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Diphtheria

  • To identify cases and prevent further transmission.
  • To monitor the epidemiology and so inform the development of better prevention strategies both in Australia and in source countries.

Infectious Agent

The agents are Corynebacterium diphtheriae and Corynebacterium ulcerans.

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

Toxigenic C. diphtheriae can cause respiratory diphtheria.

Infections of the skin are usually caused by nontoxigenic C. diphtheriae, but occasionally can be caused by toxigenic C. diphtheriae (cutaneous diphtheria).

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

Toxigenic Corynebacterium ulcerans may also cause an exudative pharyngitis in humans clinically indistinguishable from classical diphtheria, as well as skin infections similar to cutaneous diphtheria.

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Notification Criteria

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

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

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

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

Clinical evidence - 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:

1. 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)
AND
    b.  the other has an illness which starts approximately 2–5 days after this contact

AND

2.  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.

Laboratory Aspects
The Queensland reference laboratory does not perform phenotypic toxin testing for diphtheria toxin. C. diphtheriae and C. ulcerans isolates are screened for the diphtheria toxin by nucleic acid testing (NAT) designed to detect the phage encoded diphtheria toxin gene, tox. The detection of the tox gene indicates that the strain is toxin-gene positive NOT necessarily toxigenic. It is possible that in a small percentage of toxin-gene positive isolates (possibly 10% or less), the toxin gene possesses genetic mutations which may render the gene non-functional, meaning diphtheria toxin is not expressed (Zakikhany et al 2014, Doyle et al 2017). However, these isolates may have the potential to revert to a functional toxin gene. The reference laboratory performs genomic sequencing to analyse the gene sequence of the toxin gene and to infer if the gene encodes functional diphtheria toxin.

For the practical response purposes of this guideline and for consistency with the national case definition, detection of tox gene by NAT is evidence of and equivalent to isolation of toxigenic C. diphtheriae or toxigenic C. ulcerans.

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 reported.

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

Probable case
A probable case requires:

1. Laboratory suggestive evidence AND clinical evidence - probable case

OR

2. Clinical evidence - probable case AND epidemiological evidence.

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Public Health Significance and Occurrence

A full review of these guidelines was undertaken in 2018 due to increasing notifications of cutaneous toxigenic C. diphtheriae and toxigenic C. ulcerans. Additionally, there have been two recent Queensland cases of respiratory diphtheria. The public health management of these infections can be complex and further complicated by antibiotic resistance. There has also been limited evidence about the use of newer generation antibiotics for public health management. The review considered guidelines from other countries and the scientific literature and sought expert opinions from infectious disease physicians.

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, with only four cases of respiratory diphtheria occurring in the last 25 years. For most of these cases there was a link with overseas travel. A significant feature in the majority of these cases was the detection of a strain of toxigenic diphtheria that was resistant to penicillin. There has been an increase in sporadic cutaneous diphtheria cases in Australia in the last 5 years. Typically, cases have sustained a wound that has become infected whilst they have been travelling overseas.

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) (Vitek and Wharton 1998).

During the past decade, many developing countries have achieved high childhood vaccination coverage and a marked reduction in diphtheria cases. Rarely, outbreaks occur in well-vaccinated populations. Sporadic cases (and some deaths) have been reported from the UK (2008, 2009), France (2011) and Australia (2018). These cases were attributed to contact with people from endemic areas (Annex A).

As diphtheria has almost disappeared from Australia, 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.

Like C. diphtheriae, C. ulcerans may produce an exotoxin and is associated with rare zoonotic infections involving both classical diphtheria and milder illness.

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Clinical Features

There are two main forms of disease: respiratory and cutaneous.

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.

Respiratory diphtheria is classically due to infection with C. diphtheriaeC. ulcerans may also present with the same clinical features.

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.

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Reservoir

C. diphtheriae: Humans

C. ulcerans: A range of domestic and wild animals

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Mode of Transmission

C. diphtheriae: 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.

C. ulcerans: Historically been associated with drinking raw or unpasteurised milk products. It has also been linked to direct contact with domestic and farm animals. Transmission of C. ulcerans between humans has never been confirmed. Four instances of detection of asymptomatic C. ulcerans nasopharyngeal carriage among contacts of confirmed cases raise the possibility of human-to-human transmission, despite the likelihood of exposure to a common animal source.

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Incubation Period

Usually 2 to 5 days, occasionally longer.

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Period of Communicability

C. diphtheriae 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. Estimates of the time for cessation of infectivity from the onset of antibiotic therapy range from 2 to less than 4 days. The rare chronic carrier may shed organisms for 6 months or more.

C. ulcerans
Transmission of C. ulcerans between humans has never been confirmed.

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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.

Management

Cutaneous diphtheria

Cases

Investigation

Cases are likely to be notified because of a wound culture growing C. diphtheriae.

Ensure toxin testing has been ordered (through QHFSS). While awaiting toxin testing results, obtain clinical history including symptoms and history of travel. Ascertain diphtheria vaccination status, referring to records if available. Ensure wound/s is/are covered.

Infection with non-toxigenic strains does not usually result in severe consequences. Once a wound infection is found to be due to a non-toxigenic strain, public health follow up can cease.

If the infection is due to toxigenic C. diphtheriae, proceed with treatment, restriction and contact tracing as follows. Ensure the laboratory with the culture specimen undertakes sensitivity testing that includes the antibiotics recommended for treatment/clearance as per Annex B. Non-standard sensitivity testing may be needed for erythromycin, and may be organised by consultation with the relevant micro lab.

An Expert Advisory Group (EAG) is NOT usually required for cases of cutaneous diphtheria, but may be called at the discretion of the public health physician managing the case. Particularly, an EAG may be appropriate for situations that are extraneous to these guidelines.

Treatment

Antitoxin is not required to treat cutaneous diphtheria.

Proceed with antibiotic treatment as per Annex B and in accordance with antibiotic sensitivity testing results.

Patients should be vaccinated (with the age-appropriate formulation) 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. 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.

Restriction

Manage open wounds with contact precautions. Additionally, droplet precautions should be used until initial nasopharyngeal and throat swabs are known to be negative or until completion of 72 hours of a course of appropriate antibiotic therapy, whichever is shorter.

Exclude from work, school and child care until:

  • Initial nasopharyngeal and throat swabs are negative

AND

  • the wound/s are clinically improving as identified by the treating doctor and can be covered with an occlusive waterproof dressing OR the wounds have healed

AND

  • completion of 72 hours of an appropriate antibiotic course.

If initial nasopharyngeal and throat swabs are negative and the wounds have healed at the completion of antibiotic therapy, no further swabs are needed.

If initial nasopharyngeal or throat swabs are positive, indicating carriage, follow the exclusion principles and the requirement for repeat swabs as per a case of respiratory diphtheria.

Cases with wounds that are not continually improving over a course of an appropriate antibiotic need to be assessed by an infectious diseases physician as soon as this is recognised. In this instance, repeat swabs may be considered on a case-by-case basis. If the wounds have incompletely healed at the time of completion of antibiotic therapy, a further course of antibiotics should be considered in consultation with an infectious diseases physician. If the wound has continued to improve over the duration of the first antibiotic course, further swabs are not usually required.

C.ulcerans

Investigation and management of cases of cutaneous infection caused by toxigenic C. ulcerans is the same as for toxigenic C. diphtheriae infections.  Ensure empiric antibiotic therapy based on Annex B is consistent with the sensitivity profile for the isolate.

Droplet precautions and exclusion may not be needed for cutaneous C. ulcerans cases, in the absence of respiratory symptoms and based on risk assessment +/- EAG opinion.

Contacts

Contact Tracing
Only if confirmed as toxigenic C. diphtheria or C. ulcerans

Purpose
To identify co-primary or secondary cases. To identify asymptomatic carriers and to prevent / eliminate carriage.

Definition
Individuals who travelled with the case to the country where the wound was sustained or infected.

OR

Individuals who were in contact with the case after the onset of wound / infection of the wound in the case AND:

  • are household or household-like members (including sexual contacts)

OR

  • had direct contact with the wound without wearing gloves and a mask

OR

  • had close contact for 20 hours or more with the case (e.g. in child care settings) if the wound was uncovered.

NB – in reference to the final dot point above regarding close contact for 20 hours or more - The following groups would generally NOT be considered to have had close contact with the case:

  • Casual visitors to the home of the case
  • School or university classroom contacts
  • Those who work in the same room as the case.

If the case does not give either a history of sustaining the wound/s overseas or a history of an onset of infection of an existing wound that commenced whilst overseas or very shortly after returning from abroad, close contacts should also include:

  • anyone else who had household or household-like contact with the case in the 7 days preceding onset of the wound/s or onset of symptoms of infection in a chronic wound.

NOTE: if the initial nasopharyngeal and/or throat swabs of a case with cutaneous diphtheria are positive (indicating nasopharyngeal carriage), contact tracing should expand to include contacts and subsequent investigation as per the respiratory diphtheria section of this guideline.

Investigation

Health care workers treating the case:

Identify the procedures used to treat the case’s wound/s and what infection control procedures were used while undertaking wound care. Importantly, identify if any potential exposure to droplets was likely to have occurred. For example, droplets may be generated when vigorously washing the wound or irrigating the wound under pressure.

All contacts should have their immunisation history checked.

All contacts as defined above (with the exception of health care workers who had brief contact with the wound while wearing gloves and did not perform procedures likely to generate droplets) should have nasopharyngeal and throat swabs taken. These should be taken prior to the commencement of antibiotics where this is applicable. If asymptomatic contacts return a positive nasopharyngeal or throat swab, they should be managed as asymptomatic carriers (see the box “Asymptomatic nasopharyngeal carriers” under the respiratory diphtheria section of these guidelines.).

Prophylaxis              

All contacts as defined above require clearance antibiotics except:

  • travel companions who are asymptomatic and do not also fall into another contact category
  • health care workers or others who had brief contact with the wound while wearing gloves and did not perform procedures likely to generate droplets.

Refer to Annex C for recommended antibiotics and dosages.

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.

Restriction

Contacts requiring clearance antibiotics should be excluded from occupations involving:

  • contact with infants aged 6 months and under
  • the care of the sick, elderly, and those requiring dependent care
  • contact with immunosuppressed individuals.

until cultures from the nose, and throat (taken prior to commencement of antibiotics) are proved to be negative for toxigenic diphtheria bacilli OR they have completed 72 hours of a course of appropriate antibiotics, whichever is shorter. If a health care worker has been assessed as a close contact requiring clearance antibiotics and is required to return to work prior to fulfilling either of these criteria, they should wear a mask when in contact with patients.

Counselling

All contacts should be advised to monitor themselves for symptoms of diphtheria for 7 days and seek medical advice promptly should symptoms appear.

C. ulcerans

Exclusion of asymptomatic contacts is generally not required. Otherwise, investigation and management of contacts of cases of toxigenic cutaneous C. ulcerans infection is the same as for toxigenic cutaneous C. diphtheriae infections. Due to the zoonotic nature of C. ulcerans infection, it is important to identify any potential animal source. Where the case’s infection has been acquired in Queensland and the case has had contact with animals during the incubation period, liaison with Biosecurity Queensland is recommended to discuss the practicality of screening companion animals, livestock or other identified animals.

Respiratory diphtheria

Cases (see also Annex D flowchart)

Investigation

Obtain clinical history and confirm picture is of respiratory disease.

Ensure swabs for culture and toxin testing have been ordered and notify QHFSS.

Identify if the Corynebacterium diphtheriae 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 any skin lesions), 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, diphtheria antitoxin (DAT) 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 (see Annex B).

While antibiotics are required to eradicate the organism, stop further toxin production and help prevent transmission, DAT is considered the mainstay of treatment for respiratory diphtheria. DAT neutralises circulating toxin. Toxin already bound to tissue is unaffected. Therefore, DAT does not reverse symptoms caused by bound toxin. Rather, it limits disease progression meaning that early administration is critical, with degree of protection being inversely proportional to delay in administration.

DAT is not listed on the Australian Register of Therapeutic Goods and must be accessed using the Special Access Scheme (SAS) of the Therapeutic Goods Act 1998. Queensland holds a limited supply of DAT and the standard operating procedure which outlines how to obtain DAT is found on the Queensland Health Communicable disease control guidance webpage and at the following link: https://www.health.qld.gov.au/__data/assets/pdf_file/0022/444505/diphtheria-antitoxin.pdf .

Note that approval for the release of DAT from Central Pharmacy is required from the Executive Director or Medical Director on-call (ED or MD), Communicable Diseases Branch. The final decision to administer DAT rests with the treating clinician.

DAT is derived from equine serum. There is the potential risk of a hypersensitivity reaction ranging from acute anaphylaxis to serum sickness. Sensitivity testing should be considered in accordance with the Product Information before giving the antitoxin.

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.

Patients should be vaccinated (with the age-appropriate formulation) 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. 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.

Asymptomatic nasopharyngeal carriers

Isolation of toxigenic Corynebacterium diphtheriae or C. ulcerans from the nose or throat of 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. Repeat nasopharyngeal and throat swabs and follow exclusion principles as for a case of respiratory diphtheria.

Counselling

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

C.ulcerans

Investigation and management of cases of respiratory infection caused by toxigenic C. ulcerans is the same as for toxigenic C. diphtheriae infections. Ensure empiric antibiotic therapy based on Annex B is consistent with the sensitivity profile for the isolate.

Contacts (see also Annex D flowchart)

Contact Tracing

Only if toxigenic strain of C. diphtheriae or C. ulcerans.

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 OR in contact with the case after illness onset in the case until 2 cultures from both throat and nose (and any skin lesions), not less than 24 hours apart, and not less than 24 hours after cessation of antimicrobial therapy, fail to show C. diphtheriae 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 close contact for 20 hours or more with the case e.g. in child care settings.

Where the case has travelled within an incubation period, consider the above definitions in relation to that travel history on a case-by-case basis.

People (e.g. hospital staff) who have taken appropriate infection control precautions need not be considered contacts.  Appropriate infection control precautions are gloves and a mask. Staff who have cared for the case without a mask should be considered contacts.

Guidance on contact definitions in settings such as schools or prisons is provided in Table 1 (Special Situations).

Investigation
Contacts as defined above (regardless of their vaccination status) should have throat and nasopharyngeal swabs taken for culture (ideally before the commencement of antibiotics), receive prompt antibiotic 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              

Contacts as defined above require antibiotic prophylaxis. See Annex C for recommended antibiotics and dosages.

The risk of transmission and identification of contacts of respiratory diphtheria requiring prophylaxis in other settings such as schools or prisons should be assessed on a case-by-case basis with reference to Table 1 (see Special Situations). An EAG may be beneficial in these situations. Examples of those unlikely to be classified as contacts requiring prophylaxis include:

  • casual visitors to the home of the case
  • school or university classroom contacts
  • those who work in the same room as the case
  • healthcare workers with brief exposures to the case in the absence of transmission-based precautions.

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.

Restriction

All asymptomatic contacts should avoid contact with people vulnerable to diphtheria until 72 hours of an appropriate course of antibiotics have been completed OR until cultures from the nose, throat and any lesions are proved to be negative for toxigenic diphtheria bacilli.

Asymptomatic contacts should be excluded from:

  • occupations involving the care of the sick, immunosuppressed, elderly, those requiring dependent care, and infants aged 6 months and under
  • school and childcare.

Until cultures from the nose, throat and any lesions are negative for toxigenic diphtheria bacilli or until 72 hours of an appropriate course of antibiotics have been completed, whichever is shorter.

Health care workers who have cared for a case of respiratory diphtheria without a mask should be excluded as above until negative swabs are returned.

C. ulcerans

Exclusion of asymptomatic contacts is generally not required. Otherwise, investigation and management of contacts of cases of toxigenic cutaneous C. ulcerans infection is the same as for toxigenic cutaneous C. diphtheriae infections. Due to the zoonotic nature of C. ulcerans infection, it is important to identify any potential animal source. Where the case’s infection has been acquired in Queensland and the case has had contact with animals during the incubation period, liaison with Biosecurity Queensland is recommended to discuss the practicality of screening companion animals, livestock or other identified animals.

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 respiratory diphtheria requires an Outbreak Control Team or Incident Management approach. Key issues include nomination of roles 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.

  • 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 or the co-ordinating public health unit.

Non-respiratory diphtheria cases may be managed locally by the public health unit.

Special situations

As each individual setting will differ, the following is a guide to the identification and management of contacts in these situations. The underpinning principle is consideration of whether transmission is likely to have occurred due to proximity and duration of contact, and if so, to reduce the chance of carriage which may lead to disease in susceptible close contacts or more broadly.

Regardless of risk category, all contacts should be alert for the symptoms of diphtheria infection (skin and/or respiratory) for at least 7 days after contact and seek medical advice if concerned.

Table 1: Guidelines for management of contacts of cases of toxigenic diphtheria (respiratory and cutaneous) in various settings
(Resp = respiratory, Cut = cutaneous, HH = household)

Setting

Case type

Contact definition

Contact category

Vaccination  

Exclusion *

Antibiotics

Swabs4

Advice1

Household

Resp

and

Cut

All household members and those who have spent the majority of a day and/or overnight in the same house as the case after onset of symptoms (and in 7 days prior to symptoms for resp)2

HH

Yes

Yes

*(C.ulcerans – exclusion of asymptomatic contacts is not generally required)

Yes

Yes

Yes

Residential institutions including prisons, hospital wards (patients) and boarding schools

Resp

and

Cut

Direct wound contact, sleeping in same room overnight

HH-like

Yes

Yes *

Yes

Yes

Yes

Resp

and

Cut

Sleeping in same connected space and sharing living facilities (apart from sharing open recreational spaces)

Communal

Yes

No

No

Yes

Yes

Resp

and

Cut

All other (including sharing open recreational spaces only)

Social

Opportunistic3

No

No

No

Yes

Air Travel

Resp

Passengers seated immediately adjacent to symptomatic case on flight of ≥8hrs

HH-like

Yes

Yes *

Yes

Yes

Yes

Cut

Passengers seated immediately adjacent to case on flight (of ≥8hrs)

Communal (possible HH-like)

Consider EAG to discuss management of contacts.

Considerations

-   Positive initial NP/throat swab

-   Uncovered wound/ Direct wound contact

-   Respiratory symptoms in case

Schools (not boarding schools)

Resp

Very close / prolonged contact

Possible HH-like

Consider EAG

 

Other classroom contact

Social

Opportunistic3

No

No

No

Yes

Cut

Classroom contacts

Social

(unless direct wound contact)

Opportunistic3

No

No

No

Yes

Child care

(continued next page)

Resp

Staff and children who are known to have had close contact with the symptomatic case for ≥20 hours

HH-like

Yes

Yes *

Yes

Yes

Yes

Child care

(continued from previous page)

Resp

All staff and children in the same room as the case (or having otherwise close contact when classes are mixed etc) for ≤20 hours cumulative from 7 days preceding symptoms in the case until last attendance of case while symptomatic

Communal

Yes

No

No

Yes

Yes

 

Resp

All other children and staff at the centre

Social

Opportunistic3

No

No

No

Yes

 

Cut

Staff and children who are known to have had close contact for 20hours or more if the case’s wound was uncovered and/or staff or children in direct contact with the case’s wound

HH-like

Yes

Yes *

Yes

Yes

Yes

  

All staff and children in the same room as the case (or having otherwise close contact when classes are mixed etc) if the case’s wound was uncovered5

Communal

Yes

No

No

Yes

Yes

  

All other children and staff at the centre or all children and staff if the case’s wound was covered

Social

Opportunistic3

No

No

No

Yes

Health care workers

Resp

Cared for the case without a mask

HH-like

Yes

Yes *

Yes

Yes

Yes

 

Cut

Had contact with the wound without wearing a mask and had likely exposure to droplets (gloves worn)

HH-like

Yes

Yes *

Yes

Yes

Yes

 

Cut

Had contact with the wound wearing gloves. No / unlikely exposure to droplets

Social

Opportunistic3

No

No

No

Yes

  1. Provide advice re vaccination, mode of transmission, signs and symptoms
  2. Consider travel history when defining contacts – see contact definitions in main text of guideline
  3. Recommend as opportunistic measure through usual health care provider
  4. Swabs should ideally be nasopharyngeal and throat swabs, however, in institutional settings where there may be requirement to swab large numbers of contacts, nasal or deep nasal swabs and throat swabs may be substituted to decrease the risks associated with aerosol-generating NP swabs and improve timeliness
  5. Consider vaccination status in assessment of contact definition

*     C.ulcerans – exclusion of asymptomatic contacts is not generally required

Aircraft:

The risk of transmission of C. diphtheriae on an aircraft is low, especially for flights of less than 8 hours duration. Should a case of symptomatic respiratory diphtheria travel on a long-distance flight while infectious, the passengers seated immediately adjacent to them should be considered household-like contacts.

There is usually no requirement to contact trace those in adjacent seats in the following circumstances:

  • Someone subsequently diagnosed with respiratory diphtheria travelled on a long-distance flight during their incubation period.
  • Someone with cutaneous diphtheria and negative initial nasopharyngeal and throat swabs travelled on a long-distance flight.

Consideration could be given to contact tracing adjacent seats of a long-distance flight in the instance that someone with cutaneous diphtheria travelled with an uncovered infected wound and/or returns positive initial nasopharyngeal and/or throat swabs. In these instances, it is recommended to call an EAG to discuss further.

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Preventive measures

  • The most effective preventive measure is widespread vaccination with diphtheria toxoid.
  • Maintain continual improvements in Australian 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 heading overseas should be vaccinated if they have not had a booster in the last 10 years.
  • Support vaccination programs among other countries in our region.

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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.

Doyle CJ, Mazins A, Graham RM, Fang NX, Smith HV, Jennison AV. 2017. Sequence Analysis of Toxin Gene-Bearing Corynebacterium diphtheriae Strains, Australia. Emerg Infect Dis. 23(1):105-107.

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.

Vitek CR, Wharton M.  1998.  Diphtheria in the former Soviet Union: Reemergence of a pandemic disease.  Emerging Infectious Diseases 4(4):539-550.

Zakikhany K, Neal S, Efstratiou A. 2014. Emergence and molecular characterisation of non-toxigenic tox gene-bearing Corynebacterium diphtheriae biovar mitis in the United Kingdom, 2003-2012. Euro Surveill. 19(22), article 3.

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Annex A: Countries with Endemic Diphtheria

RegionsCountries
Africa Algeria, Angola, Egypt, Eritrea, Ethiopia, Guinea, Niger, Nigeria, Sudan, Zambia and other sub-Saharan countries
Americas Bolivia, Brazil, Colombia, Dominican Republic, Ecuador, Haiti, and Paraguay
Asia/South Pacific Bangladesh, Bhutan, Burma (Myanmar), Cambodia, China, India, Indonesia, Laos, Malaysia, Mongolia, Nepal, Pakistan, Papua New Guinea, Philippines, Thailand, and Vietnam
Middle East Afghanistan, Iran, Iraq, Saudi Arabia, Syria, Turkey, and Yemen
Europe Albania, Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Russia, Tajikistan, Turkmenistan, Ukraine and Uzbekistan

Source:

Source = Centers for Disease Control and Prevention. CDC Health Information for International Travel 2012: The Yellow Book. Atlanta: US. Department of Health and Human Services, Public Health Service, 2012. Available from https://books.google.com.au/books?id=5vCQpr1WTS8C&pg=PA163&lpg=PA163&dq=countries+with+endemic+diphtheria&source=bl&ots=ORI8bF-JBW&sig=ldie3C9q0pSyR_X5lh8PL_cVj-o&hl=en&sa=X&ved=0ahUKEwiOzL215IrXAhVEo5QKHagBD5Q4ChDoAQg-MAM#v=onepage&q=countries%20with%20endemic%20diphtheria&f=false , accessed 25/10/17.

Travel to the Solomon Islands and Fiji, has also been recorded for cutaneous diphtheria cases in Queensland.

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Annex B: Treatment for Cases of Diphtheria

DAT is considered the mainstay of treatment for respiratory diphtheria, while antibiotics are required to eradicate the organism, stop further toxin production and help prevent transmission. DAT neutralises circulating toxin. Toxin already bound to tissue is unaffected, meaning DAT does not reverse symptoms caused by bound toxin. Rather, it limits disease progression making early administration critical, with the degree of protection being inversely proportional to delay in administration.

DAT is not listed on the Australian Register of Therapeutic Goods and must be accessed using the Special Access Scheme (SAS) of the Therapeutic Goods Act 1998. Queensland holds a limited supply of DAT and the standard operating procedure which outlines how to obtain DAT is found in Annex D.

Note that approval for the release of DAT from Central Pharmacy is required from the Executive Director or Medical Director on-call (ED or MD), Communicable Diseases Branch. The final decision to administer DAT rests with the treating clinician.

DAT is derived from equine serum. There is the potential risk of a hypersensitivity reaction ranging from acute anaphylaxis to serum sickness. Sensitivity testing should be considered in accordance with the Product Information before giving antitoxin.

Give children and adults the same dose. Preferred route is IV, particularly in severe cases. DAT may be given IM in mild or moderate cases. Additional doses may be considered based on the person’s symptoms and response at the request of the treating team, noting that repeated DAT doses are not usually associated with additional benefit.

DAT Treatment for cases12(see CDC documentation: https://www.cdc.gov/diphtheria/downloads/protocol.pdf)

Type of Diphtheria

Dose (units)

Pharyngeal or laryngeal    disease ≤2 days duration

20,000 U to 40,000 U

Nasopharyngeal lesions

40,000 U to 60,000 U

Extensive disease of ≥3    days duration or diffuse swelling of the neck

80,000 U to 120,000 U

Cutaneous disease

Not usually recommended. 
If required: 20,000 U to  40,000 U

Antibiotic treatment for cases

Note that penicillin resistant isolates have been identified in Queensland. Choice of antibiotics and dosing regimen should take into account antibiotic sensitivities, clinical tolerance and severity of disease. Check sensitivity of isolate and seek the advice of an Infectious Diseases Physician to guide antibiotic treatment.

Age/weightAgentDoseDuration*Route

< 9kg

Procaine
Penicillin G

300,000 U BID 14 days1 IM
≥ 9 kg Procaine
Penicillin G
600,000 U BID 14 days1 IM
When patient can swallow comfortably
Child2/Adult Penicillin V
OR
Erythromycin3
125-250mg QID
OR
125-500mg QID
14 days1

14 days1
PO

PO
1  Total treatment time is 14 days (ie. if taking IM antibiotic for 10 days would complete treatment with 4 additional days of PO antibiotic)
2  Use a lower dose in children < 6 years of age
3 Where erythromycin is recommended, discuss with Clinical Microbiologist to ensure sensitivity testing is undertaken

1 CDC (2017): https://www.cdc.gov/diphtheria/downloads/protocol.pdf

2 American Academy of Pediatrics (2015). Red book: 2015 report of the Committee on Infectious Diseases 30th ed. Elk Grove Village, IL: AAP

Alternative antibiotics including clindamycin and doxycycline may be recommended by an Infectious Diseases Physician based on antibiotic sensitivities. If microbiological clearance is not achieved, an additional 10-day course of antibiotics is recommended on the advice on an Infectious Diseases Physician.

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

Note that penicillin resistant isolates have been identified in Queensland. Choice of antibiotics and dosing regimen should take into account antibiotic sensitivities, clinical tolerance and nature of contact with the case. Check sensitivities of isolate before recommending antibiotic prophylaxis and seek the advice of an Infectious Diseases Physician if sensitivities are awaited or conflict with recommended antibiotics. Alternative antibiotics may be recommended by an Infectious Diseases Physician based on antibiotic sensitivities.

Table 1: First-line antibiotics for use in contacts and asymptomatic carriers

AgeAgentDoseRouteDuration
Infant or child < 6 years old

Benzathine penicillin

OR

Erythromycin1,2

600,000 units = 450mg

IM Single dose
40 mg/kg in 4 divided doses (up to 1g/day) PO 7 days3
Child ≥6 years or adult

Benzathine penicillin

OR

Erythromycin1,2

1.2 million units = 900mg IM Single dose
125–500 mg QID PO

7 days3

1  Where a macrolide antibiotic is recommended, discuss with Clinical Microbiologist to ensure sensitivity testing is undertaken
2  If erythromycin cannot be tolerated an alternative macrolide such as azithromycin or clarithromycin should be given
3  Antibiotic courses of up to 10 days duration may be used in some situations, where considered clinically appropriate

Table 2: Alternative antibiotics for use in adults ≥12 years based on available sensitivities

Antibiotic

Dose

Route

Duration

Clindamycin

150-300 mg QID

PO

7 days

Doxycycline1 2

Initially 200 mg on day 1 (100 mg BD) followed by 100 mg daily

PO

7 days

1  Use in adult contacts ≥50 kg in weight. Doxycycline is contraindicated in pregnancy and breast feeding

2  Where penicillin and macrolide antibiotics are contraindicated, not tolerated or impractical, doxycycline may be considered for children aged 8-11 years who weigh ≥50 kg

Notes:

  • Diphtheria antitoxin has no proven role in the prophylaxis of contacts or the treatment of carriers.
  • Consider use of benzathine penicillin (where sensitivities allow) for contacts who cannot be kept under surveillance or where adherence to an oral antibiotic regimen may be in doubt.
  • 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.

Table 3: Antibiotic sensitivities of 72 C. diphtheriae isolates*, Sullivan Nicolaides Pathology, Queensland, 2002-20123

Antibiotic

Percentage (%) of isolates sensitive

Cephalothin (n = 71)

100

Erythromycin/ clindamycin (n = 70)

100

Trimethoprim/ sulfamethoxazole (n = 72)

86

Penicillin (n = 72)

97

Tetracycline (n = 70)

96

Vancomycin (n = 54)

100

*71 non-toxigenic isolates and a single toxigenic isolate among a total of 72

3 May MLA, McDougall RJ and Robson JM (2014). Corynebacterium diphtheriae and the returned tropical traveller. J Travel Med;21:39-44

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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 nasopharyngeal and throat swabs at 14 days post antibiotic treatment is recommended.

(2) DAT is available form Queensland Health Central Pharmacy. The process for obtaining DAT, including required approvals, is available at https://www.health.qld.gov.au/__data/assets/pdf_file/0022/444505/diphtheria-antitoxin.pdf.

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 (see Annex B).

(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 contact: see Respiratory Diphtheria - Contacts - Definition.

(5) Antibiotic prophylaxis for contacts: see Annex C.

(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 nasopharyngeal and throat swabs collected for follow up cultures at a minimum of two weeks following completion of the antibiotic course.

Source

Adapted from - 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: 26 September 2019