CHAPTER 47: DIPHTHERIA AND OTHER CORYNEBACTERIAL INFECTIONS

Diphtheria is a nasopharyngeal and skin infection caused by Corynebacterium diphtheriae. Toxigenic strains of C. diphtheriae produce a protein toxin that causes systemic toxicity, myocarditis, and polyneuropathy. The toxin is associated with the formation of pseudomembranes in the pharynx during respiratory diphtheria. While toxigenic strains most frequently cause pharyngeal diphtheria, nontoxigenic strains commonly cause cutaneous disease.

ETIOLOGY

C. diphtheriae is a gram-positive bacillus that is unencapsulated, nonmotile, and nonsporulating. The organism was first identified microscopically in 1883 by Klebs and a year later was isolated in pure culture by Löffler in Robert Koch’s laboratory. The bacteria have a characteristic club-shaped bacillary appearance and typically form clusters of parallel rays, or palisades, that are referred to as “Chinese characters.” The specific laboratory media recommended for the cultivation of C. diphtheriae rely upon tellurite, colistin, or nalidixic acid for the organism’s selective isolation from other autochthonous pharyngeal microbes. C. diphtheriae may be isolated from individuals with both nontoxigenic (tox^–) and toxigenic (tox⁺) phenotypes. Uchida and Pappenheimer demonstrated that corynebacteriophage beta carries the structural gene tox, which encodes diphtheria toxin, and that a family of closely related corynebacteriophages are responsible for toxigenic conversion of tox^– C. diphtheriae to the tox⁺ phenotype. Moreover, lysogenic conversion from a nontoxigenic to a toxigenic phenotype has been shown to occur in situ. Growth of toxigenic strains of C. diphtheriae under iron-limiting conditions leads to the optimal expression of diphtheria toxin and is believed to be a pathogenic mechanism during human infection.

EPIDEMIOLOGY

While in many regions diphtheria has been controlled in recent years with effective vaccination, there have been sporadic outbreaks in the United States and Europe. Diphtheria is still common in the Caribbean, Latin America, and the Indian subcontinent, where mass immunization programs are not enforced. Large-scale epidemics of diphtheria have occurred in the post-Soviet ­independent states. Additional outbreaks have been reported in Algeria, China, and Ecuador.

C. diphtheriae is transmitted via the aerosol route, usually during close contact with an infected person. There are no significant reservoirs other than humans. The incubation period for respiratory diphtheria is 2–5 days, but disease onset has occurred as late as 10 days after exposure. Prior to the vaccination era, most individuals over the age of 10 were immune to C. diphtheriae; infants were protected by maternal IgG antibodies but became susceptible after ~6 months of age. Thus, the disease primarily affected children and nonimmune young adults. In temperate regions, respiratory diphtheria occurs year-round but is most common during winter months.

The development of diphtheria antitoxin in 1898 by von Behring and of the diphtheria toxoid vaccine in 1924 by Ramon led to the near-elimination of diphtheria in Western countries. The annual incidence rate in the United States peaked in 1921 at 191 cases per 100,000 population. In contrast, since 1980, the annual figure in the United States has been <5 cases per 100,000. Nevertheless, pockets of colonization persist in North America, particularly in South Dakota, Ontario, and recently the state of Washington. Immunity to diphtheria induced by childhood vaccination gradually decreases in adulthood. An estimated 30% of men 60–69 years old have antitoxin titers below the ­protective level. In addition to older age and lack of vaccination, risk factors for diphtheria outbreaks include alcoholism, low socioeconomic status, crowded living conditions, and Native American ethnic background. An outbreak of diphtheria in Seattle, Washington, between 1972 and 1982 comprised 1100 cases, most of which were cutaneous. During the 1990s in the states of the former Soviet Union, a much larger diphtheria epidemic included more than 150,000 cases and more than 5000 deaths. Clonally related toxigenic C. diphtheriae strains of the ET8 complex were associated with this outbreak. Given that the ET8 complex expressed a toxin against which the prevalent diphtheria toxoid vaccine was effective, the epidemic was attributed to failure of the public health infrastructure to effectively vaccinate the population. Beginning in 1998, this epidemic was controlled by mass vaccination programs. During the epidemic, the incidence rate was high among individuals between 16 and 50 years of age. Socioeconomic instability, migration, deteriorating public health programs, frequent vaccine shortages, delayed implementation of vaccination and treatment in response to cases, and lack of public education and awareness were contributing factors.

Significant outbreaks of diphtheria and diphtheria-related mortality continue to be reported from many developing countries, particularly in Africa and Asia. Statistics collected by the World Health Organization indicated the occurrence of ~7000 reported diphtheria cases in 2008 and ~5000 diphtheria deaths in 2004. Although ~82% of the global population has been adequately vaccinated, only 26% of countries have successfully vaccinated >80% of individuals in all districts.

Cutaneous diphtheria is usually a secondary infection that follows a primary skin lesion due to trauma, allergy, or autoimmunity. Most often, these isolates lack the tox gene and thus do not express diphtheria toxin. In tropical latitudes, cutaneous diphtheria is more common than respiratory diphtheria. In contrast to respiratory disease, cutaneous diphtheria is not reportable in the United States. Nontoxigenic strains of C. diphtheriae have also been associated with pharyngitis in Europe, causing outbreaks among men who have sex with men and persons who use illicit IV drugs.

PATHOGENESIS AND IMMUNOLOGY

Diphtheria toxin produced by tox⁺ strains of C. diphtheriae is the primary virulence factor in clinical disease. The toxin is synthesized in precursor form; is released as a 535-amino-acid, single-chain protein; and, in sensitive species (e.g., guinea pigs and humans, but not mice or rats), has a 50% lethal dose of ~100 ng/kg of body weight. The toxin is produced in the pseudomembranous lesion and is taken up in the bloodstream, from which it is distributed to all organ systems in the body. Once bound to its cell surface receptor (a heparin-binding epidermal growth factor–like precursor), the toxin is internalized by receptor-mediated endocytosis and enters the cytosol from an acidified early endosomal compartment. In vitro, the toxin may be separated into two chains by digestion with serine proteases: the N-terminal A fragment and the C-terminal B fragment. Delivery of the A fragment into the eukaryotic cell cytosol results in irreversible inhibition of protein synthesis by NAD⁺-dependent ADP-ribosylation of elongation factor 2. The eventual result is the death of the cell.

In 1926, Ramon at the Institut Pasteur found that formalinization of diphtheria toxin resulted in the production of a nontoxic but highly immunogenic diphtheria toxoid. Subsequent studies showed that immunization with diphtheria toxoid elicited antibodies that neutralized the toxin and prevented most disease manifestations. In the 1930s, mass immunization of children and susceptible adults with diphtheria toxoid commenced in the United States and Europe.

Individuals with a diphtheria antitoxin titer of >0.01 U/mL are at low risk of disease. In populations where a majority of individuals have protective antitoxin titers, the carrier rate for toxigenic strains of C. diphtheriae decreases and the overall risk of diphtheria among susceptible individuals is reduced. Nevertheless, individuals with nonprotective titers may contract diphtheria through either travel or exposure to individuals who have recently returned from regions where the disease is endemic.

Characteristic pathologic findings of diphtheria include mucosal ulcers with a pseudomembranous coating composed of an inner band of fibrin and a luminal band of neutrophils. Initially white and firmly adherent, in advanced diphtheria the pseudomembranes turn gray or even green or black as necrosis progresses. Mucosal ulcers result from toxin-induced necrosis of the epithelium accompanied by edema, hyperemia, and vascular congestion of the submucosal base. A significant fibrinosuppurative exudate from the ulcer develops into the pseudomembrane. Ulcers and pseudomembranes in severe respiratory diphtheria may extend from the pharynx into medium-sized bronchial airways. Expanding and sloughing membranes may result in fatal airway obstruction.

APPROACH TO PATIENT

CLINICAL MANIFESTATIONS

Respiratory diphtheria

The clinical diagnosis of diphtheria is based on the constellation of sore throat; adherent tonsillar, pharyngeal, or nasal pseudomembranous lesions; and low-grade fever. In addition, diagnosis requires the isolation of C. diphtheriae or histopathologic isolation of compatible gram-positive organisms. The Centers for Disease Control and Prevention (CDC) recognizes confirmed respiratory diphtheria (laboratory proven or epidemiologically linked to a culture-confirmed case) and probable respiratory diphtheria (clinically compatible but not laboratory proven or epidemiologically linked). Carriers are defined as individuals who have positive cultures for C. diphtheriae and who either are asymptomatic or have symptoms but lack pseudomembranes. Most patients seek medical care for sore throat and fever several days into the illness. Occasionally, weakness, dysphagia, headache, and voice change are the initial manifestations. Neck edema and difficulty breathing are evident in more advanced cases and carry a poor prognosis.

The systemic manifestations of diphtheria stem from the effects of diphtheria toxin and include weakness as a result of neurotoxicity and cardiac arrhythmias or congestive heart failure due to myocarditis. Most commonly, the pseudomembranous lesion is located in the tonsillopharyngeal region. Less commonly, the lesions are located in the larynx, nares, and trachea or bronchial passages. Large pseudomembranes are associated with severe disease and a poor prognosis. A few patients develop massive swelling of the tonsils and present with “bull-neck” diphtheria, which results from massive edema of the submandibular and paratracheal region and is further characterized by foul breath, thick speech, and stridorous breathing. The diphtheritic pseudomembrane is gray or whitish and sharply demarcated. Unlike the exudative lesion associated with streptococcal pharyngitis, the pseudomembrane in diphtheria is tightly adherent to the underlying tissues. Attempts to dislodge the membrane may cause bleeding. Hoarseness suggests laryngeal diphtheria, in which laryngoscopy may be diagnostically helpful.

Cutaneous diphtheria

This dermatosis is characterized by punched-out ulcerative lesions with necrotic sloughing or pseudomembrane formation (Figure 47-2). The diagnosis requires cultivation of C. diphtheriae from lesions, which most commonly occur on the lower and upper extremities, head, and trunk.

Infections due to non-diphtheriae Corynebacterium species and nontoxigenic C. diphtheriae

Non-diphtheriae species of Corynebacterium and related genera (discussed below) as well as nontoxigenic strains of C. diphtheriae itself have been found in bloodstream and respiratory infections, often in individuals with immunosuppression or chronic respiratory disease. These organisms can cause disease manifestations and should not necessarily be dismissed as colonizers.

Other clinical manifestations

C. diphtheriae causes rare cases of endocarditis and septic arthritis, most often in patients with preexisting risk factors, such as abnormal cardiac valves, injection drug use, or cirrhosis.

COMPLICATIONS

Airway obstruction poses a significant early risk in patients presenting with advanced diphtheria. Pseudomembranes may slough and obstruct the airway or may advance to the larynx or into the tracheobronchial tree. Children are particularly prone to obstruction because of their small airways.

Polyneuropathy and myocarditis are late toxic manifestations of diphtheria. During a diphtheria outbreak in the Kyrgyz Republic in 1999, myocarditis was found in 22% and neuropathy in 5% of 656 hospitalized patients. The mortality rate was 7% among patients with myocarditis as opposed to 2% among those without myocardial manifestations. The median time to death in hospitalized patients was 4.5 days. Myocarditis is typically associated with dysrhythmia of the conduction tract and dilated ­cardiomyopathy.

Polyneuropathy is seen 3–5 weeks after the onset of diphtheria and has a slow indolent course. However, patients may develop severe and prolonged neurologic abnormalities. The disorders typically occur in the mouth and neck, with lingual or facial numbness as well as dysphonia, dysphagia, and cranial nerve paresthesias. More ominous signs include weakness of respiratory and abdominal muscles and paresis of the extremities. Sensory manifestations and sensory ataxia also are observed. Cranial nerve dysfunction typically precedes disturbances of the trunk and extremities because of proximity to the site of infection. Autonomic dysfunction also is associated with polyneuropathy and can lead to hypotension. Polyneuropathy is typically reversible in patients who survive the acute phase.

Other complications of diphtheria include pneumonia, renal failure, encephalitis, cerebral infarction, pulmonary embolism, and serum sickness from antitoxin therapy.

DIAGNOSIS

The diagnosis of diphtheria is based on clinical signs and symptoms plus laboratory confirmation. Respiratory diphtheria should be considered in patients with sore throat, pharyngeal exudates, and fever. Other symptoms may include hoarseness, stridor, or palatal paralysis. The presence of a pseudomembrane should prompt strong consideration of diphtheria. Once a clinical diagnosis of diphtheria is made, diphtheria antitoxin should be obtained and administered as rapidly as possible.

Laboratory diagnosis of diphtheria is based either on cultivation of C. diphtheriae or toxigenic Corynebacterium ulcerans from the site of infection or on the demonstration of local lesions with characteristic histopathology. Corynebacterium pseudodiphtheriticum, a nontoxigenic organism, is a common component of the normal throat flora and does not pose a significant risk. Throat samples should be submitted to the laboratory for culture with the notation that diphtheria is being considered. This information should prompt cultivation on special selective medium and subsequent biochemical testing to differentiate C. diphtheriae from other nasopharyngeal commensal corynebacteria. All laboratory isolates of C. diphtheriae, including nontoxigenic strains, should be submitted to the CDC.

A diagnosis of cutaneous diphtheria requires laboratory confirmation since the lesions are not characteristic and are indistinguishable from other dermatoses. Diphtheritic ulcers occasionally—but not consistently—have a punched-out appearance (Fig. 47-2). Patients in whom cutaneous diphtheria is identified should have the nasopharynx cultured for C. diphtheriae. The laboratory medium for cutaneous diphtheria specimens is the same as that used for respiratory diphtheria: Löffler’s or Tinsdale’s selective medium in addition to nonselective medium such as blood agar. As has been mentioned, respiratory diphtheria remains a notifiable disease in the United States, whereas cutaneous diphtheria is not.

TREATMENT

PROGNOSIS

Fatal pseudomembranous diphtheria typically occurs in patients with nonprotective antibody titers and in unimmunized patients. The pseudomembrane may actually increase in size from the time it is first noted. Risk factors for death include bullneck diphtheria; myocarditis with ventricular tachycardia; atrial fibrillation; complete heart block; an age of >60 years or <6 months; alcoholism; extensive pseudomembrane elongation; and laryngeal, tracheal, or bronchial involvement. Another important predictor of fatal outcome is the interval between the onset of local disease and the administration of antitoxin. Cutaneous diphtheria has a low mortality rate and is rarely associated with myocarditis or peripheral neuropathy.

PREVENTION

Vaccination

Sustained campaigns for vaccination of children and adequate boosting vaccination of adults are responsible for the exceedingly low incidence of diphtheria in most developed nations. Currently, diphtheria toxoid vaccine is coadministered with tetanus vaccine (with or without acellular pertussis). DTaP (a full-level diphtheria and tetanus toxoids and acellular pertussis vaccine) is currently recommended for children up to the age of 7; DTaP replaced the earlier whole-cell pertussis vaccine DTP in 1997. Tdap is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine formulated for adolescents and adults. Tdap was licensed for use in the United States in 2005 and is the recommended booster vaccine for children 11–12 years old and the recommended catch-up vaccine for children 7–10 and 13–18 years of age. It is recommended that all adults (i.e., persons >19 years old) receive a single dose of Tdap if they have not received it previously, regardless of the interval since the last dose of Td (tetanus and reduced-dose diphtheria toxoids, adsorbed). Tdap vaccination is a priority for health care workers, pregnant women, adults anticipating contact with infants, and adults not previously vaccinated for pertussis. Adults who have received acellular pertussis vaccine should continue to receive decennial Td booster vaccinations. The vaccine schedule is detailed in Chap. 5.

Prophylaxis administration to contacts

Close contacts of diphtheria patients should undergo throat culture to determine whether they are carriers. After samples for throat culture are obtained, antimicrobial prophylaxis should be considered for all contacts, even those whose cultures are negative. The options are 7–10 days of oral erythromycin or one dose of IM benzathine penicillin G (1.2 million units for persons ≥6 years of age or 600,000 units for children <6 years of age).

Contacts of diphtheria patients whose immunization status is uncertain should receive the appropriate diphtheria toxoid–containing vaccine. The Tdap vaccine (rather than Td) is now the booster vaccine of choice for adults who have not recently received an acellular pertussis–­containing vaccine. Carriers of C. diphtheriae in the ­community should be treated and vaccinated when identified.

Nondiphtherial corynebacteria, referred to as diphtheroids or coryneforms, are frequently considered colonizers or contaminants; however, they have been associated with invasive disease, particularly in immunocompromised patients. These organisms have been isolated from the bloodstream, particularly in association with catheter infection, endocarditis, prosthetic valve infection, meningitis, neurosurgical shunt infection, brain abscess, and peritonitis and often in the setting of chronic ambulatory peritoneal dialysis, osteomyelitis, septic arthritis, urinary tract infection, empyema, and pneumonia, among other infections. Patients infected with these organisms usually have significant medical comorbidity or are immunosuppressed. The nondiphtherial coryneforms are a diverse collection of bacteria that are taxonomically grouped together in the genus Corynebacterium on the basis of their 16S rDNA signature nucleotides. Despite the shared rDNA signatures, these isolates are quite diverse. For example, their guanine-cytosine content ranges from 45% to 70%. Several nondiphtheroid corynebacteria, including Corynebacterium jeikeium and Corynebacterium urealyticum, are associated with resistance to multiple antibiotics. Rhodococcus equi is associated with necrotizing pneumonia and granulomatous infection, particularly in immunocompromised individuals.

MICROBIOLOGY AND LABORATORY DIAGNOSIS

These organisms are non-acid-fast, catalase-positive, aerobic or facultatively anaerobic rods. 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 media, such as Löffler’s, Tinsdale’s, or telluride medium. These cultivation idiosyncrasies have led to a complex taxonomic categorization of the organisms.

EPIDEMIOLOGY

Humans are the natural reservoirs for several nondiphtherial coryneforms, including C. xerosis, C. pseudodiphtheriticum, C. striatum, C. minutissimum, C. jeikeium, C. urealyticum, and Arcanobacterium haemolyticum. Animal reservoirs are responsible for carriage of Arcanobacterium pyogenes, C. ulcerans, and C. pseudotuberculosis. Soil is the natural reservoir for R. equi.

C. pseudodiphtheriticum is a component 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. Infections with C. ulcerans and C. pseudotuberculosis have been associated with the consumption of raw milk from infected cattle.

C. ulcerans

This organism causes a diphtheria-like illness and produces both diphtheria toxin and a dermonecrotic toxin. The organism is a commensal in horses and cattle and has been isolated from cow’s milk. C. ulcerans causes exudative pharyngitis, primarily during summer months, in rural areas, and among individuals exposed to cattle. In contrast to diphtheria, this infection is considered a zoonosis whose person-to-person transmission has not been documented. 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, in unimmunized contacts, administration of the appropriate diphtheria toxoid–containing vaccine) should be conducted. The organism grows on Löffler’s, Tinsdale’s, and telluride agars 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)

Infection caused by C. pseudotuberculosis is rare and is 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 raw 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.

C. jeikeium (group JK)

Originally described in American hospitals, C. jeikeium infection was subsequently reported in Europe. After a 1976 survey of diseases caused by nondiphtherial corynebacteria, CDC group JK emerged as an important opportunistic pathogen among neutropenic and HIV-infected patients. The organism has now been designated a separate species. C. jeikeium forms small, gray to white, glistening, nonhemolytic colonies on blood agar. It lacks urease and nitrate reductase and does not ferment most ­carbohydrates. The ­predominant syndrome associated with C. jeikeium is sepsis with pneumonia, endocarditis, meningitis, osteomyelitis, and epidural abscess. Risk factors for C. jeikeium infection include hematologic malignancy, neutropenia from comorbid conditions, prolonged ­hospitalization, exposure to multiple antibiotics, and skin disruption. There is evidence that C. jeikeium is part of the inguinal, axillary, genital, and perirectal flora of hospitalized patients.

Broad-spectrum antimicrobial therapy appears to select for colonization. Gram’s staining shows gram-positive coccobacillary forms slightly resembling streptococci. Moreover, C. jeikeium is resistant to all antibiotics tested except vancomycin. Effective therapy involves removal of the infectious source, whether a catheter, prosthetic joint, or prosthetic valve. Efforts have been made to prevent C. jeikeium infection by improving hygienic conditions for high-risk patients in intensive care settings with antibacterial soap.

C. urealyticum (group D2)

Identified as a urease-positive nondiphtherial Corynebacterium in 1972, C. urealyticum is an opportunistic pathogen causing sepsis and urinary tract infection. C. urealyticum 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. 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. Vancomycin therapy has been used successfully in severe infections.

C. minutissimum (erythrasma)

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. This microbe has also been associated with bacteremia in patients with hematologic malignancy. Erythrasma responds to topical erythromycin, clarithromycin, clindamycin, or fusidic acid, although more severe infections may require oral macrolide therapy.

Other nondiphtherial corynebacterial infections

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, skin, face, and upper torso of healthy individuals. Also nontoxigenic, this organism has been associated with invasive opportunistic infections in severely ill or immunocompromised patients. C. amycolatum is 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 identified in children with otitis media; it is susceptible to fluoroquinolones, rifampin, tetracycline, and vancomycin but resistant to penicillin G and variably susceptible to macrolides. C. pseudodiphtheriticum (C. hoffmanii) is a nontoxigenic species that is part of the normal human flora. Human infections—particularly endocarditis of either prosthetic or natural valves and invasive pneumonia—have been reported 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 the human respiratory tract and blood. C. afermentans subspecies lipophilum belongs to CDC group ANF-1 and has been isolated from human blood and abscesses. C. accolens has been isolated from wound drainage, throat swabs, and sputum and is typically identified as a satellite of staphylococcal organisms; this species has been associated with endocarditis. C. bovis is a veterinary commensal that has not been clearly associated with human disease. C. aquaticum is a water-dwelling organism that is occasionally isolated from patients using medical devices (e.g., for chronic ambulatory peritoneal dialysis or venous access).

Rhodococcus

Rhodococcus species are phylogenetically related to the corynebacteria. These gram-positive coccobacilli have been associated with tuberculosis-like infections in humans with granulomatous pathology. While R. equi is best known, other species have been identified, including R. (Gordonia) bronchialis, R. (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 and as a cause of related infections in cattle, sheep, and swine. It 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 cannot ferment carbohydrates or liquefy gelatin and is often acid fast. An intracellular pathogen of macrophages, R. equi can cause granulomatous necrosis and caseation. This organism has most commonly been identified in pulmonary infection, but infections of brain, bone, and skin also have 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 by HIV infection. Subcutaneous nodular lesions have also been identified. The involvement of R. equi should be considered when any patient presents with a tuberculosis-like syndrome.

Infection due to R. equi has been treated successfully with antibiotics that penetrate intracellularly, including macrolides, clindamycin, rifampin, and trimethoprim-sulfamethoxazole. β-Lactam antibiotics have not been useful. The organism is routinely susceptible to vancomycin, which is considered the drug of choice.

Other related species

Actinomyces pyogenes

This organism, a well-known pathogen of cattle, sheep, goats, and pigs, causes seasonal leg ulcers in rural Thailand. A few human cases of sepsis, endocarditis, septic arthritis, pneumonia, meningitis, and empyema have been reported. This species is susceptible to β-lactams, tetracyclines, aminoglycosides, and fluoroquinolones.

Arcanobacterium haemolyticum

A. haemolyticum was identified as an agent of wound infections in U.S. soldiers in the South Pacific during World War II. It appears to be a human commensal of the nasopharynx and skin, but has also been implicated in 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, synergy, or opportunistic secondary infection with Epstein-Barr virus. A. haemolyticum has also been reported as a cause of bacteremia, soft tissue infections, 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.