Actinomycosis is an infection caused by actinomyces israelii or related actinomycete bacteria. These bacteria resemble fungi and cause diseases of the mouth, jaw, chest, and pelvis.

Types and causes

The most common form of actinomycosis affects the jaw area. A painful swelling appears and pus and characteristic yellow granules discharge through small openings that develop in the skin. Poor oral hygiene may contribute to this form of the infection.

Another form of actinomycosis affects the pelvis in women, causing lower abdominal pain and bleeding between menstrual periods. This form was associated mainly with a type of IUD, no longer in use, that did not contain copper.

Rarely, forms of the disorder affect the appendix or lung.

Actinomycosis is usually treated successfully with antibiotic drugs.

Actinomycoses in detail - technical

Essentials

Actinomycoses are sporadically occurring endogenous polymicrobial inflammatory processes in which fermentative (facultatively anaerobic or capnophilic) actinomycetes of the genera Actinomyces and Propionibacterium, but rarely also Bifidobacterium, may act as the principal pathogens. Clinically, the subacute to chronic, granulomatous as well as suppurative disease tends to progress slowly and usually gives rise to multiple abscesses and draining sinus tracts. Because the term ‘actinomycosis’ denotes a polyaetiological inflammatory syndrome rather than a condition attributable to a single actinomycete species, it should only be used in the plural.

Aetiology of human actinomycoses

Actinomyces israelii and A. gerencseriae are by far the most frequent and most characteristic pathogens aetiologically involved in the human form of the disease. A. gerencseriae emerged from the former sero- and biovariety 2 of A. israelii in 1990. A third species of filamentous fermentative Gram-positive bacteria, Propionibacterium propionicum (formerly Arachnia propionicum), is a much less common cause of actinomycotic infections (Table 1).

Several other fermentative actinomycetes have occasionally been isolated from actinomycosis-like lesions (Table 1). In a given case, however, it is often difficult to decide whether these organisms are primary pathogens or merely contaminants, especially when the specimen has had contact with mucosal secretions or when two different actinomycete species have been isolated from the same specimen (Table 1). Nevertheless, A. naeslundii, A. odontolyticus, A. viscosus, A. meyeri, and Bifidobacterium dentium (formerly Actinomyces eriksonii) have all been reported to be capable of producing human infections clinically identical to those caused by A. israelii, A. gerencseriae, or P. propionicum, while A. bovis, the classic agent of bovine actinomycosis, has never been recovered with certainty from human infective processes (Table 1). Fermentative actinomycetes previously termed A. naeslundii and A. viscosus underwent considerable taxonomic and nomenclatural changes recently (Henssge et al., 2009). According to these changes, organisms now named A. viscosus only occur in animals, particularly in hamsters. Human isolates of the former species A. naeslundii and A. viscosus have been assigned to A. naeslundii sensu stricto and the new species A. oris and A. johnsonii.

Pathogenesis and pathology

Most of the fermentative actinomycetes pathogenic to humans are found regularly and abundantly in the mouths of healthy adults. However, these microbes occur only sporadically or in low numbers in the digestive, respiratory, and genital tracts, as well as in the mouths of babies before teething and of adults without any natural teeth or tooth implants. Therefore, these actinomycetes may be considered facultatively pathogenic commensals of the human mucous membranes, which, apart from the very rare actinomycotic wound infections following human bite or fist fight traumata, produce disease exclusively as endogenous pathogens.

For active invasion of the tissue, the classic pathogenic fermentative actinomycetes apparently require a negative redox potential, which may result either from insufficient blood supply (caused by circulatory or vascular diseases, crush injuries, or foreign bodies) or from the reducing and necrotizing capacity of other microbes in the lesion. Defective functions of the immune system do not specifically predispose to actinomycotic infections.

Synergistic polymicrobial infection

True actinomycoses are essentially always synergistic mixed infections, in which the actinomycetes act as the specific component, the so-called guiding organisms that decide on the characteristic course and the late symptoms of the disease. The so-called concomitant microbes (Table 2), which may vary considerably in composition (about 100 aerobic and anaerobic species) and number (up to 10 per case) of species from case to case, are often responsible for the clinical picture at the beginning of the infection and for certain complications; they are also part of the resident or transient surface microflora of the mucous membranes of humans.

Particularly pronounced synergistic interactions appear to exist between pathogenic fermentative actinomycetes, especially Actinomyces israelii and A. gerencseriae, and Actinobacillus actinomycetemcomitans, which has recently been reclassified as Aggregatibacter actinomycetemcomitans. The latter organism, the species designation of which refers to its characteristic association with actinomycetes (Latin actinomycetem comitans = accompanying an actinomycete), may even sustain the inflammatory process under similar clinical symptoms after chemotherapeutic elimination of the causative actinomycete.

Histopathology

Initially an inflammatory granulation tissue develops, which usually breaks down to form either an acute abscess or chronic multiple abscesses with proliferation of connective tissue. The pathognomonic sulphur granules are formed primarily in the infected tissue, but may also appear as free structures in abscess content or sinus discharge. They are then of the highest diagnostic importance.

Sulphur granules, which were originally designated Drusen in Harz’s first description of Actinomyces bovis in 1877, are macroscopically visible (up to 1 mm in diameter) yellowish or reddish to brownish particles that exhibit a cauliflower-like appearance under the microscope at low magnifications. They consist of a conglomerate of filamentous actinomycete microcolonies formed in vivo and surrounded by tissue reaction material, especially polymorphonuclear granulocytes. At high magnification, a Gram-stained smear of the completely crushed granule reveals the presence of clusters of Gram-positive interwoven branching filaments with radially arranged peripheral hyphae and of a variety of other Gram-positive and Gram-negative rods and cocci, which represent the concomitant flora. A club-shaped layer of hyaline material may be seen on the tips of peripheral filaments, which can aid in the differentiation of actinomycotic sulphur granules from macroscopically similar particles of various other microbial and nonmicrobial origins.

Clinical manifestations

The primary actinomycotic lesion usually develops in tissue adjacent to a mucous membrane at sites such as the cervicofacial, thoracic, and abdominal areas. The infection tends to progress slowly and to penetrate without regard to natural organ borders, or to spread haematogenously even to distant sites. Remission and exacerbation of symptoms with and without antimicrobial treatment is characteristic. As in other endogenous microbial diseases, the incubation period of actinomycoses is not defined.

Cervicofacial actinomycoses

In the vast majority of cases, actinomycotic lesions primarily involve the face or neck. Conditions predisposing to these cervicofacial infections include tooth extractions, fractures of the jaw, periodontal abscesses, foreign bodies penetrating the mucosal barrier (bone splinters, fish bones, awns of cereals), or suppurating tonsillar crypts.

Initially, the cervicofacial actinomycoses present either as an acute, usually odontogenic, abscess or cellulitis of the floor of the mouth, or as a slowly developing chronic hard painless reddish or livid swelling. Small acute actinomycotic abscesses may heal after surgical drainage alone. More often, however, the acute initial stage is followed by a subacute to chronic course if no specific antimicrobial treatment is given, thereby imitating the primarily chronic form, which is characterized by regression and cicatrization of central suppurative foci while the infection progresses peripherally producing hard painless livid infiltrations. These may lead to multiple new areas of liquefaction, fistulae, which often discharge pus containing sulphur granules, and multilocular cavities with poor healing and a tendency to recur after temporary regressions of the inflammatory symptoms.

With inappropriate or no treatment, cervicofacial actinomycoses extend slowly, even across organ borders, and may become life-threatening by invasion of the cranial cavity, the mediastinum, or the bloodstream.

Thoracic actinomycoses

Thoracic manifestations, which are much less common than the cervicofacial form (Table 3), usually develop after aspiration or inhalation of material from the mouth (dental plaque or calculus, tonsillar crypt contents) or a foreign body that contains or is contaminated with the causative agents. Occasionally, this form of disease may result from extension of an actinomycotic process of the neck, from an abdominal infection perforating the diaphragm, or from a distant focus by haematogenous spread.

Primary pulmonary actinomycoses present as bronchopneumonic infiltrations that may imitate tuberculosis or bronchial carcinoma radiographically, appearing as single dense or multiple spotted shadows in which cavitations may develop. If not diagnosed and treated properly, pulmonary infections may extend through to the pleural cavity producing empyema, to the pericardium, or to the chest wall; they may even appear as a paravertebral (psoas) abscess tracking down to the groin. Detailed aetiology, pathogenesis, and clinical relevance of a condition termed ‘endobronchial actinomycosis’ remain to be definitely clarified.

Actinomycoses of the abdomen and pelvis 

Women who wear intrauterine contraceptive devices (IUCD) or vaginal pessaries for long periods often show a characteristic colonization of the cervical canal and the uterine cavity, but particularly of the thread of the IUCD, by various fermentative actinomycetes and other anaerobes resembling the synergistic actinomycotic flora. However, this colonization only rarely results in an invasive actinomycotic process.

Most abdominal actinomycoses present as slowly growing tumours, which, in the absence of sinus tracts discharging pus with sulphur granules, are difficult to differentiate from malignant neoplasms such as colonic, rectal, ovarian, or cervical carcinomas. By direct extension, any abdominal tissue or organ may be involved including muscle, liver, spleen, kidney, fallopian tubes, ovaries, testes, bladder, or rectum. Haematogenous liver abscesses have been seen, especially associated with genital actinomycoses.

Actinomycotic infections of the central nervous system

Actinomycoses of the brain and the spinal cord are very rare. They may arise from direct extension of cervicofacial infections. Haematogenous spread is also possible, particularly from primary lesions in the lungs or abdomen. The spinal canal may be directly involved from these sites. Brain abscess is much more common than meningitis.

Actinomycoses of the bone

In contrast to bovine actinomycosis which usually affects the skeleton, bone involvement in humans is very rare. It usually develops by direct extension from soft tissue infection resulting in a periostitis with new bone formation visible by radiography. If the bone itself is invaded, localized areas of bone destruction surrounded by increased bone density usually develop. Mandible, ribs, and spine are most frequently involved.

Actinomycotic endocarditis

Endocarditis due to fermentative actinomycetes has occasionally been described. However, detailed bacteriological information on this condition is not yet available so that it remains to be seen whether it may rightly be termed actinomycosis or has merely to be considered an aetiological variant of the common form of endocarditis caused by indigenous oral microbes.

Cutaneous actinomycoses

Actinomycotic lesions of the skin are extremely rare. Usually, they originate from wounds that were contaminated with saliva or dental plaque following human bites or fist fights, but they may also result from haematogenous spread. Symptoms are similar to those of cervicofacial actinomycoses.

Diagnosis

Clinical symptoms are often misleading, especially in the early stages of the disease, histopathological appearances are unreliable, and diagnosis chiefly rests on bacteriological methods.

Radiography

In cervicofacial cases, radiography is useful only for detecting bone involvement. A pulmonary infiltrate associated with a proliferative lesion or destruction of ribs is highly suggestive of either actinomycosis or a tumour. Radiography may also help to locate the abdominal processes and to identify the involvement of organs such as liver, kidney, urinary bladder, or ureter. In general, however, radiographic changes are not diagnostic.

Laboratory diagnosis

Clinical chemistry and haematology

Small localized actinomycotic lesions are not usually associated with abnormalities. In advanced cases, however, especially those in the thoracic or the abdominal area, a raised erythrocyte sedimentation rate and pronounced leucocytosis may be seen. When the central nervous system is involved, a polymorphonuclear or mononuclear pleocytosis is commonly found. The protein content of the cerebrospinal fluid is frequently elevated and the sugar content moderately depressed.

Bacteriology

Pus specimens containing sulphur granules and occasionally looking like semolina should prompt the clinician to ask and the bacteriologist to look specifically for actinomycetes using suitable cultural techniques and other methods.

Pus, sinus discharge, bronchial secretions, granulation tissue, or biopsy materials are suitable specimens. Precautions must be taken to prevent contamination of the specimen by the indigenous mucosal flora. In cases of cervicofacial actinomycoses, pus should therefore be obtained only by transcutaneous puncture of the abscesses or by transcutaneous needle biopsy. When abscesses have already been incised, a sufficient amount of pus should be collected instead of using only a swab. Because sputum always contains oral actinomycetes, bronchial secretions should be obtained by transtracheal aspiration, or material should be collected by transthoracic percutaneous needle biopsy. Percutaneous puncture of suspected abscesses is often the only way of obtaining suitable specimens for diagnosing abdominal actinomycoses.

The transport of specimens to the bacteriological laboratory should be as fast as possible, preferably by messenger. Alternatively, a reducing transport medium such as one of the modifications of Stuart’s medium should be used. The specimen should arrive in the laboratory within 24 h, although it has occasionally proved possible to isolate actinomycetes from samples that took 7 days or more to get to the diagnostic laboratory by post.

A quick and comparatively reliable tentative diagnosis is possible microscopically when sulphur granules are present. The demonstration of concomitant bacteria in Gram-stained smears prepared from crushed granule material allows the differentiation of actinomycotic granules from similar particles produced by Nocardia spp., Actinomadura spp., or Streptomyces spp.

Use of transparent culture media and careful microscopic examination of the cultures, preferably on Fortner plates, after at least 2, 7, and 14 days of incubation enables a specialized laboratory to detect possible actinomycete colonies and to subculture them for identification. Isolation and definite identification to the species level may require a further 1 to 2 weeks. Techniques such as the application of gene probes or the polymerase chain reaction for detecting and identifying fermentative actinomycetes are not yet widely used.

Serological diagnosis

None of the routine serological methods has yet provided satisfactory results because sensitivity and specificity have been found to be too low.

Treatment

As the aetiology of human actinomycoses is always polymicrobial, the antibacterial drugs used for treatment should in principle cover both the causative actinomycetes and all of the concomitant bacteria. This usually requires the administration of drug combinations in which aminopenicillins currently represent the therapeutic basis because they are slightly more active against the pathogenic actinomycetes than is penicillin G and because they are able to inhibit Aggregatibacter (Actinobacillus) actinomycetemcomitans which is usually resistant to narrow-spectrum penicillins. However, the presence of concomitant β-lactamase producers such as Bacteroides fragilis, B. thetaiotaomicron, or Staphylococcus aureus (β-lactamase producing) may impair the therapeutic efficacy of aminopenicillins and that of many other β-lactams so that the combination with a β-lactamase inhibitor is advisable or even necessary.

For cervicofacial actinomycoses, amoxicillin plus clavulanic acid has proved to be the treatment of choice. Three doses of 2.0 g amoxicillin plus 0.2 g clavulanic acid every day for 1 week and three doses of 1.1 g of the combination for an additional 7 days usually result in complete cure. Thoracic actinomycoses mostly respond to the same regimen. However, it is advisable to maintain doses of 2.2 g 3 times a day for 2 weeks, and to continue treatment for 3 to 4 weeks. Advanced pulmonary cases may require the addition of 2 g ampicillin three times a day in order to increase the tissue concentration of aminopenicillin and, depending on the composition of the concomitant flora, the use of an antimicrobial specifically active against resistant Enterobacteriaceae; the application of drugs such as metronidazole or clindamycin against strict anaerobes is only necessary as an adjunct to the aminopenicillins in chronic cases with reduced blood supply.

Since in abdominal actinomycoses Enterobacteriaceae and β-lactamase producing Bacteroides spp. are usually present and the correct diagnosis is mostly established late, suitable antimicrobial combinations for these cases are amoxicillin plus clavulanic acid plus metronidazole plus tobramycin (gentamicin) or ampicillin plus clindamycin plus an aminoglycoside. Imipenem might also be a good choice, but this drug has not yet been widely used for treating actinomycotic infections.

Neither clindamycin nor metronidazole should be used alone. Clindamycin is almost completely ineffective against Aggregatibacter (Actinobacillus) actinomycetemcomitans and metronidazole shows no activity at all against pathogenic actinomycetes. The use of further combinations, including additional aminoglycosides, cephalosporins, or β-lactamase-stable penicillins, may be necessary depending on the presence of unusual aerobic organisms. In patients allergic to penicillins, tetracyclines or possibly cephalosporins may be tried instead of aminopenicillins. Incision of abscesses and drainage of pus may still be necessary as an adjunct to the antimicrobial chemotherapy and may help to accelerate recovery and to decrease the risk of relapses.

Prognosis

The prognosis of cervicofacial and cutaneous actinomycotic infections is good provided that the diagnosis is established early and antimicrobial treatment is adequate. However, thoracic, abdominal, and systemic manifestations remain serious conditions that require all possible diagnostic and therapeutic efforts. Without proper treatment, the prognosis is grave.

Epidemiology

Actinomycoses are not transmissible and cannot be brought under control by vaccination or by measures that prevent spread. Sporadically, they occur worldwide. In Germany, the incidence of the disease was estimated to range from 1 in 40 000 (acute and chronic cases together) to 1 in 80 000 (chronic cases alone) per year, but appears to be decreasing in recent years.

Men are affected 2 to 4 times more frequently by cervicofacial actinomycoses than are women. However, the male to female ratio appears to vary with age. Although actinomycoses may be found in patients of any age, men are predominantly affected between their 20th and 50th years and women in the second to fourth decade of their lives. Before puberty and in old age, actinomycoses occur sporadically in patients of both sexes without the pronounced predisposition of men.

Other diseases caused by fermentative actinomycetes

Fermentative actinomycetes play some part in dental caries and periodontal disease, but are clearly not the most important microbes contributing to these important health problems. Lacrimal canaliculitis with and without conjunctivitis is commonly caused by fermentative actinomycetes, in particular P. propionicum, but less frequently also by Actinomyces israelii, A. gerencseriae, A. naeslundii, A. oris, or A. odontolyticus. The concomitant flora, when present, is usually less complex than that of typical actinomycoses. Removal of the lacrimal concretions that are usually present and local application of antimicrobials always result in prompt cure.

Arcanobacterium pyogenes and A. haemolyticum (formerly Corynebacterium (Actinomyces) pyogenes and C. haemolyticum) cause acute pharyngitis, urethritis, or cutaneous or subcutaneous suppurations. The recently described species Actinomyces neuii subsp. neuii and subsp. anitratus, A. graevenitzii, A. europaeus, A. radingae, A. turicensis, A. funkei, A. cardiffensis, A. hongkongensis, A. oricola, A. urogenitalis, and A. dentalis, as well as Arcanobacterium (Actinomyces) bernardiae, Actinobaculum schaalii, and Varibaculum cambriense have been isolated from various clinical sources including abscesses and blood cultures, and may also be associated with mixed bacterial flora. A. turicensis and possibly A. urogenitalis seem to be particularly common in genital infections, while A. radingae was found only in patients with skin-related pathologies and A. nasicola was isolated from pus from the nasal antrum. A. europaeus, A. turicensis, and A. urogenitalis as well as Actinobaculum schaalii, A. urinale, and A. massiliae were detected in predominantly elderly patients with urinary tract infections, and A. radicidentis was isolated from infected root canals of teeth.

Further reading