eMedicine Specialties > Infectious Diseases > Bacterial Infections

Corynebacterium Infections

Author: Lynda A Frassetto, MD, Associate Clinical Professor, Department of Internal Medicine, University of California at San Francisco School of Medicine
Contributor Information and Disclosures

Updated: Jun 30, 2008

Introduction

Background

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 recently been recognized as pathogenic, especially in immunocompromised hosts.

Approximately 20 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 CoryneRegNet³ 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.

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.^6,7

Pathophysiology

C diphtheriae

C diphtheriae infection is typically 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 Image 1).

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.

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.⁸

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 3 distinct pilus structures: the main pilus shaft (SpaA) and 2 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.⁹     

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.¹⁰ 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.

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 fact, many of these organisms cannot be speciated or typed easily, even in research laboratories, although recent advances in PCR technology are improving our ability to identify these bacteria. Seven or 8 major species or groups are labeled. The review by Coyle and Lipsky is an in-depth evaluation of the role of coryneform bacteria in causing 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)

Some of these species are also pathogenic in animals, especially in livestock; others appear specific to humans. 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. While most species (eg, C ulcerans) are sensitive to many antibiotics, some (eg, group D2) can be 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 per100,000 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.

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.¹¹

• The KyrgyzRepublic 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 15-34 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%).¹²
• 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 40-49 years (case fatality rate of 19%).¹³
• 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.¹⁴
• 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.¹⁵
• Diphtheroids: Infections with the nondiphtherial corynebacteria are reported worldwide. 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.

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 1972-1982.¹⁶
• 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 40-49 years has been attributed to their low levels of immunity.
• Diphtheroids: Infections are reported in children and elderly persons.

Clinical

History

• C diphtheriae
  • Respiratory: Following an incubation period of 2-4 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 1-2 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 30-90 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 6 (5%) of the 133 patients, 1 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. Antimicrobial resistance is also more common in isolates from immunosuppressed 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.

Physical

• 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 Image 2).
  • 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 Image 3), 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 10-25% 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.
  • 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.¹⁷ More recently, a review of clinical samples from the National Microbiology Laboratory in Canada has demonstrated C ulcerans isolates from blood cultures.¹⁸
  • C striatum is 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. One case of C striatum meningitis was also reported recently.¹⁹
  • 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.²⁰
  • 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. Removal of the indwelling catheter is often necessary.
  • 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.²¹
  • Cases of Corynebacterium macginleyi keratitis following eye surgery have been reported.²² 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.²³

• Search for CME/CE on This Topic »