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ACS Infectious Diseases Apr 2024Effective treatment of gonorrhea is threatened by the increasing prevalence of strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we...
Effective treatment of gonorrhea is threatened by the increasing prevalence of strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido β-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R group. Crystal structures show that the ureido β-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of β-lactams with improved activity against ESC-resistant .
Topics: Humans; Ceftriaxone; Neisseria gonorrhoeae; Gonorrhea; Penicillin-Binding Proteins; Cefoperazone; Cephalosporins; Piperacillin; beta-Lactams
PubMed: 38446051
DOI: 10.1021/acsinfecdis.3c00713 -
Antibiotics (Basel, Switzerland) Oct 2023Antibiotics are widely used for prophylaxis and therapy, reducing morbidity and mortality produced by bacterial pathogensin pigs, including infections caused by . The...
Antibiotics are widely used for prophylaxis and therapy, reducing morbidity and mortality produced by bacterial pathogensin pigs, including infections caused by . The aim of this study was to characterise antibiotic resistance phenotypes and genotypes in isolates in pigs in West Romanian grower farms. Differential phenotypic susceptibility profiles and the contribution of resistance genes to phenotypic expression of susceptibility or resistance were evaluated. A total of 76 isolates were identified and confirmed by the MicroScan Walk Away System. The occurrence of four resistance genes, ampC, blaZ, blaTEM and tetK in strains resistant to 13 antibiotics was assessed. Of the isolates, 0% showed resistance to meropenem, 3.9% to tigecycline and 10.5% to piperacillin/tazobactam, whereas, in contrast, 100% were resistant to ampicillin and mezlocillin, 76.31% to piperacillin and 59.3% to tetracycline. The prevalence of resistance genes in resistant isolates detected by q-PCR analysis was 97.0% for ampC, 96% for blaZ, 32.9% for blaTEM and 58.8% for tetK. Penetrance (the proportion of individuals carrying a particular variant of a gene that also expresses an associated trait) was 50% for ampC (32% for amoxicillin/clavulanate, 62% for cefazolin, 32% for cefepime, 100% for cefotaxime, 56% for cefuroxime and 99% for ampicillin), 65% for blaZ (32% for amoxicillin/clavulanate and 99% for ampicillin), 51% for blaTEM (81% for piperacillin) and 44% for the tetK gene (83% for tetracycline). The result of phenotypic antibiotic resistance testing may indicate the presence of plasmid-borne resistance, with a diagnostic odds ratio of a positive phenotypic resistance for tetK being 4.52. As a management decision, the maximum penetrance admitted for using a specific antibiotic for infections in pigs is recommended to be less than 20%.
PubMed: 37887245
DOI: 10.3390/antibiotics12101544 -
Frontiers in Pharmacology 2023Acute kidney injury (AKI) is a common adverse reaction observed with the clinical use of cefoperazone-sulbactam sodium and mezlocillin-sulbactam sodium. Based upon...
Risk-factor analysis and predictive-model development of acute kidney injury in inpatients administered cefoperazone-sulbactam sodium and mezlocillin-sulbactam sodium: a single-center retrospective study.
Acute kidney injury (AKI) is a common adverse reaction observed with the clinical use of cefoperazone-sulbactam sodium and mezlocillin-sulbactam sodium. Based upon real-world data, we will herein determine the risk factors associated with AKI in inpatients after receipt of these antimicrobial drugs, and we will develop predictive models to assess the risk of AKI. Data from all adult inpatients who used cefoperazone-sulbactam sodium and mezlocillin-sulbactam sodium at the First Affiliated Hospital of Shandong First Medical University between January 2018 and December 2020 were analyzed retrospectively. The data were collected through the inpatient electronic medical record (EMR) system and included general information, clinical diagnosis, and underlying diseases, and logistic regression was exploited to develop predictive models for the risk of AKI. The training of the model strictly adopted 10-fold cross-validation to validate its accuracy, and model performance was evaluated employing receiver operating characteristic (ROC) curves and the areas under the curve (AUCs). This retrospective study comprised a total of 8767 patients using cefoperazone-sulbactam sodium, of whom 1116 developed AKI after using the drug, for an incidence of 12.73%. A total of 2887 individuals used mezlocillin-sulbactam sodium, of whom 265 developed AKI after receiving the drug, for an incidence of 9.18%. In the cohort administered cefoperazone-sulbactam sodium, 20 predictive factors ( < 0.05) were applied in constructing our logistic predictive model, and the AUC of the predictive model was 0.83 (95% CI, 0.82-0.84). In the cohort comprising mezlocillin-sulbactam sodium use, nine predictive factors were determined by multivariate analysis ( < 0.05), and the AUC of the predictive model was 0.74 (95% CI, 0.71-0.77). The incidence of AKI induced by cefoperazone-sulbactam sodium and mezlocillin-sulbactam sodium in hospitalized patients may be related to the combined treatment of multiple nephrotoxic drugs and a past history of chronic kidney disease. The AKI-predictive model based on logistic regression showed favorable performance in predicting the AKI of adult in patients who received cefoperazone-sulbactam sodium or mezlocillin-sulbactam sodium.
PubMed: 37361226
DOI: 10.3389/fphar.2023.1170987 -
Scientific Reports Jun 2023It has been revealed that the administration of an antimicrobial prophylaxis (AP) reduces the rate of surgical site (SSI) following colorectal cancer surgery....
It has been revealed that the administration of an antimicrobial prophylaxis (AP) reduces the rate of surgical site (SSI) following colorectal cancer surgery. Nevertheless, the optimal timing of this medication remains unclear. The aim of this study was to determine more precisely the optimal time for administering antibiotics and to see if this could reduce the number of possible surgical site infections. The files of individuals who underwent colorectal cancer surgery at the University Hospital Brandenburg an der Havel (Germany) between 2009 and 2017 were analyzed. Piperacillin/tazobactam, cefuroxime/metronidazole and mezlocillin/sulbactam were administered as AP regimens. Timing of AP was obtained. The primary objective was the rate of SSIs based on CDC criteria. Multivariate analysis took place to identify risk factors for SSIs. A total of 326 patients (61.4%) received an AP within 30 min, 166 (31.3%) between 30 and 60 min, 22 (4.1%) more than 1 h before surgery, and 15 (2.8%) after surgery. In 19 cases (3.6%) a SSI occurred during hospital stay. A multivariate analysis did not identify AP timing as a risk factor for the occurrence of SSIs. With significance, more surgical site occurrences (SSO) were diagnosed when cefuroxime/metronidazole was given. Our results suggest that AP with cefuroxime/metronidazole is less effective in reducing SSO compared with mezlocillin/sulbactam and tazobactam/piperacillin. We assume that the timing of this AP regimen of < 30 min or 30-60 min prior to colorectal surgery does not impact the SSI rate.
Topics: Humans; Surgical Wound Infection; Cefuroxime; Metronidazole; Retrospective Studies; Sulbactam; Mezlocillin; Antibiotic Prophylaxis; Anti-Bacterial Agents; Anti-Infective Agents; Colorectal Neoplasms; Piperacillin; Tazobactam
PubMed: 37296185
DOI: 10.1038/s41598-023-36588-1 -
Microbial Pathogenesis Apr 2023In this study, we collected feces of Tibetan piglets from Nyingchi area for isolation, culture, identification, virulence gene analysis and drug resistance analysis of...
In this study, we collected feces of Tibetan piglets from Nyingchi area for isolation, culture, identification, virulence gene analysis and drug resistance analysis of Escherichia Coli. The results demonstrated a 41.3% isolation rate of Diarrheagenic Escherichia Coli from Tibetan pigs with the main phylogenetic groups: group A (68.6%) and group B2 (15.7%). Typical E.coli accounted for 76.5%. The highest detection rates of porcine virulence genes were E.coli heat-resistant enterotoxin STb (58.82%) and F107 fimbrial subunit (23.53%). The highest detection rates of virulence genes from Tibetan pigs were fimC (80.39%) and ompA (76.47%). A drug sensitivity test showed that Diarrheagenic Escherichia Coli from Tibetan pigs had high drug resistance rates to mezlocillin, doxycycline and gentamicin. This study comprehensively analyzed the species composition, virulence and drug resistance of Diarrheagenic Escherichia Coli from Tibetan pigs, which provided a clearer and more targeted idea for the prevention and treatment of yellow and white dysentery in Tibetan pigs in the future.
Topics: Animals; Swine; Escherichia coli Infections; Virulence; Tibet; Phylogeny; Diarrhea; Escherichia coli; Drug Resistance
PubMed: 36842515
DOI: 10.1016/j.micpath.2023.106046 -
Annals of Clinical Microbiology and... Nov 2022Pulmonary cryptococcosis (PC) and mixed pulmonary infection are difficult to be diagnosed due to the non-specificity and their overlapping clinical manifestations. In...
BACKGROUND
Pulmonary cryptococcosis (PC) and mixed pulmonary infection are difficult to be diagnosed due to the non-specificity and their overlapping clinical manifestations. In terms of the clinical diagnosis of PC and mixed pulmonary infection, conventional tests have limitations such as a long detection period, a limited range of pathogens, and low sensitivity. Metagenomics next-generation sequencing (mNGS) is a nascent and powerful method that can detect pathogens without culture, to diagnose known and unexplained infections in reduced time.
CASE PRESENTATION
A 43-year-old female was admitted to the hospital after suffering from a cough for one month. At the time of admission, a contrast-enhanced chest CT revealed multiple nodules and plaques in her right lung, as well as the formation of cavities. The blood routine assays showed evidently increased white blood cell count (mainly neutrophils), CRP, and ESR, which suggested she was in the infection phase. The serum CrAg-LFA test showed a positive result. Initially, she was diagnosed with an unexplained pulmonary infection. Bronchoalveolar lavage fluid (BALF) samples were collected for microbial culture, immunological tests and the mNGS. Microbial culture and immunological tests were all negative, while mNGS detected Corynebacterium striatum, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Cryptococcus neoformans. The diagnosis was revised to PC and bacterial pneumonia. Lung infection lesions were healed after she received targeted anti-infection therapy with mezlocillin and fluconazole. In a follow-up after 2 months, the patient's symptoms vanished.
CONCLUSIONS
Here, we demonstrated that mNGS was capable of accurately distinguishing Cryptococcus from M. tuberculosis in pulmonary infection, and notably mNGS was capable of swiftly and precisely detecting pathogens in mixed bacterial and fungal pulmonary infection. Furthermore, the results of mNGS also have the potential to adjust anti-infective therapies.
Topics: Humans; Female; Adult; Sensitivity and Specificity; Metagenomics; Pneumonia; High-Throughput Nucleotide Sequencing; Lung; Coinfection; Cryptococcosis; Mycobacterium tuberculosis; Mycoses
PubMed: 36434704
DOI: 10.1186/s12941-022-00545-z -
The Journal of Antimicrobial... Dec 2022
PubMed: 36346101
DOI: 10.1093/jac/dkac371 -
The Journal of Antimicrobial... Nov 2022
Topics: Infant; Infant, Newborn; Humans; Mezlocillin; Bacterial Infections; Kinetics
PubMed: 36205004
DOI: 10.1093/jac/dkac335 -
The Journal of Antimicrobial... Nov 2022
Topics: Infant; Infant, Newborn; Humans; Mezlocillin; Bacterial Infections; Kinetics
PubMed: 36101504
DOI: 10.1093/jac/dkac305 -
The Journal of Antimicrobial... Jul 2022Mezlocillin is used in the treatment of neonatal infectious diseases. However, due to the absence of population pharmacokinetic studies in neonates and young infants,...
OBJECTIVES
Mezlocillin is used in the treatment of neonatal infectious diseases. However, due to the absence of population pharmacokinetic studies in neonates and young infants, dosing regimens differ considerably in clinical practice. Hence, this study aimed to describe the pharmacokinetic characteristics of mezlocillin in neonates and young infants, and propose the optimal dosing regimen based on the population pharmacokinetic model of mezlocillin.
METHODS
A prospective, open-label pharmacokinetic study of mezlocillin was carried out in newborns. Blood samples were collected using an opportunistic sampling method. HPLC was used to measure the plasma drug concentrations. A population pharmacokinetic model was developed using NONMEM software.
RESULTS
Ninety-five blood samples from 48 neonates and young infants were included. The ranges of postmenstrual age and birth weight were 29-40 weeks and 1200-4000 g, respectively, including term and preterm infants. A two-compartment model with first-order elimination was developed to describe the population pharmacokinetics of mezlocillin. Postmenstrual age, current weight and serum creatinine concentration were the most important covariates. Monte Carlo simulation results indicated that the current dose of 50 mg/kg q12h resulted in 89.2% of patients achieving the therapeutic target, when the MIC of 4 mg/L was used as the breakpoint. When increasing the dosing frequency to q8h, a dose of 20 mg/kg resulted in 74.3% of patients achieving the therapeutic target.
CONCLUSIONS
A population pharmacokinetic model of mezlocillin in neonates and young infants was established. Optimal dosing regimens based on this model were provided for use in neonatal infections.
Topics: Anti-Bacterial Agents; Creatinine; Humans; Infant; Infant, Newborn; Infant, Premature; Mezlocillin; Microbial Sensitivity Tests; Monte Carlo Method; Prospective Studies
PubMed: 35662337
DOI: 10.1093/jac/dkac176