In vitro susceptibility of Helicobacter pylori to, and in vivo suppression by, antimicrobials used in selective decontamination of the digestive tract

Peter H. J. van der Voorta,b,*, René W. M. van der Hulstc,d, Durk F. Zandstraa, Arie van der Endee, Alfons A. M. Geraedtsf and Guido N. J. Tytgatc

a Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam; b Department of Intensive Care, Medical Centre Leeuwarden-Zuid, Leeuwarden; c Department of Gastroenterology, Academic Medical Center, Amsterdam; d Department of Internal Medicine and Gastroenterology, Kennemer Gasthuis, Haarlem; e Department of Medical Microbiology, Academic Medical Center, Amsterdam and f Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The incidence of bleeding related to stress ulcers is reduced in critically ill patients in whom gut decontamination has been performed; this may be a result of suppression of Helicobacter pylori infection. We determined the susceptibility of H. pylori to the applied antibiotics. In nine of 10 critically ill patients (using intravenous cefotaxime and topical polymyxin, tobramycin and amphotericin B (PTA) given by nasogastric tube) and all six volunteers (using PTA alone), H. pylori was suppressed as long as the topical antibiotics were ingested. The in vitro studies revealed that all strains were susceptible to cefotaxime and tobramycin. The strains were not susceptible to polymyxin or amphotericin B.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Helicobacter pylori plays a pivotal role in the development of ulcer disease, and could also be a risk factor for stress ulceration in critically ill patients.1 We have shown that patients treated with selective decontamination of the digestive tract (SDD) appear to have a lower incidence of bleeding related to stress ulcers, which may at least in part be related to suppression of H. pylori infection.2 In a previous study we found that H. pylori was suppressed effectively in critically ill patients who were treated with SDD among other antibiotics.3 In the present study we investigated whether H. pylori is suppressed by the full SDD regimen, containing both the topical and the systemic SDD antibiotics, while no other antibiotics are given. In addition, we investigated the role of the topical SDD antibiotics in H. pylori-positive volunteers. In vitro studies were performed to determine the susceptibility of H. pylori to these SDD antibiotics and other antibiotics used frequently in the intensive care unit (ICU).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ten patients with H. pylori infection, as detected by laser-assisted ratio analyser (LARA) [13C]urea breath test and serology, were included. All patients were treated with SDD which consisted of three parts: (i) a mixture of the non-absorbable PTA antibiotics (polymyxin E 100 mg, tobramycin 80 mg and amphotericin B 500 mg), which was given by nasogastric tube four times daily during the entire intensive care stay; (ii) a 2% solution of PTA in Orabase paste which was administered topically to the oropharynx four times daily throughout the ICU stay and (iii) cefotaxime 1000 mg iv four times daily during the first 4 days of admission. The use of other antibiotics or proton pump inhibitors was prohibited. The study was approved by local ethical and scientific committees.

Six volunteers with H. pylori infection, as detected by LARA [13C]urea breath test and serology were studied. They took the topical PTA antibiotics four times daily with food for 7 days. The volunteers did not use proton pump inhibitors or other medication.

Detection of H. pylori

Urea breath test. A LARA [13C]urea breath test (Alimenterics, Morris Plains, NJ, USA) was performed immediately after admission to the ICU and institution of mechanical ventilation.4 Repeated tests were done on the third and every seventh day until discharge from the ICU. Patients were not followed up after discharge from the ICU. The volunteers performed a LARA [13C]urea breath test before treatment and 1 day and 8 weeks after cessation of treatment. Previously, we have shown the LARA [13C]urea breath test to be an easy and reliable method of detecting H. pylori.4,5

Serology. IgG antibodies against H. pylori were detected by enzyme-linked immunosorbent assay (HM-CAP ELISA Enteric Products Inc., Stony Brook, NY, USA). A cut-off of 1.8 U/L was used. Sera were drawn immediately after ICU admission, on the third day and every seventh day thereafter.

Culture and MICs

Upper gastrointestinal endoscopy was performed within 6 h after ICU admission before any antibiotic treatment was given. Antrum and corpus biopsies were stored in phosphate-buffered saline and kept in a refrigerator until bacteriological culturing within 12 h. Cultures were prepared by rubbing biopsy specimens on the surface of horse blood agar plates (5% defibrinated horse blood Columbia agar base (Oxoid CM 331); Unipath, Basingstoke, UK) and horse blood agar plates containing Dent supplement (Unipath). Cultures were incubated at 35°C for 10 days in a microaerophilic atmosphere (5% O2, 10% CO2 and 85% N2). H. pylori was identified on the basis of typical colony morphology, characteristic appearance on Gram staining, and positive urease, oxidase and catalase tests. The susceptibility to antibiotics was assessed by Etest (AB Biodisk, Solna, Sweden) on horse blood agar plates in a microaerophilic atmosphere according to the manufacturer's instructions. Susceptibility to polymyxin E was assessed by agar diffusion on horse blood agar using tablets containing 150 µg polymyxin (Neo-Sensitabs, Rosco, Denmark).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In nine of the 10 ICU patients, the LARA [13C]urea breath test converted from positive to negative within 7 days of SDD treatment (seven converted within 3 days and two within 7 days). In these patients, repeated urea breath tests remained negative as long as the topical antibiotics were administered (range 3.5–33 days, mean 10.8 and median 7.8 days).

In all six volunteers who ingested PTA but who did not receive cefotaxime, the urea breath test converted to negative within 7 days of treatment. However, a repeated test after 8 weeks showed eradication in only one of six volunteers.

Eleven unique strains of H. pylori obtained from seven critically ill patients were cultured and their susceptibility to antibiotics was determined (TableGo).


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Table. MICs (mg/L) as determined by Etest of 11 Helicobacter pylori strains from critically ill patients for antibiotics that are used frequently in the ICU and in SDD
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study we determined the suppressive effects on H. pylori of the antibiotics used for SDD. H. pylori was suppressed effectively in all but one of the patients who were treated with the full SDD regimen, consisting of PTA antibiotics administered topically and cefotaxime administered intravenously. Follow up was obtained in only one patient and revealed successful H. pylori eradication. Treatment with topical PTA antibiotics alone also resulted in suppression of H. pylori infection. To determine the role of the individual antibiotics we performed in vitro susceptibility tests. We showed that cefotaxime and tobramycin were the two agents from the SDD regimen that were active against H. pylori (TableGo). As the topical PTA antibiotics did not include cefotaxime and as H. pylori was not susceptible to polymyxin and amphotericin B, tobramycin effectively acted as monotherapy for H. pylori in the volunteers. Some antibiotics have been shown to be efficacious for H. pylori as monotherapy.6 In the present study monotherapy with oral tobramycin resulted in a modest eradication rate (one out of six persons). In contrast, suppression of H. pylori infection occurred in all but one patient during their ICU stay.

In general, topical treatment of H. pylori may have advantages over systemic treatment. Non-absorbable antibiotics lack systemic effects and may therefore lead to lesser side effects and greater patient compliance. PTA are non-absorbable antibiotics that are effective in decontaminating the digestive tract of potentially pathogenic microorganisms.7 The Gram-positive flora is not affected by these antibiotics and therefore colonization resistance remains intact. The widespread use of these antibiotics in critically ill patients has not been associated with emergence of antimicrobial resistance.8–10 Previously, we found that the presence of H. pylori infection in critically ill patients was associated with greater severity of gastric mucosal lesions.1 In the present study we showed that H. pylori is suppressed effectively by SDD antibiotics. These findings may explain why stress ulceration was virtually absent in a group of patients treated with SDD.2


    Notes
 
* Correspondence address. Department of Intensive care, Medical Centre Leeuwarden-Zuid, PO Box 888, 8901 BR Leeuwarden, The Netherlands. Tel: +31-58-2866777; Fax: +31-58-2866715; E-mail: phjvdvoort{at}wxs.nl Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Van der Voort, P. H. J., Van der Hulst, R. W. M., Zandstra, D. F., Geraedts, A. A. M., Van der Ende, A. & Tytgat, G. N. J. (1999). Increased prevalence of Helicobacter pylori in critically ill patients with stress ulceration. Critical Care 3, Suppl. 1, P188.

2 . Zandstra, D. F. & Stoutenbeek, C. P. (1994). The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. Intensive Care Medicine 20, 335–40.[ISI][Medline]

3 . Van der Voort, P. H. J., Van der Hulst, R. W. M., Zandstra, D. F., Geraedts, A. A. M. & Tytgat, G. N. J. (1998). Suppression of Helicobacter pylori infection under selective decontamination of the digestive tract. Intensive Care Medicine 24, Suppl. 1, S7.

4 . Van der Voort, P. H. J., van der Hulst, R. W. M., Zandstra, D. F., Geraedts, A. A. M. & Tytgat, G. N. J. (1999). Detection of Helicobacter pylori in mechanically ventilated intensive care patients: the LARA-13C-urea breath test and serology. Clinical Intensive Care 10, 91–5.

5 . Van der Hulst, R. W. M., Lamouliatte, H., Megraud, F. & Tytgat, G. N. J. (1999). Laser-assisted ratio analyser 13C-urea breath testing for the detection of H. pylori infection: a prospective diagnostic European multicenter study. Alimentary Pharmacology and Therapeutics 13, 1171–7.[ISI][Medline]

6 . Peterson, W. L., Graham, D. Y., Marshall, B., Blaser, M. J., Genta, R. M., Klein, P. D. et al. (1993). Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized, double-blind trial. American Journal of Gastroenterology 88, 1860–4.[ISI][Medline]

7 . Stoutenbeek, C. P., van Saene, H. K. F., Miranda, D. R. & Zandstra, D. F. (1984). The effect of selective decontamination of the digestive tract on colonization and infection rate in multiple trauma patients. Intensive Care Medicine 10, 185–92.[ISI][Medline]

8 . D'Amico, R. D., Pifferi, S., Leonetti, C., Torri, V., Tinazzi, A. & Liberati, A. (1998). Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials. British Medical Journal 316, 1275–85.[Abstract/Free Full Text]

9 . Stoutenbeek, C. P., van Saene, H. K. F. & Zandstra, D. F. (1987). The effect of oral nonabsorbable antibiotics on the emergence of resistant bacteria in patients in an intensive care unit. Journal of Antimicrobial Chemotherapy 19, 513–20.[Abstract]

10 . Tetteroo, G. W. M., Wagenvoort, J. H. T. & Bruining, H. A. (1994). Bacteriology of selective decontamination: efficacy and rebound colonization. Journal of Antimicrobial Chemotherapy 34, 139–48.[Abstract]

Received 2 March 2000; returned 15 May 2000; revised 30 June 2000; accepted 19 July 2000





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