Diphtheria.

Diphtheria is a potentially fatal infection mostly caused by toxigenic Corynebacterium diphtheriae strains and occasionally by toxigenic C. ulcerans and C. pseudotuberculosis strains. Diphtheria is generally an acute respiratory infection, characterized by the formation of a pseudomembrane in the throat, but cutaneous infections are possible. Systemic effects, such as myocarditis and neuropathy, which are associated with increased fatality risk, are due to diphtheria toxin, an exotoxin produced by the pathogen that inhibits protein synthesis and causes cell death. Clinical diagnosis is confirmed by the isolation and identification of the causative Corynebacterium spp., usually by bacterial culture followed by enzymatic and toxin detection tests. Diphtheria can be treated with the timely administration of diphtheria antitoxin and antimicrobial therapy. Although effective vaccines are available, this disease has the potential to re-emerge in countries where the recommended vaccination programmes are not sustained, and increasing proportions of adults are becoming susceptible to diphtheria. Thousands of diphtheria cases are still reported annually from several countries in Asia and Africa, along with many outbreaks. Changes in the epidemiology of diphtheria have been reported worldwide. The prevalence of toxigenic Corynebacterium spp. highlights the need for proper clinical and epidemiological investigations to quickly identify and treat affected individuals, along with public health measures to prevent and contain the spread of this disease.

Corynebacterium diphtheriae bloodstream infection: the role of antitoxin.

A 65-year-old male patient presented with fever, fast atrial fibrillation and frank haematuria on return to Ireland from travel in East Africa. He had a systolic murmur leading to a clinical suspicion of endocarditis. He had no specific clinical features of diphtheria. Blood cultures were taken and empiric therapy commenced with benzylpenicillin, vancomycin and gentamicin. Corynebacterium diphtheriae was detected on blood culture. The isolate was submitted to a reference laboratory for evaluation of toxigenicity. While initially there was concern regarding the possibility of myocarditis, a clinical decision was made not to administer diphtheria antitoxin in the absence of clinical features of respiratory diphtheria, in the presence of invasive infection and with presumptive previous immunisation. There is no specific guidance on the role of antitoxin in this setting. The issue is not generally addressed in previous reports of C. diphtheriae blood stream infection.

Adult diphtheria in Malaysia: A case report.

In November 2016, a 28-year-old Malay man presented to the emergency department in respiratory distress, with a history of fever and sore throat. A clinical diagnosis of acute diphtheria was made and the patient was isolated and ventilated in the intensive care unit, and received diphtheria antitoxin and intravenous antibiotics. Initial laboratory findings failed to confirm diphtheria, leading to discontinuation of antibiotics and quarantine. Public health measures were reinstated after a reference laboratory cultured Corynebacterium diphtheriae. Although there was no contact with ill persons, investigation revealed incomplete immunisation history, and injection of high dose steroids prior to onset of symptoms.

Microbe Profile: Corynebacterium diphtheriae - an old foe always ready to seize opportunity.

Corynebacterium diphtheriae is a globally important Gram-positive aerobic Actinobacterium capable of causing the toxin-mediated disease, diphtheria. Diphtheria was a major cause of childhood mortality prior to the introduction of the toxoid vaccine, yet it is capable of rapid resurgence following the breakdown of healthcare provision, vaccination or displacement of people. The mechanism and treatment of toxin-mediated disease is well understood, however there are key gaps in our knowledge on the basic biology of C. diphtheriae particularly relating to host colonisation, the nature of asymptomatic carriage, population genomics and host adaptation.

Characterization of serum anti-diphtheria antibody activity following administration of equine anti-toxin for suspected diphtheria.

There is a global shortage of equine-derived diphtheria anti-toxin (DAT) for diphtheria treatment. There are few existing data on serum antibody concentrations and neutralizing activity post-treatment to support development of new therapeutics. Antibody concentrations were quantified by ELISA and anti-toxin neutralizing activity by cytotoxicity assay in serum from 4 patients receiving DAT for suspected diphtheria. Using linear mixed effects modeling, estimated mean (SE) half-life was 78.2 (20.0) hours. Maximum serum neutralizing activity ranged from 28.42-38.64 AU/mL with an estimated mean AUC1-72 of 1396.7 (399.3) AU/mL*hr. These data provide a standard of comparison for development of novel anti-toxins to replace DAT.

Diphtheria, pertussis, and tetanus: evidence-based management of pediatric patients in the emergency department

Diphtheria, pertussis, and tetanus are potentially deadly bacterial infections that are largely preventable through vaccination, though they remain in the population. This issue reviews the epidemiology, pathophysiology, diagnosis, and current recommended emergency management of these conditions. Disease-specific medications, as well as treatment of the secondary complications, are examined in light of the best current evidence. Resources include obtaining diphtheria antitoxin from the United States Centers for Disease Control and Prevention and best-practice recommendations with regard to testing, involvement of government health agencies, isolation of the patient, and identification and treatment of close contacts. Most importantly, issues regarding vaccination and prevention are highlighted.

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model.

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

Primer caso de difteria en España después de 30 años. Lecciones aprendidas / No disponible

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Vacunación antidiftérica / No disponible

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Access to diphtheria antitoxin for therapy and diagnostics.

The most effective treatment for diphtheria is swift administration of diphtheria antitoxin (DAT) with conjunct antibiotic therapy. DAT is an equine immunoglobulin preparation and listed among the World Health Organization Essential Medicines. Essential Medicines should be available in functioning health systems at all times in adequate amounts, in appropriate dosage forms, with assured quality, and at prices individuals and the community can afford. However, DAT is in scarce supply and frequently unavailable to patients because of discontinued production in several countries, low economic viability, and high regulatory requirements for the safe manufacture of blood-derived products. DAT is also a cornerstone of diphtheria diagnostics but several diagnostic reference laboratories across the European Union (EU) and elsewhere routinely face problems in sourcing DAT for toxigenicity testing. Overall, global access to DAT for both therapeutic and diagnostic applications seems inadequate. Therefore--besides efforts to improve the current supply of DAT--accelerated research and development of alternatives including monoclonal antibodies for therapy and molecular-based methods for diagnostics are required. Given the rarity of the disease, it would be useful to organise a small stockpile centrally for all EU countries and to maintain an inventory of DAT availability within and between countries.

[Throat disease in the periphery of Europe: the introduction of diphteria antitoxin in Romsdal county]. / Halsesyke i Europas utkant--da difteriantitoksinet kom til Romsdals amt.

Diphteria played a key role in establishing the bacteriological model for explaining infectious disease. This understanding of bacteriological factors spurred research that culminated in the development of diphteria antitoxin, the first effective therapeutic cure for an epidemiological disease. Prior to the introduction of antitoxin, isolation and disinfection were regarded as the key defences against diphteria. The opportunity to combine antitoxin therapy with existing methods for combatting the disease was a key factor for the rapid spread of the antitoxin. Diphteria antitoxin was first used in Romsdal county in 1895. Initially the serum had to be ordered from manufacturers abroad, which restricted its application in the district. Few available doctors and long transport routes were reasons that prevented the antitoxin from reaching its full potential. Industrial manufacturing methods were an obstacle to serum production in peripheral areas. In Norway, production of serum gradually got underway in Kristiania, which was one factor that caused mortality from diphteria to decline faster there than in other parts of the country. In this article we will elucidate the relationship between the centre and the periphery in the spread of medical advances by studying the implementation of diphteria antitoxin in Romsdal county.

Contribución al estudio de la difteria / No disponible

Conocida desde la antigüedad, la difteria adquiere especial incidencia en España en el siglo XVI, siendo ya entonces conocida como garrotillo, por la similitud de la muerte de estos enfermos con los ajusticiados mediante garrote. Durante gran parte de los siglos XVII y XVIII, tuvo una presencia muy limitada en España. Bretonneau, es el primero que estudia la enfermedad en profundidad, entre 1818 y 1820, durante la epidemia de Tours (Francia), dándole el nombre de difteritis. A mediados del siglo XIX, vuelve a España y a otros países de Europa y poco después se extiende a todos los continentes, con una mortalidad que, al finalizar el siglo, era aún del 42%. A comienzos del siglo XX, la antitoxina diftérica de Behring supone un cambio importante en el pronóstico de la difteria y, a partir de 1923, se da el paso definitivo en el control de la enfermedad, mediante la anatoxina de Ramón

Known since ancient times, diphteria acquired a special incidence in Spain in the XVI century. Known then by "garrotillo", due to the similaraties its mortal victims showed with those executed by " garrote". Diphteria had a limited incidence in Spain during the XVII and XVIII centuries. Bretonneau was the first one to study this entity in depth between 1818 and 1820, during an epidemy in Tours, France and named it diphteritis. Around the middle of the XIX century, diphteria returns to Spain, and to other countries in Europe, and it is spread out to other continents. Its mortality by the end of XIX century was estimated at 42%. At the beginning of the XX century, the diphteric antitoxin of Behring established an important change in the prognosis of diphteria. A definite step to control the pathological entity was taken in 1923, by the use of the anatoxin of Ramón

Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication.

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 µg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.

Concurrent diphtheria and infectious mononucleosis: difficulties for management, investigation and control of diphtheria in developing countries.

We report a case of concurrent diphtheria and infectious mononucleosis in an 11-year-old Brazilian child. Two days after specific treatment for diphtheria was started the patient was discharged following clinical recovery. This case highlights the difficulties in the clinical diagnosis of diphtheria in partially immunized individuals, and for the management and control of diphtheria in developing countries.