Gut resident Escherichia coli profile predicts the eighteen-month probability and antimicrobial susceptibility of urinary tract infections.

Background: Community-acquired UTI is the most common bacterial infection managed in general medical practice that can lead to life-threatening outcomes. While UTIs are primarily caused by Escherichia coli colonizing the patient's gut, it is unclear whether the gut resident E. coli profiles can predict the person's risks for UTI and optimal antimicrobial treatments. Thus, we conducted an eighteen-month long community-based observational study of fecal E. coli colonization and UTI in women aged 50 years and above. Methods and Findings: We enrolled a total of 1,804 women distributed among age groups 50-59 yo (437 participants), 60-69 yo (632), 70-79 yo (532), and above 80 yo (203), lacking antibiotic prescriptions for at least one year. The provided fecal samples were plated for the presence of E. coli and other enterobacteria resistant to trimethoprim/sulfamethoxazole (TMP/STX), ciprofloxacin (CIP) and 3rd generation cephalosporins (3GC). E. coli was also characterized as belonging to the pandemic multi-drug resistant clonal groups ST131 (subclone H30) and ST1193. Following sample collection, the women were monitored for 18 months for occurrence of UTI.E. coli was cultured from 90.8% fecal samples, with 24.1% containing bacteria resistant to TMP/STX, 19.4% to CIP, and 7.9% to 3GC. In 62.5% samples, only all-susceptible E. coli were present. Overall, there were no age-related differences in resistance prevalence. However, while the total E. coli H30 and ST1193 carriage rates were similar (4.3% and 4.2%, respectively), there was a notable increase of H30 carriage with age (P = .001), while carriage decreased with age for ST1193 (P = .057).Within 18 months, 184 women (10.2%) experienced at least one episode of UTI - 10.9% among the gut E. coli carriers and 3.0% among the non-carriers (P=.0013). The UTI risk among carriers of E. coli H30 but not ST1193 was significantly above average (24.3%, P = .0004). The UTI probability increased with age, occurring in 6.4% of 50-59 yo and 19.7% of 80+ yo (P<.001), with the latter group being especially at high risk for UTI, if they were colonized by E. coli H30 (40.0%, P<.001).E. coli was identified in 88.1% of urine samples, with 16.1% resistant to TMP/STX, 16.1% to CIP, 4.2% to 3GC and 73.1% to none of the antibiotics. Among tested urinary E. coli resistant to antibiotics, 86.1% matched the resistance profile of E. coli in the fecal samples, with the clonotyping and whole genome sequencing confirming the matching strains' identity. Positive predictive value (PPV) of using gut resistance profiles to predict UTI pathogens' susceptibility to TMP/STX, CIP, 3GC and all three antibiotics were 98.4%, 98.3%, 96.6% and 95.3%, respectively. Corresponding negative predictive values (NPV) were 63.0%, 54.8%, 44.4% and 75.8%, respectively. The AUC ROC curve values for the accuracy of fecal diagnostic testing for the prediction of UTI resistance ranged .86-.89. The fecal test-guided drug-bug mismatch rate for empirical (pre-culture) prescription of TMP-SXT or CIP is reduced to ≤2% in 89.6% of patients and 94.8% of patients with an optional 3GC prescription. Conclusion: The resistance profile and clonal identity of gut colonizing E. coli, along with the carrier's age, can inform personalized prediction of a patients' UTI risk and the UTI pathogen's antibiotic susceptibility within an 18-month period.

Preventing severe hypoglycemia in adults with type 2 diabetes (PHT2): Design, delivery and evaluation framework for a randomized controlled trial.

BACKGROUND: Severe hypoglycemia is a common and feared complication of medications used to lower blood glucose levels in individuals with diabetes. Psychoeducational interventions can prevent severe hypoglycemia in individuals with type 1 diabetes (T1D). We aim to determine the effectiveness of this approach among adults with type 2 diabetes (T2D) at elevated risk for severe hypoglycemia. METHODS: Preventing Hypoglycemia in Type 2 diabetes (PHT2) is a two-arm, parallel, randomized controlled trial. Participants are eligible if they are adults with T2D receiving care at an integrated group practice in Washington state and have experienced one or more episodes of severe hypoglycemia in the prior 12 months or have impaired awareness of hypoglycemia (Gold score ≥ 4). Participants are randomized to proactive nurse care management with or without my hypo compass, an evidence-based, psychoeducational intervention combining group and individual self-management training. For this study, my hypo compass was adapted to be suitable for adults with T2D and from an in-person to a virtual intervention over videoconference and telephone. The primary outcome is any self-reported severe hypoglycemia in the 12 months following the start of the intervention. Secondary outcomes include biochemical measures of hypoglycemia, self-reported hypoglycemia awareness, fear of hypoglycemia, and emergency department visits and hospitalizations for severe hypoglycemia. The study includes a process evaluation to assess implementation fidelity and clarify the causal pathway. CONCLUSION: The PHT2 trial will compare the effectiveness of two approaches for reducing severe hypoglycemia in adults with T2D. TRIAL REGISTRATION: clinicaltrials.gov, # NCT04863872.

Increase in the community circulation of ciprofloxacin-resistant Escherichia coli despite reduction in antibiotic prescriptions.

BACKGROUND: Community circulating gut microbiota is the main reservoir for uropathogenic Escherichia coli, including those resistant to antibiotics. Ciprofloxacin had been the primary antibiotic prescribed for urinary tract infections, but its broad use has been discouraged and steadily declined since 2015. How this change in prescriptions affected the community circulation of ciprofloxacin-resistant E. coli is unknown. METHODS: We determined the frequency of isolation and other characteristics of E. coli resistant to ciprofloxacin in 515 and 1604 E. coli-positive fecal samples collected in 2015 and 2021, respectively. The samples were obtained from non-antibiotic-taking women of age 50+ receiving care in the Kaiser Permanente Washington healthcare system. RESULTS: Here we show that despite a nearly three-fold drop in the prescription of ciprofloxacin between 2015 and 2021, the rates of gut carriage of ciprofloxacin-resistant E. coli increased from 14.2 % to 19.8% (P = .004). This is driven by a significant increase of isolates from the pandemic multi-drug resistant clonal group ST1193 (1.7% to 4.2%; P = .009) and isolates with relatively few ciprofloxacin-resistance determining chromosomal mutations (2.3% to 7.4%; P = .00003). Though prevalence of isolates with the plasmid-associated ciprofloxacin resistance dropped (59.0% to 30.9%; P = 2.7E-06), the isolates co-resistance to third generation cephalosporins has increased from 14.1% to 31.5% (P = .002). CONCLUSIONS: Despite reduction in ciprofloxacin prescriptions, community circulation of the resistant uropathogenic E. coli increased with a rise of co-resistance to third generation cephalosporins. Thus, to reduce the rates of urinary tract infections refractory to antibiotic treatment, greater focus should be on controlling the resistant bacteria in gut microbiota.

The alarming rise of bacteria causing infections that are difficult to treat with antibiotics, known as multidrug-resistant bacteria, is a major problem in medicine. The reduction in the use of antibiotics has been encouraged to control the spread of antibiotic-resistant bacteria. Some multidrug-resistant bacteria reside in the gut of healthy individuals and can cause various forms of urinary tract infections (UTIs). Ciprofloxacin is an antibiotic that was widely used to treat UTIs, but strong recommendations to reduce its prescription have been recently introduced. We compared the presence of bacteria in the gut that could not be killed by ciprofloxacin in women aged 50 and above who do not use antibiotics and reside in the Seattle area. Despite a nearly three-fold drop in the prescription of ciprofloxacin between 2015 and 2021, antibiotic-resistant bacteria in the gut were found more frequently, affecting one in five women. Our study demonstrates that antibiotic-resistant bacteria continue to be present even when antibiotic prescriptions are reduced, demonstrating the need to undertake further similar studies.

Increase in the Rate of Gut Carriage of Fluoroquinolone-Resistant Escherichia coli despite a Reduction in Antibiotic Prescriptions.

Background : Fluoroquinolone use for urinary tract infections has been steadily declining. Gut microbiota is the main reservoir for uropathogenic Escherichia coli but whether the carriage of fluoroquinolone-resistant E. coli has been changing is unknown. Methods . We determined the frequency of isolation and other characteristics of E. coli nonsuceptible to fluoroquinolones (at ³0.5 mg/L of ciprofloxacin) in 515 and 1605 E. coli -positive fecal samples collected in 2015 and 2021, respectively, from non-antibiotic- taking women of age 50+ receiving care in the Seattle area Kaiser Permanente Washington healthcare system. Results . Between 2015 and 2021 the prescription of fluoroquinolones dropped nearly three-fold in the study population. During the same period, the rates of gut carriage of fluoroquinolone-resistant E. coli increased from 14.4 % to 19.9% (P=.005), driven by a significant increase of isolates from the recently emerged, pandemic multi-drug resistant clonal group ST1193 (1.7% to 4.3%; P=.007) and those with an incomplete set of or no fluoroquinolone-resistance determining mutations (2.3% to 7.5%; P<.001). While prevalence of the resistance-associated mobile genes among the isolates dropped from 64.1% to 32.6% (P<.001), co-resistance to third generation cephalosporins has increased 21.5% to 33.1%, P=.044). Conclusion . Despite reduction in fluoroquinolone prescriptions, gut carriage of fluoroquinolone-resistant uropathogenic E. coli increased with a rise of previously sporadic lineages and co-resistance to third generation cephalosporins. Thus, to reduce the rates of antibiotic resistant urinary tract infections, greater focus should be on controlling the gut carriage of resistant bacteria.

Sex Differences in Comorbid Mental and Substance Use Disorders Among Primary Care Patients With Opioid Use Disorder.

OBJECTIVE: The authors sought to characterize the 3-year prevalence of mental disorders and nonnicotine substance use disorders among male and female primary care patients with documented opioid use disorder across large U.S. health systems. METHODS: This retrospective study used 2014-2016 data from patients ages ≥16 years in six health systems. Diagnoses were obtained from electronic health records or claims data; opioid use disorder treatment with buprenorphine or injectable extended-release naltrexone was determined through prescription and procedure data. Adjusted prevalence of comorbid conditions among patients with opioid use disorder (with or without treatment), stratified by sex, was estimated by fitting logistic regression models for each condition and applying marginal standardization. RESULTS: Females (53.2%, N=7,431) and males (46.8%, N=6,548) had a similar prevalence of opioid use disorder. Comorbid mental disorders among those with opioid use disorder were more prevalent among females (86.4% vs. 74.3%, respectively), whereas comorbid other substance use disorders (excluding nicotine) were more common among males (51.9% vs. 60.9%, respectively). These differences held for those receiving medication treatment for opioid use disorder, with mental disorders being more common among treated females (83% vs. 71%) and other substance use disorders more common among treated males (68% vs. 63%). Among patients with a single mental health condition comorbid with opioid use disorder, females were less likely than males to receive medication treatment for opioid use disorder (15% vs. 20%, respectively). CONCLUSIONS: The high rate of comorbid conditions among patients with opioid use disorder indicates a strong need to supply primary care providers with adequate resources for integrated opioid use disorder treatment.

The impact of selection bias on vaccine effectiveness estimates from test-negative studies.

INTRODUCTION: Estimates of vaccine effectiveness (VE) from test-negative studies may be subject to selection bias. In the context of influenza VE, we used simulations to identify situations in which meaningful selection bias can occur. We also analyzed observational study data for evidence of selection bias. METHODS: For the simulation study, we defined a hypothetical population whose members are at risk for acute respiratory illness (ARI) due to influenza and other pathogens. An unmeasured "healthcare seeking proclivity" affects both probability of vaccination and probability of seeking care for an ARI. We varied the direction and magnitude of these effects and identified situations where meaningful bias occurred. For the observational study, we reanalyzed data from the United States Influenza VE Network, an ongoing test-negative study. We compared "bias-naïve" VE estimates to bias-adjusted estimates, which used data from the source populations to correct for sampling bias. RESULTS: In the simulation study, an unmeasured care-seeking proclivity could create selection bias if persons with influenza ARI were more (or less) likely to seek care than persons with non-influenza ARI. However, selection bias was only meaningful when rates of care seeking between influenza ARI and non-influenza ARI were very different. In the observational study, the bias-naïve VE estimate of 55% (95% CI, 47--62%) was trivially different from the bias-adjusted VE estimate of 57% (95% CI, 49--63%). CONCLUSIONS: In combination, these studies suggest that while selection bias is possible in test-negative VE studies, this bias in unlikely to be meaningful under conditions likely to be encountered in practice. Researchers and public health officials can continue to rely on VE estimates from test-negative studies.

Tamoxifen Initiation After Ductal Carcinoma In Situ.

BACKGROUND: Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15-year period in an integrated health care setting to identify factors related to initiation. METHODS: Female Group Health Cooperative enrollees ages 18-89 years with a DCIS diagnosis during 1996-2011 were eligible for inclusion. Endocrine therapy was identified through pharmacy records. Tumor and treatment information were from tumor registry reports; demographics and other risk factors were from questionnaires and electronic medical records. Relative risks (RRs) and 95% confidence intervals (CIs) for endocrine therapy initiation were calculated using multivariable generalized linear models. RESULTS: We identified 727 women with a DCIS diagnosis, including 163 (22%) who initiated endocrine therapy (149 tamoxifen, 14 aromatase inhibitor). Younger women were more likely to initiate endocrine therapy (RR 1.69; 95% CI 1.16-2.46 for ages 45-54 vs. 65-74 years). Compared with breast-conserving surgery (BCS) with radiation, women who had BCS alone (RR 0.46; 95% CI 0.25-0.84) or mastectomy (RR 0.54; 95% CI 0.39-0.75) were less likely to use endocrine therapy. ER testing increased from 4% of DCIS cases in 2001 to 71% in 2011; however, endocrine therapy initiation decreased from 58% of ER+ DCIS in 2001-2005 to 37% in 2009-2011. CONCLUSION: Increasing ER testing since 2001 has not corresponded to parallel increases in endocrine therapy initiation. Age, surgery, and radiation were the primary factors associated with initiation. IMPLICATIONS FOR PRACTICE: National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status.

Self-Collected Nasal Swabs for Respiratory Virus Surveillance.

We tested whether 135 patients reporting acute respiratory illness (ARI) could self-collect nasal swab specimens and ship them for laboratory testing. Most subjects (78.2%) collected and shipped their specimens without errors; 10.5% excluded ≥1 packing components; 12.9% made ≥1 packing errors. Self-swabbing at home is feasible for confirming ARI etiology.

Vaccination site and risk of local reactions in children 1 through 6 years of age.

OBJECTIVE: Our objective was to assess whether the occurrence of medically attended local reactions to intramuscularly administered vaccines varies by injection site (arm versus thigh) in children 1 to 6 years of age. METHODS: This is a retrospective cohort study of children in the Vaccine Safety Datalink population from 2002 to 2009. Site of injection and the outcome of medically attended local reactions were identified from administrative data. RESULTS: The study cohort of 1.4 million children received 6.0 million intramuscular (IM) vaccines during the study period. The primary analyses evaluated the IM vaccines most commonly administered alone, which included inactivated influenza, hepatitis A, and diphtheria-tetanus-acellular pertussis (DTaP) vaccines. For inactivated influenza and hepatitis A vaccines, local reactions were relatively uncommon, and there was no difference in risk of these events with arm versus thigh injections. The rate of local reactions after DTaP vaccines was higher, and vaccination in the arm was associated with a significantly greater risk of this outcome compared with vaccination in the thigh, both for children 12 to 35 months (relative risk: 1.88 [95% confidence interval: 1.34-2.65]) and 3 to 6 years of age (relative risk: 1.41 [95% confidence interval: 0.84-2.34]), although this difference was not statistically significant in the older age group. CONCLUSIONS: Injection in the thigh is associated with a significantly lower risk of a medically attended local reaction to a DTaP vaccination among children 12 to 35 months of age, supporting current recommendations to administer IM vaccinations in the thigh for children younger than 3 years of age.