The article outlines new WHO guidelines for managing diphtheria outbreaks, emphasising prompt diagnosis, updated antibiotic therapy with macrolides like azithromycin, & an escalating dosing regimen for diphtheria antitoxin based on disease severity.

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According to the new recommendations, physicians may administer injections of diphtheria antitoxin without first performing a standard skin sensitivity test.

Depending on the severity of the disease and the time the symptoms started, doctors should give patients with suspected or confirmed diphtheria a gradually increasing dosage. Furthermore, physicians need to treat patients with azithromycin rather than penicillin.  

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This guideline was prompted by what?  

1. Even after the immunisation campaign against diphtheria was started at the beginning of the century, outbreaks of the disease have persisted in areas with subpar vaccination rates.
2. The COVID-19 epidemic, population relocation, and structural instability of health services have had a detrimental influence on vaccination coverage.
3. There are now recurring outbreaks of diphtheria in every WHO area as well as a protracted epidemic in some West African nations. Even though diphtheria is curable and prevented, effective therapy requires prompt diagnosis of the clinical condition and prompt delivery of the proper medication, which includes DAT and adequate antibiotics.
4. Rapid distribution networks and a restricted worldwide supply have made it difficult to get DAT. The goal of the WHO Clinical Management of diphtheria guideline is to compile the most recent evidence-based guidelines into a single resource to assist medical professionals in treating patients with diphtheria acutely.
5. This guideline addresses specific demands from physicians and the relevant health ministries in the impacted nations. Clinicians in the outbreak-affected nations currently have little to no clinical experience treating patients with diphtheria and have restricted access to testing for antibiotic susceptibility.  

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Assessment in a clinical setting  

Strains of Corynebacterium diphtheriae are responsible for respiratory diphtheria. These strains have a preference for the upper respiratory tract, which includes the nose and throat. They also generate a toxin that may cause systemic problems and airway impairment in severe instances, in addition to localised sickness.  

The bacterial toxin that causes diphtheria inflames the epithelial mucosa, resulting in an exudate that may appear as a distinctive greyish-white "pseudomembrane" in the tonsils, larynx, pharynx, or nasopharynx (or a combination of these). Respiratory obstruction may arise due to the fibrinous pseudomembrane.

A swollen neck may result from the toxin's disruption of protein synthesis, cell death, and epithelial collapse. The toxin then spreads to nearby lymph nodes. The kidneys, neurological system, and myocardial (heart) may all be impacted by the poison spreading throughout the blood. Additionally, C. diphtheriae may result in wound and skin infections. This recommendation does not go into additional detail about cutaneous diseases.  

Previous WHO operational advice describes the severity of diphtheria.  

Severe/extensive illness: duration of three or more days, or widespread neck swelling (the so-called "bull neck"), respiratory difficulty, or hemodynamic instability (6)(7). Mild disease: localised laryngeal or pharyngeal disease of two days.  

According to a recent comprehensive study, 29% of unvaccinated people infected with toxin-producing strains die from their infection. When resources are scarce, case fatality percentages may vary greatly and could reach 50% in some epidemics.  

Transfer: The most common way that diphtheria transmits between people is via the air, with direct contact occurring less commonly. Usually, the incubation phase lasts between two and five days.  

The current therapies include: using DAT to neutralise the unbound toxin; using antibiotics to stop the development of more germs; and providing supportive care and monitoring to avoid and cure problems such as myocarditis and airway blockage.

Urgent airway intervention may be lifesaving for individuals whose airways are about to become obstructed. Basic airway manoeuvres, endotracheal intubation, cricothyroidotomy (a surgical or needle procedure), and tracheostomy are among the alternatives. The expertise of the medical professionals providing treatment will determine the advantages and disadvantages of each strategy.  

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Recommendation for the administration of antibiotics  

1. Antibiotics are used to stop bacteria from growing and producing toxins, which lowers the danger of more organ damage, as well as to stop bacteria from spreading to other people.
2. Penicillins, such as benzylpenicillin, procaine penicillin, and penicillin V, have been used in the past, but macrolides, such as erythromycin or azithromycin, have also been utilised.
3. The frequency of antimicrobial resistance in C. diphtheriae strains varies by geography and time and affects both groups. Therefore, the only way to determine local resistance patterns is by bacterial susceptibility testing.
4. More resistance to penicillin than the macrolide class of antibiotics has been shown in recent research. In close quarters with infected patients, antibiotics are also used to prevent the spread of diphtheria; WHO guidelines on this subject are being developed.  

Practical advice

Erythromycin and azithromycin are macrolide antibiotics. Macrolide antibiotics may be administered parenterally; however, this is usually reserved for situations in which oral administration is not feasible, such as when a patient is unable to take oral medicine. The selection of the macrolide will depend on its practicality and availability. The following dosage recommendations are made:

1. Administer azithromycin once a day, either intravenously or orally.

• For kids: 10–12 mg/kg once daily, up to 500 mg daily maximum.
• 500 mg once a day for adults.

2 Every six hours, give erythromycin intravenously or orally.
Adult and paediatric dosage: 10–15 mg/kg every 6 hours, with a daily maximum of 500 mg or 2 grams.
antibiotics with penicillins
In the event that susceptibility testing reveals penicillin sensitivity and macrolide antibiotics are unavailable, WHO gives practical information regarding penicillin. Penicillin may be administered parenterally or orally (intramuscular or intravenous). The main purpose of parenteral administration, particularly in patients with advanced illness, is to attain sufficient tissue concentrations.
3. Intramuscular injection of procaine benzylpenicillin (penicillin G) is recommended.

•  Adult and paediatric dose: 50 mg/kg once a day. The daily maximum is 1.2 g.

4. Aqueous benzylpenicillin (penicillin G) may be infused slowly into the vein or administered intramuscularly.

• Adult and paediatric dosage: 100,000 units/kg daily administered as a split dose of 25,000 IU/kg every six hours. The daily maximum is 4 MIU or 2.4 g.

5. Take oral phenoxymethylpenicillin V.

• Adult and paediatric dosage: 50 mg/kg daily given in split doses every six hours (10–15 mg/kg for each dose). 500 mg at most per dosage).

Antibiotic management and monitoring are crucial during a diphtheria epidemic, especially in light of any increases in antibiotic resistance, which may be identified by antibiotic sensitivity testing.

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Guidelines about diphtheria antitoxin (DAT)

The recommended course of therapy for patients with diphtheria is diphtheria antitoxin (DAT). DAT has been around since the late 19th century and has a big effect on mortality. Based on a systematic review, the relative mortality reduction is 76% (RR 0.24 [95% CI 0.22–0.28]), and earlier administration is more effective.

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Recommendation on DAT sensitivity testing

DAT dosage recommendation

As opposed to giving all patients a fixed dose of diphtheria antitoxin, the WHO recommends giving patients with suspected or confirmed symptomatic diphtheria a single dose, with the dose chosen based on the severity of the disease and the amount of time since symptom onset [Conditional recommendation, very low certainty evidence].

Synopsis of the recommendation

Clinical question: How are antibiotics and diphtheria antitoxin (DAT) used to treat diphtheria?
The context:

1. This clinical practice guideline was quickly created in response to the rising number of diphtheria outbreaks throughout the world.
2. 2023 saw outbreaks of diphtheria in Guinea, Nigeria, and other nearby nations, underscoring the critical need for evidence-based clinical practice standards for the disease's management.
3. Many doctors in the afflicted areas have never treated severe diphtheria and its associated consequences since outbreaks are so irregular.

Updated recommendations: 

1. The World Health Organisation advises against administering penicillin medicines in patients with suspected or confirmed diphtheria and instead suggests using macrolide antibiotics (erythromycin, azithromycin) [Strong recommendation, ].
2. The World Health Organisation advises against routinely testing for sensitivity in individuals with confirmed or suspected diphtheria before administering diphtheria antitoxin (DAT) [Strong recommendation].
3. In contrast to a fixed dose for all patients [conditional recommendation, very low certainty evidence], the WHO recommends an escalating dosing regimen for diphtheria antitoxin (DAT) in patients with suspected or confirmed symptomatic diphtheria. This regimen is based on disease severity and time since symptom onset.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.