Nondiphtherial corynebacteria, which are also referred to as diphtheroids or coryneforms, are a widely diverse collection of bacteria that are taxonomically lumped together on the basis of their 16S rDNA signature nucleotides. The diversity of this group is exemplified by the wide range in guanine-plus-cytosine content (45–70%). Although frequently considered colonizers or contaminants, the nondiphtherial corynebacteria have been associated with invasive disease, particularly in immunocompromised patients. Specifically, for example, these organisms have been implicated in bacteremia, endocarditis, and other serious infections, particularly in association with catheters and prosthetic devices. Patients infected with nondiphtherial corynebacteria usually have significant medical comorbidity or immunosuppression. Several of these organisms, including C. jeikeium and C. urealyticum, are associated with resistance to multiple antibiotics. The related organism Rhodococcus equi is associated with necrotizing pneumonia and granulomatous infection, particularly in immunocompromised individuals. Other related species that can cause infections in humans are Actinomyces (formerly Corynebacterium) pyogenes and Arcanobacterium (formerly Corynebacterium) haemolyticum.
Microbiology and Laboratory Diagnosis
These organisms are non-acid-fast, catalase-positive, aerobic or facultatively anaerobic bacilli. Their colonial morphologies vary widely; some species are small and α-hemolytic (similar to lactobacilli), whereas others form large white colonies (similar to yeasts). Many nondiphtherial coryneforms require special medium (e.g., Löffler's, Tinsdale's, or telluride medium) for growth.
Humans are the natural reservoirs for several nondiphtherial coryneforms, including C. xerosis, C. pseudodiphtheriticum, C. striatum, C. minutissimum, C. jeikeium, C. urealyticum, and A. haemolyticum. Animal reservoirs are responsible for carriage of A. pyogenes, C. ulcerans, and C. pseudotuberculosis. Soil is the natural reservoir for R. equi.
C. pseudodiphtheriticum is part of the normal flora of the human pharynx and skin. C. xerosis is found on the skin, nasopharynx, and conjunctiva; C. auris in the external auditory canal; and C. striatum in the anterior nares and on the skin. C. jeikeium and C. urealyticum are found in the axilla, groin, and perineum, particularly in hospitalized patients. C. ulcerans and C. pseudotuberculosis infections have been associated with the consumption of raw milk from infected cattle.
Specific Nondiphtherial Coryneforms
This organism causes a diphtherialike illness and produces both diphtheria toxin and a dermonecrotic toxin. C. ulcerans is a commensal in horses and cattle and has been isolated from cow's milk. The organism causes exudative pharyngitis, primarily during summer months, in rural areas, and among individuals exposed to cattle. In contrast to diphtheria, C. ulcerans infection is considered a zoonosis, and pigs have been identified as a source of human infection; person-to-person transmission has not been established. Nevertheless, treatment with antitoxin and antibiotics should be initiated when respiratory C. ulcerans is identified, and a contact investigation (including throat cultures to determine the need for antimicrobial prophylaxis and vaccination with the appropriate diphtheria toxoid–containing vaccine for unimmunized human contacts) should be conducted. The organism grows on Löffler's, Tinsdale's, and telluride media as well as blood agar. In addition to exudative pharyngitis, cutaneous disease due to C. ulcerans has been reported. C. ulcerans is susceptible to a wide panel of antibiotics. Erythromycin and macrolides appear to be the first-line agents.
C. pseudotuberculosis (ovis)
Infections caused by C. pseudotuberculosis are rare and are reported almost exclusively from Australia. C. pseudotuberculosis causes suppurative granulomatous lymphadenitis and an eosinophilic pneumonia syndrome among individuals who handle horses, cattle, goats, and deer or who drink unpasteurized milk. The organism is an important veterinary pathogen, causing suppurative lymphadenitis, abscesses, and pneumonia, but is rarely a human pathogen. Successful treatment with erythromycin or tetracycline has been reported, with surgery also performed when indicated.
After a 1976 survey of diseases caused by nondiphtherial corynebacteria, CDC group JK was recognized as an important opportunistic pathogen among neutropenic patients and later emerged in HIV-infected patients as a cause of AIDS-associated opportunistic infection. Accordingly, the organism was reclassified as a separate species, C. jeikeium. The predominant syndrome associated with C. jeikeium is sepsis, which can occur in conjunction with pneumonia, endocarditis, meningitis, osteomyelitis, or epidural abscess. Risk factors for C. jeikeium infection include hematologicmalignancy, neutropenia from comorbid conditions, prolonged hospitalization, exposure to multiple antibiotics, and skin disruption. There is evidence that C. jeikeium is part of the normal flora of the inguinal, axillary, genital, and perirectal areas in hospitalized patients.
Broad-spectrum antimicrobial therapy appears to select for colonization. Originally described in the United States, C. jeikeium has also been reported in Europe. The gram-positive coccobacilli, which slightly resemble streptococci, grow as small, gray to white, glistening, nonhemolytic colonies on blood agar. C. jeikeium lacks urease and nitrate reductase and does not ferment most carbohydrates. It is resistant to most antibiotics tested except for vancomycin. Effective therapy involves removal of the source of infection, be it a catheter, a prosthetic joint, or a prosthetic valve. There have been efforts to prevent C. jeikeium infection by use of antibacterial soap in the care of high-risk patients in intensive care settings.
C. urealyticum (Group D2)
Identified as a urease-positive nondiphtherial Corynebacterium in 1972, C. urealyticum is an opportunistic cause of sepsis and urinary tract infection. This organism appears to be the etiologic agent of a severe urinary tract syndrome known as alkaline-encrusted cystitis: a chronic inflammatory bladder infection associated with deposition of ammonium magnesium phosphate on the surface and walls of ulcerating lesions in the bladder. Obstructive uropathy due to this organism has been reported in renal transplant recipients. In addition, C. urealyticum has been associated with pneumonia, peritonitis, endocarditis, osteomyelitis, and wound infection. It is similar to C. jeikeium in its resistance to most antibiotics except vancomycin, which has been used successfully in the treatment of severe infections.
Erythrasma is a cutaneous infection producing reddish-brown, macular, scaly, pruritic intertriginous patches. The dermatologic presentation under the Wood's lamp is of coral-red fluorescence. C. minutissimum appears to be a common cause of erythrasma, although there is evidence for a polymicrobial etiology in certain settings. In addition, this fluorescent microbe has been associated with bacteremia in patients with hematologicmalignancy. Erythrasma responds to topical erythromycin, clarithromycin, clindamycin, or fusidic acid, although more severe infections may require oral macrolide therapy.
Other Nondiphtherial Corynebacteria
C. xerosis is a human commensal found in the conjunctiva, nasopharynx, and skin. This nontoxigenic organism is occasionally identified as a source of invasive infection in immunocompromised or postoperative patients and prosthetic joint recipients. C. striatum is found in the anterior nares and on the skin, face, and upper torso of normal individuals. Also nontoxigenic, this organism has been associated with invasive opportunistic infections in severely ill or immunocompromised patients. C. amycolatum is a species isolated from human skin and is identified on the basis of a unique 16S ribosomal RNA sequence associated with opportunistic infection. C. glucuronolyticum is a nonlipophilic species that causes male genitourinary tract infections such as prostatitis and urethritis. These infections may be successfully treated with a wide variety of antibacterial agents, including β-lactams, rifampin, aminoglycosides, or vancomycin; however, the organism appears to be resistant to fluoroquinolones, macrolides, and tetracyclines. C. imitans has been identified in Eastern Europe as a nontoxigenic cause of pharyngitis. C. auris has been isolated from children with otitis media and is susceptible to fluoroquinolones, rifampin, tetracycline, and vancomycin but resistant to penicillin G and variably susceptible to macrolides. C. pseudodiphtheriticum (C. hofmannii) is a nontoxigenic component of the normal human flora. Human infections—particularly endocarditis of either prosthetic or native valves and invasive pneumonia—have been identified only rarely. Although C. pseudodiphtheriticum may be isolated from the nasopharynx of patients with suspected diphtheria, it is part of the normal flora and does not produce diphtheria toxin. C. propinquum, a close relative of C. pseudodiphtheriticum, is part of CDC group ANF-3 and is isolated from human respiratory tract specimens and blood. C. afermentans subspecies lipophilum belongs to CDC group ANF-1 and has been isolated from human blood and abscess infections. C. accolens has been isolated from wound drainage, throat swabs, and sputum and is typically identified as a satellite of staphylococcal organisms; it has been associated with endocarditis. C. bovis is a veterinary commensal that has not been clearly identified as a cause of human disease. C. aquaticum is a water-associated organism that is occasionally isolated from patients using medical devices (e.g., for chronic ambulatory peritoneal dialysis or venous access).
Rhodococcus species are phylogenetically related to the corynebacteria. These gram-positive coccobacilli have been associated with tuberculosis-like infections in humans with granulomatous pathology. Although R. equi is best known, other species have been identified, including R. (also Gordonia) bronchialis, R. (also Tsukamurella) aurantiacus, R. luteus, R. erythropolis, R. rhodochrous, and R. rubropertinctus. R. equi has been recognized as a cause of pneumonia in horses since the 1920s; it causes related infections in cattle, sheep, and swine. R. equi is found in soil as an environmental microbe. The organisms vary in length; appear as spherical to long, curved, clubbed rods; and produce large, irregular mucoid colonies. R. equi does not ferment carbohydrates or liquefy gelatin and is often acid-fast. An intracellular pathogen of macrophages, R. equi can cause granulomatous necrosis and caseation. The organism has been identified most commonly in pulmonary infections, but infections of brain, bone, and skin have also been reported. Most commonly, R. equi disease manifests as nodular cavitary pneumonia of the upper lobe—a picture similar to that seen in tuberculosis or nocardiosis. Most patients are immunocompromised, often with HIV infection. Subcutaneous nodular lesions have also been identified. The involvement of R. equi should be considered in any patient presenting with a tuberculosis-like syndrome.
Infection due to R. equi has been treated successfully with antibiotics that penetrate intracellularly, including macrolides, clindamycin, rifampin, trimethoprim-sulfamethoxazole, tigecycline, and linezolid. β-Lactam antibiotics have not been useful. The organism is routinely susceptible to vancomycin, which is considered the drug of choice although there may be a role for oral therapies with bactericidal agents such as linezolid.
A cause of seasonal leg ulcers in humans in rural Thailand, A. pyogenes is a well-known pathogen of cattle, sheep, goats, and pigs. A few human cases of sepsis, endocarditis, septic arthritis, pneumonia, meningitis, and empyema have been reported. The agent is susceptible to β-lactams, tetracycline, aminoglycosides, and fluoroquinolones.
A. haemolyticum was identified as an agent of wound infections in U.S. soldiers in the South Pacific during World War II. This organism appears to be a commensal of the human nasopharynx and skin but has been implicated as a cause of pharyngitis and chronic skin ulcers. In contrast to the much more common pharyngitis caused by Streptococcus pyogenes, A. haemolyticum pharyngitis is associated with a scarlatiniform rash on the trunk and proximal extremities in about half of cases; this illness is occasionally confused with toxic shock syndrome. Because A. haemolyticum pharyngitis primarily affects teenagers, it has been postulated that the rash-pharyngitis syndrome may represent copathogenicity or synergy with EBV or opportunistic secondary infection complicating EBV infection. A. haemolyticum has also been reported as a cause of bacteremia, soft tissue infection, osteomyelitis, and cavitary pneumonia, predominantly in the setting of underlying diabetes mellitus. The organism is susceptible to β-lactams, macrolides, fluoroquinolones, clindamycin, vancomycin, and doxycycline. Penicillin resistance has been reported.