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Social identities impact the way individuals see themselves and their career options but career theories have been slow to the call in exploring how social identities interface with theoretical assumptions. The purpose of this study was to examine how social identities affect and inform specific dimensions identified by cognitive information processing (CIP) theory as being essential for effective career decision-making, that is, self-knowledge, options knowledge, decision-making process and skills, career beliefs, and overall career decision. Seventy-six students across ten sections of an undergraduate CIP-based career development course answered questions on an anonymous survey related to how their social identities impacted aspects of their career decision-making. Frequencies for social identities were calculated for each CIP dimension, and 11 categories identified for open-ended responses using the consensual qualitative research-modified approach accompanied pre-determined domains based on CIP theory. Across each component, the most common SI was age and generational differences. While students expressed the influence of social identities as occurring in each CIP dimension, statements related to the self-concept category occurred most often and were present in each domain. Our findings support previous work that the presence and impact of SIs on career decision-making components is undeniable, but also not universal. CIP theory provides a structure and avenues for discussing the role of social identities in career decision-making. [ABSTRACT FROM AUTHOR]

Background: African American women have an elevated risk for experiencing depressive symptoms, and discrimination, stress, and coping contribute to symptoms of depression. Aims: We aimed to examine the associations between discrimination, stress, and coping on symptoms of depression among young African American mothers. Methods: In this retrospective study, we utilized a hierarchical linear regression to explore the effects of perceived racial discrimination, stress, and general and discrimination-related coping responses on depressive symptoms in a sample of African American mothers (N = 250). The data were drawn from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure study (InterGEN), a study conducted between 2014 and 2019 and based in Connecticut. Results: After accounting for maternal age, level of education, and income, greater perceived racial discrimination (p =.03), higher levels of stress (p <.001), greater engagement in avoidance coping (p <.001), and use of passive coping responses to discrimination (p =.04) were uniquely associated with increased depressive symptoms. Other forms of coping, specifically, problem-solving and support seeking, did not appear to influence depressive symptoms in this sample. Conclusion: The findings highlight the negative impact of discrimination, heightened stress, and maladaptive coping on the emotional health of young African American mothers. [ABSTRACT FROM AUTHOR]

Background People who inject drugs (PWID) are at high risk of severe wounds, invasive infections, and overdoses. To date, there are few data on the bacterial and chemical contaminants PWID are exposed to when using illicitly manufactured fentanyls and stimulants. Methods Previously used injection drug use equipment was recovered in St Louis, Missouri, by harm reduction organizations over a 12-month period. Syringe residue was analyzed for bacterial contaminants by routine culturing followed by whole genome sequencing of single bacterial isolates. Chemical adulterants in syringe residue were identified by liquid chromatography–mass spectrometry. Results Bacteria were cultured from 58.75% of 160 syringes analyzed. Polymicrobial growth was common and was observed in 23.75% of samples. Bacillus cereus was the most common pathogen present and was observed in 20.6% of syringe residues, followed closely by Staphylococcus aureus at 18.8%. One hundred syringes underwent mass spectrometry, which demonstrated that chemical adulterants were common and included caffeine, diphenhydramine, lidocaine, quinine, and xylazine. Conclusions Analysis of syringe residue from discarded drug use equipment demonstrates both chemical and biological contaminants, including medically important pathogens and adulterants. [ABSTRACT FROM AUTHOR]

Background The rise in injection drug use (IDU) has led to an increase in drug-related infections. Harm reduction is an important strategy for preventing infections among people who inject drugs (PWID). We attempted to evaluate the harm reduction counseling that infectious diseases physicians provide to PWID presenting with infections. Methods An electronic survey was distributed to physician members of the Emerging Infections Network to inquire about practices used when caring for patients with IDU-related infections. Results In total, 534 ID physicians responded to the survey. Of those, 375 (70%) reported routinely caring for PWID. Most respondents report screening for human immunodeficiency virus (HIV) and viral hepatitis (98%) and discussing the risk of these infections (87%); 63% prescribe immunization against viral hepatitis, and 45% discuss HIV preexposure prophylaxis (PrEP). However, 55% of respondents (n = 205) reported not counseling patients on safer injection strategies. Common reasons for not counseling included limited time and a desire to emphasize antibiotic therapy/medical issues (62%), lack of training (55%), and believing that it would be better addressed by other services (47%). Among respondents who reported counseling PWID, most recommended abstinence from IDU (72%), handwashing and skin cleansing before injection (62%), and safe disposal of needles/drug equipment used before admission (54%). Conclusions Almost all ID physicians report screening PWID for HIV and viral hepatitis and discussing the risks of these infections. Despite frequently encountering PWID, fewer than half of ID physicians provide safer injection advice. Opportunities exist to standardize harm reduction education, emphasizing safer injection practices in conjunction with other strategies to prevent infections (eg, HIV PrEP or hepatitis A virus/hepatitis B virus vaccination). [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus represents the leading cause of complicated bloodstream infections among persons who inject drugs (PWID). Standard of care (SOC) intravenous (IV) antibiotics result in high rates of treatment success but are not feasible for some PWID. Transition to oral antibiotics may represent an alternative treatment option. Methods We evaluated all adult patients with a history of injection drug use hospitalized from January 2016 through December 2021 with complicated S. aureus bloodstream infections, including infective endocarditis, epidural abscess, vertebral osteomyelitis, and septic arthritis. Patients were compared by antibiotic treatment (standard of care intravenous [SOC IV] antibiotics, incomplete IV therapy, or transition from initial IV to partial oral) using the primary composite endpoint of death or readmission from microbiologic failure within 90 days of discharge. Results Patients who received oral antibiotics after an incomplete IV antibiotic course were significantly less likely to experience microbiologic failure or death than patients discharged without oral antibiotics (P <.001). There was no significant difference in microbiologic failure rates when comparing patients who were discharged on partial oral antibiotics after receiving at least 10 days of IV antibiotics with SOC regimens (P >.9). Conclusions Discharge of PWID with partially treated complicated S. aureus bacteremias without oral antibiotics results in high rates of morbidity and should be avoided. For PWID hospitalized with complicated S. aureus bacteremias who have received at least 10 days of effective IV antibiotic therapy after clearance of bacteremia, transition to oral antibiotics with outpatient support represents a potential alternative if the patient does not desire SOC IV antibiotic therapy. [ABSTRACT FROM AUTHOR]

Background: Over the past two decades, the United States has experienced a dramatic increase in the rate of injection drug use, injection associated infections, and overdose mortality. A hospital-based program for treating opioid use disorder in people who inject drugs presenting with invasive infections was initiated at an academic tertiary care center in 2020. The goal of this program was to improve care outcomes, enhance patient experiences, and facilitate transition from the hospital to longer term addiction care. The purpose of this study was to interview two cohorts of patients, those admitted before vs. after initiation of this program, to understand the program's impact on care from the patient's perspective and explore ways in which the program could be improved. Methods: Thirty patients admitted to the hospital with infectious complications of injection drug use were interviewed using a semi-structured format. Interviews were transcribed and coded. Emergent themes were reported. Limited descriptive statistics were reported based on chart review. Results: Thirty interviews were completed; 16 participants were part of the program (admitted after program implementation) while 14 were not participants (admitted prior to implementation). Common themes associated with hospitalization included inadequate pain control, access to medications for opioid use disorder (MOUD), loss of freedom, stigma from healthcare personnel, and benefits of having an interprofessional team. Participants in the program were more likely to report adequate pain control and access to MOUD and many cited benefits from receiving care from an interprofessional team. Conclusions: Patients with opioid use disorder admitted with injection related infections reported improved experiences when receiving care from an interprofessional team focused on their addiction. However, perceived stigma from healthcare personnel and loss of freedom related to hospitalization were continued barriers to care before and after implementation of this program. [ABSTRACT FROM AUTHOR]

Objectives: To identify the barriers to accessing health care and social services faced by people who inject drugs (PWID) during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This report is a sub-analysis of a larger qualitative study. Semi-structured interviews were conducted with PWID admitted to an academic medical center from 2017 to 2020 for an invasive injection-related infection. Standard qualitative analysis techniques, consisting of both inductive and deductive approaches, were used to identify and characterize the effects of COVID-19 on participants. Results: Among the 30 PWID interview participants, 14 reported barriers to accessing health and addiction services due to COVID-19. As facilities decreased appointment availability or transitioned to telemedicine, PWID reported being unable to access services. Social distancing led to isolation or loneliness during hospital stays and in the community. Recovery meetings and support groups, critical to addiction recovery, were particularly affected. Other participants reported that uncertainty and fear of contracting the virus generated changes in behavior that led them to avoid seeking services. Conclusions: COVID-19 has disrupted health systems and social services, leading PWID to experience unprecedented barriers to accessing and maintaining health and addiction services in both inpatient and outpatient settings. Opioid use disorder management must be understood as a holistic process, and a multidisciplinary approach to ensuring comprehensive care, even in the midst of this pandemic, is needed. [ABSTRACT FROM AUTHOR]

Background Persons who inject drugs (PWID) are frequently admitted for serious injection-related infections (SIRIs). Outcomes and adherence to oral antibiotics for PWID with patient-directed discharge (PDD) remain understudied. Methods We conducted a prospective multicenter bundled quality improvement project of PWID with SIRI at 3 hospitals in Missouri. All PWID with SIRI were offered multidisciplinary care while inpatient, including the option of addiction medicine consultation and medications for opioid use disorder (MOUD). All patients were offered oral antibiotics in the event of a PDD either at discharge or immediately after discharge through an infectious diseases telemedicine clinic. Additional support services included health coaches, a therapist, a case manager, free clinic follow-up, and medications in an outpatient bridge program. Patient demographics, comorbidities, 90-day readmissions, and substance use disorder clinic follow-up were compared between PWID with PDD on oral antibiotics and those who completed intravenous (IV) antibiotics using an as-treated approach. Results Of 166 PWID with SIRI, 61 completed IV antibiotics inpatient (37%), while 105 had a PDD on oral antibiotics (63%). There was no significant difference in 90-day readmission rates between groups (P  = .819). For PWID with a PDD on oral antibiotics, 7.6% had documented nonadherence to antibiotics, 67% had documented adherence, and 23% were lost to follow-up. Factors protective against readmission included antibiotic and MOUD adherence, engagement with support team, and clinic follow-up. Conclusions PWID with SIRI who experience a PDD should be provided with oral antibiotics. Multidisciplinary outpatient support services are needed for PWID with PDD on oral antibiotics. [ABSTRACT FROM AUTHOR]

To define the care cascade for patients with serious injection drug use related infections (SIRI) in a tertiary hospital system and compare outcomes of those who did and did not participate in an opioid use disorder (OUD) treatment referral program. The medical records of patients admitted with both OUD and SIRI including endocarditis, osteomyelitis, septic arthritis, epidural abscess, thrombophlebitis, myositis, bacteremia, and fungemia from 2016-2019 were retrospectively reviewed. Patient demographics, clinical covariates, 90-day readmission rates, and outcomes data were collected. We compared data from those who were successfully referred to outpatient care through Engaging Patients in Care Coordination (EPICC), a peer recovery specialist-run OUD treatment referral program, to those who did not receive outpatient referral. During the study period 334 persons who inject opioids were admitted with SIRI. Fourteen admitted patients died and were excluded from the analysis. The all-cause readmission rate was lower among patients referred to the EPICC program (18/76 [23.7%]) compared to those not referred to EPICC (100/244 [41.0%]) (OR 0.44; 95% CI 0.25–0.80). An OUD care cascade evaluation for patients with SIRI demonstrated that referral to peer recovery services with outpatient OUD treatment was associated with reduced 90-day readmission rate. [ABSTRACT FROM AUTHOR]

Background Persons who inject drugs (PWID) are frequently admitted for serious injection-related infections (SIRIs). PWID are also at risk for sexually transmitted infections (STIs). Methods We conducted a multicenter quality improvement project at 3 hospitals in Missouri. PWID with SIRI who received an infectious diseases consultation were prospectively identified and placed into an electronic database as part of a Centers for Disease Control and Prevention–funded quality improvement project. Baseline data were collected from 8/1/2019 to 1/30/2020. During the intervention period (2/1/2020–2/28/2021), infectious diseases physicians caring for patients received 2 interventions: (1) email reminders of best practice screening for HIV, viral hepatitis, and STIs; (2) access to a customized EPIC SmartPhrase that included checkboxes of orders to include in assessment and plan of consultation notes. STI screening rates were compared before and after the intervention. We then calculated odds ratios to evaluate for risk factors for STIs in the cohort. Results Three hundred ninety-four unique patients were included in the cohort. Initial screening rates were highest for hepatitis C (88%), followed by HIV (86%). The bundled intervention improved screening rates for all conditions and substantially improved screening rates for gonorrhea, chlamydia, and syphilis (30% vs 51%, 30% vs 51%, and 39 vs 60%, respectively; P  < .001). Of patients who underwent screening, 16.9% were positive for at least 1 STI. In general, demographics were not strongly associated with STIs. Conclusions PWID admitted for SIRI frequently have unrecognized STIs. Our bundled intervention improved STI screening rates, but additional interventions are needed to optimize screening. [ABSTRACT FROM AUTHOR]

Background: The Benefits and Barriers Model proposes both benefits and barriers associated with nonsuicidal self‐injury (NSSI) and that a negative association with the self plays a key role in the initial selection of and acute motivation for NSSI. The current investigation builds upon previous findings by assessing the added benefit of targeting self‐criticism in the treatment of NSSI. Methods: Sample included 40 participants (30 females; Mage = 14.92) enrolled in dialectical behavior therapy for adolescents within a partial hospitalization program. All study participants received dialectical behavior therapy for adolescents, and those randomized to the experimental condition received an additional brief cognitive intervention developed to decrease self‐criticism. Results: There was no evidence of an indirect effect of targeting self‐criticism upon NSSI at post‐treatment via post‐treatment self‐criticism (b = −0.98, p =.543); however, there was evidence of a significant interaction between treatment condition and self‐criticism at pretreatment in the prediction of NSSI at post‐treatment (b = 0.33, p =.030). Analyses of simple slopes indicated the conditional direct effect of targeting self‐criticism varied as a function of patient's level of self‐criticism at the onset of treatment, such that individuals −1 SD below the mean (b = −5.76, p=.037) and at average pretreatment levels of self‐criticism (b = −4.09, p=.042), but not + 1 SD above the mean (b = −2.42, p=.056), experienced fewer incidents of NSSI at post‐treatment. Conclusions: The results of this investigation support the added benefit of targeting self‐criticism in the treatment of NSSI for adolescents. [ABSTRACT FROM AUTHOR]

Objectives: To identify the incidence, characteristics, and factors associated with against medical advice (AMA) discharge among hospitalized patients with opioid use disorder (OUD) and injection related infections (eg, endocarditis, osteomyelitis, epidural abscesses). Methods: This retrospective cohort study evaluated adults with OUD admitted to an academic medical center from January 1, 2016 to January 7, 2019 for an invasive injection related infection. Multivariable logistic regression was used to determine independent factors associated with AMA discharge. Results: Among 262 adults admitted with serious injection related infections and comorbid OUD, 138 received inpatient medications for opioid use disorder (MOUD). Univariate analysis showed a decreased odds ratio (OR) of AMA discharge when patients received MOUD inpatient (OR 0.55; 95% CI 0.34-0.91.). Adjusting for covariates associated with social determinants of health and other substance use, inpatient receipt of MOUD was associated with a decreased risk of AMA discharge (adjusted OR 0.49; 95% CI 0.028-0.84). Conclusions: Among patients with OUD and serious injection related infections, inpatient initiation of MOUD is associated with decreased risk of AMA discharge. [ABSTRACT FROM AUTHOR]

Background Persons who inject drugs (PWID) are at risk of invasive infections; however, hospitalizations to treat these infections are frequently complicated by against medical advice (AMA) discharges. This study compared outcomes among PWID who (1) completed a full course of inpatient intravenous (IV) antibiotics, (2) received a partial course of IV antibiotics but were not prescribed any antibiotics on AMA discharge, and (3) received a partial course of IV antibiotics and were prescribed oral antibiotics on AMA discharge. Methods A retrospective, cohort study of PWID aged ≥18 years admitted to a tertiary referral center between 01/2016 and 07/2019, who received an infectious diseases consultation for an invasive bacterial or fungal infection. Results 293 PWID were included in the study. 90-day all-cause readmission rates were highest among PWID who did not receive oral antibiotic therapy on AMA discharge (n = 46, 68.7%), compared with inpatient IV (n = 43, 31.5%) and partial oral (n = 27, 32.5%) antibiotics. In a multivariate analysis, 90-day readmission risk was higher among PWID who did not receive oral antibiotic therapy on AMA discharge (adjusted hazard ratio [aHR], 2.32; 95% confidence interval [CI], 1.41–3.82) and not different among PWID prescribed oral antibiotic therapy on AMA discharge (aHR, .99; 95% CI,.62–1.62). Surgical source control (aHR, .57; 95% CI,.37–.87) and addiction medicine consultation (aHR, .57; 95% CI,.38–.86) were both associated with reduced readmissions. Conclusions Our single-center study suggests access to oral antibiotic therapy for PWID who cannot complete prolonged inpatient IV antibiotic courses is beneficial. [ABSTRACT FROM AUTHOR]

Background: Patients with opioid use disorder (OUD) are frequently admitted for invasive infections. Medications for OUD (MOUD) may improve outcomes in hospitalized patients.Methods: In this retrospective cohort of 220 admissions to a tertiary care center for invasive infections due to OUD, we compared 4 MOUD treatment strategies: methadone, buprenorphine, methadone taper for detoxification, and no medication to determine whether there were differences in parenteral antibiotic completion and readmission rates.Results: The MOUDs were associated with increased completion of parenteral antimicrobial therapy (64.08% vs 46.15%; odds ratio [OR] = 2.08; 95% CI, 1.23-3.61). On multivariate analysis, use of MOUD maintenance with either buprenorphine (OR = 0.38; 95% CI, .17-.85) or methadone maintenance (OR = 0.43; 95% CI, .20-.94) and continuation of MOUD on discharge (OR = 0.35; 95% CI, .18-.67) was associated with lower 90-day readmissions. In contrast, use of methadone for detoxification followed by tapering of the medication without continuation on discharge was not associated with decreased readmissions (OR = 1.87; 95% CI, .62-5.10).Conclusions: Long-term MOUDs, regardless of selection, are an integral component of care in patients hospitalized with OUD-related infections. Patients with OUD should have arrangements made for MOUDs to be continued after discharge, and MOUDs should not be discontinued before discharge. [ABSTRACT FROM AUTHOR]

Background No International Classification of Diseases, 10th revision (ICD-10), diagnosis code exists for injection drug use–associated infective endocarditis (IDU-IE). Instead, public health researchers regularly use combinations of nonspecific ICD-10 codes to identify IDU-IE; however, the accuracy of these codes has not been evaluated. Methods We compared commonly used ICD-10 diagnosis codes for IDU-IE with a prospectively collected patient cohort diagnosed with IDU-IE at Barnes-Jewish Hospital to determine the accuracy of ICD-10 diagnosis codes used in IDU-IE research. Results ICD-10 diagnosis codes historically used to identify IDU-IE were inaccurate, missing 36.0% and misclassifying 56.4% of patients prospectively identified in this cohort. Use of these nonspecific ICD-10 diagnosis codes resulted in substantial biases against the benefit of medications for opioid use disorder (MOUD) with relation to both AMA discharge and all-cause mortality. Specifically, when data from all patients with ICD-10 code combinations suggestive of IDU-IE were used, MOUD was associated with an increased risk of AMA discharge (relative risk [RR], 1.12; 95% CI, 0.48–2.64). In contrast, when only patients confirmed by chart review as having IDU-IE were analyzed, MOUD was protective (RR, 0.49; 95% CI, 0.19–1.22). Use of MOUD was associated with a protective effect in time to all-cause mortality in Kaplan-Meier analysis only when confirmed IDU-IE cases were analyzed (P  = .007). Conclusions Studies using nonspecific ICD-10 diagnosis codes for IDU-IE should be interpreted with caution. In the setting of an ongoing overdose crisis and a syndemic of infectious complications, a specific ICD-10 diagnosis code for IDU-IE is urgently needed. [ABSTRACT FROM AUTHOR]

We interviewed persons who inject drugs (PWID) to understand perceptions of pre-exposure prophylaxis (PrEP) to prevent HIV infection. Knowledge of PrEP was poor. Patients felt that PrEP was for sexual intercourse rather than injection drug use, and PWID managed on medications for opioid use disorder felt that they had no need for PrEP. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae (the pneumococcus) is a common colonizer of the human nasopharynx. Despite a low rate of invasive disease, the high prevalence of colonization results in millions of infections and over one million deaths per year, mostly in individuals under the age of 5 and the elderly. Colonizing pneumococci form well-organized biofilm communities in the nasopharyngeal environment, but the specific role of biofilms and their interaction with the host during colonization and disease is not yet clear. Pneumococci in biofilms are highly resistant to antimicrobial agents and this phenotype can be recapitulated when pneumococci are grown on respiratory epithelial cells under conditions found in the nasopharyngeal environment. Pneumococcal biofilms display lower levels of virulence in vivo and provide an optimal environment for increased genetic exchange both in vitro and in vivo, with increased natural transformation seen during co-colonization with multiple strains. Biofilms have also been detected on mucosal surfaces during pneumonia and middle ear infection, although the role of these biofilms in the disease process is debated. Recent studies have shown that changes in the nasopharyngeal environment caused by concomitant virus infection, changes in the microflora, inflammation, or other host assaults trigger active release of pneumococci from biofilms. These dispersed bacteria have distinct phenotypic properties and transcriptional profiles different from both biofilm and broth-grown, planktonic bacteria, resulting in a significantly increased virulence in vivo. In this review we discuss the properties of pneumococcal biofilms, the role of biofilm formation during pneumococcal colonization, including their propensity for increased ability to exchange genetic material, as well as mechanisms involved in transition from asymptomatic biofilm colonization to dissemination and disease of otherwise sterile sites. Greater understanding of pneumococcal biofilm formation and dispersion will elucidate novel avenues to interfere with the spread of antibiotic resistance and vaccine escape, as well as novel strategies to target the mechanisms involved in induction of pneumococcal disease. [ABSTRACT FROM AUTHOR]

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex from human milk with both tumoricidal and bactericidal activities. HAMLET exerts a rather specific bactericidal activity against some respiratory pathogens, with highest activity against Streptococcus pneumoniae, but lacks activity against most other bacterial pathogens, including Staphylococci. Still, ion transport associated with death in S. pneumoniae is also detected to a lower degree in insensitive organisms. In this study we demonstrate that HAMLET acts as an antimicrobial adjuvant that can increase the activity of a broad spectrum of antibiotics (methicillin, vancomycin, gentamicin and erythromycin) against multi-drug resistant Staphylococcus aureus, to a degree where they become sensitive to those same antibiotics, both in antimicrobial assays against planktonic and biofilm bacteria and in an in vivo model of nasopharyngeal colonization. We show that HAMLET exerts these effects specifically by dissipating the proton gradient and inducing a sodium-dependent calcium influx that partially depolarizes the plasma membrane, the same mechanism induced during pneumococcal death. These effects results in an increased cell associated binding and/or uptake of penicillin, gentamicin and vancomycin, especially in resistant stains. Finally, HAMLET inhibits the increased resistance of methicillin seen under antibiotic pressure and the bacteria do not become resistant to the adjuvant, which is a major advantageous feature of the molecule. These results highlight HAMLET as a novel antimicrobial adjuvant with the potential to increase the clinical usefulness of antibiotics against drug resistant strains of S. aureus. [ABSTRACT FROM AUTHOR]

The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal. [ABSTRACT FROM AUTHOR]

In a new respiratory virus pandemic, optimizing allocation of scarce medical resources becomes an urgent challenge. Infection prognosis takes on particular importance when allocating scarce antiviral antibodies and drugs, which are most effective when administered before the onset of severe disease. During arrival of the COVID-19 pandemic to the United States in 2020, we conducted a prognostic biomarker discovery and validation effort based upon metabolomic profiling with a liquid-chromatography-mass spectrometer (LC-MS) type used clinically for rapid toxicology. We obtained urine specimens from 163 patients presenting for evaluation. We obtained LC-MS profiles in the initial cohort and used machine learning methods to define a simplified urine metabolomic signature associated with respiratory failure or death by 90 days. This signature was composed of three metabotypes linked to intestinal microbiome metabolism and anticonvulsant use, with a receiver-operator characteristic area under the curve (ROC AUC) of 89.4%. Blinded application of this signature to the subsequent validation cohort yielded a ROC AUC of 81.2%. A model trained on the two baseline metabotypes present before intubation exhibited similar performance in the validation cohort. This study demonstrates the plausibility and promise of rapid metabolome-based prognostic discovery and validation in the opening wave of a pandemic. The approach used here could be used to inform therapeutic and resource allocation decisions early in a future epidemic.IMPORTANCEIn a new respiratory virus pandemic, the ability to identify patients at greatest risk for severe disease is essential to direct scarce medical resources to those most likely to benefit from them. Tools to predict disease severity are best developed early in a pandemic, but laboratory-based resources to develop these may be limited by available technology and by infection precautions. Here, we show that an accessible metabolic profiling approach could identify a prognostic signature of severe disease in the initial wave of COVID-19, when patients presenting for care often exceeded the available doses of convalescent plasma and remdesivir. In a future pandemic, this approach, alongside efforts to identify clinical disease severity predictors, could improve patient outcomes and facilitate therapeutic trials by identifying individuals at high risk for severe disease., Competing Interests: The authors declare no conflict of interest.

Background: To end the HIV and hepatitis C virus (HCV) epidemics, people who use drugs (PWUD) need more opportunities for testing. While inpatient hospitalizations are an essential opportunity to test people who use drugs (PWUD) for HIV and HCV, there is limited research on rates of inpatient testing for HIV and HCV among PWUD., Methods: Eleven hospital sites were included in the study. Each site created a cohort of inpatient encounters associated with injection drug use. From these cohorts, we collected data on HCV and HIV testing rates and HIV testing consent policies from 65 276 PWUD hospitalizations., Results: Hospitals had average screening rates of 40% for HIV and 32% for HCV, with widespread heterogeneity in screening rates across facilities. State consent laws and opt-out testing policies were not associated with statistically significant differences in HIV screening rates. On average, hospitals that reflexed HCV viral load testing on HCV antibody testing did not have statistically significant differences in HCV viral load testing rates. We found suboptimal testing rates during inpatient encounters for PWUD. As treatment (HIV) and cure (HCV) are necessary to end these epidemics, we need to prioritize understanding and overcoming barriers to testing., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Streptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines, aim to eliminate asymptomatic carriage with vaccine-type pneumococci. However, this has resulted in serotype replacement with, so far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virus-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally induced pneumococcal disease can be conferred without disturbing the desirable preexisting commensal colonization of the nasopharynx., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Streptococcus pneumoniae (the pneumococcus) is a common colonizer of the human nasopharynx. Despite a low rate of invasive disease, the high prevalence of colonization results in millions of infections and over one million deaths per year, mostly in individuals under the age of 5 and the elderly. Colonizing pneumococci form well-organized biofilm communities in the nasopharyngeal environment, but the specific role of biofilms and their interaction with the host during colonization and disease is not yet clear. Pneumococci in biofilms are highly resistant to antimicrobial agents and this phenotype can be recapitulated when pneumococci are grown on respiratory epithelial cells under conditions found in the nasopharyngeal environment. Pneumococcal biofilms display lower levels of virulence in vivo and provide an optimal environment for increased genetic exchange both in vitro and in vivo, with increased natural transformation seen during co-colonization with multiple strains. Biofilms have also been detected on mucosal surfaces during pneumonia and middle ear infection, although the role of these biofilms in the disease process is debated. Recent studies have shown that changes in the nasopharyngeal environment caused by concomitant virus infection, changes in the microflora, inflammation, or other host assaults trigger active release of pneumococci from biofilms. These dispersed bacteria have distinct phenotypic properties and transcriptional profiles different from both biofilm and broth-grown, planktonic bacteria, resulting in a significantly increased virulence in vivo. In this review we discuss the properties of pneumococcal biofilms, the role of biofilm formation during pneumococcal colonization, including their propensity for increased ability to exchange genetic material, as well as mechanisms involved in transition from asymptomatic biofilm colonization to dissemination and disease of otherwise sterile sites. Greater understanding of pneumococcal biofilm formation and dispersion will elucidate novel avenues to interfere with the spread of antibiotic resistance and vaccine escape, as well as novel strategies to target the mechanisms involved in induction of pneumococcal disease.

Streptococcus pneumoniae is a leading cause of infectious disease globally. Nasopharyngeal colonization occurs in biofilms and precedes infection. Prior studies have indicated that biofilm-derived pneumococci are avirulent. However, influenza A virus (IAV) infection releases virulent pneumococci from biofilms in vitro and in vivo. Triggers of dispersal include IAV-induced changes in the nasopharynx, such as increased temperature (fever) and extracellular ATP (tissue damage). We used whole-transcriptome shotgun sequencing (RNA-seq) to compare the S. pneumoniae transcriptome in biofilms, bacteria dispersed from biofilms after exposure to IAV, febrile-range temperature, or ATP, and planktonic cells grown at 37°C. Compared with biofilm bacteria, actively dispersed S. pneumoniae, which were more virulent in invasive disease, upregulated genes involved in carbohydrate metabolism. Enzymatic assays for ATP and lactate production confirmed that dispersed pneumococci exhibited increased metabolism compared to those in biofilms. Dispersed pneumococci also upregulated genes associated with production of bacteriocins and downregulated colonization-associated genes related to competence, fratricide, and the transparent colony phenotype. IAV had the largest impact on the pneumococcal transcriptome. Similar transcriptional differences were also observed when actively dispersed bacteria were compared with avirulent planktonic bacteria. Our data demonstrate complex changes in the pneumococcal transcriptome in response to IAV-induced changes in the environment. Our data suggest that disease is caused by pneumococci that are primed to move to tissue sites with altered nutrient availability and to protect themselves from the nasopharyngeal microflora and host immune response. These data help explain pneumococcal virulence after IAV infection and have important implications for studies of S. pneumoniae pathogenesis., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Both Streptococcus pyogenes and Streptococcus pneumoniae are widely thought to rapidly die outside the human host, losing infectivity following desiccation in the environment. However, to date, all literature investigating the infectivity of desiccated streptococci has used broth-grown, planktonic populations. In this study, we examined the impact of biofilm formation on environmental survival of clinical and laboratory isolates of S. pyogenes and S. pneumoniae as both organisms are thought to colonize the human host as biofilms. Results clearly demonstrate that while planktonic cells that are desiccated rapidly lose viability both on hands and abiotic surfaces, such as plastic, biofilm bacteria remain viable over extended periods of time outside the host and remain infectious in a murine colonization model. To explore the level and extent of streptococcal fomite contamination that children might be exposed to naturally, direct bacteriologic cultures of items in a day care center were conducted, which demonstrated high levels of viable streptococci of both species. These findings raise the possibility that streptococci may survive in the environment and be transferred from person to person via fomites contaminated with oropharyngeal secretions containing biofilm streptococci.

Membrane depolarization and ion fluxes are events that have been studied extensively in biological systems due to their ability to profoundly impact cellular functions, including energetics and signal transductions. While both fluorescent and electrophysiological methods, including electrode usage and patch-clamping, have been well developed for measuring these events in eukaryotic cells, methodology for measuring similar events in microorganisms have proven more challenging to develop given their small size in combination with the more complex outer surface of bacteria shielding the membrane. During our studies of death-initiation in Streptococcus pneumoniae (pneumococcus), we wanted to elucidate the role of membrane events, including changes in polarity, integrity, and intracellular ion concentrations. Searching the literature, we found that very few studies exist. Other investigators had monitored radioisotope uptake or equilibrium to measure ion fluxes and membrane potential and a limited number of studies, mostly in Gram-negative organisms, had seen some success using carbocyanine or oxonol fluorescent dyes to measure membrane potential, or loading bacteria with cell-permeant acetoxymethyl (AM) ester versions of ion-sensitive fluorescent indicator dyes. We therefore established and optimized protocols for measuring membrane potential, rupture, and ion-transport in the Gram-positive organism S. pneumoniae. We developed protocols using the bis-oxonol dye DiBAC4(3) and the cell-impermeant dye propidium iodide to measure membrane depolarization and rupture, respectively, as well as methods to optimally load the pneumococci with the AM esters of the ratiometric dyes Fura-2, PBFI, and BCECF to detect changes in intracellular concentrations of Ca(2+), K(+), and H(+), respectively, using a fluorescence-detection plate reader. These protocols are the first of their kind for the pneumococcus and the majority of these dyes have not been used in any other bacterial species. Though our protocols have been optimized for S. pneumoniae, we believe these approaches should form an excellent starting-point for similar studies in other bacterial species.

Unlabelled: Streptococcus pneumoniae is a common human nasopharyngeal commensal colonizing 10% to 40% of healthy individuals, depending on age. Despite a low invasive disease rate, widespread carriage ensures that infection occurs often enough to make S. pneumoniae a leading bacterial cause of respiratory disease worldwide. However, the mechanisms behind transition from asymptomatic colonization to dissemination and disease in otherwise sterile sites remain poorly understood but are epidemiologically strongly linked to infection with respiratory viruses. In this report, we show that infection with influenza A virus and treatment with the resulting host signals (febrile-range temperatures, norepinephrine, extracytoplasmic ATP, and increased nutrient availability) induce the release of bacteria from biofilms in a newly developed biofilm model on live epithelial cells both in vitro and during in vivo colonization. These dispersed bacteria have distinct phenotypic properties different from those of both biofilm and broth-grown, planktonic bacteria, with the dispersed population showing differential virulence gene expression characteristics resulting in a significantly increased ability to disseminate and cause infection of otherwise sterile sites, such as the middle ear, lungs, and bloodstream. The results offer novel and important insights into the role of interkingdom signaling between microbe and host during biofilm dispersion and transition to acute disease., Importance: This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx.

Unlabelled: Transformation of genetic material between bacteria was first observed in the 1920s using Streptococcus pneumoniae as a model organism. Since then, the mechanism of competence induction and transformation has been well characterized, mainly using planktonic bacteria or septic infection models. However, epidemiological evidence suggests that genetic exchange occurs primarily during pneumococcal nasopharyngeal carriage, which we have recently shown is associated with biofilm growth, and is associated with cocolonization with multiple strains. However, no studies to date have comprehensively investigated genetic exchange during cocolonization in vitro and in vivo or the role of the nasopharyngeal environment in these processes. In this study, we show that genetic exchange during dual-strain carriage in vivo is extremely efficient (10(-2)) and approximately 10,000,000-fold higher than that measured during septic infection (10(-9)). This high transformation efficiency was associated with environmental conditions exclusive to the nasopharynx, including the lower temperature of the nasopharynx (32 to 34°C), limited nutrient availability, and interactions with epithelial cells, which were modeled in a novel biofilm model in vitro that showed similarly high transformation efficiencies. The nasopharyngeal environmental factors, combined, were critical for biofilm formation and induced constitutive upregulation of competence genes and downregulation of capsule that promoted transformation. In addition, we show that dual-strain carriage in vivo and biofilms formed in vitro can be transformed during colonization to increase their pneumococcal fitness and also, importantly, that bacteria with lower colonization ability can be protected by strains with higher colonization efficiency, a process unrelated to genetic exchange., Importance: Although genetic exchange between pneumococcal strains is known to occur primarily during colonization of the nasopharynx and colonization is associated with biofilm growth, this is the first study to comprehensively investigate transformation in this environment and to analyze the role of environmental and bacterial factors in this process. We show that transformation efficiency during cocolonization by multiple strains is very high (around 10(-2)). Furthermore, we provide novel evidence that specific aspects of the nasopharyngeal environment, including lower temperature, limited nutrient availability, and epithelial cell interaction, are critical for optimal biofilm formation and transformation efficiency and result in bacterial protein expression changes that promote transformation and fitness of colonization-deficient strains. The results suggest that cocolonization in biofilm communities may have important clinical consequences by facilitating the spread of antibiotic resistance and enabling serotype switching and vaccine escape as well as protecting and retaining poorly colonizing strains in the pneumococcal strain pool.

The human nasopharynx is the main reservoir for Streptococcus pneumoniae (the pneumococcus) and the source for both horizontal spread and transition to infection. Some clinical evidence indicates that nasopharyngeal carriage is harder to eradicate with antibiotics than is pneumococcal invasive disease, which may suggest that colonizing pneumococci exist in biofilm communities that are more resistant to antibiotics. While pneumococcal biofilms have been observed during symptomatic infection, their role in colonization and the role of host factors in this process have been less studied. Here, we show for the first time that pneumococci form highly structured biofilm communities during colonization of the murine nasopharynx that display increased antibiotic resistance. Furthermore, pneumococcal biofilms grown on respiratory epithelial cells exhibited phenotypes similar to those observed during colonization in vivo, whereas abiotic surfaces produced less ordered and more antibiotic-sensitive biofilms. The importance of bacterial-epithelial cell interactions during biofilm formation was shown using both clinical strains with variable colonization efficacies and pneumococcal mutants with impaired colonization characteristics in vivo. In both cases, the ability of strains to form biofilms on epithelial cells directly correlated with their ability to colonize the nasopharynx in vivo, with colonization-deficient strains forming less structured and more antibiotic-sensitive biofilms on epithelial cells, an association that was lost when grown on abiotic surfaces. Thus, these studies emphasize the importance of host-bacterial interactions in pneumococcal biofilm formation and provide the first experimental data to explain the high resistance of pneumococcal colonization to eradication by antibiotics.