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Actinomycosis: a frequently forgotten disease Lyudmila Boyanova*,1, Rossen Kolarov2, Lyudmila Mateva3, Rumyana Markovska1 & Ivan Mitov1

Abstract Actinomycosis is a rare subacute or chronic, endogenous infection mainly by Actinomyces species, showing low virulence through fimbriae and biofilms. Cervicofacial, thoracic, abdominal, pelvic and sometimes cerebral, laryngeal, urinary and other regions can be affected. Actinomycosis mimics other diseases, often malignancy. Disease risk in immunocompromised subjects needs clarification. Diagnosis is often delayed and ‘sulfur granules’ are helpful but nonspecific. Culture requires immediate specimen transport and prolonged anaerobic incubation. Imaging, histology, cytology, matrix-assisted laser desorption ionization time-of-flight mass spectrometry and molecular methods improve the diagnosis. Actinomycetes are β-lactam susceptible, occasionally resistant. Treatment includes surgery and/or long-term parenteral then oral antibiotics, but some 1–4-week regimens or oral therapy alone were curative. For prophylaxis, oral hygiene and regular intrauterine device replacement are important.

Actinomycosis is a rare disease that can affect many organs of the human body, can present various clinical signs and can resemble malignancy or other diseases. There are difficulties in diagnosis of the infection and in optimizing the treatment regimens. Moreover, many of the associated publications are case reports. The aim of this review is to encompass the current topics and new approaches in the field. Causative agents Actinomycosis is an uncommon subacute/chronic infection caused by anaerobic or microaerophilic/ capnophilic bacteria, mainly within the Actinomyces genus [1,2] . Actinomyces genus belongs to family Actinomycetaceae (the single member of order Actinomycetales) that also includes Arcanobacterium, Actinobaculum, Mobiluncus, Trueperella and Varibaculum [3] . The genomic evolution of the members of the family Actinomycetaceae is dynamic. It has been observed that events of gain or loss of genes in the species of the family contribute to changes in the bacterial behavior and habitat [3] . Although the infection can be associated with bacteria of different genera (Actinomyces, Propionibacterium and Bifidobacterium), in most (≥98%) cases, the causative agents are Actinomyces spp. While some of the species may cause diseases in humans or animals, the actinomycetes are usually soil dwelling bacteria, for example, Actinomyces israelii can be detected in decaying organic matters [4] . Recently, a new species with the proposed name Actinomyces naturae sp. nov. has been isolated from environmental sources [5] .

Keywords 

• A. israelii • Actinomyces • actinomycosis • diagnosis • immunocompromised • molecular methods • prophylaxis • shorter regimens • treatment • virulence

Department of Medical Microbiology, Medical University of Sofia, Bulgaria University Hospital of Maxillofacial Surgery, Sofia, Bulgaria 3 Department of Gastroenterology, University Hospital St Ivan Rilski, Sofia, Bulgaria *Author for correspondence: [email protected] 1 2

10.2217/FMB.14.130 © 2015 Future Medicine Ltd

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Review  Boyanova, Kolarov, Mateva, Markovska & Mitov The clinically important Actinomyces spp. belong to the normal oral flora but also to the gastrointestinal and genital flora of humans and animals and, so, the actinomycosis is an endogenous infection. Actinomyces spp. have been reported to be within the prevalent oral bacteria of the infants [6] . In the oral cavity, the bacteria can be found in dental plaque, carious teeth, periodontal pockets and tonsillar crypts [7] . Actinomyces spp. were previously thought to be fungi due to their branching filaments, however, they are typical bacteria according to their structural characteristics and antibiotic susceptibility patterns [8] . A number of species within the Actinomyces genus are the most common causative agents of human diseases – A. israelii as well as Actinomyces gerencseriae, Actinomyces odontolyticus, Actinomyces meyeri, Actinomyces naeslundii, Actinomyces viscosus, Actinomyces pyogenes, Actinomyces georgiae and Actinomyces graevenitzii [1,7,9–11] . Propionibacterium propionicum (ex-Arachnia propionica) and Bifidobacterium dentium (ex-Actinomyces eriksonii) are also linked to infections [1] . Among all infections with the involvement of Actinomyces spp., Danish authors have reported Actinomyces turicensis and A. meyeri in 22.2% each; A. israelii, Actinomyces neuii and Actinomyces radingae in 11.1% each; and A. odontolyticus, A. viscosus, A. naeslundii and A. gerencseriae in 5.6% each [12] . According to two recent studies [2,13] , the most frequent causative agent of the actinomycosis is A. israelii (median, 72.7% of cases), but other species such as A. naeslundii (median, 7.0%), A. viscosus (median, 4.8%), P. propionicum (median, 3.3%), A. gerencseriae (median, 2.0%), A. odontolyticus (median, 1.4%) and A. meyeri (median, 1.0%) have been detected as well. B. dentium, A. georgiae, and A. neuii have been isolated in 20% and pelvic region in approximately 3–5% (Figure 1) [2,20,31,32] . ●●Cervicofacial (head & neck) actinomycosis

Cervicofacial actinomycosis is the most frequent disease form and usually presents as a chronic,

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Ref. [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [2] [13] [13] [2] [13]

painless or occasionally painful soft-tissue swelling of the submandibular or perimandibular region, draining sinus tracts with sulfur granules, difficulties in chewing and chronic/relapsing course of the infection [27] . It is important that the duration of the symptoms before diagnosis can be long, ranging from 4 days to 1 year [13] . Risk factors for cervicofacial and oral actinomycosis are dental procedures such as dental extractions, dental caries, trauma, gingivitis, chronic tonsillitis, periodontal disease, otitis or mastoiditis, possibly diabetes and immunosuppression, malnutrition, and local tissue injuries by tumors, surgery, or irradiation [13,33–34] . It is generally accepted that the risk for actinomycosis is comparable in immunocompromised and immunocompetent subjects [35] . It is known, however, that the chronic hyperglycemia in diabetic patients is associated with higher rates of infections compared with those in nondiabetic subjects as well as with structural changes in the tissues and impaired wound healing [36] . In addition, two cases of cutaneous actinomycosis

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Figure 1. Proportion of the forms of the actinomycosis.

associated with immunosuppressive anti-TNF-α therapy have been recently reported [35] . The possibly elevated risk for actinomycosis in the immunocompromised subjects requires evaluation in more studies. Importantly, a fatality was reported in an elderly, immunocompromised patient due to actinomycosis of the tonsil causing a hemorrhage [37] . ●●Thoracic actinomycosis

Risk factors for thoracic actinomycosis are aspiration of oropharyngeal secretions in patients with poor dental hygiene, seizure disorder or alcoholisms or, rarely, penetration of the bacteria by esophageal perforation [7,38] . Thoracic actinomycosis exhibits a pulmonary infiltrate, causing cough and hemoptysis (most common clinical signs), chest wall pain, weight loss, sputum production or draining sinuses from the chest wall (in up to 11% of cases) and later can be disseminated to the pleura, pericardium or chest wall [7,27,39,40] . Some patients had the history of tuberculosis or bronchiectasis [40] . The duration of symptoms before the diagnosis ranged from 1 to 12 (usually 3) months [13,39] . Differential diagnosis can involve lung cancer (most often), mycobacterial infections, pulmonary aspegilloma, lung abscess and pneumonia  [39] . A. graevenitzii has been recently associated with thoracic actinomycosis [11] . ●●Abdominal (gastrointestinal)

actinomycosis

Risk factors for the abdominal form can be abdominal operations, perforated acute appendicitis or colonic diverticulitis, mesenteric

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vascular insufficiency, ingestion of foreign bodies, caesarean sections or presence of prosthetic devices such as intrauterine device (IUD) contraceptives [31,38] . The disease presents classically as a slowly growing tumor, usually (in 65%) at the ileocecal region (less often at the stomach, duodenum, liver, rectum or several organs), causing vague abdominal pain, weight loss, low-grade fever, nausea or vomiting [16,27,31] . Abdominal actinomycosis can exhibit indolent and nonspecific signs, thus, its preoperative diagnosis can be a clinical challenge [26] . Hepatic disease has been observed in 15% of immunocompetent subjects with abdominal actinomycosis [7] . Actinomycosis of the rectum was described and clinically resembled a malignant tumor [41] . Cases of splenic and esophageal actinomycosis were also found [42,43] . Abdominal actinomycosis can occur at any age, with a peak incidence approximately age 40 years [31] . ●●Pelvic actinomycosis

Actinomycosis of the female genital tract is most often observed in women with prolonged IUD use (for >2 years, usually 7 years), vaginal pessaries or tampons [2,20,24,44] . In Japan, >90% of women with pelvic actinomycosis were IUD users [44] . The bacteria from the perineum can reach the vagina and cervix and the traumatic effect/mild inflammation caused by the IUDs facilitates the growth of Actinomyces spp. and other anaerobes  [18] . It seems that metal-containing IUDs were less frequently colonized by Actinomyces spp. compared with the plastic IUDs [18] .

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Actinomycosis: a frequently forgotten disease  Importantly, 1.6–11.6% (often 7%) of the IUD users are infected by Actinomyces spp., most often A. israelii  [18,20,45] . The presence of Actinomyces spp. in cervical smears shows an increased risk for developing actinomycosis  [18] . In a French study, the Actinomyces frequency increased with the IUD duration of wearing: 15% of smears were positive after 2–3 years, 30% after 4–5 years and 50% after 6–7 years [32] . Abdominal surgery, perforated appendicitis, tubo-ovarian abscesses and tumors can also be associated with pelvic or abdominal actinomycosis [46] . Differential diagnosis of the pelvic actinomycosis often involves genital tumors, pelvic inflammatory disease and endometriosis [18] . Uterus, fallopian tubes, ovaries and bladder can be affected by the female pelvic actinomycosis. Pyometra perforation with peritonitis by A. israelii has been described in woman with diabetes mellitus but without IUDs [17] . The symptoms are often nonspecific and the most common clinical complaints are lower abdominal discomfort, abnormal vaginal bleeding or discharge [27,46] . ●●Disseminated actinomycosis

Although seldom, disseminated actinomycosis may result from hematogenous dissemination of the infection and can affect multiple organs/tissues, most often the lungs and liver [1] . The disseminated disease resembles metastatic tumors due to the many nodules, however, the clinical signs can be minimal [1] . ●●Actinomycosis of the CNS

Cerebral actinomycosis can present as a brain/ epidural abscess, meningitis or meningoencepalitis or subdural empyema [23] . Hematogenous spread from the teeth or thorax or the direct extension of the cervicofacial infection can lead to actinomycosis of the CNS. Cerebral actinomycosis as a brain (thalamic) abscess caused by A. meyeri has been recently reported in an immunocompetent patient [23] . Among the actinomycosis forms, the cerebral actinomycosis is linked to the highest mortality rate and neurologic complications observed in half of the patients [26] . ●●Actinomycosis of the bone & skin

Mandibular actinomycosis was associated with involvement of the masseter, lateral/medial pterygoid muscles, parotid/submandibular

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glands or parapharyngeal space [47] . The bone infection is frequently an extension of soft tissue infection and less often the result of traumas such as fractures or hematogenous spread. A. meyeri cervical actinomycosis with paravertebral abscess and spondylitis was reported in an immunocompetent man [48] . There is also a report about actinomycosis and osteomyelitis of the temporal bone [49] . Cutaneous actinomycosis has been observed in immunosuppressed patients with rheumatoid arthritis and psoriasis [35] . This actinomycosis form often results from injury or spread from different organs [50] . Primary penile actinomycosis clinically mimicking an epidermal cyst has been observed in a 26-year-old man without immune suppression [50] . ●●Others sites

Actinomycosis of the larynx was found in immunocompromised patients [51,52] . Vocal cord actinomycosis mimicking a laryngeal carcinoma or papilloma has been described as well [53] . Many patients with laryngeal actinomycosis had a history of laryngeal cancer and symptoms that mimic the tumor or tumor relapse [54] . Actinomycosis case affecting the middle ear and mastoid due to A. meyeri was also observed [55] . Although rare, the actinomycosis of the urinary tract poses serious risks. Actinomycosis of the urinary bladder, renal actinomycosis with associated renal vein thrombosis and a fatal case of combined renal/thoracic actinomycosis were observed [56–58] . Actinomycosis may appear very late after an intervention or trauma. Orbital actinomycosis can originate from oral cavity, paranasal sinuses and trauma [59] . In one case, orbital actinomycosis developed after an uncommonly long delay of one year following a severe scalp injury [59] . Differential diagnosis of the infection can be abscesses, subperiosteal hematomas, orbital pseudotumors and lymphangiomas [59] . A case of secondary actinomycosis that affects the muscles (psoas) was observed in a woman 3 months after her IUD removal [60] . Recently, a case of sepsis caused by A. naeslundii and Pseudomonas aeruginosa has been reported in a patient with abdominal actinomycosis and prior (two month beforehand) colonoscopy [61] . Cardiac (in most cases pericardial) involvement can occur in about 2% of actinomycosis cases [26,62] . The cardiac infection is frequently a result of direct spread of thoracic or

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Review  Boyanova, Kolarov, Mateva, Markovska & Mitov mediastinal actinomycosis and rarely of hematogenous spread [62] . A case of acute cardiac tamponade due to multiple abscesses of the liver has been reported [62] . The great imitator Clinical picture of the actinomycosis can mimic different diseases, for example, tumors, tuberculosis, nocardiosis, fungal or other diseases [16,34] , consequently, diagnosis may be very difficult. Gram staining of Nocardia spp. is morphologically similar to that of Actinomyces spp. and many clinical signs of the chronic infections are also similar. Most commonly, the actinomycosis presents as a slowly progressive, indolent infiltration with dense fibrosis, multiple abscesses, fistulas and draining sinuses. Rarely, the infection is acute and rapidly progressive [34] . Pulmonary actinomycosis shows no specific clinical/radiologic signs and can be misdiagnosed as lung cancer (most often), tuberculosis, lung abscess, fungal infections or pulmonary infarctions [7,39,40] . The abdominal actinomycosis in tumor-like form can mimic the digestive cancers, Crohn’s disease, appendicitis, diverticulitis, intestinal tuberculosis, and amebiasis [16,31] . There are many reports about cases of actinomycosis that were initially diagnosed as tumors. Mixed infection of A. israelii, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, and Fusobacterium nucleatum was initially thought to be a perispinal tumor [19] . A. naeslundii actinomycosis involving the hard palate of a diabetic patient was first thought to be epithelial malignant tumor [34] . Urachal actinomycosis was initially mistaken with urachal adenocarcinoma [63] . Abdominal actinomycosis with involvement of the abdominal wall was initially diagnosed as carcinoma of the transverse colon  [16] . Similarly, a patient was operated on urgently because of suspected colon cancer with bowel obstruction [64] . Pelvic actinomycosis may be mistakenly identified as advanced ovarian cancer [65] . Due to the nonspecific symptoms, only 4.5–10% of the abdominopelvic actinomycosis cases were diagnosed before surgery [24] . Simultaneous presence of both actinomycosis & other diseases Importantly, a simultaneous presence of both actinomycosis and another severe disease can occur. Cases of both biliary actinomycosis and

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gallbladder adenocarcinoma and rectal actinomycosis over an anorectal melanoma have been reported [26,66–67] . Coinfections can also occur. Simultaneous occurrence of actinomycosis and aspergillosis in a maxillary sinus and a coinfection of actinomycosis of the cecum and entamoeba infection have been described [68,69] . Coinfection with both A. naeslundii and Neisseria gonorrhoeae can also occur in some patients carrying IUDs [70] . Thus, the complex and thorough evaluation of the patients should not be omitted. Diagnostics Diagnosis of the actinomycosis can be very difficult and is frequently delayed owing to prolonged and nonspecific clinical signs [7] . Laboratory findings, showing mild leukocytosis as well as increased C-reactive protein levels and erythrocyte sedimentation rate can be observed [27,44] . Clinical observation is the start of the diagnostic process. For instance, the cervicofacial actinomycosis should be suspected in patients with persistent or recurrent head and neck swelling, especially in the presence of poor dental hygiene and fistulas (sinus tracts) yielding sulfur granules [31,38] . However, the growth of Actinomyces spp. does not always mean actinomycosis and, conversely, negative test results cannot rule out the disease [13] . Only the consideration of both clinical findings and the results of the diagnostic methods can provide an accurate and reliable diagnosis of the infection. In our previous study, the accurate diagnosis of facial actinomycosis of a patient was made 6 months after the start of the disease followed by numerous short-term inappropriate antibiotic therapies [33] . ●●Imaging

Imaging can reveal some specific feature of the actinomycosis, such as a highly infiltrative mass with suppurative necrosis inside. For example, a strongly enhanced mass with lack of reactive lymph nodes or only a few of them at the computed tomographic image is suggestive for cervicofacial actinomycosis [71] . Specific imaging results can help with the diagnosis of mandibular actinomycosis [47] . Significance of pelvic ultrasound and angioscanner to assess the patients of reproductive tract actinomycosis has been emphasized by Marret et al. [32] . Imaging can also facilitate the differentiation between actinomycosis and malignancy.

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Actinomycosis: a frequently forgotten disease  CT scan is especially helpful for the diagnosis of the pelvic actinomycosis since, unlike the ultrasound, the high-resolution diagnostic imaging of the technique can distinguish between malignant and nonmalignant diseases [18] . ●●Clinical specimens

Microbiological diagnosis of actinomycosis is the isolation of the causative agent from a sterile body site. The best clinical specimens are deep needle aspirates, pus, sulfur granules from draining sinuses and tissue biopsy specimens (Figure 2) . Conversely, swabs, urine, sputum or bronchial washing specimens are unsuitable  [7,27,39] . Invasive procedures, for example, bronchoscopic and surgical biopsies or semi-invasive procedures are needed to confirm the diagnosis of pulmonary actinomycosis [40] . Specimens from the uterine cavity, fimbrial lumen or pelvis are appropriate to diagnose pelvic actinomycosis [18] . ●●’Sulfur’ granules

The yellowish ‘sulfur granules’ of diameter usually ≤1 mm, looking usually like hair tufts, represent microcolonies of Actinomyces spp. and co-infecting bacteria in the center enclosed by

clubbed filaments and polymorphonuclear neutrophils  [8,27,38] . The granules can be crushed between two slides, stained, for example, by Gram or methylene-blue staining, and evaluated by microscopy. It should be taken into account, however, that the granules are not specific to actinomycosis and similar observations can be found in Nocardia brasiliensis and Streptomyces madurae infections [16,27] . Moreover, the presence of the sulfur granules is inconsistent and has been found in half of the cases of abdominal actinomycosis [31] . ●●Culture

Optimal diagnosis for actinomycosis should be performed quickly and reliably, while the culture can be a helpful complement to the other diagnostic methods that offer faster results. The clinical specimens (see section ‘Clinical specimens’) should be transported immediately in anaerobic transport media and cultured under anaerobic conditions [27] . Immediate transport of the specimens is of utmost importance for the isolation of Actinomyces spp. Notably, it is recommended to transport the specimens to the laboratory and to process them in ≤15 min [72] .

Clinical observations

Anamnesis

Clinical specimens

Imaging

Direct staining

Review

Conventional staining

Clinical laboratory findings

Histopathology

Molecular methods Real-time PCR

Molecular methods

Culture Gram staining

16S rRNA gene sequencing

Isolation

FISH

Molecular methods

Conventional biochemical tests Susceptibility testing

MALDI TOF DNA–DNA hybridization

Figure 2. Diagnostic methods for actinomycosis. MALDI-TOF: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

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Review  Boyanova, Kolarov, Mateva, Markovska & Mitov It is crucial that the laboratory is warned about the clinical suspicion of actinomycosis as the Actinomyces spp. are fastidious and slowgrowing, anaerobic or microaerophilic bacteria that require prolonged anaerobic incubation of cultures (5–20 days, often 7–14 days), [31,73] . Culture results can be negative in 5.5 to >50%, usually in half of the cases of actinomycosis  [7,13,34] . Therefore, obtaining several specimens in case of suspicion of actinomycosis is necessary to improve the detection of the bacteria by the culture. The culture can fail because of preceding antibiotic therapy or poor methodology [9] . The growth of coinfecting bacteria makes the diagnosis even more complicated. It is recommended to use two media in parallel for isolation of Actinomyces spp., for example, a nonselective medium, such as fastidious anaerobe agar or enriched Columbia agar with 5% sheep blood and a selective medium containing metronidazole 10 mg/l to suppress most anaerobes, and nalidixic acid 30 mg/l to inhibit the majority of aerobes, mainly Gram-negative bacilli [31,73] . Arginine glycerin salt agar has also been used [44] . Actinomyces spp. are beaded, branched, filamentous or pleomorphic Gram-positive (irregularly staining) rods. By Gram staining, A. israelii appears as Gram-positive straight or slightly curved rods, sometimes with bulge terminals. Other species such as A. meyeri can appear as small bacilli singly or in pairs with V-like arrangements like the corynebacteria [31,73] . The presence of the ‘sulfur’ granules as well as Gram staining can be helpful for the diagnosis of the actinomycosis. Diagnosis can also be made by histopathology. Some Actinomyces colonies appear as molar tooth colonies on solid media or as breadcrumb colonies in liquid media [1] . For instance, the colonies of A. israelii and A. gerensceriae can show breadcrumb or molar tooth appearance; those of A. odontolyticus are red/brown, smooth and convex; and those of A. naeslundii, A. meyeri and A. georgiae exhibit smooth and convex appearance with white color [73] . However, at times, the colonies of A. israelii are not molar tooth-like but are nonspecific, and the bacteria can be overlooked [12] . Importantly, the use of only phenotypic tests based on biochemical characteristics may lead to misidentifications [10] . However, the phenotypic tests were useful for identification of strains with closely related DNA sequences [12] .

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Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDITOF MS) can be a helpful technique for rapid identification of the bacteria. In a study of Ng et al. [74] , MALDI-TOF MS correctly identified 97% of isolates to the species level versus only 33% by API Coryne. Susceptibility testing of Actinomyces spp. is not regularly performed but can be valuable. It is important that if L-cystein is present in the susceptibility testing media, the activity of the β-lactams can be reduced [12] . ●●Histopathology

Actinomycotic granuloma, often housing sulfur granules, can be observed as a complex of threads and club-shaped patterns, with granulomatous border tissue containing fibroblasts, plasma cells, giant cells and polymorphonucleates [8] . Staining by hematoxylin and eosin, periodic acid-Schiff and Grocott-Gomori’s (or Gömöri) methenamine silver stain, among others, can be used [50] . Histopathological evaluation usually (in threefourths of the cases) reveals only few (≤3) ‘sulfur granules,’ exhibiting basophilic central part and radiating border of eosinophilic clubs by hematoxylin and eosin staining [75] . The histopathological method is highly important. For instance, Actinomyces spp. were found in 32% of formalin-fixed, paraffin-embedded archival specimens (12 serial sections/case) stained with hematoxylin and eosin and periodic acid-Schiff from patients with clinical suspicions of cervicofacial actinomycosis who were negative by the culture and traditional hematoxylin and eosin examination [76] . Better detection of pelvic actinomycosis can be performed by cytology compared with pathology or bacteriology. Imprint IUD cytology before surgery was helpful in women with clinically suspected pelvic actinomycosis [44] . ●●Molecular methods

Precise species identification is important for the therapy of the patients and the associated clinical outcome. However, the conventional methods could be insufficient to identify Actinomyces spp. and there are newly discovered species. Therefore, molecular methods, for example, 16S rRNA gene sequencing, DNA–DNA hybridization, real-time PCR and fluorescence in situ hybridization, can be of utmost importance for the correct identification of Actinomyces spp. [9,11,38,46] . For instance, the accurate identification of Actinomyces hongkongensis from a pelvic

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Actinomycosis: a frequently forgotten disease  abscess of a woman with pelvic actinomycosis was not possible by the conventional phenotypic tests but was performed by partial 16S rRNA gene sequencing [46] . For diagnosis of genital Actinomyces spp., the advantage of PCR over Pap smear examination has been reported by Kaya et al. [77] . DNA sequencing by paraffin-embedded samples can also be useful for the diagnosis [78] . TaqManbased real-time PCR has been carried out to detect numerous bacteria, including Actinomyces spp. [79] . Molecular methods are successfully applied to differentiate between Actinomyces and Nocardia spp. as both bacteria may cause similar clinical syndromes [10] . In situ hybridization using DNA probes directed against variable regions of 16S ribosomal RNA genes of Actinomyces and Nocardia spp. was a rapid and specific technique to distinguish between Actinomyces and Nocardia spp. in formalin-fixed, paraffin-embedded tissue specimens [80] . ●●Other methods

Immunofluorescence may be used to detect the bacteria inside the granules. The results should be interpreted with caution as Actinomyces spp. participate in the normal flora of the oral cavity, intestinal tract and female genital tract. Serologic tests are not useful in diagnosing actinomycosis, however, in a patient, only the serologic test was Actinomyces positive [7,27] . Therefore, if clinical suspicion of actinomycosis is present but the diagnostic tests used are negative, the serology can be used to confirm the diagnosis. Treatment Actinomyces spp. are usually susceptible to numerous antibiotics with some small differences between species (Table 2) . A number of antibiotics that have poor or no activity against Actinomyces spp. are metronidazole, aminoglycosides, aztreonam, co-trimoxazole, penicillinaseresistant penicillins (e.g., oxacillin), cephalexin and, importantly, fluoroquinolones [12,27] . Unpredictable antibiotic resistance in some Actinomyces strains is present. Some A. graevenitzii strains were resistant to ceftriaxone and piperacillin/tazobactam and one P. propionicum strain was blaTEM positive [11,81] . In a Danish study, resistance to meropenem and tetracycline as well as high moxifloxacin minimum inhibitory concentrations (1–32 mg/l in

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21 of 34 strains) were found in Actinomyces strains [12] . These results highlight the need for accurate identification of the bacteria, especially in severe infections. ●●General principle

Most often, treatment of only Actinomyces infection without targeting the coinfecting bacteria is curative, although in some cases, the therapy should be directed against all the clinically important pathogens [2,7] . The question about the need of treatment of all pathogens needs further clarification. Moreover, in addition to actinomycosis, Actinomyces spp. can be found in infections without the distinguishing actinomycetic granuloma, and, according to a Danish study, in some of these cases, the prolonged therapy for the actinomycosis may be unnecessary [12] . The key principle of the therapy of the actinomycosis is to use high doses of antibiotics for a prolonged period (2–6-week intravenous therapy + 6–12-month oral therapy) due to induration of infected tissue, the lack of adequate blood supply and the resulting poor antibiotic penetration into the tissue [7,24] . Penicillin G is the drug of choice for treating actinomycosis. The severe forms of cervicofacial, thoracic and abdominal/pelvic actinomycosis have been treated with parenteral (intravenous) penicillin (dose for adults, penicillin G, usually 12–24 million U daily, 18–24 million U daily for the thoracic form) for 2–6 weeks that has later (after clinical improvement) been replaced by oral penicillin V (or amoxicillin) for at least 6 (6–12) months [1,27,38,40] . Other regimens involve intravenous amoxicillin/ampicillin followed by oral amoxicillin. Alternative agents are amoxicillin/clavulanic acid, imipenem and ceftriaxone as well as chloramphenicol, erythromycin, doxycycline and clindamycin in allergy or nonresponse to penicillin. Prolonged treatment is frequently needed to treat the infection and to prevent relapses. Antibiotic therapy can be combined with surgical treatment for several purposes, for example, to drain abscesses or to relieve obstruction in some cases. Surgical approach is needed in cases of widespread necrotic tissue, fistulas, sinus tracts, in patients nonresponsive to antibiotic therapy and to exclude the presence of malignant tumors [13] . For example, the pulmonary actinomycosis responds well to antibiotic treatment if the infection is not complicated by hemoptysis or bronchopleural fistula, however, the

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Review  Boyanova, Kolarov, Mateva, Markovska & Mitov Table 2. Susceptibility of Actinomyces spp. and Propionibacterium propionicum to some antibiotics according to recent publications. Agent

Species

Detection method

Strains (n)

Resistant strains (n)

MICs (mg/l)

Benzylpenicillin    

Actinomyces spp. Actinomyces spp. Propionibacterium propionicum Actinomyces spp. Actinomyces spp. Actinomyces spp. Actinomyces spp. Actinomyces spp. P. propionicum Actinomyces israelii Actinomyces spp. Actinomyces spp. Actinomyces spp. Actinomyces spp. P. propionicum Actinomyces spp. Actinomyces spp.

E test RT-PCR RT-PCR

34 3 3

0 0 1

≤0.5 NA NA

[12]

E test E test E test E test RT-PCR RT-PCR ADM E test E test E test RT-PCR RT-PCR E test NA

34 34 34 34 3 3 1 34 34 34 3 3 34 NA

0 1 0 0 0 0 1 elevated MIC 0 21 1 0 0 0 All

≤2 0.012–32 ≤1.5 ≤0.094 NA NA 2 ≤0.75 0.064–32 0.094–16 NA NA ≤0.125 NA

[12]

Piperacillin/tazobactam Meropenem Clindamycin Erythromycin Macrolides Macrolides Clarithromycin Linezolid Moxifloxacin Tetracycline     Tigecycline Metronidazole

Ref. [81] [81]

[12] [12] [12] [81] [81] [33] [12] [12] [12] [81] [81] [12] [1]

ADM: Agar dilution method; NA: Not applicable; RT-PCR: Real-time PCR.

surgical approach is valuable in case of persistent hemoptysis [40] . In IUD users with pelvic inflammatory disease, IUD removal and treatment for 2–6 weeks with wide spectrum antibiotics are advisable even if no Actinomyces spp. are detected [1,18] . If advanced pelvic actinomycosis is suspected, the appropriate treatment should start (see above). If Actinomyces spp. are found but the women are asymptomatic, close follow-up is recommended, but not IUD removal is needed [1] . ●●Shorter regimens, oral therapy alone

& new treatments

Importantly, shorter than conventional treatment regimens have also been successful (Table 3) . Notably, mild cervicofacial actinomycosis has been treated successfully by regimens including oral penicillin or tetracycline for ≤2 months [38] . In the study of Moghimi et al.  [13] , the regimens for cervicofacial actinomycosis usually included penicillin and metronidazole for about 1–4 weeks. Although metronidazole is inactive against Actinomyces spp., as the actinomycosis is usually a mixed infection, in the study of Moghimi et al.  [13] , the most common parenteral regimen for cervicofacial actinomycosis has been penicillin G 12 million U/day + metronidazole 500 mg 3/day, the latter to inhibit most coinfecting anaerobes. The start of the therapy

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was by intravenous antibiotics with an earlier shift to oral therapy when clinical improvement was observed [13] . Closer observation of the patients is required, mainly when shorter treatment regimens are planned [38] . In 2000–2010, for cervicofacial actinomycosis, most (>84%) patients were treated with intravenous antibiotics, incision and drainage/debridement of the affected tissues and about 16% of the patients were treated with oral antibiotics [13] . Some patients with mild pulmonary actinomycosis without complications can be treated with oral antibiotics only, however, surgical approach is required for those with complicated pulmonary actinomycosis, including hemoptysis or bronchopleural fistula [40] . The penicillin G antibiotic regimen was recommended to treat patients with thoracic actinomycosis without surgery, while the success of cephalosporins was similar to that of penicillin G for the patients who underwent surgery [40] . The subjects treated with oral antibiotics only had favorable clinical outcome [40] . In the study of Park et al., the cure of thoracic actinomycosis was achieved by antibiotic therapy with (93.3%) or without surgery (84.9%) [84] . It should be mentioned, however, that relapses and treatment failure can occur, especially in the group of the patients treated by medical therapy alone. Importantly, the lack of antibiotic response after one month was the single independent factor for poor treatment outcomes,

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Actinomycosis: a frequently forgotten disease  while no significant difference was linked to comorbidity, lesion, antibiotic therapy duration and initial surgical treatment [84] . The surgical treatment can provide a small advantage in treating the pulmonary form of the disease. In the study of Song et al., amoxicillin– clavulanate (intravenous or oral administration) followed by oral therapy was used for average of 5 months to treat 23 patients with thoracic actinomycosis  [39] . The therapy was curative for 78% of the patients, and the remainder recovered after surgery. However, the treatment success was much higher (94%) among the 17 patients treated by surgery followed by short-term antibiotic therapy [39] . Treatment duration of the abdominopelvic actinomycosis should be established by more studies. With proper control, shorter (2 months) regimens combined with image-guided percutaneous drainage can be used for the pelvic infection [32,46] . Other authors, however, recommend at least 4-week treatment for the abdominal actinomycosis for full recovery [64] . For the drainage of abdominal abscesses and sinuses, the surgical approach is necessary [16] .

Review

In a Korean study of patients with abdominopelvic actinomycosis treated mainly by surgical resection and intravenous penicillin, the treatment duration was 3 months in 60% of the patients, 6 months in 25%, 4 months in 10% and 1 month in 5%, and no recurrence was observed in a 37.5-month follow-up [24] . In a Turkish study, Onal et al. found that in three cases, the outpatient treatment of pelvic actinomycosis by ceftriaxone, following surgery and parenteral penicillin, was curative [85] . Cerebral actinomycosis has been treated successfully with ampicillin for 6 months and rifampicin for the first several weeks to improve the antibiotic penetration in the brain tissue [23] . Some new treatments of the actinomycosis may emerge. There is a preliminary report about bactericidal effect of Nd:YAG laser application against A. israelii [86] . Further studies will assess the therapeutic value of the laser therapy. Prevention Prophylactic measures against cervicofacial and pulmonary actinomycosis are the good oral hygiene and regular dental care [27,40] .

Table 3. Some antibiotic regimens for actinomycosis. Actinomycosis (patients [n])

Intravenous antibiotics (duration)

Oral antibiotics (duration)

General suggestion (NA)

PenG 18–24 MU/day q4h (2–6 weeks) PenG 10–20 MU/day (2–6 weeks) PenG 12 MU/day + Met (1–16 days) Cli 600 mg 3/day (4 days) None

Deep-seated infections (NA) Cervicofacial (10) Cervicofacial (1) Cervicofacial (2) Oral (1) Pulmonary (thoracic, 20) Pulmonary (thoracic, 15)

None PenG 18–24 MU/day (2–6 weeks) None

Pulmonary (thoracic, 17) Pulmonary (thoracic, 23)

Antibiotics (4–12 days) Antibiotics (0–2 days)

Abdominal (2)

PenG 16 MU/day (1–2 months) PenG 16 MU/day (15 days) PenG 20 MU/day (6 weeks) None

Abdominal (1) Pelvic (1) Pelvic (2)

Total antibiotic duration

Surgery

Cure

Ref.

PenV 1–2 g/day q6h (6–12 months) NA

NA

NA

[82]

PenV 2–4 g/day (6–12 months)

NA

Signs†

NA

[1]

Fen 500 mg 4/day + Met 500 mg 4/day (7 days) Cli 600 mg 3/day (7 days) AmC 625 mg 3/day (18 days and unknown) Amo 500 mg 3/day (4 weeks) Amo 750–1000 mg/day (6–12 months) AmC 1500–1750/250–375 mg/day (5 months) Antibiotics (1–4.5 months) Antibiotics (4–6 months)

1–3 weeks

Present

9/10

[13]

11 days 18 days and unknown 4 weeks ≥6.5 months

Present 1/2

1/1 2/2

[13]

None None

1/1 20/20

[2,40]

None

13/15

[39]

Present None

16/17 18/23

[39]

Dox 200 mg/day (6–11 months)

Median, 5 months 1.1–5.8 months 4.0–6.1 months 8–12 weeks

Present

2/2

[31]

Amo 2 g/day (6 months) Amp 2 g/day (2 months) PenV 3g/day (3 months)

6.5 months 3.5 months 3 months

Present Present Present

1/1 1/1 2/2

[83]

[13] [34]

[39]

[31] [83]

If extensive necrotic tissue, fistulas and large abscess. AmC: Amoxicillin–clavulanate; Amo: Amoxicillin; Amp: Ampicillin; Cli: Clindamycin; Dox: Doxycycline; Fen: Feneticillin; Met: Metronidazole; MU: Million units; NA: Not available or nonapplicable; PenG: Penicillin G; PenV: Phenoxypenicillin.

†

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623

Review  Boyanova, Kolarov, Mateva, Markovska & Mitov The IUD users should undergo annual gynecological examinations; moreover, the IUDs should be replaced every 5 years [18] . However, according to Marret et al.  [32] , the risk for Actinomyces colonization of the IUDs increases after 3 to 4 years only, so the replacement period can potentially be shortened. Conclusion Actinomycosis is a rare subacute/chronic infection caused by anaerobic or microaerophilic/capnophilic bacteria, mainly within the Actinomyces genus, and less often by P. propionicum and B. dentium. Prevalence of the causative agents of the actinomycosis is changing and new species are involved. Most infections are mixed infections. Actinomyces virulence is low with a few virulence factors such as fimbriae, peptidoglycan and biofilm production. Many organs and tissues in the human body can be affected by the actinomycosis. The most common forms of the disease are the cervicofacial, thoracic, abdominal and pelvic actinomycosis, however, infections of the CNS, bones and skin, larynx, urinary bladder and even sepsis have been reported. Clinical signs of the actinomycosis can be nonspecific, frequently including indolent infiltration with abscesses and draining sinuses and can mimic other diseases, most often malignancy. Common risk factors for actinomycosis are poor oral hygiene and dental procedures for the cervicofacial form; poor dental hygiene, seizure disorder and alcoholisms for the thoracic form; abdominal operations, perforated appendicitis/ diverticulitis, mesenteric vascular insufficiency and foreign body ingestion for the abdominal form; prolonged IUD use for the pelvic form and injury or dissemination from other organs for the cutaneous form. The elevated risk for actinomycosis in immunocompromised subjects such as those with diabetes is a topic that requires further evaluation. Diagnosis of the infection is often delayed due to the prolonged and nonspecific clinical signs and is difficult owing to the slow growth of Actinomyces spp., their presence as a normal flora and the growth of coinfecting bacteria, and requires careful consideration of both clinical signs and laboratory results. Aspirates, pus, sulfur granules from draining sinuses and tissue biopsies are the most appropriate specimens, however, swabs, urine and sputum specimens are unsuitable. The ‘sulfur granules’ are suggestive for actinomycosis but are not specific for the disease. Culture

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results are negative in about half of the cases. For successful isolation, immediate transport of the specimens, use of both selective and nonselective media and prolonged anaerobic incubation are important. MALDI-TOF is a promising method for rapid identification of the species. Different histopathological staining methods and imprint IUD cytology, computed tomographic imaging as well as immunofluorescence help with the diagnosis. For the accurate identification of Actinomyces spp., the molecular methods such as 16S rRNA gene sequencing, DNA–DNA hybridization and fluorescence in situ hybridization are often required, while the serology is less appropriate. Actinomyces spp. are usually susceptible to numerous antibiotics, however, antibiotic resistant strains of A. graevenitzii and P. propionicum were reported. The usual treatment of the actinomycosis requires high doses of parenteral and then oral antibiotics for a prolonged (6 to >12 month) period as well as surgical approach. Currently, shorter 1–4 week treatment regimens are reported to be successful. Only oral therapy has been curative for mild cervicofacial and thoracic actinomycosis. Therapeutic use of the laser therapy should be further evaluated. For prevention of the infection, good oral hygiene, regular dental and gynecological examinations and IUD replacement every 3–5 years are highly recommended. Future perspective Further studies should be carried out to evaluate the current occurrence of the actinomycosis in different countries and patient groups and the presence or lack of association between the risk for actinomycosis and different diseases or treatments linked to immune suppression. The culture media and methods for better isolation of Actinomyces spp. should be improved and the benefit of MALDI-TOF for rapid and accurate identification of the bacteria should be assessed. There is a need for further development of molecular techniques, including realtime PCR and multiplex PCR as well as commercially available tests for rapid identification of the most common causative agents of the actinomycosis. The need for combination therapy for both Actinomyces spp. and coinfecting microbes versus the treatment of only Actinomyces spp. should be clarified. New shorter than conventional regimens or treatment adjuncts for the disease should be evaluated and applied. As Actinomyces spp. are biofilm producers, the possible role of

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Actinomycosis: a frequently forgotten disease 

Review

Executive summary Causative agents ●●

Common causative agents of the actinomycosis are Actinomyces spp., including Actinomyces israelii, Actinomyces

naeslundii and Actinomyces viscosus in four-fifths of the cases, but other Actinomyces spp. and bacteria from other bacterial genera can also be involved. ●●

Changing prevalence of the causative agents of the actinomycosis reveals A. naeslundii as the second most frequent Actinomyces species and the involvement of new species such as Actinomyces cardiffensis in the etiology.

●●

The causative agents are slow growing Gram-positive anaerobic or microaerophilic/capnophilic bacteria with low virulence, involving fimbriae and peptidoglycan in some species and biofilm production.

The disease ●●

Actinomycosis is an infrequent, endogenous and chronic infection with nonspecific signs, showing draining sinuses, abscesses and fibrosis, and often mimicking other diseases, especially tumors.

●●

The most common forms of the disease are the cervicofacial, thoracic, abdominal and pelvic actinomycosis; however,

numerous organs and tissues such as CNS, bone, skin, larynx, urinary bladder, pericardium and others can be affected. ●●

Actinomycosis has been reported in both immunocompetent and immunocompromised subjects, but the latter may be at elevated risk for the disease.

●●

Actinomyces spp. can cause the disease after disruption of the mucosal barrier and the infection can be facilitated by the coinfecting bacteria.

●●

Fatality still occurs in some cases of actinomycosis.

Diagnostics ●●

Both the presence of clinical signs and laboratory results should be taken into account for the diagnosis.

●●

The results of the culture for isolation and identification of Actinomyces spp. are unsatisfactory but can be improved by immediate transport of the specimens, use of several media and matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

●●

Molecular techniques are most often needed for accurate species identification of the bacteria.

●●

Useful diagnostic methods are imaging, histological/cytological methods and immunofluorescence.

Treatment & prevention ●●

The usual therapy of the actinomycosis consists of intravenous penicillin, shifting to oral antibiotics for a total about

1 year; however, new shorter 1–4-week regimens as well as only oral antibiotic regimens for mild cervicofacial/thoracic actinomycosis have been successfully used. ●●

Surgical approach is required in many cases but a prompt diagnosis of the infection could be helpful to avoid the surgical treatment.

●●

Although rare, antibiotic resistance can occur, b-lactam resistant Actinomyces graevenitzii and Propionibacterium propionicum strains being found.

●●

The application of laser therapy is promising.

●●

Good dental hygiene and intrauterine device substitution every 5 (or better 3–4) years are highly recommended as prophylactic measures against the actinomycosis.

Future perspective ●●

Some topics for further studies are the assessment of current worldwide prevalence of actinomycosis and the role of immune suppression as a supposed risk factor.

●●

Diagnostic improvement can involve optimization of the culture, wider application of new techniques, such as matrixassisted laser desorption ionization time-of-flight mass spectrometry and molecular techniques, and development of new molecular methods.

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625

Review  Boyanova, Kolarov, Mateva, Markovska & Mitov Executive summary (cont.) Future perspective (cont.) ●●

The actinomycosis is a polymicrobial infection, however, when to treat only the Actinomyces spp. or when to target all the important isolates should be more evaluated.

●●

Treatment improvement can involve optimization of the present/development of new short regimens or antibiotic

treatment alone and new approaches such as laser therapy or maybe addition of antibiofilm agents to the treatment regimens. agents with antibiofilm activity for prevention and treatment of the actinomycosis should be elucidated. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a

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Identification of the actinomycetes 16S

Future Microbiol. (2015) 10(4)

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