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 clinicians. Thus this entity remains a diagnostic challenge.
Three 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. An awareness of the full spectrum of the disease, prompting clinical suspicion, will expedite its diagnosis and treatment and will minimize the unnecessary surgical interventions, morbidity, and mortality that are reported all too often.
Actinomycosis is most commonly caused by A. israelii. A. naeslundii, A. odontolyticus, A. viscosus, A. meyeri, and A. gerencseriae are established but less common causes. 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. The contribution of these other species 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 to the reclassification of some actinomycetes as Arcanobacterium. Increasing data support the Actinomyces species A. europaeus, A. neuii, A. radingae, A. graevenitzii, A. turicensis, A. cardiffensis, A. houstonensis, A. hongkongensis, A. lingnae, and A. funkei as well as two former Actinomyces species now classified as Arcanobacterium (A. pyogenes and A. bernardiae) as additional causes of human actinomycosis.
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. Factors that have probably contributed to the decrease in actinomycosis incidence since the advent of antibiotics include improved dental hygiene and the initiation of antimicrobial treatment before the disease develops fully. 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.
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. 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; treatment with infliximab, glucocorticoids, or bisphosphonates; and radio- or chemotherapy. Ulcerative mucosal infections (e.g., by herpes simplex virus or cytomegalovirus) may facilitate the development of actinomycosis.
Actinomycosis occurs most frequently at an oral, cervical, or facial site, usually as a soft tissue swelling, abscess, or mass lesion that is often mistaken for a neoplasm. 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 (Chap. 31). Radiation therapy and especially bisphosphonate treatment have been recognized as contributing to an increasing incidence of actinomycotic infection of the mandible and maxilla (Fig. 163-1). Otitis, sinusitis, and canaliculitis (most commonly due to Propionibacterium propionicum) also can develop. Pain, fever, and leukocytosis are variably reported. Contiguous extension to the cranium, cervical spine, or thorax is a potential sequela.
Bisphosphonate-associated maxillary osteomyelitis due to A. viscosus. A sulfur granule is seen within the bone. (Reprinted with permission from NH Naik and TA Russo. © 2009 University of Chicago Press.)
Thoracic actinomycosis usually follows an indolent 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 ringlike rim enhancement may be seen. Cavitary disease or hilar adenopathy may develop. More than 50% of cases include pleural thickening, effusion, or empyema (Fig. 163-2). Rarely, pulmonary nodules or endobronchial lesions occur. Pulmonary lesions suggestive of actinomycosis may cross fissures or pleura; may involve the mediastinum, contiguous bone, or chest wall; or may be associated with a sinus tract. In the absence of these findings, thoracic actinomycosis is usually mistaken for a neoplasm or for pneumonia due to more usual causes.
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.)
Mediastinal infection is uncommon, usually arising from thoracic extension but rarely resulting from perforation of the esophagus, from trauma, or from 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 and isolated disease of the breast have been described.
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 gall stones or bile during laparoscopic 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 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. 295). 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. 163-3). Isolated disease presumably develops via hematogenous seeding from cryptic foci. Imaging and percutaneous techniques have resulted in improved diagnosis and treatment.
Hepatic-splenic actinomycosis. A. Computed tomogram showing multiple hepatic abscesses and a small splenic lesion due to A. 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.)
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.
Actinomycotic involvement of the pelvis occurs most commonly in association with an IUCD. When an IUCD is in place or has recently been 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. Actinomycosis can also present months after IUCD removal. 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. 163-4). Unfortunately, because the diagnosis is often delayed, a “frozen pelvis” mimicking malignancy or endometriosis can develop by the time of recognition.
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).
Identification of Actinomyces-like organisms (ALOs) on Papanicolaou-stained specimens, which occurs on average in 7% of women using an IUCD, has a low positive predictive value for a diagnosis of pelvic infection. Although the risk appears small, the consequences of infection are significant. Therefore, until more quantitative data become available, it seems prudent to remove the IUCD in the presence of symptoms that cannot be accounted for, regardless of whether ALOs are detected, and—if advanced disease is excluded—to initiate a 14-day course of empirical treatment for possible early pelvic actinomycosis. The detection of ALOs in the absence of symptoms warrants education of the patient and close follow-up but not removal of the IUCD unless a suitable contraceptive alternative is agreed on.
Central Nervous System Disease
Actinomycosis of the central nervous system (CNS) is rare. Single or multiple brain abscesses are most common. 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 meningitis, epidural or subdural space infection, and cavernous sinus syndrome.
Musculoskeletal and Soft Tissue Infection
Actinomycotic infection of bone is usually due to adjacent soft-tissue infection but may be associated with trauma (e.g., fracture of the mandible), osteoradionecrosis and bisphosphonate osteonecrosis (limited to mandibular and maxillary bones), or hematogenous spread. Because of slow disease progression, new bone formation and bone destruction are seen concomitantly. Infection of an extremity is uncommon and is usually a result of trauma. Skin, subcutaneous tissue, muscle, and bone (with periostitis or acute or chronic osteomyelitis) are involved alone or in various combinations. Cutaneous sinus tracts frequently develop.
Hematogenous dissemination of disease from any location rarely results in multiple-organ involvement. The lungs and liver are most commonly affected, with the presentation of multiple nodules mimicking disseminated malignancy. The clinical presentation may be surprisingly indolent given the extent of disease.
The diagnosis of actinomycosis is rarely considered. All too often, the first mention of actinomycosis is 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 positive emission tomography 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 diagnosis is most commonly made by microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues. Occasionally, these granules are identified grossly from draining sinus tracts or pus. Although sulfur granules are a defining characteristic of actinomycosis, granules are also found in mycetoma (Chaps. 162 and 206) 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. Primary isolation usually requires 5–7 days but may take as long as 2–4 weeks. Although not routinely used, 16S rRNA gene amplification and sequencing have been successfully applied to increase diagnostic sensitivity. 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.
Decisions about treatment are based on the collective clinical experience of the past 50 years. Actinomycosis requires prolonged treatment with high doses of antimicrobial agents. 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. Less extensive disease, particularly that involving the oral-cervicofacial region, may be cured with a shorter course. 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. Suitable alternative antimicrobial agents and those deemed unreliable are listed in Table 163-1. Although 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.
Table 163-1 Appropriate and Inappropriate Antibiotic Therapy for Actinomycosisa |Favorite Table|Download (.pdf)
Table 163-1 Appropriate and Inappropriate Antibiotic Therapy for Actinomycosisa
|Extensive successful clinical experienceb|
Penicillin: 3–4 million units IV q4h
Amoxicillin: 500 mg PO q6h
Erythromycin: 500–1000 mg IV q6h or 500 mg PO q6h
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 q6h
|Anecdotal successful clinical experience|
|Agents that should be avoided|
|Agents predicted to be efficacious on the basis of in vitro activity|
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 child-bearing 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) or when suitable medical therapy fails, surgical intervention may be appropriate.