Occupational asthma induced by cephalosporins. (1/31)

A 20-yr-old pharmaceutical worker who developed attacks of shortness of breath and wheezing 9 months after beginning work on a process in which cefadroxil powder was bottled or encapsulated will be described. Skin test with cefaxodril was negative. Baseline spirometry and methacholine inhalation test were normal. A controlled bronchial challenge test was carried out in a closed-circuit system with assessment of respirable dust concentration. Exposure to cefadroxil powder at a mean concentration of 10 mg x m(-3) for 10 min elicited an isolated immediate asthmatic response, but no response was observed to control challenge with lactose. Single-blind oral challenge test with amoxicillin up to 500 mg was well tolerated, whereas the oral challenge with cephalexin (25 mg) elicited an immediate asthmatic response. This patient had developed occupational asthma caused by inhalation of cefadroxil as confirmed by specific inhalation test. Since she tolerated oral amoxicillin, a synthetic penicillin with the side-chain identical to that of cefadroxil, it seems that she may be sensitized to the dihydrothiazine ring of cephalosporins.  (+info)

Enzymatic synthesis of beta-lactam antibiotics using penicillin-G acylase in frozen media. (2/31)

Penicillin-G acylase (EC 3.5.1.11) from Escherichia coli catalyzed the synthesis of various beta-lactam antibiotics in ice at -20 degrees C with higher yields than obtained in solution at 20 degrees C. The initial ratio between aminolysis and hydrolysis of the acyl-enzyme complex in the synthesis of cephalexin increased from 1.3 at 20 degrees C to 25 at -20 degrees C. The effect on the other antibiotics studied was less, leading us to conclude that freezing of the reaction medium influences the hydrolysis of each nucleophile-acyl-enzyme complex to a different extent. Only free penicillin-G acylase could perform transformations in frozen media: immobilized preparations showed a low, predominantly hydrolytic activity under these conditions.  (+info)

beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. (3/31)

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.  (+info)

Intestinal peptide transport: ex vivo uptake studies and localization of peptide carrier PEPT1. (4/31)

The nature of protein breakdown products and peptidomimetic drugs such as beta-lactams is crucial for their transmembrane transport across apical enterocyte membranes, which is accomplished by the pH-dependent high-capacity oligopeptide transporter PEPT1. To visualize oligopeptide transporter-mediated uptake of oligopeptides, an ex vivo assay using the fluorophore-conjugated dipeptide derivative D-Ala-Lys-N(epsilon)-7-amino-4-methylcoumarin-3-acetic acid (D-Ala-Lys-AMCA) was established in the murine small intestine and compared with immunohistochemistry for PEPT1 in murine and human small intestine. D-Ala-Lys-AMCA was accumulated by enterocytes throughout all segments of the murine small intestine, with decreasing intensity from the top to the base of the villi. Goblet cells did not show specific uptake. Inhibition studies revealed competitive inhibition by the beta-lactam cefadroxil, the angiotensin-converting enzyme inhibitor captopril, and the dipeptide glycyl-glutamine. Controls were performed using either the inhibitor diethylpyrocarbonate or an incubation temperature of 4 degrees C to exclude unspecific uptake. Immunohistochemistry for PEPT1 localized immunoreactivity to the enterocytes, with the highest intensity at the apical membrane. This is the first study that visualizes dipeptide transport across the mammalian intestine and indicates that uptake assays using D-Ala-Lys-AMCA might be useful for characterizing PEPT1-specific substrates or inhibitors.  (+info)

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung. (5/31)

BACKGROUND: Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. METHODS: Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. RESULTS: PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. CONCLUSIONS: These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics.  (+info)

Evaluation of cefuroxime axetil and cefadroxil suspensions for treatment of pediatric skin infections. (6/31)

A randomized, single-blind, multicenter study was conducted to evaluate the safety and efficacy of cefuroxime axetil and cefadroxil suspensions for the treatment of skin or skin structure infections in 287 children. Each drug was given at a dosage of 30 mg/kg of body weight per day in two divided doses. Staphylococcus aureus and Streptococcus pyogenes, or a combination of the two, were the primary pathogens isolated from infected skin lesions. A satisfactory bacteriological response (cure or presumed cure) was obtained in 97.1 and 94.3% of children in the cefuroxime axetil and cefadroxil groups, respectively (P greater than 0.05). Satisfactory clinical responses (cure or improvement) were more likely to occur in cefuroxime axetil recipients than in cefadroxil recipients (97.8 versus 90.3%; P less than 0.05). Both regimens were equally well tolerated, with adverse events occurring in 7.9 and 6.1% of cefuroxime axetil and cefadroxil recipients, respectively. There were more patients who refused to take cefuroxime axetil (7 of 189) than there were who refused to take cefadroxil (0 of 98), but the difference was not statistically significant (P = 0.1). In this study, cefuroxime axetil was at least as effective as cefadroxil in resolving skin and skin structure infections in children.  (+info)

Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice. (7/31)

The choroid plexus uptake of [(3)H]cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability. At normal pH (7.4) and temperature (37 degrees C), the uptake of 1 microM cefadroxil was reduced by 83% in PEPT2(-/-) mice as compared with PEPT2(+/+) mice (p < 0.001). A further reduction was achieved in null animals by reducing the temperature to 4 degrees C, or by adding saturating concentrations of unlabeled cefadroxil or p-aminohippurate (p < 0.05). Glycylsarcosine coadministration could inhibit the uptake of cefadroxil in PEPT2(+/+) mice (p < 0.01) but not PEPT2(-/-) mice. Although a proton-stimulated uptake of cefadroxil was demonstrated in PEPT2(+/+) mice (pH 6.5 versus pH 7.4; p < 0.01), no pH dependence was observed in PEPT2(-/-) mice. Kinetic parameters for cefadroxil (without p-aminohippurate) in wild-type mice were: V(max) = 5.4 pmol/mg/min, K(m) = 34 microM, and K(d) = 0.0069 microl/mg/min; in the presence of p-aminohippurate, the parameters were: V(max) = 4.1 pmol/mg/min, K(m) = 27 microM, and K(d) = 0.0064 microl/mg/min. In null animals, the kinetic parameters of cefadroxil (without p-aminohippurate) were: V(max) = 2.7 pmol/mg/min, K(m) = 110 microM, and K(d) = 0.0084 microl/mg/min; in the presence of p-aminohippurate, only a K(d) = 0.010 microl/mg/min was observed. Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of cefadroxil's uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms. These findings demonstrate that PEPT2 is the primary transporter responsible for cefadroxil uptake in the choroid plexus. Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.  (+info)

In vitro activities of Ro 40-6890 against 164 predominantly intestinal members of the families Enterobacteriaceae and Vibrionaceae. (8/31)

The in vitro activities of Ro 40-6890, the active metabolite of a novel orally absorbable cephalosporin ester, Ro 41-3399, against 164 nonfastidious aerobic gram-negative rods of predominantly intestinal origin from patients with diarrhea were evaluated by the agar dilution method recommended by the National Committee for Clinical Laboratory Standards. Ro 40-6890 was inhibitory (MIC for 90% of isolates [MIC90], 0.12 micrograms/ml) against the majority of intestinal members of the families Enterobacteriaceae and Vibrionaceae (Vibrio spp., Aeromonas spp., and Plesiomonas shigelloides). The potency of Ro 40-6890 was very similar to that of cefotaxime (MIC90, 0.12 micrograms/ml) and distinctly higher than those of cefadroxil (MIC90, > or = 128 micrograms/ml) and amoxicillin-clavulanic acid (MIC90, 32 micrograms/ml-2 micrograms/ml).  (+info)

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