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This study determined the antimicrobial susceptibility of Escherichia coli causing community-acquired, acute, uncomplicated, non-recurrent urinary tract infection in unselected women aged 18-65 years and compared the results with those obtained 8 years earlier in the first ECO·SENS study (1999-2000). During 2007-2008, urine samples were taken from 1697 women in Austria, Greece, Portugal, Sweden and the UK. The countries were chosen to represent areas of Europe indicated to have more (Greece and Portugal) or less (UK, Austria and Sweden) problems with resistance. Antimicrobial susceptibility testing of 903 E. coli isolates (150-200 isolates per country) to 14 antimicrobials was performed by disk diffusion using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. In E. coli, resistance to mecillinam, cefadroxil (representing oral cephalosporins), nitrofurantoin, fosfomycin trometamol, gentamicin and the third-generation cephalosporins cefotaxime and ceftazidime was <2%, with the following exceptions: gentamicin in Portugal (2.8%); fosfomycin in Greece (2.9%); and cephalosporins in Austria (2.7-4.1%). Resistance levels were higher for amoxicillin/clavulanic acid (2.0-8.9%) and ciprofloxacin (0.5-7.6%) and much higher to ampicillin (21.2-34.0%), sulfamethoxazole (21.2-31.3%), trimethoprim (14.9-19.1%) and trimethoprim/sulfamethoxazole (14.4-18.2%). Resistance to quinolones and trimethoprim increased between the ECO·SENS I (1999-2000) and ECO·SENS II (2007-2008): nalidixic acid 4.3% to 10.2%; ciprofloxacin 1.1% to 3.9%; and trimethoprim 13.3% to 16.7%. In the previous study, no isolates with extended-spectrum β-lactamase were found; however, in the present study 11 isolates were identified as having either CTX-M or AmpC.
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Clinical efficacy was studied with cefadroxil powder for syrup in 35 pediatric patients including 20 acute tonsillitis and pharyngitis, 6 scarlet fever, 2 cervical lymphadenitis and 7 urinary tract infections. The results indicated a 97% effectiveness when 'excellent' and 'good' ratings were combined. A mild skin rash was observed in 1 patient.
Ciprofloxacin is a new antibacterial agent of the 4-quinolone group. With an agar dilution technique we compared its activity on 365 clinical isolates with those of norfloxacin, nalidixic acid, ampicillin, mezlocillin, cefadroxil, cefuroxime, ceftazidime, ceftriazone , cefotaxime, latamoxef (moxalactam), and gentamicin. Ciprofloxacin was overall the most active agent tested against aerobic Gram-negative species, with the MIC90 values for all species being below 1 mg/l (excepting Providencia stuartii with 4 mg/l), and the large majority being below 0.12 mg/l. Many of the strains were selected on the basis of resistance to beta-lactam agents or gentamicin, and ciprofloxacin was also active against these. There was little difference in the activity of ciprofloxacin at inocula of 10(4) or 10(6) cfu. Strains with higher MIC's of the related agents norfloxacin and nalidixic acid were less susceptible to ciprofloxacin . Ciprofloxacin was less active against Gram-positive species (typical MIC90 values were 0.5 or 1 mg/l) and obligate anaerobes (4 mg/l for Bacteroides fragilis). The activity of ciprofloxacin in broth dilution tests was little affected by pH over the range 6.0-8.0, or by human serum or tissue fluid; its activity was reduced by the presence of urine. Binding to human serum protein was 20-28%. Ciprofloxacin was rapidly bacterial in broth at concentrations near to its MICs. By exposure to subinhibitory concentrations of ciprofloxacin it was possible to increase its MIC for bacteria in daily subcultures. The final MIC values after ten days were often about 16-fold greater than those observed initially.
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The intestinal transport of cefadroxil is directly proportional to PepT1 expression, suggesting that the PepT1 expression level in the rat small intestine is the major determinant of the absorption of peptide-like compounds.
Clarithromycin is a new macrolide analog of erythromycin with activity against a number of dermatologic pathogens.
Sartans are very effective drugs for treatment of hypertension, heart failure, and other cardiovascular disorders. They antagonize the effects of angiotensin II at the AT(1) receptor and display p.o. bioavailability rates of 13 to 80%. Because some sartans sterically resemble dipeptide derivatives, we investigated whether they are transported by peptide transporters. We first assessed the effects of sartans on [(14)C]glycylsarcosine uptake into Caco-2 cells expressing H(+)/peptide transporter (PEPT) 1 and into SKPT cells expressing PEPT2. Losartan, irbesartan, valsartan, and eprosartan inhibited [glycine-1-(14)C]glycylsarcosine ([(14)C]Gly-Sar) uptake into Caco-2 cells in a competitive manner with K(i) values of 24, 230, 390, and >1000 microM. Losartan and valsartan also strongly inhibited the total transepithelial flux of [(14)C]Gly-Sar across Caco-2 cell monolayers. In SKPT cells, [(14)C]Gly-Sar uptake was inhibited with K(i) values of 2.2 microM (losartan), 65 microM (irbesartan), 260 microM (valsartan), and 490 microM (eprosartan). We determined by the two-electrode voltage-clamp technique whether the compounds elicited transport currents by PEPT1 or PEPT2 when expressed in Xenopus laevis oocytes. No currents were observed for any of the sartans, but the compounds strongly and reversibly inhibited peptide-induced currents. Uptake of valsartan, losartan, and cefadroxil was quantified in HeLa cells after heterologous expression of human PEPT1 (hPEPT1). In contrast to cefadroxil, no PEPT1-specific uptake of valsartan and losartan was found. We conclude that the sartans tested in this study display high-affinity interaction with PEPTs but are not transported themselves. However, they strongly inhibit hPEPT1-mediated uptake of dipeptides and cefadroxil.
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Co-administration of piperine, an alkaloid isolated from Piper nigrum L. enhanced bioavailability of beta lactam antibiotics, amoxycillin trihydrate and cefotaxime sodium significantly in rats. The improved bioavailability is reflected in various pharmacokinetic parameters viz. tmax, Cmax, t(1/2) and AUC, of these antibiotics. The increased bioavailability could be attributed to the effect of piperine on microsomal metabolising enzymes or enzymes system.
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A prospective randomized trial with a cost analysis.
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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).
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Seventeen full-length, peer-reviewed controlled trials reporting clinical outcomes of systemic antimicrobial treatment for canine pyoderma were identified. Outcomes specific to superficial or deep pyoderma were reported in nine and five studies, respectively. Five studies reported outcomes only for nondifferentiated pyoderma depth. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. A good level of evidence was identified supporting the high efficacy of subcutaneously injected cefovecin in superficial pyoderma and for oral amoxicillin-clavulanic acid in deep pyoderma. A fair level of evidence was identified for moderate to high efficacy of oral amoxicillin-clavulanic acid, clindamycin, cefadroxil, trimethoprim-sulphamethoxazole and sulfadimethoxine-ormetoprim in superficial pyoderma and oral pradofloxacin, oral cefadroxil and subcutaneously injected cefovecin in deep pyoderma. Eleven trials reported observations of adverse effects in treated pyoderma cases by intervention group; four dogs were withdrawn owing to the severity of adverse effects.
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The purpose of this study was to compare the bacteriologic and clinical efficacy of oral cephalexin twice vs. three times daily vs. cefadroxil once daily as therapy for group A beta-hemolytic streptococcal (GABHS) tonsillopharyngitis. A prospective open-label, observational cohort study was conducted over 18 months (January 2000-June 2001). Children enrolled had an acute onset of symptoms and signs of a tonsillopharyngeal illness and a laboratory-documented GABHS infection. Follow-up examination and laboratory testing occurred 21 +/- 4 days following enrollment. Two hundred seventy-one patients were enrolled (intent to treat group): 63 received cephalexin twice daily, 124 received cephalexin three times daily, and 84 received cefadroxil once daily. Fifty-three children did not return for the follow-up visit, leaving 218 patients in the per-protocol group: 54 cephalexin twice-daily treated, 94 cephalexin 3-times daily treated, and 70 cefadroxil once-daily treated. In the per-protocol group, bacteriologic cure for those treated with cephalexin twice daily was 87%, for cephalexin 3 times daily, it was 81% and for cefadroxil once daily it was 81% (p = 0.61). The clinical cure rate for cephalexin twice-daily treatment was 91%; for three-times daily, it was 86%; and for cefadroxil once daily, it was 84% (p = 0.56). Because treatment allocation was not randomized, logistic regression analysis was used to adjust for treatment group differences. Younger age of patient was significantly associated with bacteriologic (p = 0.04) and clinical (p = 0.01) failure independent of treatment group but in the adjusted logistic model no differences were found among the 3 treatment regimens. Cephalexin dosed twice daily or three times daily and cefadroxil dosed once daily appear equivalent in bacteriologic and clinical cure of GABHS tonsillopharyngitis.
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A total of 5116 non-fastidious bacterial strains isolated from either blood or urine culture were collected from 20 geographically distributed centres within the UK. Upon receipt the strains were identified and the minimum inhibitory concentrations of ten antimicrobial agents in hospital usage were determined for each of the strains. All laboratories submitted a similar range of bacterial species and in species normally considered as sensitive the overall rates of resistance to the different antibiotics tested were: amikacin 2.4%, gentamicin 3.7%, netilmicin 2.6%, tobramycin 3.4%, ampicillin 41.7%, cefadroxil 11.6%, cefotaxime 1.4% [corrected], cefuroxime 4.3%, ciprofloxacin 0.6% and trimethoprim 13.0%. For those strains resistant to one or more aminoglycosides the mechanisms of resistance responsible were determined from the aminoglycoside-resistance patterns of the strains to 16 different aminoglycoside antibiotics. The predominant mechanisms of resistance found were APH(2") + AAC(6') production in staphylococci. AAC(2') production in Providencia spp., and AAC(3) production in the other Gram-negative genera.
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A new chemiluminescence reaction, the luminol-Cu(2+) reaction, was investigated for the determination of thirteen (13) cephalosporin antibiotics, namely cefalexin, cefadroxil, cefradine, cefazolin sodium, cefaclor, cefuroxime axetil, cefotaxime sodium, cefoperazone sodium, ceftriaxone sodium, ceftazidime, cefetamet pivoxil hydrochloride, cefixime, and cefpodoxime. It was found that, without adding any special oxidant, strong chemiluminescent (CL) signal could be produced from the reaction of the alkaline luminol with the above-mentioned antibiotics in the presence of Cu(2+). The experimental conditions for the reaction were carefully optimized with flow-injection mode. The detection limits are 0.3 ng/mL cefalexin, 3 ng/mL cefadroxil, 0.3 ng/mL cefradine, 0.02 μg/mL cefazolin sodium, 0.8 ng/mL cefaclor, 0.02 μg/mL cefuroxime axetil, 5 ng/mL cefotaxime sodium, 0.02 μg/mL cefoperazone sodium, 0.8 ng/mL ceftriaxone sodium, 1 ng/mL ceftazidime, 0.08 ng/mL cefetamet pivoxil hydrochloride, 0.8 ng/mL cefixime, and 2 ng/mL cefpodoxime. The proposed method was validated by direct application to commercial formulations and spiked milk samples containing cefradine. A possible reaction mechanism is also discussed.
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The Delvotest method detection limits per manufacturer's instructions at a fixed reading time of 3 h for 24 antimicrobial agents were determined in ewe milk by photometric measurement. For each drug, eight concentrations were tested on 20 ewe milk samples from individual ewes. Detection limits, determined by means of logistic regression models, were (microg/kg): 3, amoxycillin; 2, ampicillin; 18, cloxacillin; 1, penicillin "G"; 34, cefadroxil; 430, cephalosporin "C"; 40, cephalexin; 20, cefoperazone; 33, Ceftiofur; 18, cefuroxime; 6100, streptomycin; 1200, gentamycin; 2600, neomycin; 830, erythromycin; 100, tylosin; 180, doxycycline; 320, oxytetracycline; 590, tetracycline; 88, sulfadiazine; 44, sulfamethoxazole; 140, sulfametoxypyridazine; 48, sulfaquinoxaline; 12,000, chloramphenicol; and 290, trimethoprim. Whereas the beta-lactam antibiotics, sulphonamides, and tylosin were detected by Delvotest method at levels equal to those of maximum residue limits, its sensitivity needs to be enhanced to detect aminoglycosides, tetracyclines, streptomycin, chloramphenicol, and trimethoprim residues in ewe milk or to develop an integrated residue detection system for ewe milk with different sensitive microorganisms for each group of antiinfectious agents.
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We determined the in vitro susceptibilities of eight Borrelia burgdorferi isolates to five oral cephalosporins. MICs for B. burgdorferi 297 were 23 micrograms/ml (cephalexin), 45 micrograms/ml (cefadroxil), 91 micrograms/ml (cefaclor), 0.13 microgram/ml (cefuroxime), 0.8 microgram/ml (cefixime), and 0.02 microgram/ml (ceftriaxone). When B. burgdorferi isolates were exposed to concentrations twice the MIC of cefuroxime, cefixime, or ceftriaxone, at least 72 h of incubation was required to kill 99% of the organisms.
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This work focused on the extraction of violacein from an isolated strain of C. violaceum and determined the combinatory effect of violacein with commercial antibiotics against various pathogens.
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Cefadroxil (CDX), a new semisynthetic cephalosporin derivative, was administered to 20 patients with acute or chronic otolaryngological infections and following results were obtained. Of 11 cases with acute infections such as acute otitis media, acute otitis externa and postoperative maxillary cyst, excellent, good and fair results were obtained in 10 cases, the efficacy ratio being 91%, while the efficacy ratio in 9 cases with chronic infections such as chronic pharyngolaryngitis and chronic otitis media was 56%. CDX is, therefore, extremely effective for acute otolaryngological infections. No severe side effect was observed, although there were 2 cases with minor adverse effects, one with drug induced eruption and the other with stomatitis.
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A 77-year-old patient is described who developed pemphigus vulgaris temporally with the administration of cefadroxil. The disease improved when the drug was discontinued but was exacerbated with the administration of ampicillin. This may be the first case of possible cefadroxil-induced and only the second case of ampicillin-induced pemphigus vulgaris reported. The pathophysiology, diagnosis, and treatment of pemphigus vulgaris is briefly described. Drug-induced pemphigus is reviewed. By far the most incriminated drug has been penicillamine. It is postulated that the sulfhydryl group of penicillamine alters the intercellular cement substance into an antigenic structure with subsequent antibody formation. The chemical similarity between penicillamine, the penicillins, and the cephalosporins is alluded to and the potential for cross-sensitivity between the penicillins and cephalosporins is emphasized. Although the pemphigus vulgaris could have occurred by chance, it seems probable that it was drug-induced.
PEPT2 is functionally expressed in H441 cells, making the cell line a good in vitro model to study PEPT2 function and its regulation in human distal lung.
Pyoderma caused by Peptostreptococcus tetradius in a pup was successfully treated with cefadroxil. Although this bacterium is rarely found in veterinary medicine, it is a known pathogen in human beings and should be considered as a potential causative agent in pyodermas in which anaerobes are suspected.
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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.
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Cefpodoxime proxetil (CPDX-PR, CS-807) is a new oral cephem derivative drug in which carboxylic acid was esterified to the 4-position of CPDX (oxime type cephem antibiotic). CPDX-PR is hydrolyzed mainly with esterase in intestinal wall and CPDX exists as an active form in body fluid. While there are numerous study reports using CPDX-PR in tablet forms in Japan, the dry syrup formula for pediatric use was newly developed. The dry syrup of CPDX-PR was orally administered 20 minutes after meal to the 6 boys of ages from 8 years and 1 month to 10 years and 10 months, with doses of 3 and 6 mg/kg, respectively, for 3 cases each. Serum concentrations and urinary concentrations and recovery rate of the drug were investigated. In addition to the above, the clinical and bacteriological studies were performed in a total of 105 cases consisting of children with ages ranging from 2 months to 11 years and 8 months, upon administering an average dose of 3.4 mg/kg, 3 to 4 times per day (96 cases of 3 times and 9 cases of 4 times). The 105 cases included 13 cases of pharyngitis, 21 cases of tonsillitis, 4 cases of acute bronchitis, 6 cases of pneumonia, 1 case of pleurisy, 13 cases of scarlet fever, 41 cases of urinary tract infection, 3 cases of posthitis and 3 cases of bacillary dysentery. Drug sensitivity test was performed for the following strains: (i) Strains retained by our department; 52 strains of Streptococcus pyogenes, 18 strains of Streptococcus agalactiae, and 11 strains of Bordetella pertussis, and (ii) strains isolated from cases to which CPDX-PR was administered; 2 strains of Staphylococcus aureus, 8 strains of S. pyogenes, 2 strains of Haemophilus influenzae, 10 strains of Escherichia coli, and 1 strain of Proteus mirabilis. Drug sensitivities of the strains retained by our department were tested with the inoculum sizes of 10(8) and 10(6) cfu/ml for R-3746 (Na-salt of CPDX), cefaclor (CCL), cephalexin (CEX), amoxicillin (AMPC), and methicillin (DMPPC), and those against strains separated from the cases to which CPDX-PR was administered were tested with the same inoculum sizes for R-3746, CCL, CEX, cefadroxil, ampicillin (ABPC), DMPPC and cloxacillin (MCIPC). Adverse reactions and abnormal clinical laboratory test results were also examined.(ABSTRACT TRUNCATED AT 400 WORDS)
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Little is known about the antimicrobial resistance mechanisms in Klebsiella pneumoniae from swine in China. Thus, this paper aims to demonstrate the β-lactam resistance phenotypes and genotypes of K. pneumoniae isolates from swine in southwestern China, detect possible new β-lactamase variants, and determine whether or not the variants differ in their antibiotic resistance. Isolates from 58 unrelated diseased swine were collected from 61 pig farms in southwestern China from 2007 to 2009. Among the 58 isolates, 75.8-100% were resistant to β-lactam, 62.0-68.97% to fluoroquinolone, 44.8-46.55% to aminoglycoside, and 8.62-17.24% to β-lactam inhibitors. PCR amplification and DNA sequencing showed that bla(TEM-1) was detected in 100% (n=58) of the isolates, bla(SHV) in 82.76% (n=48), bla(CTX-M) in 39.66% (n=23), and bla(OKP) in 17.24% (n=10). The bla(SHV) types included bla(SHV-1), bla(SHV-11), bla(SHV-12), and bla(SHV-27). None of the isolates harbored bla(KPC), bla(LEN), or bla(GES) gene. Four novel variants (bla(OKP-A-13), bla(OKP-A-14), bla(OKP-A-15), and bla(OKP-A-16)) were identified among the 10 OKP β-lactamase-producing K. pneumoniae isolates resistant to ampicillin, amoxicillin, oxacillin, cefalexin, and cefadroxil. Plasmid analysis and PCR amplification indicated that bla(TEM-1) genes were detected in the total plasmid. Molecular typing by pulsed-field gel electrophoresis revealed the presence of 10 distinct pulsotypes of OKP producer isolates. Plasmid DNA digested with XbaI yielded two to six bands of ca. 0.15-30 kb. Transformants of the 10 OKP producer isolates showed no differences in their antibiotic susceptibility, except for the pulsotype B transformant, which carried bla(CTX-M). In China, β-lactam resistance appeared to be common among K. pneumoniae isolates from swine, suggesting that K. pneumoniae may be a reservoir for the dissemination of β-lactam resistance among Chinese pig farms.
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The sample is placed in the sample vessel of a RH cell and the moisture content of the air flow is controlled. From the RH cell the air flow is conducted into a subsequent perfusion cell in which a saturated salt solution has been loaded. The RH cell and perfusion cells are positioned in the sample sides of two twin calorimetric units. Depending on the moisture content in the outlet flow leaving the preceding RH cell, the heat flow signal from the subsequent perfusion cell will vary. By means of blank measurement with identical settings, the rate of water sorption can be calculated and, by integration, the amount of sorbed water is obtained.
A preliminary study revealed that similarly to the antibiotics amoxillin, thiamphenicol, erythromycin and doxycycline, the oral cephalosporin cefadroxil (CAS 66592-87-8) can be administered simultaneously with the mucolytic n-acetylcysteine (CAS 616-91-1). In the present study 12 healthy male volunteers received in a randomised cross-over design a single oral dose of 1000 mg cefadroxil or a single oral dose of 1000 mg cefadroxil (Bidocef) plus 200 mg n-acetylcysteine. The two study days were separated by a wash-out period of one week. To determine the pharmacokinetic profile of cefadroxil, plasma and sputum were analysed by HPLC at defined intervals. Regarding the bioavailability of cefadroxil, the free combination is bioequivalent to the individual component. After administration of cefadroxil plus n-acetylcysteine, a higher cefadroxil concentration was found in the sputum compared to an administration of cefadroxil alone. However, the difference was not statistically significant. According to the results, simultaneous administration of the oral cephalosporin cefadroxil and the mucolytic n-acetylcysteine is possible without changes in the bioavailability of cefadroxil being observed.
We evaluated the dose-dependent (saturable) gastrointestinal absorption of cefatrizine, an aminocephalosporin transported by peptide carriers, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. With an increase in oral dose (mumol/5 ml/kg) from 5 (low) to 50 (high), the intestinal absorption rate constant (ka), which was estimated by analysis of gastrointestinal disposition, decreased markedly, from 0.301 to 0.056 min-1. This decrease was ascribable to the saturability of intestinal membrane transport, of which the concentration dependency in the perfused intestine was similar in extent to the dose dependency in ka. However, the apparent absorption rate constant (ka'), which was estimated by analysis of plasma concentrations after oral administration, decreased only modestly from 0.037 to 0.023 min-1. This was associated with the result that, at the low dose, ka' was far smaller than ka and comparable with k(g) (gastric emptying rate constant), suggesting gastric emptying-limited absorption. At the high dose, where intestinal cefatrizine absorption was less efficient, ka' was closer to ka than k(g). It was also observed that the bioavailability was close to unity, independent of dose, suggesting that the intestinal transit time is long enough to achieve complete absorption, even at the high dose, where intestinal cefatrizine absorption is less efficient. Thus, it was found that the effect of saturability in the intestinal transport of cefatrizine is apparently attenuated in its overall gastrointestinal absorption because of the involvement of gastric emptying and intestinal transit time as additional physiological factors to define absorption. It was also found that a scaling factor is required to correlate the intestinal membrane transport between in vitro (in situ) and in vivo, though this remains to be verified to be utilized for developing oral drug delivery strategies and optimizing oral drug therapy.
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To investigate whether multiple peptide transporters mediate absorption of beta-lactams carrying different charges at physiological pH, we used the human intestinal cell line Caco-2 and Xenopus laevis oocytes expressing the cloned rabbit intestinal peptide transporter PepT1. Characteristics of transport of the anionic cefixime and the zwitterionic cefadroxil were assessed by 1) flux studies using radiolabeled compounds, by 2) measuring changes in pHin in cells and oocytes as a consequence of substrate-mediated proton influx and 3) by applying the two-electrode voltage clamp technique to assess the electrophysiological phenomena associated with beta-lactam transport in oocytes expressing PepT1. Both beta-lactams were rapidly taken up into Caco-2 cells and oocytes expressing PepT1 by a pH-dependent and saturable transport pathway. Mutual inhibition suggested that acidic and zwitterionic compounds may share a common transporter. Cefixime and cefadroxil caused a significant decline in intracellular pH as a consequence of proton coupled substrate influx. Uptake of cefixime and cefadroxil via PepT1 expressed in oocytes was electrogenic indicating that transport of both beta-lactams is associated with movement of net positive charge. The more acidic pH required for rheogenic cefixime uptake in both cell systems, when compared to cefadroxil uptake in both cell systems, when compared to cefadroxil uptake, and the concomitant faster intracellular acidification indicates that cefixime most likely is taken up only in its nonionized form with an additional proton being cotransported. This is supported by the observation that cefixime uptake at different pH correlated significantly with the percentage of the nonionized species being present. From our studies we conclude that a single peptide transport system can mediate electrogenic uptake of the neutral form of beta-lactam antibiotics into intestinal epithelial cells.
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Amorphous lactose and cefadroxil undergo recrystallization when the moisture level in the surroundings exceeds the threshold values specific to each compound. During the sorption phase, heat is evolved fairly linearly as a function of consumed moisture, and also after the recrystallization, the heats indicate linear behavior. The heat values for the desorption phase of amorphous lactose and the adsorption of crystalline lactose coincide. With the different anhydrous forms of theophylline, the hydration takes place more rapidly in the metastable form 1, and generally, the process is more energetic in form 1. In all cases, the gravimetric results agree with the water sorption uptakes calculated from the calorimetric data.
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The new oral cephalosporins cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate enhanced activity against Enterobacteriaceae susceptible to the established compounds as well (e.g. cefuroxime, cefaclor, cefadroxil). In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten include in their spectrum species hitherto resistant to oral cephalosporins (Proteus vulgaris, Providencia spp., Yersinia enterocolitica). Besides, the majority of these compounds demonstrate relevant activity (MIC50 equal to or below 2 mg/l) against Enterobacter spp., Citrobacter freundii, Serratia spp. and Morganella morganii. Ceftibuten is the most potent oral cephalosporin against most of the Enterobacteriaceae. Non-fermentative bacilli (Acinetobacter spp., Pseudomonas spp.) remain completely resistant to oral cephalosporins (except some Acinetobacter species against cefdinir and Pseudomonas cepacia against ceftibuten). Antistaphylococcal activity for oral cephalosporins is highest for cefdinir followed by BAY 3522, cefprozil, cefuroxime and cefpodoxime. Loracarbef, cefaclor and cefadroxil are about equally active, while the other compounds are only weakly active (cefixime) or inactive (cefetamet, ceftibuten). Enterococci are insensitive to new generation oral cephalosporins as they have been to established compounds. The most active oral cephalosporins against hemolytic streptococci are cefdinir and cefprozil. Streptococcus pneumoniae, Streptococcus milleri and Streptococcus mitior are most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522. Penicillin resistant pneumococci have to be regarded as resistant to all oral cephalosporins. Fastidious pathogens like Haemophilus spp., Moraxella catarrhalis and Neisseria gonorrhoeae are more susceptible to cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten than to the other oral cephalosporins. The activity of oral cephalosporins is only weak against Listeria spp., Helicobacter pylori and anaerobic pathogens (except BAY 3522). Bordetella pertussis remains resistant to all absorbable cephalosporins. Progress in antibacterial activity of oral cephalosporins was mainly achieved by cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten against Enterobacteriaceae and the fastidious pathogens and against staphylococci and the nonenterococcal streptococci by cefdinir, BAY 3522, cefprozil and cefpodoxime.