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Background Despite concerns that antimicrobial treatment of prevalent infections may select for drug-resistant bacteria, the effects of antimicrobial treatment on colonization dynamics have not been well quantified. Methods We measured impacts of antimicrobial treatment on nasopharyngeal carriage of penicillin-susceptible Streptococcus pneumoniae (PSSP) and penicillin-nonsusceptible (PNSP) lineages at the end of treatment and 15, 30, and 60 days after treatment in a previously conducted randomized, double-blinded, placebo-controlled trial of amoxicillin-clavulanate for stringently defined acute otitis media. Results In intention-to-treat analyses, immediate treatment with amoxicillin-clavulanate reduced PSSP carriage prevalence by 88% (95% confidence interval [CI], 76%-96%) at the end of treatment and by 27% (-3%-49%) after 60 days but did not alter PNSP carriage prevalence. By the end of treatment, 7% of children who carried PSSP at enrollment remained colonized in the amoxicillin-clavulanate arm, compared with 61% of PSSP carriers who received placebo; impacts of amoxicillin-clavulanate persisted at least 60 days after treatment among children who carried PSSP at enrollment. Amoxicillin-clavulanate therapy reduced PSSP acquisition by >80% over 15 days. Among children who carried PNSP at enrollment, no impacts on carriage prevalence of S. pneumoniae, PSSP, or PNSP were evident at follow-up visits. Conclusions Although the absolute risk of carrying PNSP was unaffected by treatment, antimicrobial therapy conferred a selective impact on colonizing pneumococci by accelerating clearance and delaying acquisition of PSSP.

Background While circulation of respiratory syncytial virus (RSV) results in high rates of hospitalization, particularly among young children and elderly individuals, little is known about the role of different age groups in propagating annual RSV epidemics. Methods We evaluate the roles played by individuals in different age groups during RSV epidemics in the United States between 2001 and 2012, using the previously defined relative risk (RR) statistic estimated from the hospitalization data from the Healthcare Cost and Utilization Project. Transmission modeling was used to examine the robustness of our inference method. Results Children aged 3-4 years and 5-6 years each had the highest RR estimate for 5 of 11 seasons included in this study, with RSV hospitalization rates in infants being generally higher during seasons when children aged 5-6 years had the highest RR estimate. Children aged 2 years had the highest RR estimate during one season. RR estimates in infants and individuals aged ≥11 years were mostly lower than in children aged 1-10 years. Highest RR values aligned with groups for which vaccination had the largest impact on epidemic dynamics in most model simulations. Conclusions Our estimates suggest the prominent relative roles of children aged ≤10 years (particularly among those aged 3-6 years) in propagating RSV epidemics. These results, combined with further modeling work, should help inform RSV vaccination policies.

In 2009, Streptococcus pneumoniae, or pneumococcus, caused approximately 44 000 cases of invasive pneumococcal disease (IPD) and about 5000 deaths in the United States [1]. In addition, pneumococcus is responsible for a considerable burden of respiratory disease globally [2]. Antibiotic nonsusceptibility is a major concern; understanding the dynamics by which pneumococcus develops nonsusceptibility will help maintain the efficacy of these drugs. There are currently over 90 known serotypes of S. pneumoniae, of which only a small proportion account for most invasive disease and most nonsusceptible infections in the United States. Before introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, the proportion of penicillin-nonsusceptible and macrolide-nonsusceptible isolates from invasive disease was increasing [3–5]. Previous studies have correlated differential use of antimicrobials with different rates of nonsusceptibility across geographic areas, as well as changing patterns of usage and nonsusceptibility over time [6–11]. When PCV7 was introduced, the 7 serotypes included in the vaccine accounted for 78% of penicillin-nonsusceptible strains [3]. In the decade since, rates of disease caused by these 7 serotypes declined by 99%, and serotypes not included in PCV7 have increased significantly, a phenomenon known as serotype replacement. Some of the replacing serotypes (eg, 19A, 15A, 23A, 35B, 6C) have shown high and/or increasing levels of antimicrobial nonsusceptibility, raising the question of whether antimicrobial use may in part be responsible for the increased prevalence [12–14]. In the pre-PCV7 era, geographic differences in proportions of nonsusceptibility to penicillin and macrolides resulted from geographic variation in selective pressure for nonsusceptibility [10, 15]. In pneumococci, selective pressure may affect nonsusceptibility in 2 ways: by increasing the prevalence of nonsusceptibility within each serotype, and/or by increasing the prevalence of serotypes in which the prevalence of nonsusceptibility is high. The frequencies of pneumococcal serotypes within a population reflect multiple selective pressures imposed by natural and vaccine-induced host immunity [16], and it is in principle possible that selection by antimicrobial use may also affect this pattern. In the pre-PCV7 era, no evidence of such an effect was found; the impact of differences in antimicrobial selective pressure was seen solely in varying prevalence of nonsusceptibility within each serotype, but not in variations in the prevalence of the more nonsusceptible serotypes [15]. Understanding the interplay between antimicrobial use pressures and changing serotype distributions has important policy implications for both antimicrobial stewardship and vaccination programs. In this study, we assessed geographical, serotype, and temporal variation in the frequency of drug nonsusceptibility, with a particular focus on the question of whether, contrary to pre-PCV7 observations, there was evidence that geographic variation in the intensity of selective pressure for nonsusceptibility was reflected in greater prevalence of nonsusceptible serotypes.

Background Treatment of Neisseria gonorrhoeae infection is empirical and based on population-wide susceptibilities. Increasing antimicrobial resistance underscores the potential importance of rapid diagnostic tests, including sequence-based tests, to guide therapy. However, the usefulness of sequence-based diagnostic tests depends on the prevalence and dynamics of the resistance mechanisms. Methods We define the prevalence and dynamics of resistance markers to extended-spectrum cephalosporins, macrolides, and fluoroquinolones in 1102 resistant and susceptible clinical N. gonorrhoeae isolates collected from 2000 to 2013 via the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project. Results Reduced extended-spectrum cephalosporin susceptibility is predominantly clonal and associated with the mosaic penA XXXIV allele and derivatives (sensitivity 98% for cefixime and 91% for ceftriaxone), but alternative resistance mechanisms have sporadically emerged. Reduced azithromycin susceptibility has arisen through multiple mechanisms and shows limited clonal spread; the basis for resistance in 36% of isolates with reduced azithromycin susceptibility is unclear. Quinolone-resistant N. gonorrhoeae has arisen multiple times, with extensive clonal spread. Conclusions Quinolone-resistant N. gonorrhoeae and reduced cefixime susceptibility appear amenable to development of sequence-based diagnostic tests, whereas the undefined mechanisms of resistance to ceftriaxone and azithromycin underscore the importance of phenotypic surveillance. The identification of multidrug-resistant isolates highlights the need for additional measures to respond to the threat of untreatable gonorrhea.

Streptococcus pneumoniae (pneumococcus) remains a major cause of pneumonia, meningitis, and sepsis worldwide, especially in young children. The 7-valent pneumococcal polysaccharide conjugate vaccine, PCV7 (Prevnar (Prevenar); Pfizer), contains capsule polysaccharide antigen of 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F). Its routine use among infants has had a significant impact on vaccine serotype (VT) invasive pneumococcal disease (IPD) and nasopharyngeal (NP) carriage among age groups targeted for vaccination and other age groups; however, concomitant increases in IPD and carriage due to serotypes not included in the vaccine (nonvaccine serotypes [NVTs]) have been observed [1–4]. Pneumococcal NP carriage studies conducted during (1998–2000) and immediately after (2001–2002) a community-randomized PCV7 efficacy trial among Navajo and White Mountain Apache children also identified increased carriage with NVTs [5–7]. The increased prevalence of some vaccine-associated serotypes (VATs, a subgroup of NVTs defined as serotypes within the same serogroup as VTs) and other NVT strains since routine use of PCV7 has been temporally associated with observed increases in the rate of NVT IPD in the United States and in other routine-use countries [8–10]. However, the increased incidence of NVT IPD does not tell us whether NVTs have an increased invasive potential or whether the niche left empty by VTs has only given NVTs more opportunity to colonize and therefore more opportunity to cause disease. Invasive potentials of serogroups in the absence of vaccination have been shown to be geographically and temporally stable [11]. The objective of this study was to determine serotype-specific carriage among Navajo and White Mountain Apache children and adults after 8 years of routine PCV7 use and 12 years after initial use in their communities and to assess whether invasive potentials of serotypes have changed in the setting of long-term PCV7 use. These communities are known to have high prevalence of pneumococcal colonization and IPD rates >4-fold that of the general US population [12]. Based on findings from pre-PCV7 studies [11], we hypothesized that there would be no change in the invasive potential of pneumococcal serotypes. Finally, analysis of individual and household characteristics can identify risk factors associated with carriage in this population. Because IPD episodes are preceded by pneumococcal colonization, identifying modifiable carriage risk factors informs additional disease prevention methods.

During the last 20 years, a dramatic increase in antibiotic resistance among pneumococci has been observed and linked to increasing antibiotic consumption [1-4]. Several studies have suggested that reduction in antibiotic consumption leads to a reduction in the antibiotic resistance of Streptococcus pneumoniae in the community [2, 5-7]. However, other studies could not demonstrate such an effect [8-10]. The relationship between antibiotic consumption and resistance is complex. Some antimicrobial agents select resistant pneumococcal strains more effectively than others [8, 11-15]. Moreover, the rate of the decrease in resistance expected after a decrease in antibiotic use depends on both the fitness cost of resistance for the bacteria and the extent of the reduction in consumption [16, 17]. If fitness cost is minimal or if the reduction in antibiotic use is small, antibiotic resistance may continue increasing, albeit perhaps more slowly, or it may decline gradually. However, if resistance exacts a strong fitness cost (with respect to transmissibility) on the bacteria, then a quick and significant decrease in resistance would be expected after a major decrease in antibiotic consumption [18]. A recent study in rats suggested that penicillin resistance in S. pneumoniae, particularly high-level resistance, carries a substantial fitness cost [19]. Another recent study showed a fitness cost of fluoroquinolone-resistant mutants of S. pneumoniae [20]. A complicating factor is the presence of dual and multiple resistance, because reduction mainly in the use of a single antibiotic may not result in the expected reduction in resistance, because of coselection of resistance caused by the continued use of other antibiotics [18]. Surveillance of antibiotic prescriptions in children

Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non–vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a “serotype filter”: its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.

Antibodies to pneumococcus are thought to represent the primary mechanism of naturally acquired resistance to colonization. Here, however, we show that, in patients with chronic obstructive pulmonary disease (COPD), resistance to pneumococcal colonization is not associated with higher concentrations of serum anti-capsular or -noncapsular antibodies. We compared preacquisition serum antibody concentrations to capsular antigens 6B, 7F, 14, 19F, and 23F from patients with COPD who did and did not acquire pneumococcal respiratory tree colonization over the course of 2 years. Colonized patients did not have lower anti-capsular antibody concentrations than control subjects who did not acquire pneumococcus. We found no difference in functional antibody concentrations between colonized patients and control subjects. Furthermore, colonized patients had significantly higher preacquisition concentration of antibody directed against the whole cell and pneumococcal surface protein A than control subjects. We thus conclude that, in adult patients with COPD, resistance to pneumococcal colonization is unlikely to be determined by higher serum antibody concentrations to pneumococcal antigens.

Author(s): Hanage, William P; Huang, Susan S; Lipsitch, Marc; Bishop, Cynthia J; Godoy, Daniel; Pelton, Stephen I; Goldstein, Richard; Huot, Heather; Finkelstein, Jonathan A | Abstract: BackgroundIn response to the selective pressure of pneumococcal conjugate vaccine, increased asymptomatic carriage of antibiotic-nonsusceptible nonvaccine serotypes (NVTs) has been observed. Possible mechanisms include de novo acquisition of resistance, serotype switching, introduction of new clones, and expansion of existing clones.MethodsTo investigate the process of increased antibiotic nonsusceptibility among replacing serotypes, we applied multilocus sequence typing to samples of 126 and 222 pneumococci collected in 2001 and 2004, respectively, from the nasopharynges of children l7 years of age in 16 Massachusetts communities.ResultsWe found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of NVTs, particularly in serotypes 19A, 15A, and 35B. In 19A, several unrelated clones increased in frequency, whereas, in the other 2 serotypes, single resistant lineages were responsible for the increased prevalence of resistant strains.ConclusionsThe decreased prevalence of antibiotic resistance with the introduction of heptavalent pneumococcal conjugate vaccine is likely to be partially eroded over time as vaccine-included serotypes are replaced by resistant clones of NVTs. The clinical significance of this will depend on the pathogenic potential of replacing clones to cause local (e.g., otitis media) or invasive disease.

Background. Immunization with pneumococcal conjugate vaccines (PCVs) reduces nasopharyngeal colonization by Streptococcus pneumoniae. We attempted to correlate postvaccination serum serotype-specific pneumococcal anticapsular immunoglobulin (Ig) G concentrations with new acquisitions of vaccine-type (VT) serotypes and the VT-related serotype 6A. Methods. A total of 132 day care center attendees aged 12-35 months received a 9-valent PCV (PnCRM9) and were followed for 2 years for new nasopharyngeal acquisitions of S. pneumoniae. A total of 132 control subjects received a meningococcus type C conjugate vaccine. Serum serotype-specific pneumococcal anticapsular IgG concentrations were determined at 1 month after complete immunization. Results. A logistic regression model of the probability of having a new acquisition of S. pneumoniae (for serotypes 9V, 14, 19F, and 23F) as a function of the IgG concentration showed a negative coefficient, indicating that higher IgG concentrations led to a decreasing probability of having a new acquisition, and achieved statistical significance for serotypes 14 and 19F. Similarly, a new acquisition of serotype 6A was shown to be significantly inversely related to the anti-6B IgG concentration. An effect of the IgG concentration on duration of carriage was not demonstrated. Conclusion. The magnitude of herd protection against S. pneumoniae provided by a PCV may depend on the magnitude of IgG concentrations.

Nasopharyngeal carriage of Streptococcus pneumoniae is required for transmission of the bacteria and for invasive disease. There have been conflicting reports as to whether protection against carriage is serotype specific and which immune mechanisms drive carriage. Analyzing longitudinal carriage data from Israeli toddlers in day care, we found a lower risk of colonization with types 6A, 14, and 23F after previous exposure to the homologous type. Nonsignificant trends suggesting possible protection derived from prior exposure were found for types 19A and 23A. Furthermore, we found that, for types 14 and 23F, this specific protection correlated with increased serotype-specific antibody concentration. We found no evidence of specific protection for type 6B, group 15, or type 19F. Our findings imply that at least some serotypes generate anti-capsular antibodies that can reduce the risk of carriage in unimmunized toddlers.

Background We evaluated the impact of resistant penicillin-binding protein (PBP) allele acquisition on the ability of penicillin-resistant (PEN-R) pneumococcal strains to compete with penicillin-susceptible (PEN-S) ancestors for upper-respiratory-tract (URT) colonization. Methods PEN-S serotype 2, 6B, and 9V strains were transformed into derivatives expressing an increasing number of PEN-R PBP forms (2X, 2X-1A, and 2X-1A-2B for serotype 2 and 2X, 2X-2B, and 2X-2B-1A for 6B and 9V). Infant rats were inoculated intranasally with a mix of a PEN-R and PEN-S strains. For consecutive days, samples were collected for assessment of the ratio of PEN-S to PEN-R cells colonizing the URT. The selective index (SI), defined as the change in the natural logarithm of the ratio of PEN-S to PEN-R strains from the inoculum to the nasal-wash samples, quantified differences in fitness. Results SIs significantly > 0 (indicating a cost of resistant allele acquisition) were observed 4-5 days after colonization in all but serotype 6B pbp2x transfomants. Additional replacements with low-affinity forms of pbp2b and pbp1a genes reduced further ability to compete in all strains. Conclusions The cost of penicillin-resistance acquisition for the Streptococcus pneumoniae strain competing with its susceptible ancestor to colonize the URT increases with the number of resistant pbp alleles acquired.