Approach

Successful treatment of diphtheria depends on rapid neutralization of free toxin by prompt administration of antitoxin and eradication of Corynebacterium diphtheriae with antibiotics. In addition, prevention and/or early recognition of complications is essential to improving outcomes.

Patients with respiratory diphtheria require hospitalization, close monitoring, prompt treatment with diphtheria antitoxin, appropriate antibiotic therapy, and supportive care. ECG monitoring, oxygen saturation monitoring, and careful airway management are important in severe cases. Airway compromise by the diphtheritic membrane and pharyngeal edema may necessitate early intubation and mechanical ventilation. Patients with cutaneous diphtheria usually have mild disease and are often treated as outpatients.

Close patient contacts need to be swabbed, treated with prophylactic antibiotics, and monitored appropriately.[27][40]

Protective immunity does not always develop after recovery, so vaccination of patients, contacts, and the general population is important for diphtheria prevention and control.[1]​​​[49]

Antitoxin therapy

Diphtheria antitoxin is the mainstay of therapy and should be administered promptly, as soon as there is a strong clinical suspicion of respiratory diphtheria.​[12][40][44]​​​​[50]​​​ Laboratory confirmation of the diagnosis should not delay administration of antitoxin, as patients can deteriorate quickly. Antitoxin can only neutralize free toxin in the serum, and the efficacy of antitoxin decreases significantly after the onset of mucocutaneous symptoms, which signal the movement of toxin into the cells.

In the US, antitoxin is only available to physicians from the Centers for Disease Control and Prevention (CDC) through a Food and Drug Administration (FDA)-Investigational New Drug protocol.[40][51] Currently available diphtheria antitoxin is equine-derived, although efforts are ongoing to develop an antitoxin of human origin.[52] The amount of antitoxin required depends on the site and size of the pseudomembrane, the duration of illness, and the overall clinical condition of the patient. Doses may differ between guidelines and you should consult your local guidance for more information.​​[44][53]

There is a risk of adverse reactions with equine antitoxin, including self-limiting acute febrile illness, serum sickness, and rare life-threatening anaphylaxis. Previously, guidelines recommended sensitivity testing is carried out before administration of the full dose of antitoxin.[51] However, a study looking at the outcomes of a large-scale diphtheria antitoxin administration program in Bangladesh during the 2017-2018 outbreak described low severe adverse reaction rates, and reported that skin sensitivity testing was poorly predictive of which patients would react to systemic antitoxin; routine use of skin sensitivity testing was therefore discontinued in this outbreak setting (trained staff were present to rapidly detect and treat adverse reactions).[54]​ The World Health Organization (WHO) strongly recommends against routine sensitivity testing prior to administration of antitoxin.[44]​ Patients who are identified as at high risk of antitoxin hypersensitivity may undergo a desensitization procedure prior to administration of the full dose. This can be achieved with a series of intravenous injections of small amounts of diluted serum, administered at 15-minute intervals.[51][53]

Desensitization and full-dose antitoxin administration should only be performed by those familiar with treatment of anaphylaxis and in a facility where appropriate drugs and resuscitation equipment are immediately available. Some physicians advocate pre-medication with oral or parenteral antihistamines and corticosteroids.[51][53][54] If signs of anaphylaxis occur, administration of antitoxin must be stopped and epinephrine administered immediately.

Patients should receive their full dose of antitoxin as a single dose, or immediately after desensitization, to minimize the risk of subsequent (re-)sensitization from repeated doses of equine serum.[51][53]

Cutaneous diphtheria does not usually warrant antitoxin administration. However, its use may still be considered, as systemic sequelae of cutaneous diphtheria have been reported, albeit rarely.[5]

Antibiotics

Antibiotics are not a substitute for treatment with antitoxin, but serve to prevent further production of toxin by eradicating C diphtheriae. They also treat localized cutaneous infections. In addition, antibiotics prevent transmission of the disease to contacts.​

If available, local antimicrobial susceptibility testing should be carried out to guide antibiotic treatment.[40][44]

The WHO recommends an oral macrolide antibiotic (e.g., azithromycin, erythromycin) as first-line treatment in preference to penicillin antibiotics in patients with suspected or confirmed diphtheria infection. Penicillins were previously recommended as first-line treatment and can still be used where macrolides are unavailable and penicillin susceptibility has been microbiologically confirmed. However, due to increasing concerns about penicillin resistance, macrolides are now preferred as the first-line treatment.[44]

Antibiotic recommendations may differ between guidelines. In the US, the CDC currently only recommends erythromycin or penicillin.[42]​ In the UK, the UK Health Security Agency (UKHSA) recommends all macrolides (including clarithromycin) for mild disease, and combination therapy (with a macrolide plus intravenous penicillin and the possibility of adding a third option) for severe disease.[40]

A 14-day course of antibiotics is generally deemed acceptable for treatment of respiratory or cutaneous diphtheria.​[40]​​[55]​ Oral administration is preferred, unless patients are severely ill or unable to swallow, in which case parenteral therapy may be given initially. Clinicians should consult their local guidelines for further information as treatment duration recommendations may vary. For example, the UK guidelines suggest that a 7 to 10-day course may be sufficient if azithromycin is used, but recommend 14 days for all other antibiotics.[40]

Two negative cultures, taken at least 24 hours apart, indicate successful treatment. If either culture is positive, a further 10 days' treatment is initiated.​[40][42]​​​​​ In outbreak settings where microbiological facilities are insufficient to permit repeated sample processing for culture, patients are often deemed to be sufficiently noninfectious to lift isolation and infection control measures after 48 hours of antibiotic therapy.​[56]

Asymptomatic close contacts

Prompt identification and investigation of close contacts (i.e., all household contacts and those who have had intimate respiratory or habitual physical contact with the patient) is a high priority. These individuals should be monitored for illness through the incubation period (up to 10 days) and told to seek urgent medical attention if symptoms develop. In addition, cultures from swabs of the nose, throat, and any cutaneous lesion should be performed. If their immunizations are not up to date, they should receive an age-appropriate vaccine containing diphtheria toxoid.​​​[42][49]​

Close contacts should also receive a course of prophylactic antibiotics. US guidelines, based on clinical trial evidence, recommend oral erythromycin or penicillin for diphtheria chemoprophylaxis.[42]​​​​​​​​ UK guidelines support use of oral azithromycin or clarithromycin, which are more tolerable to patients, simpler to administer, and have not been associated with any reported treatment failures.[40] If there is history of intolerance to the oral antibiotics or concerns about adherence, a single dose of intramuscular penicillin G benzathine may be used.[40]​​[42]​​​​​​ The WHO guidelines do not currently offer any recommendations for the prevention of infection in close contacts, but do recommend macrolides in preference to penicillins for the treatment of diphtheria.[44]

Health and social care staff who have had unprotected (e.g., not wearing a facemask), close, face-to-face contact with an infected patient or their secretions should be managed as close contacts, with nasal and pharyngeal cultures taken and prophylactic antibiotics prescribed. Examples of close contact include: performing a physical examination on, feeding, or bathing a patient; bronchoscopy; intubation; or administration of bronchodilators. Exposure to cutaneous diphtheria lesions may include unprotected contact with the lesions or their drainage, such as when changing lesion dressings, or handling potentially infectious secretions without wearing recommended personal protective equipment (PPE) (i.e., gown and gloves).[57]​​[58]​ Staff should be excluded from work until culture results are known; if cultures are negative for toxin-producing C diphtheriae, they may return to work whilst completing post-exposure antibiotic therapy.[58]​ Daily monitoring for the development of signs and symptoms of diphtheria for up to 10 days after the last exposure should be implemented.[40]​​[42]​​​​​ Close contacts of confirmed or probable cases of diphtheria who work in other high-risk occupations should follow the same guidance as healthcare workers with regards to exclusion from work. Examples are those who work with unimmunized children and those involved in milk production (risk for C ulcerans).[40]

Diphtheria toxoid vaccination status should be assessed in all close contacts. If they are not up to date, the person should receive an age-appropriate vaccine containing diphtheria toxoid as a booster or to bring them back on schedule for their immunization program.[42]​​[49]

Asymptomatic carriers

Close contacts who are symptom-free but found to have positive cultures (i.e., asymptomatic carriers) are placed in isolation and treated with antibiotics. Antibiotic treatment options for asymptomatic carriers are the same as those used for acute disease.​​[40] Those with respiratory colonization require respiratory and contact isolation measures, while those with cutaneous colonization require contact isolation only. Normally these patients are managed at home. Isolation is continued until two successive cultures, taken at least 24 hours apart following cessation of antibiotic therapy, are negative.[42]​​​ Again, in outbreak settings where microbiological facilities are insufficient to permit repeated sample processing for culture, patients are often deemed to be sufficiently noninfectious to lift isolation and infection control measures after 48 hours of antibiotic therapy.​[56]

Positive posttreatment culture results warrant a repeat course of antibiotic treatment.​​[40]

An age-appropriate booster dose of diphtheria toxoid is also given to asymptomatic carriers if they have not received one within the previous 5 years.

Referrals and consults

Prompt otolaryngeal referral should be sought for people with respiratory compromise or severe neurologic complications involving the laryngeal nerves. Cardiology referral may be considered due to the risk of toxic cardiomyopathy and myocarditis.

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