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Diphtheria

Queensland Health Guidelines for Public Health Units

Revision History

VersionDateChanges
1.0 September 2007 Full revision of guidelines
2.0 January 2012 Full revision of guidelines

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Infectious Agent

The agent is Corynebacterium diphtheriae. Some strains of C. diphtheriae produce diphtheria toxin, a protein that can cause myocarditis, polyneuropathy and other systemic toxic effects.

Respiratory diphtheria is usually caused by toxigenic C. diphtheriae.

Infections of the skin (cutaneous diphtheria) are usually caused by nontoxigenic C. diphtheriae.

Infections at other sites, including the bloodstream, endocardium, bones and joints are almost invariably caused by non-toxigenic C. diphtheriae.

Corynebacterium ulcerans may also cause an exudative pharyngitis in humans clinically indistinguishable from diphtheria and toxigenic strains occur. There is no clearly documented person to person spread of C. ulcerans. However, the clinical and public health management of all toxigenic strains is identical.

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Notification Criteria

Laboratory definitive evidence
Isolation of toxigenic* Corynebacterium diphtheriae or toxigenic* C. ulcerans from site of clinical evidence.

Laboratory suggestive evidence
Isolation of C. diphtheriae or C. ulcerans from a respiratory tract specimen (toxin production unknown).

Clinical evidence

  • Confirmed case
    - Upper respiratory tract infection
    OR
    - Skin lesion
  • Probable case
    - Upper respiratory tract infection with an adherent membrane of the nose, pharynx, tonsils or larynx.

Epidemiological evidence

An epidemiological link is established when there is:
Contact between two people involving a plausible mode of transmission at a time when:

  • a.  one of them is likely to be infectious (usually 2 weeks or less and seldom more than 4 weeks after onset of symptoms)

    b.  the other has an illness which starts approximately 2-5 days after this contact.

AND

At least one case in the chain of epidemiologically-linked cases (which may involve many cases) is laboratory confirmed.

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Notification Procedure

Pathology Laboratories
To notify urgently on confirmation of diagnosis by telephone or facsimile.

Attending Medical Practitioners/ Medical Superintendents (or Delegates)
To notify urgently on clinical suspicion by telephone or facsimile.

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Reporting to NOCS

Both confirmed cases and probable cases should be notified.

Confirmed case
A confirmed case requires laboratory definitive evidence and clinical evidence.

Probable case
A probable case requires:

  • Laboratory suggestive evidence and clinical evidence

OR

  • Clinical evidence and epidemiological evidence.

*as indicated by detection of toxin gene by nucleic acid testing

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Public Health Significance and Occurrence

Diphtheria was one of the most common causes of death among children in the pre-vaccine era. Since the introduction and widespread use of diphtheria toxoid vaccine, diphtheria has been well controlled in Australia. The most recent confirmed cases (one fatal case and two asymptomatic cases) of diphtheria infection were reported in Queensland in 2011. A significant feature of these cases was the detection of a strain of toxigenic diphtheria that was highly resistant to penicillin.

Diphtheria remains endemic in many parts of the world including countries of the Caribbean, Latin America and Eastern Europe. A massive outbreak of diphtheria began in the Russian Federation in 1990 and spread to all countries of the former Soviet Union and Mongolia. Contributing factors included increased susceptibility among adults due to waning of vaccine-induced immunity, failure to fully immunise children due to disrupted routine immunisation programs, unwarranted contraindications, anti-vaccine movements and declining socioeconomic conditions. This epidemic declined after reaching a peak in 1995. It was responsible for more than 150,000 reported cases and 5,000 deaths (1990 -1997).

During the past decade, many developing countries have achieved marked reduction in diphtheria cases with high childhood vaccination coverage. Rarely, outbreaks occur in well-vaccinated populations. Sporadic cases (and some deaths) have been reported from the UK (2008, 2009) and France (2011). These cases were attributed to contact with people from endemic areas (Annex A).

Diphtheria has almost disappeared from Australia, but sporadic cases do occur rarely, usually in unvaccinated individuals. There is now little possibility of acquiring natural immunity, and no opportunity to boost declining immunity with subclinical infection. Therefore a high vaccination rate must be maintained to protect the population from resurgence of the disease. An increase in the incidence of infections from toxigenic strains could follow introduction of cases or carriers from overseas, or from local emergence of a virulent strain.

The purpose of prompt notification is to assure early, appropriate treatment including access to diphtheria antitoxin, to ensure appropriate laboratory specimens are collected prior to commencement of treatment, to identify and evaluate contacts, and to provide antimicrobial prophylaxis to prevent further transmission.

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Clinical Features

There are two main forms of disease: respiratory and cutaneous. Non-respiratory diphtheria is most commonly non-toxigenic.

Respiratory diphtheria
Respiratory diphtheria is most often an upper respiratory tract illness. Onset is often gradual, with symptoms of fever, sore throat and weakness. Dysphagia, headache and altered voice occur in fewer than half of patients. Neck oedema and difficulty breathing occur in <10% and are associated with an increased risk of death. Primary infection most often involves the tonsils and pharynx, but may also involve the larynx, nose, trachea and bronchi. Isolated spots of grey or white exudate appear, which extend and coalesce over 24 hours to form a confluent, sharply demarcated pseudomembrane. It progressively thickens, becomes tightly adherent to the underlying tissue, and darkens in colour. This pseudomembrane is caused by liberation of a specific cytotoxin.

Systemic manifestations are due primarily to toxic effects of diphtheria toxin. Myocarditis and polyneuropathy are the prominent toxic manifestations. Cardiac effects usually begin about 1 week after onset of illness and may include dysrhythmias, conduction disturbances and dilated cardiomyopathy. Polyneuropathy typically begins 3 to 5 weeks after onset of diphtheria and has a slow course, cranial nerve pareses, respiratory and abdominal muscle weakness, quadripareses or quadriplegia, peripheral sensory disturbances and a variety of autonomic disturbances. Resolution of polyneuropathy is complete in survivors.

The case fatality rate of respiratory diphtheria is 5 to 10%, even with appropriate treatment.

Cutaneous diphtheria and other sites of infection
Cutaneous diphtheria presents either as:

  • secondary infection of existing skin lesions or
  • primary punched out ulcers with well-demarcated edges and a cover of necrotic slough or membrane.

C. diphtheriae is an occasional cause of invasive infections, including septicaemia, endocarditis and septic arthritis.

Non-respiratory diphtheria is usually non-toxigenic.

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Reservoir

Humans

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Mode of Transmission

Respiratory droplets or direct contact with respiratory secretions or infected exudate of infected person or carrier; more rarely, contact with articles soiled with discharges from lesions of infected people. Unpasteurised milk has served as a vehicle.

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Incubation Period

Usually 2 to 5 days, occasionally longer.

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Period of Communicability

Variable. Until virulent bacilli have disappeared from discharges and lesions; usually 2 weeks or less, seldom more than 4 weeks. Effective antimicrobial therapy terminates shedding. The rare chronic carrier may shed organisms for 6 months or more.

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Susceptibility and Resistance

Infection can occur in vaccinated as well as unvaccinated people. Lifelong immunity is generally (but not always) acquired following disease or inapparent infection. Prior vaccination reduces the frequency and severity of disease and frequency of carriage. Vaccination with toxoid provides prolonged but not lifelong immunity. Immunity is antibody related and primarily against the toxin rather than the bacteria; therefore, immune persons can still harbour the organism. There is no clearly defined level of antitoxin demonstrated to provide complete protection. Levels between 0.01 IU/mL and 0.09 IU/mL are regarded as providing basic immunity, while levels of > 0.1 IU/mL may be needed for full protection. Infants born to immune mothers have passive protection, which is usually lost before the sixth month of age. Serosurveys in Australia indicate decreasing levels of adult immunity.

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Management

Non-respiratory diphtheria cases

Investigation

  • Cases are likely to be notified because of positive culture.
  • Ensure toxin testing has been ordered (through QHFSS).
  • Obtain clinical history and exclude respiratory disease.
  • Identify if the Corynebacterium diphtheriae or C. ulcerans is toxigenic (via QHFSS).
  • Ascertain diphtheria vaccination status, referring to records if available.
  • In the unlikely event the infection is due to toxigenic C. diphtheriae, manage cases and contacts according to respiratory diphtheria protocol.
  • Antitoxin is not required to treat cutaneous diphtheria.

Restriction
Manage with contact precautions.

Contact Tracing
No, unless toxigenic.

Respiratory diphtheria cases

Investigation

  • Obtain clinical history and confirm picture is of respiratory disease.
  • Ensure swabs for culture and toxin testing have been ordered and liaise with QHFSS.
  • Identify if the Corynebacterium diphtheriae or C. ulcerans is toxigenic.
  • Ascertain diphtheria vaccination status, referring to records if available.

Restriction
Standard plus droplet precautions for pharyngeal diphtheria until 2 cultures from both throat and nose (and skin lesions in toxigenic cutaneous diphtheria), not less than 24 hours apart, and not less than 24 hours after cessation of antimicrobial therapy, fail to show C. diphtheriae. A repeat culture should be done 2 weeks after antibiotic therapy is completed. Ensure appropriate infection control of materials contaminated with respiratory discharges.

Treatment
In suspected respiratory diphtheria, antitoxin and antibiotics should be given immediately after bacteriological specimens are taken (nose and throat cultures and serum for antitoxin testing). Antibiotic treatment should cater for the possibility of penicillin resistance (Annex B).

Diphtheria antitoxin (DAT) is derived from horse serum because sera of sufficient titre are not available from humans. Due to the presence of foreign protein, diphtheria antitoxin may provoke acute severe allergic reactions or serum sickness. A test dose should be administered to exclude hypersensitivity. If there is evidence of hypersensitivity, it may be necessary to administer diphtheria antitoxin under corticosteroid, adrenaline and antihistamine cover. Antitoxin may be given intramuscularly or diluted for administration in an intravenous infusion. Expert advice should be sought with respect to dose - refer to Annex B.

DAT is available from Queensland Health Central Pharmacy, phone 07 3120 8500 during work hours Monday to Friday. Contact RBWH switch on 3636 8111 for after hours access.

Princess Alexandra Hospital Pharmacy will also hold supplies of DAT. Contact the on call pharmacist through PAH switchboard on 3176 2111.

Patients should be vaccinated in the convalescent phase of their disease as clinical infection may not induce adequate immunity. Previously vaccinated children and adults should receive one booster dose of diphtheria-containing vaccine (DTPa for children and ADT or dTpa for adults). Previously unvaccinated individuals should receive a full three-dose course of diphtheria vaccination (ie. DTPa for children and dTpa/ADT for adults).

Isolation of toxigenic Corynebacterium diphtheriae or C. ulcerans in an asymptomatic person, especially in the context of contact tracing, requires appropriate antibiotic treatment and vaccination as determined by the person's vaccination history. Such cases do not usually require consideration of DAT.

Counselling
The case should be advised of the nature of the infection and its mode of transmission.

Contacts

Contact Tracing
Yes

Purpose
To treat incubating disease and to eliminate carriage.

Definition
Individuals who were in contact with the case in the seven days preceding onset of illness in the case AND:

  • are household, or household-like, members OR
  • were directly exposed to the oral secretions of the case e.g. intimate kissing/sexual contacts, or via mouth-to-mouth resuscitation OR
  • had direct contact with the skin lesions of a toxigenic case OR
  • had close contact for 20 hours or more with the case e.g. in child care settings
People (e.g. hospital staff) who have taken appropriate infection control precautions need not be considered contacts.

Investigation
All contacts (regardless of their vaccination status) should have nose and throat cultures taken, receive prompt antimicrobial prophylaxis and maintain surveillance for 7 days for evidence of disease. In some situations this may require daily clinical examination for symptoms and signs of diphtheria. All contacts should have their immunisation history checked and brought up to date if necessary.

Prophylaxis

  • 7-10 days of oral erythromycin (children 40 mg/kg/day, adults 1g/day) OR
  • IMI benzathine penicillin in a single dose (1g for persons < 6 years of age and 2g for those 6 years and older).

Note: As a high rate (27%) of erythromycin resistance has been reported from one country, antibiotic sensitivities should be checked. Consider the possibility of emerging resistance to penicillin. Roxithromycin, azithromycin or ciprofloxacin may be alternatives (seek IDP opinion re suitability).

Vaccination (using DTPa, ADT or dTpa depending on age)Previously vaccinated contacts should receive a booster dose of diphtheria toxoid if more than 5 years have elapsed since their last dose. Unvaccinated or incompletely vaccinated contacts should commence a primary or catch up course of diphtheria vaccination. Refer to the current edition of The Australian Immunisation Handbook for vaccination details.

RestrictionAll contacts should be excluded from:

  • contact with children
  • occupations involving the care of the sick and dependent
  • occupations involving the handling of foods
  • school
until cultures from the nose, throat and any lesions are proved to be negative for toxigenic diphtheria bacilli.

Counselling
All contacts should be advised of the nature of the infection and its mode of transmission.

Other Control Measures

The response to a confirmed case of diphtheria requires a State Outbreak Control Team approach with each component PHU adopting an incident management framework. Key issues include nomination of roles (epidemiology coordinator, clinical coordinator, microbiology coordinator) to ensure efficient reporting and communication of issues within the response framework.

Early communication of risk to affected institutions is essential.

Communication to external stakeholders and the media will involve discussion of often sophisticated medical concepts eg. 'carriage' of the organism in vaccinated populations. It is imperative that early discussion take place with agreement on the key public health messages including the requirement to consider approval from the Director General of Queensland Health to release information that may be in the public interest, eg. the immunisation status of a case.

  • Public health unit to inform the Communicable Diseases Branch and adjacent public health units of the notification.
  • Health education: Discuss the possibility of a media release by the Communicable Diseases Branch.
  • Encourage high rates of vaccination coverage, in accordance with the current edition of The Australian Immunisation Handbook.

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Preventive measures

  • Education measures are important. Inform the public, particularly parents of young children, of the hazards of diphtheria and the need for vaccination.
  • The most effective preventive measure is widespread vaccination with diphtheria toxoid. Encourage the use of combined diphtheria and tetanus toxoid vaccine or a combined diphtheria, tetanus and pertussis vaccine, and discourage the use of monovalent tetanus toxoid vaccine.
  • Maintain continual improvements in childhood and adult vaccination coverage rates.
  • Special efforts should be made to ensure that people at higher risk of exposure eg. health care workers, are fully vaccinated.
  • Travellers to countries where diphtheria may be endemic should be vaccinated if they have not had a booster in the last 10 years.

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Summary

Prepare a summary report of the investigation for the Communicable Diseases Branch, on request.

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References

Alberta Health and Wellness. Public Health Notifiable Disease Management Guidelines - Diphtheria. Jan 2011. Government of Alberta. Available from http://www.health.alberta.ca/documents/Guidelines-Diphtheria-2011.pdf, accessed 16/5/2011.

Bonnet JM, Begg NT. Control of diphtheria: guidance for consultants in communicable disease control. Communicable Dis Public Health. 1999;2:242-249.

Centre for Disease Control, Northern Territory. Guidelines for the Control of Diphtheria in the Northern Territory. 2004. Northern Territory Government Department of Health and Community Services.

Farixo KM, Strebel PM, Chen RT et al. Fatal respiratory disease due to Corynebacterium diphtheriae: Case report and review of guidelines for management, investigations, and control. Clinical Infectious Diseases 1993;16:59-68.

Gidding HF, Backhouse JL, Burgess MA, Gilbert GL, Immunity to diphtheria and tetanus in Australia: a national serosurvey. MJA 2005; 183 (6): 301-304.

Health Protection Agency. Death in a child infected with toxigenic Corynebacterium diphtheriae in London. Health Protection Report. 2008; 19 (2). Available from http://www.hpa.org.uk/hpr/archives/2008/news1908.htm#diph, accessed 6/5/2011.

Heymann, D. (Ed). 2008. Control of Communicable Diseases Manual,19th edition. American Public Health Association: Washington.

Bishai WR, Murphy JR. Diphtheria and other infections caused by corynebacteria and related species. In Harrison's Online, 17th Edition. 2008.

The Immunological Basis for Immunization Series: Diphtheria-Module 2. Available from http://www.who.int/vaccines-documents/DocsPDF-IBI-e/mod2_e.pdf, accessed 16 May 2011

MacGregor RR.  Corynebacterium diphtheriae. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Edition. 2009.

National Health and Medical Research Council. 2008. The Australian Immunisation Handbook, 9th edition. National Capital Printing: Canberra.

Perkins S, Cordery R, Nixon G, et al. Investigations and control measures following a non-travel associated case of toxigenic corynebacterium diphtheriae, London, United Kingdom, December 2009 - January 2010. Euro Surveill. 2010; 15 (16): pii=19544. Available from http://www.eurosurveillance.org/ViewArticle.aspx?Articleid=19544, accessed 6/5/2011.

Rousseau C, Belchior E, Broche B, Badell E, Guiso N, Laharie I, Patey O, Lévy-Bruhl D. Diphtheria in the south of France, March 2011 . Euro Surveill. 2011;16(19):pii=19867. Available from http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19867, accessed 13/5/2011.

Tejpratap S.P. Tiwari, M.D. Centers for Disease Control and Prevention. Manual for the Surveillance of Vaccine-Preventable Diseases, 4th edition 2008-2009. Diphtheria. Available from http://www.cdc.gov/vaccines/pubs/surv-manual/default.htm, accessed 16/5/2011.

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Annex A: Countries with Endemic Diptheria

RegionsCountries
Africa Algeria, Angola, Egypt, Niger, Nigeria, Sudan, and other sub- Saharan countries
Americas Bolivia, Brazil, Colombia, Dominican Republic, Ecuador, Haiti, and Paraguay
Asia/South Pacific Afghanistan, Bangladesh, Bhutan, Burma (Myanmar), Cambodia, China, India, Indonesia, Laos, Malaysia, Mongolia, Nepal, Pakistan, Papua New Guinea, Philippines, Thailand, and Vietnam
Middle East Iran, Iraq, Saudi Arabia, Syria, Turkey, and Yemen
Europe Albania, Russia, and countries of the former Soviet Union

Source:
Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010. Atlanta: US. Department of Health and Human Services, Public Health Service, 2009. Available from http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/diphtheria.aspx, accessed 16/5/2011.

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Annex B: Treatment for Cases of Diptheria

Administration and dosages of diphtheria antitoxin (DAT)

DAT is available under the Special Access Scheme from Queensland Health Central Pharmacy, phone 07 3120 8500 during work hours Monday to Friday. Contact RBWH switch on 3636 8111 for after hours access.

Princess Alexandra Hospital Pharmacy will also hold supplies of DAT. Contact the on call pharmacist through PAH switchboard on 3176 2111.

DAT is derived from equine serum. There is the potential risk of a hypersensitivity reaction ranging from acute anaphylaxis to serum sickness. Use of a test dose should be considered in accordance with the Product Instructions.

DAT Treatment for cases
Give children and adults the same dose.

Type of DiphtheriaDose (units)Route (single dose*)
Nasal 10 000 - 20 000 IM
Tonsillar 15 000 - 25 000 IM or slow IV
Pharyngeal or laryngeal 20 000 - 40 000 IM or slow IV
Cutaneous 20 000 - 40 000 IV
Combined types or delayed diagnosis (or nasopharyngeal with membrane present) 40 000 - 60 000 IV
Extensive disease of ≥ 3 days duration and/or severe swelling of neck (bull-neck) 80 000 - 120 000 IV
* additional doses may be warranted based on the person's symptoms and response

Antibiotic treatment for cases
(Recommendations may alter due to penicillin resistant case in 2011 - seek IDP advice)

Age/weightAgentDoseDuration*Route
< 9kg Procaine Pen G 300 000 U BID 14 days IM
equal to or greater than 9kg Pen G 600 000 U BID 14 days IM

When patient can swallow comfortably

Child **/Adult Penicillin V
OR
Erythromycin
125-250mg QID
OR
125-500mg QID
14 days

14 days
PO

PO
* Total treatment time is 14 days (ie. if taking IM antibiotic for 10 days would complete treatment with 4 additional days of PO antibiotic)
**Use a lower dose in children < 6 years of age.

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Annex C: Antibiotic prophylaxis for contacts and treatment for carriers (asymptomatic cases) of diphtheria

(Recommendations may alter due to penicillin resistant case in 2011 - seek IDP advice)

AgeAgentDoseRouteDuration
< 6 years old Penicillen G benzathine OR 600 000 units IM Single dose
Enthromycin 40mg/kg in 4 divided doses PO 7-10 days
6 years and older Penicillen G benzathine OR 1.2 million units IM Single dose
Enthromycin 1g/day in 4 divided doses PO 7-10 days

Notes:

  • Diphtheria antitoxin has no proven role in the prophylaxis of contacts or the treatment of carriers.
  • Contacts who cannot be kept under surveillance should receive penicillin G benzathine IM and not erythromycin, because adherence to an oral regimen is less likely.
  • Identified carriers should have nose and throat swabs collected a minimum of two weeks following completion of treatment and, if still positive, should receive an additional 10 day course of antibiotics with further follow-up cultures.
  • Consider amending prophylaxis in light of antibiotic sensitivities of isolates of toxigenic Corynebacterium diphtheriae or C. ulcerans.

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Annex D: Recommendations for the management of diphtheria cases, carriers and contacts

Management of Diptheria Flowchart

Notes:

  1. Strict isolation should be maintained until two cultures are negative at least 24 hours apart after completion of antimicrobial therapy. Follow up nose and throat swabs at 14 days post-antibiotic treatment is recommended.
  2. DAT is available from Queensland Health Central Pharmacy, phone 07 3120 8500 during work hours Monday to Friday. Contact RBWH switch on 3636 8111 for after hours access.
    Princess Alexandra Hospital Pharmacy will also hold supplies of DAT. Contact the on-call pharmacist through PAH switchboard on 3176 2111.
    Before administration, patients should be tested for sensitivity to horse serum and, if necessary, desensitised. The recommended dosage and route of administration depend on the extent and duration of disease.
  3. Antimicrobial therapy is not a substitute for antitoxin treatment. Parenteral antibiotics are recommended until the patient can swallow comfortably, at which point oral antibiotics can be used.
  4. Close contacts include all household members and other persons with a history of direct face to face exposure to the case for > 20 hours in the preceding week and health care staff directly exposed to the oral secretions of the case or who have dressed the wounds of a toxigenic cutaneous diphtheria case.
  5. A single dose of benzathine penicillin G (600,000 units IM for persons <6 years of age and 1.2 million units IM for persons ≥6 years of age) or a 7 to 10-day course of oral erythromycin (40 mg/kg per d for children and 1 g/d for adults) has been recommended.
  6. Persons who continue to harbour the organism after treatment with either penicillin or erythromycin should receive an additional 10-day course of antibiotics and should have further nose and throat swabs collected for follow up cultures at a minimum of two weeks following completion of the antibiotic course.

Source:
Alberta Health and Wellness. Public Health Notifiable Disease Management Guidelines - Diphtheria. Jan 2011. Government of Alberta, Canada. Appendix E available from http://www.health.alberta.ca/documents/Guidelines-Diphtheria-2011.pdf (accessed 16/5/2011).

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Last updated: 23 January 2012