Effect of green tea on the gastrointestinal absorption of amoxicillin in rats.

BACKGROUND: The investigation of food-drug and plant-drug interactions has become increasingly important. In case of antibiotics, it is essential to achieve and maintain a plasma concentration sufficient for the antimicrobial action. Although, on theoretical basis, the interaction of polyphenols and antibiotics may be hypothesized, experimental data are lacking to assess its clinical relevance. The aim of our study was to assess the interaction between one of the most widely used antibiotics, amoxicillin, and green tea, the most frequently consumed drink with high polyphenol content. METHODS: The effects of green tea on the plasma level of amoxicillin was studied in an in vivo experiment in rats. The plasma level of amoxicillin was monitored by LC-MS/MS for 240 min after oral administration. The polyphenol content of green tea was determined by the Folin-Ciocalteu method. RESULTS: The peak plasma concentration of amoxicillin significantly decreased upon its co-administration with green tea, although the AUC0-240 of the antibiotic did not decrease significantly in the group treated with amoxicillin suspended in green tea. CONCLUSIONS: Our results suggest a potentially relevant interaction between green tea and amoxicillin, worth being further studied in humans.

Bioavailability enhancement studies of amoxicillin with Nigella.

BACKGROUND & OBJECTIVES: Nigella sativa Linn. is extensively used in the Indian diasporas as spice, which may interact with co-administered drugs and affect their intestinal availability. The purpose of this study was to investigate the effect of Nigella on bioavailability of amoxicillin in animal model. METHODS: Everted rat intestinal sacs were used for in vitro experiment to study the transfer of amoxicillin across the gut. Amoxicillin (6 mg/ml) was co-infused with 3 and 6 mg of methanol and hexane extract of Nigella seeds separately. The amount of amoxicillin that traversed the gut was followed spectrophotometrically at 273 nm. For in vivo studies Wistar albino rats were used. Amoxicillin (25 mg/kg, po) was co-administered with hexane extract of Nigella seeds (25 mg/kg, po). The amount of amoxicillin in rat plasma was determined by UPLC-MS/MS method. RESULTS: The in vitro studies both with methanol and hexane extracts of Nigella increased the permeation of amoxicillin significantly (P<0.001) as compared to control. Permeation was also found to be significantly higher for the hexane extract (P<0.001) in comparison to methanol extract at the same dose levels. In vivo experiments revealed that Cmax of amoxicillin in rat plasma when administered orally alone and in combination with hexane extract increased correspondingly from 4138.251 ± 156.93 to 5995.045 ± 196.28 ng/ml while as AUC 0→t increased from 8890.40 ± 143.33 to 13483.46 ± 152.45 ng/ml.h. INTERPRETATION & CONCLUSIONS: Nigella enhanced amoxicillin availability in both in vivo and in vitro studies. As the increase in bioavailability is attributed, in part, to enhanced diffusivity across intestine, our study indicated that Nigella increased intestinal absorption of amoxicillin.

Pharmacokinetic/pharmacodynamic evaluation of amoxicillin, amoxicillin/clavulanate and ceftriaxone in the treatment of paediatric acute otitis media in Spain.

INTRODUCTION: Acute otitis media is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents. Ninety-three per cent of the cases diagnosed in Spain are treated with antibiotics, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens. The aim of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the empirical treatment of acute otitis media, looking at the pharmacokinetic variability and the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for AOM in Spain, Streptococcus pneumoniae and Haemophilus influenzae. METHODS: Free-drug plasma concentrations were simulated and the probability of target attainment at each minimum inhibitory concentration and the cumulative fraction of response (CFR) were determined. Microbiological susceptibility information was extracted from SAUCE 3 surveillance. RESULTS: CFR with amoxicillin varied from 83% to 96% against S. pneumoniae and from 78% to 86% against H. influenzae. CFR was always >85% with amoxicillin/clavulanate. With the 3-day ceftriaxone regimen, the probability of achieving free concentrations above MIC at 72 hours significantly increased compared to the single dose, with which CFR ranged from 70% to 84%. CONCLUSIONS: High-dose amoxicillin (at least 80 mg/kg/day) should be the first-line therapy in uncomplicated infections, whereas amoxicillin/clavulanate (40 mg/kg/day) should be the choice when additional coverage for H. influenzae is desired. Administration of 3 daily doses of ceftriaxone increases bacteriological eradication probability when compared with one-day regimen, although additional clinical evaluations are necessary to establish the best target attainment with ceftriaxone.

Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime.

The purpose of this project was to develop and validate a pharmacokinetic model and to quantify the rate and extent of distribution between plasma and skin of two beta-lactam antibiotics, amoxicillin (AMX) and cefuroxime (CFX), which are frequently administered systemically to treat skin and skin structure infections. Dosing regimens are usually based on plasma concentration, however, concentrations at the target site are better correlated with the effect. For each antibiotic, three different i.v. bolus doses were administered to three female rabbits according to a randomized cross-over design and plasma samples were collected serially. Skin concentrations were obtained by continuous microdialysis. Skin and unbound plasma concentrations were fitted simultaneously using a semi-physiological model and the transfer constants plasma/skin (K(in)) and skin/plasma (K(out)) were estimated. K(in) and K(out) were then used to predict skin concentrations from the plasma levels obtained from an oral administration of AMX or from an i.v. bolus of CFX. The predicted skin profiles were similar to those measured by microdialysis during the actual experiments. In conclusion, this study shows that it is possible to generate a reasonable prediction of skin pharmacokinetics from any plasma level once a careful characterization of the transfer process between plasma and skin has been made.

Efficacy of amoxycillin-clavulanate in an experimental model of murine pneumonia caused by AmpC-non-hyperproducing clinical isolates of Escherichia coli resistant to cefoxitin.

The algorithms included in most automated systems used for antimicrobial susceptibility testing (e.g., Vitek 2) consider that Escherichia coli isolates resistant to cefoxitin are AmpC-hyperproducers and, consequently, resistant also to amoxycillin-clavulanate. However, a recent study revealed that 30% of E. coli clinical isolates resistant to cefoxitin remained susceptible in vitro to amoxycillin-clavulanate. The aim of the present study was to evaluate the in-vivo efficacy of amoxycillin-clavulanate in the treatment of an experimental model of pneumonia, using two clonally related isolates (with identical repetitive extragenic palindromic sequence (REP)-PCR patterns) of AmpC-non-hyperproducing and OmpF-lacking E. coli (Ec985 and Ec571) that were resistant to cefoxitin and susceptible to cefotaxime and amoxycillin-clavulanate. MICs were determined using a microdilution technique, and in-vitro bactericidal activity was tested using time-kill assays. The in-vivo efficacy of amoxycillin, amoxycillin-clavulanate and cefotaxime against both isolates was tested in a murine pneumonia model using immunocompetent C57BL/6 mice. Ec571 (a TEM-1/2 producer) was resistant to amoxycillin, whereas Ec985 (a TEM-1/2 non-producer) was susceptible. Amoxycillin, amoxycillin-clavulanate and cefotaxime were bactericidal for Ec985, and amoxycillin-clavulanate and cefotaxime were bactericidal for Ec571 at different concentrations and time-points, as determined using time-kill assays. Treatment with amoxycillin, amoxycillin-clavulanate and cefotaxime reduced the bacterial lung concentration of Ec985 compared with non-treated controls (p <0.05), whereas amoxycillin-clavulanate and cefotaxime showed efficacy against Ec571 when compared with the control and amoxycillin groups (p <0.05). Regardless of the exact underlying mechanism(s) of resistance, amoxycillin-clavulanate was effective in the experimental murine model in the treatment of pneumonia caused by AmpC-non-hyperproducing strains of E. coli resistant to cefoxitin.

Single-dose oral amoxicillin or linezolid for prophylaxis of experimental endocarditis due to vancomycin-susceptible and vancomycin-resistant Enterococcus faecalis.

Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States and 3 g in the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens might fail against vancomycin-resistant and/or aminoglycoside-resistant isolates. The present study tested oral linezolid as an alternative. Rats with catheter-induced aortic vegetations were given prophylaxis simulating human pharmacokinetics of oral amoxicillin (2- to 3-g single dose), oral linezolid (600 mg, single or multiple oral doses every 12 h), or intravenous vancomycin (1-g single dose). Rats were then inoculated with the minimum inoculum infecting 90% of the animals (90% infective dose [ID(90)]) or with 10 times the ID(90) of the vancomycin-susceptible E. faecalis strain JH2-2 or the vancomycin-resistant (VanA phenotype) E. faecalis strain UCN41. Amoxicillin was also tested with two additional vancomycin-susceptible E. faecalis strains, 309 and 1209. Animals were sacrificed 3 days later. All the tested bacteria were susceptible to amoxicillin and gentamicin. Single-dose amoxicillin provided 100% protection against all four isolates at both the ID(90) and 10 times the ID(90). In contrast, linezolid required up to four consecutive doses to provide full protection against the vancomycin-resistant isolate. Vancomycin protected only against the vancomycin-susceptible strain. The high efficacy of single-dose oral amoxicillin suggests that this regimen could be used for prophylaxis in both moderate-risk and high-risk patients without additional aminoglycosides. Linezolid appears to be less reliable, at least against the vancomycin-resistant strain.

Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci.

OBJECTIVES: Daptomycin was tested in vitro and in rats with experimental endocarditis against the ampicillin-susceptible and vancomycin-susceptible Enterococcus faecalis JH2-2, the vancomycin-resistant (VanA type) mutant of strain JH2-2 (strain JH2-2/pIP819), and the ampicillin-resistant and vancomycin-resistant (VanB type) Enterococcus faecium D366. METHODS: Rats with catheter-induced aortic vegetations were treated with doses simulating intravenously kinetics in humans of daptomycin (6 mg/kg every 24 h), amoxicillin (2 g every 6 h), vancomycin (1 g every 12 h) or teicoplanin (12 mg/kg every 12 h). Treatment was started 16 h post-inoculation and continued for 2 days. RESULTS: MICs of daptomycin were 1, 1 and 2 mg/L, respectively, for strains JH2-2, JH2-2/pIP819 and D366. In time-kill studies, daptomycin showed rapid (within 2 h) bactericidal activity against all strains. Daptomycin was highly bound to rat serum proteins (89%). In the presence of 50% rat serum, simulating free concentrations, daptomycin killing was maintained but delayed (6-24 h). In vivo, daptomycin treatment resulted in 10 of 12 (83%), 9 of 11 (82%) and 11 of 12 (91%) culture-negative vegetations in rats infected with strains JH2-2, JH2-2/pIP819 and D366, respectively (P < 0.001 compared to controls). Daptomycin efficacy was comparable to that of amoxicillin and vancomycin for susceptible isolates. Daptomycin, however, was significantly (P < 0.05) more effective than teicoplanin against the glycopeptide-susceptible strain JH2-2 and superior to all comparators against resistant isolates. CONCLUSIONS: These results support the use of the newly proposed daptomycin dose of 6 mg/kg every 24 h for treatment of enterococcal infections in humans.

Gastric juice, gastric tissue and blood antibiotic concentrations following omeprazole, amoxicillin and clarithromycin triple therapy.

BACKGROUND: Amoxicillin and clarithromycin are key antibiotics in proton pump inhibitor-based Helicobacter pylori eradication therapies. AIMS: To study gastric mucus and tissue concentrations and collect basic data about optimal antibacterial doses. METHODS: Plasma, gastric mucosa and gastric juice antibiotic concentrations were measured following either low- or high-dose amoxicillin (750 or 1000 mg b.i.d.) and clarithromycin (400 or 500 mg b.i.d.) given in combination with omeprazole 20 mg bid to 12 male volunteers in an open crossover design. Gastric juice and mucosal biopsy collection was performed either 2 (n=6) or 6 hours (n=6) after dosing. RESULTS: Amoxicillin concentrations 2 hours after high dosage were gastric juice > gastric body > antral mucosa > plasma. At 6 hours, plasma and gastric juice concentrations were still above the MIC for amoxicillin-susceptible bacteria but no antibiotic was detectable in mucosa samples. Clarithromycin concentrations after high dosage were gastric juice > mucosa > serum; all above the MIC for clarithromycin-susceptible bacteria at both 2 and 6 hours. CONCLUSIONS: Both dosage regimens provided effective antibiotic concentrations in gastric juice at 2 hours. After dosing, both antibiotics demonstrated high gastric tissue concentrations via local diffusion while clarithromycin also provided sustained delivery (6 hours) via gastric mucosa penetration.

In vitro bactericidal activity of peak serum concentrations of co-amoxiclav, amoxicillin and vancomycin against methicillin-resistant Staphylococcus aureus.

In order to explore the bactericidal activity of concentrations similar to the peak serum concentrations obtained after a single i.v. dose of 2,000/200 mg co-amoxiclav and 500 mg vancomycin, killing curves with co-amoxiclav (69/10 microg/ml), amoxicillin (69 microg/ml), clavulanic acid (10 microg/ml), and vancomycin (15 microg/ml) were performed against two isogenic (ss-lactamase positive and negative) methicillin-resistant Staphylococcus aureus strains in cation-supplemented Mueller-Hinton broth with 2% NaCl incubated at 35 degrees C. Colony counts were performed at 0, 1, 2, 3 and 4 hours in Mueller- Hinton plates supplemented with 4% NaCl and 25 microg/ml oxacillin to measure the resistant population. Similar initial inocula reductions were obtained for amoxicillin-clavulanic acid and vancomycin for both strains, and significant differences were found in comparison to the control. Clavulanic acid decreased the growth rate of the ss-lactamase negative strain when compared to control curves. The penicillin-binding protein 2a affinity of old ss-lactams in conjunction with clavulanic acid overcoming ss-lactamase resistance may explain these results.

Amoxicillin concentrations in the serum of Atlantic salmon (Salmo salar L) during furunculosis therapy.

The effectiveness of the delivery of amoxicillin to Atlantic salmon, undergoing chemotherapy in natural outbreaks of furunculosis in sea-cages, was investigated by measuring the concentration of the drug in serum samples. Five groups of 50 sera from three outbreaks were collected two hours after oral treatment with doses of 80 or 120 mg/kg bodyweight. Amoxicillin was detected in 82, 82, 92, 100 and 90 per cent of the sera in the five groups (limit of detection 0.16 microgram/ml). Many sera contained less than the minimum inhibitory concentration of amoxicillin for the causative agent Aeromonas salmonicida (0.3 microgram/ml), but a concentration more than double the minimum inhibitory concentration was achieved in 2, 2, 56, 32 and 44 per cent of the samples. There was wide variation in the serum concentrations between individuals in the same population and between populations receiving the same treatment; this variation was associated with population factors, the severity of infection and the accuracy of medicating the feed.

Nonlinearity of amoxicillin absorption kinetics in human.

Specialised gastrointestinal absorption of amoxicillin has been suggested in man and has been demonstrated in animals. In order to study the rate and extent of amoxicillin absorption, six healthy subjects were given 500 mg IV and two oral doses (500 mg and 3 g as a suspension). Absorption kinetics was analysed by compartmental modelling, noncompartmental methods and by calculation of absorption rates using deconvolution. Dose-dependency of the extent of amoxicillin absorption was observed, with a lower than expected mean maximum plasma concentration (49%), and fraction of the dose absorbed (39%) after the 3 g dose calculated from the 500 mg dose, assuming kinetic linearity. Zero-order kinetics of absorption was apparent in some subjects after the 500 mg dose, both from model fitting and absorption rate profile. However, no pattern consistent with pure first-order or zero-order absorption was observed after both oral doses in any individual. The dose-dependency of amoxicillin absorption was confirmed by a trend to an increased time of absorption for the high dose. The results show the variable nature and nonlinearity of the gastrointestinal absorption of amoxicillin and indicate the involvement of a number of factors, in addition to simple diffusion.

Therapeutic effect of aspoxicillin on experimental pneumonia with Klebsiella pneumoniae in mice.

The therapeutic effects of aspoxicillin (ASPC) on an experimental pneumonia in mice were compared with those of piperacillin (PIPC) and mezlocillin (MZPC) under various administration schedules. The pneumonia was induced with K. pneumoniae B-54 by the aerosol method. Fifty mg/kg of each penicillin was subcutaneously injected into mice starting from 12 h after infection. At 3- and 6-h interval regimens, ASPC caused the infected mice to survive longer than the other penicillins. The decrease of viable bacterial counts in the lung after a single or repeated injection of ASPC occurred more rapidly than with the other drugs. The concentration of ASPC in the lung after a single injection was higher than that of the other drugs and the concentration was maintained above the MIC for about 2 h. The therapeutic effects of these penicillins on this model reflected well their concentrations in the lung. Among these penicillins, ASPC gave the highest maximum level and persisted longest in the lung, so is shown to have a therapeutic effect superior to PIPC and MZPC on this model of pneumonia. The findings obtained in this experimental pneumonia model were concluded to correlate well with the good clinical efficacy of ASPC compared to PIPC.

Serum bactericidal activity of two newer quinolones against Salmonella typhi compared with standard therapeutic regimens.

The bactericidal activity of two newer quinolones, ciprofloxacin and ofloxacin, against eight strains of Salmonella typhi was examined by the serum dilution test and studies of bacterial killing kinetics in human serum, and compared to standard regimens. Bactericidal titers for ciprofloxacin ranged from 1:388 to 1:119 two hours and from 1:119 to 1:57 six hours after volunteers received an oral dose of 500 mg. The respective titers obtained after a 200 mg oral dose of ofloxacin were somewhat lower, but still exceeded 1:16 in all instances. Studies of bacterial killing kinetics demonstrated a rapid bactericidal action of both drugs against all strains tested. Compared to the classical anti-typhoid agents chloramphenicol, cotrimoxazole and amoxicillin, the new quinolones showed both markedly higher bactericidal titers and more rapid killing of Salmonella typhi in human serum.

Pharmacokinetic and therapeutic trial of sultamicillin in acute sinusitis.

Sultamicillin, an antibiotic combining ampicillin and the beta-lactamase inhibitor sulbactam, was administered to 13 patients diagnosed as having acute sinusitis. Specimens from sinus were obtained for all 13 patients by transantral puncture. Pharmacokinetics, bacteriology, and therapeutic efficacy were assessed. Eighty-five percent (11 of 13) were cured; two treatment failures were subsequently shown to have chronic (rather than acute) sinusitis during surgical exploration. Diarrhea was frequently encountered, and Clostridium difficile-associated enteritis was documented for one patient. Beta-lactamase-producing organisms were not encountered in this study; however, this study provides impetus for further controlled clinical trials.

Evaluation of amino penicillins in experimental infections in mice.

The therapeutic activity of bacampicillin compared to that of ampicillin and amoxycillin was evaluated against experimental infections in mice. Median curative doses (CD50) were determined in groups of animals challenged with bacterial suspensions injected intraperitoneally together with mucin and treated orally with the penicillins. When treated directly after the infection bacampicillin was slightly more active than ampicillin, whereas it was significantly more active than ampicillin and at least as active as amoxycillin when the treatment was instituted not until four hours after infection. Bacterial counts made on various organ homogenates from infected animals four hours after the infection showed that a generalized infection with high bacterial concentrations had developed. Penicillin administration caused a significant reduction in the bacterial counts and the bactericidal activity in vivo obtained after administration of bacampicillin appeared as good as that of amoxycillin.

[Pharmacokinetic and clinical research on a new antibiotic combination (amoxicillin and flucloxacillin in equivalent-weight dose)]. / Ricerca farmacocinetica e clinica su una nuova associazione antibiotica (amoxicillina e flucloxacillina in dosi equiponderali)

A controlled double-blind biometric and an open clinical trial were conducted to determine the therapeutic effectiveness of a new equal-dose w/w association of amoxicillin and flucloxacillin. The following conclusions were drawn. Both antibiotics were present in high serum levels; those of flucloxacillin were higher and more persistent. Analysis of variance on 89 patients pointed to the superiority of the association by comparison with amoxicillin alone. The clinical study made it clear that the broad and complementary spectrum of the association, its synergy, absence of toxicity and good gastric tolerance make it a valuable and effective therapeutic aid, also in presence of germs that produce beta-lactase.