Actinomyces species (Actinomycoses)

Authors: Tasaduq Fazili MD, FACP

Previous Author (First Edition, 2002): Michael M. McNeil, M.D., MP.H. , Dr. med. habil., Klaus P. Schaal


Actinomycosis is an uncommon, indolent, progressively invasive bacterial infection caused by organisms of the Actinomyces species, which are non-motile, filamentous, branching, gram-positive and predominantly anaerobic bacteria. These organisms belong to the phylum, Actinobacteria, in the order Actinomycetales, and family, Actinomycetaceae. They are related to other genera like Corynebacterium, Propionobacterium, Mycobacteriium and Nocardia.

More than thirty species of Actinomyces have been described thus far, at least half of which are pathogenic to humans (r94).

The most common agents in this disease are A. israelii and A. gerencseriae, but at least four other Actinomyces species (A. naeslundii, A. viscosus, A. odontolyticus, and A. meyeri), Propionibacterium propionicum (formerly Arachnia propionica), and Bifidobacterium dentium (formerly Actinomyces eriksonii) may also be responsible for similar or identical clinical symptoms. Furthermore, eight new Actinobacillus species (A. europaeus, A. funkei, A. graevenitzii, A. neuii, A. radicidentis, A. radingae, A. turicensis, and A.urogenitalis) (13, 22, 23, 44, 59, 64, 100) as well as the related taxon Actinobaculum schaalii (43) have recently been described that were all derived from clinically less specific inflammatory conditions, and two former Actinomyces species (A. bernardiae and A. pyogenes) have been placed in the genus Arcanobacterium (72).

Actinomyces bovis causes granulomatous infections in cattle; however, this species has never been proven as a human pathogen and earlier reports of human A. bovis infections most probably were due to A. israelii (5, 47). Ten additional Actinobacillus species have as yet solely been isolated from animal sources.

Members of the genera Actinomyces, Actinobaculum, Propionibacterium, and Bifidobacterium are morphologically similar, anaerobic to less stringently anaerobic (provided by Fortner's method) (22) to capnophilic or aerotolerant (facultatively anaerobic), nonsporulating, gram-positive bacteria that tend to form branching rods and filaments and have a fermentative type of carbohydrate metabolism. Filamentous, microscopic colonies of Actinomyces species can be detected within 2 to 4 days of anaerobic incubation at 36 ± 1 °C. Mature colonies require 7 to 14 days to develop. Characters that differentiate these four genera from each other and from other anaerobically growing nonsporulating gram-positive bacteria are derived from cell wall or whole-cell analysis, acid end-product analysis, and certain physiological tests. These last tests are particularly necessary for differentiating between the various Actinomyces species (80), but rapid and reliable identification to the species level may also be achieved by using serologic techniques such as direct or indirect immunofluorescence.

Actinomycosis-producing actinomycetes may be distinguished from aerobic, filamentous bacteria such as Nocardia species, Rothia dentocariosa, or Corynebacterium (Bacterionema) matruchotii by the type of carbohydrate metabolism (nocardiae are aerobes), by differences in cell wall composition (nocardiae and C. matruchotii contain meso-diaminopimelic acid, arabinose and galactose as well as mycolic acids in their walls), by partial acid-fastness and aerial filaments (nocardiae), and by resistance to penicillin (nocardiae). R. dentocariosa, which is often difficult to distinguish from aerobically growing Actinomyces species, is characterized by its ability to reduce nitrate as well as nitrite.

Characteristic actinomycotic lesions usually do not develop in the absence of concomitant flora that may consist of aerobic and/or anaerobic species (49, 83). Aerobic cultures chiefly yield coagulase-negative staphylococci, Staphylococcus aureus, α-hemolytic and β-hemolytic streptococci as well as Enterobacteriaceae from abdominal and pelvic actinomycoses; whereas, anaerobic cultures chiefly yield Actinobacillus (Haemophilus) actinomycetemcomitans (25% of cases), so-called microaerophilic streptococci (mainly S. milleri), Fusobacterium spp., Bacteroides, Prevotellaand Porphyromonas spp., Leptotrichia buccalis, Eikenella corrodens and Capnocytophaga spp. (79).

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Actinomyosis is a subacute to chronic bacterial disease that is characterized by slowly progressing suppurative fibrosing inflammation, development of draining sinus tracts that may discharge characteristic "sulfur granules," and direct dissemination via contiguous tissues. It most commonly involves the cervicofacial area, thorax or abdomen, including the pelvis, but rarely also the central nervous system (CNS), skin or bone (85, 87). The disease is worldwide in distribution and more common in males.

The etiology of human actinomycoses is complex in two respects: the principal etiological agents of the disease do not belong to a single species, but to a variety of different members of the genera Actinomyces, Propionibacterium, and Bifidobacterium. Furthermore, essentially all of the typical actinomycotic lesions contain between one and 10 bacterial species in addition to the pathogenic actinomycetes (37, 38, 46, 83). These concomitant bacteria apparently act as synergistic pathogens that strengthen the comparatively low invasive power of the pathogenic actinomycetes and are in particular responsible for the early symptoms of the disease and for treatment failures (68). Since the etiologic term "actinomycosis" therefore circumscribes a polyetiologic inflammatory syndrome rather than a disease attributable to a single pathogen, it appears to be more appropriate to refer to this group of closely related conditions as "actinomycoses" in the plural.

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Cervicofacia Actinomycosis:

Cervicofacial actinomycosis is the most common form, accounting for about 50 % of all cases (99).

Characteristic risk factors are poor oral hygiene resulting in periodontal abscesses or dental decay; orofacial trauma; foreign bodies penetrating the mucosal barrier such as bone splinters, fish bones or spicules of grass or grain; and dental procedures. One to several weeks after dental extraction or mouth trauma, or spontaneously, the infection typically causes a painful, indurated cutaneous and soft tissue swelling ("woody" fibrosis) or presents as typical odontogenic abscess. The slowly enlarging inflammatory mass is most frequently located in tissue adjacent to the body of the mandible (53.6%), but may also involve cheek (16.4%), chin (13.3%), ramus and angle of the mandible (10.7%), upper jaw (5.7%) and mandibular joint (0.3%) (33). Over ensuing weeks to months, the overlying skin may develop a bluish discoloration and become adherent, and the mass may become fluctuant and develop draining extra or intra-oral sinuses that may extrude sulfur granules. Trismus may be prominent early in the patient's course; however, cervical lymphadenopathy is uncommon. Direct extension may involve the tongue, sinuses, and meninges and rarely, contribute to periostitis or osteomyelitis of the mandible (74).

Thoracic Actinomycosis:

Actinomycosis of the lung and pleura comprises 15-20% of cases and is usually secondary to aspiration but rarely may occur secondary to hematogenous dissemination. A low-grade pneumonitis develops that tends to invade the pleura, possibly resulting in empyema necessitatis and a draining chest wall fistula(e) (39). Prior to pleural invasion, the patient's symptoms may be minimal and nonspecific (malaise, weakness); however, progression of infection may be associated with fever, productive cough (rarely hemoptysis), and weight loss, which may be severe. Pleuropulmonary actinomycosis may be complicated by direct extension into the mediastinum, pericardium, thoracic vertebrae, or subphrenic spaces, occasionally leading to paravertebral or even psoas abscesses. Pulmonary actinomycosis may disseminate hematogenously, and multiple subcutaneous nodules or neurologic symptoms resulting from a brain abscess may be the presenting manifestation of the disease.

Abdominopelvic Actinomyosis:

Actinomycosis of the abdominopelvic region is responsible for about 20% of cases, and can be divided into gastrointestinal and pelvic disease.

Gastrointestinal Actinomycosis:

Actinomycosis of the gastrointestinal tract most commonly develops in the ileocecal region, but it may also primarily involve the esophageal, gastric or anorectal areas (11). There is often a previous history of appendicitis. Fever, abdominal pain, a palpable mass, and the development of an external sinus may be the presenting features. Alternatively, the diagnosis may be considered only after an indurated draining sinus fails to heal following surgical drainage of a presumed appendiceal abscess. Purulent drainage may contain sulfur granules. In some patients, a primary ileocecal infection may cause secondary pelvic actinomycosis.

Pelvic Actinomycosis:

Pelvic actinomycosis has been recognized with increasing frequency. Predisposing factors include intrauterine devices (IUDs), vaginal pessaries, prolapse of the uterus, and septic abortion (19). Symptoms may include pelvic pain, leukorrhea, menorrhagia, and amenorrhea, associated with fever, malaise, weakness, and weight loss, in any combination. Actinomycosis should be considered in any woman with a history of IUD use who presents with abdominal pain or a pelvic mass. Recently, Fiorino reviewed 92 cases of actinomycotic abscesses associated with IUD use or intravaginal foreign bodies (21). The patients had a mean age of 37 years (range 20-77), and had been using an IUD for an average of 8 years. Presenting symptoms included abdominal pain, and weight loss, and these patients frequently demonstrated vaginal discharge, fever, anemia and leukocytosis. Almost 90% of patients were found at surgery to have uni- or bilateral tubo-ovarian abscesses. The inflammatory process commonly involved other organs directly, or indirectly by adhesions or compression, in particular the large and small bowel, bladder, ureters, and liver.

Actinomycosis of the Central Nervous System:

Actinomycoses of the brain and the spinal cord are rare conditions. CNS involvement may follow thoracic or abdominal infections by hematogenous spread or may result from direct dissemination of a cervicofacial lesion. It usually presents as a brain abscess that, depending on its localization, may lead to a headache, increased intracranial pressure, focal seizures, hemiparesis, aphasia, ataxia, or abnormal reflexes. Several cases of brain abscesses due to A. meyeri have been reported. This species has a higher predilection for dissemination than other species.

Actinomycosis of the Bone and Skin:

In contrast to animal actinomycoses, osseous involvement is very uncommon in humans. It usually results from direct extension of an adjacent soft tissue focus leading to periostitis and finally to localized areas of bone destruction surrounded by areas of increased bone density. The mandible, ribs, and spine are the bones most frequently involved.

Cutaneous actinomycotic infections are extremely rare and mostly result from wounds that were contaminated with saliva or dental plaque material, either by human bites or as a consequence of fist-fight trauma. Hematogenous spread to the skin has also been observed. The clinical picture of these cutaneous or wound actinomycoses (punch actinomycoses) is very similar to that of the cervicofacial form (78).

Other Conditions Caused by Fermentative Actinomycetes:

Some Actinomyces species (e.g. A. naeslundii, A. viscosus, A. odontolyticus) may be involved in the complex etiology of caries and periodontal disease. In addition, these and other species, in particular the recently described ones, may cause non-specific suppurative lesions such as wound infections, abscesses or empyemas, as well as infections of the urogenital tract, infections of root canals of teeth and even endocarditis and septicemia.

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A definitive diagnosis cannot be made solely on clinical grounds. The diagnosis of actinomycosis may be difficult and often depends on a heightened level of clinical suspicion and prior notification of the clinical laboratorian and pathologist. Bronchoscopy and bronchoalveolar lavage fluid examination and culture may be useful in thoracic actinomycosis (14, 45), but may also produce misleading results due to contamination of the specimens with the normal oropharyngeal microflora. Detection of the causative agents by Gram stain and culture from an appropriately obtained specimen is needed. Exudates and biopsy material are particularly suitable for examination, and should be cultured promptly under anaerobic conditions.

After a sample is obtained, it should be examined by standard histologic methods, anaerobic culture for 2 weeks, and immunofluorescence if available. Culture is the least reliable method of verifying infection (in Fiorino's series only 35% of cultures were positive for fermentative actinomycetes (r21) when standard aerobic and anaerobic culture techniques are used. However, an 86% success rate has been reported for samples cultured in the presence of metronidazole, which inhibits the growth of faster growing anaerobes (92), and, as indicated by the overall number of culture-proven cases (47, 69, 81) and the percentage of culture-positive IUD specimens (17, 18), even better results may be obtained when transparent agar media, Fortner's (22) method for producing a semianaerobic atmosphere, and microscopic examination of the cultures for up to 14 days of incubation at 36 ± 1°C are used (81). The last procedure also facilitates the detection of actinomycete colonies among a usually large amount of various colony types of concomitant microbes.

Because of the polymicrobial nature of the disease, culture and Gram stain of abscess aspirates, sinus discharge, bronchial secretions or biopsy specimens may have important implications for the choice of adjunctive antibiotics. Microorganisms may be scarce in pathologic specimens, so detection may require diligent searching of multiple tissue sections (55). The presence of sulfur granules is highly suggestive but not diagnostic of disease. These sulfur granules are visible with the unaided eye (diameter up to 1 mm) as yellowish to reddish to brownish particles that consist of spherical segments of filamentous actinomycete microcolonies, various concomitant bacteria and surrounding tissue reaction material, in particular polymorphonuclear granulocytes. Serodiagnosis of actinomycosis by detection of precipitating or other antibodies has not been a particularly useful diagnostic test (28, 81). Demonstration of pathogenic actinomycetes from smears of lesions by immunofluorescence is a more promising technique. More recently, molecular genotypic techniques have been utilized for identification of Actinomyces species. 16 S ribosomal RNA (rRNA) gene sequencing is now becoming the standard method of identification in most academic and reference laboratories (12).

Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry is a newer, promising technology that can accurately identify Actinomyces at the genus level, although precise species identification can sometimes be difficult (57).

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Nearly all of the microbes etiologically involved in the development of human actinomycoses belong to the indigenous microflora of the human mucous membranes, in particular in the oral cavity, but also in the gastrointestinal and female genital tracts. Thus, most members of the actinomycotic flora possess low inherent pathogenicity so that local tissue ischemia resulting from circulatory or vascular diseases, crush injuries, or foreign bodies, or from the reducing and necrotizing capacity of simultaneously present additional microbes is necessary to allow the infection to establish itself in tissues, and to invade surrounding healthy areas. In consequence, apart from "punch actinomycoses" following human bites or fist-fight injuries, the disease is always endogenous in origin and therefore neither liable to cause outbreaks nor to be transmitted from person to person.

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Single Drug(s)

In vitro antimicrobial susceptibility testing of fermentative actinomycetes is rarely required, as these results are quite predictable (47, 49, 59, 84). In addition, in vitro activity may not correlate with clinical outcome (e.g., streptomycin; see below). One study examined 74 strains (seven species); minimum inhibitory concentrations (MICs) for penicillin G were 0.03 to 0.5 mg/mL for all strains of A. israelii and 0.06 to 0.5 mg/mL for all other actinomycetes, except for one strain of A. naeslundii and three of four A. bovis strains (MIC, 1.0 mg/mL) (49). Erythromycin was the most active antimicrobial agent in vitro (MIC, 0.12 mg/mL or less). Cephaloridine, minocycline, and clindamycin were also very active in vitro (MIC, 0.003 to 1.0 mg/mL), for a few strains other than A. israelii, the MIC for clindamycin ranged from 2.0 to 8.0 mg/mL. The MIC for cephalothin, ampicillin, lincomycin, tetracycline, doxycycline, and chloramphenicol was within the therapeutic range for all strains of A. israelii and most other species. Metronidazole displayed conspicuously unimpressive in vitro activity, as did the aminoglycosides (49, 59). Lerner found that bothActinomyces and P. propionicum are highly susceptible to penicillin G, erythromycin, clindamycin, and minocycline, and that cephalothin, ampicillin, lincomycin, tetracycline, and chloramphenicol are also active at therapeutic concentrations (49). Peabody and Seabury (65) reviewed in vitro and clinical data up to 1960 for sulfadiazine, streptomycin, erythromycin, chloramphenicol, and the tetracyclines. Cures had been achieved with each alone, or in combinations; in vitro data suggest that Actinomyces are inhibited by chloramphenicol (0.005 to 0.01 mg/mL), erythromycin (0.005 to 0.1 mg/mL), and several tetracyclines. Even streptomycin, considerably less active in vitro, produced excellent clinical results in some cases. Cures have been reported with isoniazid and even stilbamidine (65). In addition, rifampin therapy for suspected tuberculosis may mask undiagnosed pulmonary actinomycosis (40). Fluoroquinolones, aztreonam, fosfomycin, and other aminoglyocosides generally have poor activity against Actinomyces species and P. propionicum (91, 95).

From the short review of the literature given above and numerous additional reports published during the past 40 years, it must be concluded that many details concerning both the in vitro susceptibility of fermentative actinomycetes to antibacterial drugs and the clinical efficacy of these drugs are still controversial. Schaal and Pape (84) demonstrated convincingly that the results of in vitro susceptibility tests of fermentative actinomycetes are highly dependent on the individual test procedures used. For instance, with the agar dilution test, the use of different commercial agar media changed the MICs of P. propionicum for ampicillin, tetracycline, and gentamicin by two to three dilutions. Such discrepancies may even be more pronounced when the results of agar dilution and broth dilution techniques are compared. Disk-diffusion methods are in general not suitable for testing fermentative actinomycetes, at least as far as the slow-growing anaerobic strains are concerned (84).

Different results concerning the clinical efficacy of certain antibacterial drugs may be related to differences in the definition of clinical cure, difficulties in diagnosing human actinomycoses unambiguously, and insufficient characterization of the concomitant actinomycotic flora. The last factor is of particular clinical importance (59) because several characteristic companions of the pathogenic fermentative actinomycetes differ greatly in their antibiotic susceptibility patterns from the actinomycetes themselves. This is especially true for certain black pigmented Bacteroidaceae,Bacteroides species sensu stricto and A. actinomycetemcomitans, but also for aerobically growing members of the synergistic flora such as Staphylococcus aureus or Enterobacteriaceae. Thus, at least 5% of the black pigmented Bacteroidaceae, 10% of the A. actinomycetemcomitans strains and more than 30% of the members of the genus Bacteroides sensu stricto are highly resistant to benzyl penicillin. Therapeutically sufficient susceptibility is only exhibited by 80% of the black-pigmented Bacteroidaceae, 60% of the A. actinomycetemcomitans strains and a few percent of theBacteroides species (59). A detailed description of the in vitro susceptibility of the common concomitant bacteria species to antibiotics would be beyond the scope of this chapter. However, it is well known that strict anaerobes are usually susceptible to nitroimidazoles (e.g., metronidazole) or clindamycin and also to aminopenicillins combined with β-lactamase inhibitors, and carbapenems (e.g., imipenem). A. actinomycetemcomitans, although often resistant or only moderately susceptible to penicillin G, is nearly always susceptible to aminopenicillins such as ampicillin or amoxicillin. The susceptibility patterns of staphylococci and Enterobacteriaceae cannot be predicted and therefore require individual susceptibility test results for optimal treatment. Moreover, it should be noted that all of the fermentative actinomycetes are resistant to metronidazole and that A. actinomycetemcomitans is usually resistant to lincomycins including clindamycin (59). As aminoglycosides (e.g., gentamicin, tobramycin, amikacin) are not active against anaerobes both in vitro and in vivo, these drugs may only be considered when the concomitant flora contains Enterobacteriaceae or other gram-negative aerobically growing rods that are resistant to combinations of aminopenicillins with β-lactamase inhibitors.

Combination Drugs

There are no data on the efficacy of antimicrobial combinations and synergism studies for fermentative actinomycetes.

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General - Drug(s) of Choice

Penicillin in high doses, given over a period of weeks to months, has long been considered the antimicrobial therapy of choice for deep-seated actinomycoses. Prolonged treatment with large doses of the drug is required to achieve drug serum concentrations high enough to ensure drug penetration into areas of fibrosis and suppuration and possibly to penetrate the granules themselves (36). The standard recommendations for penicillin therapy have been to administer intravenous penicillin G, (150,000--200,000 U/kg/day or 10--20 million units per day in divided doses for adults) for 4 to 6 weeks (or for at least 3 to 4 weeks after the patient appears cured), followed by oral penicillin (e.g., phenoxymethylpenicillin, 2--4 g per day, to patient tolerance) for 6 to 12 additional months or even longer duration to prevent relapse. Complications in a given patient -- such as dissemination, critical locations (e.g., CNS involvement), or inability to perform definitive surgery -- may alter or extend this regimen (96).

Clinical resistance to this type of penicillin G treatment may not be a major problem; however, there have been reports of clinical failures and apparently considerably more therapeutic problems that were not published in the literature following penicillin G therapy alone (26, 78). In addition, there have been observations that appear to support the development of acquired resistance to penicillin (7). Garrod claimed that unsuccessful penicillin treatment might be accompanied by increased in vitro resistance; the MICs for two strains of A. israelii increased from 0.03 U/mL to 0.2 U/mL and greater than 0.5 U/mL, respectively (27). Boand and Novak (7) found that strains of A. bovis (probably A. israelii) did not adapt readily to penicillin with serial passage in subinhibitory concentrations of the drug, al­though four of six strains developed two- to fourfold resistance. In vivo development of acquired antimicrobial resistance byActinomyces species, particularly to penicillin G, has not been reported subsequently. When the response to penicillin is poor, a search should be made for an undrained abscess, although it is more likely that unsatisfactory therapeutic results are due to the presence of resistant concomitant bacterial species.

The therapeutic concept outlined above is primarily based on the view that the pathogenic fermentative actinomycetes are the principal or even sole target against which the antimicrobial chemotherapy has to be directed. Considering the impressive amount of bacteriologic data that indicate that human actinomycoses are essentially always synergistic mixed infections, it appears at least worthy to discuss whether or not this concept should be modified. Pulverer and Schaal (68) as well as several other authors have reported on characteristic clinical treatment failures of penicillin G therapy. These findings could be related to the presence either of A. actinomycetemcomitans or of β-lactamase producing Bacteroides species, Staphylococcus aureus, or Enterobacteriaceae. SinceBacteroides species or Enterobacteriaceae are commonly found as concomitant organisms in abdominal and pelvic actinomycoses, the latter usually do not respond well to penicillin G treatment. In contrast, β-lactamase producers as well as penicillin G-resistant strains of A. actinomycetemcomitans are less common in the cervicofacial form of the disease so that many of these cases may be effectively treated with high doses of benzyl penicillin.

Compared with narrow-spectrum penicillins, the aminopenicillins are similarly active against the pathogenic fermentative actinomycetes, but clearly much more effective against A.actinomycetemcomitans both in vitro and in vivo. Thus, therapy with comparatively high doses of aminopenicillins such as ampicillin or amoxicillin (4-8g/day for adults) effectively helps to avoid the characteristic treatment failures or relapses of cervicofacial infections caused by A. actinomycetemcomitans. However, aminopenicillins are also susceptible to β-lactamases so that the presence of bacterial β-lactamase producers may impair their therapeutic efficacy. Therefore, general treatment schemes for human actinomycoses should include drugs that are effective not only against the causative actinomycetes and A. actinomycetemcomitans but also against potential producers of β-lactamases such as Staphylococcus aureus, various gram-negative anaerobes of the familyBacteroidaceae and, in case of abdominal and pelvic actinomycoses, certain Enterobacteriaceae.

On the basis of the above considerations, the current recommendations for antibiotic treatment of human actinomycoses, according to which several hundred cases were treated essentially without any therapeutic failure or relapse, are as follows (78):

Cervicofacial and Thoracoabdominal

For cervicofacial actinomycoses, a combination of amoxicillin and clavulanic acid is the treat­ment of choice. The standard dose is 2.2 g amoxicillin plus clavulanic acid every 8 h for 1 week and then a lower dose of 1.1 g of the same combination every 8 h for another week. Only rarely will delayed clinical improvement of long-term chronic cervicofacial infections indicate that antibiotic treatment of 3 or even 4 weeks, duration is required. Parenteral administration of the drugs is recommended; prolonged oral treatment was never found to be necessary (78). For thoracic actinomycoses, the same therapeutic scheme may be sufficient, although this is still somewhat controversial. Kolditz et al retrospectively reviewed forty nine patients with pulmonary actinomycosis of whom twenty four were treated with ≤ 6 months of antibiotic therapy, and had a 100% clinical cure rate. On the other hand, all six patients that had antibiotics for < 3 months developed recurrence or local complications. The authors recommend against using antibiotic courses of less than 3 months in patients with pulmonary actinomycosis (41). In addition, patients with either advanced chronic pulmonary or abdominal disease may require the addition of 2 g ampicillin every 8 h to increase the aminopenicillin tissue levels (ampicillin is used in addition to amoxicillin to avoid possible side effects associated with high doses of amoxicillin). Treatment of abdominal and pelvic actinomycoses occasionally demands the combination of amoxicillin/clavulanic acid with an aminoglycoside such as tobramycin or gentamicin to inhibit resistant concomitant Enterobacteriaceae.

Special Infection

Endocarditis: Cardiac infection caused by Actinomyces and related species is rare, occurring in less than 2% of reported cases (42). This usually follows local extension of adjacent intrathoracic infective foci (most commonly pulmonary lesions); thus, endocardial involvement is usually secondary to involvement of the myocardium and pericardium. In their recent review of a total of eight cases (seven from the literature) of primary actinomycotic endocarditis, Lam et al. (42) found that the disease affects all ages and occurs predominantly in males. No specific clinical feature distinguishes primary actinomycotic endocarditis from bacterial endocarditis caused by other organisms. In 63% of cases, blood cultures were positive, but detailed information on the species of actinomycetes and possible concomitant organisms etiologically involved is not available.

The recommended initial therapy is high doses of parenteral penicillin (51). Five patients reviewed by Lam et al. received penicillin in daily doses ranging from 60,000 units to 20 million units; duration of treatment ranged from 4 weeks to 10 months (42). In addition, these investigators opted to treat their patient with a 6-week course of intravenous penicillin (18 million units daily) followed by 6 months of oral medication. Both the optimal duration of therapy and the optimal choice of drug in these patients is unknown; Gutschik (29) suggested at least a 4-week course of parenteral penicillin followed by a 4-to 6-week course of oral penicillin. But, despite the use of several alternative agents to penicillin for other forms of actinomycosis, their effectiveness for treatment of endocarditis has not been shown (4). In Lam's series, surgical intervention in actinomycotic endocarditis occurred in 50% patients (42). With penicillin therapy, the survival rate was 80% (four of five patients). Four patients died because the diagnosis was missed or because ineffective antibiotics were administered. However, the prognosis overall was considered to be good with early diagnosis and appropriate antibiotic therapy.

CNS Involvement: CNS involvement by actinomycosis has been recently reviewed in detail (88). Types of CNS lesions include, in order of frequency, brain abscess, meningitis or meningoencephalitis, subdural empyema, and epidural abscess. For nonmeningitic lesions, the clinical presentation is commonly that of a "space-occupying lesion." Optimal management in these patients comprises adequate surgical drainage and prolonged (4--6 months) antimicrobial therapy (88). In Smego's review of 70 reported cases of CNS actinomycosis (88), several classes of antimicrobial agents were used for therapy. In most cases (62%), penicillin G was included in the antibiotic regimen. Other agents included sulfonamides, chloramphenicol, erythromycin, tetracycline, minocycline, streptomycin, ampicillin, gentamicin, metronidazole, isoniazid, potassium iodide, and bacitracin and polymyxin (the last two agents both administered intraoperatively into the abscess cavity or operative site, as well as intrathecally). The median duration of antimicrobial therapy was 2.3 months (range, 2 weeks to 22 months); however, the mean duration for survivors was 4.9 months. Surgical procedures were performed in conjunction with antimicrobial therapy in most of these patients, with the exception of those with meningitis. These procedures included total excision of lesions, open surgical drainage, and closed needle aspiration of lesions. Among these patients, the overall rate of clinical improvement or cure was 72%; however, neurologic sequelae (seizures, motor or sensory deficits, aphasia, deafness, cerebellar ataxia, and visual field defects) were seen in 54% of treated survivors (88). Importantly, relapse occurred in only one patient (32). Initially this patient responded to needle aspiration drainage and combination penicillin G, chloramphenicol, sulfadiazine, and tetracycline (given for an unknown duration) but relapsed after 29 months, with evidence of multiple brain abscesses at surgery. Nevertheless, with surgical excision of these lesions and penicillin G (again for an unreported duration), the patient made a complete recovery. The severity of these infections is apparent from Smego's findings. Despite therapy, the overall mortality from these infections was 28%, and 54% of survivors had neurologic sequelae. A poor prognosis was correlated with disease onset more than 2 months before diagnosis and treatment, no antimicrobial therapy, no surgery, and needle aspiration drainage of abscess lesions (88).

Underlying Diseases

Predisposing Conditions: Actinomycosis usually occurs in immunocompetent persons, but may occur in persons with diminished host defenses. Actinomyces species are generally of low pathogenicity and cause disease only in the setting of antecedent tissue injury. Sabbe and colleagues recently reviewed 294 Actinomyces-like clinical isolates using specific probes for the newly classified Actinomyces species A. turicensis, A. radingae, A. europaeus and concluded that these were not infrequent pathogens and were found in a wide range of human infections (75). A. neuii has also been recovered from immunosuppressed patients with a variety of infections including abscesses, diabetic foot ulcers, cellulitis, and bacteremia (25). Disease due to actinomycetes is often associated with trauma, surgery, aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract, and the presence of intrauterine devices. Implantation of these organisms into damaged tissue eventually leads to chronic, indurated, suppurative infections, often with draining sinuses and fibrosis. Disseminated infection is thought to occur most often in debilitated patients or in patients with impaired immune systems such as those with autoimmune disorders, malignancy, acquired immunodeficiency syndrome (AIDS), and immunosuppressive therapy (89).

Acquired Immunodeficiency Syndrome (AIDS): The relationship between HIV infection and actinomycosis is not well understood. HIV infection does not appear to predispose an individual to develop actinomycosis and actinomycosis is not considered an AIDS-defining opportunistic infection. Despite the impairments of cellular and humoral immunity that accompany HIV infection, the prevalence of actinomycosis in the HIV-infected population has remained low (8). In their review of the English language literature through June 2000, Chaudhry and Greenspan found a total of only 17 reported cases of actinomycosis in HIV-infected and AIDS patients (9). Clinical presentations in these patients included in order of frequency, cervicofacial, thoracic and abdominopelvic disease; there were no reports of cerebral, cutaneous and disseminated actinomycosis. Additionally, there were no reported cases of pelvic actinomycosis in HIV-infected patients. Thirteen of these patients were diagnosed on the basis of histopathologic findings in the context of a consistent history and presentation. Only 4 patients had a positive anaerobic tissue culture for Actinomyces species and in only 3 patients were cultures positive together with demonstration of sulfur granules in infected tissue. Cultures were negative (8 patients), not performed (1 patient), and information regarding cultures was lacking (4 patients). In four severely immunocompromised culture negative patients, acute or subacute necrotizing, ulcerative oropharyngeal actinomycosis progressed rapidly with craniofacial spread and a fatal outcome despite apparent appropriate antimicrobial and operative management. In each of three patients with pulmonary infection, the diagnosis was considered to be "atypical pneumonia" until sulfur granules were identified histologically in transbronchial tissue specimens. Abdominal actinomycosis cases included "actinomycotic esophagitis" (4 patients), perianal actinomycosis (1 patient) and enteritis (1 patient). Combination antibiotic and surgical therapy for actinomycosis is often required in HIV-infected patients and optimal antibiotic treatment is unchanged on account of the patient's positive HIV status. Clinicians should be aware of the possibility of actinomycosis as the cause of a persistent inflammatory lesion in HIV-infected patients.

Alternative Therapy

Antimicrobial agents for use as alternative oral or parenteral therapy in patients with actinomycosis include tetracyclines, erythromycin, clindamycin, and imipenem (65, 78). Tetracyclines may be used in the nonpregnant penicillin-allergic patient and have been reported to be possibly as effective as penicillin in the cervicofacial form of the disease (52). Doxycycline in combination with penicillin has been used successfully in the therapy for muscular actinomycosis in an alcoholic patient and in women with salpingitis (15, 67). Erythromycin also appears to be an acceptable alternative to penicillins (49). Clindamycin orally for a 16-day course has been used in combination with surgical incision and drainage of infected foci in patients with acute mandibular actinomycosis (3, 60), and used in a penicillin-allergic patient with osteomyelitis of the thoracic spine (6). However, clindamycin resistance is common in A. actinomycetemcomitans (59) so treatment failures may occur when this organism is present in the concomitant flora. In addition, Morris and Sewell (54) reported a patient with mixed anaerobic necrotizing pneumonia that did not respond clinically to clindamycin. The patient subsequently developed disseminated infection, and clindamycin-resistant A. actinomycetemcomitans and A. israelii were isolated; the patient was subsequently successfully treated with a regimen consisting of penicillin, ciprofloxacin, and cefazolin. Imipenem may be the most appropriate alternative for penicillins given its high in vitro and in vivo efficacies against both the fermentative actinomycetes and many of the common concomitant species. However, to date, this drug has only rarely been used for treating actinomycotic infections, although it has been used effectively in a diabetic patient with relapsing abdominothoracic actinomycosis unresponsive to a combination of surgery and 4- to 6-week courses of intravenous penicillin G (16), and in a patient with thoracic actinomycosis (101). A recent report by Yew and colleagues reports eight patients treated initially with a 4-week course of imipenem (2 weeks of intravenously administered drug [500 mg at 8 hourly intervals] and 2 weeks of intramuscularly administered drug [500 mg at 12 hourly intervals]) (102). Seven of these patients showed a good clinical, radiographic and bronchoscopically-documented response and 5 remained relapse free after follow up for 18--44 months (mean 30.2 months). One patient was lost to follow up. One patient with treatment failure subsequently received intravenous imipenem for 4 weeks (500 mg 8 hourly) with clinical and radiographic improvement followed by consolidation oral Penicillin G (2 g/day) for a further 12 months, and 3 months after completion of penicillin therapy was asymptomatic with minimal residual radiographic atelectasis. One patient who relapsed 3 months after cessation of initial imipenem therapy underwent bronchoscopy and was found to have an endobronchial foreign body and following its removal received a second 4-week course of intravenous imipenem (500 mg 8 hourly for 2 weeks followed by 500 mg 12 hourly for 2 weeks) and consolidation oral penicillin for 4 months and was asymptomatic after the 4 week parenteral carbapenem and remained free from disease relapse at 32 months after cessation of all drug therapy. Additional alternative drugs that supposedly led to complete cure in selected cases of actinomycosis patients include ciprofloxacin (a prolonged course of this therapy in a patient with a 20-year history of actinomycosis with extensive abdominal and pelvic disease unresponsive to penicillin therapy resulted in an unexpected clinical response (53) and ceftriaxone (administered intravenously once daily on an outpatient basis to a woman with pleural disease and chest wall muscle infection 86). Oral cephalexin and the semisynthetic penicillins oxacillin and dicloxacillin are considerably less active against fermentative actinomycetes in vitro and probably best avoided (49). Smego and Foglia (89) have suggested chloramphenicol, orally or intravenously in a dosage of 50-60mg/kg per day divided every 6 hours, is the preferred agent for treating actinomycosis of the CNS in patients who are allergic to the penicillins, and there is one report of its use to treat A. muris endocarditis (90).

Combination Therapy: Since concomitant bacteria resistant to penicillin or other β-lactam first-line drugs are quite common, the combination of ampicillin and metronidazole or clindamycin has been suggested (20, 84). However, metronidazole alone is not suitable for treating actinomycotic infections because fermentative actinomycetes are generally resistant to this drug (49, 59). In particular, abdominal or thoracic infections that may more frequently contain β-lactamase-producing Bacteroides species and/or Enterobacteriaceae may benefit from addition of metronidazole or clindamycin and an aminoglycoside as a fourth drug (78, 82).

Is Long-term Antibiotic Therapy Necessary for Limited Disease?

Patients with either mild cervicofacial infections or selected pelvic infections who undergo surgery may warrant a shorter course of antibiotic therapy (2, 89). Patients with mild cervicofacial infections may be adequately treated with a 2-month course of oral penicillin or one of the tetracyclines (e.g., doxycycline 100 mg given orally twice daily), without surgical intervention (89). In addition, from their review of 11 cases of pelvic actinomycosis (7 patients had an intrauterine device) who were treated with surgery and penicillin (6 patients for 12 months, 3 patients for 6 months and 2 patients for less than or equal 3 months), Attad and colleagues concluded that in cases where disease is localized to the pelvis and the abscess can be completely removed surgically, a 3 month period of antibiotic therapy can be effective (2).

When using the German therapeutic concept outlined above, long-term antibiotic treatment of human actinomycoses was never found to be needed. As far as early or subacute stages of the cervicofacial form of the disease are concerned, administration of amoxicillin plus clavulanic acid together with incision of the lesions and drainage of pus as adjunctive surgical measures have nearly always resulted in complete cure within two weeks. Only rarely, chronic and extensive cervicofacial processes may require up to four weeks of treatment. Thoracic and abdominal actinomycoses may also respond appropriately to a two-week antibiotic regimen, but the - intravenous- therapy has often to be continued for four and rarely six weeks. In advanced chronic cases, addition ofampicillin to increase aminopenicillin tissue levels or, depending on the composition of the concomitant flora, of metronidazole (or clindamycin) or aminoglycosides may be necessary to achieve prompt cure. Provided that choice of agent, dosage, and duration of primary antibiotic treatment had been adequate, subsequent oral administration of antibiotics of whatever kind never appeared to be an eventual or even essential prerequisite for a favorable outcome of the treatment (79).

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There are no commercially available vaccines for use in the prevention of actinomycosis, but before the modern antibacterial drugs had been introduced into therapy a polyvalent heterovaccine developed by Lentze was shown to provide comparatively good therapeutic results especially in severe chronic cases that had not responded to any other treatment (47).

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Antimicrobial susceptibility testing (minimal inhibitory concentration, minimum bactericidal concentration) and monitoring pre- and post-dose serum drug (penicillin, amoxicillin) levels are probably not indicated in the routine management of this infection since there is almost uniform susceptibility of the fermentative actinomycetes to penicillins. However, clinical nonresponse in a patient to penicillin therapy despite in vitro susceptibility usually indicates co-infection with other resistant microbes.

Imaging Studies

The use of modern radiographic and imaging studies has doubtlessly contributed significantly to improved early recognition and the overall survival of patients with all forms of actinomycosis during the last decade. In addition to providing an earlier diagnosis of actinomycotic infections, repeated imaging studies may be very useful for monitoring a patient's response to antimicrobial therapy, so that the need for possible surgical intervention can be reevaluated.

Chest Radiography: In patients with thoracic actinomycosis, the chest radiograph appearance may be extremely variable. A triad of chronic consolidation, pleural effusion and rib periostitis may be present (97). Development of a pleural effusion without evidence of parenchymal disease in a patient with underlying chronic pulmonary disease may be a significant finding and suggests a need for diagnostic pleural fluid analysis (31). Alternatively, parenchymal lesions mimicking a tumor may be present or cavitary disease resembling tuberculosis may occur. Evidence of adjacent rib erosions may be another useful radiographic sign suggesting formation of an empyema (73).

Other Imaging Studies: A computed tomographic (CT) scan may be an extremely useful diagnostic test that allows for better characterization of both the pattern and extent of disease compared with chest radiographs (10, 63). Intracerebral actinomycotic lesions may show a characteristic ring-shaped contrast enhancement with a low-density center and low-density perifocal edema. Typical CT findings of thoracic actinomycosis include chronic segmental air-space consolidation that contains low-attentuation areas with peripheral enhancement and adjacent pleural thickening (10). The usefulness of abdominal CT examinations has recently been reviewed by Ha (10 patients with abdominal CT) (30). Radionucleotide scanning, (i.e., radionuclide angiography in two cases of hepatic actinomycosis, and bone and gallium scintography in a patient with polyostotic actinomycosis of the upper limb), has been reported (1, 93). In addition, magnetic resonance imaging scanning has been reported to be useful in pelvic actinomycosis in association with IUD use (61, 66), cervicofacial actinomycosis (76), CNS and cervical actinomycosis (4, 63, 70, 71, 77), and actinomycosis with multiple liver abscesses (56). Positron Emission Tomographic (PET) scan imaging has also been found useful in the management of a patient with thoracic actinomycosis (35).



Early effective antimicrobial therapy may obviate the need for surgery or facilitate a more conservative surgical approach. The indications for surgery for patients with actinomycosis must be individualized on the basis of the nature and extent of disease, the presence of complications, and the patient's clinical response to specific antimicrobial therapy. In addition to antibiotic therapy, optimal management of actinomycosis likely may include surgical drainage of empyema and large abscesses and excision of sinus tracts and recalcitrant fibrotic lesions (98). Recently, Fiorino reported that a preoperative diagnosis was made in only 17% patients with pelvic actinomycosis, and emphasized the need for a heightened clinical suspicion and an aggressive diagnostic evaluation (smear, culture, and biopsy) of these patients (21). Although some infected patients require extensive surgery, the conservative management approach may avoid hysterectomy or salpingo-oophorectomy (i.e., sterilizing procedures) for women of childbearing age.

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Actinomycosis is an infrequent sporadic human disease. The natural reservoir for A. israelii and other agents responsible for actinomycosis is man. In the normal oral cavity, these microorganisms grow as saprophytes in dental plaque, and in tonsillar crypts, without apparent invasion or cellular response in adjacent tissues. There are no specific measures for preventing actinomycosis; however, maintenance of good oral and dental hygiene, particularly removal of dental plaque, may reduce risk of oral infection including low-grade periodontal disease withActinomyces species (89). Actinomycosis is a non-notifiable disease and investigation of contacts and a source of infection is not indicated. Similarly, the care of infected patients does not require specific isolation precautions be maintained. Clinicians and patients should be aware of the risk of actinomycosis when intrauterine devices are used.

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Empiric Antimicrobial Therapy

Empirical antimicrobial therapy may mask the clinical manifestations of actinomycosis, since actinomycetes are extremely susceptible to penicillin and other broad-spectrum antibiotics, and is not recommended.

Detection of Actinobacillus on Cervical Smear

Among users of IUDs, the incidence of Papanicolaou smears positive for actinomycetes has ranged from 0 to 31% (mean, 7%) (19). Possible explanations for such variability include differing levels of stringency applied to the evaluation of these smears and misinterpretation of smear findings. Given this variability in Actinomyces detection on Papanicolaou smear, other methods have been suggested to yield more consistent results including endometrial biopsy specimens, cultures of material adherent to IUDs, and the use of immunofluorescence to evaluate cervical smears. Cultures of material adherent to an IUD, and of cervical secretions collected immediately after removal of an IUD revealed fermentative actinomycetes in 8% (18) to nearly 15% (85) of the specimens examined. The following species were identified: A. israelii, 41.2%; A. gerencseriae, 17.3%; A. naeslundii, 4.9%; A. odontolyticus, 2.5%; A. viscosus, 18.5%; A. meyeri, 3.7%; P. propionicum, 1.2%; B. dentium, 1.2%; and R. dentocariosa, 1.2% (total number of isolates: 81) (83). Studies using current methods of actinomycetes detection have shown an increased risk of infection with increased duration of IUD use (21). Currently, the relationship between a Papanicolaou smear positive for actinomycetes and eventual development of pelvic actinomycosis is unclear, and there appears to be no indication for antibiotic treatment in the asymptomatic patient with an incidental finding of actinomycetes on routine cervical smear (8, 19, 21, 50). According to recent consensus guidelines (8), removal of an IUD is advised in a woman who is found to have Actinobacillus-like organisms on a cervical smear and either has symptoms of pelvic infection or who clinically has a pelvic infection and/or pelvic mass not due to other cause. However, a woman with Actinobacillus-like organisms on cervical smear who is asymptomatic and without clinical signs of pelvic infection may have the IUD left in place if the patient is fully counseled regarding the potential risk and symptoms of pelvic actinomycosis and management options and agrees to regular 6 month follow up visits that include a pelvic examination (8).

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