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There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 10 4 M -1 · sec -1 , and prolonged active site residence times ( t 1/2 , 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC 90 , 0.25 μg/ml), KPCs (MIC 90 , 1 μg/ml), class C cephalosporinases (MIC 90 , 1 μg/ml), and OXA-48-type carbapenemases (MIC 90 , 1 μg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo , whereas ceftibuten alone was ineffective (50% effective dose [ED 50 ], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED 50 , 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales .

The pharmacokinetics and clinical efficacy of ceftazidime, a cephalosporin with activity against Pseudomonas aeruginosa, were studied in children with cystic fibrosis. Ceftazidime had high in vitro activity against P. aeruginosa strains isolated from our patients, with a mean MIC90 of 8 micrograms/ml. The first dose of 50 mg/kg IV of ceftazidime achieved serum concentrations of 40.8 +/- 19.7 micrograms/ml at one hour and 3.8 +/- 1 micrograms/ml at four hours after administration (mean values +/- SD). The MIC90 was exceeded by serum concentrations for up to three hours. The elimination of the drug from the blood followed a biexponential decay with an elimination half-life of 60.4 +/- 6.8 min and a total body clearance of 6.0 +/- 3.1 ml/min/kg. Renal clearance of the drug accounted for 75% of the total clearance; these are higher values than those reported for adults. Peak concentrations of ceftazidime in the sputum two hours after a single administration were 4.13 +/- 2.06 micrograms/ml; after seven and 14 days of treatment, sputum concentrations were significantly lower. Eleven children with acute pulmonary exacerbation were treated for 14 days with ceftazidime at a dose of 150 mg/kg/day (12 treatment courses). Significant clinical and radiologic improvements were obtained in nine of 12 patients. In six of 11 cases the P. aeruginosa count decreased by 10(4) CFU/ml. Ceftazidime was well tolerated, and no side effects appeared during treatment.

Blood levels and urinary excretion of 6R,7R-3-carbamoyloxy-methyl-7-(2Z)-2-methoxyimino-(fur-2-yl)-acetamido-ceph-3-em-4-carboxylate sodium salt (cefuroxime) were determined in cirrhotic patients without ascites and in healthy volunteers after an i.m. injection of 750 mg and an i.v. injection of 1 g. An average peak serum level of 23.9 micrograms/ml in the case of cirrhotic patients and 22.5 micrograms/ml in the case of volunteers was reached 0.5 h after the i.m. dose, followed by a gradual decrease. An average serum level of 78.8 micrograms/ml in the case of cirrhotic patients was obtained 5 min after i.v. injection. During the first 6 h after administration of the 750 mg i.m. dose and the first 4 h after the administration of the 1 g i.v. dose, 90% of the administered dose were excreted in the urine, in the case of both cirrhotic patients and volunteers. These results show that the pharmacokinetic features of cefuroxime are not affected in cirrhotic patients without ascites; therefore the antibiotic is particularly suitable for acute infections in hospital, and also for cirrhotic patients without ascites without any difference in the dosage.

We investigated the pharmacokinetics of cefuroxime sodium, a new parenteral beta-lactam antibiotic, in 15 patients with stable chronic renal failure during intermittent peritoneal dialysis (IPD). Eight patients were administered 1 g cefuroxime as an intravenous bolus 1 h before the start of dialysis. Mean plasma levels of cefuroxime fell from 80 mcg/ml at 1 h to 40 mcg/ml at 6-8 h. At 24 h, concentrations were higher than 20 mcg/ml. In peritoneal fluid cefuroxime reached 16.7 mcg/ml at 1 h and 7.55 mcg/ml at 6 h. Seven patients received cefuroxime added to the dialysis solution at a dose of 2.5 g/10 liters. After 6 h of dialysis, cefuroxime reached plasma levels of 60 mcg/ml; after 24 h, concentrations were 37.5 mcg/ml. These results demonstrate that cefuroxime, administered by the i.v. route, easily diffuses from blood to peritoneal fluid and, from peritoneal fluid to blood when added to the dialysis solution. In both cases concentrations reached by cefuroxime are sufficient to treat peritoneal infections associated with peritoneal dialysis.

Adequate drug concentration at the infection site is a very important objective of antibiotic therapy. In this study we investigated the pharmacokinetics of the new methoximine, cefuroxime, in peritoneal and pleural fluids in 16 patients. After a 1-g dosage of cefuroxime, its concentration reaches a peak in ascitic fluid within 4-5 h. With a 2-g dose the peak level is reached in 2-3 h. After 5 h, cefuroxime concentration in ascites exceeds that in serum. Cefuroxime diffuses readily into the peritoneal space, where high concentrations (8-10 mcg/ml) are maintained for at least 6 h. Data on the kinetics in pleural fluid also seem to show high antibiotic diffusion rates, even if concentrations are never as high as those in blood at the same time following 1 g i.v. These favorable kinetic properties are probably due to low serum protein binding and to slow renal excretion.

The antibacterial activity and pharmacokinetics of the beta-lactamase-stable cephalosporin cefuroxime and the gram-negative beta-lactamase-susceptible cephalosporin cefazolin were compared in two contrasting infection models in which Proteus morganii 82, which produces chromosomally mediated beta-lactamase, was the pathogen. In the rat paw model, characterized by high numbers of localized bacteria, cefazolin was destroyed at the site of infection and consequently did not produce a therapeutic response. In the mouse intraperitoneal model cefazolin was also inactive, despite peritoneal concentrations being unaffected by high counts of the beta-lactamase-producing P. morganii in the body cavity. In contrast the pharmacokinetics of cefuroxime was unaffected by the presence of the beta-lactamase-producing P. morganii, and good therapeutic responses were seen in both models.