Roger Baxter

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.)

Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children

BACKGROUND In the United States, children receive five doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before 7 years of age. The duration of protection after five doses of DTaP is unknown. METHODS We assessed the risk of pertussis in children in California relative to the time since the fifth dose of DTaP from 2006 to 2011. This period included a large outbreak in 2010. We conducted a case-control study involving members of Kaiser Permanente Northern California who were vaccinated with DTaP at 47 to 84 months of age. We compared children with pertussis confirmed by a positive polymerase-chain-reaction (PCR) assay with two sets of controls: those who were PCR-negative for pertussis and closely matched controls from the general population of health-plan members. We used logistic regression to examine the risk of pertussis in relation to the duration of time since the fifth DTaP dose. Children who received whole-cell pertussis vaccine during infancy or who received any pertussis-containing vaccine after their fifth dose of DTaP were excluded. RESULTS We compared 277 children, 4 to 12 years of age, who were PCR-positive for pertussis with 3318 PCR-negative controls and 6086 matched controls. PCR-positive children were more likely to have received the fifth DTaP dose earlier than PCR-negative controls (P<0.001) or matched controls (P=0.005). Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval, 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year. CONCLUSIONS Protection against pertussis waned during the 5 years after the fifth dose of DTaP. (Funded by Kaiser Permanente).

Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente.

Objective: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. Methods: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. Results: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16–34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. Conclusion: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.

The Vaccine Safety Datalink: A Model for Monitoring Immunization Safety

The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.

Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.

ames J. Sejvara,∗, Katrin S. Kohla, Jane Gidudua, Anthony Amatob, Nandini Bakshic, Roger Baxterc, ale R. Burwend, David R. Cornblathe, Jan Cleerbout f, Kathryn M. Edwardsg, Ulrich Heiningerh, ichard Hughes i, Najwa Khuri-Bulos j, Rudolf Korinthenbergk, Barbara J. Lawl, Ursula Munrom, elena C. Maltezoun, Patricia Nello,1, James Oleskep, Robert Sparksq, Priscilla Velentgasr, atricia Vermeers, Max Wiznitzer t, The Brighton Collaboration GBS Working Group2

Measles-Mumps-Rubella-Varicella Combination Vaccine and the Risk of Febrile Seizures

OBJECTIVE: In February 2008, we alerted the Advisory Committee on Immunization Practices to preliminary evidence of a twofold increased risk of febrile seizures after the combination measles-mumps-rubella-varicella (MMRV) vaccine when compared with separate measles-mumps-rubella (MMR) and varicella vaccines. Now with data on twice as many vaccine recipients, our goal was to reexamine seizure risk after MMRV vaccine. METHODS: Using 2000–2008 Vaccine Safety Datalink data, we assessed seizures and fever visits among children aged 12 to 23 months after MMRV and separate MMR + varicella vaccines. We compared seizure risk after MMRV vaccine to that after MMR + varicella vaccines by using Poisson regression as well as with supplementary regressions that incorporated chart-review results and self-controlled analyses. RESULTS: MMRV vaccine recipients (83 107) were compared with recipients of MMR + varicella vaccines (376 354). Seizure and fever significantly clustered 7 to 10 days after vaccination with all measles-containing vaccines but not after varicella vaccination alone. Seizure risk during days 7 to 10 was higher after MMRV than after MMR + varicella vaccination (relative risk: 1.98 [95% confidence interval: 1.43–2.73]). Supplementary analyses yielded similar results. The excess risk for febrile seizures 7 to 10 days after MMRV compared with separate MMR + varicella vaccination was 4.3 per 10 000 doses (95% confidence interval: 2.6–5.6). CONCLUSIONS: Among 12- to 23-month-olds who received their first dose of measles-containing vaccine, fever and seizure were elevated 7 to 10 days after vaccination. Vaccination with MMRV results in 1 additional febrile seizure for every 2300 doses given instead of separate MMR + varicella vaccines. Providers who recommend MMRV should communicate to parents that it increases the risk of fever and seizure over that already associated with measles-containing vaccines.

Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI)

BACKGROUND Previous studies have demonstrated a correlation between Clostridium difficile anti-toxin A serum antibodies and protection against symptomatic disease and recurrence. METHODS A neutralizing monoclonal antibody to C. difficile toxin A (CDA1) developed by MBL and Medarex, Inc. was studied in a phase II, randomized, double-blind, placebo-controlled trial in patients receiving standard of care treatment for C. difficile infection (CDI). Twenty-nine subjects received a single intravenous infusion of 10mg/kg CDA1 and 17 subjects received placebo and were evaluated for recurrence of CDI during the 56-day study period. Serum antibodies against C. difficile toxin A and B were measured by ELISA and cytotoxicity assay at various time points before and after infusion. FINDINGS CDI recurrence occurred in 5 of 29 (17%) in the CDA1 group and 3 of 17 (18%) (p=NS) in the placebo group with a trend toward delay in time to recurrence in the group treated with CDA1. The geometric mean concentration of antibody to an epitope of the receptor-binding domain of toxin B (0.300 and 1.20microg/ml, respectively; p=0.02) and geometric mean titer of neutralizing B antibody (8.00 and 100, respectively; p=0.02) at study day 28 were lower for those subjects with recurrence compared to those who did not recur. In addition, a significantly greater proportion of subjects who recurred were infected with the epidemic BI/NAP1/027 strain compared with those that did not recur (88% vs. 22%; p=0.002). Finally, in a multiple logistic regression analysis neutralizing anti-toxin B at day 14 (p<0.001), anti-toxin A at day 28 (p<0.001) and infection with the BI/NAP1/027 strain at enrollment (p=0.002) were all predictive of CDI recurrence. INTERPRETATION In this prospective study, lower concentrations of neutralizing anti-toxin B and anti-toxin A antibody and infection with the BI/NAP1/027 strain of C. difficile were significantly associated with recurrence of CDI.

Influenza Vaccination and Mortality: Differentiating Vaccine Effects From Bias

It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.

Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine.

Background: The introduction of routine vaccination with heptavalent conjugated pneumococcal vaccine has changed the overall incidence of bacteremia in children 3 months–3 years old. Objective: To describe the changing incidence and etiology of bacteremia in previously healthy toddlers presenting to outpatient clinical settings. Methods: Retrospective case series of all blood cultures obtained between September 1998 and August 2003 in Kaiser Permanente Northern California outpatient clinics and emergency departments from previously healthy children 3 months–3 years old. Results: Implementation of routine vaccination with the conjugated pneumococcal vaccine resulted in an 84% reduction of Streptococcus pneumoniae bacteremia (1.3–0.2%) and a 67% reduction in overall bacteremia (1.6–0.7%) in the study population. The rate of blood culture isolation of contaminating organisms remained unchanged at 1.8%; therefore, by the end of the study, >70% of organisms identified in blood cultures were contaminants. During the 5 study years, total blood cultures drawn decreased by 35% in outpatient pediatric clinics but remained unchanged in emergency departments. By 2003, one-third of all pathogenic organisms isolated from blood cultures were Escherichia coli, one-third were non-vaccine serotype S. pneumoniae, the majority of the remaining one-third were Staphylococcus aureus, Salmonella spp., Neisseria meningitidis and Streptococcus pyogenes. In our population of children routinely immunized with the conjugated pneumococcal vaccine, a white blood cell count >15,000 by itself is a poor predictor of bacteremia in the febrile toddler (sensitivity, 74.0%; specificity, 54.5%; positive predictive value, 1.5%; negative predictive value, 99.5%). Conclusion: In the United States, routine vaccinations with Haemophilus influenzae type b and S. pneumoniae vaccines have made bacteremia in the previously healthy toddler a rare event. As the incidence of pneumococcal bacteremia has decreased, E. coli, Salmonella spp. and Staphylococcus aureus have increased in relative importance. The use of the white blood cell count alone to guide the empiric use of antibiotics is not indicated. New guidelines are needed to approach the previously healthy febrile toddler in the outpatient setting.

Mycobacterial diseases and antitumour necrosis factor therapy in USA

Objective In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. Methods At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000–2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. Results Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). Conclusions Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.