Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, August 1999, p. 1909-1913, Vol. 43, No. 8
Laboratoire de Bactériologie-Virologie,
Received 26 October 1998/Returned for modification 7 March
1999/Accepted 26 May 1999
The delivery of antibiotics into Helicobacter
pylori-infected human stomachs is still poorly understood. Human
embryonic gastric xenografts in nude mice have recently been proposed
as a new model for the study of H. pylori infection. Using
this model, we compared the penetration of amoxicillin, after
intraperitoneal administration of a dose of 20 mg/kg of body weight,
into the gastric mucosae of infected and uninfected xenografts. The
concentrations of this drug in serum and superficial gastric mucosae
were determined at 20 min and 1 and 3 h after injection. Ten mice
with H. pylori-infected grafts (n = 5) or
uninfected grafts (n = 5) were studied. Mucosal samples were obtained by cryomicrotomy. The concentrations in serum
were similar to those obtained in the serum of humans after oral
administration of 1 g of amoxicillin. The mean area under the
tissue concentration-versus-time curve from 0 to 3 h obtained for
mice with infected grafts was significantly higher than that obtained
for the animals with uninfected grafts (P = 0.01).
These results suggest that the penetration of amoxicillin into the
superficial gastric mucosa may be substantially increased in the case
of H. pylori infection. Thus, human xenografts in nude mice
represent a new, well-standardized model for investigation of systemic
delivery of drugs into H. pylori-infected gastric mucosa.
In vitro, Helicobacter
pylori is naturally susceptible to most antibiotics.
Unfortunately, when administered to a human, no single-antibiotic
therapy is able to achieve a high eradication rate (1, 10, 20, 27,
32, 34). This lack of clinical efficacy may be explained by
acquired resistance, poor compliance, insufficient antibiotic
penetration into the site of infection, and/or a low level of drug
stability at this location. The relative ineffectivness of
administration of single antibiotics has empirically led to the use of
triple therapies that consist of combinations of two antibiotics
(amoxicillin, clarithromycin, or imidazoles) with an antisecretory drug
(proton pump inhibitor or H2-receptor antagonist) and that
have been shown to be the most effective (8). However,
today, these recommended therapies do not result in eradication in all
patients. The search for optimal H. pylori treatment was
essentially based on the results of a great number of clinical trials.
Until now, no pharmacological approach has been systematically used to
improve existing therapeutic regimens or to search for new treatments.
This may be explained by the absence of a convenient and suitable
experimental model (18). The study of gastric penetration of
antibiotics should ideally be performed with patients with H. pylori infection. However, gastric pharmacokinetic studies with
humans have involved the use of gastric biopsy specimens. These biopsy
specimens may include deep, vascularized layers, which increases the
risk of contamination of the specimen with drugs from the systemic
circulation, and do not target precisely the ecological niche of
H. pylori. Moreover, these studies with humans may also be
difficult for ethical reasons. On the other hand, extrapolation to
humans of pharmacokinetic results obtained with uninfected guinea pigs,
which is the only animal model that has been used to study the gastric
penetration of antibiotics (35-37), remains difficult. An
in vitro model consisting of gastric mucosae obtained from rats and
mounted in Ussing chambers has recently been developed (12).
This is a convenient model for investigation of the characteristics of
local or systemic delivery of drugs to the stomach, although it may
have a poor correlation to the situation in humans, particularly when
systemic delivery is predominant. In such a model, it may be difficult to mimic the in vivo pharmacokinetics observed in humans. Moreover, the
use of human gastric mucosa infected with H. pylori would be
more appropriate for extrapolation to humans.
The severe combined immunodeficient mice, in which human fetal thymic
and liver tissues have been implanted, was recently proposed as a model
for determination of the in vivo effectiveness of different therapeutic
agents on immunodeficiency virus infection (28). We have
previously developed a new model of H. pylori infection in
nude mice using human gastric xenografts which exhibit differentiated
human gastric epithelium (19). The aim of this work was to
investigate the usefulness of this model for the study of amoxicillin
penetration into the infected human stomach after parenteral administration.
H. pylori infection model.
Ten pangenic, 6- to 8 week-old, Swiss nude mice purchased from Iffa Credo (Lyon, France) were
used. They were housed in individual cages, fed a commercial rodent
diet, and given water ad libitum. All animal experimentation was
performed in accordance with the institutional guidelines and approval
of the Service Vétérinaire de la Santé et de la
Protection Animale (Direction Générale de l'Alimentation
du Ministère de l'Agriculture et de la Forêt).
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Gastric Penetration of Amoxicillin in a Human
Helicobacter pylori-Infected Xenograft Model
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Study design and sampling.
The pharmacokinetic study was
performed 3 to 5 days after the evaluation of the infection. At this
time, mice with infected (mean ± standard deviation [SD]
weight, 30.5 ± 3.76 g) and uninfected (mean ± SD
weight, 29.8 ± 4.31 g) xenografts were anesthetized, and a
catheter in Teflon was microsurgically placed in the femoral artery for
blood collection. The grafts were then microsurgically opened as
described above, and gastric juice was taken for pH determination. For
the kinetic study, animals were maintained under anesthesia. Each mouse
was given a single intraperitoneal dose of amoxicillin (20 mg/kg). This
permitted attainment, as observed in a preliminary study (unpublished
data), of a maximum measured concentration in serum (measured
Cmax) and an area under the serum
concentration-versus-time curve from 0 to 3 h
(AUC0-3) close to those calculated from data obtained for
humans after the administration of a 1-g single oral dose of
amoxicillin (6). Blood samples (50 to 100 µl) were
collected prior to dosing and at 20 min and 1 and 3 h after
intraperitoneal administration. All blood samples were immediately
centrifuged at 1,600 × g at 4°C. The serum was then
removed and was stored at 
80°C until analysis. Concomitantly, large
gastric antral biopsy specimens (4 by 4 by 1 mm) were surgically
obtained from areas devoid of any hemorrhagic lesions and were rinsed
in 0.1 M phosphate buffer (pH 7.5). Then, the superficial gastric
mucosa was immediately removed at a depth of 300 µm by standardized
cryomicrotomy at 20°C (Cryomicrotome HM 500M; Microm, Francheville,
France) as described previously (17), with sections of 3 µm put into preweighed Eppendorf caps. The caps containing the
mucosal material was reweighed without delay and were stored at
80°C until drug assays. The weights varied between 10 and 20 mg.
Drug assay. (16). All chemicals and solvents used were of high-performance liquid chromatography (HPLC) grade. Titrated powder of sodium amoxicillin (SmithKline Beecham Laboratories, Nanterre, France) was dissolved in ultrapure water to give a stock solution of 100 mg/liter. The latter was further diluted in ultrapure water and human blank pooled serum (1:9 [vol/vol]) to obtain calibration standards with concentrations of 0.1, 1, and 10 µg/ml for the determination of concentrations in serum. For the determination of concentrations in the mucosa, standard solutions with concentrations of 0.1, 0.5, and 5 µg/ml were prepared in 0.1 M phosphate buffer (pH 7.5).
Two hundred microliters of either the standard amoxicillin solutions or diluted unknown samples was mixed with an equal volume of acetonitrile in 5-ml screw-cap glass tube. After vortex mixing for 15 s and shaking by rotation (20 rpm) for 10 min, the samples were centrifuged at 1,600 × g for 10 min at 4°C. The supernatant was transferred to another screw-cap glass tube, and 2 ml of methylene chloride was added. After shaking and centrifugation as described above, the upper aqueous layer was removed before injection into the HPLC system. Gastric mucosal material was suspended in 200 µl of 0.1 M phosphate buffer (pH 7.5). After vortex mixing for 5 min, this solution was kept at 4°C for 2 h. Then, mucosal samples as well as standard solutions were processed in the same way described above for serum samples. The isocratic HPLC system consisted of a 110 A solvent delivery module (Beckman, Fullerton, Calif.), a model 210 sample injection valve equipped with a 50-µl sample loop (Beckman), and a model 160 variable-wavelength detector (Beckman). Chromatograms were processed with a Beckman recording data processor with Gold, version 6.01, software. Separations were performed on a high-speed analytical column (inner diameter, 75 by 4.6 mm) packed with 3-µm-diameter particles (Ultrasphere XL-ODS; Beckman). The mobile phase consisted of 2 M ammonium acetate-0.1 M tetrabutylammonium-acetonitrile-water (0.75:5:13:81.25 [vol/vol/vol/vol]) adjusted to pH 7.5 with sodium hydroxide. The flow rate was set at 1 ml/min, and the eluent was monitored at 227 nm. Serum and tissue samples obtained before dosing were used as blank samples. For serum and gastric mucosa, the standard curves displayed excellent linearity, and r2 values generally exceeded 0.999. The interassay reproducibility was assessed by using the standard solutions. The between-group variances, as determined with concentrations of 0.1, 1, and 10 µg/ml for control serum samples and 0.1, 0.5, and 5 µg/ml for control mucosal samples, were 1.8, 2, 4.5, 2, 3.5, and 5%, respectively. The lower limit of quantitation was 0.01 µg/ml for serum.Pharmacokinetic analysis. The measured Cmax was obtained by direct observation of the individual kinetic profiles. The AUC0-3 was calculated by using the trapezoidal rule and included all datum points obtained for serum or mucosa. Results are given as mean ± SDs. Mean values were compared by the paired Student t test (Stat.ITCF 5 software; Institut Technique des Céréales et des Fourrages, Paris, France). A P value of less than 0.05 was considered significant.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
As shown previously (19), the gastric juice pH was consistent with that found in H. pylori infection since it was increased in all infected xenografts (pH range, 5 to 7.5) and remained low in uninfected xenografts (pH range, 1 to 2). No macroscopic blood contamination was evidenced in mucosal or gastric juice samples.
In mice with uninfected xenografts, amoxicillin concentrations in serum
decreased from 18.76 ± 5.57 µg/ml at 20 min to 5.14 ± 2.28 µg/ml at 3 h (Table 1). These
concentrations were not statistically different from those observed at
the same time in mice with infected xenografts. The mean measured
Cmax in the serum of mice with infected
(19.03 ± 2.16 µg/ml) or uninfected (19.12 ± 5.10 µg/ml)
xenografts (Table 2) were similar to
those observed in humans after administration of a 1-g oral single dose
of amoxicillin (19.7 ± 5.4 µg/ml) (6).
Cmax was reached in serum at 20 min in all mice
except for the serum of one mouse with an uninfected xenograft, which
exhibited a Cmax at 1 h. Moreover, the mean
AUC0-3s observed for the serum of both groups of mice
(infected mice, 30.04 ± 5.65 µg · h/ml; uninfected mice,
33.29 ± 8.85 µg · h/ml) were similar to the mean
AUC0-3s calculated from data obtained for humans after
administration of the same oral dose mentioned above
(AUC0-3, 36.94 µg · h/ml) (6).
|
|
The highest concentrations of amoxicillin in superficial gastric mucosa
were measured in the samples of either the uninfected or infected
xenografts taken at 1 h except for one graft in each group (taken
at 20 min) (Table 3). Amoxicillin
concentrations in the uninfected antral mucosae were significantly
lower than those observed in serum at 20 min (P = 0.0003) and at 1 h (P = 0.004), with ratios
of the concentration in the mucosa to that in serum (mucosa/serum
ratio) at the two times ranging from 0.07 to 0.29 and 0.15 to 0.48, respectively. In the infected grafts, the mean concentration in serum
was significantly higher than the mean concentration in the mucosa at
20 min (P = 0.005). Mean amoxicillin concentrations in
the mucosa were not statistically different (P = 0.7)
from those observed in serum at 1 h in the infected group (range
of mucosa/serum ratios, 0.60 to 1.16) and at 3 h in both groups
(infected group, P = 0.3 [range of mucosa/serum ratios, 0.77 to 1.50]; uninfected group, P = 0.1
[range of mucosa/serum ratios, 0.41 to 1.20]). In infected xenografts
the mean concentrations in the mucosa were at least twofold higher than
those in uninfected xenografts at each time point. The mean of the
AUC0-3 for mucosa to that for serum (mucosa/serum
AUC0-3 ratio was also significantly higher for infected
xenografts than for uninfected xenografts (P = 0.01)
(Table 3).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
Until now only a few studies of gastric penetration of antibiotics
have been performed with H. pylori-infected patients
(5, 11, 33). This may be partially explained by the fact
that in these studies the number and the nature of regimens that can be
ethically used are limited. Other in vivo studies have always been
performed with uninfected animals (35-37). However, gastric H. pylori infection may modify the gastric penetration of
drugs by altering the mucus, the mucosal circulation, and/or the pH gradients in the stomach (14, 29, 30). This renders
necessary the use of H. pylori-infected models for the study
of the gastric pharmacokinetics of antibiotics. Thus, the current model
represents an interesting new alternative to pharmacokinetic studies
with humans. However, in experimental infection in animals,
particularly rodents, it is well known that the drug kinetics differ
from those observed in humans (4). Thus, the half-lives of
-lactam antibiotics are significantly longer in humans than in
animals (31). In our model, the use of the intraperitoneal
route (20 mg/kg) allowed us to circumvent this difference in half-life
and resulted in mean Cmax and
AUC0-3 values for serum similar to those observed for the
serum of humans after oral intake of 1 g of amoxicillin. Nevertheless, because the sampling period lasted for only 3 h, it
cannot be concluded that half-lives are actually identical in humans
and the animal model. Only Cmax and the
AUC0-3 are similar. Additional sampling times would have
resulted in more precise profiles of the pharmacokinetics of
amoxicillin in mice. However, in our study, the number of blood samples
was limited in order to avoid a substantial decrease in the total blood
volume of the animals, which would have affected the pharmacokinetic behavior of amoxicillin.
In our study, the mean amoxicillin concentrations observed in the gastric superficial mucosa ranged from 2.05 to 5.06 and from 4.92 to 10.14 µg/g in uninfected or infected grafts, respectively. These values are lower than those reported in human gastric mucosa (entire mucosal biopsy specimens) obtained 47 min to 2 h (15 to >322 µg/g) after the administration of a single 500-mg oral dose of amoxicillin (21). This may be due to the fact that when amoxicillin is given orally, its concentrations in the gastric mucosa may reflect both local absorption and diffusion from the systemic circulation. Another explanation for this difference may be that the concentration measured by using biopsy specimens may correspond to the amoxicillin concentration present locally and that present in the systemic circulation since biopsy specimens may also include the deep, vascularized layers of the gastric wall. In the stomach, H. pylori lives in the mucus layer and also adheres to gastric epithelial cells, especially at the intercellular junctions. Moreover, it has been shown that H. pylori may invade epithelial cells in vivo (3, 19, 25). The superficial gastric mucosa may therefore more adequately represent this microniche. Westblom et al. (35) used scraping with a glass slide to remove this portion from the stomach of adult guinea pigs to study the intragastric penetration of clindamycin. However, the distance between the luminal surface of the gastric mucosa and the muscularis mucosa may vary in the same stomach because of gastroplication. Freezing allows better stretching of the gastric mucosa, which minimizes gastroplication. This may explain why cryomicrotomy may represent a more reproducible way to obtain gastric superficial mucosa (17). However, in guinea pigs, pharmacokinetic studies were performed with the superficial mucosa of the whole stomach, which permitted retrieval of enough material to detect even low levels of antibiotics, but one animal was killed at each time point. In our study, the pharmacokinetics of amoxicillin in the gastric mucosa have been studied at all time points with the same animal. The use of large biopsy specimens was necessary to be able to detect concentrations above the detection threshold, and so specimens from only a limited number of time points could be studied.
Antibiotics are usually given orally to eradicate H. pylori, but they may act after local or subsequent systemic delivery. The latter would play a role in therapeutic efficacy (18). Our results suggest that this penetration may be enhanced by H. pylori infection, since the concentrations of amoxicillin in the mucosa were significantly higher in mice with infected xenografts than those with in uninfected xenografts. This could also be due to contamination of mucosal samples with blood, the risk of which would be increased by the important neoangiogenesis observed in all the infected xenografts. However, this seems unlikely or at least negligible since no macroscopic blood contamination was detected at the time of sampling and since cryomicrotomy prevents any significant contamination from interstitial tissue and plasma (17). Amoxicillin is unstable at normal gastric pH (pH 1 to 2) (9). Thus, the lower concentrations observed in the superficial mucosa of uninfected grafts, in which the gastric juice pH was low, may be due to the hydrolytic degradation of amoxicillin in vivo but also ex vivo for acid-containing samples. However, all biopsy specimens were immediately rinsed with phosphate buffer (pH 7.5) and frozen. This renders any ex vivo degradation unlikely. The increased amoxicillin concentrations in the infected mucosa may be due to enhanced diffusion because of local vessel proliferation, capillary dilatation, and/or a better stability of amoxicillin at higher intraluminal pH.
Irrespective of the infection status, the concentrations of amoxicillin in the mucosa were always above the reported MICs at which 90% of isolates are inhibited (0.06 to 0.25 µg/ml) for H. pylori at neutral pH (13, 15) and were also at least 10-fold higher than the minimal bactericidal concentration (0.1 µg/ml), as determined by Mégraud et al. (22). Some investigators (2, 22) have suggested that the bactericidal activity of amoxicillin against H. pylori may be concentration dependent. Thus, the high concentrations obtained at 1 h in the gastric mucosa may be sufficient to obtain a good bactericidal effect. If our results were extrapolated to humans, they would suggest that the lack of eradication observed after therapies with amoxicillin in combination with proton pump inhibitors (26) would not be explained by low levels of antibiotic penetration but would more likely be explained by amoxicillin resistance (7) or other not well known mechanisms, including the possible intracellular localization of H. pylori (3, 19, 25). However, as the nature of the bactericidal effect of amoxicillin against H. pylori is still controversial (23, 24), it remains hazardous to draw any conclusion about this point and the nature of the effect requires further studies.
Our model permits study of the gastric penetration of xenobiotic agents into infected human gastric mucosa. In this study, it has been applied to the study of the systemic delivery of amoxicillin. However, it could also be used to study the local delivery of drugs in the superficial gastric mucosa, the penetration of antibiotics into tissue, and the effects of antibiotics against H. pylori in vivo. Therefore, it represents a new well-standardized model for the investigation of new anti-H. pylori agents.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Laboratoire de Bactériologie, Hôpital Central, 29 Avenue du Maréchal de Lattre de Tassigny, 54035 Nancy Cedex, France. Phone: (33) 3 83 85 21 96. Fax: (33) 3 83 85 26 73. E-mail: a.lozniewski{at}chu-nancy.fr.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
| 1. | Bayerdorffer, E., and R. Ottenjann. 1988. The role of antibiotics in Campylobacter pylori associated peptic ulcer disease. Scand. J. Gastroenterol. 23:93-100. |
| 2. | Berry, V., K. Jennings, and G. Woodnutt. 1995. Bactericidal and morphological effects of amoxicillin on Helicobacter pylori. Antimicrob. Agents Chemother. 39:1859-1861[Abstract]. |
| 3. | Bode, G., P. Malfertheiner, and H. Ditschuneit. 1990. Pathogenetic implications of ultrastructural findings in Campylobacter pylori related gastroduodenal disease. Scand. J. Gastroenterol. 23(Suppl. 142):25-39. |
| 4. | Carbon, C. 1990. Significance of tissue levels for prediction of antibiotic efficacy and determination of dosage. Eur. J. Clin. Microbiol. Infect. Dis. 9:510-516[Medline]. |
| 5. | Cardaci, G., J. R. Lambert, R. G. King, N. Onishi, and P. Midolo. 1995. Reduced amoxicillin uptake into human gastric mucosa when gastric juice pH is high. Antimicrob. Agents Chemother. 39:2084-2087[Abstract]. |
| 6. |
Croydon, E. A. P., and R. Sutherland.
1970.
 -Amino-p-hydroxybenzylpenicillin: absorption and excretion in man.
Antimicrob. Agents Chemother.
1:427-433.
|
| 7. | Dore, M. P., A. Piana, M. Carta, A. Atzei, B. M. Are, I. Mura, G. Massarelli, A. Maida, A. R. Sepulveda, D. Y. Graham, and G. Realdi. 1998. Amoxycillin resistance is one reason for failure of amoxycillin-omeprazole treatment of Helicobacter pylori infection. Aliment. Pharmacol. Ther. 12:635-639[Medline]. |
| 8. | Dunn, B. E., H. Cohen, and M. J. Blaser. 1997. Helicobacter pylori. Clin. Microbiol. Rev. 10:720-741[Abstract]. |
| 9. |
Erah, P. O.,
A. F. Goddard,
D. A. Barrett,
P. N. Shaw, and R. C. Spiller.
1997.
The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection.
J. Antimicrob. Chemother.
39:5-12 |
| 10. | Glupczynski, Y., M. Labbe, A. Burette, M. Delmee, V. Avesani, and C. Bruck. 1987. Treatment failure of ofloxacin in Campylobacter pylori infection. Lancet i:1096. |
| 11. | Goddard, A. F., M. J. Jessa, D. A. Barrett, P. N. Shaw, C. Cederberg, and R. C. Spiller. 1996. Effect of omeprazole on the distribution of metronidazole, amoxicillin and clarithromycin in human gastric juice. Gastroenterology 111:358-367[Medline]. |
| 12. | Goddard, A. F., and R. C. Spiller. 1997. In vitro assessment of gastric mucosal transfer of anti-Helicobacter therapeutic agents. Antimicrob. Agents Chemother. 41:1246-1249[Abstract]. |
| 13. | Gotoh, A., Y. Kawakami, T. Akahane, T. Akamatsu, T. Shimizu, K. Kiyosawa, and T. Katsuyama. 1997. Susceptibility of Helicobacter pylori isolates against agents commonly administered for eradication therapy and the efficacy of chemotherapy. Microbiol. Immunol. 41:7-12[Medline]. |
| 14. | Guslandi, M., M. Sorghi, and A. Tittobello. 1994. Does Helicobacter pylori affect gastric microcirculation? Ital. J. Gastroenterol. 26:383-384[Medline]. |
| 15. |
Irie, Y.,
K. Tateda,
T. Matsumoto,
S. Miyazaki, and K. Yamaguchi.
1997.
Antibiotic MICs and short time-killing against Helicobacter pylori: therapeutic potential of kanamycin.
J. Antimicrob. Chemother.
40:235-240 |
| 16. | Jehl, F., C. Gallion, and H. Monteil. 1990. High-performance liquid chromatography of antibiotics. J. Chromatogr. 531:509-548[Medline]. |
| 17. | Lozniewski, A., M. Weber, J. D. De Korwin, M. C. Conroy, P. Franck, J. Floquet, A. Le Faou, and J. C. Burdin. 1995. Use of cryomicrotomy to study gastric diffusion of amoxicillin in guinea pigs. Antimicrob. Agents Chemother. 39:766-768[Abstract]. |
| 18. | Lozniewski, A., J. D. De Korwin, F. Muhale, and F. Jehl. 1998. Gastric diffusion of antibiotics used against Helicobacter pylori. Int. J. Antimicrob. Agents 9:181-193. |
| 19. |
Lozniewski, A.,
F. Muhale,
R. Hatier,
M. C. Conroy,
A. Le Faou,
M. Weber, and A. Duprez.
1999.
Human embryonic gastric xenografts in nude mice: a new model of Helicobacter pylori infection.
Infect. Immun.
67:1798-1805 |
| 20. | McNulty, C. A. M., J. C. Gearty, B. Crump, M. Davis, I. A. Donovan, V. Melikian, D. M. Lister, and R. Wise. 1986. Campylobacter pyloridis and associated gastritis: investigator blind, placebo controlled trial of bismuth salicylate and erythromycin ethylsuccinate. Br. Med. J. 298:645-649. |
| 21. |
McNulty, C. A. M.,
J. C. Dent,
G. A. Ford, and S. P. Wilkinson.
1988.
Inhibitory antimicrobial concentrations against Campylobacter pylori in gastric mucosa.
J. Antimicrob. Chemother.
22:729-738 |
| 22. |
Mégraud, F.,
P. Trimoulet,
H. Lamouliatte, and L. Boyanova.
1991.
Bactericidal effect of amoxicillin on Helicobacter pylori in an in vitro model using epithelial cells.
Antimicrob. Agents Chemother.
35:869-872 |
| 23. | Midolo, P. D., J. D. Turnidge, and W. J. Munckhof. 1996. Is bactericidal activity of amoxicillin against Helicobacter pylori concentration dependent? Antimicrob. Agents Chemother. 40:1327-1328[Medline]. |
| 24. |
Midolo, P. D.,
J. D. Turnidge, and J. R. Lambert.
1997.
Bactericidal activity and synergy studies of proton pump inhibitors and antibiotics against Helicobacter pylori in vitro.
J. Antimicrob. Chemother.
39:331-337 |
| 25. |
Noach, L. A.,
T. M. Rolf, and G. N. J. Tytgat.
1994.
Electron microscopy study of association between Helicobacter pylori and gastric and duodenal mucosa.
J. Clin. Pathol.
47:699-704 |
| 26. | Penston, J. G., and K. E. L. McColl. 1997. Eradication of Helicobacter pylori: an objective assessment of current therapies. Br. J. Clin. Pharmacol. 43:223-243[Medline]. |
| 27. | Peterson, W. L., D. Y. Graham, B. Marshall, M. J. Blaser, R. M. Genta, P. D. Klein, C. W. Stratton, J. Drnec, P. Prokocimer, and N. Siepman. 1993. Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized, double-blind trial. Am. J. Gastroenterol. 88:1860-1864[Medline]. |
| 28. | Pettoello-Mantovani, M., T. R. Kollmann, C. Raker, A. Kim, S. Yurasov, R. Tudor, H. Wilshire, and H. Goldstein. 1997. Saquinavir-mediated inhibition of human immunodeficiency virus (HIV) infection in SCID mice implanted with human fetal thymus and liver tissue: an in vivo model for evaluating the effect of drug therapy on HIV infection in lymphoid tissues. Antimicrob. Agents Chemother. 41:1880-1887[Abstract]. |
| 29. | Sarosiek, J., A. Slomiany, and B. L. Slomiany. 1988. Evidence for weakening of gastric mucus integrity by Campylobacter pylori. Scand. J. Gastroenterol. 23:585-590[Medline]. |
| 30. | Sarosiek, J., B. J. Marshall, D. A. Peura, S. Hoffman, T. Feng, and R. W. McCallum. 1991. Gastroduodenal mucus gel thickness in patients with Helicobacter pylori: a method for assessment of biopsy specimens. Am. J. Gastroenterol. 86:729-734[Medline]. |
| 31. |
Sawada, Y.,
M. Hanano,
Y. Sugiyama, and T. Iga.
1984.
Prediction of the disposition of -lactam antibiotics in humans from pharmacokinetic parameters in animals.
J. Pharmacokinet. Biopharm.
12:241-261[Medline].
|
| 32. |
Stone, J. W.,
R. Wise,
I. A. Donovan, and J. Gearty.
1988.
Failure of ciprofloxacin to eradicate Campylobacter pylori from the stomach.
J. Antimicrob. Chemother.
22:92-93 |
| 33. | Unge, P., and H. Gnarpe. 1988. Pharmacokinetic, bacteriological and clinical aspects of the use of doxycycline in patients with active duodenal ulcer associated with Campylobacter pylori. Scand. J. Infect. Dis. 53(Suppl):70-73. |
| 34. | Unge, P., A. Gad, H. Gnarpe, and J. Olsson. 1989. Does omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients with antral gastritis? Scand. J. Gastroenterol. 24(Suppl.167):49-54. |
| 35. |
Westblom, T. U.,
D. E. Duriex,
E. Madan, and R. B. Belshe.
1990.
Guinea pig model for antibiotic transport across gastric mucosa: inhibitory tissue concentrations of clindamycin against Helicobacter pylori (Campylobacter pylori) following two separate dose regimens.
Antimicrob. Agents Chemother.
34:25-28 |
| 36. | Westblom, T. U., and D. E. Duriex. 1991. Enhancement of antibiotic concentrations in gastric mucosa by H2-receptor antagonist. Dig. Dis. Sci. 36:25-28[Medline]. |
| 37. | Westblom, T. U., and D. E. Duriex. 1991. Pharmacokinetics of cefuroxime and ciprofloxacin in gastric mucosa: comparison to in vitro inhibitory concentrations against Helicobacter pylori. Microbiologica 14:37-43[Medline]. |
Antimicrobial Agents and Chemotherapy, August 1999, p. 1909-1913, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Sherwood, P V, Wibawa, J I D, Atherton, J C, Jordan, N, Jenkins, D, Barrett, D A, Shaw, P N, Spiller, R C
(2002). Impact of acid secretion, gastritis, and mucus thickness on gastric transfer of antibiotics in rats. Gut
51: 490-495
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»