Cefuroxime

The broadly conserved cyclic di-AMP (c-di-AMP) is a conditionally essential bacterial second messenger. The pool of c-di-AMP is fine-tuned through diadenylate cyclase and phosphodiesterase activities, and direct binding of c-di-AMP to proteins and riboswitches allows the regulation of a broad spectrum of cellular processes. c-di-AMP has a significant impact on intrinsic β-lactam antibiotic resistance in Gram-positive bacteria; however, the reason for this is currently unclear. In this work, genetic studies revealed that suppressor mutations that decrease the activity of the potassium (K+) importer KupB or the glutamine importer GlnPQ restore cefuroxime (CEF) resistance in diadenylate cyclase (cdaA) mutants of Lactococcus lactis Metabolite analyses showed that glutamine is imported by GlnPQ and then rapidly converted to glutamate, and GlnPQ mutations or c-di-AMP negatively affects the pools of the most abundant free amino acids (glutamate and aspartate) during growth. In a high-c-di-AMP mutant, GlnPQ activity could be increased by raising the internal K+ level through the overexpression of a c-di-AMP-insensitive KupB variant. These results demonstrate that c-di-AMP reduces GlnPQ activity and, therefore, the level of the major free anions in L. lactis through its inhibition of K+ import. Excessive ion accumulation in cdaA mutants results in greater spontaneous cell lysis under hypotonic conditions, while CEF-resistant suppressors exhibit reduced cell lysis and lower osmoresistance. This work demonstrates that the overaccumulation of major counter-ion osmolyte pools in c-di-AMP-defective mutants of L. lactis causes cefuroxime sensitivity.IMPORTANCE The bacterial second messenger cyclic di-AMP (c-di-AMP) is a global regulator of potassium homeostasis and compatible solute uptake in many Gram-positive bacteria, making it essential for osmoregulation. The role that c-di-AMP plays in β-lactam resistance, however, is unclear despite being first identified a decade ago. Here, we demonstrate that the overaccumulation of potassium or free amino acids leads to cefuroxime sensitivity in Lactococcus lactis mutants partially defective in c-di-AMP synthesis. It was shown that c-di-AMP negatively affects the levels of the most abundant free amino acids (glutamate and aspartate) in L. lactis Regulation of these major free anions was found to occur via the glutamine transporter GlnPQ, whose activity increased in response to intracellular potassium levels, which are under c-di-AMP control. Evidence is also presented showing that they are major osmolytes that enhance osmoresistance and cell lysis. The regulatory reach of c-di-AMP can be extended to include the main free anions in bacteria.

BackgroundEradicating Helicobacter pylori infection is clinically challenging, notably in cases with penicillin allergy. Cephalosporin could be used in lieu of amoxicillin to eradicate Helicobacter pylori. The current work aimed to assess therapeutic efficacy and safety of a cefuroxime-based quadruple regimen in treatment-naïve individuals with penicillin allergy, as well as patient compliance.MethodsIn the present prospective single-center cohort study, 152 Helicobacter pylori infected individuals with penicillin allergy received eradication therapy with cefuroxime (500 mg twice/day), levofloxacin (500 mg once/day), esomeprazole (20 mg twice/day) and bismuth potassium citrate (220 mg twice/day; 14 days). Safety and compliance were evaluated 1 to 3 days upon eradication. The urea breath test was carried out 8 to 12 weeks upon eradication for efficacy assessment.ResultsThis quadruple antimicrobial regimen eradicated the pathogen at 85.5% (95% confidence interval (CI) 79.6-90.8%), 88.4% (95% CI 83.0-93.2%) and 90.1% (95% CI 85.2-94.4%) in intention-to-treat, modified intention-to-treat and per-protocol analyses, respectively, with resistance rates of 4.6 and 40.0% in the background of cefuroxime and levofloxacin, respectively. Meanwhile, 21.3% of patients had adverse reactions, but none was serious. A total of 95.3% of patients showed good compliance. Poor compliance and cefuroxime resistance were detected by uni- or multivariate analyses as independent factors predicting therapeutic failure. Eradication rates in patients with dual levofloxacin and cefuroxime susceptibility, isolated levofloxacin resistance, isolated cefuroxime resistance and dual resistance were 97.2, 84.0, 50.0, and 0%, respectively (P = 0.002).ConclusionsCefuroxime, levofloxacin, esomeprazole, and bismuth achieved decent efficacy, safety and compliance as first-line antimicrobial regimen in patients with Helicobacter pylori and penicillin allergy.

ImportanceWorld Health Organization guidelines recommend administering surgical antimicrobial prophylaxis (SAP), including cefuroxime, within 120 minutes prior to incision. However, data from clinical settings supporting this long interval is limited.ObjectiveTo assess whether earlier vs later timing of administration of cefuroxime SAP is associated with the occurrence of surgical site infections (SSI).Design, setting, and participantsThis cohort study included adult patients who underwent 1 of 11 major surgical procedures with cefuroxime SAP, documented by the Swissnoso SSI surveillance system between January 2009 and December 2020 at 158 Swiss hospitals. Data were analyzed from January 2021 to April 2023.ExposuresTiming of cefuroxime SAP administration before incision was divided into 3 groups: 61 to 120 minutes before incision, 31 to 60 minutes before incision, and 0 to 30 minutes before incision. In addition, a subgroup analysis was performed with time windows of 30 to 55 minutes and 10 to 25 minutes as a surrogate marker for administration in the preoperating room vs in the operating room, respectively. The timing of SAP administration was defined as the start of the infusion obtained from the anesthesia protocol.Main outcomes and measuresOccurrence of SSI according to Centers for Disease Control and Prevention definitions. Mixed-effects logistic regression models adjusted for institutional, patient, and perioperative variables were applied.ResultsOf 538 967 surveilled patients, 222 439 (104 047 men [46.8%]; median [IQR] age, 65.7 [53.9-74.2] years), fulfilled inclusion criteria. SSI was identified in 5355 patients (2.4%). Cefuroxime SAP was administered 61 to 120 minutes prior to incision in 27 207 patients (12.2%), 31 to 60 minutes prior to incision in 118 004 patients (53.1%), and 0 to 30 minutes prior to incision in 77 228 patients (34.7%). SAP administration at 0 to 30 minutes was significantly associated with a lower SSI rate (adjusted odds ratio [aOR], 0.85; 95% CI, 0.78-0.93; P Conclusions and relevanceIn this cohort study, administration of cefuroxime SAP closer to the incision time was associated with significantly lower odds of SSI, suggesting that cefuroxime SAP should be administrated within 60 minutes prior to incision, and ideally within 10 to 25 minutes.

AimsCefuroxime axetil exists in several dosage forms for oral administration, and is indicated for treatment of respiratory, genitourinary, skin and soft tissue infections. Evolving patterns of bacterial susceptibility, expressed as increasing minimum inhibitory concentrations (MICs), warrant monitoring of antibiotic efficacy. Here we investigate the performance of different cefuroxime axetil doses required to yield the desired target exposure against the predominant pathogens for each indication.MethodsThe pharmacokinetics of cefuroxime in plasma/serum and urine was characterized after oral, intravenous and intramuscular administration. Covariates included the effect of weight on clearance and volume of distribution, and formulation on absorption parameters. Subsequently, systemic cefuroxime concentrations over time were simulated to assess the time above the MIC (T > MIC) and the probability of target attainment (PTA) for different dosing regimens in adults and children.ResultsTablet doses of 250 and 500 mg twice daily achieved the target T > MIC (40%) and PTA (≥90%) for MICs up to 0.25 and 0.5 mg/L, respectively, thereby covering most European Committee on Antimicrobial Susceptibility Testing breakpoints for key pathogens. Due to its absorption profile, the oral suspension covers even higher MICs, up to 1.0 mg/L. As cefuroxime is mostly excreted unchanged in urine, cefuroxime axetil doses of 250 mg twice daily for urinary tract infection yield a PTA of 100% for MIC values up to 8 mg/L.ConclusionsOur analysis provides insight into the performance of different doses and dosing regimens for cefuroxime axetil for key pathogens. As resistance patterns evolve, and differ between countries or regions, cefuroxime doses may require adjustments considering local bacterial susceptibility.