Surveillance of vancomycin-resistant enterococci reveals shift in dominating clusters from vanA to vanB Enterococcus faecium clusters, Denmark, 2015 to 2022.

BackgroundVancomycin-resistant enterococci (VRE) are increasing in Denmark and Europe. Linezolid and vancomycin-resistant enterococci (LVRE) are of concern, as treatment options are limited. Vancomycin-variable enterococci (VVE) harbour the vanA gene complex but are phenotypically vancomycin-susceptible.AimThe aim was to describe clonal shifts for VRE and VVE in Denmark between 2015 and 2022 and to investigate genotypic linezolid resistance among the VRE and VVE.MethodsFrom 2015 to 2022, 4,090 Danish clinical VRE and VVE isolates were whole genome sequenced. We extracted vancomycin resistance genes and sequence types (STs) from the sequencing data and performed core genome multilocus sequence typing (cgMLST) analysis for Enterococcus faecium. All isolates were tested for the presence of mutations or genes encoding linezolid resistance.ResultsIn total 99% of the VRE and VVE isolates were E. faecium. From 2015 through 2019, 91.1% of the VRE and VVE were vanA E. faecium. During 2020, to the number of vanB E. faecium increased to 254 of 509 VRE and VVE isolates. Between 2015 and 2022, seven E. faecium clusters dominated: ST80-CT14 vanA, ST117-CT24 vanA, ST203-CT859 vanA, ST1421-CT1134 vanA (VVE cluster), ST80-CT1064 vanA/vanB, ST117-CT36 vanB and ST80-CT2406 vanB. We detected 35 linezolid vancomycin-resistant E. faecium and eight linezolid-resistant VVEfm.ConclusionFrom 2015 to 2022, the numbers of VRE and VVE increased. The spread of the VVE cluster ST1421-CT1134 vanA E. faecium in Denmark is a concern, especially since VVE diagnostics are challenging. The finding of LVRE, although in small numbers, ia also a concern, as treatment options are limited.

Life Satisfaction Factors, Stress, and Depressive Symptoms among Young Women Living in Urban Kampala: Findings from the TOPOWA Project Pilot Studies.

Young women living in Kampala, Uganda, often face adversities related to Social Determinants of Mental Health (SDoMH) including poverty, food scarcity, environmental stressors such as high levels of community violence, and lack of adequate healthcare access. Two consecutive pilot studies were conducted to assess the feasibility and acceptability of survey questions, wearable fitness trackers, and daily diaries before launching a larger prospective cohort study. Preliminary associations between SDoMH factors with depressive symptoms, stress levels, and life satisfaction were examined among the total sample of 60 women across two pilot studies. A total of 32.2% of respondents (out of n = 59) reported being depressed most or all of the time in the past 30 days. Frequent depressive symptoms correlated with food insecurity (χ2 = 5.38, df = 1, p = 0.02). Higher stress levels were significantly associated with lower overall life satisfaction scores (t = 2.74, df = 6.20, p = 0.03). Additionally, frequent depressive symptoms were associated with lower satisfaction scores in the living conditions and lifestyle domain (t = 2.22, df = 36.18, p = 0.03). However, overall life satisfaction scores and other domains (social relationships and personal independence) were not statistically associated with frequent depressive symptoms. Identifying the most impactful SDoMH factors among young women in Kampala can inform targeted approaches to improve mental health outcomes.

Comparison of morbidity and mortality after bloodstream infection with vancomycin-resistant versus -susceptible Enterococcus faecium: a nationwide cohort study in Denmark, 2010-2019.

The emergence of bloodstream infections (BSI) caused by vancomycin-resistant Enterococci (VRE) has caused concern. Nonetheless, it remains unclear whether these types are associated with an excess risk of severe outcomes when compared with infections caused by vancomycin-susceptible Enterococci (VSE). This cohort study included hospitalized patients in Denmark with Enterococcus faecium-positive blood cultures collected between 2010 and 2019 identified in the Danish Microbiology Database. We estimated 30-day hazard ratio (HR) of death or discharge among VRE compared to VSE patients adjusted for age, sex, and comorbidity. The cohort included 6071 patients with E. faecium BSI (335 VRE, 5736 VSE) among whom VRE increased (2010-13, 2.6%; 2014-16, 6.3%; 2017-19; 9.4%). Mortality (HR 1.08, 95%CI 0.90-1.29; 126 VRE, 37.6%; 2223 VSE, 37.0%) or discharge (HR 0.89, 95%CI 0.75-1.06; 126 VRE, 37.6%; 2386 VSE, 41.6%) was not different between VRE and VSE except in 2014 (HR 1.87, 95% CI 1.18-2.96). There was no interaction between time from admission to BSI (1-2, 3-14, and >14 days) and HR of death (P = 0.14) or discharge (P = 0.45) after VRE compared to VSE, despite longer time for VRE patients (17 vs. 10 days for VSE, P < 0.0001). In conclusion, VRE BSI was not associated with excess morbidity and mortality. The excess mortality in 2014 only may be attributed to improved diagnostic- and patient-management practices after 2014, reducing time to appropriate antibiotic therapy. The high level of mortality after E. faecium BSI warrants further study.

Mixed method examination of alcohol and suicidality among actively suicidal adults who engage in heavy episodic drinking.

Suicide is a serious public health problem in the United States. Alcohol use has been substantially documented as a risk factors for suicide, yet it is unclear how alcohol is associated with suicidal ideation (SI) and behavior (SIB) at the event level. We examined the association between alcohol use and SI using a mixed methods approach that included daily assessments from 13 adults who engage in heavy episodic drinking with current SI and qualitative interviews among 12 of those adults. Participants were recruited on social media. Separate mixed effects logistic regression models indicated that individuals' alcohol use on a given day was associated with SI (OR = 1.37), and suicidal urges (OR = 1.41). Adjusting for repeated measures, the expected marginal mean for intensity of SI (EMM = 3.33) and urges (EMM = 2.94) were higher on days with reported drinking behavior than days without reported drinking (EMM = 2.68 and EMM = 2.62 respectively). Qualitative data indicated that the association between alcohol use and SIB is more complex than a single directionality. Instead, the association can be unidirectional, bidirectional, and/or dependent on factors including mental health and amount of alcohol consumed. Overall, these findings emphasize a need for integrated alcohol and SIB interventions while providing insight on possible daily, just-in-time adaptations.

Risk factors for methicillin-resistant Staphylococcus aureus colonization in a level-IV neonatal intensive care unit: a retrospective study.

Objective: To identify risk factors associated with methicillin-resistant Staphylococcus aureus (MRSA) colonization in neonatal patients during an MRSA outbreak to minimize future outbreaks. Design: Retrospective case-control study. Setting: Level-IV neonatal intensive care unit (NICU) at Copenhagen University Hospital, Rigshospitalet, Denmark. Patients: Neonates with either MRSA or methicillin-susceptible Staphylococcus aureus (MSSA). Methods: Methicillin-resistant Staphylococcus aureus-positive neonates were matched with those colonized or infected with MSSA in a 1:1 ratio. The control group was selected from clinical samples, whereas MRSA-positive neonates were identified from clinical samples or from screening. A total of 140 characteristics were investigated to identify risk factors associated with MRSA acquisition. The characteristics were categorized into three categories: patient, unit, and microbiological characteristics. Results: Out of 1,102 neonates screened for MRSA, between December 2019 and January 2022, 33 were MRSA positive. They were all colonized with an MRSA outbreak clone (spa type t127) and were included in this study. Four patients (12%) had severe infection. Admission due to respiratory diseases, need for intubation, need for peripheral venous catheters, admission to shared rooms with shared toilets and bath facilities in the aisles, and need for readmission were all correlated with later MRSA colonization (P < 0.05). Conclusion: We identified clinically relevant diseases, procedures, and facilities that predispose patients to potentially life-threatening MRSA infections. A specific MRSA reservoir remains unidentified; however, these findings have contributed to crucial changes in our NICU to reduce the number of MRSA infections and future outbreaks.

Hey ChatGPT, Let's Talk About Sexual Consent.

Access to sexual health education, such as education on sexual consent, is limited in the US. Artificial intelligence (AI), such as ChatGPT, provides a potential opportunity to increase access to sexual consent information and education. However, what ChatGPT knows about sexual consent and if this aligns with the current evidence-based literature on sexual consent is unclear. The goal of this research commentary was to explore what ChatGPT knows about sexual consent with a focus on: 1) the definition of consent, 2) how consent could be communicated, and 3) the impact that substances have on consent. We also examined the reliability of ChatGPT's responses by having three different researchers ask ChatGPT the same set of questions. Across our questions, ChatGPT provided similar and comprehensive responses that discussed key features of consent - that consent is freely given or reversible. ChatGPT provided examples of different verbal and nonverbal cues people can use to communicate and interpret consent and discussed the ways that substances can impact consent communication. Overall, ChatGPT could be a potential resource for educators and young people who seek information about sexual consent; however, we should proceed with caution. ChatGPT is not a replacement for an educator but rather a way to increase access to education.

Emergence of linezolid-resistant Enterococcus faecium in a tertiary hospital in Copenhagen.

Linezolid is used as first-line treatment of infections caused by vancomycin-resistant Enterococcus faecium. However, resistance to linezolid is increasingly detected. The aim of the present study was to elucidate the causes and mechanisms for the increase in linezolid-resistant E. faecium at Copenhagen University Hospital - Rigshospitalet. We therefore combined patient information on linezolid treatment with whole-genome sequencing data for vancomycin- or linezolid-resistant E. faecium isolates that had been systematically collected since 2014 (n=458). Whole-genome sequencing was performed for multilocus sequence typing (MLST), identification of linezolid resistance-conferring genes/mutations and determination of phylogenetically closely related strains. The collection of E. faecium isolates belonged to prevalent vancomycin-resistant MLST types. Among these, we identified clusters of closely related linezolid-resistant strains compatible with nosocomial transmission. We also identified linezolid-resistant enterococcus isolates not genetically closely related to other isolates compatible with de novo generation of linezolid resistance. Patients with the latter isolates were significantly more frequently exposed to linezolid treatment than patients with related linezolid-resistant enterococcus isolates. We also identified six patients who initially carried a vancomycin-resistant, linezolid-sensitive enterococcus, but from whom vancomycin-resistant, linezolid-resistant enterococci (LVRE) closely related to their initial isolate were recovered after linezolid treatment. Our data illustrate that linezolid resistance may develop in the individual patient subsequent to linezolid exposure and can be transmitted between patients in a hospital setting.

Physical Limitations, Health Rumination/Worry, and Depressive Symptoms: Gender Differences among African Americans.

Although studies have documented the relationships between physical health, health rumination/worry, and mental health, few investigations have assessed these linkages within African American communities. Using a community-based sample of residents in historically lower-income, African American communities (N = 306), this study assesses the mediating role of health rumination/worry in the physical limitation-depressive symptom relationship, and the moderating effect of gender on the relationship between health rumination/worry-depressive symptoms. Findings demonstrate that health rumination/worry explains half of the physical limitation-depressive symptom relationship, and the relationship between health rumination/worry and depressive symptoms is stronger for African American men than women. The findings underscore the importance of intersectional research for policy efforts aimed at reducing mental health morbidities within African American communities.

An Endogenous Retrovirus Vaccine Encoding an Envelope with a Mutated Immunosuppressive Domain in Combination with Anti-PD1 Treatment Eradicates Established Tumours in Mice.

Endogenous retroviruses (ERVs) account for 8% of our genome, and, although they are usually silent in healthy tissues, they become reactivated and expressed in pathological conditions such as cancer. Several studies support a functional role of ERVs in tumour development and progression, specifically through their envelope (Env) protein, which contains a region described as an immunosuppressive domain (ISD). We have previously shown that targeting of the murine ERV (MelARV) Env using virus-like vaccine (VLV) technology, consisting of an adenoviral vector encoding virus-like particles (VLPs), induces protection against small tumours in mice. Here, we investigate the potency and efficacy of a novel MelARV VLV with a mutated ISD (ISDmut) that can modify the properties of the adenoviral vaccine-encoded Env protein. We show that the modification of the vaccine's ISD significantly enhanced T-cell immunogenicity in both prime and prime-boost vaccination regimens. The modified VLV in combination with an α-PD1 checkpoint inhibitor (CPI) exhibited excellent curative efficacy against large established colorectal CT26 tumours in mice. Furthermore, only ISDmut-vaccinated mice that survived CT26 challenge were additionally protected against rechallenge with a triple-negative breast cancer cell line (4T1), showing that our modified VLV provides cross-protection against different tumour types expressing ERV-derived antigens. We envision that translating these findings and technology into human ERVs (HERVs) could provide new treatment opportunities for cancer patients with unmet medical needs.

Within-patient horizontal transfer of pOXA-48 from a hypervirulent Klebsiella pneumoniae SL218 to Serratia marcescens following spread of the K. pneumoniae isolate among hospitalised patients, Denmark, 2021.

A hypervirulent Klebsiella pneumoniae SL218 (ST23-KL57), phylogenetically distinct from the classical hypervirulent SL23 (ST23-KL1) lineage, was transmitted between hospitalised patients in Denmark in 2021. The isolate carried a hybrid resistance and virulence plasmid containing bla NDM-1 and a plasmid containing bla OXA-48 (pOXA-48); the latter plasmid was horizontally transferred within-patient to Serratia marcescens. The convergence of drug resistance and virulence factors in single plasmids and in different lineages of K. pneumoniae is concerning and requires surveillance.

Effects of biological sex and oral contraceptive pill use on cutaneous microvascular endothelial function and nitric oxide-dependent vasodilation in humans.

The purpose of this study was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilation between women in either menstrual or placebo pill phases of their respective hormonal exposure [either naturally cycling (NC) or using oral contraceptive pills (OCPs)] and men. A planned subgroup analysis was then completed to assess endothelial function and NO-dependent vasodilation between NC women, women using OCP, and men. Endothelium-dependent and NO-dependent vasodilation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1 °C/s), and pharmacological perfusion through intradermal microdialysis fibers. Data are represented as means ± standard deviation. Men displayed greater endothelium-dependent vasodilation (plateau, men: 71 ± 16 vs. women: 52 ± 20%CVCmax, P < 0.01), but lower NO-dependent vasodilation (men: 52 ± 11 vs. women: 63 ± 17%NO, P = 0.05) compared with all women. Subgroup analysis revealed NC women had lower endothelium-dependent vasodilation (plateau, NC women: 48 ± 21%CVCmax, P = 0.01) but similar NO-dependent vasodilation (NC women: 52 ± 14%NO, P > 0.99), compared with men. Endothelium-dependent vasodilation did not differ between women using OCP and men (P = 0.12) or NC women (P = 0.64), but NO-dependent vasodilation was significantly greater in women using OCP (74 ± 11%NO) than both NC women and men (P < 0.01 for both). This study highlights the importance of directly quantifying NO-dependent vasodilation in cutaneous microvascular studies. This study also provides important implications for experimental design and data interpretation.NEW & NOTEWORTHY This study supports differences in microvascular endothelial function and nitric oxide (NO)-dependent vasodilation between women in low hormone phases of two hormonal exposures and men. However, when separated into subgroups of hormonal exposure, women during placebo pills of oral contraceptive pill (OCP) use have greater NO-dependent vasodilation than naturally cycling women in their menstrual phase and men. These data improve knowledge of sex differences and the effect of OCP use on microvascular endothelial function.

NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner.

Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.

Assessing the National Representativeness of Estimates of Antimicrobial-Resistant Urogenital Neisseria gonorrhoeae in US Men, Gonococcal Isolate Surveillance Project, 2008-2018.

BACKGROUND: The percentage of Neisseria gonorrhoeae (GC) isolates with resistance or elevated minimum inhibitory concentrations to antimicrobials has steadily increased. Current estimates are based on the Gonococcal Isolate Surveillance Project (GISP), a sentinel surveillance study of male GC in the United States. This analysis seeks to assess for adjustment before treating aggregated GISP estimates as nationally representative of all reported male urogenital infections. METHODS: We used multilevel regression with poststratification (MRP) to compute national estimates of the proportion of antimicrobial resistance (AMR) (defined as exceeding minimum inhibitory concentration thresholds) in male GC using data from 2008 to 2018 GISP and case reports. Sensitivity analyses investigated the impact of analysis assumptions and unmeasured variables. We additionally produced estimates of 2018 AMR GC cases among US men. RESULTS: National estimates were consistent with unweighted estimates. The estimated proportion of incident AMR GC infections in men with urogenital GC in 2018 was 51.5% (95% confidence interval [CI], 50.1%-52.9%), equating to an estimated 366,300 incident AMR GC infections in US men aged 15 to 39 years. Estimates of AMR for tested antimicrobials in male GC infections in 2018 ranged from 0.16% (95% CI, 0.08%-0.24%) for ceftriaxone to 29.9% (95% CI, 28.6%-31.1%) for ciprofloxacin. Sensitivity analyses revealed that unmeasured data on sex of sex partners could substantially impact weighted estimates. CONCLUSIONS: Antimicrobial resistance among reported incident male urogenital GC infections remains rare for ceftriaxone, the current standard of care. Aggregated GISP data are generally representative of men in the US who are reported with urogenital gonorrhea.

Microvascular endothelial function following cessation of long-term oral contraceptive pill use: A case report.

NEW FINDINGS: What is the main observation in this case? The main observation of this case report is substantial improvement in cutaneous microvascular endothelial function after cessation of long-term use of a fourth-generation oral contraceptive pill. This improvement appears independent of relative changes in the contribution of nitric oxide. What insights does it reveal? Our findings suggest that cessation of long-term, fourth-generation oral contraceptive pill use improves endothelial function within 20 months of cessation. ABSTRACT: The purpose of this case report was to evaluate in vivo endothelial function and nitric oxide (NO)-dependent vasodilatation before and after the cessation of long-term (11-12 years) fourth-generation oral contraceptive pill (OCP) use in one young, healthy and premenopausal woman. This retrospective analysis includes data from six experimental visits: three visits during months 133-144 of fourth-generation OCP use and three visits 19-22 months after OCP cessation. Endothelium-dependent and NO-dependent vasodilatation were assessed in the cutaneous microvasculature using laser-Doppler flowmetry, a rapid local heating protocol (39°C, 0.1°C/s) and pharmacological perfusion through intradermal microdialysis fibres. The participant had consistent medical history and lifestyle behaviours throughout both hormonal exposures. Data are presented as the mean (SD). Endothelium-dependent vasodilatation was 42 (10)% of site-specific maximal cutaneous vascular conductance (CVCmax ) during OCP use and 63 (10)%CVCmax after OCP cessation (49% increase). Nitric oxide-dependent vasodilatation was 70 (5)% contribution of NO during OCP use and 60 (15)%NO after OCP cessation (15% reduction). Baseline blood flow was greater after OCP cessation, but maximal blood flow was reduced. Data from this case report support a substantial increase in cutaneous microvascular endothelial function assessed via local heating after cessation of long-term use of a fourth-generation OCP, which does not appear to be attributable to increased NO bioavailability. Overall, these data suggest an improvement in endothelial and microvascular function after the cessation of long-term use of a fourth-generation OCP.

Vancomycin-resistant Enterococcus faecium: should we screen on admission?

Denmark has experienced an increase in the proportion of invasive vancomycin-resistant Enterococcus faecium (VRE) since 2002 (e.g. <4% in 2015, 7.1% in 2017 and 12% in 2018). At Rigshospitalet, we employ active screening at departments with high prevalence or in case of outbreaks. This includes the collection of rectal swabs specifically for VRE screening. Our purpose was to describe the carrier prevalence of vancomycin-resistant enterococci among acute patients admitted to the Neurointensive Care Unit, Department of Neuroanaesthesiology, Rigshospitalet, Copenhagen, Denmark (NICU). Between April 2018 and January 2019, we investigated 99 consecutive rectal swabs from patients admitted to NICU. The primary outcome was prevalence of VRE carriage. The median age was 64 years (range 23-87) and gender was equally distributed (Female = 47, Male = 46). 26 (28%) had previously been admitted within 179 days and 67 patients (72%) had no hospital admissions within 180 days prior to the admission to NICU. Of the 93 rectal swabs, 2 (2%, 95% CI 0.26-7.55%) were positive for vanA and none were positive for vanB. Routine screening of all patients at admission may be effective in hospital settings with high VRE prevalence, whereas the benefit of screening for VRE in hospitals with a low prevalence may be restricted to specific patient populations.

Deviations from typical paths: a novel approach to working with GPS data in the behavioral sciences.

BACKGROUND: Behavioral science researchers are increasingly collecting detailed location data such as second-by-second GPS tracking on participants due to increased ease and affordability. While intraindividual variability has been discussed in the travel literature for decades, traditional methods designed for studying individual differences in central tendencies limit the extent to which novel questions about variability in lived experiences can be answered. Thus, new methods of quantifying behavior that focus on intraindividual variability are needed to address the context in which the behavior occurs and the location tracking data from which behavior is derived. METHODS: We propose deviations from typical paths as a data processing technique to separate individual-level typical travel behavior from a location tracking data set in order to highlight atypical travel behavior as an outcome measure. RESULTS: A simulated data example shows how the method works to produce deviation measures from a location dataset. Analysis of these deviations offers additional insights compared to traditional measures of maximum daily distance from home. CONCLUSIONS: This process can be integrated into larger research questions to explore predictors of atypical behavior and potential mechanisms of behavior change.

Alcohol use and alcohol-related consequences based on gender and sexual orientation among college students.

BACKGROUND AND OBJECTIVES: Research has not yet investigated how the association between alcohol and alcohol-related consequences differs across cisgender heterosexual women (CHW), cisgender heterosexual men (CHM), and sexual and gender minority (SGM) college students. METHODS: Participants were N = 754 college students (34.5% CHW [n = 260]; 34.5% CHM [n = 260]; 31.0% SGM [n = 234]) between the ages 18 and 25 who completed a survey on sexual orientation, gender identity, alcohol use (i.e., average drinks per week), and alcohol-related consequences. RESULTS: Among individuals who reported alcohol use, CHM reported significantly more drinks per week compared to CHW and SGM. The logistic model of a zero-inflated negative binomial regression indicated that excess zeros in the alcohol-related consequences were more likely among (1) nondrinkers and (2) SGM compared to CHM. The count portion of the model indicated that, among drinkers, there was a positive association between drinks per week and alcohol-related consequences. Estimated alcohol-related consequences per drink were 1.90% higher among CHW than CHM and 2.76% higher among SGM than CHM. Exploratory analyses did not find significant differences in outcomes between cisgender female and male sexual minority students. DISCUSSION AND CONCLUSION: Findings suggest that although CHW and SGM students consume less alcohol than CHM, these students experience more alcohol-related consequences per drink. SCIENTIFIC SIGNIFICANCE: This study advances the field's knowledge of alcohol use patterns and consequences among SGM college students. There is a need for alcohol education programming that is tailored to the unique experiences, identities, and minority stressors of SGM college students.

Efficacy of piperacillin-tazobactam and cefotaxime against Escherichia coli hyperproducing TEM-1 in a mouse peritonitis infection model.

OBJECTIVES: Piperacillin-tazobactam (TZP) is a frequently prescribed antibiotic in hospital settings. Reports suggest in vivo efficacy of TZP, despite in vitro resistance of isolates susceptible to cephalosporins. Escherichia coli (E. coli) isolates hyperproducing TEM-1 ß-lactamase possess this phenotype. This study investigated the influence of tazobactam (TAZ) concentration on piperacillin (PIP) inhibition of such isolates and compared the in vivo efficacy of TZP with cefotaxime (CTX) in an infection model. METHODS: The PIP MICs for E. coli isolates, either hyperproducing TEM-1 because of promoter substitutions (n = 4) or because of gene amplification (n = 2) or producing an inhibitor-resistant TEM-35 (IRT) (n = 1), were determined using increasing concentrations of TAZ in a checkerboard setup. Furthermore, the efficacy of TZP and CTX against the isolates was investigated in a mouse peritonitis model using antibiotic exposures mimicking human conditions. Isolates producing either OXA-48 or CTX-M-15 ß-lactamases were included as controls. RESULTS: Using TAZ concentrations ≤ 64 mg/L, one isolate hyperproducing TEM-1 had a PIP MIC of 8 at TAZ 16 mg/L and two additional isolates at TAZ 64 mg/L. In the mouse peritonitis infection model, reduction of bacterial load in the peritoneum was larger for TZP than CTX only for the CTX-M-15-producing isolate. Larger reductions in bacterial load were observed after CTX treatment than TZP treatment for seven of the eight remaining test isolates. CONCLUSIONS: Piperacillin-tazobactam treatment of E. coli isolates hyperproducing TEM-1 was less effective than CTX treatment and may, for some isolates, be comparable with TZP treatment of isolates producing established resistance markers as IRT or OXA-48.