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Anaerobic Gram-Positive Nonsporulating Bacilli (Including Actinomycosis)
Anaerobic gram-positive, nonsporulating bacilli of clinical significance include Actinomyces , Bifidobacterium , Eubacterium , Lactobacillus , Mobiluncus , and Cutibacterium (formerly Propionibacterium ) . A taxonomic revision has placed all Propionibacterium species of the skin microbiota within a new genus: Cutibacterium . Cutibacterium acnes is the best studied species. Actinomyces and Cutibacterium are the most common clinical pathogens and can be differentiated by biochemical reactions and metabolic products. Both show indole-positive reactions. Typically, Cutibacterium produces copious amounts of propionic acid and acetic acid, whereas Actinomyces produces acetic acid in addition to succinic and lactic acid. Actinomyces and Cutibacterium do not have mitochondria or a nuclear membrane. Actinomyces has diaminopimelic and muramic acid in the cell wall, whereas Cutibacterium has lysine. The genus Mobiluncus consists of gram-variable or gram-negative, curved rods with tapered ends, sometimes occurring in pairs with a gull wing appearance. Previously aligned with Bacteroidaceae, Mobiluncus is more closely related to Actinomyces.
Cutibacterium Species
Cutibacterium spp. are pleomorphic, occasionally branching, anaerobic aerotolerant, diphtheroid, gram-positive bacteria. C. acnes is an important part of the normal flora of human skin, and it lives in and around sweat glands and sebaceous glands. Newer genomic, transcriptomic, and phylogenetic studies have allowed better understanding of this pathogen’s importance as the causes of chronic and recurrent infection. C. acnes is present in a biofilm with reduced metabolic activity in medical device–related infections and is most common in children with altered host defenses. Predisposing conditions include a history of surgical manipulation, the presence of a foreign body or medical device, trauma, malignant disease, and primary or acquired immunodeficiency. Cutibacterium spp. (especially C. acnes ) can cause bloodstream infection in immunocompromised people. C. acnes is catalase positive and causes pneumonia in children with chronic granulomatous disease, as well as the following infections: endocarditis in patients with prosthetic or damaged heart valves ; conjunctivitis in contact lens wearers; and infections related to ventriculoperitoneal (VP) shunts, prosthetic joints, peritoneal dialysis, or intravascular catheters. C. acnes osteomyelitis most often follows orthopedic surgical procedures or instrumentation and placement of hardware (e.g., following spinal fusion). Infections can be divided into early (first postoperative month) or late infections. Although C. acnes and Staphylococcus epidermidis are the most common bacterial causes of late postoperative infections, C. acnes also is found in 10%–40% of early postoperative infections.
C. acnes causes inflammation of acne lesions. It causes host proinflammatory activity, thus targeting molecules involved in innate cutaneous immunity, keratinocytes, and sebaceous glands of the pilosebaceous follicle and leading to the development of comedones. In otherwise healthy adolescents with moderate to severe acne, C. acnes can be a rare cause of osteomyelitis, even in the absence of orthopedic surgical procedures or instrumentation. C. acnes also can cause delayed VP shunt infection identified only when cerebrospinal fluid (CSF) and shunt catheters routinely are cultured anaerobically. C. acnes VP shunt infections more often follow valve puncture or distal catheter revision for distal obstruction. Compared with other causes of infection, children with C. acnes VP shunt infections tend to be less systemically ill, and they have only mild CSF pleocytosis and minor changes in CSF glucose and protein concentrations. Because of the slower rate of growth of C. acnes , CSF and catheter tips must be incubated for 5–7 days anaerobically when this organism is suspected. C. acnes can be isolated alone, but more commonly it is mixed with other aerobic or anaerobic bacteria in the following infections: brain abscesses; subdural empyema; parotid, pulmonary, or dental infections, peritonitis; and osteomyelitis. Isolation, however, most frequently represents skin contamination of cultures. Repeated isolation or visualization of Cutibacterum on Gram stain is required to identify true infection. Cutibacterium avidum , also a skin commensal, has recently been recognized as a potential pathogen.
Surgical debridement, incision and drainage, and removal of foreign material are important in the management of Cutibacterium infections. Topical and oral antibiotics play a role in the treatment of moderate to severe acne. The rate of antibiotic resistance, especially to macrolides and tetracyclines, has increased since 2000. One study of children and adults with moderate to severe acne found that antibiotic-experienced (in the penicillin receding 2–6 months) patients were more likely to be colonized with C. acnes resistant to clindamycin, erythromycin, and tetracycline. In a recent study from Singapore, clindamycin resistance (27.2%) was most common followed by erythromycin (26.8%), doxycycline (22.9%), tetracycline (14.6%) and minocycline (1.7%) resistance.
When nonskin clinical isolates of C. acnes were examined for antimicrobial susceptibility, approximately 3% were resistant to tetracycline, 15% to clindamycin, and 18% to erythromycin. No isolate was resistant to linezolid, penicillin, or vancomycin. The variability in C. acnes susceptibility to clindamycin argues for routine antimicrobial susceptibility testing when contemplating treatment other than with penicillin for treatment of significant infections. Metronidazole does not have predictable activity against Cutibacterium and cannot be used for therapy.
Actinomyces Species
Actinomyces spp. are filamentous, branching, gram-positive, pleomorphic, non–spore-forming, catalase-negative, anaerobic, or microaerophilic/capnophilic bacilli. Although many species have been associated with disease in humans, actinomycetes usually are soil dwelling organisms. Actinomyces cannot be distinguished from Nocardia on Gram stain. However, Nocardia spp. grow aerobically and stain with acid-fast technique, and Actinomyces spp. do neither. With the use of 16S (small subunit) ribosomal RNA (16S rRNA) sequencing, at least 30 species of Actinomyces have been identified. A. israelii is the predominant disease-causing species (median, 73% of cases), although other Actinomyces spp., including A. naeslundii (frequent Actinomyces spp.), A. meyeri , A. odontolyticus , A. gerencseriae , and A. viscosus , have also have been implicated. , Most actinomycotic infections are polymicrobial, involving other aerobic and anaerobic bacteria. Co-isolates depend on the source or site of infection and include Aggregatibacter (formerly Actinobacillus ) actinomycetemcomitans , Eikenella corrodens , Bacteroides , Fusobacterium , Capnocytophaga , aerobic and anaerobic streptococci, Staphylococcus , and Enterobacteriaceae.
Pathogenesis
Actinomyces spp. generally have low virulence and are part of the normal flora of the mouth, other sites in the gastrointestinal tract, and the female genital tract. Actinomyces spp. are prevalent in the mouth from infancy and are recoverable from periodontal pockets, carious teeth, dental plaque, and tonsillar crypts. , Actinomyces infections have an endogenous source and are infrequent in children <10 years of age, but these infections are underrecognized probably because of fastidious growth requirements. Actinomyces spp. take advantage of breaches in mucosal barriers or obstruction or aspiration to become pathogenic. , Cervicofacial and oral disease is associated with trauma, dental procedures, eruption of a molar tooth, oral surgical procedures, or dental infection. Pulmonary infections usually follow aspiration of oropharyngeal or gastrointestinal secretions. Other less common routes of infection are extension from cervicofacial disease or spread from the abdomen and, rarely, dissemination through blood from other sites of infection (e.g., pelvic or orofacial). Gastrointestinal infection frequently follows loss of mucosal integrity, which can occur with appendicitis, trauma, or foreign bodies. The use of an intrauterine contraceptive devices and cerclage have been linked to the actinomycosis of the female genital tract.
Actinomyces infections are uncommon and indolent but invasive. Infection generally is polymicrobial and can involve any body organ, including the heart. Other copathogens with Actinomyces act synergistically by enhancing the spread of infection through inhibition of host defenses and reduction of local oxygen tension. The diagnosis often is delayed because of nonspecific and prolonged symptoms. Patients with chronic granulomatous disease have an unusual susceptibility to Actinomyces. Cases of cutaneous actinomycosis have been associated with anti–tumor necrosis factor therapy, HIV infection, and solid organ transplantation.
Clinical Manifestations
Unique characteristics of actinomycosis are indolent inflammation with spreading (“burrowing”) through soft and bony tissue planes to contiguous sites or along fascial planes to remarkably distant sites. The hallmark of actinomycosis is spread that fails to respect tissue planes. Classically, small abscesses form at the site of origin, with extension to form multiple sinus tracts that can drain yellow, gritty, purulent material (sulfur granules) composed of spheroid colonies of radiating club-shaped filaments, neutrophils, debris, and granulomatous reaction. Actinomyces grows in tissues in microscopic or macroscopic clusters of tangled filaments surrounded by neutrophils. The differential diagnosis includes other chronic infections at these sites, including tuberculosis, nocardiosis, and complications of foreign bodies. The most common sites of infection are cervicofacial, abdominopelvic, thoracic, and central nervous system.
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