Corynebacterium Infections

Corynebacteria (from the Greek words koryne, meaning club, and bacterion, meaning little rod) are gram-positive, catalase-positive, aerobic or facultatively anaerobic, generally nonmotile rods. The genus contains the species Corynebacterium diphtheriae and the nondiphtherial corynebacteria, collectively referred to as diphtheroids. Nondiphtherial corynebacteria, originally thought to be mainly contaminants, have increasingly over the past 2 decades been recognized as pathogenic, especially in immunocompromised hosts.

Approximately 30 years ago, taxonomic changes were made to diverse genera previously included within the coryneform groups. The reclassification is based on the degree of homology of RNA oligonucleotides between groups. Based on this reclassification, for example, Corynebacterium haemolyticum became Arcanobacterium haemolyticum and the JK group became Corynebacterium jeikeium.[1] More recently, Van den Velde and colleagues have suggested that species of corynebacteria would be more correctly identified based on their cellular fatty acid profiles (ie, for the C14 to C20 fatty acids).[2]

Advances in molecular biology and genome analysis now also allow for detailed descriptions of DNA-binding transcription factors and transcriptional regulatory networks. This was first described for Corynebacterium glutamicun. Web-based resources are available online at CoryneRegNet[3] and CoryneCenter.[4]

Prior to the 1990s, the incidence of diphtheria had been declining. However, an epidemic of diphtheria in the former Soviet Union was first noticed in the Russian Republic in 1990 and then spread to the other newly independent states, peaking in the mid-1990s. In some endemic locations, such as India, 44% of throat and nasal swabs tested positive for C diphtheriae and Corynebacterium pseudodiphtheriticum.[5] Today, the more common scenario is nondiphtherial corynebacterial bacteremia associated with device infections (venous access catheters, heart valves, neurosurgical shunts, peritoneal catheters), as well as meningitis, septic arthritis, and urinary tract infections.

For more information about C diphtheriae infections, please see Diphtheria.

Most recently, an increase in nondiphtherial corynebacterial infections of the skin and soft tissues has been reported.[6, 7, 8, 9, 10, 11, 12, 13, 14]

Nondiphtherial corynebacteria also cause chronic and subclinical diseases in domestic animals and can lead to significant economic losses for farmers. Examples of widespread and difficult-to-control infections include Corynebacterium pseudotuberculosis caseous lymphadenitis in sheep, goats, and alpacas; C pseudotuberculosis ulcerative dermatitis in cattle; and urinary tract infections and mastitis (affecting milk production) in cattle due to infection with Corynebacterium renale, Corynebacterium cystidis, Corynebacterium pilosum, and Corynebacterium bovis.[15, 16]

C diphtheriae

C diphtheriae infection typically is characterized by a local inflammation, usually in the upper respiratory tract, associated with toxin-mediated cardiac and neural disease. Three strains of C diphtheriae are recognized, in decreasing order of virulence: gravis, intermedius, and mitis. These strains all produce an identical toxin, but the gravis strain is potentially more virulent because it grows faster and depletes the local iron supply, allowing for earlier and greater toxin production. Toxin production is encoded on the tox gene, which, in turn, is carried on a lysogenic beta phage. When DNA of the phage integrates into the host bacteria's genetic material, the bacteria develop the capacity to produce this polypeptide toxin.

The tox gene is regulated by a corynebacterial iron-binding repressor (DtxR). In the presence of ferrous iron, the DtxR-iron complex attaches to the tox gene operon, inhibiting transcription. In an iron-poor environment, the DtxR molecule is released and the tox gene is transcribed (see the illustration below).

The toxin is a single polypeptide with an active (A) domain, a binding (B) domain, and a hydrophobic segment known as the T domain, which helps release the active part of the polypeptide into the cytoplasm. In the cytosol, the A domain catalyzes the transfer of an adenosine diphosphate-ribose molecule to one of the elongation factors (eg, elongation factor 2 [EF2]) responsible for protein synthesis. This transfer inactivates the factor, thereby inhibiting cellular protein synthesis. Inhibiting all the protein synthesis in the cell causes cell death.

In this manner, the toxin is responsible for many of the clinical manifestations of the disease. As little as 0.1 µg can cause death in guinea pigs. In 1890, von Behring and Kitasato demonstrated that sublethal doses of the toxin induced neutralizing antibodies against the toxin in horses. In turn, this antiserum passively protected the animals against death following challenge infection. By the early 1900s, treating the toxin with heat and formalin was discovered to render it nontoxic. When injected into recipients, the treated toxin induced neutralizing antibodies. By the 1930s, many Western countries began immunization programs using this toxoid.

Adhesion of pathogenic corynebacteria to host cells is a crucial step during infection. Adhesion to host cells is mediated by filaments called fimbrae or pili; the minor pilins SpaB and SpaC are specific adhesins that covalently bind the bacteria to the cell membranes of the respiratory epithelium.[17]

More recently, iron levels have been shown to regulate the adhesion properties of the bacteria; iron-limited conditions promote changes in the cell-surface residues, leading to increased hemagglutination activity and decreased binding to glass.[18]

The disease occurs mainly in temperate zones and is endemic in certain regions of the world. Most US cases are sporadic or occur in nonimmunized persons. Humans are the only known reservoir for the disease. The primary modes of dissemination are by airborne respiratory droplets, direct contact with droplets, or infected skin lesions. Asymptomatic respiratory carrier states are believed to be important in perpetuating both endemic and epidemic disease. Immunization reduces the likelihood of carrier status.

Bacteria usually gain entry to the body through the upper respiratory tract, but entry through the skin, genital tract, or eye is also possible. The cell surface of C diphtheriae has three distinct pilus structures: the main pilus shaft (SpaA) and two small pili (SpaB, SpaC). Adherence to respiratory epithelial cells can be greatly diminished by blocking production of these two minor pili or by using antibodies directed against them.[19]

In most cases, C diphtheriae infection grows locally and elicits toxin rather than spreading hematogenously. The characteristic membrane of diphtheria is thick, leathery, grayish-blue or white and composed of bacteria, necrotic epithelium, macrophages, and fibrin. The membrane firmly adheres to the underlying mucosa; forceful removal of this membrane causes bleeding. The membrane can spread down the bronchial tree, causing respiratory tract obstruction and dyspnea.

The toxin-induced manifestations involve mainly the heart, kidneys, and peripheral nerves. Cardiac enlargement due to myocarditis is common. The kidneys become edematous and develop interstitial changes. Both the motor and sensory fibers of the peripheral nerves demonstrate fatty degenerative changes and disintegration of the medullary sheaths. The anterior horn cells and posterior columns of the spinal canal can be involved, and the CNS may develop signs of hemorrhage, meningitis, and encephalitis. Death is mainly due to respiratory obstruction by the membrane or toxic effects in the heart or nervous system.

In recent years, the epidemiology of C diphtheriae infection has been changing. Increasing numbers of skin, pharyngeal, and bacteremic infections with nontoxigenic bacteria have been reported. Among 828 cultures of nontoxigenic C diphtheriae isolated from different regions of Russia from 1994-2002, 14% carried the gene for the toxin.[20] Molecular characterization based on polymerase chain reaction (PCR) of some of these nontoxigenic strains have demonstrated that the bacteria often contain functional DtxR proteins, which could potentially produce toxin.[21]

Other corynebacteria (ie, diphtheroids)

Nondiphtherial corynebacteria are ubiquitous in nature and commonly colonize human skin and mucous membranes. Only recently has the role of these organisms in human infections been appreciated. In the past, many of these organisms cannot be speciated or typed easily, even in research laboratories; now recent advances in PCR technology are improving our ability to identify these bacteria. Coyle and Lipsky in 1990 reviewed some of the common coryneform bacteria that cause infections.[1]

Specific pathogenic groups or species include the following:

• Corynebacterium ulcerans

• C pseudotuberculosis (also known as Corynebacterium ovis)

• Corynebacterium pyogenes

• A haemolyticum

• Corynebacterium aquaticum

• C pseudodiphtheriticum (also known as Corynebacterium hofmannii)

• Group D2 (also known as Corynebacterium urealyticum)

• Group E

• C jeikeium (ie, group JK)

Since then, more than 80 species have been described,[22]  of which two thirds are either pathogenic in animals, especially in livestock; or can be transmitted to humans by zoonotic contact. Depending on the species, both skin and internal-organ systems can be affected, particularly in patients who are elderly, are immunosuppressed, or have multiorgan dysfunction. Recent genomic analyses of diphtheroids demonstrated diversified genomic island containing genes for virulence and multidrug resistance.[11]  This helps explain why some (eg, group D2) are highly resistant and require susceptibility testing for optimal treatment.

Frequency

United States

C diphtheriae

In immunized persons, the rate of C diphtheriae infection since 1980 has been extremely low (< 5 cases per 100,000 population). Although infection can occur in immunized persons, prior immunization decreases disease frequency and severity. However, disease incidence started to fall even before the widespread use of toxoid. This decline may have been due to a decreasing incidence of bacterial carriers. In addition, immunized persons are less likely to be carriers of toxigenic phages.

Persons who have never been immunized or those incompletely immunized or with waxing immunity are at an increased risk for infection. In the United States, this group mainly consists of poorer individuals and immigrants.

Diphtheroids

Infections with nondiphtherial corynebacteria are being reported more frequently, especially those associated with medical devices such as intravascular catheters, artificial valves, and CNS drainage devices.

Moazzez et al (2007) found that 16% of breast abscesses in an urban county hospital were due to diphtheroids.[23]

International

C diphtheriae infection: In the early 1990s, the World Health Organization (WHO) reported that diphtheria was still endemic in many parts of the world (eg, Brazil, Nigeria, the Indian subcontinent, Indonesia, Philippines, some parts of the former Soviet Union [especially St. Petersburg and Moscow]), with epidemics also reported in republics of the former Soviet Union. The February 2000 supplement (vol.181) of the Journal of Infectious Diseases contains an in-depth evaluation of the epidemic.[24]

The Kyrgyz Republic experienced a widespread resurgence of diphtheria from 1994-1998. Among 676 patients hospitalized with respiratory diphtheria, 163 (24%) were carriers, 186 (28%) had tonsillar forms, 78 (12%) had combined types or delayed diagnosis, and 201 (30%) had severe forms. The highest age-specific incidence rates occurred among persons aged 15 years to 34 years; 70% of cases were among those aged 15 years or older. Myocarditis occurred among 151 patients (22%), and 19 patients died (case fatality rate of 3%).[25]

In another epidemic in the Republic of Georgia from 1993-1996, 659 cases and 68 deaths were reported (case fatality rate of 10%). More than 50% of the cases and deaths were in children aged 14 years and younger (case fatality rate of 16%) and in adults aged 40 years to 49 years (case fatality rate of 19%).[26]

During 2007-2008, 10 European countries screened patients with respiratory infections with throat swabs; carriage rates for nontoxigenic Corynebacterium organisms ranged from 0 to 4 cases per 1000 patients.[27]

Sporadic C diphtheriae infections are reported annually. These include skin and bloodstream infections. A review of 85 isolates from the United Kingdom from 1998-2003 revealed that most the reports came from one hospital in London, suggesting that the true incidence may be higher.[28]

Another recent review of C diphtheriae infections in Brazil and South America emphasized a shift in biotype, with an increase in the dissemination of an atypical sucrose-fermenting biotype, which appears to have an enhanced ability to colonize and to spread.[29]

In New Zealand, C diphtheria infections were associated with infective endocarditis in children in 12% of cases (10 of 85 cases) from 1994-2012.[30]

Diphtheroids

Infections with the nondiphtherial corynebacteria are reported worldwide.[31] Some (eg, group D2) originally reported in Europe are now found in the United States, while the JK group initially reported in the United States is found in Europe.

Egwari et al (2008) found that, in east Africa, 9.7% of odontogenic infections that progressed to sepsis were due to diphtheroids.[32]

The incidence of C ulcerans infections in the United Kingdom associated with contact with exposed animals has increased over the past 2 decades, becoming more common than C diphtheriae infections.[33]

C ulcerans has also been reported in Latin America and one fatal case was noted in Brazil in 2008, in an elderly woman with disseminated disease resistant to penicillin and clindamycin.[34]

Mortality/Morbidity

C diphtheriae

Mortality rates are highest at the extremes of age and in insufficiently immunized persons. However, even partial immunization confers a reduced risk of severe disease. Death usually occurs within the first week, either from asphyxia or heart disease.

Immunity to diphtheria waxes in the absence of booster injections of toxoid or natural infection. Therefore, persons traveling to endemic areas should receive booster injections. At one time, diphtheria immunization was considered lapsed if more than 4 years had elapsed since the last booster. This estimate is probably still relevant for persons traveling to high-risk areas, particularly those in high-risk jobs, such as medical personnel. Otherwise, the routine recommendation is currently for booster injections every 10 years. Annual updates are made each year by the CDC. A complete Adult Immunization Schedule is available from the CDC's National Immunization Program.

Diphtheroids

These infections tend to occur in patients who are elderly, neutropenic, or immunocompromised or who have prosthetic devices (eg, heart valves, dialysis catheters, neurologic shunts).

Race

C diphtheriae

The respiratory form of this disease has no racial predilection. Since 1972, the prevalence of the cutaneous form of the disease has increased in the United States, with a high attack rate among Native Americans and in indigent areas where crowding and poor personal and community hygiene are common. Three outbreaks of C diphtheriae infection, 86% of which were cutaneous, were recorded in Seattle's Skid Road from 1972-1982.[35]

Diphtheroids

No racial predilection exists.

Sex

No sexual predilection is reported for any of the corynebacterial diseases.

Age

C diphtheriae

The incidence of infection in children who are not immunized is reported as 70 times higher than in children who have received primary immunization. In the recent epidemics in the republics of the former Soviet Union, the high rate of infection among adults aged 40 years to 49 years has been attributed to their low levels of immunity.

Diphtheroids

Infections are reported in children and elderly persons.

Vaccination is the key to preventing C diphtheriae infections. Public health services and individual physicians are important resources for providing appropriate treatments. Vaccination is especially important for high-risk groups (eg, children, elderly individuals, immigrants from areas of continued endemic infections).

Infections with other diphtheroids are becoming an increasingly important problem in immunocompromised individuals; updated education of physicians caring for these patients is needed.

For patient education resources, see the Children's Health Center and Public Health Center, as well as Immunization Schedule, Children and Immunization Schedule, Adults.

C diphtheriae

Respiratory: After an incubation period of 2 days to 4 days, patients typically report upper respiratory tract symptoms (eg, nasal discharge, sore throat). The posterior pharynx and tonsillar pillars are most often involved. Onset is often sudden, with low-grade fevers, malaise, and membrane development on one or both tonsils, with extension to other parts of the respiratory system.

Cardiac: The toxic effect in the myocardium characteristically occurs within 1 week to 2 weeks following onset of infection, often when the upper respiratory tract symptoms are improving. Manifestations are due to arrhythmias and congestive heart failure (CHF).

Neurologic: Neurological symptoms can occur immediately or after several weeks. Bulbar symptoms generally occur within the first 2 weeks after disease onset and can range from mild symptoms (eg, difficulty swallowing) to bilateral symmetric paresis of the palatal and ocular muscles. The bulbar symptoms may remit or progress to paralysis of the proximal and then distal skeletal muscles over the next 30 days to 90 days. Although recovery can be very slow, patients generally regain complete neurologic function. Secondary complications include aspiration from bulbar paralysis and bronchopneumonia from respiratory muscle dysfunction.

Skin: Cutaneous infections can occur, often in more tropical climates, presenting as nonhealing ulcers. A recent surveillance study of Native Americans presenting to the Indian Health Service clinics in South Dakota recovered C diphtheriae from six (5%) of the 133 patients, one of whom had skin ulcers.

Diphtheroids

Because these corynebacteria are also pathogenic in animals (eg, C ulcerans, C pseudotuberculosis, C ovis), a history of exposure to sick animals or to animal products (eg, milk, offal, hides) is common. C ulcerans generally causes respiratory symptoms, while C ovis produces a suppurative lymphadenitis.

In hosts colonized with diphtheroids (eg, groups D2, JK), bacteria can be recovered from both skin and mucosal surfaces. Corynebacterium striatum and C pseudodiphtheriticum (or C hofmannii) are normal inhabitants of the anterior nares and skin. Symptoms relate to the organ system affected. Immunocompromised patients appear to have higher colonization rates than healthy persons and may be at a greater risk of developing an infection after being colonized. Bittar et al demonstrated that children with cystic fibrosis in France were often colonized by C pseudodiphtheriticum, while healthy children were not.[17] Antimicrobial resistance is also more common in isolates from immunosuppressed patients.  Bnaya et al[10]  reported that 30% of peritoneal dialysis patients (9/30) with nontubulous peritonitis demonstrated diphtheroid or corynebacteria spp. Catheter removal was required in most patients.

The methods of transmission for nondiphtherial corynebacteria are incompletely understood. Transmission from patient to patient, from colonized hospital staff to patients, and from environmental contamination to patients have all been suggested. In antibiotic-resistant corynebacteria, transmission of the plasmid responsible for the resistance may be important.

C diphtheriae - Respiratory signs

Nasal infection may present as serosanguineous or seropurulent drainage.

With tonsillar and pharyngeal infection, exudates coalesce to form the characteristic pseudomembrane of diphtheria.

The membrane usually is grayish-white, although it can become blackish or greenish with necrosis (see the photograph below).

The extent of disease correlates with the severity of symptoms. Extension of the membrane to the posterior pharyngeal wall, soft palate, or nasopharynx is associated with profound malaise, weakness, cervical adenopathy, and swelling (see the photograph below), which can distort the airway and cause stridor.

Symptoms of hoarseness, dyspnea, stridor, and a loud brassy cough are associated with extension into the larynx and bronchial tree.

Edema and membrane formation can cause further respiratory distress and respiratory muscle fatigue, requiring intubation.

In fatal diphtheria, the airways are edematous, with necrosis of the epithelium covered by the pseudomembrane, and the lungs are hemorrhagic.

C diphtheriae - Cardiac signs

Subtle evidence of myocarditis may occur in many patients, but 10% to 25% of patients develop clinical cardiac dysfunction.

Signs of CHF (eg, cardiomegaly, volume overload) are not uncommon.

C diphtheriae - Nervous system signs

Signs of cranial nerve dysfunction can occur within a few days of disease onset, with paralysis of the soft palate and posterior pharyngeal wall causing dysphagia and regurgitation.

Although the motor component is usually affected most severely, both sensory and motor nerves are affected by the peripheral neuritis that occurs later.

The symptoms start in the proximal muscle groups of the extremities and spread distally.

In mild cases, only the hip girdle muscles may be affected; these patients have trouble getting out of a chair unassisted. In these patients, the motor reflexes of the lower extremities may be normal.

In the most extreme cases, respiratory muscle dysfunction occurs and patients may require respiratory support.

Interestingly, reports show that the paralysis disappears at the same rate that it appears.

Even in extremely serious cases, the neuropathy is reversible with few or no sequelae.

In severe cases, the paralysis can spread to the trunk and cause temporary bowel and bladder dysfunction.

Paresthesias, which mainly occur distally, are the most commonly reported sensory abnormalities.

C diphtheriae - Skin signs

C diphtheriae can cause skin infections with nonhealing ulcers.

A vesicle or pustule develops initially and progresses to one or more punched-out lesions that measure from a few millimeters to several centimeters, with curved elevated margins.

The lesions are initially painful and may be covered with eschar.

After a few weeks, the lesions become painless and often have a serosanguineous exudate.

Diphtheroids

Signs of diphtheroid-associated infection relate to the affected organ systems. Species of corynebacteria recovered from skin ulcers include C ulcerans, C bovis, and A haemolyticum. Those associated with bacteremia and sepsis include C pyogenes; C bovis; Corynebacterium xerosis; and groups D2, E, and JK. Case reports depict that these organisms are associated with endocarditis, prosthetic device infection, pneumonia, septic arthritis, and osteomyelitis.

Type D2 was originally identified as a pathogen causing chronic or recurrent cystitis, bladder stones, and pyelonephritis. People with prior urinary tract abnormalities or who have recently undergone urologic procedures are at highest risk for this disease. C urealyticum has been associated with chronic nephrolithiasis and renal failure.[36]

A haemolyticum is reported to cause as many as 10% of all pharyngitis cases in patients aged 10-30 years. These bacteria are capable of producing an extracellular toxin that can cause an erythrogenic rash associated with the pharyngitis.

C ulcerans usually causes skin infections but is occasionally associated with pharyngitis and respiratory disease. In 1996, a 54-year-old, otherwise healthy woman in Indiana who had never received diphtheria immunization developed a membranous pharyngitis with a toxin-producing strain of these bacteria.[37] More recently, a review of clinical samples from the National Microbiology Laboratory in Canada has demonstrated C ulcerans isolates from blood cultures.[38]

C striatum is an emerging nosocomial pathogen.[12]  It has been found on catheters in patients who are neutropenic and have malignancies and has been recovered from the blood of patients with pleuropulmonary infections, endocarditis, and peritonitis. C striatum found in 11 hospitalized patients with COPD exacerbations and pneumonia was found to be multidrug resistant.[13]

In one heart transplant patient, C striatum was repeatedly cultured from sputum and bronchial lavage fluid.[39] One case of C striatum meningitis was also reported recently.[40]

C pseudodiphtheriticum infection is also found in immunocompromised hosts, associated with both native and prosthetic valve endocarditis, pneumonia, lung abscesses, tracheobronchitis, and suppurative lymphadenitis. In 1995, Manzella and colleagues reviewed the clinical and microbiological features of 17 cases of bronchitis and pneumonia due to C pseudodiphtheriticum that required hospitalization.[41] A more recent study from Brazil found C pseudodiphtheriticum caused urinary tract infections in 29%, respiratory infections in 27%, and intravenous access site infections in 19%.[42]

Group JK can be found on the skin of healthy people. Patients with prolonged hospitalization, neutropenia, or on a prolonged course of antibiotics have a high prevalence for highly resistant JK bacteria. The most common manifestation is endocarditis with bacteremia, often associated with indwelling catheters or artificial valves. A recent review of C JK endocarditis demonstrated that most were treated with many weeks of combined antibiotic therapies, including vancomycin, erythryomycin, ceftazidime, rifampin and doxycycline.[14]

Corynebacteria is often found in the semen of men with inflammatory prostatitis; Türk et al found that more than half of these were isolates were Corynebacterium seminale.[43] However, diphtheroids can be found in the semen of both healthy men and those with chronic prostatitis syndrome.[44]

Moazzez et al (2007) found that 16% of breast abscesses in an urban county hospital were due to diphtheroids.[23] Granulomatous mastitis due to Corynebacterium group G, diagnosed by fine-needle aspirate and culture, was reported by Mathelin et al (2005).[45]   More recently, Williams et al (2021)[9]  found that 52% (22/44) of bacteria in granulomatous mastitis were diphtheroids; corynebacteria and cutibacteria species. In this review, clarithryomycin as the most commonly used antibiotic. 

Cases of Corynebacterium macginleyikeratitis following eye surgery have been reported.[46] In these cases, the bacteria was relatively resistant to extended-spectrum penicillins and fluoroquinolones.

Corynebacterium resistens is a newly described, multidrug-resistant species associated with fatal bacteremia in immunocompromised patients in Japan.[47]

C diphtheriae

Obtain clinical specimens and information regarding the patient's contacts.

Obtain a CBC count and urinalysis because patients often have a moderate elevation in leukocytes and may have mild proteinuria (1+ to 2+ by dipstick).

In the past, C diphtheriae grew on a nutritionally inadequate medium devised by Friedrich Loeffler; the diphtheria organisms initially outgrew the other throat flora. With the Loeffler stain, the bacteria show metachromatic granules and a palisading morphology said to resemble Chinese characters.

Today, diagnoses of C diphtheriae infection can be confirmed definitively by culture on blood agar or selective tellurite media, which inhibits the growth of normal oral flora; C diphtheriae develops a black colony with a characteristic gray-brown halo. Potentially toxigenic species (eg, C diphtheriae, C ulcerans, C pseudotuberculosis) have cystinase but not pyrazinamidase activity.

Traditionally, toxin production was demonstrated by injecting toxin material into guinea pigs and watching to see if they died. The Elek plate test for biologic activity of the toxin, an immunoprecipitation test, was developed in 1949 and replaced the in vivo guinea pig test. Even though the test was recently modified and standardized, interpretation can be difficult.

Other recent tests for toxigenicity include PCR detection of the A and B subunits of the tox gene, PCR detection of the A fragment of the toxin, and rapid enzyme immunoassay using a monoclonal antibody to the A fragment. However, some studies identify bacterial isolates that contain the A fragment of the toxin, which is not biologically active. Reports from Russia and Ukraine suggest that the number of these false-positive results is increasing.

The modified Elek tests take 24 hours to 48 hours for results; PCR detection and the enzyme immunoassay test reportedly yield results within a few hours.

Epidemiologic studies have also used typing of ribosomal bacterial RNA to detect and type strains of pathogenic corynebacteria.[48]

Diphtheroids

In the past, diphtheroid species were identified by culture. A wide variety of colony types may be observed. Many require special media to grow (eg, sheep's blood agar, Loeffler or tellurite plates) and some grow quite slowly. The colony types also have a range of biochemical characteristics, making identification difficult. For this reason, clinical suspicion of diphtheroid infection requires communication with the microbiology laboratory so that the appropriate cultures can be processed. More recently, 16S ribosomal ribonucleic acid (rRNA) probes have been designed for the identification of both genus and species of corynebacteria.  A minireview by Bernard (2012) [22]  also discusses more recent laboratory techniques for speciation, such as matrix-assisted laser desoprtoin ionization - time of flight (AMLDI-TOF), where bacterial proteins are liberated from the cell, ionized, detected by mass spectrometry, and the resulting pattern compared to a bacterial protein database. 

As mentioned above, toxigenic strains of C ulcerans and C pseudotuberculosis are reported. Therefore, consider testing for toxin production.

Cerebrospinal fluid (CSF) abnormalities include pleocytosis and elevated protein levels; the degree of inflammation in the CSF does not appear to correlate with the degree of neurologic dysfunction.

Several systems for isolating and detecting specific bacterial proteins may be useful for identifying corynebacterium species.[49] A multiplex PCR system for C diphtheriae, C ulcerans, and C pseudotuberculosis has been reported; it can simultaneously identify and determine the toxigenicity of these corynebacterial species with zoonotic potential.[50, 51]

Electrocardiography

ECG changes include conduction abnormalities and repolarization changes. As many as 30% of patients with respiratory tract diphtheria demonstrate abnormal ECG results within a week to 10 days of developing respiratory symptoms.

Patients who develop clinical or ECG changes associated with cardiac disease have a mortality rate that is three times to four times higher than patients with normal ECG results.

Autopsy

At autopsy, the heart is pale brown, soft, and enlarged, with a characteristic streaky appearance.

Neutral fat accumulations are observed in approximately 50% of patients, with extensive hyaline degeneration and necrosis with inflammatory changes.

Electron microscopy demonstrates swollen disorganized mitochondria that contain dense osmophilic granules.

The coronary vessels, valves, endocardial surfaces, and epicardial surfaces are unaffected.

Microscopic examination of the affected nerves shows myelin sheath and axon degeneration. In particular, the large myelinated fibers are affected, demonstrating characteristic segmental demyelination.

In fatal cases, the kidneys demonstrate interstitial edema and necrosis at autopsy.

For the initial office visit or emergency department treatment, see Diphtheria in the Medscape Reference Emergency Medicine section.

C diphtheriae

Since the early 1900s, diphtheria antitoxin (DAT), produced in horses, has been the mainstay of therapy. The antiserum works only to neutralize the toxin before it enters the cell. The antiserum is thought to be more effective in less severely ill patients and in those who are treated earlier in the disease course. Therefore, more severely ill patients and those with longer symptom duration are given higher doses than those with less severe disease of shorter duration. Whether this is an effective way of dosing the antiserum has never been tested.

Many people show signs of hypersensitivity reactions to the horse antiserum, and a test dose is usually given, with epinephrine available in case the patient has a severe reaction. However, because the mortality rate associated with antiserum has declined markedly, desensitization with increasing doses of antiserum is recommended.

Antibiotics treatment is the second arm of treatment. The goal is both to kill the organism and to terminate toxin production. Many antibiotics are effective, including penicillin, erythromycin, clindamycin, rifampin, and tetracycline; erythromycin or penicillin is the treatment of choice and is usually given for 14 days.

Supportive care is also important, including rest, airway management, observation for development of secondary lung infections, and management of cardiac and neurologic disease complications.

Diphtheroids

Antibiotics are the treatment of choice for nondiphtherial corynebacteria infections. Many species and groups are sensitive to various antibiotics, including penicillins, macrolide antibiotics, rifampin, and fluoroquinolones. However, antibiotic susceptibility can vary, and susceptibility testing is recommended. A review by Riegel et al on identification and antimicrobial sensitivity in 415 corynebacterial isolates from clinical specimens of patients hospitalized in Strasbourg, France, demonstrated that many species or groups were susceptible to ampicillin, cefotaxime, and rifampicin.[52] Many species or groups were resistant to erythromycin, and 2 groups (ie, JK, C urealyticum) were resistant to nearly every drug tested.

Another review, by Spanik et al, examined risk factors for disease with corynebacteria.[53] Of 123 episodes of breakthrough bacteremia during antibiotic prophylaxis in patients with cancer, 10% were from corynebacteria causing indwelling catheter infections. In this review, catheter removal and modification of antimicrobial therapy, depending on susceptibility testing, were independent risk factors for an improved outcome.

In another review of antimicrobial treatment options for corynebacterial mastitis, Corynebacterium kroppenstedtii was susceptible to most antibiotics except beta lactams, while Corynebacterium tuberculostearicum was resistant to most antibiotics.[7]  Clarithryomycin has also been used for treatment of granulomatous mastitis, although typically therapy must be continued for months.[9]

The mainstay of treatment for these infections is nonsurgical. However, a case report discussed necrotizing lymphadenitis that was unresponsive to repeated antibiotic therapy, requiring surgical drainage and adequate debridement of the infected area.[54]

The World Health Organization expanded its network of laboratories after the outbreaks of diphtheria in the Russian republics; the Diphtheria Surveillance Network integrates epidemiologic and microbiologic aspects of potentially toxigenic corynebacteria.[48]

In 2014, the WHO published a flowchart for case classification of suspected or documented corynebacterial infections.[55]  This includes infections of C diphtheriae as well as diphtheroid organisms.

The US Centers for Disease Control and Prevention (CDC) is the source for antitoxin (ie, DAT) in the United States. If treating suspected cases of diphtheria, contact the diphtheria duty officer at 800-CDC-INFO (800-232-4636).

Report all suspected cases of diphtheria to local and state health departments. Local infectious disease specialists who work with the CDC are available 24 hours a day through the local public health department for help with symptoms and disease management.

Cardiologists, pulmonary specialists, and neurologists may help in the care of patients who have specific disease complications.

Vaccination

As mentioned above, childhood immunization is the prevention method of choice. Diphtheria/tetanus/pertussis (DTP) vaccine, given at ages 2, 4, and 6 months; at age 15 months to 18 months; and at least 5 years later (age 4-6 y) is the immunization regimen recommended by the American Academy of Pediatrics, the Advisory Committee on Immunization Practices, and the American Academy of Family Physicians.

Unvaccinated people older than 7 years or people whose immunization status is unknown should receive three doses of the adult formulation of the tetanus-diphtheria toxoid (Td). The first two doses are given 4 weeks to 8 weeks apart, and the third dose is given 6 months to 12 months later.

The first booster dose of Td should be given at least 5 years after the last immunization and every 10 years thereafter. A reduced antigen booster (combined with tetanus and pertussis) is available that is highly immunogenic with low reactogenicity.[56]

Adverse reactions include local induration, pain, redness, and, occasionally, low-grade fevers. Serum sickness hypersensitivity reactions are reported in some adults.

Vaccination coverage levels are monitored by the CDC National Immunization Survey, which estimates vaccination coverage for the 50 states. Compared with the baseline year of 1992, national coverage with 4 or more doses of DTP increased significantly, from 55% to 78%.

In comparison, some industrialized countries have much lower immunization levels. In a recent seroepidemiologic study from Spain, only 26% of the sample population of 3944 men and women aged 5 years to 59 years were fully protected and more than 85% of those aged 20 years to 39 years had little or no protection against diphtheria.[57] In other Western countries, serologic protection was found in 50% to 80% of subjects, with some countries showing a greater protection rate in older subjects (eg, Sweden) and some countries showing a greater protection rate in younger subjects (eg, Germany, France, Turkey, Slovakia).

Risks for travelers, therefore, are higher in parts of the world where immunization levels are low and the disease is prevalent. The Health Protection Agency Centre for Infections in the United Kingdom recommends boosters every 10 years for travelers planning to visit areas of endemic disease.[58] The CDC has an up-to-date Web site on diphtheria prevention for the public at www.cdc.gov/travel/diseases/dtp.htm.

In 2008, the Advisory Committee on Immunization Practices (ACIP) issued guidelines on the prevention of pertussis, tetanus, and diphtheria in pregnant and postpartum women and their infants. Details can be found at http://www.medscape.com/viewarticle/574587. In 2012, the American College of Obstetrics and Gynecology announced their findings that the toxoid in Tdap vaccine was not associated with adverse fetal outcomes and published their revised guidelines.[59]

For C diphtheriae infection, the therapy is antitoxin and antibiotic treatment. Many antibiotics previously were effective, including penicillin, erythromycin, clindamycin, rifampin, and tetracycline. More recently, resistance to penicillins, erythromycins, and clindamycin has been reported[60, 61] ; this is especially true for nontoxigenic C diphtheriae strains tested in Europe.[62]

For the nondiphtherial corynebacteria, antibiotic susceptibility testing is often required to determine the best treatment.

Booster treatment with diphtheria toxoid is also given often. Please see Deterrence/Prevention for a discussion of vaccinations with toxoid.

Class Summary

These agents are administered to neutralize toxin responsible for diphtheria.

Diphtheria antitoxin (DAT)

Dose given depends on site of infection and length of time patient is symptomatic. In US, DAT available from CDC. Contact diphtheria duty officer at 404-639-8255 from 8 AM to 4:30 PM (EST) or at 404-639-2889 all other times. Report all suspected cases of diphtheria to local and state health departments.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.  Prolonged therapy with multi-drug combinations may be necessary for infections with nondiphtherial corynebacteria. 

Vancomycin (Vancocin)

Antibiotic useful against gram-positive organisms; corynebacteria are very often susceptible. Useful to treat septicemia, skin structure infections, and IV line infections/bacteremias.

Rifampin (Rifadin)

Nondiphtherial corynebacteria often are susceptible.

Linezolid (Zyvox)

Linezolid prevents formation of the functional 70S initiation complex, which is essential for the bacterial translation process. It is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Corynebacteria are very often susceptible.[23] Linezolid is used as an alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.

Tetracycline (Sumycin, Actisite, Achromycin V)

Tetracycline treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Corynebacteria are often susceptible.[23] It inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).

Tigecycline (Tygacil)

Tigecycline is a glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. It inhibits bacterial protein translation by binding to the 30S ribosomal subunit, and it blocks entry of amino-acyl tRNA molecules in ribosome A site.

It is indicated for complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp (includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Bacteroides fragilis. It is also generally effective against corynebacteria diphtheroids.[45]

Clarithyromycin

Clarithryomycin belongs to the class of macrolide antibiotics, with a wide spectrum of activity against gram positive organisms - e.g., diphtheroids, staphylococcus, streptococcus - gram negative organisms, and anaerobic bacteria.