a Laboratório de Bacteriologia, Instituto Nacional de Saúde; b Faculdade de Farmácia de Lisboa; c Unidade de Gastrenterologia, Serviço de Patologia Clínica, Hospital de D. Estefânia; d Unidade de Gastrenterologia Pediátrica, Hospital de Santa Maria; e Clínica Universitária de Medicina Interna e Gastrenterologia, Hospital de Pulido Valente, Lisboa, Portugal
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Abstract |
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Introduction |
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Dual or triple therapy, including two of the following antibioticsamoxycillin, tetracycline, metronidazole or clarithromycin, plus a proton pump inhibitor, bismuth salt or ranitidine bismuth citrateis the therapy most frequently used to eradicate H. pylori.1
Resistance to metronidazole is reported worldwide with a prevalence ranging from 20 to 35% in developed countries and 80 to 90% in developing regions. The prevalence of clarithromycin resistance is usually <10% in developed countries. However, in southern Europe the rate of resistance to clarithromycin and metronidazole is higher than in northern or central Europe.2
The infection eradication rate decreases from 95% in sensitive strains to 75% in metronidazole-resistant H. pylori isolates, and to 40% in clarithromycin-resistant strains.3
The aims of this study were to assess the evolution of resistance to antibiotics of choice in anti-H. pylori treatment over the last 10 years in the Lisbon area and to correlate resistance profiles with demographic and therapeutic features. Although fluoroquinolones are not frequently used to eradicate H. pylori strains, ciprofloxacin was included in this study because its use has been suggested in failure of treatment with the antibiotics previously mentioned.4 In Portugal, the prevalence of resistance to quinolones in other organisms has increased considerably in the last few years.
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Materials and methods |
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Demographic and clinical status data were collected for each patient. The distribution of patients by gender was 45% female and 55% male, with age ranging from 5 to 89 years (mean = 46; mode = 50).
Strains were isolated from gastric biopsy samples, taken during endoscopy. Identification was performed according to conventional tests and the MICs for isolates, of metronidazole (n = 448), clarithromycin (n = 394), amoxycillin (n = 394), tetracycline (n = 394) and ciprofloxacin (n = 371), were assessed by the Etest on MuellerHinton agar plus 10% horse blood.
The breakpoints used to define resistance were: metronidazole (>8 mg/L), clarithromycin (>1 mg/L), amoxycillin (>0.5 mg/L) according to Glupczvnski et al.,2 tetracycline (>4 mg/L) and ciprofloxacin (>1 mg/L) according to the NCCLS.
Statistical analyses were performed with chi-squared and Fisher's exact tests.
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Results |
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All the isolates tested were sensitive to amoxycillin (MIC90 0.023 mg/L) and tetracycline (MIC90 0.125 mg/L). Clarithromycin also showed a high in vitro activity (MIC50 0.023 mg/L), but 19.0% of the isolates were resistant and about 50% had high-level resistance (MIC 256 mg/L). Metronidazole had reduced activity (MIC50 1.0 mg/L) and 30.6% of the isolates were resistant to this compound. An overall resistance rate of 9.6% to ciprofloxacin was found (MIC50 0.094 mg/L).
In isolates from patients previously exposed to metronidazole or clarithromycin, the prevalence of resistance was 75 and 47%, respectively, while in the remaining isolates the rate of resistance was 28.8 and 13.5% (P < 0.01).
In adult patients, 30.8% of H. pylori strains isolated from women were resistant to metronidazole, 20.1% to clarithromycin and 11.7% to ciprofloxacin. In isolates from men the prevalence of resistance was lower to clarithromycin (16.9%) and ciprofloxacin (8.4%), but slightly higher to metronidazole (31.7%). However, no statistically significant association was found between gender and resistance to any of those antibiotics.
Table I presents the prevalence of resistance and antimicrobial susceptibility of H. pylori by age group in strains isolated in 199899. In paediatric patients, the frequency of strains resistant to clarithromycin (44.8%) was much higher than in adults (22.0%) (P < 0.01). On the other hand, the prevalence of strains resistant to metronidazole was significantly higher in isolates from adult patients (34.1%) than that observed in isolates from children (19.0%) (P < 0.05). Simultaneous resistance to these antibiotics was found in 8.6% of the isolates from paediatric patients and in 11.4% from adult patients. None of the 58 isolates from children was resistant to ciprofloxacin, while in isolates from adult patients the rate of resistance was 20.9%.
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Discussion |
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In conclusion, in the Lisbon area the isolation of strains of H. pylori resistant to antibiotics used in eradication therapy (namely nitroimidazoles and macrolides), as well as to fluoroquinolones, is frequent. Resistance to clarithromycin is particularly common in strains isolated from paediatric patients. These findings stress the importance of monitoring the prevalence of resistance in order to select the most effective treatment.
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Notes |
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References |
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2 . Glupczvnski, Y., Mégraud, F., Anderson, L. P. & Lopez-Brea, M. (1999). Antibiotic susceptibility of Helicobacter pylori in Europe in 1998: results of the third multicentre study. Gut 45, Suppl. 3, A3.[ISI]
3 . Bazzoli, F., Berretti, D., De Luca, L., Nicolini, G., Pozzato, P., Fossi, S. et al. (1999). What can be learnt from the new data about antibiotic resistance? Are there any practical consequences of Helicobacter pylori antibiotic resistance? European Journal of Gastroenterology and Hepatology 11, Suppl. 2, S3942.[ISI][Medline]
4 . Dresner, D., Coyle, W., Nemec, R., Peterson R., Duntemann, T. & Lawson, J. M. (1996). Efficacy of ciprofloxacin in the eradication of Helicobacter pylori. Southern Medical Journal 89, 7758.[ISI][Medline]
5 . López-Brea, M., Domingo, D., Sanchez, I. & Alarcon, T. (1997). Evolution of resistance to metronidazole and clarithromycin in Helicobacter pylori clinical isolates from Spain. Journal of Antimicrobial Chemotherapy 40, 27981.[Abstract]
6 . Iovene, M. R., Romano, M., Pilloni, A. P., Giordano, B., Montella, F., Caliendo, S. et al. (1999). Prevalence of antimicrobial resistance in eighty clinical isolates of Helicobacter pylori. Chemotherapy 45, 814.[ISI][Medline]
7 . Rokkas, T. (2000). Prevalence of Helicobacter pylori resistance. (Personal communication) in GEPH & EHPSG, Estoril, Portugal.
8 . Birac, C., Bouchard, S., Camou, C., Lamouliatte, H., Lamireau, T. & Mégraud, F. (1999). Six year follow-up of resistance to antibiotics of Helicobacter pylori in Bordeaux, France. Gut 45, Suppl. 3, A107.
9 . Mentis, A. F., Roma, E., Pangalis, A. & Katsiyiannakis, E. (1999). Susceptibilities of Helicobacter pylori strains isolated from children with gastritis to selected antibiotics. Journal of Antimicrobial Chemotherapy 44, 7212.[Medline]
10 . Caldeira, L., Silva, E., Santos, P., Inês, M. & Raposo, P. (1999) Dispensa de antibacterianos em Medicina Humana Comunitária (INFARMED. Ministério da Saúde), Lisbon.
Received 26 April 2000; returned 21 July 2000; revised 7 August 2000; accepted 24 August 2000