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Background:The spatial and temporal extent of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) environmental contamination has not been precisely defined. We sought to elucidate contamination of different surface types and how contamination changes over time.Methods:We sampled surfaces longitudinally within COVID-19 patient rooms, performed quantitative RT-PCR for the detection of SARS-CoV-2 RNA, and modeled distance, time, and severity of illness on the probability of detecting SARS-CoV-2 using a mixed-effects binomial model.Results:The probability of detecting SARS-CoV-2 RNA in a patient room did not vary with distance. However, we found that surface type predicted probability of detection, with floors and high-touch surfaces having the highest probability of detection: floors (odds ratio [OR], 67.8; 95% credible interval [CrI], 36.3–131) and high-touch elevated surfaces (OR, 7.39; 95% CrI, 4.31–13.1). Increased surface contamination was observed in room where patients required high-flow oxygen, positive airway pressure, or mechanical ventilation (OR, 1.6; 95% CrI, 1.03–2.53). The probability of elevated surface contamination decayed with prolonged hospitalization, but the probability of floor detection increased with the duration of the local pandemic wave.Conclusions:Distance from a patient’s bed did not predict SARS-CoV-2 RNA deposition in patient rooms, but surface type, severity of illness, and time from local pandemic wave predicted surface deposition.

Background Seasonal fluctuations in antibiotic prescribing for respiratory tract diagnoses (RTDs) have been identified, but characteristics and appropriateness of these variations have not been well described. The objectives of this study were to describe seasonal variations for RTDs and to determine whether seasonal variation in prescribing is associated with inappropriate use. Methods From July 1, 2016 through June 30, 2017, antibiotic prescribing was analyzed for 31 primary care practices comparing winter (October-March) and summer (April-September) months. ICD-10 codes for RTDs were described as tier 1, 2, or 3 based on whether antibiotics are almost always, sometimes, or almost never indicated, respectively. Twenty visits from each of 60 providers were randomly selected and manually reviewed to determine a gold standard of antibiotic appropriateness in order to characterize the appropriateness of these seasonal variations. Associations between season and diagnosis tier, season and appropriateness, and individual provider seasonal changes in antibiotic prescribing and provider characteristics were determined. Results There was a lower proportion of visits with tier 3 diagnoses in winter months (68% v. 74%, p< 0.01), but a greater proportion of tier 2 diagnoses (29% v. 23%, p< 0.01). There were greater proportions of visits in which an antibiotic was prescribed for both tier 2 (80% vs 74%, p< 0.01) and tier 3 diagnoses (23% v. 16%, p< 0.01) in winter months. Using medical record review, inappropriate antibiotics were prescribed more frequently for RTDs in winter compared to summer months (73% v. 64%, p< 0.01). Greater individual provider difference in proportion of RTD visits in which an antibiotic was prescribed from summer to winter was associated with family medicine v. internal medicine specialty (8.2% v. 5.1%, p< 0.01), nonteaching v. teaching practice (8.1% v. 2.9%, p< 0.01), and nonurban v. urban setting (9.1% v. 3.9%, p< 0.01). Conclusion Although there was a greater proportion of tier 2 compared to tier 3 RTDs in winter months, winter months were associated with more inappropriate prescribing than in summer months. More investigation is needed to understand the drivers for seasonal variations in RTDs and inappropriate prescribing. Disclosures Kathleen Degnan, MD, Gilead: Grant/Research Support Michael Z. David, MD PhD, Contrafect: Grant/Research Support|GSK: Advisor/Consultant|Johnson and Johnson: Advisor/Consultant.

Background Methicillin-resistant S. aureus (MRSA) is a common antibiotic-resistant human pathogen that spreads from person to person. Asymptomatic host colonization precedes both skin and soft tissue infections (SSTI) and bloodstream infections (BSI), but it is not known how closely related MRSA strains are that cause infections at different body sites. Methods Using Illumina whole genome sequencing, we compared the strain types and genomes of MRSA isolates from 132 SSTIs and 145 sequential BSIs at 3 Philadelphia hospitals in 7/2018-1/2021. We investigated the epidemiological links and genomic clusters among isolates causing BSI and SSTIs. Results Abscesses were the most common type of SSTIs (65/132, 49%). Clonal complex (CC) 8 was the most identified CC among both SSTI strains (102/132, 77%) and BSI strains (73/145, 50%). While CC5 was more commonly found among BSIs than SSTIs (50/145, 34% vs. 19/132, 13%). Outbreak clusters with 15 or fewer SNPs were identified. Three clusters that contained only strains from SSTIs were all CC8, and the five clusters that only contained strains from BSIs had three CC5 clusters and two CC8 clusters. Among eight clusters that included at least one SSTI and one BSI strain, only one was composed of CC5 and the others were all CC8 strains. Within these eight clusters the SSTIs were from cellulitis infections (4/8), an abscess (3/8), or an infected ulcer (1/8). Conclusion We found that CC8 strains were the most common among both SSTIs and BSIs. CC5 strains, however, were more commonly found in BSIs than SSTIs, and among outbreak clusters in the BSI strains. Eight outbreak clusters were identified that linked strains causing SSTIs or BSIs, seven of the clusters contained only CC8 strains. While abscesses were the most common infection type to cause an SSTI, within the outbreak clusters containing strains from both SSTIs and BSIs, both cellulitis and abscess were equally identified. Disclosures Michael Z. David, MD PhD, Contrafect: Grant/Research Support|GSK: Advisor/Consultant|Johnson and Johnson: Advisor/Consultant.

Background We previously conducted a study in primary care practices assessing the impact of an educational session paired with peer comparison feedback on antibiotic prescribing, demonstrating a reduction in overall prescribing for respiratory tract diseases (RTDs). However, the lasting effects of this intervention on antibiotic prescribing patterns without ongoing feedback are unknown. Methods To study the long-term effects of this feedback on antibiotic prescribing, we analyzed prescribing trends for 14 months after the initial study. We collected encounter-level data, including patient and provider information, ICD-10 codes, and antibiotics prescribed. RTDs were grouped into tiers based on prescribing appropriateness: tier 1 (almost always indicated), tier 2 (may be indicated), and tier 3 (rarely indicated). A χ2 test was used to compare proportions of antibiotic prescribing between three time periods: pre-intervention, intervention, and post-intervention (following cessation of provider feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between the period and antibiotic prescribing. Results We analyzed 260,900 encounters (127,324 pre-intervention, 58,431 during the intervention, and 75,145 post-intervention) from 28 practices, with patient, provider and practice characteristics in Table 1. Rates of antibiotic prescribing for RTD visits were higher in the post-intervention period than the intervention period (28.9% vs 23.0%, p< 0.001), but remained lower than the 35.2% pre-intervention rate (Figure 1, p< 0.001). In multivariable analyses, the odds of receiving a prescription was higher in the post-intervention compared to the intervention period for tier 2 (OR 1.19, 95% CI 1.10–1.30, p< 0.05) and tier 3 (OR 1.20, 95% CI 1.12–1.30) indications, but was still lower when compared to the pre-intervention period for each tier (OR 0.66, 95% CI 0.59–0.73 for tier 2; OR 0.68, 95% CI 0.61–0.75 for tier 3) (Table 2). Table 1 includes patient, provider, and encounter level demographics. Table 2 includes the results of the multivariable analysis. Figure 1 is a graph of proportion of encounters with an antibiotic prescribed over time. The time period associated with the intervention is highlighted and graphs are separated by tier of appropriateness of antibiotic prescribing associated with the encounter. Conclusion The effects of this targeted educational and feedback program last beyond the intervention period, but without ongoing provider feedback there is a trend toward increased prescribing. Future studies are needed to determine optimal strategies to maintain the efficacy of this intervention. Disclosures Kathleen Degnan, MD, Gilead: Grant/Research Support Michael Z. David, MD PhD, Contrafect: Grant/Research Support|GSK: Advisor/Consultant|Johnson and Johnson: Advisor/Consultant.

Background The impact of the US Centers for Medicare & Medicaid Services (CMS) Severe Sepsis and Septic Shock: Management Bundle (SEP-1) core measure on overall antibacterial utilization is unknown. Methods We performed a retrospective multicenter longitudinal cohort study with interrupted time–series analysis to determine the impact of SEP-1 implementation on antibacterial utilization and patient outcomes. All adult patients admitted to 26 hospitals between 1 October 2014 and 30 September 2015 (SEP-1 preparation period) and between 1 November 2015 and 31 October 2016 (SEP-1 implementation period) were evaluated for inclusion. The primary outcome was total antibacterial utilization, measured as days of therapy (DOT) per 1000 patient-days. Results The study cohort included 701 055 eligible patient admissions and 4.2 million patient-days. Overall antibacterial utilization increased 2% each month during SEP-1 preparation (relative rate [RR], 1.02 per month [95% confidence interval {CI}, 1.00–1.04]; P = .02). Cumulatively, the mean monthly DOT per 1000 patient-days increased 24.4% (95% CI, 18.0%–38.8%) over the entire study period (October 2014–October 2016). The rate of sepsis diagnosis/1000 patients increased 2% each month during SEP-1 preparation (RR, 1.02 per month [95% CI, 1.00–1.04]; P = .04). The rate of all-cause mortality rate per 1000 patients decreased during the study period (RR for SEP-1 preparation, 0.95 [95% CI, .92–.98; P = .001]; RR for SEP-1 implementation, .98 [.97–1.00; P = .01]). Cumulatively, the monthly mean all-cause mortality rate/1000 patients declined 38.5% (95% CI, 25.9%–48.0%) over the study period. Conclusions Announcement and implementation of the CMS SEP-1 process measure was associated with increased diagnosis of sepsis and antibacterial utilization and decreased mortality rate among hospitalized patients.

Background Studies have shown that healthcare-associated infections (HAIs) due to methicillin-resistant Staphylococcus aureus (MRSA) can lead to substantial healthcare costs in acute care settings. However, little is known regarding the consequences of these infections on patients in long-term care centers (LTCCs). The purpose of this study was to estimate the attributable cost of MRSA HAIs in LTCCs within the Department of Veterans Affairs (VA). Methods We performed a retrospective cohort study of patients admitted to VA LTCCs between 1 January 2009 and 30 September 2015. MRSA HAIs were defined as a positive clinical culture at least 48 hours after LTCC admission so as to exclude community-acquired infections. Positive cultures were further classified by site (sterile or nonsterile). We used multivariable generalized linear models and 2-part models to compare the LTCC and acute care costs between patients with and without an MRSA HAI. Results In our primary analysis, there was no difference in LTCC costs between patients with and without a MRSA HAI. There was, however, a significant increase in the odds of being transferred to an acute care facility (odds ratio, 4.40 [95% confidence interval {CI}, 3.40–5.67]) and in acute care costs ($9711 [95% CI, $6961–$12 462]). Conclusions Our findings of high cost and increased risk of transfer from LTCC to acute care are important because they highlight the substantial clinical and economic impact of MRSA infections in this population.

Background Staphylococcusaureus skin and soft tissue infections (SA-SSTIs) are common in healthcare and community settings, and recurrences occur at variable frequency, even after successful initial treatment. Knowing the exact burden and timing of recurrent disease is critical to planning and evaluating interventions to prevent recurrent SSTIs. Methods In this retrospective study, SSTI cases in patients aged ≥18 years at 3 US medical centers (Columbia, Chicago, Vanderbilt) between 2006 and 2016 were analyzed according to a biennial cohort design. Index SSTIs (with or without key comorbidities), either microbiologically confirmed to be SA-SSTI or not microbiologically tested (NMT-SSTI), were recorded within 1 calendar year and followed up for 12 months for recurrent infections. The number of index cases, proportion of index cases with ≥1 recurrence(s), time to first recurrence, and number of recurrences were collected for both SA-SSTI and NMT-SSTI events. Results In the most recent cohorts, 4755 SSTI cases were reported at Columbia, 2873 at Chicago, and 6433 at Vanderbilt. Of these, 452, 153, and 354 cases were confirmed to be due to S. aureus. Most cases were reported in patients without key comorbidities. Across centers, 16.4%–19.0% (SA-SSTI) and 11.0%–19.2% (NMT-SSTI) of index cases had ≥1 recurrence(s). In patients without key comorbidities, more than 60% of index SSTIs with recurrences had only 1 recurrence, half of which occurred in the first 3 months following primary infection. Conclusions SA-SSTI recurrences are common among healthy adults and occur in at least 1 in 6 individuals during the 1 year following the primary event., The number of Staphylococcus aureus skin and soft tissue infections patients recorded at 3 US medical centers during 2006–2016 was stable and lacked key comorbidities. Most patients with recurrences had 1 recurrence, half of which occurred in the first 3 months following primary infection.

BACKGROUND The optimal choice of initial antibiotic therapy for patients with high-risk febrile neutropenia (FN) in children is unclear and varies by the institution on the basis of local antibiograms and epidemiology of specific pathogens. The authors evaluated the appropriateness of antibiotics for the empiric treatment of FN in pediatric patients with cancer in our institution on the basis of changes in the epidemiology of organisms isolated from blood cultures (BCx). METHODS The authors conducted a retrospective medical record review of pediatric patients who received any oncology care (including patients with cancer and patients who had stem cell transplant) at University of Chicago Medicine Comer Children's Hospitals (March 2009 to December 2016) with a diagnosis of FN who had at least 1 BCx obtained. They reviewed pathogens isolated from BCx and determined whether they were pathogens or contaminants using the Infectious Diseases Society of America (IDSA) guidelines and the team's decision to treat. They investigated the microbiologic spectrum and susceptibility patterns of pathogens causing bacteremia in pediatric FN and whether the empiric therapy chosen may have affected clinical outcomes. RESULTS A total of 667 FN episodes were identified in 268 patients. BCx were negative in 497 (74.5%) and were determined to be contaminants in 27 (4%). In 143 episodes (21.5%), the BCx were positive for a pathogenic species. Polymicrobial bacteremia was identified in 25 episodes; a total of 176 pathogens were isolated. The majority of pathogens (95/176, 54%) were Gram-positive (GP), whereas 64 of 162 (36%) were Gram-negative (GN), 5 were fungal, and 4 were mycobacterial. The most common GP pathogens were viridans group streptococci (VGS) (n=34, 19.3%), coagulase-negative staphylococci (n=25, 14%), and methicillin-susceptible Staphylococcus aureus (n=12, 6.8%). Of aerobic GN bacilli, 15 (8.5%) were AmpC producers and 3 (1.7%) carried extended-spectrum beta-lactamases. There was no increase in the prevalence of multidrug-resistant GN isolates during the study period. Patients with VGS and multidrug-resistant GN bacteremia were more likely to be admitted to the pediatric intensive care unit [odds ratio (OR), 3.24; P=0.017; and OR, 2.8; P=0.07, respectively]. There were trends toward a higher prevalence of GP pathogens causing bacteremia and the emergence of VGS with decreased penicillin sensitivity. The prevalence of bacteremia with VGS was higher in acute myelogenous leukemia and neuroblastoma (OR, 2.3; P

Infectious Diseases Society of America guidelines defines febrile neutropenia (FN) patients as high risk, if they have an absolute neutrophil count (ANC) ≤100 cells/µL anticipated to last7 days. However, data evaluating the clinical significance of the depth and duration of neutropenia are limited.We conducted a retrospective cohort study of pediatric oncology patients presenting with FN to examine whether the effects of the depth and duration of neutropenia prior to presentation were predictive of blood stream infection (BSI), invasive fungal disease (IFD), pediatric intensive care unit (PICU) admission or length of stay.A total of 585 FN episodes (FNEs) were identified in 265 patients. ANC at the time of presentation was100 in 411 (70%), 100-500 in 119 (20%), and500 cells/μL with subsequent decline to500 cells/μL in the next 48 hours in 55 (10%) of FNEs. In the group with ANC500 with subsequent decline in 48 hours, rates of IFD and BSI were higher when compared with ANC100 cells/μL [odds ratio (OR) = 5.9, 95% confidence interval (CI): 0.7-29.6] and (OR = 2.35, 95% CI: 01.02-5.4), and patients in this group were more likely to be admitted to the PICU (OR= 5.1, 95% CI: 1.134-19.46). No difference in outcomes was identified when the groups of ANC100 and ANC of 100-500 cells/μL were compared. Neutropenia7 days prior to FNE was an independent risk factor for BSI (OR = 2.88, 95% CI: 1.55-5.35 and increased length of stay.Clinicians should not be reassured when patients present with FN and initial ANC500 cells/mL after recent chemotherapy if continued decline is expected as patients in this group are at high risk of IFD, BSI and PICU admission.

Background Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. Methods We evaluated non–intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. Results Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47–.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88–1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. Conclusions An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. Clinical Trials Registration NCT03517007.

BackgroundThough detection of transmission clusters of methicillin-resistant Staphylococcus aureus (MRSA) infections is a priority for infection control personnel in hospitals, the transmission dynamics of MRSA among hospitalized patients with bloodstream infections (BSIs) has not been thoroughly studied. Whole genome sequencing (WGS) of MRSA isolates for surveillance is valuable for detecting outbreaks in hospitals, but the bioinformatic approaches used are diverse and difficult to compare.MethodsWe combined short-read WGS with genotypic, phenotypic, and epidemiological characteristics of 106 MRSA BSI isolates collected for routine microbiological diagnosis from inpatients in two hospitals over 12 months. Clinical data and hospitalization history were abstracted from electronic medical records. We compared three genome sequence alignment strategies to assess similarity in cluster ascertainment. We conducted logistic regression to measure the probability of predicting prior hospital overlap between clustered patient isolates by the genetic distance of their isolates.ResultsWhile the three alignment approaches detected similar results, they showed some variation. A pangenome-based alignment method was most consistent across MRSA clonal complexes. We identified nine unique clusters of closely-related BSI isolates. Most BSI were healthcare-associated and community-onset. Our logistic model showed that with 13 single nucleotide polymorphisms the likelihood that any two patients in a cluster overlapped in a hospital was 50 percent.ConclusionsMultiple clusters of closely related MRSA isolates can be identified using WGS among strains cultured from BSI in two hospitals. Genomic clustering of these infections suggest that transmission resulted from a mix of community spread and healthcare exposures long before BSI diagnosis.SummaryMultiple clusters of closely related MRSA bloodstream infections were identified using WGS in two hospitals using three bioinformatic workflows. Genomic epidemiology suggests that transmission resulted from a mix of community spread and healthcare exposures long before symptom onset.

Most studies of children with prolonged fever and neutropenia (PFN) have focused on invasive fungal disease (IFD) as the etiology of fever and not on other causes. Data are lacking regarding risk factors and adverse outcomes in pediatric cancer patients with PFN compared with those whose fevers resolve more rapidly. Retrospective medical record review was performed for all cancer patients with febrile neutropenia (FN) in the pediatric oncology unit at University of Chicago Medicine Comer Children’s Hospital from March 2009 to July 2016. Resolving febrile neutropenia (RFN), lasting less than 96 hours, and PFN episodes (≥ 96 hours) were compared to identify risk factors and outcomes associated with PFN. A total of 572 FN episodes were identified in 265 patients. PFN occurred in 119 (21%) FN episodes (50 patients) and RFN occurred in 453 (79%) FN episodes (215 patients). In multivariable analysis, autologous stem cell transplant (odds ratio [OR] 6.5, P 39°C at the time of presentation (OR 2.4, P

Background:Multidrug-resistant organisms (MDROs) colonizing the healthcare environment have been shown to contribute to risk for healthcare-associated infections (HAIs), with adverse effects on patient morbidity and mortality. We sought to determine how bacterial contamination and persistent MDRO colonization of the healthcare environment are related to the position of patients and wastewater sites.Methods:We performed a prospective cohort study, enrolling 51 hospital rooms at the time of admitting a patient with an eligible MDRO in the prior 30 days. We performed systematic sampling and MDRO culture of rooms, as well as 16S rRNA sequencing to define the environmental microbiome in a subset of samples.Results:The probability of detecting resistant gram-negative organisms, including Enterobacterales, Acinetobacter spp, and Pseudomonas spp, increased with distance from the patient. In contrast, Clostridioides difficile and methicillin-resistant Staphylococcus aureus were more likely to be detected close to the patient. Resistant Pseudomonas spp and S. aureus were enriched in these hot spots despite broad deposition of 16S rRNA gene sequences assigned to the same genera, suggesting modifiable factors that permit the persistence of these MDROs.Conclusions:MDRO hot spots can be defined by distance from the patient and from wastewater reservoirs. Evaluating how MDROs are enriched relative to bacterial DNA deposition helps to identify healthcare micro-environments and suggests how targeted environmental cleaning or design approaches could prevent MDRO persistence and reduce infection risk.

Staphylococci producing exfoliative toxins are the causative agents of staphylococcal scalded skin syndrome (SSSS). Exfoliative toxin A (ETA) is encoded by eta, which is harbored on a temperate bacteriophage ΦETA. A recent increase in the incidence of SSSS in North America has been observed; yet it is largely unknown whether this is the result of host range expansion of ΦETA or migration and emergence of established lineages. Here, we detail an outbreak investigation of SSSS in a neonatal intensive care unit, for which we applied whole-genome sequencing (WGS) and phylogenetic analysis of Staphylococcus aureus isolates collected from cases and screening of healthcare workers. We identified the causative strain as a methicillin-susceptible S. aureus (MSSA) sequence type 582 (ST582) possessing ΦETA. To then elucidate the global distribution of ΦETA among staphylococci, we used a recently developed tool to query extant bacterial WGS data for biosamples containing eta, which yielded 436 genomes collected between 1994 and 2019 from 32 countries. Applying population genomic analysis, we resolved the global distribution of S. aureus with lysogenized ΦETA and assessed antibiotic resistance determinants as well as the diversity of ΦETA. The population is highly structured with eight dominant sequence clusters (SCs) that generally aligned with S. aureus ST clonal complexes. The most prevalent STs included ST109 (24.3%), ST15 (13.1%), ST121 (10.1%), and ST582 (7.1%). Among strains with available data, there was an even distribution of isolates from carriage and disease. Only the SC containing ST121 had significantly more isolates collected from disease (69%, n = 46) than carriage (31%, n = 21). Further, we identified 10.6% (46/436) of strains as methicillin-resistant S. aureus (MRSA) based on the presence of mecA and the SCCmec element. Assessment of ΦETA diversity based on nucleotide identity revealed 27 phylogroups, and prophage gene content further resolved 62 clusters. ΦETA was relatively stable within lineages, yet prophage variation is geographically structured. This suggests that the reported increase in incidence is associated with migration and expansion of existing lineages, not the movement of ΦETA to new genomic backgrounds. This revised global view reveals that ΦETA is diverse and is widely distributed on multiple genomic backgrounds whose distribution varies geographically.

Background Inappropriate antibiotic prescribing is common in primary care (PC), particularly for respiratory tract diagnoses (RTDs). However, the optimal approach for improving prescribing remains unknown. Methods We conducted a stepped-wedge study in PC practices within a health system to assess the impact of a provider-targeted intervention on antibiotic prescribing for RTDs. RTDs were grouped into tiers based on appropriateness of antibiotic prescribing: tier 1 (almost always indicated), tier 2 (may be indicated), and tier 3 (rarely indicated). Providers received education on appropriate RTD prescribing followed by monthly peer comparison feedback on antibiotic prescribing for (1) all tiers and (2) tier 3 RTDs. A χ 2 test was used to compare the proportion of visits with antibiotic prescriptions before and during the intervention. Mixed-effects multivariable logistic regression analysis was performed to assess the association between the intervention and antibiotic prescribing. Results Across 30 PC practices and 185 755 total visits, overall antibiotic prescribing was reduced with the intervention, from 35.2% to 23.0% of visits (P Conclusions A provider-focused intervention reduced overall antibiotic prescribing for RTDs without affecting prescribing for infections that likely require antibiotics. Future research should examine the sustainability of such interventions, potential unintended adverse effects on patient health or satisfaction, and provider perceptions and acceptability.

Objective:To determine metrics and provider characteristics associated with inappropriate antibiotic prescribing for respiratory tract diagnoses (RTDs).Design:Retrospective cohort study.Setting:Primary care practices in a university health system.Participants:Patients seen by an attending physician or advanced practice provider (APP) at their primary care office visit with International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM)–coded RTDs.Methods:Medical records were reviewed for 1,200 randomly selected office visits in which an antibiotic was prescribed to determine appropriateness. Based on this gold standard, metrics and provider characteristics associated with inappropriate antibiotic prescribing were determined.Results:Overall, 69% of antibiotics were inappropriate. Metrics utilizing prespecified RTDs most strongly associated with inappropriate prescribing were (1) proportion prescribing for RTDs for which antibiotics are almost never required (eg, bronchitis) and (2) proportion prescribing for any RTD. Provider characteristics associated with inappropriate antibiotic prescribing were APP versus physician (72% vs 58%; P = .02), family medicine versus internal medicine (76% vs 63%; P = .01), board certification 1997 or later versus board certification before 1997 (75% vs 63%; P = .02), nonteaching versus teaching practice (73% vs 51%; P < .01), and nonurban vs urban practice (77% vs 57%; P < .01).Conclusions:Metrics utilizing proportion prescribing for RTDs for which antibiotics are almost never required and proportion prescribing for any RTD were most strongly associated with inappropriate prescribing. APPs and clinicians with family medicine training, with board certification 1997 or later, and who worked in nonteaching or nonurban practices had higher proportions of inappropriate prescribing. These findings could inform design of interventions to improve prescribing and could represent an efficient way to track inappropriate prescribing.

Here, we announce the complete genome sequence of an exfoliative toxin-producing strain of Staphylococcus aureus sequence type 582 (ST582), isolated from a case of staphylococcal scalded-skin syndrome. The genome consists of a single circularized unitig with a total length of 2,792,190 bp carrying 2,699 genes. The genome is the basis for future epidemiological and genomic studies.

The diagnosis of a skin and soft tissue infection (SSTI) requires careful attention to a patient's history, physical examination, and diagnostic test results. We review for many bacterial, viral, fungal, and parasitic pathogens that cause SSTIs the clues for reaching a diagnosis, including reported past medical history, hobbies and behaviors, travel, insect bites, exposure to other people and to animals, environmental exposures to water, soil, or sand, as well as the anatomic site of skin lesions, their morphology on examination, and their evolution over time. Laboratory and radiographic tests are discussed that may be used to confirm a specific diagnosis.

Background: Early administration of antibiotics in sepsis is associated with improved patient outcomes, but safe and generalizable approaches to de-escalate or discontinue antibiotics after suspected sepsis events are unknown. Methods: We used a modified Delphi approach to identify safety criteria for an opt-out protocol to guide de-escalation or discontinuation of antibiotic therapy after 72 hours in non-ICU patients with suspected sepsis. An expert panel with expertise in antimicrobial stewardship and hospital epidemiology rated 48 unique criteria across 3 electronic survey rating tools. Criteria were rated primarily based on their impact on patient safety and feasibility for extraction from electronic health record review. The 48 unique criteria were rated by anonymous electronic survey tools, and the results were fed back to the expert panel participants. Consensus was achieved to either retain or remove each criterion. Results: After 3 rounds, 22 unique criteria remained as part of the opt-out safety checklist. These criteria included high-risk comorbidities, signs of severe illness, lack of cultures during sepsis work-up or antibiotic use prior to blood cultures, or ongoing signs and symptoms of infection. Conclusions: The modified Delphi approach is a useful method to achieve expert-level consensus in the absence of evidence suifficient to provide validated guidance. The Delphi approach allowed for flexibility in development of an opt-out trial protocol for sepsis antibiotic de-escalation. The utility of this protocol should be evaluated in a randomized controlled trial.

Background Candida endocarditis is a rare, sometimes fatal complication of candidemia. Past investigations of this condition are limited by small sample sizes. We used the Vizient clinical database to report on characteristics of patients with Candida endocarditis and to examine risk factors for in-hospital mortality. Methods This was a multicenter, retrospective cohort study of 703 inpatients admitted to 179 US hospitals between October 2015 and April 2019. We reviewed demographic, diagnostic, medication administration, and procedural data from each patient’s initial encounter. Univariate and multivariate logistic regression analyses were used to identify predictors of in-hospital mortality. Results Of 703 patients, 114 (16.2%) died during the index encounter. One hundred fifty-eight (22.5%) underwent an intervention on a cardiac valve. On multivariate analysis, acute and subacute liver failure was the strongest predictor of death (odds ratio [OR], 9.2; 95% confidence interval [CI], 4.8 –17.7). Female sex (OR, 1.9; 95% CI, 1.2–3.0), transfer from an outside medical facility (OR, 1.8; 95% CI, 1.1–2.8), aortic valve pathology (OR, 2.7; 95% CI, 1.5–4.9), hemodialysis (OR, 2.1; 95% CI, 1.1–4.0), cerebrovascular disease (OR, 2.2; 95% CI, 1.2–3.8), neutropenia (OR, 2.5; 95% CI, 1.3–4.8), and alcohol abuse (OR, 2.9; 95% CI, 1.3–6.7) were also associated with death on adjusted analysis, whereas opiate abuse was associated with a lower odds of death (OR, 0.5; 95% CI, 0.2–0.9). Conclusions We found that the inpatient mortality rate was 16.2% among patients with Candida endocarditis. Acute and subacute liver failure was associated with a high risk of death, whereas opiate abuse was associated with a lower risk of death., Among 703 patients with Candida endocarditis admitted to 179 medical centers, in-hospital mortality was 16.2%. Acute and subacute liver failure was the strongest predictor of in-hospital mortality in this cohort.

BACKGROUND The approach to recurrent febrile neutropenia (FN) in children with cancer has not been sufficiently addressed and was cited as a research gap in the International Pediatric Fever and Neutropenia (IPFNP) Guideline 2017. METHODS Retrospective medical record review for all pediatric cancer patients with a diagnosis of FN was performed. Variables were collected at 2 different time sets (at day 1 and day 4 of presentation). Three FN syndromes have been defined based on the duration and time course of the fever: (1) primary: fever resolved before 96 hours and did not follow with recurrent fever; (2) prolonged fever: episodes failing to defervesce after at least 96 hours of antibacterial therapy; (3) recurrent fever: a new episode of fever >72 hours after resolution of the initial fever when a patient remained neutropenic and on antibiotics or if a fever developed within 1 week after antibiotic discontinuation. These entities were compared with define risk factors and adverse outcomes associated with recurrent fever. RESULTS A total of 633 FN episodes (FNEs) were identified in 268 patients. Each FNE was classified as primary (n=453, 71.5%), prolonged (n=119, 18.7%), or recurrent (n=61, 9.7%). In multivariable analysis, acute myelogenous leukemia (odds ratio [OR]=4.6, 95% confidence interval [CI]: 2.95-7.24), allogeneic stem cell transplant (SCT) (OR=4.9, 95% CI: 2.61-7.35), absolute lymphocyte count

Background The incidence of skin and soft-tissue infections (SSTIs), for which human immunodeficiency virus (HIV) is a significant risk factor, in United States emergency departments (EDs) increased dramatically after 2000 with the emergence of community-associated methicillin-resistant Staphylococcus aureus. Few studies have examined SSTI incidence among HIV-infected and non–HIV-infected patients in the United States after 2010. Methods Data were obtained for patient encounters at all academic medical center EDs affiliated with the Vizient clinical data warehouse assigned an SSTI-associated code based on the International Classification of Diseases, Ninth Revision, between 1 January 2009 and 31 December 2014. The rate was calculated per 1000 ED encounters by year and stratified by SSTI, HIV infection, or both, and by age group, race, payer type, and region of care. Poisson regression was used to assess temporal change over the study period. Results In 2009–2014, a total of 47317 HIV-associated and 820440 SSTI-associated encounters were recorded among 25239781 ED patient encounters. The rate of SSTIs decreased by 8% among all patients and by 14.6%, among those with HIV infection. The SSTI incidence overall decreased from 32.0 to 29.7 per 1000 ED encounters between 2009 and 2014. HIV-infected patients had a significantly higher rate of SSTIs than HIV-uninfected patients (adjusted rate ratio, 1.91; 95% confidence interval, 1.84–1.99). Conclusions The decline in SSTI incidence in US EDs between 2009 and 2014 is a remarkable epidemiologic shift from the increase in SSTIs after 2000, and further research is necessary to assess reasons for this decrease.

Background There are limited data regarding SARS-CoV-2 (SC2) environmental contamination in staff areas of healthcare settings. We performed environmental sampling of staff areas in wards where coronavirus disease 19 (COVID-19) patients received care and compared findings to surfaces within COVID-19 patient rooms. Methods The study was conducted at the Hospital of the University of Pennsylvania (Philadelphia, PA) from 9/15/20-1/26/21. Sampling of 20cm2 surfaces in staff common areas (breakroom high-touch surfaces comprising tables and microwave/refrigerator handles; bathroom surfaces comprising toilet, sink, and doorknob; and floors), nurse workstations (computer mice and floors), and COVID-19 patient rooms (high-touch surfaces comprising bedrail, computer mice/keyboards, and doorknobs; bathroom surfaces; and floors) was performed using flocked swabs one or more times per week. Specimens underwent RNA extraction and quantitative real-time polymerase chain reaction to detect the SC2 N1 region. Median comparisons were performed using Wilcoxon rank sum test. Trends in odds were evaluated using Score test. Results Proportions of surface specimens with detectable SC2 RNA are summarized in Table 1. Median copy numbers were lower among staff toilets compared to COVID-19 patient toilets (135.6 vs. 503.8 copies/specimen, p=0.02), lower among staff breakroom compared to patient room high-touch surfaces (104.3 vs. 220.3 copies/specimen, p=0.007), and similar between staff and patient room samples from sinks and floors. At nurse workstations, SC2 RNA was detected among 22/177 (12.4%) computer mouse and 147/178 (82.6%) floor samples. Odds of SC2 detection increased by study week among common area (p< 0.001) and nurse workstation samples (p< 0.001) (Figures 1 and 2). Table 1. SARS-CoV-2 (SC2) RNA detection on staff common area and coronavirus disease 19 (COVID-19) patient room surfaces at the Hospital of the University of Pennsylvania, 9/15/20-1/26/21. Figure 1. Proportion of environmental surface specimens with detectable SARS-CoV-2 RNA from a) staff common areas and b) nurse workstations of inpatient wards where coronavirus disease-19 patients received care at the Hospital of the University of Pennsylvania, 9/15/20-1/26/21. Figure 2. Proportion of environmental surface specimens with detectable SARS-CoV-2 RNA in staff common areas of inpatient wards where coronavirus disease-19 patients received care at the Hospital of the University of Pennsylvania, 9/15/20-1/26/21, by surface type: a) staff breakroom surfaces, b) staff bathroom surfaces, c) staff common area floors. Conclusion A low prevalence of detectable SC2 RNA was observed among staff area high-touch surfaces; however, the likelihood of detection increased over time. Environmental SC2 RNA detection may reflect primary contamination from infected healthcare workers or secondary contamination from contact with infected patients, though a direct relationship between surface SC2 RNA viral detection and transmission risk has not been established. Disclosures Michael Z. David, MD PhD, GSK (Board Member) Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))

OBJECTIVETo examine trends in Staphylococcus aureus infections in adults and children at a single academic center in 2006–2014.DESIGNRetrospective cohort study.SETTINGInpatient, outpatient, and emergency department settings in a private, tertiary referral center.PATIENTSPatients with an infection culture that grew S. aureus in January 1, 2006, through March 31, 2014.METHODSThe first isolate per year for each patient was classified as community-associated (CA-), healthcare-associated (HA-), or HA-community–onset S. aureus. The incidence density of S. aureus, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA) infections were calculated per quarter year.RESULTSOverall, 5,491 MRSA and 5,398 MSSA isolates were included. MRSA infections decreased by an average of 5.2% annually (PPP=.004). MSSA infections at all anatomic sites increased by an average of 1.9% annually (P=.007) in adults and decreased 5.1% annually (PPPCONCLUSIONSIn 2006–2014, MRSA SSTI incidence decreased among children and adults. MSSA SSTI incidence density increased in children and adults, suggesting that current empiric SSTI treatment recommendations may not be optimal. Adults experienced an overall increase in MSSA infections, which may prompt consideration of the need for horizontal infection control practices to decrease MSSA infection risk.Infect Control Hosp Epidemiol 2017;38:1226–1234

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major public health problem. Vancomycin and teicoplanin have been in clinical use for several decades but their drawbacks are well described. In the last 10 years, several antibiotics have been made available for clinical use. Daptomycin and linezolid have been extensively used during this period. Other agents such as ceftaroline, ceftobiprole, dalbavancin, oritavancin, tedizolid and telavancin have been approved by regulatory agencies since 2009. Many others, such as the newer tetracyclines, fluoroquinolones, oxazolidinones and pleuromutilins, are in various stages of development. In addition, an ongoing multicentre trial is investigating the role of combination of vancomycin or daptomycin with β-lactam antibiotics. This review discusses the role of the newer antibiotics, reflecting the views of the 6th MRSA Consensus Conference meeting of the International Society of Chemotherapy MRSA Working Group that took place in 2016.

Background MRSA BSIs have 15-50% mortality and are commonly diagnosed in US hospitals. However, the frequency of hospital transmission of MRSA causing BSI is unknown. Methods We performed Illumina shotgun whole genome sequencing (WGS) of 106 sequential MRSA isolates from different adults with a BSI at two Philadelphia academic hospitals in a single health system in July 2018-June 2019. We abstracted clinical data from the electronic medical record. Genomic data were analyzed preliminarily using the Staphopia Analysis Pipeline. Results Among 106 subjects, 51.9% were male, 47.2% were white, 46.2% were black, 23.6% were < 40 years of age, and mean age was 53.1 years (s.d. 17 years). One isolate had WGS data that were inadequate for analysis. Of 105 genomes, 52 were clonal cluster (CC) 8, 22 were sequence type (ST) 5, and 16 were ST105; the remaining 15 strains belonged to 8 other CCs. Of CC8 strains, 44 were USA300 and 6 were USA500. There were 6 clusters (i.e., < 35 SNP differences in the core genome) among the 105 isolates. Four clusters were CC5 and two were CC8 strains. One cluster of CC5 strains involved 3 subjects, and 5 clusters involved 2 subjects. One cluster of ST8/USA300 strains were separated by only 1 SNP (Fig a). This and two other clustered pairs were from subjects who had overlapping hospital stays. Two of these paired subjects had an overlap in the same unit while the third pair was in the hospital together on a number of occasions (total of 40 days overlap) but never simultaneously in the same unit. The other three clustered pairs did not have temporally overlapping hospital stays, suggesting transmission via a hospital reservoir. One of these three pairs had hospitalizations overlapping in time, one at each study hospital, before each of them had infections with the related MRSA strains. There was not a clear-cut clustering of SNP distances among the isolate genomes into transmission and non-transmission groups, with some pairs of patient isolates separated by 40-80 SNPs (Fig. b). Figure 1. Conclusion We were able to discern from WGS data alone that some MRSA BSIs in 2 hospitals were likely due to strains transmitted between patients. Universal WGS of BSI strains may detect MRSA outbreaks in real time, even in the absence of overlapping hospitalizations, and is an emerging strategy to detect healthcare transmission of MRSA. Disclosures Michael Z. David, MD PhD, GSK (Consultant)

Background Identifying risk factors for environmental contamination with multidrug-resistant organisms (MDROs) is essential to prioritize methods for prevention of hospital transmission. Methods Patients admitted to an ICU with an MDRO detected on clinical culture in the prior 30 days were enrolled. Patients (4 body sites) and high-touch objects (HTO) (3 composite sites) in ICU rooms were sampled. Environmental transmission was defined by shared MDRO species cultured on patient and HTO cultures obtained on multiple time points during the patient’s stay. Risk factors for environmental transmission were identified with logistic regression. Results Forty-five patients were included (median 2 days of longitudinal sampling [IQR 1–4 days]). Enrollment anatomic cultures included extended-spectrum beta-lactamase-producing Enterobacterales (ESBLE) (n=12, 27%), carbapenem-resistant organisms (CRO) (n=4, 9%), methicillin-resistant S.aureus (MRSA) (n=11, 24%), vancomycin-resistant Enterococci (VRE) (n=4, 9%), and C.difficile (CDIFF) (n=14, 31%). Patient colonization during serial sampling was common with CRO (n=21, 47%), ESBLE (n=16, 36%), and VRE (n=16, 36%) and less so with MRSA (n=7, 16%) and CDIFF (n=5, 11%). Detection of MDROs on environmental surfaces was also common with identification of CRO in 47% of patient rooms (n=21) and ESBLE in 29% (n=13); MRSA (n=2, 4%), VRE (n=9, 20%), and CDIFF (n=3, 7%) were rarer. Patient to environment transmission was observed in 40% of rooms (n=18). Thirteen (29%) rooms had foreign MDRO contamination (i.e., one not detected on a body culture), most (n=10) with CRO. Environmental MDROs were most common in bathroom/sinks (n=22), followed by surfaces near the patient (n=10), and least common surfaces often touched by staff within the room (n=6). On multivariable logistic regression, naïve to clustering by patient, recent receipt of a proton pump inhibitor (OR 2.35, 95% CI 1.00 – 5.52, P=0.049) and presence of one or more wounds (OR 2.56, 95% CI 1.05 – 6.26, P=0.038) were significantly associated with environmental transmission (OR 1.56, 95% CI 1.01 – 2.43, P=0.046) (Table 1). Conclusion MDRO contamination of patient rooms is common with detection of organisms attributed to, and foreign to, the occupant. Disclosures Michael Z. David, MD PhD, GSK (Consultant)

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

Staphylococcus aureus is the most commonly identified airway colonizer of cystic fibrosis (CF) patients, and infections with methicillin-resistant S. aureus (MRSA) are associated with poor outcomes. Yet, little is known about the intrahost evolution of S. aureus among CF patients. We investigated convergent evolution and adaptation of MRSA among four CF patients with long-term respiratory carriage. For each patient, we performed whole-genome sequencing on an average of 21 isolates (range: 19-23) carried for a mean of 1,403 days (range: 903-1,679), including 25 pairs of isolates collected on the same day. We then assessed intrahost diversity, population structure, evolutionary history, and signatures of adaptation in the context of patient age, antibiotic treatment, and co-colonizing microbes. We conducted tests of gene-wide diversifying selection and identified instances of switched intergenic regions (IGRs), which may be associated with gene expression. Phylogenetic analysis delineated distinct multilocus sequence type ST5 (n=3) and ST72 (n=1) clonal populations in addition to sporadic, non-clonal isolates, and uncovered a putative transmission event. Variation in antibiotic resistance was observed within clonal populations, even among isolates collected on the same day. Coalescent analysis revealed rates of molecular evolution ranging from 2.21 to 8.64 nucleotide polymorphisms per genome per year. Estimated lineage ages were consistent with acquisition of colonization in early childhood and subsequent persistence of multiple sub-populations. Selection analysis focused on 1,622 core genes shared by all four clonal populations (n=79). Eleven genes were variable in three subjects - most notable, ATP-dependent protease clpX, 2-oxoglutarate dehydrogenase odhA, fmtC, and transcription-repair coupling factor mfd. Only one gene, staphylococcal protein A (spa), was found to have evidence of gene-wide diversifying selection. We identified three instances of intrahost IGR switching events, two of which flanked genes related to quorum sensing. The ecology of microbes in the airways of CF patients is undeniably complex, posing challenges for management. We illustrate appreciable intrahost diversity as well as persistence of a dominant lineage. We also show that intrahost adaptation is a continual process, despite purifying selective pressure, and provide targets that should be investigated further for their function in CF adaptation.Contribution to the FieldStaphylococcus aureus is the most commonly identified airway colonizer of cystic fibrosis (CF) patients, and infections with methicillin-resistant S. aureus (MRSA) are associated with poor outcomes. Yet, little is known about the intrahost evolution of S. aureus among CF patients. We investigated convergent evolution and adaptation of MRSA among four CF patients with long-term respiratory carriage. We found that each patient possessed a single predominant strain in addition to transient non-clonal isolates. Considerable genomic diversity was observed among intrahost populations including variation in antibiotic resistance, even among isolates collected on the same day. This finding has implications for treatment. Estimated lineage ages were consistent with acquisition of colonization in early childhood and subsequent persistence of multiple sub-populations. The scarcity of non-synonymous substitutions suggests chronic S. aureus carriage in CF patients provides a sufficient opportunity for purifying selection to act. Eleven genes were found to be variable in three patients and present possible candidates for loci experiencing gene-wide diversifying selection. Overall, we show that intrahost adaptation is a continual process, despite purifying selective pressure, and provide targets that should be investigated further for their function in CF adaptation.

The Morbidity and Mortality Weekly Reports of the U.S. Centers for Disease Control and Prevention document a raw proxy for counts of pertussis cases in the U.S., and the Project Tycho (PT) database provides an improved source of these weekly data. These data are limited because of reporting delays, variation in state-level surveillance practices, and changes over time in diagnosis methods. We aim to assess whether Google Trends (GT) search data track pertussis incidence relative to PT data and if sociodemographic characteristics explain some variation in the accuracy of state-level models. GT and PT data were used to construct auto-correlation corrected linear models for pertussis incidence in 2004–2011 for the entire U.S. and each individual state. The national model resulted in a moderate correlation (adjusted R2 = 0.2369, p

SUMMARYSkin and soft tissue infection (SSTIs) due to Staphylococcus aureus, particularly community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), are common in human immunodeficiency virus (HIV)-infected populations in the United States. Studies have differed as to the importance of epidemiological and immunological factors in this relationship, and have employed conflicting strategies for variable selection in multivariate analyses. Developments in causal inference methods in epidemiology have emerged in the last decade to clarify relationships between variables and identify appropriate variables to include in and exclude from multivariate analysis. In this paper, we develop a causal diagram to clarify the pathways linking CA-MRSA and HIV. We focus on the role played by trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, prescribed to many severely immunocompromised HIV patients and potentially protective against SSTIs, which both mediates and moderates the relationship between immunological parameters and SSTI risk. We demonstrate, using simulated data, that statistical models may yield biased results if they do not account for how HIV viral load may also be a marker of adherence to TMP-SMX prophylaxis. We conclude with a proposed causal model that includes both the epidemiological as well as immunological factors that may explain the increased risk of initial and recurrent SSTI risk in HIV-infected populations.

Background Candida endocarditis is a rare, sometimes fatal complication candidemia. Our understanding of this condition is limited to findings from case series and small observational studies. Using the Vizient clinical database, a repository for clinical and administrative data from 117 academic medical centers and more than 300 affiliated hospitals, we assembled the largest cohort of Candida endocarditis patients to date, reporting patient characteristics and risk factors for death. Methods Using ICD-10 code B37.6 (Candidal Endocarditis) we identified 703 inpatients at 179 United States hospitals from October 2015 through April 2019. We examined demographic, diagnostic, and procedural data from each patient’s initial encounter. With univariate and multivariate logistic regression analyses we identified predictors of in-hospital mortality. Results Of 703 patients, 402 (57.2%) were male, 421 (59.9%) used tobacco, 213 (30.3%) had documented opiate abuse, 128 (18.2%) had other illicit drug abuse documented, and 190 (27.0%) had documented hepatitis C infection. Among the 703 patients, 114 (16.2%) died during the index encounter. On multivariate analysis, liver failure was the strongest predictor of death (OR 8.4, 95% CI 4.4 – 15.9), and female sex (OR 1.8, 95% CI 1.1 – 2.9), transfer from an outside facility (OR 1.7, 95% CI 1.1 – 2.7), underlying aortic valve pathology (OR 2.8, 95% CI 1.5 – 4.9), hemodialysis (OR 2.0, 95% CI 1.0 – 3.8), cerebrovascular disease (OR 2.2, 95% CI 1.2 – 3.8), neutropenia (OR 2.5, 95% CI 1.3 – 4.7) and alcohol abuse (OR 2.9, 95% CI 1.3 – 6.7) were also associated with higher odds of in-hospital death. In the same analysis, opiate abuse was associated with a lower odds of in-hospital death (OR 0.4, 95% CI 0.2 – 0.8). Table 1. Characteristics of 703 patients with Candida endocarditis Table 2. Factors associated with in-hospital death in multivariate regression analysis Conclusion We found that for patients Candida endocarditis inpatient mortality was 16.2% and liver failure was associated with a high risk of death while opiate abuse was protective. Further investigation is necessary to better understand these associations. Disclosures Michael Z. David, MD PhD, GSK (Consultant)

Background USA300 methicillin-resistant Staphylococcus aureus (MRSA) is a community- and hospital-acquired pathogen that frequently causes infections but also can survive on the human body asymptomatically as a part of the normal microbiota. We devised a comparative genomic strategy to track colonizing USA300 at different body sites after an initial infection. We sampled ST8 S. aureus from subjects at the site of a first known MRSA infection. Within 60 days of this infection and again 12 months later, each subject was tested for asymptomatic colonization in the nose, throat and perirectal region. 93 S. aureus strains underwent whole genome shotgun sequencing. Results Among 28 subjects at the initial sampling time, we isolated S. aureus from the nose, throat and perirectal sites from 15, 11 and 15 of them, respectively. Twelve months later we isolated S. aureus from 9 subjects, with 6, 3 and 3 strains from the nose, throat and perirectal area, respectively. Genome sequencing revealed that 23 patients (ages 0–66 years) carried USA300 intra-subject lineages (ISLs), defined as having an index infection isolate and closely related colonizing strains. Pairwise distance between strains in different ISLs was 48 to 162 single nucleotide polymorphisms (SNPs) across the core regions of the chromosome, whereas within the same ISL it was 0 to 26 SNPs. Strains in ISLs from the same subject differed in plasmid and prophage content, and contained deletions that removed the mecA-containing SCCmec and ACME regions. Five strains contained frameshift mutations in agr toxin-regulating genes. Persistence of an ISL was not associated with clinical or demographic subject characteristics. We inferred that colonization with the ISL occurred about 18 weeks before the first assessment of asymptomatic colonization. Conclusions Clonal lineages of USA300 may continue to colonize people at one or more anatomic sites up to a year after an initial infection and experience loss of the SCCmec, loss and gain of other mobile genetic elements, and mutations in the agr operon. Electronic supplementary material The online version of this article (10.1186/s12866-018-1336-z) contains supplementary material, which is available to authorized users.

Background: Although the relevance of humoral immunity for protection against S. aureus skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti-S. aureus antibodies due to S. aureus colonization or infection, we hypothesized that the titers of antibodies to S. aureus in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum. Methods: To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the S. aureus surfome and secretome in subjects with active culture-confirmed S. aureus SSTIs (cases) and in controls with no infection, using a novel S. aureus protein microarray. Results: Most S. aureus SSTI patients (n = 60) and controls (n = 142) had antibodies to many of the tested S. aureus antigens. Univariate analysis showed statistically weak differences in the IgG levels to some antigens in the SSTI patient (case) sera compared with controls. Antibody levels to most tested antigens did not increase comparing acute with 40-day serum. Multiple logistic regression identified a rich subset of antigens that, by their antibody levels, together correctly differentiated all cases from all controls. Conclusions: Antibodies directed against S. aureus antigens were present both in patients with S. aureus SSTIs and in uninfected control patients. We found that SSTI patients and controls could be distinguished only based on differences in antibody levels to many staphylococcal surface and secreted antigens. Our results demonstrate that in the studied population, the levels of anti-S. aureus antibodies appear largely fixed, suggesting that there may be some level of unresponsiveness to natural infection.

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Immunosuppressive medical conditions are risk factors for mortality from severe infections. It is unknown whether hospital characteristics affect this risk.To determine whether the odds of death for an immunosuppressed patient with sepsis relative to a nonimmunosuppressed patient with sepsis varies according to the hospital's yearly case volume of immunosuppressed patients with sepsis.Patients with sepsis at hospitals in the Vizient database were characterized as immunosuppressed or not immunosuppressed on the basis of diagnosis codes and medication use. Hospitals were grouped into quartiles based on their average volumes of immunosuppressed patients with sepsis per year. Multilevel logistic regression with clustering of patients by hospital was used to determine whether the odds of in-hospital death from sepsis owing to a suppressed immune state varied by hospital quartile.There were 350,183 patients with sepsis at 60 hospitals in the Vizient database from 2010 to 2012. Immunosuppressed patients with sepsis at the 15 hospitals in the lowest quartile (64 to 224 immunosuppressed patients with sepsis per year) had an increased odds of in-hospital death relative to nonimmunosuppressed patients with sepsis at these hospitals (adjusted odds ratio, 1.38; 95% confidence interval, 1.27-1.50; P 0.001). The odds of in-hospital death for immunosuppressed patients with sepsis relative to nonimmunosuppressed patients with sepsis was similar for patients at hospitals in the second, third, and fourth quartiles (225 to 1,056 immunosuppressed patients with sepsis per year). The adjusted odds of death from sepsis owing to a suppressed immune state of 1.21 (95% confidence interval, 1.18-1.25; P 0.001) for patients at these 45 hospitals was significantly less than for patients at the 15 hospitals in the lowest quartile (P = 0.004 for difference).The risk of death from sepsis owing to a suppressed immune state was greatest at hospitals with the lowest volume of immunosuppressed patients with sepsis. Further study is needed to determine whether this finding is related to differences in patient characteristics or in care delivery at hospitals with different amounts of exposure to immunosuppressed patients.

Background The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. Methods Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. Results Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17–3.17, p = 0.01; and HR 1.13, 95% CI 1.01–1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69–11.5, p

Objective Despite the rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) otologic infections, choice of treatment remains controversial. Only fluoroquinolone-containing ototopical preparations are approved by the US Food and Drug Administration for middle ear application. Furthermore, American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines advocate ototopical monotherapy for both tympanostomy tube otorrhea and acute otitis externa. Unfortunately, MRSA may be ciprofloxacin resistant. This causes confusion regarding antibiotic selection, because susceptibility profiles reflect a minimum inhibitory concentration (MIC), referenced against systemic, not ototopical, drug delivery dosing. The goal of this study is to determine the ciprofloxacin MIC for ciprofloxacin-resistant MRSA isolates from otologic infections and compare that value to the expected drug concentration achieved by fluoroquinolone ear drops and determine MRSA genotype for each isolate. Study Design In vitro assay with retrospective medical record review. Setting Tertiary care university hospital. Subjects and Methods Thirty otologically sourced ciprofloxacin-resistant MRSA isolates collected from adult and pediatric patients. MICs were calculated by broth dilution method. Isolates underwent multilocus sequence typing and polymerase chain reaction for arcA and Panton-Valentine leukocidin to establish the genotype. Results MICs ranged from 16 to 1025 µg/mL. There was a relationship between MIC and genotype; of the 7 isolates with an MIC value greater than 512 µg/mL, 6 were sequence type (ST)8. Conclusion These findings support the practice of ototopical monotherapy for patients with uncomplicated ciprofloxacin-resistant MRSA otitis externa. However, they raise concern that ototopical therapy may not be adequate to treat highly resistant strains of MRSA infecting the middle ear space.