Katherine E. Fleming-Dutra

Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011

IMPORTANCE The National Action Plan for Combating Antibiotic-Resistant Bacteria set a goal of reducing inappropriate outpatient antibiotic use by 50% by 2020, but the extent of inappropriate outpatient antibiotic use is unknown. OBJECTIVE To estimate the rates of outpatient oral antibiotic prescribing by age and diagnosis, and the estimated portions of antibiotic use that may be inappropriate in adults and children in the United States. DESIGN, SETTING, AND PARTICIPANTS Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, annual numbers and population-adjusted rates with 95% confidence intervals of ambulatory visits with oral antibiotic prescriptions by age, region, and diagnosis in the United States were estimated. EXPOSURES Ambulatory care visits. MAIN OUTCOMES AND MEASURES Based on national guidelines and regional variation in prescribing, diagnosis-specific prevalence and rates of total and appropriate antibiotic prescriptions were determined. These rates were combined to calculate an estimate of the appropriate annual rate of antibiotic prescriptions per 1000 population. RESULTS Of the 184,032 sampled visits, 12.6% of visits (95% CI, 12.0%-13.3%) resulted in antibiotic prescriptions. Sinusitis was the single diagnosis associated with the most antibiotic prescriptions per 1000 population (56 antibiotic prescriptions [95% CI, 48-64]), followed by suppurative otitis media (47 antibiotic prescriptions [95% CI, 41-54]), and pharyngitis (43 antibiotic prescriptions [95% CI, 38-49]). Collectively, acute respiratory conditions per 1000 population led to 221 antibiotic prescriptions (95% CI, 198-245) annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1000 population, among all conditions and ages combined in 2010-2011, an estimated 506 antibiotic prescriptions (95% CI, 458-554) were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate antibiotic prescriptions. CONCLUSIONS AND RELEVANCE In the United States in 2010-2011, there was an estimated annual antibiotic prescription rate per 1000 population of 506, but only an estimated 353 antibiotic prescriptions were likely appropriate, supporting the need for establishing a goal for outpatient antibiotic stewardship.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Prevention of Pneumonia

Background: Pneumonia is the leading cause of morbidity and mortality among children <5 years of age globally. Pneumococcal conjugate vaccines (PCVs) are known to provide protection against vaccine serotype pneumococcal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule. Methods: We conducted a systematic review of studies published from 1994 to 2010 (supplemented post hoc with studies from 2011) documenting the effect of PCV dosing schedules on clinical and radiologically confirmed pneumonia, pneumococcal pneumonia and empyema among children of ages targeted to receive vaccine. Data on 2- and 3-dose schedules were included. Percent change of pneumonia incidence rates from baseline to most recent year post-PCV introduction was calculated. Results: We identified 42 primary citations that evaluated PCV schedules and pneumonia. Thirty-seven (88%) were from North America, Europe or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies (both observational) compared multiple schedules within the study. We found evidence of reduced clinical and radiologically confirmed pneumonia incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 observational studies), 3+0 (5 randomized trials, 2 observational studies) and 3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude of disease impact did not differ among schedules. Evidence for impact on pneumococcal pneumonia and empyema varied. Conclusions: All schedules (2+1, 3+0 and 3+1) reduced clinical and radiologically confirmed pneumonia. Quantifying differences in pneumonia disease impact between schedules was difficult due to heterogeneity among studies in design, case definition and population. These findings support World Health Organization recommendations for 3-dose schedules administered as either 3+0 or 2+1 regimens. Pneumonia impact data are still needed on expanded serotype PCV products, developing country settings and the role for a booster dose.

Core Elements of Outpatient Antibiotic Stewardship

The Core Elements of Outpatient Antibiotic Stewardship provides a framework for antibiotic stewardship for outpatient clinicians and facilities that routinely provide antibiotic treatment. This report augments existing guidance for other clinical settings. In 2014 and 2015, respectively, CDC released the Core Elements of Hospital Antibiotic Stewardship Programs and the Core Elements of Antibiotic Stewardship for Nursing Homes. Antibiotic stewardship is the effort to measure and improve how antibiotics are prescribed by clinicians and used by patients. Improving antibiotic prescribing involves implementing effective strategies to modify prescribing practices to align them with evidence-based recommendations for diagnosis and management. The four core elements of outpatient antibiotic stewardship are commitment, action for policy and practice, tracking and reporting, and education and expertise. Outpatient clinicians and facility leaders can commit to improving antibiotic prescribing and take action by implementing at least one policy or practice aimed at improving antibiotic prescribing practices. Clinicians and leaders of outpatient clinics and health care systems can track antibiotic prescribing practices and regularly report these data back to clinicians. Clinicians can provide educational resources to patients and families on appropriate antibiotic use. Finally, leaders of outpatient clinics and health systems can provide clinicians with education aimed at improving antibiotic prescribing and with access to persons with expertise in antibiotic stewardship. Establishing effective antibiotic stewardship interventions can protect patients and improve clinical outcomes in outpatient health care settings.

Systematic Review of the Indirect Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Pneumococcal Disease and Colonization

Background: To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups. Methods: We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia. Results: Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule. Conclusions: Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Nasopharyngeal Carriage

Background: Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine type (VT) pneumococci, an important driver of vaccine programs’ overall benefits. The dosing schedule that best reduces carriage is unclear. Methods: We performed a systematic review of English language publications from 1994 to 2010 (supplemented post hoc with studies from 2011) reporting PCV effects on VT carriage to assess variability in effect by dosing schedule. Results: We identified 32 relevant studies (36 citations) from 12,980 citations reviewed. Twenty-one (66%) evaluated PCV7; none used PCV10 or PCV13. Five studies evaluated 2 primary doses and 13 three primary doses. After the first year of life, 14 evaluated 3-dose primary series with PCV booster (3+1), seven 3 doses plus 23-valent polysaccharide booster “3+1PPV23,” five “3+0,” four “2+1,” three “2+1PPV23” and two “2+0.” Four studies directly compared schedules. From these, 3 primary doses reduced VT carriage more than 2 doses at 1–7 months following the series (1 study significant; 2 borderline). In a study, the 2+1 schedule reduced VT carriage more than 2+0 at 18, but not at 24 months of age. One study of a 23-valent pneumococcal polysaccharide vaccine booster showed no effect. All 16 clinical trials with unvaccinated controls and 11 observational studies with before-after designs showed reduction in VT carriage. Conclusions: The available literature demonstrates VT-carriage reduction for 2+0, 2+1, 3+0 and 3+1 PCV schedules, but not for 23-valent pneumococcal polysaccharide vaccine booster. Comparisons between schedules show that 3 primary doses and a 2+1 schedule may reduce carriage more than 2 primary doses and a 2+0 schedule, respectively.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Invasive Pneumococcal Disease Among Young Children

Background: Pneumococcal conjugate vaccines (PCV) are being implemented globally using a variety of different schedules. The optimal schedule to maximize protection of vaccinated children against vaccine-type invasive pneumococcal disease (VT-IPD) is not known. Methods: To assess the relative benefit of various PCV dosing schedules, we conducted a systematic review of studies published in English from 1994 to 2010 (supplemented post hoc with studies from 2011) on PCV effectiveness against VT-IPD among children targeted to receive vaccine. Data on 2-dose and 3-dose primary series, both with and without a booster (“2+0,” “2+1,” “3+0” and “3+1”), were included. For observational studies using surveillance data or case counts, we calculated percentage reduction in VT-IPD before and after PCV introduction. Results: Of 4 randomized controlled trials and 31 observational studies reporting VT-IPD among young children, none evaluated a 2+0 complete series, 7 (19%) evaluated 2+1, 4 (11%) 3+0 and 27 (75%) 3+1. Most (86%) studies were from North America or Europe. Only 1 study (observational) directly compared 2 schedules (3+0 vs. 3+1); results supported the use of a booster dose. In clinical trials, vaccine efficacy ranged from 65% to 71% with 3+0 and 83% to 94% with 3+1. Surveillance data and case counts demonstrate reductions in VT-IPD of up to 100% with 2+1 (6 studies) or 3+1 (17 studies) schedules and up to 90% with 3+0 (2 studies). Reductions were observed as early as 1 year after PCV introduction. Conclusions: These data support the use of 2+1, 3+0 and 3+1 schedules, although most data of PCV impact on VT-IPD among young children are from high-income countries using 3+1. Differences between schedules for impact on VT-IPD are difficult to discern based on available data.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Immunogenicity

Background: Despite the breadth of studies demonstrating benefits of pneumococcal conjugate vaccine (PCV), uncertainty remains regarding the optimal PCV dosing schedule in infants. Methods: We conducted a systematic literature review of PCV immunogenicity published from 1994 to 2010 (supplemented post hoc with studies from 2011). Studies included for analysis evaluated ≥2 doses of 7-valent or higher product (excluding Aventis-Pasteur PCV11) administered to nonhigh-risk infants ⩽6 months of age. Impact of PCV schedule on geometric mean antibody concentration (GMC) and proportion of subjects over 0.35 mcg/mL were assessed at various time points; the GMC 1 month postdose 3 (for various dosing regimens) for serotypes 1, 5, 6B, 14, 19F and 23F was assessed in detail using random effects linear regression, adjusted for product, acellular diphtheria-tetanus-pertussis/whole-cell diphtheria- tetanus-pertussis coadministration, laboratory method, age at first dose and geographic region. Results: From 61 studies, we evaluated 13 two-dose (2+0) and 65 three-dose primary schedules (3+0) without a booster dose, 11 “2+1” (2 primary plus booster) and 42 “3+1” schedules. The GMC after the primary series was higher following 3-dose schedules compared with 2-dose schedules for all serotypes except for serotype 1. Pre- and postbooster GMCs were generally similar regardless of whether 2 or 3 primary doses were given. GMCs were significantly higher for all serotypes when dose 3 was administered in the second year (2+1) compared with ⩽6 months of age (3+0). Conclusions: While giving the third dose in the second year of life produces a higher antibody response than when given as part of the primary series in the first 6 months, the lower GMC between the 2-dose primary series and booster may result in less disease protection for infants in that interval than those who completed the 3-dose primary series. Theoretical advantages of higher antibodies induced by giving the third dose in the second year of life, such as increased protection against serotype 1 disease, longer duration of protection or more rapid induction of herd effects, need to be evaluated in practice.

Effect of the 2009 Influenza A(H1N1) Pandemic on Invasive Pneumococcal Pneumonia

BACKGROUND Because pneumococcal pneumonia was prevalent during previous influenza pandemics, we evaluated invasive pneumococcal pneumonia (IPP) rates during the 2009 influenza A(H1N1) pandemic. METHODS We identified laboratory-confirmed, influenza-associated hospitalizations and IPP cases (pneumococcus isolated from normally sterile sites with discharge diagnoses of pneumonia) using active, population-based surveillance in the United States. We compared IPP rates during peak pandemic months (April 2009-March 2010) to mean IPP rates in nonpandemic years (April 2004-March 2009) and, using Poisson models, to 2006-2008 influenza seasons. RESULTS Higher IPP rates occurred during the peak pandemic month compared to nonpandemic periods in 5-24 (IPP rate per 10 million: 48 vs 9 (95% confidence interval [CI], 5-13), 25-49 (74 vs 53 [CI, 41-65]), 50-64 (188 vs 114 [CI, 85-143]), and ≥65-year-olds (229 vs 187 [CI, 159-216]). In the models with seasonal influenza rates included, observed IPP rates during the pandemic peak were within the predicted 95% CIs, suggesting this increase was not greater than observed with seasonal influenza. CONCLUSIONS The recent influenza pandemic likely resulted in an out-of-season IPP peak among persons ≥5 years. The IPP peaks magnitude was similar to that seen during seasonal influenza epidemics.

The Differential Impact of Coadministered Vaccines, Geographic Region, Vaccine Product and Other Covariates on Pneumococcal Conjugate Vaccine Immunogenicity

Background: Antipneumococcal capsular polysaccharide antibody concentrations are used as predictors of vaccine efficacy against vaccine serotype (ST) pneumococcal disease among infants. While pneumococcal conjugate vaccines (PCV) are recommended globally, factors associated with optimal PCV immune response are not well described. We aimed to systematically assess local setting factors, beyond dosing schedule, which may affect PCV antibody levels. Methods: We conducted a literature review of PCV immunogenicity, abstracting data from published reports, unpublished sources, and conference abstracts from 1994 to 2010 (and ad hoc 2011 reports). Studies included in this analysis evaluated ≥ 2 primary doses of PCV before 6 months of age in non–high-risk populations, used 7-valent or higher PCV products (excluding Aventis-Pasteur and Merck products) and provided information on geometric mean concentration (GMC) for STs 1, 5, 6B, 14, 19F or 23F. Using random effects meta-regression, we assessed the impact of geographic region, coadministered vaccines and PCV product on postprimary GMC, adjusting for dosing schedule and ELISA laboratory method. Results: Of 12,980 citations reviewed, we identified 103 vaccine study arms for this analysis. Children in studies from Asia, Africa and Latin America had significantly higher GMC responses compared with those in studies from Europe and North America. Coadministration with acellular pertussis DTP compared with whole-cell DTP had no effect on PCV immunogenicity except for ST14, where GMCs were higher when coadministered with acellular pertussis DTP. Vaccine product, number of PCV doses, dosing interval, age at first dose and ELISA laboratory method also affected the GMC. Conclusions: PCV immunogenicity is associated with geographic region and vaccine product; however, the associations and magnitude varied by ST. Consideration of these factors is essential when comparing PCV immunogenicity results between groups and should be included in the evidence base when selecting optimal PCV vaccine schedules in specific settings.

Methods for a systematic review of pneumococcal conjugate vaccine dosing schedules.

Background: Streptococcus pneumoniae causes a considerable amount of morbidity and mortality in children <5. However, pneumococcal conjugate vaccines (PCVs) can prevent much of this burden. Until recently, PCVs were mostly available only in developed countries using a variety of dosing schedules. As more lower income countries make decisions to introduce PCV into their national immunization programs, an optimal schedule with which to administer PCV has become a key policy question. Methods: We performed a systematic review of English literature published from 1994 to 2010 on the effects of PCV dosing schedules on immunogenicity, nasopharyngeal carriage, invasive pneumococcal disease and pneumonia. Data were independently double abstracted and cleaned for analysis. Descriptive analyses were performed. Results: We identified 12,980 citations from the literature search (12,976) and secondary means (44). Double review of titles and abstracts yielded 769 articles that underwent full data abstraction. Of these, 350 were further analyzed and are presented in separate reports in this supplement. Conclusions: This article presents the methods utilized in our systematic review. Because of the heterogenity of the study methods of the reports identified by this review, we did not conduct formal meta-analyses. However, these methods allow us to present a full landscape of the literature on PCV dosing schedules.