VA Class:IM300

ATC Class:J07CA06

AHFS Class:

• Antitoxins and Immune Globulins 80:04

Generic Name(s):

• Diphtheria Antitoxin

Diphtheria antitoxin (equine) is a sterile solution of refined and concentrated protein (mainly immunoglobulins) containing antitoxic antibodies prepared from the serum of horses hyperimmunized with diphtheria toxoid.105,106

Diphtheria antitoxin (equine) is used in the treatment of probable or confirmed diphtheria.100,101,105,106,107,110 Although not routinely recommended for postexposure prophylaxis,100,101,102 diphtheria antitoxin (equine) is recommended in exceptional circumstances for postexposure prophylaxis in individuals with known or suspected exposure to toxigenic Corynebacteria .106,107 Diphtheria antitoxin (equine) has not been commercially available in the US since 1996.103,106

Sensitivity testing must be conducted in all individuals prior to administration of diphtheria antitoxin (equine) to determine whether they are sensitive to the antitoxin; desensitization should be performed if needed .100,101,106(See Dosage and Administration: Sensitivity Testing and Desensitization.)

Treatment of Diphtheria

Diphtheria antitoxin (equine) is used for the treatment of suspected or confirmed diphtheria in conjunction with appropriate anti-infectives.100,101,105,106 Medical management of respiratory diphtheria also includes respiratory support and cardiac monitoring (e.g., for cardiac rhythm disturbances or other manifestations of myocarditis) as needed.100,101,106

The CDC states that diphtheria antitoxin (equine) may be released under the IND protocol for the treatment of adults or children with probable or confirmed respiratory diphtheria.106 Clinical respiratory diphtheria is defined as an upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane of the tonsil(s), pharynx, larynx, and/or nose.106 A confirmed case of respiratory diphtheria is a clinical case where C. diphtheriae has been isolated from respiratory specimens (nasal or throat swab, membrane tissue) or a clinical case that is epidemiologically linked to a laboratory-confirmed diphtheria case.106 A probable case of respiratory diphtheria is a clinically compatible case that is not laboratory confirmed and is not epidemiologically linked to a laboratory-confirmed case.106

Diphtheria antitoxin (equine) also may be released under the IND protocol for the treatment of adults or children with isolated or localized diphtheria lesions in the nose, eye, skin, or other anatomical sites and in whom there are signs of systemic toxicity (fever, tachycardia, weakness).106 The antitoxin is not routinely indicated for the treatment of cutaneous diphtheria (skin lesions only) since toxigenic sequelae are rare if the infection is limited to the skin and the individual has previously received active immunization against diphtheria (primary vaccination series and recommended age-appropriate booster doses using preparations containing diphtheria toxoid adsorbed).106 Although it is unclear whether diphtheria antitoxin (equine) is beneficial in the treatment of cutaneous diphtheria,101 some clinicians suggest that use of the antitoxin may be indicated in some patients since toxic sequelae have been reported rarely in patients with cutaneous lesions.101,106

Diphtheria antitoxic antibodies present in diphtheria antitoxin (equine) combine with and neutralize toxins produced by toxigenic strains of C. diphtheriae .100 Although the antitoxin can neutralize circulating (unbound) toxin and will prevent progression of the disease, antitoxin will not neutralize toxin that is already fixed to tissues.100 Therefore, anti-infective therapy (e.g., 14-day regimen of oral or IV erythromycin, IV or IM penicillin G, or IM penicillin G procaine) is used as an adjunct to diphtheria antitoxin (equine) and may eliminate C. diphtheriae from infected sites, prevent spread of the bacteria and further toxin production, and prevent or terminate the diphtheria carrier state.101,102,114 Anti-infectives appear to be of no value in neutralizing diphtheria toxin and should not be considered a substitute for the antitoxin.101 Patients usually are no longer contagious 48 hours after initiation of anti-infective therapy.100 It has been suggested that eradication of the organism be confirmed by 2 consecutive negative cultures after completion of anti-infective therapy.100,101

Diphtheria antitoxin (equine) should be administered as soon as possible in patients with probable or confirmed respiratory diphtheria.100,101,106 Although all patients must undergo sensitivity testing and, if needed, desensitization prior to administration of diphtheria antitoxin (equine)100,101,106 (see Dosage and Administration: Sensitivity Testing and Desensitization), administration of the antitoxin should not be delayed while waiting for bacteriologic confirmation of the diagnosis since patients with diphtheria can deteriorate rapidly.100,101,104,106

Because diphtheria infection may not confer immunity, active immunization with an age-appropriate preparation containing diphtheria toxoid adsorbed should be initiated or completed during convalescence in any previously unvaccinated or incompletely vaccinated individuals.100,101,102,104,114 (See Diphtheria and Tetanus Toxoids Adsorbed/ Tetanus and Diphtheria Toxoids Adsorbed 80:08 and see Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed/Tetanus Toxoid and Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed 80:08.)

Postexposure Prophylaxis of Diphtheria

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), CDC, and American Academy of Pediatrics (AAP) state that routine use of diphtheria antitoxin (equine) is not recommended for prophylaxis of diphtheria in contacts of patients with respiratory or cutaneous diphtheria.100,101,102

The CDC states that diphtheria antitoxin (equine) may be recommended as part of the postexposure prophylaxis regimen in the following exceptional circumstances on a case-by-case basis.106 After detailed discussion with the CDC, the antitoxin may be released under the IND protocol for postexposure prophylaxis in contacts with known exposure to toxigenic C. diphtheriae (or possibly other toxigenic Corynebacteria ), contacts who are incompletely vaccinated against diphtheria or have an unknown vaccination history and have had a known or suspected exposure to toxigenic Corynebacteria , or contacts who cannot be kept under surveillance for the development of clinical symptoms or will be unavailable for follow-up and were exposed to an individual with known or suspected infection with toxigenic Corynebacteria .106

The ACIP, CDC, and AAP state that, regardless of their vaccination status, all household and other close contacts of an individual with culture-confirmed or suspected diphtheria should promptly receive postexposure prophylaxis with an appropriate anti-infective (single IM dose of penicillin G benzathine or oral erythromycin given for 7-10 days).100,101,102,106 In addition, individuals exposed to diphtheria who previously received less than 3 doses of a preparation containing diphtheria toxoid adsorbed or whose vaccination status is unknown should receive an immediate dose of an age-appropriate preparation containing diphtheria toxoid adsorbed, and the primary vaccination series should be completed according to the recommended schedule.100,101,102 Contacts who previously completed the primary vaccination series against diphtheria should receive an immediate booster dose of an age-appropriate preparation of diphtheria toxoid adsorbed if it has been 5 years or longer since their last booster dose.100,101,102 (See Diphtheria and Tetanus Toxoids Adsorbed/Tetanus and Diphtheria Toxoids Adsorbed 80:08 and see Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed/Tetanus Toxoid and Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed 80:08.)

All household and other close contacts of an individual with culture-confirmed or suspected diphtheria should be closely observed for symptoms of diphtheria for 7 days.100,101,102,106 At the first sign of illness, treatment with diphtheria antitoxin (equine) should be initiated immediately.100,106 (See Uses: Treatment of Diphtheria.)

For additional information on anti-infective postexposure prophylaxis of diphtheria in contacts, see Uses: Diphtheria in the Erythromycins General Statement 8:12.12.04.

Administration

Diphtheria antitoxin (equine) is administered by slow IV infusion or, alternatively, by IM injection.106 IV administration is preferred, especially for the treatment of severe diphtheria.101,106 The IM route may be used for the treatment of mild or moderate cases.106

Prior to administration of diphtheria antitoxin (equine), sensitivity testing and, if necessary, desensitization must be performed. 100,101,106(See Dosage and Administration: Sensitivity Testing and Desensitization.)

If diphtheria antitoxin (equine) is indicated for the treatment or prophylaxis of diphtheria, it should be given as soon as sensitivity testing and, if necessary, desensitization has been completed.101,106 (See Dosage and Administration: Sensitivity Testing and Desensitization.) Administration of the antitoxin should not be delayed pending bacteriologic confirmation of the diagnosis.100,101,106 Any delay in administration of diphtheria antitoxin (equine) can lead to life-threatening respiratory obstruction, myocarditis, and other complications.103

Respiratory specimens (nasal or throat swab, membrane swab or tissue) for bacteriologic culture (and possibly polymerase chain reaction [PCR] testing) should be obtained before and after administration of diphtheria antitoxin (equine).106 Testing for diphtheria antibodies in a serum specimen obtained prior to administration of the antitoxin may aid in the diagnosis of diphtheria102,106 since diphtheria antibody titers less than 0.01 international units/mL indicate susceptibility to the disease.102,104,106,114 Although the serum test cannot be used to confirm the diagnosis, diphtheria antibody titers of 0.1 international units/mL or greater are generally considered protective100,104,114 and suggest that a diagnosis of diphtheria is less likely.106

Diphtheria antitoxin (equine) should be warmed to 32-34°C prior to administration; care should be taken not to exceed 34°C since this may denature proteins contained in the antitoxin.106

For IV administration, the appropriate dose of diphtheria antitoxin (equine) should be diluted with 250-500 mL of 0.9% sodium chloride injection and administered by IV infusion over 2-4 hours.106

Diphtheria antitoxin (equine) may be given simultaneously with a preparation containing diphtheria toxoid adsorbed, using different syringes and different administration sites.112 (See Drug Interactions: Diphtheria Toxoid Adsorbed.)

Restricted Distribution of Diphtheria Antitoxin (Equine)

Diphtheria antitoxin (equine) has not been commercially available in the US since 1996.103,106 However, a preparation of diphtheria antitoxin (equine) that is manufactured in Brazil and is similar to the previously available US preparation can be obtained from the US Centers for Disease Control and Prevention (CDC) under an investigational new drug (IND) protocol.103,105,106,107 Because early treatment with diphtheria antitoxin (equine) may be critical to survival,106,114 the antitoxin is stored at CDC quarantine stations located in major airports throughout the US and can be delivered to any US location within hours.103,105

Diphtheria antitoxin (equine) is distributed by the CDC under the IND protocol only for the treatment of probable or confirmed diphtheria or, under exceptional circumstances, for postexposure prophylaxis of diphtheria.105,106 The decision to release the antitoxin is made by CDC medical epidemiologists in consultation with the treating clinician.105,106 To obtain diphtheria antitoxin (equine), clinicians should contact the CDC at 404-639-8257 from 8:00 a.m. to 4:30 p.m. EST Monday-Friday or the CDC Director's Emergency Operation Center (DEOC) at 770-488-7100 after hours, on weekends, and holidays.103,105,106,111

Dosage

Treatment of Diphtheria

For the treatment of diphtheria, diphtheria antitoxin (equine) is given as a single dose.106 Repeated doses are not recommended and may increase the risk of adverse reactions.106

The recommended dose of diphtheria antitoxin (equine) for the treatment of diphtheria is the same for adults and children and depends on the site and size of the diphtheritic membrane, degree of toxicity, and duration of illness.101,106 The presence of soft, diffuse cervical lymphadenitis suggests moderate to severe toxin absorption.101

The usual IV or IM dose of diphtheria antitoxin (equine) in adults and children is 20,000-40,000 units for the treatment of pharyngeal or laryngeal disease of 48 hours' duration or 40,000-60,000 units for the treatment of nasopharyngeal disease.101,106 For adults or children with systemic or extensive disease of 3 or more days' duration or with diffuse swelling of the neck, a dose of 80,000-120,000 units should be given.101,106

If diphtheria antitoxin (equine) is used for the treatment of cutaneous diphtheria in adults or children with skin lesions only (see Uses: Treatment of Diphtheria), a dose of 20,000-40,000 units has been recommended.101,106

The patient should be closely observed and supportive therapy should be initiated and continued until all local and systemic symptoms have been controlled or another causative organism has been identified.106 Appropriate anti-infective therapy (e.g., 14-day regimen of oral or parenteral erythromycin, IM or IV penicillin G, or IM penicillin G procaine) also should be initiated.100,101 (See Uses: Treatment of Diphtheria.)

Postexposure Prophylaxis of Diphtheria

Diphtheria antitoxin (equine) is used for postexposure prophylaxis of diphtheria only in exceptional circumstances in individuals with known or suspected exposure to toxigenic Corynebacteria .106 (See Uses: Postexposure Prophylaxis of Diphtheria.)

If diphtheria antitoxin (equine) is used for postexposure prophylaxis in adults or children, a single dose of 10,000 units should be given IM.106 However, the most appropriate dosage may depend on the length of time since exposure, the extent of the exposure, and the medical condition of the exposed individual.106

The exposed individual also should receive a postexposure prophylaxis regimen that includes an appropriate anti-infective (single dose of IM penicillin G benzathine or oral erythromycin given for 7-10 days) and, if indicated, an age-appropriate preparation containing diphtheria toxoid adsorbed.100,101,102 (See Uses: Postexposure Prophylaxis of Diphtheria.)

Sensitivity Testing and Desensitization

Because of the risk of anaphylaxis (see Cautions), all patients must undergo sensitivity testing prior to administration of diphtheria antitoxin (equine) using a protocol recommended by the US Centers for Disease Control and Prevention (CDC).101,106 Sensitivity to diphtheria antitoxin (equine) is assessed using a scratch, prick, or puncture skin test; if the skin test is negative, an intradermal test is performed.101,106 All patients with positive sensitivity tests to diphtheria antitoxin (equine) and those with a history of hypersensitivity reactions to equine proteins (even with a negative or equivocal sensitivity test) should undergo desensitization to the antitoxin.101,106

Health-care personnel performing sensitivity testing and desensitization to diphtheria antitoxin (equine) should be prepared to treat anaphylaxis and cardiovascular collapse and to maintain airway patency.101,106 Epinephrine and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.101,106

Sensitivity Testing

The initial test for sensitivity to diphtheria antitoxin (equine) is a superficial scratch, prick, or puncture skin test.101,106 After a skin site on the volar surface of the patient's arm is cleaned with alcohol and air dried, a superficial scratch, prick, or puncture should be made using a sterile needle or other sterile sharp instrument to break the skin (but not draw blood).101,106 A single drop of a 1:100 dilution of the serum (prepared by diluting 0.1 mL of antitoxin serum in 10 mL of 0.9% sodium chloride injection) should be applied to the test site.101,106 A reduced dose should be used for initial testing in patients with a history suggesting increased sensitivity risk.106 Positive (histamine) and negative (physiologic saline) control tests should be performed concurrently using the same technique and different sites.101,106 The histamine control test must be positive (a wheal at the positive scratch site surrounded by an erythematous area) for valid interpretation.101,106 When read at 15-20 minutes, a positive scratch sensitivity test for the antitoxin is a wheal with surrounding erythema at least 3 mm larger than the negative control test.101,106 If the scratch sensitivity test is positive , the patient must undergo desensitization before administration of diphtheria antitoxin (equine).106 If the scratch sensitivity test is negative , an intradermal test should be performed.101,106

For the intradermal sensitivity test, 0.02 mL of a 1:1000 dilution of the serum in 0.9% sodium chloride injection should be administered interadermally into the patient's forearm; this quantity should raise a small intradermal wheal.101,106 If this initial intradermal test is negative, the procedure should be repeated using a 1:100 dilution of the serum.101,106 Individuals with a negative history for animal allergy and negative history for prior exposure to animal serum may undergo intradermal testing initially with the stronger dilution (1:100) of serum without prior testing with the lower dilution (1:1000).101,106 Positive (histamine) and negative (physiologic saline) intradermal control tests should be performed concurrently at different sites.101,106 The intradermal test should be interpreted according to the scratch test guidelines.101,106

A positive skin sensitivity test indicates the probability of sensitivity with some correlation between the severity of the reaction on skin testing and the likelihood and severity of reaction to diphtheria antitoxin (equine).106 However, a negative skin sensitivity test does not preclude the possibility of an adverse reaction to the antitoxin.101,106 The possibility that antihistamines (and possibly tricyclic antidepressants) administered previously could interfere with sensitivity test results for a period of one day or longer (depending on the antihistamine) should be considered.106 Diphtheria antitoxin (equine) should be administered cautiously even in patients with negative skin sensitivity test results.106

Desensitization

Patients with positive sensitivity testing to diphtheria antitoxin (equine) or with a history of hypersensitivity reactions to equine proteins (even with a negative or equivocal sensitivity test to the antitoxin) should undergo desensitization.101,106 Because patients with asthma, allergic rhinitis, or urticaria and those who have these symptoms when in proximity to horses are at increased risk of developing serious anaphylactic reactions if they receive serum that originates from horses, the CDC states that such individuals also should undergo desensitization (even with a negative or equivocal sensitivity test to the antitoxin).106

Desensitization to diphtheria antitoxin (equine) can be performed using an IV or IM regimen (Table 1 and Table 2).101,106 The IV route is considered the safest route for desensitization because it offers better control.101,106 The IM regimen involves intradermal and subcutaneous administration of the antitoxin initially followed by IM administration.101,106 Some clinicians recommend concurrent treatment with an oral or IM antihistamine with or without an IV corticosteroid (e.g., hydrocortisone, methylprednisolone).101,106

The protection from anaphylaxis afforded by administering diphtheria antitoxin (equine) according to the desensitization protocol requires that there are no interruptions in the recommended sequence of administration of doses; if an interruption occurs, protection is lost .101,106

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reactions, acute febrile reactions, and serum sickness reactions, may occur in patients who receive diphtheria antitoxin (equine).101,106 Diphtheria antitoxin (equine) is prepared from the serum of horses hyperimmunized with diphtheria toxoid,105,106 and individuals with a history of asthma, allergic rhinitis, or urticaria following receipt of a preparation derived from equine serum, those with a history of asthma, allergic rhinitis, urticaria, or other symptoms of distress when in proximity to horses, and those who previously have received a preparation derived from equine serum are considered at increased risk for sensitivity reactions following receipt of the antitoxin.101,106

Recent data are not available regarding the frequency of adverse reactions to preparations derived from horse serum since such products are infrequently used.106 However, a review of 1433 diphtheria patients treated with diphtheria antitoxin (equine) between 1940 and 1950 indicated that anaphylaxis (without any fatalities) occurred in 0.6%, febrile reactions occurred in 4%, and serum sickness reactions occurred in 8.8% of patients.106

Although anaphylactic reactions to diphtheria antitoxin (equine) are mediated by IgE antibodies, febrile reactions and serum sickness are not IgE-mediated reactions and therefore usually cannot be predicted by skin sensitivity testing.101,106

Anaphylactic Reactions

In susceptible patients, anaphylactic reactions to diphtheria antitoxin (equine) usually begin within minutes after administration of the antitoxin.101,106 Although onset and severity are highly variable, more rapid onset generally is associated with more severe reactions.101,106 Manifestations of anaphylactic reactions are usually cutaneous (e.g., pruritus, flushing, urticaria, angioedema), respiratory (e.g., hoarse voice, stridor, wheeze, dyspnea, cyanosis), cardiovascular (e.g., rapid weak pulse, hypotension, arrhythmias), or GI (cramps, vomiting, diarrhea, dry mouth).101,106

If an anaphylactic reaction occurs, treatment depends on the nature and severity of the reaction.101,106 Parenteral epinephrine, antihistamines, and additional drugs (e.g., α-adrenergic blocking agents, aminophylline, β₂-adrenergic agonists, corticosteroids) may be indicated, depending on the severity of the reaction.101,106

Febrile Reactions

Febrile reactions to diphtheria antitoxin (equine), characterized by a chilly sensation, slight dyspnea, and a rapid rise in temperature, usually develop 20 minutes to one hour after administration of the antitoxin.106

Most febrile reactions are mild and can be treated with antipyretics alone;101,106 severe reactions may require physical measures (e.g., tepid water baths) to reduce the patient's temperature.106

Serum Sickness

Mild serum sickness reactions following administration of diphtheria antitoxin (equine) usually are manifested as fever, maculopapular rash, or urticaria (90% of cases); more severe reactions also may include arthritis, arthralgia, and lymphadenopathy.101,106 Rarely, angioedema, glomerulonephritis, Guillain-Barré syndrome, peripheral neuritis, or myocarditis can occur.101,106 Symptoms are usually evident 7 to 10 days (range 5-24 days) after initial exposure to diphtheria antitoxin (equine).101,106 Individuals who previously received a dose of a preparation prepared using animal serum are more likely to develop serum sickness reactions to diphtheria antitoxin (equine), and the onset of the reactions in such individuals can be as short as several hours to 3 days after administration of the antitoxin.101,106

Mild cases of serum sickness frequently resolve spontaneously over a few days to 2 weeks.106 Antihistamines, nonsteroidal anti-inflammatory agents (NSAIAs), and corticosteroids may be useful in the treatment of serum sickness reactions.101,106

Precautions and Contraindications

Prior to administration of diphtheria antitoxin (equine), careful inquiry should be made to determine whether the patient is at increased risk of sensitivity reactions to the antitoxin. 101,106Individuals with a history of asthma, allergic rhinitis, or urticaria following receipt of a preparation derived from equine serum, those with a history of asthma, allergic rhinitis, urticaria, or other symptoms of distress when in proximity to horses, and those who previously have received a preparation derived from equine serum are considered at increased risk. 101,106

Regardless of allergic history or history of prior administration of preparations containing equine serum, sensitivity testing must be performed in all individuals prior to administration of diphtheria antitoxin (equine). 100,101,106(See Dosage and Administration: Sensitivity Testing and Desensitization.)

Patients should be carefully monitored for evidence of hypotension and bronchoconstriction during sensitivity testing and desensitization to diphtheria antitoxin (equine) and during administration of the antitoxin.101,106 Health-care personnel should be prepared to treat anaphylaxis and cardiovascular collapse and to maintain airway patency if needed.101,106 Epinephrine and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.101,106

Pregnancy

Pregnancy

The US Centers for Disease Control and Prevention (CDC) states that there are no known risks associated with the use of diphtheria antitoxin (equine) during pregnancy other than those reported in other patients.109 Because diphtheria antitoxin (equine) is considered vital to the treatment of diphtheria and because of the high mortality rate in patients with diphtheria who do not receive antitoxin treatment, the benefits of the antitoxin may be greater than the possible risks to the mother or fetus.109

In susceptible women, respiratory or vulvovaginal diphtheria can occur during any trimester of pregnancy, at term, or in the postpartum period.114 Early treatment with diphtheria antitoxin (equine) improves survival and pregnancy outcomes.114 If diphtheria antitoxin (equine) is not used in the treatment of obstetric respiratory diphtheria, the mortality rate is estimated to be 50% and fetal loss or premature birth occurs in approximately a third of those who survive.114 Clinicians should consider that postpartum women with respiratory diphtheria can transmit Corynebacterium diphtheriae to their neonates.114

Diphtheria Toxoid Adsorbed

Diphtheria antitoxin (equine) may be given simultaneously with a preparation containing diphtheria toxoid adsorbed (e.g., diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed [DTaP], tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed [Tdap], diphtheria and tetanus toxoids adsorbed [DT], tetanus and diphtheria toxoids adsorbed [Td]) using different syringes and different administration sites.112 Although specific studies are not available, diphtheria antitoxin (equine) is unlikely to impair the immune response to diphtheria toxoid adsorbed.102

Diphtheria Exposure and Infection

Diphtheria is caused by toxigenic strains of C. diphtheriae or, rarely, toxigenic strains of C. ulcerans .100,101,102,106,110,113,114 Toxigenic strains of Corynebacteria produce an exotoxin that can affect the mucous membranes of the respiratory tract (respiratory diphtheria [nasal, pharyngeal, tonsillar, laryngeal]), the skin (cutaneous diphtheria), and occasionally mucous membranes at other sites (conjunctival, otic, or vulvovaginal diphtheria).100,101,102,106,110,114 The toxin interferes with enzymes necessary for protein synthesis, leading to cell damage and death.101,106 The toxin causes local tissue destruction and membrane formation and can be absorbed into the bloodstream from the site of infection and distributed throughout the body resulting in serious complications (e.g., myocarditis, neuritis, thrombocytopenia, renal dysfunction or failure).100,101,102,106,110,114

Humans are the only known reservoir of C. diphtheriae .100,101,110 Diphtheria is transmitted to close contacts by oral or respiratory droplets or by direct contact with discharge from skin lesions or, rarely, contact with items soiled with such discharge (fomites).100,101,110 Raw milk or unpasteurized dairy products also have been reported to transmit toxigenic C. ulcerans .101,113 Diphtheria can be acquired from carriers (i.e., asymptomatic individuals colonized with toxin-producing C. diphtheriae ).101,114

Following infection, the incubation period usually is 2-5 days (range 1-10 days).100,101,106,110 Although systemic complications of diphtheria can occur during the first week of illness, they usually occur later in the disease process (e.g., myocarditis usually occurs 1-2 weeks and neuritis usually occurs 2-8 weeks after disease onset).106 Most cases of diphtheria occur in individuals who are unvaccinated or incompletely vaccinated against the disease.100,101,102 The overall case-fatality rate for diphtheria is 5-10% with higher death rates (up to 20%) among individuals younger than 5 years of age and older than 40 years of age.100,104

Diphtheria is uncommon in the US,100,101,102,104 but there is evidence that toxigenic strains of Corynebacterium continue to circulate in areas of the US where the disease previously was endemic.100,106 Before widespread immunization against diphtheria was initiated in the US in the 1940s, there were approximately 100,000-200,000 cases of diphtheria and 13,000-15,000 diphtheria-related deaths each year.100 From 1980 through 2004, 57 cases of diphtheria were reported in the US with an average of 2-3 per year (range: 0-5 cases per year).100 In 1996, toxigenic C. diphtheriae was isolated from residents of a Native American community in South Dakota104,100 and toxigenic C. ulcerans was isolated from an individual in Indiana with respiratory diphtheria.104 In 1999, a resident of Washington died from an illness clinically consistent with respiratory diphtheria and toxigenic C. ulcerans was isolated from a throat swab.104 In 2003, fatal respiratory diphtheria occurred in an unvaccinated Pennsylvania resident who had returned from a trip to rural Haiti (a country where diphtheria is endemic).104,106

Diphtheria continues to circulate worldwide and is endemic in Albania, Russia, and countries of the former Soviet Union and in many countries in Africa, Latin America, Asia/South Pacific, and the Middle East.100,101,110 Travelers who are unvaccinated or incompletely vaccinated against diphtheria are at risk of acquiring the disease if they travel to these countries.102,113,114 Unvaccinated or incompletely vaccinated household or other close contacts of such travelers also are at risk.114 The CDC website ([Web]) should be consulted for information regarding where diphtheria is endemic.110

Response to Diphtheria Antitoxin (Equine)

Diphtheria antitoxin (equine) is used to provide antitoxic antibodies that can combine with and neutralize toxins produced by toxigenic strains of C. diphtheriae .100 Use of diphtheria antitoxin (equine) in patients with diphtheria results in decreased mortality, and there is evidence that the degree of benefit is inversely related to the duration of the illness at the time the antitoxin is administered.106 In one controlled trial, the mortality rate in patients who received treatment with diphtheria antitoxin (equine) was 3.3% compared with 12.2% in patients who did not receive the antitoxin.106 In another study in patients with diphtheria, the mortality rate was 4% when the antitoxin was given within 24-48 hours of illness onset, 16.1% when given on the third day of illness, and 29.9% when given 7 days or longer after illness onset.106 Because diphtheria antitoxin (equine) has no direct antibacterial effect, treatment of diphtheria includes adjunctive use of appropriate anti-infectives active against C. diphtheriae since such anti-infectives may eliminate C. diphtheriae from infected sites, prevent spread of the bacteria and further toxin production, and prevent or terminate the diphtheria carrier state.101,102,114 (See Uses: Treatment of Diphtheria.)

It is unclear whether use of diphtheria antitoxin (equine) for postexposure prophylaxis in contacts of patients with diphtheria offers any additional benefit over use of a postexposure prophylaxis regimen that includes an anti-infective active against C. diphtheriae with or without active immunization with a preparation containing diphtheria toxoid adsorbed.100,101,102 (See Uses: Postexposure Prophylaxis of Diphtheria.)

Chemistry and Stability

Chemistry

Diphtheria antitoxin (equine) is a sterile solution of refined and concentrated protein (mainly immunoglobulins) containing antitoxic antibodies prepared from the serum of horses hyperimmunized with diphtheria toxoid.105,106

Stability

Diphtheria antitoxin (equine) injection should be stored at 2-8°C.105 Care should be taken not to expose diphtheria antitoxin (equine) to temperatures exceeding 34°C since this may denature proteins contained in the antitoxin.106

Only references cited for selected revisions after 1984 are available electronically.

100. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 11th ed. Washington, DC: Public Health Foundation; 2009.

101. American Academy of Pediatrics. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

102. Centers for Disease Control Immunization Practices Advisory Committee (ACIP). Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures. MMWR Recomm Rep . 1991; 40( RR-10):1-28.

103. Centers for Disease Control and Prevention. Availability of diphtheria antitoxin through an investigational new drug protocol. MMWR Morb Mortal Wkly Rep , 2004; 53: 413.

104. Centers for Disease Control and Prevention (CDC). Fatal respiratory diphtheria in a U.S. traveler to Haiti--Pennsylvania, 2003. MMWR Morb Mortal Wkly Rep . 2004; 52:1285-6. [PubMed 14712177]

105. Centers for Disease Control and Prevention. Biologics for therapeutic use distributed by the Centers for Disease Control and Prevention. From CDC website. [Web]

106. Centers for Disease Control and Prevention. IND Protocol: Use of Diphtheria Antitoxin (DAT) for Suspected Diphtheria Cases IRB #4167. 2008 Apr. From CDC website. [Web]

107. Centers for Disease Control and Prevention. Treatment: diphtheria antitoxin. 2007 Jul. From CDC website. [Web]

109. Centers for Disease Control and Prevention. Informed Consent for Use of Diphtheria antitoxin (DAT) for suspected cases. Investigational New Drug (IND) BB 11184 IRB #4167. From CDC website. [Web]

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111. Centers for Disease Control and Prevention, Atlanta, GA: Personal communication.

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