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TEM-1 beta-lactamases can accurately catalyze the hydrolysis of the beta-lactam rings in beta-lactam antibiotics, which make beta-lactam antibiotics lose its activity, and the prerequisite for the hydrolysis procedure in the binding interaction of TEM-1 beta-lactamases with beta-lactam antibiotics is the beta-lactam rings in beta-lactam antibiotics. Therefore, the binding of TEM-1 beta-lactamase to three beta-lactam antibiotics including penicillin G, cefalexin as well as cefoxitin was explored here by frontal affinity chromatography in combination with fluorescence spectra, adsorption and thermodynamic data in the temperature range of 278-288K under simulated physiological conditions. The results showed that all the binding of TEM-1 beta-lactamase to the three antibiotics were spontaneously exothermic processes with the binding constants of 8.718×10 3 , 6.624×10 3 and 2.244×10 3 (mol/L), respectively at 288K. All the TEM-1 beta-lactamases were immobilized on the surface of the stationary phase in the mode of monolayer and there existed only one type of binding sites on them. Each TEM-1 beta-lactamase bound with only one beta-lactam antibiotic and hydrogen bond interaction and Van der Waals force were the main forces between them. This work provided an insight into the binding interactions between TEM-1 beta-lactamases and beta-lactam antibiotics, which may be beneficial for the designing and developing of new substrates resistant to TEM-1 beta-lactamases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

An understanding of antibiotic hydrolysis rates is important for predicting their environmental persistence. Hydrolysis rates and Arrhenius constants were determined as a function of pH and temperature for three common β-lactam antibiotics, ampicillin, cefalotin, and cefoxitin. Antibiotic hydrolysis rates at pH4-9 at 25 °C, 50 °C, and 60 °C were quantified, and degradation products were identified. The three antibiotics hydrolyzed under ambient conditions (pH7 and 25 °C); half-lives ranged from 5.3 to 27 d. Base-catalyzed hydrolysis rates were significantly greater than acid-catalyzed and neutral pH hydrolysis rates. Hydrolysis rates increased 2.5- to 3.9-fold for a 10 °C increase in temperature. Based on the degradation product masses found, the likely functional groups that underwent hydrolysis were lactam, ester, carbamate, and amide moieties. Many of the proposed products resulting from the hydrolysis of ampicillin, cefalotin, and cefoxitin likely have reduced antimicrobial activity because many products contained a hydrated lactam ring. The results of this research demonstrate that β-lactam antibiotics hydrolyze under ambient pH and temperature conditions. Degradation of β-lactam antibiotics will likely occur over several weeks in most surface waters and over several days in more alkaline systems., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The penetration of four cephalosporins into tissue fluid obtained with a skinabrasion technique was studied. Two oral antibiotics, cephalexin and CGP 9000, had similar pharmacology and penetrated the fluid in equivalent amounts. Cefuroxime (33% protein-bound) and cefoxitin (65-79% proteinbound) attained levels in tissue fluid which were very similar to their blood levels. The level of antibiotic in the tissues seems to be closely related to the blood level and is not adversely affected by protein binding.

Control measurements of blood flow through and cefoxitin extraction ratios across heart and lungs, liver, kidneys and gut were made under steady-state conditions in awake unrestrained sheep. The studies then were repeated with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic (to approximately T4) subarachnoid blockade with amethocaine. In the control-drug studies, it was shown that cefoxitin was cleared by the kidneys and that the cefoxitin infusion produced no significant changes in haemodynamics or in the kinetics of iodohippurate (the marker substance used for determining renal blood flow). Under general anaesthesia, there were significant reductions in renal blood flow (to 61% of the mean control value), in iodohippurate renal extraction ratio and clearance (to, respectively, 64 and 38% of the mean control values) and in cefoxitin renal extraction ratio and clearance (to, respectively, 48 and 23% of the mean control values). Under spinal anaesthesia there were no significant changes in haemodynamics or in cefoxitin or iodohippurate extraction ratios or clearances.

In 27 women with fetuses affected by beta-thalassemia major, termination of gestation between 19 and 21 weeks was induced by amniocentesis and intrauterine instillation of prostaglandin F2 alpha. Pharmacokinetics in maternal blood and amniotic fluid were studied after at least three doses of one of the following antibiotics and before prostaglandin F2 alpha infusion: (1) cefoxitin, 2 gm, intravenously, 1/2-hour infusion, three times per day; (2) moxalactam, 2 gm, intravenously, 1/2-hour infusion, three times per day; and (3) ceftazidime, 1 gm, intramuscularly, three times per day. Successful amniotic fluid levels effective against various pathogens implicated in maternal-fetal infections appeared at least 3 hours beyond administration of the drug and ranged between 2.3 and 6.7 micrograms/ml, 1.56 and 15 micrograms/ml, and 1.5 and 5 micrograms/ml for cefoxitin, moxalactam, and ceftazidime, respectively. Beyond the third-hour after infusion a percentage ratio of amniotic fluid to simultaneous maternal serum level of almost greater than or equal to 50 was constantly observed for all studied antibiotics. Cefoxitin serum levels were about the same as those in nonpregnant women, while moxalactam and ceftazidime serum levels were 50% lower than the expected level in normal individuals.

Despite the increasing popularity of antibiotic prophylaxis to reduce febrile morbidity in patients who undergo cesarean delivery, little is known of the pharmacokinetics of antibiotics in the patient at term gestation. This study was designed to elucidate the pharmacokinetics of cefoxitin when administered intravenously or by uterine and peritoneal lavage at cesarean section. Significant differences were found in the values for total body clearance area under the serum concentration-time curve (AUC), and K21 of cefoxitin administered intravenously to pregnant patients at term gestation compared to values for these parameters observed in nonpregnant patients. The concentration of cefoxitin in decidual tissue after uterine and peritoneal lavage with the antibiotic was 92.5 +/- 10.1 micrograms/gm (mean +/- SEM), whereas the concentration of cefoxitin in decidual tissue after intravenous administration of the antibiotic was 36.9 +/- 10.5 micrograms/gm (mean +/- SEM). This difference is statistically significant (p less than 0.05). We conclude that the pharmacokinetics of cefoxitin are altered in the pregnant patient as evidenced by the increased rapidity of clearance of the antibiotic (total body clearance for cefoxitin in pregnant patients, 20.41 L/hr). Moreover, uterine and peritoneal lavage results in significant tissue concentrations of antibiotic, which is of potential importance since the decidua is a presumed site of initiation of bacterial infection after cesarean section.

Limited pharmacokinetic data exist on cefoxitin, a semisynthetic cephamycin antibiotic, in the obstetric patient. Thirteen normotensive and five subjects with severe pregnancy-induced hypertension were identified within the first two postpartum days after cesarean section. After a 2 gm intravenous infusion, serial samples of blood were obtained and analyzed for cefoxitin by high-pressure liquid chromatography. Peak cefoxitin concentrations after infusion were 53.3 +/- 18.6 and 50.8 +/- 25.2 micrograms/ml for the normotensive and pregnancy-induced hypertensive groups, respectively. The only significant difference in pharmacokinetic parameters between these groups was a higher serum trough concentration of cefoxitin in the patients with pregnancy-induced hypertension as compared to the normotensive group. Because of diminished trough levels in our study patients, attention may need to be given to the adjustment of dosages in postpartum women with serious infections.

4-Hydroxy-3-methoxymandelic acid and 3,4-dihydroxymandelic acid were found to be potent adjuvants for the rectal absorption of water-soluble compounds in rats. Both adjuvants enhanced the absorption of two cephamycin antibiotics, cefmetazole and cefoxitin. Maximum plasma levels of the antibiotics were obtained within 30 min after rectal administration. The bioavailability of both antibiotics appeared to depend on the concentration of the adjuvant in the microenema, the dosage form used in these experiments. Instead of a microbial assay, a new chemical method involving high-performance liquid chromatography with an ion-pairing technique was developed for analyzing the cephamycin antibiotic plasma levels.

The authors present the results of the study of transplacental transfer of 3 recent beta lactam antibiotics: amoxicillin, cephradin and cefoxitin. The experiment was carried out in 37 pregnant women who had a premature rupture of membranes or who were undergoing a cesarean section. In these patients antibiotherapy was indicated in view of a possible superinfection. The results of the study show a worthwhile transplacental penetration of the 3 drugs tested. The concentrations achieved in umbilical cord blood and amniotic fluid increase with time and finally exceed the levels measured in maternal blood, after a period of time varying from 2 to 4 hours according to the drug and the route of administration.

The mechanism underlying the ability of phosphate derivatives to act as adjuvants and coadjuvants was examined in in vivo and in situ preparations in rats and dogs. The adjuvant effect of DL-alpha-glycerophosphate on the rectal absorption of sodium cefoxitin was greatly augmented by the presence of either sodium phytate or sodium tripolyphosphate. These coadjuvants only slightly enhanced cefoxitin rectal absorption when administered alone. Therefore, enhancement of the permeation of tripolyphosphate and phytate by alpha-glycerophosphate may be necessary before the coadjuvants can significantly affect cefoxitin absorption. The inhibitory effect of disodium 4,4'-diisothiocyano-2,2'-disulfonate stilbene, which is known to interact with the amino group in the protein fraction, on enhanced cefoxitin absorption suggests the involvement of the protein fraction in transport of cefoxitin across the rectal membrane.

The disappearance of phenylalanine and phenylalanylglycine from a perfusate circulated across rat rectal tissue was enhanced significantly in the presence of salicylate or 5-methoxysalicylate at pH 4.5, 7.4, and 8.5. The disappearance of di-, tri-, and tetraphenylalanine from a perfusate at pH 7.4, although facilitated by the presence of salicylate and 5-methoxysalicylate, was also fairly substantial when no adjuvant was present. These peptide analogues of phenylalanine also enhanced the rectal absorption of cefoxitin and cefmetazole, two highly water soluble antibiotics. Phenylalanine and phenylalanylglycine, both poorly absorbed across the rectal membrane when administered alone, did not enhance the rectal absorption of either antibiotic.

A sheep preparation has been developed which allows systematic direct studies into the sites and rates of distribution, formation and elimination of both endogenous and exogenous substances and their metabolites. Examples of some experimental applications are presented which provide information not usually available using traditional methods. Substantial metabolism at sites not usually regarded as important (e.g. limbs, lungs) was shown both for exogenous substances (procainamide and chlormethiazole) and for an endogenous substance (choline). Studies on drug clearance by kidney (cefoxitin), liver (chlormethiazole, pethidine and the optical isomers of mepivacaine) and lung (chlormethiazole) demonstrate that simple first-order elimination should not routinely be assumed to occur, as multiple sites and pathways may be involved, and kinetics may be non-linear as a result of characteristics of both organ flow and organ function. It was also shown that large changes (up to three-fold) in arterial blood drug concentrations may occur because of exogenous (anaesthesia) and endogenous (gastric recycling) perturbations, and that simple compartmental kinetics should not be assumed for either the whole body or individual organs. This preparation may be used in conjunction with traditional pharmacokinetic methods to resolve complex problems relating to interactions between drugs and the body, to establish a data base for physiological models of drug disposition, and to gain practical insights for drug treatment in patients.

Concanavalin A enhanced the rat rectal absorption of phenol red and cefoxitin at pH 7.4 and the uptake of cefoxitin into brush border membrane vesicles prepared from rat rectal membrane. The enhancing action of concanavalin A demonstrated a sodium ion dependency and was inhibited by the presence of 4,4'-diisothiocyano-2,2'-disulfonate stilbene and phlorizin. This inhibition suggests the involvement of the membrane protein fraction.

In awake unrestrained sheep the infusions i.v. of five drugs (cefoxitin, pethidine, chlormethiazole, tocainide and lignocaine) with potentially flow-limited clearance were shown to have no significant haemodynamic effects of their own, nor to have any effects on arterial or venous oxygen tensions. Under general anaesthesia (1.5% end-tidal halothane), haemodynamic changes similar to those previously documented in man occurred. Cardiac output and hepatic blood flow were decreased to 70%, and renal blood flow to 50% of control values; heart rate was unchanged and mean arterial pressure decreased by an average of 10%. Hepatic and renal vein oxygen tensions were decreased significantly. Under spinal anaesthesia, apart from a 10% decrease in hepatic blood flow, there were no significant changes in any haemodynamic variables or in the arterial or in any of the venous oxygen tensions. The i.v. infusion of adequate volumes of saline at the time of blockade probably contributed to the maintenance of these indices at their baseline values.