Evaluation of the Diagnosis and Antibiotic Prescription Pattern in Patients Hospitalized with Urinary Tract Infections: Single-Center Study from a University-Affiliated Hospital.

UTIs (urinary tract infections) are common bacterial infections with a non-negligible hospitalization rate. The diagnosis of UTIs remains a challenge for prescribers and a common source of misdiagnosis. This retrospective observational study aimed to evaluate whether recorded diagnosis by clinicians and empirical antibiotic therapy met the EAU (European Association of Urology) guideline in patients hospitalized with UTI. The study was conducted at an internal medicine unit of a tertiary care medical center in Hungary. The diagnosis was assessed based on clinical presentation, physical examination, and laboratory (including microbiological) results, considering all the potential risk factors. Diagnosis was considered misdiagnosis when not confirmed by clinical presentation or clinical signs and symptoms. Evaluation of empirical antibiotic therapy was performed only for confirmed UTIs. Empirical treatment was considered guideline-adherent when complying with the relevant recommendations. Out of 185 patients, 41.6% failed to meet EAU-based UTI diagnosis criteria, of which 27.6% were misdiagnosed and 14.1% were ABU (asymptomatic bacteriuria). The diagnosis of urosepsis recorded at admission (9.7%, 18/185) was not confirmed either by clinical or microbiological tests in five (5/18) cases. The initial empirical therapies for UTI showed a relatively low rate (45.4%) of guideline adherence regarding agent selection. The most common guideline-non-adherent therapies were combinations with metronidazole (16.7%). Dosage appropriateness assessments showed a guideline adherence rate of 36.1%, and underdosing due to high body weight was common (9.3%). Overall (agent, route of administration, dose, duration) guideline adherence was found to be substantially low (10.2%). We found a relatively high rate of misdiagnosed UTIs. Written protocols on the ward may be crucial in reducing misdiagnosis and in optimizing antibiotic use.

Pharmacological Evaluation of Newly Synthesized Cannabidiol Derivates on H9c2 Cells.

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid that can be found in Cannabis sativa and possesses numerous pharmacological effects. Due to these promising effects, CBD can be used in a wide variety of diseases, for instance cardiovascular diseases. However, CBD, like tetrahydrocannabinol (THC), has low bioavailability, poor water solubility, and a variable pharmacokinetic profile, which hinders its therapeutic use. Chemical derivatization of CBD offers us potential ways to overcome these issues. We prepared three new CBD derivatives substituted on the aromatic ring by Mannich-type reactions, which have not been described so far for the modification of cannabinoids, and studied the protective effect they have on cardiomyocytes exposed to oxidative stress and hypoxia/reoxygenation (H/R) compared to the parent compound. An MTT assay was performed to determine the viability of rat cardiomyocytes treated with test compounds. Trypan blue exclusion and lactate dehydrogenase (LDH) release assays were carried out to study the effect of the new compounds in cells exposed to H2O2 or hypoxia/reoxygenation (H/R). Direct antioxidant activity was evaluated by a total antioxidant capacity (TAC) assay. To study antioxidant protein levels, HO-1, SOD, catalase, and Western blot analysis were carried out. pIC50 (the negative log of the IC50) values were as follows: CBD1: 4.113, CBD2: 3.995, CBD3: 4.190, and CBD: 4.671. The newly synthesized CBD derivatives prevented cell death induced by H/R, especially CBD2. CBD has the largest direct antioxidant activity. The levels of antioxidant proteins were increased differently after pretreatment with synthetic CBD derivatives and CBD. Taken together, our newly synthesized CBD derivatives are able to decrease cytotoxicity during oxidative stress and H/R. The compounds have similar or better effects than CBD on H9c2 cells.

Impact of Guideline Adherence on Outcomes in Patients Hospitalized with Community-Acquired Pneumonia (CAP) in Hungary: A Retrospective Observational Study.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. This retrospective observational study evaluated the antibiotic prescription patterns and associations between guideline adherence and outcomes in patients hospitalized with CAP in Hungary. Main outcome measures were adherence to national and international CAP guidelines (agent choice, dose) when using empirical antibiotics, antibiotic exposure, and clinical outcomes. Demographic and clinical characteristics of patients with CAP in the 30-day mortality and 30-day survival groups were compared. Fisher's exact test and t-test were applied to compare categorical and continuous variables, respectively. Adherence to the national CAP guideline for initial empirical therapies was 30.61% (45/147) for agent choice and 88.89% (40/45) for dose. Average duration of antibiotic therapy for CAP was 7.13 ± 4.37 (mean ± SD) days, while average antibiotic consumption was 11.41 ± 8.59 DDD/patient (range 1−44.5). Adherence to national guideline led to a slightly lower 30-day mortality rate than guideline non-adherence (15.56% vs. 16.67%, p > 0.05). In patients aged ≥ 85 years, 30-day mortality was 3 times higher than in those aged 65−84 years (30.43% vs. 11.11%). A significant difference was found between 30-day non-survivors and 30-day survivors regarding the average CRP values on admission (177.28 ± 118.94 vs. 112.88 ± 93.47 mg/L, respectively, p = 0.006) and CCI score (5.71 ± 1.85 and 4.67 ± 1.83, p = 0.012). We found poor adherence to the national and international CAP guidelines in terms of agent choice. In addition, high CRP values on admission were markedly associated with higher mortality in CAP.

The Effect of Pharmacist-Led Intervention on Surgical Antibacterial Prophylaxis (SAP) at an Orthopedic Unit.

Perioperative antibiotic use is a common reason for antibiotic misuse. Evidence suggests that adherence to SAP guidelines may improve outcomes. The purpose of this study was to analyze the impact of pharmacist-led antibiotic stewardship interventions on SAP guideline compliance. The study was conducted at an Orthopedic Department of a tertiary care medical center. SAP compliance and antibiotic exposure in the pre-intervention and intervention period was compared using chi-square, Fisher exact, and Mann-Whitney tests, as appropriate. Prophylactic antibiotic use in orthopedic joint arthroplasties (overall guideline adherence: agent, dose, frequency, duration), clinical outcomes (length of stay-LOS, number of surgical site infections-SSIs), antibiotic exposure and direct antibiotic costs were compared between pre-intervention and intervention periods. Significant improvement in mean SAP duration (by 42.9%, 4.08 ± 2.08 vs. 2.08 ± 1.90 days, p ˂ 0.001), and overall guideline adherence regarding antibiotic use (by 56.2%, from 2% to 58.2%, p ˂ 0.001) were observed. A significant decrease was observed in antibiotic exposure in SAP (by 41%, from 6.07 ± 0.05 to 3.58 ± 4.33 DDD/patient, p ˂ 0.001), average prophylactic antibiotic cost (by 54.8%, 9278.79 ± 6094.29 vs. 3598.16 ± 3354.55 HUF/patient), and mean LOS (by 37.2%, from 11.22 ± 6.96 to 7.62 ± 3.02 days, p < 0.001); and a slight decrease in the number of confirmed SSIs was found between the two periods (by 1.8%, from 3% to 1.2%, p = 0.21). Continuous presence of the clinical pharmacist led to significant improvement in SAP guideline adherence, which was accompanied by decreased antibiotic exposure and cost.

Evolution of the Gram-Negative Antibiotic Resistance Spiral over Time: A Time-Series Analysis.

We followed up the interplay between antibiotic use and resistance over time in a tertiary-care hospital in Hungary. Dynamic relationships between monthly time-series of antibiotic consumption data (defined daily doses per 100 bed-days) and of incidence densities of Gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii) resistant to cephalosporins or carbapenems were followed using vector autoregressive models sequentially built of time-series ending in 2015, 2016, 2017, 2018, and 2019. Relationships with Gram-negative bacteria as a group were fairly stable across years. At species level, association of cephalosporin use and cephalosporin resistance of E. coli was shown in 2015-2017, leading to increased carbapenem use in these years. Association of carbapenem use and carbapenem resistance, as well as of carbapenem resistance and colistin use in case of A. baumannii, were consistent throughout; associations in case of Klebsiella spp. were rarely found; associations in case of P. aeruginosa varied highly across years. This highlights the importance of temporal variations in the interplay between changes in selection pressure and occurrence of competing resistant species.

Author Correction: A nonlinear time-series analysis approach to identify thresholds in associations between population antibiotic use and rates of resistance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A nonlinear time-series analysis approach to identify thresholds in associations between population antibiotic use and rates of resistance.

Balancing access to antibiotics with the control of antibiotic resistance is a global public health priority. At present, antibiotic stewardship is informed by a 'use it and lose it' principle, in which antibiotic use by the population is linearly related to resistance rates. However, theoretical and mathematical models suggest that use-resistance relationships are nonlinear. One explanation for this is that resistance genes are commonly associated with 'fitness costs' that impair the replication or transmissibility of the pathogen. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship-optimizing the control of resistance while avoiding over-restriction of antibiotics. Here, we evaluated the generalizability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between the use of selected antibiotics and incidence rates of carbapenem-resistant Acinetobacter baumannii (Hungary), extended-spectrum ß-lactamase-producing Escherichia coli (Spain), cefepime-resistant E. coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France) and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalizing population antibiotic use and controlling resistance. Prospective intervention studies that restrict antibiotic consumption are needed to validate these thresholds.

Utilization of Vector Autoregressive and Linear Transfer Models to Follow Up the Antibiotic Resistance Spiral in Gram-negative Bacteria From Cephalosporin Consumption to Colistin Resistance.

BACKGROUND: Increasing antibiotic resistance may reciprocally affect consumption and lead to use of broader-spectrum alternatives; a vicious cycle that may gradually limit therapeutic options. Our aim in this study was to demonstrate this vicious cycle in gram-negative bacteria and show the utility of vector autoregressive (VAR) models for time-series analysis in explanatory and dependent roles simultaneously. METHODS: Monthly drug consumption data in defined daily doses per 100 bed-days and incidence densities of gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii) resistant to cephalosporins or to carbapenems were analyzed using VAR models. These were compared to linear transfer models used earlier. RESULTS: In case of all gram-negative bacteria, cephalosporin consumption led to increasing cephalosporin resistance, which provoked carbapenem use and consequent carbapenem resistance and finally increased colistin consumption, exemplifying the vicious cycle. Different species were involved in different ways. For example, cephalosporin-resistant Klebsiella spp. provoked carbapenem use less than E. coli, and the association between carbapenem resistance of P. aeruginosa and colistin use was weaker than that of A. baumannii. Colistin use led to decreased carbapenem use and decreased carbapenem resistance of P. aeruginosa but not of A. baumannii. CONCLUSIONS: VAR models allow analysis of consumption and resistance series in a bidirectional manner. The reconstructed resistance spiral involved cephalosporin use augmenting cephalosporin resistance primarily in E. coli. This led to increased carbapenem use, provoking spread of carbapenem-resistant A. baumannii and consequent colistin use. Emergence of panresistance is fueled by such antibiotic-resistance spirals.

Comparison of rates of fecal colonization with extended-spectrum beta-lactamase-producing enterobacteria among patients in different wards, outpatients and medical students.

Because asymptomatic carriage of extended-spectrum beta-lactamase (ESBL) producers is a risk factor for infection, data on colonization dynamics are important when planning infection control. This study investigated fecal colonization with ESBL producers among inpatients, outpatients and medical students and compares the characteristics of ESBL producers among these groups. Carriage rates were investigated in 5581 fecal samples; 4343 from inpatients (330, 1397, 619 and 1864 from adult ICUs [intensive care units], adult non-ICUs, pediatric ICUs and pediatric non-ICUs, respectively), 814 from outpatients and 424 from screening of medical students. ESBL producers were characterized by co-resistance, integrons carried, and aminoglycoside resistance and ESBL genes. Dynamic regression models were built to identify relationships between combinations of time series of monthly antibiotic consumption, prevalence of carriers and infected subjects. Inpatients, ICU patients and adults showed higher prevalence than outpatients, non-ICU patients or children (7.4%, 9.3% and 12.0% vs. 3.1%, 6.1% and 4.1%, respectively). Klebsiella pneumoniae was more frequent in ICU patients; dominance of CTX-M-15 producers was more marked in adult than in pediatric inpatients. ESBL carriage was shown to be a consequence of infection in adults in the time-series analysis; antibiotic consumption had little effect. The epidemiology of colonization with ESBL producers differed between pediatric ICU, adult ICU and adult non-ICU patients. In adults, carriage of ESBL producers seems to be the consequence of infection, especially in ICU patients; the main source of colonization is nosocomial acquisition. In contrast, children are less likely to acquire colonizer strains in hospitals; importation of ESBL producers by colonized children seems to be significant.