Search Results (6,313)

The discovery of new antimicrobials is necessary to combat multidrug-resistant (MDR) bacteria, especially those that infect wounds and form prodigious biofilms, such as Acinetobacter baumannii. Antimicrobial peptides (AMPs) are a promising class of new therapeutics against drug-resistant bacteria, including gram-negatives. Here, we utilized a computational AMP design strategy combining database filtering technology plus positional analysis to design a series of novel peptides, named HRZN, designed to be active against A. baumannii. All of the HRZN peptides we synthesized exhibited antimicrobial activity against three MDR A. baumannii strains with HRZN-15 being the most active (MIC 4 µg/mL). This peptide also inhibited and eradicated biofilm of A. baumannii strain AB5075 at 8 and 16 µg/mL, which is highly effective. HRZN-15 permeabilized and depolarized the membrane of AB5075 rapidly, as demonstrated by the killing kinetics. HRZN 13 and 14 peptides had little to no hemolysis activity against human red blood cells, whereas HRZN-15, -16, and -17 peptides demonstrated more significant hemolytic activity. HRZN-15 also demonstrated toxicity to waxworms. Further modification of HRZN-15 could result in a new peptide with an improved toxicity profile. Overall, we successfully designed a set of new AMPs that demonstrated activity against MDR A. baumannii using a computational approach. Full article

A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results. Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6–12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52–72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock. Full article

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a global health concern. The antimicrobial resistance, virulence, and molecular typing of 57 CRPA isolated from 43 patients who attended a specific Tunisian hospital from September 2018 to July 2019 were analyzed. All but one were multidrug-resistant CRPA, and 77% were difficult-to-treat-resistant (DTR) isolates. The bla_VIM-2 gene was detected in four strains (6.9%), and among the 36 bla_GES-positive CRPA (62%), the bla_GES-5 gene was the predominant variant (86%). Three strains co-harbored the bla_VIM-2 and bla_GES-45 genes, and seven CRPA carried the bla_SHV-2a gene (14%). OprD alterations, including truncations by insertion sequences, were observed in 18 strains. Regarding the 46 class 1 integron-positive CRPA (81%), the bla_GES-5 gene was located in integron In717, while the bla_GES-29 and bla_GES-45 genes were found in two new integrons (In2122 and In4879), and the bla_VIM-2 gene was found in In1183 and the new integron In2142. Twenty-four PFGE patterns and thirteen sequence types (three new ones) were identified. The predominant serotype O:11 and exoU (81%) were mostly associated with ST235 and the new ST3385 clones. The seven bla_SHV-2a-CRPA from different patients belonged to ST3385 and the same PFGE pattern. The bla_GES-5- and bla_VIM-2 + bla_GES-45-positive CRPA recovered mostly from ICU patients belonged to the high-risk clone ST235. Our results highlight the alarming prevalence of bla_GES-5- and ST235-CRPA, the co-existence of bla_GES-45 and bla_VIM-2, and their location within integrons favoring their dissemination. Full article

In this study, we use real-world data to explore trends in antibiotic use in a dynamic cohort of long-term care (LTC) residents. A cross-sectional retrospective analysis of pharmacy medication supply records of 3459 LTC residents was conducted from 31 May 2016 to 31 May 2019. The primary outcome was the monthly prevalence of residents with an antibiotic episode. Secondary outcomes were the type of antibiotic used and duration of use. Over the three-year study period, residents were supplied 10460 antibiotics. On average, 18.9% of residents received an antibiotic monthly. Antibiotic use decreased slightly over time with a mean of 168/1000 (95% CI 146–177) residents using at least one antibiotic per month in June 2016 to 148/1000 (95% CI 127–156) in May 2019. The total number of antibiotic days per 100 resident days remained relatively constant over the study period: 8.8 days in 2016–2017, 8.4 in 2017–2018 and 6.4 in 2018–2019. Prolonged durations exceeding 100 days were seen for a small percentage of residents. We found extensive antibiotic use, which is a recognized contributor to antimicrobial resistance development, underscoring the necessity for quality treatment guidelines in this vulnerable population. Full article

This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC_{0–24 h} of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log₁₀ cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus. Full article

Although females have a higher rate of primary total joint arthroplasty (TJA), males have a higher rate of revision. The literature lacks studies examining the relationship between sex and outcomes following single and two-stage exchange for periprosthetic joint infection (PJI). The purpose of this study was to examine if differences exist in outcomes following revision for chronic PJI between sexes. A retrospective review was performed on all patients with an MSIS confirmed PJI who underwent a single or two-stage exchange at our institution from January 2010 to January 2021. Patient demographics, comorbidity characteristics, and outcomes were collected and compared between males and females. The primary outcome variable was disease-free survival at 1 year following definitive revision. Multivariable logistic regression analysis was performed to determine risk factors for failure. Of the 470 patients meeting final eligibility criteria, 250 were male and 226 were female (2 males and 4 females had a joint infection of either the contralateral side or a different joint and were treated as separate records). Of the patients in the cohort, 80% of the males (200/250) and 80% of the females (181/226) were found to be disease-free at 1-year follow-up (p > 0.99). Multivariable logistic regression analysis showed that nicotine use and diabetes, but not sex, were significant predictors of failure. Our study did not find a relationship between sex and outcome of revision for PJI. Further research is required to determine whether differences exist between males and females in the expression of PJI and outcomes following treatment. Full article

Background: Bedaquiline (BDQ) has been designated as a Group A drug by the World Health Organization (WHO) for the management of multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). This systematic review and meta-analysis aim to evaluate the efficacy and safety of BDQ-containing regimens for the treatment of patients with pulmonary TB. Methods: PubMed (MEDLINE), Elton B. Stephens Company (EBSCO) database, the Cochrane Register of Controlled Trials, and the China National Knowledge Infrastructure (CNKI) database were initially searched on 15 June 2022 and again on 20 March 2023. We included randomized controlled trials (RCTs) and non-randomized studies (NRSs) that administered BDQ to TB patients. The outcomes of interest were as follows: (1) efficacy, including the rate of sputum culture conversion at 8 weeks, 24 weeks, and during follow-up, as well as the rates of completion cure, death, treatment failure, and loss at follow-up and at the end of the treatment; and (2) safety, which encompassed the incidences of cardiotoxicity, hepatotoxicity, and grade 3–5 adverse events during the treatment period. Results: A total of 29 articles were included in this meta-analysis, representing 23,358 individuals. Patients who were treated with BDQ were compared with patients who were not exposed to BDQ. The use of BDQ-containing regimens demonstrated improved rates of sputum conversion in RCTs at 24 weeks (RR = 1.27, 95% CI: 1.10 to 1.46) and during follow-up (RR = 1.33, 95% CI: 1.06 to 1.66). Additionally, BDQ-containing regimens showed increased cure rates (RR = 1.60, 95% CI: 1.13 to 2.26) and decreased failure rates (RR = 0.56, 95% CI: 0.56 to 0.88). In NRSs, BDQ-containing regimens improved the sputum culture conversion rate during follow-up (RR = 1.53, 95% CI: 1.07 to 2.20), increased the rate of cure (RR = 1.86, 95% CI: 1.23 to 2.83), reduced deaths from all causes (RR = 0.68, 95% CI: 0.48 to 0.97), and reduced failure rates (RR = 0.57, 95% CI: 0.46 to 0.71). However, the use of BDQ-containing regimens was associated with increased incidences of cardiotoxicity (RR = 4.54, 95% CI: 1.74 to 11.87) and grade 3–5 adverse events (RR = 1.42, 95% CI: 1.17 to 1.73) in RCTs. NRSs also showed an association between BDQ-containing regimens and cardiotoxicity (RR = 6.00, 95% CI: 1.32 to 27.19). No significant differences were observed between intervention groups and control groups with respect to other outcomes. Conclusions: Data from both RCTs and NRSs support the efficacy of BDQ for the treatment of pulmonary tuberculosis. However, the use of BDQ is associated with a higher incidence of cardiotoxicity and serious adverse events. Comparative data on efficacy and safety are limited, and further confirmation is required, due to potential bias and discrepancies in the available studies. Full article

(1) Objectives: To describe the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin–tazobactam or meropenem monotherapy and microbiological outcome in a case series of urological patients with documented Gram-negative infections. (2) Methods: Patients admitted to the urology ward who were treated with CI piperacillin–tazobactam or meropenem monotherapy for documented Gram-negative infections and underwent real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program from June 2021 to May 2023 were retrospectively retrieved. Average steady-state (C_ss) piperacillin–tazobactam and meropenem concentrations were determined, and the free fractions (fC_ss) were calculated. Optimal PK/PD target attainments were defined as an fC_ss/MIC ratio >4 for CI meropenem and an fC_ss/MIC ratio of piperacillin >4 coupled with an fC_ss/C_T ratio for tazobactam >1 for piperacillin–tazobactam (joint PK/PD target). The relationship between beta-lactam PK/PD targets and microbiological outcome was explored. (3) Results: Sixteen urologic patients with documented Gram-negative infections (62.5% complicated urinary tract infections (cUTI)) had 30 TDM-guided ECPAs. At first TDM assessment, beta-lactam dosing adjustments were recommended in 11 out of 16 cases (68.75%, of which 62.5% decreases and 6.25% increases). Overall, beta-lactam dosing adjustments were recommended in 14 out of 30 ECPAs (46.6%). Beta-lactam PK/PD target attainments were optimal in 100.0% of cases. Microbiological failure occurred in two patients, both developing beta-lactam resistance. (4) Conclusion: A TDM-guided ECPA program may allow for optimizing beta-lactam treatment in urologic patients with documented Gram-negative infections, ensuring microbiological eradication in most cases. Full article

Aliarcobacter butzleri is a Gram-negative bacterium associated with infections of the gastrointestinal tract and widely distributed in various environments. For successful infection, A. butzleri should be able to tolerate various stresses during gastrointestinal passage, such as bile. Bile represents an antimicrobial host barrier that acts against external noxious agents and consists of a variety of bile salts. The intestinal bile salts act as detergents involved in the antimicrobial host defense; although, on the bacterial side, they could also serve as a signal to activate virulence mechanisms. The aim of this work was to understand the effects of bile salts on the survival and virulence of A. butzleri. In our study, A. butzleri was able to survive in the presence of human physiological concentrations of bile salts. Regarding the virulence features, an increase in cellular hydrophobicity, a decrease in motility and expression of flaA gene, as well as an increase in biofilm formation with a concomitant change in the type of biofilm structure were observed in the presence of sub-inhibitory concentration of bile salts. Concerning adhesion and invasion ability, no significant difference was observed. Overall, the results demonstrated that A. butzleri is able to survive in physiological concentrations of bile salts and that exposure to bile salts could change its virulence mechanisms. Full article

A total of 199 Gram-negative bacterial isolates from urinary tract infections and 162 from bloodstream infections were collected from 12 healthcare systems throughout the United States between May 2021 and August 2022. The isolates, phenotypically non-susceptible to 2nd or 3rd generation cephalosporins or carbapenems, were characterized through antimicrobial susceptibility testing and whole genome sequence analysis to obtain a broad snapshot of beta-lactamase-mediated resistance among these two sample types. Overall, 23 different carbapenemase genes were detected among 13 species (20.5% of isolates). The bla_KPC-3 and bla_KPC-2 subtypes were the most common carbapenemase genes identified, followed by bla_NDM and the co-carriage of two different bla_OXA carbapenemases by Acinetobacter baumannii isolates. All carbapenemase-producing A. baumannii isolates were mCIM negative. Extended-spectrum beta-lactamase genes were identified in 66.2% of isolates; bla_CTX-M-15 was the most common. AmpC genes, both plasmid and chromosomal, were detected in 33.2% of isolates. Importantly, 2.8%, 8.3%, and 22.2% of bla_KPC-positive organisms were susceptible to ertapenem, imipenem, and meropenem, respectively. The correlation between broth microdilution and disk diffusion results was high for most drugs except cefepime, where the detection of resistance was statistically lower by disk diffusion. Thus, there were gaps in the accuracy of susceptibility testing for some mechanisms of resistance. Full article

Background: Tuberculosis affects millions of people worldwide. The emergence of drug-resistant Mycobacterium tuberculosis strains has made treatment more difficult. A drug discovery project initiated to screen natural products identified a lead stilbene compound, and structure function analysis of hundreds of analogs led to the discovery of the SK-03-92 stilbene lead compound with activity against several non-tuberculoid mycobacteria. Methods: For this study, an MIC analysis and intracellular killing assay were performed to test SK-03-92 against M. tuberculosis grown in vitro as well as within murine macrophage cells. Results: The MIC analysis showed that SK-03-92 had activity against M. tuberculosis in the range of 0.39 to 6.25 μg/mL, including activity against single-drug-resistant strains. Further, an intracellular kill assay demonstrated that the SK-03-92 lead compound killed M. tuberculosis cells within murine macrophage cells. Conclusion: Together, the data show the SK-03-92 lead compound can kill M. tuberculosis bacteria within mammalian macrophages. Full article

Articulating hip spacers for periprosthetic joint infection (PJI) offer numerous advantages over static spacers such as improved patient mobilization, hip functionality, and soft tissue tension. Our study aimed to determine complication rates of a functional articulating spacer using a constrained liner to determine the role of acetabular cementation mantle and bone loss on the need for second-stage surgery. A retrospective review of 103 patients was performed and demographic information, spacer components and longevity, spacer-related complications, reinfection rates, and grade of bone loss and acetabular cement mantle quality were determined. There was no significant difference in spacer-related complications or reinfection rate between PJI and native hip infections. 33 of 103 patients (32.0%) elected to retain their spacers. Between patients who retained their initial spacer and those who underwent reimplantation surgery, there was not a significant difference in cement mantle grade (p = 0.52) or degree of bone loss (p = 0.78). Functional articulating antibiotic spacers with cemented constrained acetabular liners demonstrate promising early results in the treatment of periprosthetic and native hip infections. The rate of dislocation events was low. Further efforts to improve cement fixation may help decrease the need for second-stage reimplantation surgery. Full article

Most urinary tract infections (UTIs) are self-limiting and frequently present in primary care; it is common for patients to seek symptom relief. The TARGET Treating Your Infection (TYI) leaflet was used to respond to UTI symptoms for women under 65 years presenting in community pharmacies. The widespread use of these leaflets was incentivised as part of NHS England’s Pharmacy Quality Scheme (PQS) 2022–23, between October 2022 and March 2023. The TARGET TYI leaflets are aimed to support appropriate antibiotic use and antimicrobial stewardship (AMS) as well as reducing the opportunity for resistance to develop. A total of 8363 community pharmacies completed the AMS criteria within the PQS and collectively submitted data for 104,142 patients presenting with UTI symptoms. The majority, 77% (75,071), of (non-pregnant) women presented with none or only one of the three strongly predictive symptoms of dysuria, new nocturia, cloudy urine, and/or vaginal discharge and, therefore, were less likely to have a UTI, as outlined in the English UTI diagnostic guidance. Conversely, 23% (22,381) of women presented with two or more symptoms of dysuria, new nocturia, cloudy urine, and with no vaginal discharge and, therefore, they were more likely to have a UTI. The TARGET TYI UTI leaflets support community pharmacy teams to differentiate between symptoms more likely to be associated with UTIs and those that could be managed with self-care. The findings suggest that most women presenting to community pharmacies with urinary symptoms were likely to have self-limiting symptoms, and could be suitably managed with self-care, pain relief, and appropriate safety netting. Approximately one-third of patients were managed by community pharmacy team members without the need for referral to a pharmacist and one in five patients presented with escalation symptoms and were signposted to other healthcare settings. A total of 94% (97,452) of women received self-care advice of which 36% (37,565) were also provided with additional patient information leaflets. Full article

Antibiotic resistance caused by multidrug-resistant (MDR) bacteria is a major challenge to global public health. Polymyxins are increasingly being used as last-in-line antibiotics to treat MDR Gram-negative bacterial infections, but resistance development renders them ineffective for empirical therapy. The main mechanism that bacteria use to defend against polymyxins is to modify the lipid A headgroups of the outer membrane by adding phosphoethanolamine (PEA) moieties. In addition to lipid A modifying PEA transferases, Gram-negative bacteria possess PEA transferases that decorate proteins and glycans. This review provides a comprehensive overview of the function, structure, and mechanism of action of PEA transferases identified in pathogenic Gram-negative bacteria. It also summarizes the current drug development progress targeting this enzyme family, which could reverse antibiotic resistance to polymyxins to restore their utility in empiric therapy. Full article