Corynebacterium diphtheria

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Corynebacterium diphtheriae is a gram-positive bacillus that can cause a range of clinical manifestations in humans, ranging from asymptomatic infection to severe respiratory disease and skin findings.

What is the best treatment?

Treatment of respiratory disease consists of both antibiotic therapy, as well as diphtheria antitoxin (DAT).

DAT is derived from horse serum and binds to and deactivates the diphtheria toxin. It must be given early to be effective and is available through the Centers for Disease Control and Prevention (CDC).
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CDC emergency operations center: 770-488-7100

See: http://www.cdc.gov/diphtheria/dat.html
There is a 10% risk of hypersensitivity or serum sickness with DAT. A scratch test dose of 1:100 dilution should be followed by a test dose of 0.02ml of 1:1000 dilution and then a full dose.
Epinephrine should be kept at hand during these test doses, as well as during treatment.
The dose of DAT depends of severity:

For mild, early pharyngeal or laryngeal disease, 20,000-40,000 units

For moderate nasopharyngeal disease, 40,000-60,000 units

For severe disease or prolonged duration (>3 days), up to 80,000-120,000 units

For CDC treatment protocol: http://www.cdc.gov/diphtheria/downloads/protocol.pdf

Antitoxin should be administered intravenously over 1 hour.

Intramuscular administration may be considered for mild or moderate cases
Repeat administration NOT recommended
Antibiotic therapy

Adjuvant to antitoxin therapy which is the primary therapy (with supportive care)

Antibiotic options:

Erythromycin 40 mg/kg/day IV or PO (if patient can swallow)

Procaine penicillin G 300,000 units (<10 kg) or 600,000 units IM every 12 hours

Penicillin V 250 mg PO (if patients can swallow) QID

Duration 14 days for all regimens
Supportive care, including intubation and ventilator support, is a key piece of management. Intubation may be difficult given pharyngeal edema and friability, and, in some cases, tracheostomy is needed.
Repeat cultures should be obtained to document clearance of infection 48 hours after starting therapy and again at 2 weeks post treatment.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

Transmission occurs through person-to-person spread via ingestion of oral or respiratory secretions, by airborne respiratory droplets, or through skin lesions.
Asymptomatic carriers are key factors in transmission, and neither natural infection nor vaccination prevents asymptomatic pharyngeal carriage.
In temperate regions, transmission is higher in the winter months.
Prior to vaccine development, there was a case fatality rate in children of up to 10%.
Immunity can wane over time without booster vaccination.
Both toxigenic and non-toxigenic strains exist, with the toxigenic strains causing more severe disease.
In developed countries where vaccine has been used since the 1930s, the epidemiology of the strains has shifted in the vaccine era, with fewer toxigenic strains circulating. However, asymptomatic carriage with non-toxigenic strains is common, and there are occasionally mild to moderate cases of clinical disease in children, as well as distantly or incompletely vaccinated adults.
Throughout much of the developing world, diphtheria remains endemic; this includes Brazil, Nigeria, the Indian subcontinent, and countries of the former Soviet Union, among others.
Travelers or household contacts of travelers to these areas are also susceptible to infection if distantly or incompletely vaccinated
Homeless and injection drug users are at increased risk for cutaneous diphtheria

Infection control issues

Contact precautions and airborne precautions are important to decrease nosocomial spread of infectious respiratory secretions; healthcare workers should wear masks, gowns, and gloves. Follow-up cultures should be done at 48 hours after treatment and again at 2 weeks to document clearance.
Isolation should continue until two consecutive cultures 24 hours apart are negative.
Vaccination is the most effective way to prevent clinical disease
Vaccine is available as a diphtheria-tetanus-acellular pertussis (DTaP) formulation in childhood (see chapter on Childhood Routine Vaccine Schedule). There is a current recommendation to give older adults, healthcare workers, and others at risk for pertussis a single booster dose with tetanus-diphtheria-acellular pertussis (TdaP) vaccine. Routine vaccination against diphtheria and tetanus should be given every 10 years in adults and should be with tetanus diphtheria (Td) vaccine. Following acute infection, patients should be given toxoid vaccine, because natural infection does not always convey complete immunity
The state or local public health departments, as well as the CDC, should be notified of all diphtheria cases, so they may identify and evaluate contacts of cases (contact tracing).
Close contacts of cases must be promptly identified. If they have an uncertain or incomplete vaccine status, vaccine should be given immediately. Then the primary series should be completed per the usual schedule. If fully vaccinated more than 5 years prior, give an immediate booster, but there is no need for further immunization.
For all contacts, obtain nasal and pharyngeal swabs for cultures, then give prophylactic treatment with a single dose of penicillin G (1.2 million units IM for 1 for those 6 years of age or older, and 600,000 million units for those younger than 6 years of age) or erythromycin 500mg po qid for 7-10 days.

Contacts should also be evaluated for development of clinical disease for at least 7 days.

What host factors protect against this infection?

Natural infection and an asymptomatic carrier state may confer some protection against severe disease, but this is not complete.
There are no effective host mechanisms to protect against the exotoxin formed by toxigenic strains.
Vaccination is the only reliable prevention against ongoing risk of infection, but requires a booster vaccination for continued full protection if the primary vaccination series completion date is distant.

What are the clinical manifestations of infection with this organism?

Respiratory disease is the classic clinical manifestation.
Patients usually report gradual onset of malaise, sore throat, and fever.
Mild pharyngeal erythema can the lead to mild white exudate.
The classic pseudomembrane is only seen in one-third of patients with respiratory tract disease.
If disease is severe, hoarseness and stridor follow.
Some patients exhibit a classic “bull neck” due to severe pharyngeal edema and involvement of the tonsils, submandibular lymph nodes, uvula, and anterior neck.
Without prompt supportive ventilation, suffocation due to edema and/or aspiration of the pseudomembrane can occur.
Dissemination of diphtheria toxin leads to end organ disease proportional to the extent of local disease (a measure of the amount of toxin present). Disease can, therefore, be limited by prompt administration of antitoxin.
Cardiac and neurologic diseases are important complications of infection and are proportional to the severity of the respiratory infection.
Myocarditis can occur 7-14 days after the initial respiratory symptoms, is seen in up to 60 % of patients, and is evidenced by electrocardiogram (ECG) changes and mild heart block.
In 10-20 % of patients, there is evidence of cardiac compromise and, in a smaller subset, severe myocarditis with heart block; heart failure can occur and can be a major cause of mortality.
In less than 5% of patients, but especially those with severe local disease, neurologic disease, including neuropathies, cranial neuropathies, and peripheral neuritis, can occur. Prompt treatment with antitoxin can minimize the extent and duration of symptoms.
Renal failure due to antitoxin or circulatory collapse can occur.
Cutaneous disease can be caused by both toxigenic and non-toxigenic strains and appears as nonspecific, chronic, non-healing ulcers with a gray exudate. They may occur in areas of pre-existing skin lesions. Injection drug users, homeless individuals, and other impoverished groups are at higher risk.
These infections appear to confer some protection against respiratory disease, but serve as a transmission risk to other susceptible individuals.

What common complications are associated with infection with this pathogen?

Respiratory compromise and collapse in severe disease can occur.
With severe local disease and large amounts of toxin, cardiac, neurologic, and renal disease are more likely.

How should I make the diagnosis and identify the organism?

Diagnosis must be considered promptly in a patient with an unknown or distant vaccination status who presents with a clinical picture as noted above.
The peripheral white blood cell (WBC) count is usually only mildly elevated, and other labs are nonspecific.
In suspected cases, take steps to contact the CDC for consultation and to arrange to obtain antitoxin if needed. Do this earlier rather than later, as the request can always be cancelled if another cause for the clinical presentation is found.
Swabs should be obtained for gram stain and culture from the nose and pharynx, including the membrane if possible.
The laboratory should be notified, as special culture media is required (Tinsdale’s or Loffler’s agar) and specimens must be rapidly transported to the lab.
A gram stain will typically show the classic “Chinese characters” pattern of gram-positive bacilli.
Testing for toxin production should also occur. This can be via polymerase chain reaction (PCR), an Elek test performed on culture, or using EIA.
The CDC in the United States can also provide toxin testing and culture confirmation and should be contacted.

How does this organism cause disease?

C. diphtheriae is not an invasive organism, and non-toxigenic strains generally only produce a mild local inflammation
However, toxigenic strains secrete a potent exotoxin comprised of two segments, A and B. B binds to receptors on mammalian cells, and A is the active component that enters the cell and inactivates elongation factor 2, which is necessary for mammalian protein synthesis.
All cells can be affected, but key organs include the heart, nerves, and kidneys.
Within a few days of initial respiratory colonization in a susceptible individual, local exotoxin A creates a dense, necrotic pseudomembrane consisting of dead respiratory epithelial cells, organism, fibrin, and leukocytes. There is significant underlying mucosal ulceration and tissue edema.
In some cases, the edema is so severe that the airway is compromised, particularly in young children. Suffocation is a common cause of death from severe disease.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Lowe, CF, Bernard, KA, Romney, MG. “Cutaneous diphtheria in the urban poor population of Vancouver, British Columbia, Canada: a 10-year review”. J Clin Microbiol. vol. 49. 2011 Jul. pp. 2664-6.

Mancini, F, Monaco, M, Pataracchia, M, von Hunolstein, C, Pantosti, A, Ciervo, A. “Identification and molecular discrimination of toxigenic and nontoxigenic diphtheria Corynebacterium strains by combined real-time polymerase chain reaction assays”. Diagn Microbiol Infect Dis. vol. 73. 2012 Jun. pp. 111-20.

Mattos-Guaraldi, AL, Moreira, LO, Damasco, PV, Hirata Júnior, R. “Diphtheria remains a threat to health in the developing world: an overview”. Mem Inst Oswaldo Cruz. vol. 98. 2003 Dec. pp. 987-93.

Muttaiyah, S, Best, EJ, Freeman, JT, Taylor, SL, Morris, AJ, Roberts, SA. “Corynebacterium diphtheriae endocarditis: a case series and review of the treatment approach”. Int J Infect Dis. vol. 15. 2011 Sep. pp. e584-8.

Nohynek, H, Madhi, S, Grijalva, CG. “Childhood bacterial respiratory diseases: past, present, and future”. Pediatr Infect Dis J. vol. 28. 2009 Oct. pp. S127-32.

Wagner, KS, Stickings, P, White, JM, Neal, S, Crowcroft, NS, Sesardic, D, Efstratiou, A. “A review of the international issues surrounding the availability and demand for diphtheria antitoxin for therapeutic use”. Vaccine. vol. 28. 2009 Dec 10. pp. 14-20.

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