Bezlotoxumab.

Clostridium difficile infection (CDI) is mediated by actions of toxin A and toxin B. Fully human monoclonal antibodies directed against the binding domains of these toxins were developed. Despite preclinical studies suggesting efficacy for the anti-toxin A monoclonal, actoxumab, the anti-toxin B monoclonal, bezlotoxumab, alone was shown to be effective in clinical trials. Intravenous infusion of bezlotoxumab at a 10 mg/kg dosage as adjunctive treatment reduced the risk of recurrent CDI over placebo for adult patients at increased risk for CDI recurrence in 2 large randomized, double-blind trials. Significant benefit was noted for patients with 1 or more of the following predefined risks: age >65 years, history of CDI, immunocompromise, severe CDI. Overall, bezlotoxumab appeared to be safe; however, an unexplained increased risk of heart failure was noted for patients with underlying congestive heart failure. Further refinement of who would benefit most and when best to administer bezlotoxumab is warranted.

Safety, Pharmacokinetics, and Immunogenicity of Obiltoxaximab After Intramuscular Administration to Healthy Humans.

Inhalational anthrax is a highly lethal infection caused by Bacillus anthracis and a serious bioterrorism threat. Protective antigen (PA) is a critical component required for the virulence of Bacillus anthracis. Obiltoxaximab, a high-affinity monoclonal antibody that neutralizes PA, is approved in the United States for intravenous use for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Here, we explored the safety, pharmacokinetics (PK), and immunogenicity of obiltoxaximab administered by intramuscular injection at doses of 4, 8, 16, 20, and 24 mg/kg in healthy humans. Systemic exposures were approximately dose proportional, maximum serum concentrations were observed after 6-9 days, and terminal half-life ranged from 16 to 23 days. Average absolute intramuscular bioavailability was 64%. Obiltoxaximab was well tolerated, and local tolerability was acceptable up to 24 mg/kg intramuscularly, up to 6 injections per dose, and up to 5 mL per injection. No injection-site abscesses or hypersensitivity reactions occurred; no subjects developed treatment-emergent antitherapeutic antibodies over the study period of 71 days.

[Safety profile of heterologous serum produced by the Butantan Institute, in São Paulo-SP, Brazil, from 2012 to 2015]. / Perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan, São Paulo-SP, no período de 2012 a 2015.

OBJECTIVE: to describe the safety profile of the heterologous serum produced by the Butantan Institute (BI) of São Paulo-SP, Brazil. METHODS: a descriptive study of adverse events (AEs) post-exposure to serum produced by the BI, encoded in the medical terminology of the Medical Dictionary for Regulatory Activities (MedDRA), and spontaneously reported to BI from 2012 to 2015. RESULTS: 52 individuals reported AEs, mainly related to Bothrops antivenom (n=11), diphtheria antitoxin (n=9) and unspecified snakebite serum (n=9); a mean of 3.2 AEs per individual was observed; among the total of 173 AEs, 63.0% were expected considering that they were described in the package insert; most of them were classified as skin and subcutaneous tissue disorders (30.6%); there were six deaths temporally related to the use of serum, but this association was discarded. CONCLUSION: in the studied period, the serum produced by the BI had no changes in their safety profiles, considering that the AEs were expected, according to the information previously described in the package insert.

Perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan, São Paulo-SP, no período de 2012 a 2015 / Safety profile of heterologous serum produced by the Butantan Institute, in São Paulo-SP, Brazil, from 2012 to 2015 / Perfil de seguridad de los sueros heterólogos producidos por el Instituto Butantan, São Paulo-SP, Brasil, en el período de 2012 al 2015

Resumo OBJETIVO: descrever o perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan (IB) de São Paulo-SP, Brasil. MÉTODOS: estudo descritivo dos relatos de eventos adversos (EA) pós-exposição aos soros produzidos pelo IB, codificados pela terminologia do Dicionário Médico para Atividades Regulatórias (MedDRA), notificados espontaneamente ao IB entre 2012 e 2015. RESULTADOS: foram notificados 52 usuários com algum evento adverso relacionado, principalmente, aos soros antibotrópico (n=11), antidiftérico (n=9) e antiofídico não especificado (n=9); observaram-se, em média, 3,2 EA por indivíduo; dos 173 EA notificados, 63,0% eram esperados por serem eventos descritos em bula; os EA mais notificados foram categorizados como afecções dos tecidos cutâneos e subcutâneos (30,6%); houve seis óbitos temporalmente relacionados ao uso de soros, porém essa associação foi descartada. CONCLUSÃO: no período estudado, os soros produzidos pelo IB não apresentaram alteração em seu perfil de segurança, já que os EA relatados eram esperados conforme informação descrita em bula.

Abstract OBJECTIVE: to describe the safety profile of the heterologous serum produced by the Butantan Institute (BI) of São Paulo-SP, Brazil. METHODS: a descriptive study of adverse events (AEs) post-exposure to serum produced by the BI, encoded in the medical terminology of the Medical Dictionary for Regulatory Activities (MedDRA), and spontaneously reported to BI from 2012 to 2015. RESULTS: 52 individuals reported AEs, mainly related to Bothrops antivenom (n=11), diphtheria antitoxin (n=9) and unspecified snakebite serum (n=9); a mean of 3.2 AEs per individual was observed; among the total of 173 AEs, 63.0% were expected considering that they were described in the package insert; most of them were classified as skin and subcutaneous tissue disorders (30.6%); there were six deaths temporally related to the use of serum, but this association was discarded. CONCLUSION: in the studied period, the serum produced by the BI had no changes in their safety profiles, considering that the AEs were expected, according to the information previously described in the package insert.

Resumen OBJETIVO: describir el perfil de seguridad de los sueros heterólogos producidos por el Instituto Butantan (IB) de São Paulo-SP, Brasil. MÉTODOS: estudio descriptivo de los informes de eventos adversos (EAs) post-exposición a los sueros del IB y codificados según el Diccionario Médico para Actividades Regulatorias (MedDRA). RESULTADOS: 52 usuarios presentaron EAs relacionados con los sueros antibotrópico (n=11), antidiftérico (n=9) y antiofídico no especificado (n=9); se observó, en los EAs, 3,2 de media por persona; de los 173 EAs reportados, 63,0% fueron "esperados", ya que figuran descritos en la bula farmacológica; los EAs más reportados fueron los trastornos de piel y tejido subcutáneo (30,6%); hubo seis muertes, pero se descartó la asociación con el uso de suero. CONCLUSIÓN: durante el período de estudio, los sueros del IB no mostraron ningún cambio en su perfil de seguridad, ya que los EAs reportados eran esperados conforme información descrita en la bula.

Obiltoxaximab: Adding to the Treatment Arsenal for Bacillus anthracis Infection.

OBJECTIVE: To review the safety and efficacy of obiltoxaximab, a monoclonal antibody indicated for the treatment of Bacillus anthracis inhalational anthrax in adult and pediatric patients. DATA SOURCES: A MEDLINE (1946 to May, week 1, 2017) and EMBASE (1980 to 2017, week 19) search was performed using the search terms obiltoxaximab OR ETI-204 OR Anthim AND anthrax. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical studies in both animal and human models assessing the safety and efficacy of obiltoxaximab were included. DATA SYNTHESIS: A total of 5 articles have been published on clinical studies examining safety and efficacy of obiltoxaximab. Efficacy studies in 2 animal models, New Zealand White rabbits and cynomolgus macaques, showed higher rates of survival post-anthrax exposure when obiltoxaximab was administered. Safety studies in healthy human volunteers showed that it was tolerated, with a relatively low incidence of adverse events. CONCLUSION: Based on these clinical studies and the implausibility of conducting a trial in infected individuals, obiltoxaximab is a safe and efficacious addition to the anthrax antitoxin armamentarium to protect against and treat inhalational anthrax.

Pharmacokinetics and Tolerability of Obiltoxaximab: A Report of 5 Healthy Volunteer Studies.

PURPOSE: This report describes the safety, immunogenicity, and pharmacokinetic results of obiltoxaximab treatment in healthy subjects from 5 clinical trials. METHODS: Healthy men and women were enrolled in randomized, double-blind studies of obiltoxaximab versus placebo (studies 1-3), an open-label, parallel-group study of obiltoxaximab alone versus obiltoxaximab and ciprofloxacin (study 4), or a randomized, double-blind, placebo-controlled study involving administration of a second dose of obiltoxaximab 13 or 119 days after an initial dose (study 5). Obiltoxaximab was administered intravenously in all studies. The safety profile was characterized by physical examinations, including focused examinations of the skin and infusion sites; study drug infusion discontinuations; and assessment of adverse events, vital signs, electrocardiographic findings, laboratory parameters, and immunogenicity. Studies 3 to 5 were the primary safety profile studies. Pharmacokinetic parameters were calculated using noncompartmental methods. FINDINGS: Results of 2 multiple dose studies (studies 1 and 2) revealed that obiltoxaximab exposure increased proportionally. Pharmacokinetic results were consistent across studies. After administration of 16 mg/kg of obiltoxaximab, serum concentrations decreased in a biexponential or multiexponential fashion with a terminal half-life of 17 to 23 days. Mean volume of distribution was approximately 6.3 to 7.5 L, suggesting obiltoxaximab distribution outside the vascular compartment and potentially into tissues. Mean systemic clearance was approximately 0.27 L/d, suggesting that hepatic metabolism and/or renal excretion are not critical to obiltoxaximab elimination. Obiltoxaximab was generally well tolerated. Hypersensitivity reactions were the most common adverse reactions in the safety profile clinical trials, occurring in 34 of 320 subjects (10.6%) receiving obiltoxaximab and 4 of 70 subjects (5.7%) receiving placebo. The most common adverse events were headache, pruritus, upper respiratory tract infection, cough, infusion site swelling, bruising and/or pain, nasal congestion, urticaria, and extremity pain. Of the 320 subjects in the primary safety profile studies who received ≥1 dose of 16 mg/kg of obiltoxaximab, 8 (2.5%) tested positive for a exposure-emergent antiobiltoxaximab response; however, quantitative titers were low (1:20-1:320). IMPLICATIONS: On the basis of consistent results of 5 clinical trials in healthy volunteers, the pharmacokinetic properties of obiltoxaximab after a 16-mg/kg IV infusion can be considered adequately characterized, a criteria of the Animal Rule. Obiltoxaximab appears to be generally well tolerated. ClinicalTrials.gov identifiers: NCT00829582, NCT01453907, NCT01929226, NCT01952444, NCT01932242.

Phase I study evaluating the safety and pharmacokinetics of MDX-1303, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers.

MDX-1303 (Valortim) is a fully human monoclonal antibody (hMAb) with a high affinity for Bacillus anthracis protective antigen (PA). MDX-1303 binds to PA and interferes with the activity of the anthrax toxin; it was selected based on its superior functional activity in the toxin neutralization activity (TNA) assay. MDX-1303 has demonstrated efficacy in the postexposure and therapeutic settings in New Zealand White rabbits, cynomolgus monkeys, and African green monkeys. This phase I study sought to characterize the safety, tolerability, immunogenicity, and pharmacokinetics (PK)/pharmacodynamics (PD) of MDX-1303 in healthy human subjects. Cohorts of 3 to 10 subjects were administered MDX-1303 as either a single intravenous (i.v.) dose at dose levels of 0.3, 1, 3, 10, and 20 mg/kg of body weight or as a single intramuscular (i.m.) dose at 100 mg. Forty-six subjects were enrolled, and 16 (35%) of these subjects experienced one or more grade 1 adverse events considered to be related to treatment with MDX-1303. There were no grade 2 to 4 adverse events or serious adverse events (SAEs) considered to be related to treatment. The mean half-life of MDX-1303 ranged from 22 to 33 days across the i.v. administration cohorts and was approximately 32 days following i.m. administration. Systemic exposure following 100-mg i.m. administration was within the range of exposure following 1-mg/kg i.v. administration with a relative bioavailability of approximately 65%. MDX-1303 was generally well tolerated, and no anti-MDX-1303 antibodies were detected following a single dose.

A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes.

Staphylococcus aureus and Streptococcus pyogenes secrete exotoxins that act as superantigens, proteins that cause hyperimmune reactions by binding the variable domain of the T-cell receptor beta chain (Vß), leading to stimulation of a large fraction of the T-cell repertoire. To develop potential neutralizing agents, we engineered Vß mutants with high affinity for the superantigens staphylococcal enterotoxin B (SEB), SEC3, and streptococcal pyrogenic exotoxin A (SpeA). Unexpectedly, the high-affinity Vß mutants generated against SEB cross-reacted with SpeA to a greater extent than they did with SEC3, despite greater sequence similarity between SEB and SEC3. Likewise, the Vß mutants generated against SpeA cross-reacted with SEB to a greater extent than with SEC3. The structural basis of the high affinity and cross-reactivity was examined by single-site mutational analyses. The cross-reactivity seems to involve only one or two toxin residues. Soluble forms of the cross-reactive Vß regions neutralized both SEB and SpeA in vivo, suggesting structure-based strategies for generating high-affinity neutralizing agents that can cross-react with multiple exotoxins.

Treatment with monoclonal antibodies against Clostridium difficile toxins.

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. RESULTS: Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09). CONCLUSIONS: The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)

Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A.

BACKGROUND: Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. METHODS: Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. RESULTS: Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. CONCLUSION: Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

Combating high-priority biological agents: What to do with drug-allergic patients and those for whom vaccination is contraindicated?

The threat of bioterrorism continues to be a very real one. Regularly, there are news stories on bioterrorism-related topics: What biologic weapons will our enemies likely use to attack the United States? How prepared is our country to successfully counter such attacks? Although these critical questions are being addressed by the leaders of our country, allergists-immunologists, too, will have to grapple with difficult questions during these uncertain and frightening times. We care for a special group of patients with various allergic and immunologic disorders. Some of our patients have immunodeficiency disorders that might preclude them from receiving life-saving vaccines. Our patients with drug allergies are fearful that should they become infected with a biologic agent, they will not be able to receive appropriate treatment. In this article we focus on the various vaccine-related and antibiotic-related adverse effects that the allergist-immunologist might see during treatment of infections caused by Category A agents. Where possible, potential management approaches are outlined.

Reactions to tick antitoxin serum and the role of atropine in treatment of dogs and cats with tick paralysis caused by Ixodes holocyclus: a pilot survey.

OBJECTIVE: To determine the incidence and nature of adverse reactions of dogs and cats to tick antitoxin serum and to re-evaluate the role of atropine in the treatment of tick paralysis. DESIGN: A retrospective questionnaire of veterinarians. PROCEDURE: Questionnaires were posted to 320 veterinarians in tick-endemic regions of Australia. Questions referred to dogs and cats treated for tick paralysis over a period of three years: the number treated, treatment protocols and adverse systemic reactions to tick antitoxin serum. Ninety completed questionnaires were returned and responses analysed. RESULTS: Veterinarians reported that approximately 3% of dogs exhibited adverse reactions immediately following treatment with tick antitoxin serum. Eighteen percent of these reactions were described as anaphylaxis, with the remaining 82% attributed to the Bezold-Jarisch reflex. Six percent of cats treated with tick antitoxin serum reacted adversely and the majority of reactions (63%) were ascribed to the Bezold-Jarisch reflex. Atropine was used routinely by 10% of responding veterinarians in the treatment of dogs and cats with tick paralysis. A similar number of veterinarians used atropine only in selected cases. Most veterinarians (76%) reported that they never used atropine in the treatment of tick paralysis in either dogs or cats. Within the survey population, premedication with atropine reduced the number of Bezold-Jarisch reactions following tick antitoxin administration approximately five-fold in dogs and four-fold in cats. CONCLUSIONS: Data from this pilot survey indicate that more cats than dogs have adverse systemic reactions to tick antitoxin serum and that the majority of these reactions in both dogs and cats could be related to the Bezold-Jarisch reflex. The number of reactions to tick antitoxin serum in dogs and cats could be significantly reduced by the routine use of atropine prior to administration of tick antitoxin serum.

Experience with the use of an investigational F(ab')2 heptavalent botulism immune globulin of equine origin during an outbreak of type E botulism in Egypt.

During an outbreak of type E foodborne botulism in Cairo in 1991, an investigational equine F(ab')2 "despeciated" heptavalent botulism immune globulin (dBIG) was provided to the Egyptian Ministry of Health by the U.S. Army. Of 54 patients known to have been treated with antitoxins, 4 received commercially available trivalent antitoxins, 45 received dBIG, and 5 received both commercial antitoxin and dBIG. Physicians recorded side effects in 10 (22%) of 45 patients who received dBIG; in nine cases, reactions were considered "mild," and in one case they were believed to be serum sickness. In contrast, possible serum sickness during hospitalization was recorded for two of four patients who were receiving commercial antitoxins. No complications of therapy were noted for any patient who was receiving both antitoxin types. In a separate study, 31 patients were contacted about their reactions to the antitoxin by telephone after discharge from the hospital. Seven (54%) of 13 patients attributed symptoms that they experienced while they were hospitalized to receipt of dBIG, while four (44%) of nine patients who indicated that they had received commercial antitoxins and one (20%) of five who received both commercial antitoxin and dBIG reported side effects before discharge. Data on the efficacy of the antitoxins were not obtained. In our experience, equine dBIG was at least as safe as commercially available antitoxins in treating type E foodborne botulism.

Antibiotic-induced release of endotoxin: a reappraisal.

A three- to 20-fold increase in the total concentration of endotoxin occurs as a consequence of antibiotic action on gram-negative bacteria both in vitro and in vivo. There is considerable overlap between the effect of beta-lactam antibiotics and non-beta-lactam antibiotics. Moreover, there is an unexplained delay between the lethal activity of antibiotics and the release of endotoxin. Hence, the mechanism whereby antibiotic action leads to the release of endotoxin is unclear, and mechanisms other than bacterial lysis warrant consideration. The evidence that the release of endotoxin has clinical importance is conflicting, and the issue is unresolved. However, nonlytic release may have implications for the therapeutic efficacy of antiendotoxin immunotherapy. Although frequently cited in the context of the antibiotic-induced release of endotoxin, a number of important differences pertain to conditions, such as the Jarisch-Herxheimer reaction and the tumor lysis syndrome, for which there is clear evidence of an initial deterioration with effective therapy.

Vaccinations in the presence of skin diseases.

The authors collected data from the literature and from experts on the subject of vaccination of patients with dermatologic disorders. They assembled these data into categories of specific skin conditions and vaccinations. These data may be used in deciding whether or not to vaccinate, and at which stage of the dermatologic condition.

Progress in tetanus prophylaxis: the advent of human antitoxin.

Injections of tetanus antitoxin of animal origin frequently cause serious disability and sometimes death. Despite world-wide knowledge of these effects, millions of prophylactic injections of equine tetanus antitoxin are given annually, and it is continually proposed that the dosage be increased in order to obtain higher "protective" levels in the serum, a procedure which would increase the incidence and severity of reactions. Furthermore, equine antitoxin frequently fails to prevent tetanus.Tetanus antitoxin of human origin is available which carries no risk of complications and confers a higher degree of immunity more quickly than equine antitoxin. The cost of treating reactions to horse serum, together with the financial loss incurred by work-absence, far outweighs the cost of human antitoxin. In the author's opinion, the use, in this country, of antitoxin of animal origin is no longer medically acceptable and may well prove legally indefensible.