grow aerobically,

isolation is maximized under anaerobic conditions, usually requiring

5–7 days but potentially up to 2–4 weeks. The use of 16S rRNA gene

amplification and sequencing by clinical microbiology laboratories

is increasing and is enhancing diagnostic sensitivity and specificity.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) holds similar promise, but databases are

still being optimized. Because actinomycetes are components of the

normal oral and genital-tract flora, their identification in the absence

of sulfur granules in sputum, bronchial washings, and cervicovaginal

secretions is of little significance.

TREATMENT

Actinomycosis

Decisions about treatment are based on the collective clinical

experience of the past 70 years. Actinomycosis requires prolonged treatment with high doses of antimicrobial agents; suitable

antimicrobial agents and those deemed unreliable are listed in

Table 175-1. The need for intensive treatment is presumably due

to the drugs’ poor penetration of the thick-walled masses common

in this infection and/or the sulfur granules themselves, which may

represent a biofilm. Although therapy must be individualized, the

IV administration of 18–24 million units of penicillin daily for

2–6 weeks, followed by oral therapy with penicillin or amoxicillin

(total duration, 6–12 months), is a reasonable guideline for serious

infections and bulky disease. For penicillin-allergic patients, tetracyclines, ceftriaxone, or carbapenems are reasonable alternatives. Less

extensive disease, particularly that involving the oral–cervicofacial

region or the isolation of Actinomyces in the absence of tissue

changes associated with actinomycosis, may be cured with a shorter

course. For home IV therapy, the ease of once-a-day dosing makes

ceftriaxone appealing in certain circumstances; however, a greater

body of literature supporting its efficacy would be desirable. The

availability of portable infusion pumps for home therapy allows

for both the appropriate dosing and practical administration of IV

penicillin. For infections in critical sites (e.g., CNS), this approach

remains the safest until more information is available on other

agents. The pharmacokinetic properties, availability of oral and

parenteral formulations, and potential efficacy of azithromycin also

make this agent appealing. Unfortunately, few in vitro and no clinical data exist on its use to treat actinomycosis. If therapy is extended

beyond the resolution of measurable disease, the risk of relapse—a

clinical hallmark of this infection—will be minimized; CT and

MRI are generally the most sensitive and objective techniques by

which to accomplish this goal. A similar approach is reasonable

for immunocompromised patients, although refractory disease has

been described in HIV-infected individuals. While the role played

by “companion” microbes in actinomycosis is unclear, many isolates

are pathogens in their own right, and a regimen covering these

organisms during the initial treatment course is reasonable. Isolation of Actinomyces from blood cultures in the absence of defined

infection may represent contamination or transient bacteremia

from a mucosal site of colonization, in which case treatment may

not be necessary.

Combined medical–surgical therapy is still advocated in some

reports. However, an increasing body of literature now supports an

initial attempt at cure with medical therapy alone, even in extensive

disease. CT and MRI should be used to monitor the response to

therapy. In most cases, either surgery can be avoided or a less extensive procedure can be used. This approach is particularly valuable

in sparing critical organs, such as the bladder or the reproductive

organs in women of childbearing age. For a well-defined abscess,

percutaneous drainage in combination with medical therapy is a

reasonable approach. When a critical location is involved (e.g., the

epidural space, the CNS), when there is significant hemoptysis, or

TABLE 175-1 Appropriate and Inappropriate Antibiotic Therapy for

Actinomycosisa

CATEGORY AGENT

Extensive successful

clinical experienceb

Penicillin: 3–4 million units IV q4hc,d

Amoxicillin: 500 mg PO q6h

Erythromycin: 500–1000 mg IV q6h or 500 mg PO q6hc

Tetracycline: 500 mg PO q6h

Doxycycline: 100 mg IV or PO q12h

Minocycline: 100 mg IV or PO q12h

Clindamycin: 900 mg IV q8h or 300–450 mg PO q6hc

Anecdotal successful

clinical experience

Ceftriaxoned

Ceftizoxime

Imipenem-cilastatin

Piperacillin-tazobactam

Agents predicted to be

efficacious on the basis

of in vitro activity

Vancomycin

Linezolid

Quinupristin-dalfopristin

Rifampin

Ertapenemd

Tigecyclined

Azithromycind

Agents that should be

avoided

Metronidazole

Aminoglycosides

Oxacillin, dicloxacillin

Cephalexin

Fluoroquinolones

a

Additional coverage for concomitant “companion” bacteria may be required.

b

Controlled evaluations have not been performed. Dose and duration require

individualization depending on the host, site, and extent of infection. As a general

rule, a maximal parenteral antimicrobial dose for 2–6 weeks followed by oral

therapy, for a total duration of 6–12 months, is required for serious infections and

bulky disease, whereas a shorter course may suffice for less extensive disease,

particularly in the oral–cervicofacial region. Monitoring the impact of therapy with

CT or MRI is advisable when appropriate. c

Recent in vitro data have demonstrated

resistance in up to 33% of isolates. d

This agent can be considered for at-home

parenteral therapy; penicillin requires a continuous infusion pump.

1344 PART 5 Infectious Diseases

when suitable medical therapy fails, surgical intervention may be

appropriate. In the absence of optimal data, the combination of a

prolonged course of antimicrobial therapy and resection—at least

of necrotic bone for bisphosphonate-related osteonecrosis of the

jaw (BRONJ)—is a reasonable approach.

■ FURTHER READING

Barberis C et al: Antimicrobial susceptibility of clinical isolates of

Actinomyces and related genera reveals an unusual clindamycin

resistance among Actinomyces urogenitalis strains. J Glob Antimicrob

Resist 8:115, 2017.

Bonnefond S et al: Clinical features of actinomycosis: A retrospective,

multicenter study of 28 cases of miscellaneous presentations. Medicine 95:e3923, 2016.

Fong P et al: Identification and diversity of Actinomyces species in a

clinical microbiology laboratory in the MALDI-TOF MS era. Anaerobe 54:151, 2018.

Heo SH et al: Imaging of actinomycosis in various organs: A comprehensive review. Radiographics 34:19, 2014.

Jeffery-Smith A et al: Is the presence of Actinomyces spp. in blood

culture always significant? J Clin Microbiol 54:1137, 2016.

Karanfilian KM et al: Cervicofacial actinomycosis. Int J Dermatol

59:1185, 2020.

Kononen E, Wade WG: Actinomyces and related organisms in human

infections. Clin Microbiol Rev 28:419, 2015.

Lo Muzio L et al: The contribution of histopathological examination

to the diagnosis of cervico-facial actinomycosis: A retrospective analysis of 68 cases. Eur J Clin Microbiol Infect Dis 33:1915, 2014.

Lynch T et al: Species-level identification of Actinomyces isolates

causing invasive infections: Multiyear comparison of Vitek MS

(matrix-assisted laser desorption ionization-time of flight mass

spectrometry) to partial sequencing of the 16S rRNA gene. J Clin

Microbiol 54:712, 2016.

Qiu L et al: Pulmonary actinomycosis imitating lung cancer on (18)

F-FDG PET/CT: A case report and literature review. Korean J Radiol

16:1262, 2015.

Yang WT, Grant M: Actinomyces neuii: A case report of a rare cause

of acute infective endocarditis and literature review. BMC Infect Dis

19:511, 2019.

Whipple’s disease (WD), described by George Whipple in 1907, is a

chronic infection caused by Tropheryma whipplei. Most commonly,

years pass from the onset of symptoms to the recognition of the disease because of its rarity, its various manifestations mimicking other

conditions, and the need to perform nonroutine diagnostic tests. The

long-held belief that WD is an infection was supported by observations

on its responsiveness to antimicrobial therapy in the 1950s and the

identification of bacilli via electron microscopy in small-bowel biopsy

specimens in the 1960s. This hypothesis was finally confirmed by

amplification and sequencing of a partial 16S rRNA polymerase chain

reaction (PCR)–generated amplicon from duodenal tissue in 1991. The

subsequent successful cultivation of T. whipplei enabled whole-genome

sequencing and the development of additional diagnostic tests. The

development of PCR-based diagnostics has broadened our understanding of both the epidemiology of and the clinical syndromes

attributable to T. whipplei. Exposure to T. whipplei, which appears to

be much more common than has been appreciated, can be followed

by asymptomatic carriage, acute disease, or chronic infection. Chronic

infection—WD—is a rare development after exposure. “Classic” WD

176 Whipple’s Disease

Thomas A. Russo, Seth R. Glassman

is manifested by some combination of arthralgias/arthritis, weight loss,

chronic diarrhea, abdominal pain, and fever. Variable involvement

at other sites also occurs; neurologic and cardiac disease are most

common. Acute infection and chronic organ disease in the absence of

intestinal involvement (see “Isolated Infection,” below) are described

with increasing frequency. Since untreated WD is often fatal and

delayed diagnosis may lead to irreparable organ damage (e.g., in the

central nervous system [CNS]), knowledge of the clinical scenarios in

which Whipple’s should be considered and of an appropriate diagnostic

strategy is mandatory.

■ ETIOLOGIC AGENT

T. whipplei is a weakly staining gram-positive bacillus. Genomic

sequence data have revealed that the organism has a small

(<1-megabase) chromosome, with many biosynthetic pathways

absent or incomplete. This finding is consistent with a host-dependent

intracellular pathogen or a pathogen that requires a nutritionally rich

extracellular environment. It is one of the slowest growing human

pathogens, with a doubling time of 18 days. A genotyping scheme

based on a variable region has disclosed >100 genotypes to date. All

genotypes appear to be capable of causing similar clinical syndromes.

■ EPIDEMIOLOGY

WD is rare but has been increasingly recognized since the advent

of PCR-based diagnostic tools. Prevalence had been previously estimated at 1−3 cases per 1 million population, although a recent U.S.

epidemiologic survey places the number closer to 10 cases per million.

Seroprevalence studies indicate that ~50% of Western Europeans and

~75% of Africans from rural Senegal have been exposed to T. whipplei.

Higher prevalence may be attributable to differences in sanitation.

Humans are the only known host. In most studies, males more commonly develop WD; WD is more common in Caucasians and increases

with age. To date, no clear animal or environmental reservoir has been

demonstrated. However, the organism has been identified by PCR in

sewage water and human feces. Workers with direct exposure to sewage are more likely to be asymptomatically colonized than controls, a

pattern suggesting fecal–oral spread. Fecal PCR detection rates of 38%

among family members of carriers or patients with infection support

oral–oral or fecal–oral spread, although a common environmental

exposure cannot be excluded. Further, the development of acute T.

whipplei pneumonia in children raises the possibility of droplet or

airborne transmission.

■ PATHOGENESIS AND PATHOLOGY

Rates of asymptomatic carriage of T. whipplei are far higher than

rates of chronic infection (<0.01% of those exposed). Both decreased

host pathogen-specific inflammatory response and pathogen-driven

modulation of host inflammatory response likely play a role in establishing chronic infection. The human leukocyte antigen (HLA) alleles

DRB1*

13 and DQB1*

06, which stimulate humoral rather than cellmediated immune responses, are associated with an increased risk of

infection. However, only a minority of infected patients possess these

haplotypes, suggesting a role for other host factors. IRF4, a transcription factor involved with the immune response, could be such a factor

as evidenced by four related family members with WD who possessed

IFR4 haploinsufficiency due to a loss-of-function mutation; the distribution of WD in this extended family was consistent with an autosomal

dominant trait with incomplete penetrance.

Flow cytometry performed in WD patients demonstrates B-cell subset abnormalities when compared to matched controls. Chronic infection is associated with an impaired TH1 response, enhanced production

of anti-inflammatory cytokines, increased activity of regulatory T cells,

M2 polarization of macrophages with diminished antimicrobial activity and impaired phagosome–lysosome fusion and ensuing apoptosis,

and blunted development of T. whipplei–specific T cells. Therapies that

blunt cell-mediated host immune responses (e.g. systemic glucocorticoids or anti–tumor necrosis factor α [TNF-α] agents) may accelerate

progression of chronic disease. Impaired cell-mediated immunity may

play a role in establishing chronic carriage of T. whipplei as is evidenced

by higher rates of detection in the secretions of HIV-infected persons.