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Key Points Question What are targets for improving antibiotic stewardship for outpatient acute respiratory infections? Findings Among 14 987 outpatients with acute respiratory infections enrolled in this cohort study during influenza seasons, 41% were prescribed antibiotics, 41% of whom had diagnoses for which antibiotics are not indicated, primarily viral upper respiratory tract infections and bronchitis; 29% of patients with influenza confirmed through research testing were prescribed antibiotics. Among patients prescribed antibiotics, 38% with pharyngitis tested negative for group A streptococcus and 38% with sinusitis had symptoms for 3 days or less before the visit, suggesting antibiotic therapy was not required. Meaning Eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis, improving influenza diagnosis and treatment, and reinforcing prescription guidelines for pharyngitis and sinusitis could improve outpatient antibiotic stewardship., Importance Acute respiratory infections (ARIs) are the syndrome for which antibiotics are most commonly prescribed; viruses for which antibiotics are ineffective cause most ARIs. Objectives To characterize antibiotic prescribing among outpatients with ARI during influenza season and to identify targets for reducing inappropriate antibiotic prescribing for common ARI diagnoses, including among outpatients with laboratory-confirmed influenza. Design, Setting, and Participants Cohort study enrolling outpatients aged 6 months or older with ARI evaluated at outpatient clinics associated with 5 US Influenza Vaccine Effectiveness Network sites during the 2013-2014 and 2014-2015 influenza seasons. All patients received influenza testing by real-time reverse transcriptase–polymerase chain reaction for research purposes only. Antibiotic prescriptions, medical history, and International Classification of Diseases, Ninth Revision diagnosis codes were collected from medical and pharmacy records, as were group A streptococcal (GAS) testing results in a patient subset. Exposure Visit for ARI, defined by a new cough of 7 days’ duration or less. Main Outcomes and Measures Antibiotic prescription within 7 days of enrollment. Appropriateness of antibiotic prescribing was based on diagnosis codes, clinical information, and influenza and GAS testing results. Results Of 14 987 patients with ARI (mean [SD] age, 32 [24] years; 8638 [58%] women; 11 892 [80%] white), 6136 (41%) were prescribed an antibiotic. Among these 6136 patients, 2522 (41%) had diagnoses for which antibiotics are not indicated; 2106 (84%) of these patients were diagnosed as having a viral upper respiratory tract infection or bronchitis (acute or not otherwise specified). Among the 3306 patients (22%) not diagnosed as having pneumonia and who had laboratory-confirmed influenza, 945 (29%) were prescribed an antibiotic, accounting for 17% of all antibiotic prescriptions among patients with nonpneumonia ARI. Among 1248 patients with pharyngitis, 1137 (91%) had GAS testing; 440 of the 1248 patients (35%) were prescribed antibiotics, among whom 168 (38%) had negative results on GAS testing. Of 1200 patients with sinusitis and no other indication for antibiotic treatment who received an antibiotic, 454 (38%) had symptoms for 3 days or less prior to the outpatient visit, suggesting acute viral sinusitis not requiring antibiotics. Conclusions and Relevance Antibiotic overuse remains widespread in the treatment of outpatient ARIs, including among patients with laboratory-confirmed influenza, although study sites may not be representative of other outpatient settings. Identified targets for improved outpatient antibiotic stewardship include eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis and improving adherence to prescribing guidelines for pharyngitis and sinusitis. Increased access to sensitive and timely virus diagnostic tests, particularly for influenza, may reduce unnecessary antibiotic use for these syndromes., This cohort study examines patterns and appropriateness of antibiotic prescribing among children and adults with acute respiratory infections visiting outpatient clinics associated with the US Influenza Vaccine Effectiveness Network during influenza season.

Importance In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. Objectives To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. Design, Setting, and Participants This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Exposures Recommended childhood vaccines between ages 1 month and 12 years. Main Outcome and Measure The proportion of children who received all of their vaccine doses according to ACIP recommendations. Results The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life. Conclusions and Relevance Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.

Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations.Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015.The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site.Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P .001).The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.clinicaltrials.gov Identifier: NCT01942265.

Importance The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine. Objectives To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). Design, Setting, and Participants Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 19 to 25 months previously with the Vietnam vaccine and 565 vaccine-naive adults. Interventions Participants who were previously vaccinated with 90 µg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 µg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 µg [n = 55 with MF59 and n = 59 without], 7.5 µg [n = 51 with MF59 and n = 57 without], 15 µg [n = 48 with MF59 and n = 44 without], 45 µg [n = 47 with MF59 and n = 47 without], or 90 µg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28. Main Outcomes and Measures The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events. Results Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine (“boosting”); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 µg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 µg (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 µg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 µg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups. Conclusions and Relevance Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. Trial Registration clinicaltrials.gov Identifier:NCT00680069

Objective To determine whether influenza vaccination of pregnant women prevents visits for respiratory illness in their infants born during the influenza season. Design Retrospective matched cohort study. Setting Four managed care organizations in the United States. Patients A total of 41 129 infants (3160 and 37 969 born to vaccinated and unvaccinated mothers, respectively) born between 1995 and 2001. Main Exposure Maternal influenza vaccination. Infants were considered exposed if their gestational age at birth was at least 30 weeks, if the time from maternal vaccination to birth was at least 28 days, and if they were exposed to at least 14 days of the influenza season. Main Outcome Measures Incidence of acute respiratory illnesses (outpatient, emergency department, and inpatient settings combined) and incident rate ratios (IRRs) for infants exposed and unexposed to maternal vaccination during the following 4 periods: peak influenza, respiratory syncytial virus predominant, periseasonal, and summer weeks. The time to the first acute respiratory illness during peak influenza weeks was also assessed. Results During the peak influenza weeks, infant visit rates were 15.4 and 17.1 per 100 person-months for exposed and unexposed infants, respectively (IRR, 0.90; 95% confidence interval, 0.80-1.02). Adjusted IRRs for the 4 periods found a protective effect of infant female sex, whereas Medicaid status and maternal high-risk status increased infant visit rates. Maternal influenza vaccination did not reduce visit rates during any of the 4 time periods (IRR for peak influenza season, 0.96; 95% confidence interval, 0.86-1.07) and did not delay the onset of first respiratory illness. Conclusion We were unable to demonstrate that maternal influenza vaccination reduces respiratory illness visit rates among their infants.

Background To our knowledge, there are no published population-based studies on the safety of the inactivated trivalent influenza vaccine among children. Objective To screen a large population of children for evidence of increased medical visits in the 2 weeks after influenza vaccination compared with 2 control periods. Secondary analyses included shorter risk periods and restricted age categories. Design Self-control screening analysis. Children vaccinated from January 1, 1993, through December 31, 1999, were randomly divided into 2 equal groups. In group 1, risks of outpatient, emergency department, and inpatient visits during the 14 days after vaccination were compared with the risks of visits in 2 control periods. Significant plausible medically attended events identified in group 1 were then analyzed in group 2, using the same 2 control periods. Medically attended events significant in both groups were considered potentially associated with vaccination and were assessed by medical record review. Setting Five managed care organizations in the United States. Participants Children younger than 18 years who received an influenza vaccination in one of the managed care settings (N = 251 600). Main Outcome Measure Among vaccinated children seen for a medically attended event, the odds of the visit occurring in the 2 weeks after vaccination vs during 1 of the 2 control periods. Results Study participants incurred 1165, 230, and 489 different diagnoses during the 14 days after vaccination according to the outpatient, emergency department, and inpatient data, respectively. Four diagnoses were positively associated with the vaccine in both groups 1 and 2: impetigo, dermatitis, uncomplicated diabetes mellitus, and ureteral disorder not otherwise specified. After medical record review, impetigo (9 cases) in children 6 to 23 months old remained significantly associated with vaccination. Conclusion This large screening safety study did not reveal any evidence of important medically attended events associated with pediatric influenza vaccination.

Context Influenza virus is a major cause of illness, disruption to daily life, and increased use of health care in all age groups. Objective To assess the safety and effectiveness of intranasally administered trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care use among healthy, working adults. Design Randomized, double-blind, placebo-controlled trial conducted from September 1997 through March 1998. Setting Thirteen centers across the United States. Participants A total of 4561 healthy, working adults aged 18 to 64 years recruited through health insurance plans, at work sites, and from the general population. Intervention Participants were randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n=3041) or placebo (n=1520) in the fall of 1997. Main Outcome Measures Episodes of febrile illness, severe febrile illness, febrile upper respiratory tract illness, work loss, and health care use during the peak and total influenza outbreak periods, and adverse events. Results Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P=.19). However, vaccination significantly reduced the numbers of severe febrile illnesses (18.8% reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to fewer days of illness across all illness syndromes (22.9% reduction for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile upper respiratory tract illnesses), and fewer days with health care provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for febrile upper respiratory tract illnesses). Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes. Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination, but serious adverse events between the groups were not significantly different. The match between the type A(H3N2) vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain. Conclusion Intranasal trivalent LAIV vaccine was safe and effective in healthy, working adults in a year in which a drifted influenza A virus predominated.

CONTROVERSIES ABOUT how to discipline children are of concern to parents, other adults who care for children, clinicians, and policymakers. There are disparate views about some aspects of the advisability and effects of different forms of discipline and substantial variability in the amount and quality of the research that informs these opinions. To address these issues, a conference—Research on Discipline: The State of the Art, Deficits, and Implications—was sponsored by the National Institutes of Child Health and Human Development Family and Child Well-being Research Network, Chapel Hill, NC, April 25-26, 1996. The focus of the conference was on discipline research conceptualization, methodology, issues of causality, outcomes, and interventions. The aim was to review what we may conclude from previous work and to identify deficits that might be addressed in future research. Three of the papers from the conference are presented in this issue of theArchives. We highlight herein some

Objective. —Multiple outbreaks of serogroup C Neisseria meningitidis have recently been reported from diverse areas of the United States. To better define the characteristics of this increasingly important problem, we reviewed data on all known serogroup C outbreaks in the United States from January 1980 through June 1993. Data Sources. —MEDLINE searches, Centers for Disease Control and Prevention records, state health department officials, infectious disease experts, and the meningococcal vaccine manufacturer. Definition of an Outbreak. —Three or more cases of serogroup C meningococcal disease within a 3-month period, either among members of a community or persons attending a single school or other institution, for which those cases represented an attack rate of at least five per 100 000 population. Results. —Twenty-one outbreaks of serogroup C meningococcal disease were identified; eight occurred since 1991. In 1992 and the first half of 1993, approximately 180 000 doses of vaccine were administered for outbreak control, compared with approximately 34000 doses from 1980 to 1991. Approximately 50% of community-outbreak cases were between the ages of 5 and 24 years, compared with only 19% of sporadic serogroup C cases ( P Conclusions. —Serogroup C outbreaks are occurring more frequently in the United States. The effectiveness of preventive measures depends on early recognition; therefore, physicians should promptly report all cases of suspected meningococcal disease, and the causative serogroup should be established for every case. ( JAMA . 1995;273:383-389)

In Reply. —The importance of GBS as a cause of maternal morbidity is well recognized. As pointed out by Dr Greenspoon, the incidence of invasive GBS maternal infection may be underestimated in our study since cultures were not obtained from all febrile patients; this comment may apply as well to other groups of patients such as diabetics with skin and soft tissue infections. Our data provide an estimate of definite cases of GBS disease in pregnancy and in other conditions. We agree with the need for preventive strategies to decrease morbidity from GBS infections in pregnant women. However, the optimal approach is not clear. While prophylactic antibiotics for women colonized with GBS may prevent infection, the potential benefit must be balanced against cost and the risk of adverse drug reactions. If intrapartum antibiotics were given to all women colonized with GBS, it seems likely that the adverse effects would outweigh