María M. Contrini

Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against shiga-like toxin 2 in healthy adults and in pediatric patients infected with shiga-like toxin-producing Escherichia coli.

ABSTRACT Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (Cmax) ranged from 2.6 μg/ml at 0.1 mg/kg to 71.7 μg/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean Cmaxs of 19.6 and 56.1 μg/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

Incomplete hemolytic-uremic syndrome in Argentinean children with bloody diarrhea☆☆☆★★★

Argentina has an exceptionally high frequency of hemolytic-uremic syndrome (HUS). We sought to define prospectively the role of verocytotoxins (Shiga-like toxins [SLTs]) in 254 Argentinean children with grossly bloody diarrhea during spring and summer. Free fecal SLTs (I/II) and/or DNA probe-positive isolates were found in 99 (39%) of the children. During the follow-up period, HUS developed in 6 patients (4 with evidence of recent SLT infection based on stool studies); another 14 patients had some, but not all, of the abnormalities seen in typical HUS. The development of HUS or incomplete HUS in these children was significantly associated with recent SLT-Escherichia coli infection (p = 0.024). The high incidence of SLT-associated bloody diarrhea in Argentina explains, at least partially, the unusually high frequency of HUS. Our data indicate that incomplete forms of HUS may be common in patients with SLT-associated bloody diarrhea.

SHIGELLA AND SHIGA TOXIN-PRODUCING ESCHERICHIA COLI CAUSING BLOODY DIARRHEA IN LATIN AMERICA

In Latin America, Shigella and shiga toxin-producing Escherichia coli are the two leading agents in the cause of bloody diarrhea. The already high and increasing antimicrobial resistance of Shigella also is a significant problem. Shiga toxin-producing E. coli is an emerging disease with life-threatening complications: hemolytic uremic syndrome. Although E. coli O157:H7 remains the most commonly recognized serotype, recently emerging, non-O157 bacteria may be the cause of a similar spectrum of disease in humans.

Safety and immunogenicity of a pediatric formulation of inactivated hepatitis A vaccine in Argentinean children.

BACKGROUND Children are a reservoir of hepatitis A virus and must be considered as primary targets of any immunization strategy. The safety and immunogenicity were evaluated for a new formulation of an inactivated hepatitis A vaccine, Avaxim 80 units, containing one-half the antigen dose of the adult formulation. METHODS The safety of two doses of this vaccine given 6 months apart was evaluated in an open study in 537 Argentinean children 12 months to 15 years old. Immunogenicity was evaluated at Weeks 0, 2, 24 and 27 in a subgroup of 120 subjects. RESULTS Two weeks after the first vaccine dose, >99% of initially seronegative children had seroconverted (titers > or =20 mIU/ml), with a geometric mean titer of 98.5 mIU/ml. Before booster at 24 weeks all subjects had seroconverted. A strong anamnestic response was observed after the second dose at which time the geometric mean titer had increased >35-fold, and antibody titers were consistent with long term protection. Immediate adverse reactions were observed in 3 of 537 (0.6%) subjects after the first dose. Local reactions were mild and transient and did not increase with subsequent doses. Among the systemic events reported during the 7-day follow-up period, 37 cases of fever after the first dose and 22 cases after the second dose were reported. Only 3 cases of fever were clearly related to vaccination (< or =38.2 degrees C) after the first injection, all of which subsided in less than 1 day. CONCLUSIONS This study demonstrated the safety and immunogenicity of a pediatric formulation of hepatitis A vaccine in children ages 12 months to 15 years in healthy children ages 12 to 47 months.

Perspectives on Shiga-like toxin infections in Argentina

Argentina has the highest frequency of hemolytic uremic syndrome (HUS) in the world (300 cases/year). The risk of HUS in children from 6 to 48 months old is approximately 22/100,000 in Buenos Aires. In Argentina, HUS is the most frequent cause of acute renal damage and the second cause of chronic renal injury in children. We have shown that during the spring/summer season, the incidence of Shiga-like toxin (SLT)-associated bloody diarrhea in children less than 5 years old is 30 to 39%. The risk of HUS in SLT-associated bloody diarrhea is about 4 to 5%; 14% of children with SLT diarrhea developed incomplete HUS. Household contacts of children with HUS are commonly colonized with SLT-producing Escherichia coli (39%), and seroconversion occurs in 42% of these. No evidence of free fecal SLTs was observed in healthy children. In Argentina E. coli serotype O157:H7 has been associated with only 2 to 18% of HUS patients and in 4.5 to 7% of children with bloody diarrhea. Other serotypes were also recognized. About 20% of Argentine children start to eat meat at 5 months old, and 80% of them have meat in their diets at least three times a week. Eighty percent of the meat consumed is undercooked. Few data about the incidence of SLT-producing E. coli in cows in our country are available. E. coli O157:H7 was isolated in only 7.7% of calves aged 1 to 3 weeks with E. coli bacillosis from different farms in Argentina. Preliminary data show that SLT-producing E. coli were also present in stools from healthy animals and in fresh retail ground beef, determined by polymerase chain reaction.

Long-term immunity after two doses of inactivated hepatitis A vaccine, in Argentinean children.

We examined long-term anti-hepatitis A virus antibody persistence in Argentinean children 10 years after the initial study in which they received 2 doses of inactivated hepatitis A vaccine (Avaxim 80U). Of the 111 children, 48 from the initial trial were enrolled. Of 48, 47 (97.9%) participants had serum anti-hepatitis A virus antibody titers ≥20 mIU/mL, with the geometric mean concentration of 390.91 (±370.14) mIU/mL; (95% confidence interval, 282.2–499.5 mIU/mL), range, 36 to 1860.

Modeling the Long-term Persistence of Hepatitis A Antibody After a Two-Dose Vaccination Schedule in Argentinean Children.

Background: Long-term seroprotection data are essential for decision-making on the need and timing of vaccine boosters. Based on data from longitudinal serological studies, modeling can provide estimates on long-term antibody persistence and inform such decision-making. Methods: We examined long-term anti-hepatitis A virus (anti-HAV) antibody persistence in Argentinean children ⩽15 years after the initial study where they completed a 2-dose course of inactivated hepatitis A vaccine (Avaxim® 80U Pediatric, Sanofi Pasteur, Lyon, France). Blood serum samples were taken at baseline, 2 weeks (post first dose), 6 months (pre-booster), 6.5 months (post-booster), 10 years and 14–15 years after first vaccine dose. We fitted 8 statistical model types, predominantly mixed effects models, to anti-HAV persistence data, to identify the most appropriate and best fitting models for our data set and to predict individuals’ anti-HAV levels and seroprotection rates up to 30 years post vaccination. Results: Fifty-four children (mean age at enrollment 30.4 months) were enrolled up to 15 years post first vaccine dose. There were 3 distinct periods of antibody concentration: rapid rise up to peak concentration post-booster, rapid decay from post-booster to 10 years, followed by slower decay. A 3-segmented linear mixed effects model was the most appropriate for the data set. Extrapolating based on the available 14–15-year follow-up, the analysis predicted that 88% of individuals anti-HAV seronegative prior to vaccination would remain seroprotected at 30 years post vaccination and lifelong seroprotection for vaccinees seropositive prior to vaccination. Conclusions: Currently available data demonstrate that Avaxim® 80U Pediatric confers to most vaccinees a high level of seroprotection against hepatitis A infection for at least 20–30 years.

Case characteristics and use of oseltamivir in children and household contacts.

In May 2009, the onset of pandemic influenza A (H1N1) began in Buenos Aires schools and a containment program was implemented. We report the first 191 school-aged cases. Influenza (H1N1) was a mild disease in children. Oseltamivir was well tolerated and resulted in a significantly reduced duration of symptoms in this group. Oseltamivir was also effective at preventing secondary cases.

Rapid Decrease in Rates of Hospitalization Resulting From Invasive Pneumococcal Disease and Community-Acquired Pneumonia in Children Aged <60 Months After 13-Valent Pneumococcal Conjugate Vaccine Introduction in Argentina

Background In January 2012, Argentina included universal pneumococcal vaccination in the routine childhood vaccination program using a 13-valent pneumococcal conjugate vaccine (PCV13). A 2 + 1 schedule (2 doses in the first year of life and a booster dose at 12 months of age) in children aged <2 years and 2-dose catch-up immunization in children aged 13 to 24 months was administered during the first year of vaccine introduction. The purpose of this study was to assess the burdens of invasive pneumococcal disease (IPD) and/or community-acquired pneumonia (CAP) in hospitalized children younger than 5 years during the first 2 years of the program compared to those in the prevaccination period in our setting. Methods This was a multicenter, prospective, and descriptive study. Rates of hospitalization resulting from IPD and/or CAP in 5 pediatric reference centers across the country were analyzed (every 10 000 admissions). Clinical, epidemiologic, and microbiological data were recorded. Statistical analysis using Stata 8.0 was performed. Results A comparison of rates of hospitalization resulting from global IPD and/or CAP in the prevaccine (2009-2011) and postvaccine (2012-2013) periods revealed significant decreases of 50% (P = .003) and 51% (P < .0001), respectively. Significant decreases were also observed in number of hospitalizations resulting from empyema (39%; P = .03) and pneumococcal empyema (67.8%; P = .007); the reduction was not statistically significant for pneumococcal CAP (58%; P = .18). Hospital stays for IPD and/or CAP decreased by 56%. Conclusion Rapid and significant decreases in the rates of hospitalization resulting from IPD and/or CAP during the first 2 years after PCV13 introduction were observed. A longer surveillance period is required to confirm these results and the effectiveness of the vaccination program.

Pandemic influenza A/H1N1 2009 antibodies in the metropolitan area of Buenos Aires in Argentina

OBJECTIVE To estimate the infection prevalence in Buenos Aires during the outbreak of pandemic influenza A/H1N1 2009 virus (A(H1N1)pdm09). METHODS A(H1N1)pdm09-specific antibodies were measured by hemagglutination inhibition assay in human serum samples collected 6 months after the outbreak and before the introduction of the A(H1N1)pdm09 vaccine in Argentina. Baseline levels of cross-reactive antibodies to A(H1N1)pdm09 were determined by testing 162 serum samples collected before 2009. RESULTS The overall seroprevalence of A(H1N1)pdm09 in 150 children and 427 adults was 28.9% (95% confidence interval (CI) 25-33%), with a 58.0% prevalence in children <19 years of age and an 18.7% prevalence in adults ≥19 years of age (p<0.001). The prevalence was 43.5% in children <5 years old and 60.6% among children aged 5-18 years. The prevalence in adults declined with increasing age: 24.9% in 19-39-year-olds, 9.7% in 40-59-year-olds, and 8.1% in those ≥60 years old. The prevalence of specific A(H1N1)pdm09 antibodies was higher compared with the baseline in children (p=0.014), adolescents (p<0.001), and adults <40 years old (p=0.017). Seroprevalence in health care workers was not different from the rest of the population (13.6% vs. 19.3%, respectively; p=0.421). CONCLUSIONS The prevalence of specific A(H1N1)pdm09 antibodies was high at 28.9%. The highest prevalence was observed in children, adolescents, and young adults.