The association of body temperature with antibiotic therapy and mortality in patients attending the emergency department with suspected infection

BACKGROUND AND IMPORTANCE: Previous studies found that septic patients with normothermia have higher mortality than patients with fever. We hypothesize that antibiotic therapy is less frequently initiated if infectious patients present with normothermia to the emergency department (ED). OBJECTIVES: To examine the association of body temperature with the initiation of antibiotic therapy in patients attending the ED with suspected and proven infection. Additionally, the association of temperature with 30-day mortality was assessed. DESIGN, SETTINGS AND PARTICIPANTS: We conducted a retrospective cohort study between 2012 and 2016 at a tertiary university hospital. Adult patients attending the ED with a blood culture taken (i.e. suspected infection) and a positive blood culture (i.e. proven bacteremia) were included. EXPOSURE: Tympanic temperature at arrival was categorized as hypothermia (38.0°C). OUTCOME MEASURES AND ANALYSIS: Primary outcome was the initiation of antibiotic therapy. A secondary outcome was 30-day mortality. Multivariable logistic regression was used to control for covariates. MAIN RESULTS: Of 5997 patients with a suspected infection, 45.8% had normothermia, 44.6% hyperthermia and 5.6% hypothermia. Patients with hyperthermia received more often antibiotic therapy (53.5%) compared to normothermic patients (27.6%, adjusted odds ratio [95% confidence interval], 2.59 [2.27–2.95]). Patients with hyperthermia had lower mortality (4.7%) than those with normothermia (7.4%, adjusted odds ratio [95% confidence interval], 0.50 [0.39–0.64]). Sensitivity analyses in patients with proven bacteremia (n = 934) showed similar results. CONCLUSION: Normothermia in patients presenting with infection was associated with receiving less antibiotic therapy in the ED compared to presentations with hyperthermia. Moreover, normothermia was associated with a higher mortality risk than hyperthermia

Mycobacterium tuberculosis Beijing Type Mutation Frequency.

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Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field

The association of body temperature with antibiotic therapy and mortality in patients attending the emergency department with suspected infection

BACKGROUND AND IMPORTANCE: Previous studies found that septic patients with normothermia have higher mortality than patients with fever. We hypothesize that antibiotic therapy is less frequently initiated if infectious patients present with normothermia to the emergency department (ED). OBJECTIVES: To examine the association of body temperature with the initiation of antibiotic therapy in patients attending the ED with suspected and proven infection. Additionally, the association of temperature with 30-day mortality was assessed. DESIGN, SETTINGS AND PARTICIPANTS: We conducted a retrospective cohort study between 2012 and 2016 at a tertiary university hospital. Adult patients attending the ED with a blood culture taken (i.e. suspected infection) and a positive blood culture (i.e. proven bacteremia) were included. EXPOSURE: Tympanic temperature at arrival was categorized as hypothermia (38.0°C). OUTCOME MEASURES AND ANALYSIS: Primary outcome was the initiation of antibiotic therapy. A secondary outcome was 30-day mortality. Multivariable logistic regression was used to control for covariates. MAIN RESULTS: Of 5997 patients with a suspected infection, 45.8% had normothermia, 44.6% hyperthermia and 5.6% hypothermia. Patients with hyperthermia received more often antibiotic therapy (53.5%) compared to normothermic patients (27.6%, adjusted odds ratio [95% confidence interval], 2.59 [2.27–2.95]). Patients with hyperthermia had lower mortality (4.7%) than those with normothermia (7.4%, adjusted odds ratio [95% confidence interval], 0.50 [0.39–0.64]). Sensitivity analyses in patients with proven bacteremia (n = 934) showed similar results. CONCLUSION: Normothermia in patients presenting with infection was associated with receiving less antibiotic therapy in the ED compared to presentations with hyperthermia. Moreover, normothermia was associated with a higher mortality risk than hyperthermia

Unraveling antibiotic resistance mechanisms in Mycobacterium abscessus: the potential role of efflux pumps

ABSTRACT: Objectives: Mycobacterium abscessus is an opportunistic respiratory pathogen in patients with underlying lung disease. It is infamously known for its low treatment success rates because of its resistance to multiple classes of antibiotics. Further insight into M. abscessus resistance mechanisms is needed to improve treatment options. In this in vitro study, the role of efflux pumps in reaction to antibiotic stress is explored, as well as the ability of the putative efflux inhibitors, thioridazine and verapamil, to potentiate the activity of guideline-recommended antibiotics. Methods: To evaluate the effects of antibiotic stress on mycobacterial efflux pumps, M. abscessus subspecies abscessus was exposed to amikacin, cefoxitin, clarithromycin, clofazimine, and tigecycline for 24 hours. Transcriptomic responses were measured by RNA sequencing to gain insight into upregulation of efflux pump encoding genes. Subsequently, in time-kill kinetics assays, the above-mentioned antibiotics were combined with thioridazine and verapamil to evaluate their potentiating capacity. Results: All five antibiotics led to a fold change of ≥2 Log2 in expression of one or more genes encoding transporter systems. This effect was most pronounced for the ribosome-targeting antibiotics amikacin, clarithromycin, and tigecycline. Time-kill kinetics assays demonstrated synergy between amikacin, tigecycline, clofazimine, cefoxitin, and both thioridazine and verapamil. Conclusion: Antibiotic stressors induce expression of efflux pump encoding genes in M. abscessus, especially antibiotics that target the ribosome. Putative efflux inhibitors thioridazine and verapamil show synergy with various guideline-recommended antibiotics, making them interesting candidates for the improvement of M. abscessus treatment

Unraveling antibiotic resistance mechanisms in Mycobacterium abscessus: the potential role of efflux pumps

Objectives: Mycobacterium abscessus is an opportunistic respiratory pathogen in patients with underlying lung disease. It is infamously known for its low treatment success rates because of its resistance to multiple classes of antibiotics. Further insight into M. abscessus resistance mechanisms is needed to improve treatment options. In this in vitro study, the role of efflux pumps in reaction to antibiotic stress is explored, as well as the ability of the putative efflux inhibitors, thioridazine and verapamil, to potentiate the activity of guideline-recommended antibiotics. Methods: To evaluate the effects of antibiotic stress on mycobacterial efflux pumps, M. abscessus subspecies abscessus was exposed to amikacin, cefoxitin, clarithromycin, clofazimine, and tigecycline for 24 hours. Transcriptomic responses were measured by RNA sequencing to gain insight into upregulation of efflux pump encoding genes. Subsequently, in time-kill kinetics assays, the above-mentioned antibiotics were combined with thioridazine and verapamil to evaluate their potentiating capacity. Results: All five antibiotics led to a fold change of ≥2 Log2 in expression of one or more genes encoding transporter systems. This effect was most pronounced for the ribosome-targeting antibiotics amikacin, clarithromycin, and tigecycline. Time-kill kinetics assays demonstrated synergy between amikacin, tigecycline, clofazimine, cefoxitin, and both thioridazine and verapamil. Conclusion: Antibiotic stressors induce expression of efflux pump encoding genes in M. abscessus, especially antibiotics that target the ribosome. Putative efflux inhibitors thioridazine and verapamil show synergy with various guideline-recommended antibiotics, making them interesting candidates for the improvement of M. abscessus treatment

Less Is More:When to Repeat Antimicrobial Susceptibility Testing

This study investigated the frequency of change of the antimicrobial susceptibility pattern when the same isolate was found in the same patient in various situations. We used laboratory data collected over a period of 8 years (January 2014 to December 2021) at the clinical microbiology laboratory of a tertiary hospital for Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa, and Staphylococcus aureus. Antimicrobial susceptibility tests (AST) were performed using Vitek 2 automated system. We determined essential agreement and categorical agreement, and introduced the new terms essential MIC increase and change from nonresistant to resistant to present changes in antimicrobial susceptibility over time. During the study period, 18,501 successive AST were included. The risk for S. aureus to be resistant to any antibiotic upon repeated culture was,10% during a follow-up of 30 days. For Enterobacterales, this risk was approximately 10% during a follow-up of 7 days. For P. aeruginosa, this risk was higher. The longer the follow-up period, the higher the risk that the bacteria would show phenotypic resistance. We also found that some drug-bug combinations were more likely to develop phenotypical resistance (i.e., E. coli/amoxicillin-clavulanic acid and E. coli/cefuroxime). A potential consequence of our finding is that if we regard a risk of resistance below 10% as acceptable, it may be feasible to omit follow-up AST within 7 days for the microorganisms investigated in this study. This approach saves money, time, and will reduce laboratory waste. Further studies are needed to determine whether these savings are in balance with the small possibility of treating patients with inadequate antibiotics.</p

Drug Susceptibility of Mycobacterium tuberculosis Beijing Genotype and Association with MDR TB

To determine differences in the ability of Mycobacterium tuberculosis strains to withstand antituberculosis drug treatment, we compared the activity of antituberculosis drugs against susceptible Beijing and East-African/Indian genotype M. tuberculosis strains. Beijing genotype strains showed high rates of mutation within a wide range of drug concentrations, possibly explaining this genotype’s association with multidrug-resistant tuberculosis

Superior Efficacy of a Bedaquiline, Delamanid, and Linezolid Combination Regimen in a Mouse Tuberculosis Model

Background: The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required. Methods: We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens. Results: Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively. Conclusion: The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis