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Antimicrobial Agents and Chemotherapy Jul 2004The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of...
The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of ester prodrugs. Pivampicillin and cefcapene pivoxil hydrochloride (CFPN-PI), ester-type oral antibiotics, were chosen as model ester prodrugs. The level of esterase activity in Caco-2 cells was lower than that measured in the rat jejunum when p-nitrophenyl acetate was used as a substrate. Almost complete ester hydrolysis occurred before the ester prodrugs reached the basolateral side of the monolayer, and the disappearance of prodrugs was thought to be due to metabolism or transport after addition to the apical side of the monolayer. When pivampicillin and CFPN-PI were used, the amounts of ampicillin and cefcapene (CFPN) produced by hydrolysis of prodrugs were increased because intracellular degradation of prodrugs resulted in intracellular accumulation. On the other hand, when ampicillin or CFPN was used, only a small amount of the drug reached the basolateral side of the monolayers and no intracellular accumulation was observed. The permeability of CFPN-PI, the solubility of which is dependent on the acidity of gastric juice, across a Caco-2 monolayer or rat intestine, was also investigated by using an in vitro system that mimics the physiological state of the human gastrointestinal tract. The oral absorption of CFPN-PI in humans is predicted to be good either in the Caco-2 model or in the rat intestine model. It is concluded that our system may be a valuable tool for evaluation of oral absorption of ester prodrugs metabolized during permeation through the intestinal epithelium. Broader evaluation of such a system is warranted.
Topics: Animals; Caco-2 Cells; Cephalosporins; Epithelial Cells; Escherichia coli; Esters; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Nitrophenols; Prodrugs; Rats; Rats, Wistar; Serratia; Spectrophotometry, Ultraviolet; Staphylococcus aureus
PubMed: 15215116
DOI: 10.1128/AAC.48.7.2604-2609.2004 -
The Journal of Antimicrobial... Oct 2003To determine the intracellular accumulation in a macrophage cell line of ampicillin and ampicillin esters, and to measure their activity against intracellular Listeria...
Intracellular accumulation and activity of ampicillin used as free drug and as its phthalimidomethyl or pivaloyloxymethyl ester (pivampicillin) against Listeria monocytogenes in J774 macrophages.
AIMS
To determine the intracellular accumulation in a macrophage cell line of ampicillin and ampicillin esters, and to measure their activity against intracellular Listeria monocytogenes.
METHODS
Quantitative evaluation of the activity of ampicillin, phthalimidomethylampicillin (PIMA) or pivaloyloxymethylampicillin (PIVA) against intracellular L. monocytogenes, and direct measurement of cellular ampicillin concentration in J774 macrophages.
RESULTS
Ampicillin, PIMA and PIVA caused a 0.5 log decrease in cell-associated cfu within 5 h when used at an extracellular concentration of 3.6 microM [10 x MIC of ampicillin (1.25 mg/L); 1.83 mg/L for PIMA and 1.67 mg/L for PIVA]. Addition of beta-lactamase in the extracellular milieu abolished the activity of ampicillin and of PIMA but not that of PIVA. At low extracellular concentrations [0.5 x MIC ampicillin (62.5 microg/L); equimolar concentrations for PIMA (91.5 microg/L) and PIVA (83.5 microg/L)], ampicillin and PIMA lost all activity (compared with controls), but PIVA remained as active as at the higher concentration. Incubation of cells with PIVA at the low concentration (83.5 microg/L) for 20 h caused a 2 log reduction of cfu if the medium was changed every 5 h (to compensate for the degradation of extracellular PIVA). Incubation of cells with PIVA allowed for a marked (four- to 25-fold) cell accumulation of ampicillin, whereas no ampicillin accumulation was seen for cells incubated with ampicillin or with PIMA.
CONCLUSIONS
This is the first demonstration that PIVA (a prodrug of ampicillin) can be used to promote ampicillin cellular accumulation and, thereby to increase ampicillin intracellular activity. PIVA could be useful for control of the intracellular multiplication of L. monocytogenes.
Topics: Ampicillin; Animals; Cell Line, Tumor; Intracellular Fluid; Listeria monocytogenes; Macrophages; Mice; Phthalimides; Pivampicillin
PubMed: 12972457
DOI: 10.1093/jac/dkg431 -
International Journal of Pharmaceutics Sep 2003We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble...
We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.
Topics: Administration, Oral; Animals; Caco-2 Cells; Esters; Humans; In Vitro Techniques; Intestine, Small; Male; Pharmaceutical Preparations; Predictive Value of Tests; Prodrugs; Rats; Rats, Wistar; Solubility; Water
PubMed: 12954178
DOI: 10.1016/s0378-5173(03)00343-0 -
Pharmaceutical Research Apr 2003The purpose of this work was to examine and understand the cellular pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and phthalimidomethyl... (Comparative Study)
Comparative Study
Cell handling, membrane-binding properties, and membrane-penetration modeling approaches of pivampicillin and phthalimidomethylampicillin, two basic esters of ampicillin, in comparison with chloroquine and azithromycin.
PURPOSE
The purpose of this work was to examine and understand the cellular pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and phthalimidomethyl (PIMA), in comparison with lysosomotropic drugs (chloroquine, azithromycin).
METHODS
Cell culture studies (J774 macrophages) were undertaken to study uptake and release kinetics and to assess the influence of concentration, pH, proton ionophore (monensin), and MRP and P-gp inhibitors (probenecid, gemfibrozil, cyclosporin A, GF 120918). Equilibrium dialysis with liposomes were performed to directly asses the extent of drug binding to bilayers. Conformational analysis modeling of the drug penetration in bilayers was conducted to rationalize the experimental observations.
RESULTS
PIVA and PIMA showed properties in almost complete contrast with those of chloroquine and azithromycin, i.e., fast apparent accumulation and fast release at 4 degrees C as well as at 37 degrees C, saturation of uptake (apparent Kd 40 microM), no influence of monensin, MRP, or P-gp inhibitors; tight binding to liposomes (Kd approx. 40 microM); and sharp increase in calculated free energy when forced in the hydrophobic domain.
CONCLUSIONS
Although they are weak organic bases, PIVA and PIMA show none of the properties of lysosomotropic agents. We hypothesize that they remain locked onto the pericellular membrane and may never penetrate cells as such in significant amounts.
Topics: Ampicillin; Azithromycin; Cell Culture Techniques; Cell Membrane; Chloroquine; Lysosomes; Macrophages; Models, Biological; Phthalimides; Pivampicillin
PubMed: 12739771
DOI: 10.1023/a:1023203017300 -
Infection Jun 2002We examined the fecal microflora of 1-3-month-old infants during treatment with phenoxymethylpenicillin, amoxycillin, pivampicillin, cefaclor, cefadroxil, loracarbef,...
We examined the fecal microflora of 1-3-month-old infants during treatment with phenoxymethylpenicillin, amoxycillin, pivampicillin, cefaclor, cefadroxil, loracarbef, erythromycin or cotrimoxazole. Escherichia coli increased during treatment with penicillins or cephalosporins, but was not affected by erythromycin or cotrimoxazole. Other enterobacteria were acquired or increased during treatment with all agents except cotrimoxazole. Enterococci persisted or increased during phenoxymethylpenicillin, cephalosporin or cotrimoxazole treatment, whereas erythromycin and the other penicillins suppressed them. Bacteroides, bifidobacteria and lactobacilli were suppressed to undetectable levels in most infants during treatment with all agents, except phenoxymethylpenicillin and loracarbef.
Topics: Bacterial Infections; Case-Control Studies; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Erythromycin; Feces; Female; Humans; Infant; Infant, Newborn; Intestines; Male; Penicillins; Probability; Reference Values; Risk Assessment; Sampling Studies; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 12120942
DOI: 10.1007/s15010-002-2140-z -
International Journal of Antimicrobial... Apr 2001Bacteriuria in pregnancy with or without clinical symptoms is frequent and increases the risk of pyelonephritis, preterm labour, and low birth weight infants. Commonly...
Bacteriuria in pregnancy with or without clinical symptoms is frequent and increases the risk of pyelonephritis, preterm labour, and low birth weight infants. Commonly used antibiotics such as ampicillin (pivampicillin), amoxicillin, trimethoprim, and sulphonamide are currently associated with a high degree of resistance of the most common pathogen in the urinary tract, Escherichia coli. During the past few decades a number of new and efficient antibacterial antibiotics have been developed. The presumption that a specific drug is safe for both the pregnant woman and the foetus depends on how widely the drug has been used. A recent survey among general practitioners and obstetricians in Denmark, Finland, Norway, and Sweden confirmed that the beta-lactam antibiotic pivmecillinam and nitrofurantoin are the most commonly used agents in the treatment of bacteriuria in pregnancy in the Nordic countries. However, a surprisingly high number of physicians reported that they prescribe sulphonamides during the first two trimesters in spite of resistance of E. coli and possible adverse effects on the foetus.
Topics: Adult; Anti-Infective Agents, Urinary; Bacteriuria; Drug Utilization; Female; Finland; Health Care Surveys; Humans; Practice Patterns, Physicians'; Pregnancy; Pregnancy Complications, Infectious; Scandinavian and Nordic Countries; Surveys and Questionnaires
PubMed: 11295409
DOI: 10.1016/s0924-8579(00)00349-6 -
The Journal of Antimicrobial... Sep 2000Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in...
Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in this development. Within a few days after the onset of antibiotic therapy, resistant Escherichia coli, Haemophilus influenzae and Staphylococcus epidermidis can be detected in the normal flora of volunteers or patients. Horizontal spread of the resistance genes to other species, e.g. Salmonella spp., Staphylococcus aureus and Streptococcus pneumoniae, occurs by conjugation or transformation. An ecologically sound antibiotic policy favours the use of antibiotics with little or no impact on the normal flora. Prodrug antibiotics which are not active against the bacteria in the mouth and the intestine (before absorption) and which are not excreted to a significant degree via the intestine, saliva or skin are therefore preferred. Prodrugs such as pivampicillin, bacampicillin, pivmecillinam and cefuroxime axetil are favourable from an ecological point of view. Experience from Scandinavia supports this, since resistance to mecillinam after 20 years of use is low (about 5%) and stable.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Conjugation, Genetic; Drug Resistance, Microbial; Drug Utilization; Ecosystem; Health Policy; Humans; Intestines; Oropharynx; Skin; Transformation, Bacterial
PubMed: 11051626
DOI: No ID Found -
The Journal of Antimicrobial... Sep 2000Bacteriuria in pregnancy, with or without clinical symptoms, is frequent. If left untreated, it can in 20-30% of cases lead to acute pyelonephritis, which is a serious... (Review)
Review
Bacteriuria in pregnancy, with or without clinical symptoms, is frequent. If left untreated, it can in 20-30% of cases lead to acute pyelonephritis, which is a serious threat to the mother and fetus, increasing the risk of preterm labour and low birthweight infants. This paper is a review of the literature concerning antibacterial treatment of bacteriuria in pregnancy. It is crucial to ensure that drugs to be used in pregnancy are safe and effective. Established first-line drugs such as ampicillin (pivampicillin) and amoxycillin, and other commonly used treatments such as trimethoprim-sulphamethoxazole, are associated with a high degree of resistance in Escherichia coli, the most common pathogen in the urinary tract. A recent survey of physicians in Denmark, Finland, Norway and Sweden confirms that beta-lactam antibiotics (particularly pivmecillinam) and nitrofurantoin are the drugs of first choice in the treatment of bacteriuria in pregnancy in the Nordic countries. No teratogenic effects have been associated with these agents. In contrast to nitrofurantoin, pivmecillinam is also efficient against pyelonephritis. In spite of resistance in E. coli and possible adverse effects on the fetus, many physicians still prescribe sulphonamides during the first two trimesters of pregnancy.
Topics: Anti-Bacterial Agents; Anti-Infective Agents, Urinary; Bacteriuria; Female; Humans; Pregnancy; Pregnancy Complications, Infectious
PubMed: 11051621
DOI: No ID Found -
The Journal of International Medical... 2000This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in adults with acute exacerbations of chronic bronchitis (not needing parenteral antibiotic therapy, hospitalization or oxygen support). Clinical success (cure + improvement) rates were similar for both groups at the end of treatment (day 10; azithromycin, 124 of 133 [93%]; pivampicillin, 79 of 92 [86%]) and at follow-up (day 52; 98 of 126 [78%] versus 66 of 81 [81%]). The treatments produced similar levels of pathogen eradication at the end of treatment (49 of 54 [91%] versus 32 of 37 [86%]). Azithromycin-treated patients had significantly reduced chest discomfort at the end of treatment, and a trend towards improved lung function. The two groups were similar with respect to improvements in other clinical symptoms and patient well-being, and to the incidences of adverse events and treatment discontinuations. This oral azithromycin regime is an effective treatment for acute exacerbations of chronic bronchitis, similar in efficacy to the longer pivampicillin regime and may offer superior patient compliance.
Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchitis; Chronic Disease; Consumer Product Safety; Drug Tolerance; Female; Humans; Male; Penicillins; Pivampicillin; Single-Blind Method; Treatment Outcome
PubMed: 10983860
DOI: 10.1177/147323000002800301 -
The Journal of Antimicrobial... Aug 2000Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in...
Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in this development. Within a few days after the onset of antibiotic therapy, resistant Escherichia coli, Haemophilus influenzae and Staphylococcus epidermidis can be detected in the normal flora of volunteers or patients. Horizontal spread of the resistance genes to other species, e.g. SALMONELLA: spp., Staphylococcus aureus and Streptococcus pneumoniae, occurs by conjugation or transformation. An ecologically sound antibiotic policy favours the use of antibiotics with little or no impact on the normal flora. Prodrug antibiotics which are not active against the bacteria in the mouth and the intestine (before absorption) and which are not excreted to a significant degree via the intestine, saliva or skin are therefore preferred. Prodrugs such as pivampicillin, bacampicillin, pivmecillinam and cefuroxime axetil are favourable from an ecological point of view. Experience from Scandinavia supports this, since resistance to mecillinam after 20 years of use is low (about 5%) and stable.
PubMed: 10969054
DOI: No ID Found