Corynebacterium Infections

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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 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.

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 the illustration below).


View Image

The corynebacterial tox gene is regulated by the corynebacterial iron-binding repressor, labeled DtxR. Binding of ferrous iron to the DtxR molecule fo....

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.[8]

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.[9]

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.[10]

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.[11] 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.[12]

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:

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.

Epidemiology

Frequency

United States

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.[14]

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 15-34 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%).[15]

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%).[16]

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.[17]

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.[18]

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.[19]

In New Zealand, C diphtheria infections were associated with infective endocarditis in children in 12% of cases (10 of 85 cases) from 1994-2012.[20]

Diphtheroids

Infections with the nondiphtherial corynebacteria are reported worldwide.[21] 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.[22]

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.[23]

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.[24]

Mortality/Morbidity

Race

Sex

Age

History

Physical

Laboratory Studies

Several systems for isolating and detecting specific bacterial proteins may be useful for identifying corynebacterium species.[39] 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.[40]

Other Tests

Medical Care

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

Surgical Care

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.[43]

Consultations

Medication Summary

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[44, 45] ; this is especially true for nontoxigenic C diphtheriae strains tested in Europe.[46]

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.

Diphtheria antitoxin (DAT)

Clinical Context:  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

These agents are administered to neutralize toxin responsible for diphtheria.

Vancomycin (Vancocin)

Clinical Context:  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)

Clinical Context:  Nondiphtherial corynebacteria often are susceptible.

Linezolid (Zyvox)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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]

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Inpatient & Outpatient Medications

See Medication.

Deterrence/Prevention

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 15-18 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 3 doses of the adult formulation of the tetanus-diphtheria toxoid (Td). The first 2 doses are given 4-8 weeks apart, and the third dose is given 6-12 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.[47]

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 5-59 years were fully protected and more than 85% of those aged 20-39 years had little or no protection against diphtheria.[48] In other Western countries, serologic protection was found in 50-80% 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.[49] 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.[50]

Complications

See History and Lab Studies.

Prognosis

See History and Lab Studies.

Author

Lynda A Frassetto, MD, Clinical Professor, Department of Internal Medicine, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

John M Leedom, MD, Professor Emeritus of Medicine, Keck School of Medicine of the University of Southern California

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

Disclosure: Merck Grant/research funds Other

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

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The corynebacterial tox gene is regulated by the corynebacterial iron-binding repressor, labeled DtxR. Binding of ferrous iron to the DtxR molecule forms a complex that binds to the tox gene operator and inhibits transcription. Depletion of iron from the system removes the repression and allows the toxin to be produced.

The characteristic thick membrane of diphtheria infection in the posterior pharynx.

Cervical edema and cervical lymphadenopathy from diphtheria infection produce a bullneck appearance in this child. (Source: Public Domain www.immunize.org/images/ca.d/ipcd1861/img0002.htm)

The corynebacterial tox gene is regulated by the corynebacterial iron-binding repressor, labeled DtxR. Binding of ferrous iron to the DtxR molecule forms a complex that binds to the tox gene operator and inhibits transcription. Depletion of iron from the system removes the repression and allows the toxin to be produced.

The characteristic thick membrane of diphtheria infection in the posterior pharynx.

Cervical edema and cervical lymphadenopathy from diphtheria infection produce a bullneck appearance in this child. (Source: Public Domain www.immunize.org/images/ca.d/ipcd1861/img0002.htm)