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BACKGROUND: Uncomplicated skin abscesses are common, yet the appropriate management of the condition in the era of community-associated methicillin-resistant Staphylococcus aureus (MRSA) is unclear. METHODS: We conducted a multicenter, prospective, double-blind trial involving outpatient adults and children. Patients were stratified according to the presence of a surgically drainable abscess, abscess size, the number of sites of skin infection, and the presence of nonpurulent cellulitis. Participants with a skin abscess 5 cm or smaller in diameter were enrolled. After abscess incision and drainage, participants were randomly assigned to receive clindamycin, trimethoprim–sulfamethoxazole (TMP-SMX), or placebo for 10 days. The primary outcome was clinical cure 7 to 10 days after the end of treatment. RESULTS: We enrolled 786 participants: 505 (64.2%) were adults and 281 (35.8%) were children. A total of 448 (57.0%) of the participants were male. S. aureus was isolated from 527 participants (67.0%), and MRSA was isolated from 388 (49.4%). Ten days after therapy in the intention-to-treat population, the cure rate among participants in the clindamycin group was similar to that in the TMP-SMX group (221 of 266 participants [83.1%] and 215 of 263 participants [81.7%], respectively; P = 0.73), and the cure rate in each active-treatment group was higher than that in the placebo group (177 of 257 participants [68.9%], P

Background The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18–64 years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. Methods In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65–85 years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. Results The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. Conclusions Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65–85 years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85 years. Trial registration number: NCT01643941 .

Background A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. Methods In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64 years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). Results A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. Conclusions Single-dose vaccination of SA4Ag in healthy adults aged 18–64 years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571

Chronic granulomatous disease (CGD), a disease characterized by inadequate neutrophil killing of microbial pathogens, affects 4 to 5 per million live births. For many decades following its description, CGD was a fatal disease in childhood. With the development of effective preventive therapies and the early recognition of infectious complications, 90% of children with CGD now survive into adulthood. The management of CGD in adults includes unique challenges and potential disease manifestations. In this article, the authors discuss the current approach to the management of CGD in both children and adults. This includes a focus on the importance of a comprehensive multidisciplinary approach in the care of CGD and its potential complications. In addition, a novel approach to improving education about CGD, and subsequently improving adherence to preventive therapies, is discussed.

Background Staphylococcus aureus causes serious health care– and community-associated disease, requiring improved preventive measures such as vaccines. The investigational S. aureus 4-antigen vaccine (SA4Ag), comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM197, recombinant mutant clumping factor A (rmClfA), and recombinant manganese transporter protein C (rP305A or rMntC), was well tolerated, inducing robust functional immune responses to all 4 antigens through 12 months postvaccination. This is a serological extension study through 36 months postvaccination. Methods In 2 previous studies, healthy adults received SA4Ag, SA3Ag (without rMntC), or placebo; serology was also assessed at ~24 and ~36 months postvaccination. Functional immune responses (antibody responses that facilitate killing of S. aureus or neutralize S. aureus virulence mechanisms) were assessed with opsonophagocytic activity killing assays (CP5 or CP8) and a fibrinogen-binding inhibition assay (ClfA). A competitive Luminex immunoassay assessed ClfA and rMntC responses. Adverse events within 48 hours of blood draw were recorded. Results Four hundred forty subjects (18–64 years old, 255; 65–85 years old, 185) were enrolled. At 24 and 36 months postvaccination, subjects receiving SA4Ag had substantially higher geometric mean titers (GMTs) for CP5, CP8, and ClfA vs baseline; geometric mean fold rises (GMFRs) from baseline to month 36 were 2.7–8.1. For rMntC, 36-month GMTs declined from peak levels but remained above baseline for all SA4Ag groups; GMFRs from baseline to month 36 were 1.8 and 1.5 in the younger and older cohorts, respectively. Conclusions Persistent functional immune responses to S. aureus antigens were observed through 36 months in healthy adults. ClinicalTrials.gov NCT01643941 and NCT01364571.

Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors under evaluation as vaccine antigens. Clinical S. aureus isolates have the biosynthetic capability to express either CP5 or CP8 and an understanding of the relationship between CP genotype/phenotype and S. aureus epidemiology is valuable. Using whole genome sequencing, the clonal relatedness and CP genotype were evaluated for disease-associated S. aureus isolates selected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) to represent different geographic regions in the United States (US) during 2004 and 2009–10. Thirteen prominent clonal complexes (CC) were identified, with CC5, 8, 30 and 45 representing >80% of disease isolates. CC5 and CC8 isolates were CP type 5 and, CC30 and CC45 isolates were CP type 8. Representative isolates from prevalent CC were susceptible to in vitro opsonophagocytic killing elicited by anti-CP antibodies, demonstrating that susceptibility to opsonic killing is not linked to the genetic lineage. However, as not all S. aureus isolates may express CP, isolates representing the diversity of disease isolates were assessed for CP production. While approximately 35% of isolates (primarily CC8) did not express CP in vitro, CP expression could be clearly demonstrated in vivo for 77% of a subset of these isolates (n = 20) despite the presence of mutations within the capsule operon. CP expression in vivo was also confirmed indirectly by measuring an increase in CP specific antibodies in mice infected with CP5 or CP8 isolates. Detection of antigen expression in vivo in relevant disease states is important to support the inclusion of these antigens in vaccines. Our findings confirm the validity of CP as vaccine targets and the potential of CP-based vaccines to contribute to S. aureus disease prevention. Publisher PDF

BACKGROUND AND OBJECTIVES: Staphylococcus aureus (SA) is the second leading cause of late-onset sepsis among infants in the NICU. Because colonization of nasal mucosa and/or skin frequently precedes invasive infection, decolonization strategies, such as mupirocin application, have been attempted to prevent clinical infection, but data supporting this approach in infants are limited. We conducted a phase 2 multicenter, open-label, randomized trial to assess the safety and efficacy of intranasal plus topical mupirocin in eradicating SA colonization in critically ill infants. METHODS: Between April 2014 and May 2016, infants RESULTS: A total of 155 infants were randomly assigned. Mupirocin was generally well tolerated, but rashes (usually mild and perianal) occurred significantly more often in treated versus untreated infants. Primary decolonization occurred in 62 of 66 (93.9%) treated infants and 3 of 64 (4.7%) control infants (P < .001). Twenty-one of 46 (45.7%) treated infants were persistently decolonized compared with 1 of 48 (2.1%) controls (P < .001). CONCLUSIONS: Application of mupirocin to multiple body sites was safe and efficacious in eradicating SA carriage among infants in the NICU; however, after 2 to 3 weeks, many infants who remained hospitalized became recolonized.

Purpose of review Rising rates of multidrug-resistant organisms has necessitated the development of novel antimicrobials. In this review, we will highlight agents that have recently received licensure and those that are in clinical development. Recent findings In recent years, development of novel antimicrobial agents has accelerated. Although most studies have targeted the adult population, studies in pediatric patients are underway. Adequately powered clinical trials are needed to establish the safety and role of these new drugs. Summary The recent development of novel antimicrobials to combat multidrug-resistant organisms is encouraging; however, more studies in the pediatric population are needed.

Data from 1174 infants enrolled in a previous rotavirus vaccine study were analyzed to determine the effect of antibiotic exposure (from 14 days before to 7 days after vaccination) on rotavirus serum immunoglobulin A (IgA) responses. Serum IgA responses 1 month after the completion of vaccination were similar among antibiotic-exposed and nonexposed infants.

BackgroundVancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.MethodsThis was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320.ResultsTreatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI).ConclusionsHigher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs

Summary A detailed understanding of the adaptive host response to SARS-CoV-2 infection in humans is urgently needed. We developed a sensitive, high-throughput, and efficient assay using liquid bead array technology. We observed advantages over traditional ELISA for the detection and quantification of binding IgG against the receptor binding domain (RBD) of SARS-CoV-2. To determine whether COVID-19 symptom severity correlates with SARS-CoV-2 IgG, we measured anti-RBD IgG levels from 67 subjects recovered from PCR-confirmed COVID-19. We found that COVID-19 symptom severity strongly correlated with RBD IgG level (p < 0.001). These findings have substantial implications for public policy surrounding assessments of antibody responses and possible immunity, as not all cases of COVID-19 can be assumed to generate a protective antibody response, and mild disease in particular is capable of generating very low-level anti-RBD IgG levels. These findings also have important implications for the selection of donors for convalescent plasma to be used therapeutically., Graphical abstract, Highlights • We developed a sensitive, high-throughput assay for quantification of SARS-CoV-2 IgG • The assay uses liquid bead array technology for efficient and reproducible results • COVID-19 symptom severity was strongly correlated with SARS-CoV-2 SRBD IgG levels, Biological Sciences; Microbiology; Virology; Viral Microbiology

Background Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure. Methods This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes. Results 385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. Conclusion Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure. Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

Background Staphylococcus aureus is one of the earliest bacterial pathogens to colonize the lungs of children with cystic fibrosis and is an important contributor to pulmonary exacerbations. The adaptive host response to S. aureus in cystic fibrosis remains inadequately defined and has important implications for pathogenesis and potential interventions. The objectives of this study were to determine the functional antibody response to select staphylococcal exotoxins (LukAB, alpha-hemolysin, and PVL) in children with cystic fibrosis and to evaluate the relationship of this response with pulmonary exacerbations. Methods Fifty children with cystic fibrosis were enrolled and followed prospectively for 12months. Clinical characteristics and serologic profiles were assessed at routine visits and during pulmonary exacerbations, and functional antibody assessments were performed to measure neutralization of LukAB-mediated cytotoxicity. Results For each antigen, geometric mean titers were significantly higher if S. aureus was detected at the time of exacerbation. For LukAB, geometric mean titers were significantly higher at exacerbation follow-up compared to titers during the exacerbation, consistent with expression during human disease, and the humoral response capably neutralized LukAB-mediated cytotoxicity. Moreover, the presence of a positive S. aureus culture during a pulmonary exacerbation was associated with 31-fold higher odds of having a LukA titer ≥1:160, suggesting potential diagnostic capability of this assay. Conclusions The leukotoxin LukAB is expressed by S. aureus and recognized by the human adaptive immune response in the setting of pulmonary infection in cystic fibrosis. Anti-LukAB antibodies were not only predictive of positive staphylococcal culture during exacerbation, but also functional in the neutralization of this toxin.

Athletes have a higher risk of infection with Staphylococcus aureus than the general population. Most studies in athletes have included primarily male contact sports participants and have not assessed S. aureus carriage over time. We aimed to examine the epidemiology and risk factors of S. aureus carriage in a cohort of male and female collegiate athletes. We conducted a prospective cohort study of 377 varsity collegiate athletes from August 2008 to April 2010. A baseline questionnaire ascertained risk factors for colonization. Nasal and oropharyngeal swabs were obtained at enrollment and monthly thereafter to detect S. aureus colonization. The primary outcome was S. aureus colonization, both with methicillin-susceptible and methicillin-resistant S. aureus, as defined by bacterial culture and molecular confirmation. Secondary outcomes were time to colonization with S. aureus and carriage profile, defined as non-carrier, intermittent carrier, or persistent carrier. Overall, 224 contact sports and 153 non-contact sports athletes were enrolled. Contact sports athletes had a higher risk of carrying S. aureus over time: They had higher odds of being colonized with MRSA (OR 2.36; 95 % CI 1.13–4.93) and they tended to carry S. aureus for longer periods of time (intermittent carriage OR 3.60; 95 % CI 2.02–6.40; persistent carriage OR 2.39; 95 % CI 1.21–4.72). Athletes engaged in contact sports also acquired S. aureus more quickly (HR 1.61; 95 % CI 1.02–2.55). Staphylococcus aureus carriage was common in contact sports athletes. These findings suggest that efforts to prevent transmission of S. aureus among athletes should be focused on contact sports teams.

Avian H7N9 influenza viruses are group 2 influenza A viruses that have been identified as the etiologic agent for a current major outbreak that began in China in 2013 and may pose a pandemic threat. Here, we examined the human H7-reactive antibody response in 75 recipients of a monovalent inactivated A/Shanghai/02/2013 H7N9 vaccine. After 2 doses of vaccine, the majority of donors had memory B cells that secreted IgGs specific for H7 HA, with dominant responses against single HA subtypes, although frequencies of H7-reactive B cells ranged widely between donors. We isolated 12 naturally occurring mAbs with low half-maximal effective concentrations for binding, 5 of which possessed neutralizing and HA-inhibiting activities. The 5 neutralizing mAbs exhibited narrow breadth of reactivity with influenza H7 strains. Epitope-mapping studies using neutralization escape mutant analysis, deuterium exchange mass spectrometry, and x-ray crystallography revealed that these neutralizing mAbs bind near the receptor-binding pocket on HA. All 5 neutralizing mAbs possessed low numbers of somatic mutations, suggesting the clones arose from naive B cells. The most potent mAb, H7.167, was tested as a prophylactic treatment in a mouse intranasal virus challenge study, and systemic administration of the mAb markedly reduced viral lung titers.

Purpose The study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses. Methods Adults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus. Results PBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results. Conclusion CMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine.

[Figure: see text] BACKGROUND AND OBJECTIVES: Staphylococcus aureus (SA) is the second leading cause of late-onset sepsis among infants in the NICU. Because colonization of nasal mucosa and/or skin frequently precedes invasive infection, decolonization strategies, such as mupirocin application, have been attempted to prevent clinical infection, but data supporting this approach in infants are limited. We conducted a phase 2 multicenter, open-label, randomized trial to assess the safety and efficacy of intranasal plus topical mupirocin in eradicating SA colonization in critically ill infants. METHODS: Between April 2014 and May 2016, infants

Summary H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.

Improved diagnostics are needed for children with musculoskeletal infections (MSKIs). We assessed the performance of target-enriched multiplex polymerase chain reaction (TEM-PCR) in children with MSKI. TEM-PCR was concordant with culture in pathogen identification and antibiotic susceptibility testing, while increasing the overall yield of pathogen detection. This technology has the potential to inform judicious antimicrobial use early in the disease course.

The purpose of this study was to determine if a decolonization regimen reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) infections and if colonization isolates are genetically related to subsequent infectious strains. Trauma patients admitted to the intensive care unit with positive MRSA nasal swabs were randomized to either daily chlorhexidine gluconate (CHG) baths and mupirocin (MUP) ointment to the nares or soap and water baths and placebo ointment for five days. Nasal swabs performed at the end of treatment and invasive MRSA infections during the remaining hospitalization were compared with the original nasal isolate via polymerase chain reaction for genetic relatedness as well as CHG and MUP resistance genes. Six hundred and seventy-eight intensive care unit admissions were screened, and 92 (13.6%) had positive (+) MRSA nasal swabs over a 22-month period ending in 3/2014. After the five day treatment period, there were 13 (59.1%) +MRSA second nasal swabs for CHG + MUP and 9 (90%) for soap and water baths and placebo, P = 0.114. No isolates tested positive for the MUP or CHG resistance genes mupA and qacA/B but 7 of 20 (35%) contained smr. There were seven (31.8%) MRSA infections in the CHG group and six (60%) for soap, P = 0.244. All 13 patients with MRSA infections had the same MRSA isolate present in the original nasal swab. There was no difference in all-cause Gram-negative or positive infections for CHG versus soap, 12 (54.5%) versus 7 (70%), P = 0.467. CHG + MUP are ineffective in eradicating MRSA from the anterior nares but may reduce the incidence of infection. Subsequent invasive MRSA infections are typically caused by the endogenous colonization strain.

Background Influenza A/H5N1 vaccines have been poorly immunogenic. Addition of Adjuvant System 03 (AS03) markedly enhances immune responses, but the mechanisms of this enhancement are unclear. Methods We compared gene expression in peripheral blood mononuclear cells (PBMCs) between recipients of AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 vaccine on days 1, 3, 7, and 28 postvaccination. We used a systems vaccinology approach to assess functional classifications of differentially expressed (DE) genes between the two vaccine groups, identify DE genes that correlate with serologic responses, and compare these findings with previous cell-specific assessments. Results AS03-adjuvanted vaccine induced the strongest differential gene expression signals on day 1 after vaccination (Figure 1). Multiple innate immune signaling pathways were activated, including the interferon, JAK-STAT, and TNF pathways, and FC gamma receptor (Fc_R) mediated phagocytosis. Immune pathways specific for antigen processing and presentation and influenza A responses were also enriched. Early differential expression of several signal transduction (day 1) and immunoglobulin (day 7) genes were predictive of peak HAI titer (Figure 2). Compared with cell-specific responses, DE gene, and immunologic pathways of PBMCs were most similar to innate immune cell subsets. However, several pathways were unique to PBMCs, and several cell-type-specific pathways, particularly from neutrophils, were absent in PBMCs (Figure 3). Conclusion Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early differential regulation of multiple innate immune signaling pathways and enrichment of pathways involved in antigen presentation and influenza immune responses. Early expression of several genes was associated with peak HAI responses, suggesting a potential role for application of these signatures in earlier determination of vaccine responses. While PBMC and immune cell-specific results shared key innate immune signals, unique signals were identified by either approach. Disclosures L. Howard, Pfizer: Grant Investigator, Grant recipient. C. B. Creech, Pfizer: Grant Investigator, Research grant. Novartis: Grant Investigator, Research grant. K. Edwards, Novartis: Grant Investigator, Research grant. Novartis: Scientific Advisor, Consulting fee.

Background Antibiotic exposure around the time of rotavirus (RV) immunization has been suggested to diminish immune responses, but data are sparse. Methods We retrospectively analyzed data from a randomized RV vaccine study (NCT01266850) outlined in the Table. Concomitant antibiotic use, defined as receipt of an antibiotic 14 days before or 7 days after RV immunization, was recorded. The primary outcome was RV-specific IgA seroresponse (IgA ≥20 U/mL) by ELISA obtained 1 month after the last dose of RV vaccine and geometric mean titer (GMT) to strain WC3 (RV5 backbone) or strain 89–12 (RV1 backbone). Only subjects who received all scheduled vaccine doses and phlebotomy were included. Data were assessed for homogeneity across vaccine schedule groups, stratified by antibiotic exposure. We examined differences in seroresponse adjusting for treatment group, gender, race, ethnicity, and study site using logistic regression models. Results Of the 1384 immunized children, 1174 (85%) met inclusion criteria. Table: Treatment Allocation and Effect of Antibiotic Exposure on Seroresponses Groups 1 2 3 4 5 Immunization Schedule Rotateq® (RV5) 3 doses N = 206 RV5, RV1, RV1 N = 207 RV5, RV5, RV1N = 194 Rotarix® (RV1) 2 dosesN = 287 RV1, RV5, RV5N = 280 Seroresponse: Antibiotic Exposed 21/25 (84%) 20/20 (100%) 18/22 (82%) 13/15 (87%) 32/32 (100%) Seroresponse: Antibiotic Not-Exposed 167/181 (92%) 168/187 (90%) 158/172 (92%) 209/272 (77%) 238/248 (96%) Nearly 10% (n = 114) of participants were antibiotic exposed; group 4 had the least antibiotic exposure (P = 0.05). No differences in GMT or seroresponses were observed to either WC3 or 89–12 (figure) by antibiotic exposure. In the multivariable logistic regression model, there were no significant differences for gender, race, ethnicity, site, or antibiotic exposure (P-value ≥0.5 for IgA seroresponse). The only observed difference in seroresponses was by RV vaccine group (P < 0.0001). Conclusion Antibiotic administration around the time of RV vaccine did not diminish RV-specific IgA seroresponses observed 1 month after the last RV vaccine dose. Figure: Proportion mounting IgA seroresponse to rotavirus immunization, stratified by antibiotic exposure status Disclosures E. J. Anderson, NovaVax: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. AbbVie: Consultant, Consulting fee. MedImmune: Investigator, Research support. PaxVax: Investigator, Research support. Micron: Investigator, Research support. C. B. Creech, Pfizer: Grant Investigator, Research grant. Novartis: Grant Investigator, Research grant. A. L. Shane, International Scientific Association of Probiotics and Prebiotics: Member, Reimbursement of travel and lodging for attendance and presentations at international scientific meetings 2016 and prior and support for attendance at meeting at FDA in 2017 to discuss probiotic and prebiotic research. K. Edwards, Novartis: Grant Investigator, Research grant. Novartis: Scientific Advisor, Consulting fee.

Staphylococcus aureus infections pose a significant health burden. The emergence of community-associated methicillin-resistant S. aureus has resulted in an epidemic of skin and soft tissue infections (SSTI), and many patients experience recurrent SSTI. As S. aureus colonization is associated with subsequent infection, decolonization is recommended for patients with recurrent SSTI or in settings of ongoing transmission. S. aureus infections often cluster within households and asymptomatic carriers serve as reservoirs for transmission; therefore, a household approach to decolonization is more effective than measures performed by individuals alone. Other factors, such as environmental surface contamination, may also be considered. Novel strategies for the prevention of recurrent SSTI are needed.

Background Staphylococcus aureus is the leading cause of skin and soft tissue infections in the United States, and S. aureus colonization increases the risk of infection. Although athletes have a higher risk of infection with S. aureus than the general population, most studies in athletes have not assessed colonization. Methods We conducted a prospective cohort study of Vanderbilt University varsity athletes from August 2008 to April 2010. We assessed nasal and oropharyngeal colonization with methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains by obtaining swabs at enrollment and monthly thereafter until the end of the study. The athletes were also monitored for skin and soft tissue infections. Results We enrolled 377 athletes and trainers (224 in contact sports and 153 in noncontact sports). The total S. aureus colonization prevalence ranged from 34% to 62%, and for MRSA it ranged from 8% to 29%. The colonization rate in the summer was significantly higher than that in the winter (odds ratio for MRSA [ORMRSA], 1.70 [95% confidence interval (CI), 1.23-2.35]; ORMSSA, 1.38 [95% CI, 1.05-1.82]). Of 603 MRSA isolates, 75% carried the staphylococcal cassette chromosome mec (SCCmec) type IV, and 5% carried the genes encoding Panton-Valentine leukocidin. Nine symptomatic S. aureus infections occurred, 7 of which were between July and September. Conclusions The S. aureus colonization rate is higher than previously reported and fluctuated over time in this prospective cohort of athletes. The higher colonization prevalence during summer might explain the infectious outbreak during the summer months and may represent a key intervention time for preventing S. aureus disease in athletes.

We conducted a survey of pediatric infectious diseases providers in the Emerging Infections Network regarding the workup and treatment of children withStaphylococcus aureus bacteremia (SAB). We found significant practice variation in the management of children with SAB. These findings emphasize the need for further research to guide best practices.

The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus . Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied 24 distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and from healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to that seen with healthy controls and less than that seen with patients with invasive S. aureus infection. IVIg samples had lower neutralization capacity than samples from healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding but had significantly more variation in toxin neutralization. These results represent the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential.

Summary Adaptations that enable antimicrobial resistance often pose a fitness cost to the microorganism. Resistant pathogens must therefore overcome such fitness decreases to persist within their hosts. Here we demonstrate that the reduced fitness associated with one resistance-conferring mutation can be offset by community interactions with microorganisms harboring alternative mutations or via interactions with the human microbiota. Mutations that confer antibiotic resistance in the human pathogen Staphylococcus aureus led to decreased fitness, whereas coculture or coinfection of two distinct mutants resulted in collective recovery of fitness comparable to that of wild-type. Such fitness enhancements result from the exchange of metabolites between distinct mutants, leading to enhanced growth, virulence factor production, and pathogenicity. Interspecies fitness enhancements were also identified, as members of the human microbiota can promote growth of antibiotic-resistant S. aureus. Thus, inter- and intraspecies community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence.

As the influenza A H1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years.Children received 2 doses of approximately 15 or 30 µg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition titers were measured on days 0 (prevaccination), 8, 21, 29 and 42.A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 µg dosage elicited a seroprotective hemagglutination inhibition (≥ 1:40) in 20%, 47% and 93% of children in the 6-35 month, 3-9 year and 10-17 year age strata 21 days after dose 1 and in 78%, 82% and 98% of children 21 days after dose 2, respectively. The 30 µg vaccine dosage induced similar responses.The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 µg dose induced seroprotective antibody responses in most children 10-17 years of age, younger children required 2 doses, even when receiving dosages 4- to 6-fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics.

Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) disease in neonatal intensive care units has risen sharply in recent years. Prevention of MRSA infection is of utmost importance given the high virulence and broad antibiotic resistance of this pathogen. A vaccine against this organism would be ideal to prevent infection in high-risk populations such as the premature infant. S. aureus produces a wide variety of virulence factors that function to evade the natural host response to this pathogen, and previous vaccine attempts have been unsuccessful. The objective of this review is to discuss the potential for a vaccine against S. aureus and to examine past attempts at the prevention of neonatal staphylococcal disease.

The adjuvant AS03 is stockpiled for future formulations with new and existing vaccines for the control of pandemic influenza virus. We previously reported the immunogenicity of an A/H5N1 vaccine extemporaneously mixed with the AS03 adjuvant for 42 days following vaccination. This report extends those findings to 1 year after vaccination.

Therapeutics blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy.

Background Current guidelines recommend vancomycin (VAN) dosing to achieve AUC/MIC ratio ≥400 for patients (pts) with serious MRSA bloodstream infections (BSI), but supporting data were largely derived in single center retrospective studies. A recent study using a Bayesian approach to estimate the VAN AUC found that patients with MRSA BSI who had an AUCDAY2/MICBMD ≥ 650 or an AUCDAY2/MICETEST ≥ 320 had lower incidences of failure (Clin Infect Dis 59:666, 2014). This study prospectively evaluated if these VAN AUCDAY2/MIC targets were associated with lower incidences of failure (PROVIDE, Award number UM1AI104681, Antibacterial Resistance Leadership Group). Methods Prospective, multi-center (n = 14), observational study (2014–2106) of hospitalized adults with confirmed MRSA BSI treated with VAN ≥ 72h. Exclusion: (1) neutropenia; (2) cystic fibrosis; (3) renal replacement therapy; (4) APACHE-II score > 25; (5) previous MRSA BSI within 60 days. VAN exposures were estimated using maximum a posteriori probability procedure in ADAPT 5. MICBMD and MICETEST were performed at a central laboratory. Outcomes: failure (30-day mortality or MRSA BSI ≥ 7 days); acute kidney injury (AKI), ≥1.5 × increase in serum creatinine (Scr) among patients with a baseline SCR < 2.0mg/dl. The study was powered at 80% to detect a 17.5% difference in failure between AUCDAY2/MIC groups. Results Among the 265 evaluable patients, mean (SD) age was 61 (17) and APACHE-II was 12 (6). Endocarditis was definite/possible in 29%. The MIC50/90 by BMD and ETEST were 1/1 and 1.5/1.5mg/l, respectively. Failure occurred in 18%; 26% had AKI. Mean (SD) VAN duration was 18 (14) days. Mean (SD) AUCDAY2 was 586.9 (235.5) and 44% and 73% of patients achieved an AUCDAY2/MICBMD ≥ 650 and AUCDAY2/MICETEST ≥ 320. In the multivariate analyses (Figure 1), failure was not significantly different between AUCDAY2/MIC groups. In contrast, AKI was significantly more common in patients with an AUCDAY2/ MICETEST > = 320. Conclusion Achievement of higher VAN AUCDAY2/MIC exposures for patients with MRSA BSIs were not associated with better outcomes and were found to result in increased AKI. Clinicians should assess the benefits vs. risks of using VAN regimens that confer high AUCDAY2/MIC exposures for patients with MRSA BSIs. Disclosures T. P. Lodise Jr., allergan: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium; medicines company: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; melinta: Consultant, Consulting fee; motif: Consultant and Scientific Advisor, Consulting fee; paratek: Consultant and Scientific Advisor, Consulting fee; nabriva: Consultant, Consulting fee; M. J. Zervos, Merck, Inc.: Investigator, Research grant; M. Scheetz, Bayer: Scientific Advisor, Consulting fee; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, Basilea, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Research grant; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: author on several chapters, Royalties

OBJECTIVE: To compare the effectiveness of clindamycin, trimethoprim-sulfamethoxazole, and β-lactams for the treatment of pediatric skin and soft-tissue infections (SSTIs). METHODS: A retrospective cohort of children 0 to 17 years of age who were enrolled in Tennessee Medicaid, experienced an incident SSTI between 2004 and 2007, and received treatment with clindamycin (reference), trimethoprim-sulfamethoxazole, or a β-lactam was created. Outcomes included treatment failure and recurrence, defined as an SSTI within 14 days and between 15 and 365 days after the incident SSTI, respectively. Adjusted models stratified according to drainage status were used to estimate the risk of treatment failure and time to recurrence. RESULTS: Among the 6407 children who underwent drainage, there were 568 treatment failures (8.9%) and 994 recurrences (22.8%). The adjusted odds ratios for treatment failure were 1.92 (95% confidence interval [CI]: 1.49–2.47) for trimethoprim-sulfamethoxazole and 2.23 (95% CI: 1.71–2.90) for β-lactams. The adjusted hazard ratios for recurrence were 1.26 (95% CI: 1.06–1.49) for trimethoprim-sulfamethoxazole and 1.42 (95% CI: 1.19–1.69) for β-lactams. Among the 41 094 children without a drainage procedure, there were 2435 treatment failures (5.9%) and 5436 recurrences (18.2%). The adjusted odds ratios for treatment failure were 1.67 (95% CI: 1.44–1.95) for trimethoprim-sulfamethoxazole and 1.22 (95% CI: 1.06–1.41) for β-lactams; the adjusted hazard ratios for recurrence were 1.30 (95% CI: 1.18–1.44) for trimethoprim-sulfamethoxazole and 1.08 (95% CI: 0.99–1.18) for β-lactams. CONCLUSIONS: Compared with clindamycin, use of trimethoprim-sulfamethoxazole or β-lactams was associated with increased risks of treatment failure and recurrence. Associations were stronger for those with a drainage procedure.

Acute hematogenous osteomyelitis is a common disease that affects previously healthy children of all age groups. Despite its importance, there are limited data in the current literature to guide many aspects of the diagnosis and therapy of this infection. Over the last decade, our understanding of the etiology of this infection has changed, with increased recognition of Kingella kingae and the dramatic increase in community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. There is a need for the optimization of diagnostic strategies, such as MRI and serum inflammatory markers. Several recent studies have examined treatment strategies, including a rapid transition to oral antimicrobial therapy and a shortened overall course of therapy. Many new therapeutic options are on the horizon that will likely impact the management of this and other childhood bacterial infections. This review summarizes recent investigations into the optimal diagnosis and management of acute hematogenous osteomyelitis in children.

To define the molecular epidemiology of colonization and disease-associated isolates of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).Laboratory-based comparative study of clinical staphylococcal isolates.We analyzed 255 pediatric CA-MRSA isolates for molecular characteristics associated with colonization and disease. We used polymerase chain reaction to determine the presence of Panton-Valentine Leukocidin and the lantibiotic element, bsaB, and to characterize the staphylococcal cassette chromosome mec type and accessory gene regulator locus. Pulsed-field gel electrophoresis was used to determine genetic relatedness between strains.A total of 150 isolates were obtained from patients with clinical disease (37 invasive infections, 113 noninvasive infections) and 105 from subjects with nasal colonization alone. Of 150 disease-associated isolates, 123 (82%) belonged to pulsed-field gel electrophoresis group USA300, whereas only 19 (18%) of 105 colonization isolates were of the USA300 lineage. Colonization isolates were less likely to possess staphylococcal cassette chromosome mec type IV, Panton-Valentine Leukocidin, or agr type 1 (P0.001).Colonization strains of CA-MRSA in children differ significantly from those strains recovered from patients with staphylococcal infections. This suggests that only colonization with specific strain types, rather than methicillin-resistant Staphylococcus aureus colonization in general, increases the risk for CA-MRSA disease.

We collected all Staphylococcus aureus isolates from the National Children's Hospital in Costa Rica to evaluate the prevalence and molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). Of 299 S. aureus isolates, 61% were MRSA. Most MRSA isolates (94.5%) carried SCCmec IV, and 45.6% carried Panton-Valentine leukocidin-encoding genes. The high prevalence of MRSA in this population highlights the need for improvement of antibiotic prescription and infection control measures.