Diphtheria and Other Corynebacterial Infections¶

Chapter 155 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 155

Key Clinical Points¶

Diphtheria toxin inhibits protein synthesis via ADP-ribosylation of elongation factor 2 (EF-2), leading to cell death.
Antitoxin is the only effective treatment for toxin-mediated disease; antibiotics do not neutralize bound toxin.
Rapid administration of antitoxin is critical; delays significantly increase mortality risk.
Erythromycin is preferred over penicillin to stop toxin synthesis more quickly.
Corynebacterium jeikeium is a multidrug-resistant (MDR) pathogen associated with catheter infections in immunocompromised patients.
Vaccination (DTaP/Tdap) provides essential protection against diphtheria, tetanus, and pertussis.
Cutaneous diphtheria can be caused by toxigenic strains, requiring antitoxin treatment.
C. ulcerans and C. pseudotuberculosis can produce diphtheria toxin and cause severe illness.
Bull-neck diphtheria is characterized by massive swelling of the tonsils and submandibular/paratracheal edema.
Antitoxin titer >0.01 U/mL indicates immunity.

1. DEFINITION & OVERVIEW¶

Diphtheria is a nasopharyngeal and skin infection caused by Corynebacterium diphtheriae. Toxigenic strains produce a protein toxin causing systemic toxicity, myocarditis, and polyneuropathy. The toxin forms pseudomembranes in the pharynx during respiratory disease. While toxigenic strains cause pharyngeal diphtheria, nontoxigenic strains commonly cause cutaneous disease. Less commonly, C. ulcerans and C. pseudotuberculosis may cause diphtheria-like illness. Non-diphtheriae Corynebacteria can also cause infections in immunocompromised individuals.

1.1 Classification of Corynebacterial Infections¶

• Diphtheria: Toxigenic C. diphtheriae • Cutaneous Diphtheria: Nontoxigenic or Toxigenic C. diphtheriae • Diphtheria-like Illness: C. ulcerans, C. pseudotuberculosis • Nondiphtherial Corynebacteria: C. jeikeium, C. urealyticum, etc. • Other Species: Rhodococcus species, Gordonia species, Tsukamurella paurometabola, Arcanobacterium haemolyticum

2. EPIDEMIOLOGY¶

Diphtheria has been controlled in many regions through vaccination but remains endemic in parts of Africa, Asia, and Latin America. Large outbreaks occurred in post-Soviet states (1990s) and recent cases in Nigeria/Yemen (2022–2023). Respiratory diphtheria occurs year-round but peaks in winter. Cutaneous diphtheria is more common in tropical regions.

2.1 Risk Factors for Outbreaks¶

• Alcoholism • Low socioeconomic status • Crowded living conditions • Native American ethnic background • Vaccine hesitancy • Migration • Socioeconomic instability

3. ETIOLOGY & PATHOPHYSIOLOGY¶

C. diphtheriae is a gram-positive bacillus (identified 1883). Toxigenic strains produce diphtheria toxin via lysogenic conversion by corynebacteriophage beta. Iron-limiting conditions enhance toxin expression.

3.1 Toxin Mechanism¶

• Structure: 535-amino-acid single-chain protein • Potency: 50% lethal dose ≈ 100 ng/kg in sensitive species • Mechanism: ◦ Internalized via receptor-mediated endocytosis ◦ Separated into A (toxic) and B (binding) fragments ◦ A fragment inhibits EF-2 via NAD+-dependent ADP-ribosylation

3.2 Pathogenesis Cascade¶

Pharyngeal infection → pseudomembrane formation → toxin release into bloodstream → systemic distribution → receptor binding → endocytosis → cytosolic entry → EF-2 inhibition → protein synthesis arrest → cell death → myocarditis/neuropathy

4. CLINICAL FEATURES¶

Patients present with sore throat, fever, and pharyngeal pseudomembranes. Advanced cases show neck edema (bull-neck diphtheria), stridor, and dysphagia. Cutaneous disease presents as punched-out ulcers with necrotic sloughing.

4.1 Respiratory Diphtheria¶

• Sore throat • Adherent pseudomembranes in tonsils/pharynx/nasal passages • Low-grade fever • Hoarseness/stridor • Palatal paralysis • Bull-neck: Massive swelling of the tonsils and submandibular/paratracheal edema • Foul breath/thick speech

4.2 Cutaneous Diphtheria¶

• Punched-out ulcers with necrotic sloughing • Pseudomembrane formation on extremities, trunk, or head • Often secondary to trauma/allergy/autoimmune conditions • Nontoxigenic strains more common in tropical regions

4.3 Systemic Manifestations¶

• Neurotoxicity: weakness, paralysis • Myocarditis: arrhythmias, heart failure • Rare complications: endocarditis, septic arthritis (in immunocompromised patients)

5. DIFFERENTIAL DIAGNOSIS¶

Respiratory diphtheria must be differentiated from viral pharyngitis, streptococcal infections, and Lemierre’s syndrome. Cutaneous lesions require distinction from other dermatoses.

5.1 Pharyngitis Causes¶

• Respiratory viruses (≈25%) • Group A streptococci (15–30%) • Atypical bacteria (M. pneumoniae, C. pneumoniae) (15–20%) • Herpes simplex virus (≈4%)

5.2 Cutaneous Mimics¶

• Bacterial infections • Fungal infections • Other dermatoses

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnosis requires clinical suspicion and laboratory confirmation. Throat cultures on Löffler’s/Tinsdale’s medium are essential. Cutaneous cases require culture of lesions.

6.1 Laboratory Diagnosis¶

• Cultivation of C. diphtheriae/toxigenic strains • Throat swabs on selective media (Löffler’s, Tinsdale’s) • Biochemical differentiation from commensal corynebacteria • Reporting toxigenic isolates to health departments

6.2 Diagnostic Criteria¶

Confirmed respiratory diphtheria: Lab-proven or epidemiologically linked.
Probable respiratory diphtheria: Clinically compatible but not confirmed.
Carrier: Positive cultures without pseudomembranes.
Immunity Testing: Antitoxin titer >0.01 U/mL → indicates immunity.

7. MANAGEMENT & TREATMENT¶

Immediate antitoxin administration is critical for toxin-mediated disease. Erythromycin or penicillin G are first-line antibiotics. Antitoxin must be obtained from CDC after state health department notification.

7.1 Antitoxin Therapy¶

Administration: Must be administered as rapidly as possible to neutralize circulating toxin.
Source: Horse-derived antiserum; obtained from CDC via Emergency Operations Center.
Limitations: Cannot neutralize cell-bound toxin.
Safety: Requires test dose/desensitization for hypersensitive patients.

7.2 Antibiotic Therapy¶

Erythromycin: 500 mg IV q6h (children: 40–50 mg/kg/day) → preferred to stop toxin synthesis more quickly.
Penicillin G: 600,000 U IM q12h (children: 12,500–25,000 U/kg).
Alternatives: Rifampin, clindamycin, clarithromycin.
Course: 14-day course with repeat culture after 2 weeks.

7.3 Prophylaxis for Contacts¶

Antibiotics: Erythromycin for 7–10 days OR benzathine penicillin G (1.2 million units for ≥6 years).
Vaccination: Tdap for unimmunized contacts.

8. PROGNOSIS & COMPLICATIONS¶

Mortality is highest with delayed antitoxin administration. Early complications include airway obstruction and myocarditis.

8.1 Early Complications¶

• Airway obstruction from pseudomembranes • Myocarditis (arrhythmias, heart failure)

8.2 Late Complications¶

• Cardiac conduction defects • Peripheral neuropathy

8.3 Other Complications¶

• Drug-resistant strains requiring extended therapy

9. SPECIAL CONSIDERATIONS¶

Nondiphtherial Corynebacteria (e.g., C. jeikeium) are multidrug-resistant and cause catheter infections. C. ulcerans/pseudotuberculosis may produce toxin and require antitoxin.

9.1 Nondiphtherial Corynebacteria¶

• C. jeikeium: ◦ Resistance: Multidrug-resistant (MDR); resistant to most antibiotics except oxazolidines (linezolid) and glycopeptides (vancomycin). ◦ Clinical setting: Common in catheter-associated infections.

9.2 Specific Pathogens¶

• C. ulcerans & C. pseudotuberculosis: Toxigenic strains requiring antitoxin; nontoxigenic strains may cause pharyngitis outbreaks.

10. KEY PEARLS & CLINICAL TRAPS¶

Vaccination with DTaP/Tdap provides protection against diphtheria, tetanus, and pertussis. Cutaneous diphtheria may be caused by toxigenic strains requiring antitoxin. Bull-neck diphtheria is a medical emergency due to airway obstruction risk.

10.1 Vaccination Schedule¶

• DTaP: For children (4–6 doses). • Tdap: For adolescents/adults (booster every 10 years).

10.2 Prophylaxis for Contacts¶

• Antibiotics: Erythromycin or benzathine penicillin G. • Vaccination: Tdap for unimmunized contacts.