JAC Advance Access originally published online on August 18, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1103-1104; doi:10.1093/jac/dkl346
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Correspondence |
Emergence of a Helicobacter pylori isolate with reduced susceptibility to tetracycline in Germany
National Reference Centre for Helicobacter pylori, Department of Microbiology and Hygiene, Institute of Medical Microbiology and Hygiene, University Hospital Freiburg, Hermann-Herder-Strasse 11 79104 Freiburg, Germany
*Corresponding author. Tel: +49-761-203-6539; Fax: +49-761-203-6562; E-mail: erik-oliver.glocker{at}uniklinik-freiburg.de
Keywords: surveillance , antimicrobial resistance , treatment failures , H. pylori
Sir,
Helicobacter pylori persists lifelong in infected individuals and is associated with the development of peptic ulcer diseases, MALT-lymphoma or gastric cancer.1 Antimicrobial therapy, usually including two antibiotics and a proton pump inhibitor, is recommended to eradicate the bacteria. However, increasing resistances to first-line antibiotic drugs such as clarithromycin impair successful eradication of H. pylori and result in therapy failures.2 Tetracyclines, included in quadruple eradication regimens, were shown to be effective in such cases. So far, tetracycline-resistant H. pylori isolates have been extremely rare, particularly in Europe.3 Here, we report the first detection of an H. pylori strain with reduced susceptibility to tetracycline in Germany. The strain was isolated from a multimorbid 70-year-old woman suffering from antrum gastritis, chronic obstructive pulmonary disease, hypothyroidism, arthrosis and adult-onset diabetes mellitus. Between 2000 and 2005, due to relapsing bacterial lung infections, repeated antibiotic treatments including cefuroxime, ciprofloxacin, roxithromycin, levofloxacin and doxycycline were applied. In March 2005, her gastroenterologist diagnosed an H. pylori-positive antrum gastritis. As first-line eradication, a triple therapy consisting of amoxicillin (1 g, twice daily), clarithromycin (500 mg, twice daily) and a proton pump inhibitor (standard dose, twice daily) was administered. In November 2005, the still existing H. pylori-positive antrum gastritis prompted the physician to prescribe a therapy including clarithromycin (500 mg, twice daily), metronidazole (500 mg, twice daily) and a proton pump inhibitor (standard dose, twice daily). Since the patient was still complaining of dyspepsia and severe gastric pain, the gastroenterologist sent gastric tissue samples from the antrum and corpus to our diagnostic laboratory for microbiological investigation in January 2006. The gastric specimens were homogenized and cultured on Columbia-Agar-based culture medium containing 10% (v/v) washed human erythrocytes and 10% (v/v) heat inactivated horse serum (HHP-plates) under microaerophilic conditions at 37°C for 72 h. Grown bacteria were identified as H. pylori by typical morphology of the colonies, Gram-staining and biochemical reactions. Molecular genetic analysis revealed a cagA-positive and an s1a/m2 vacA genotype. Antimicrobial susceptibility to amoxicillin, metronidazole, clarithromycin, ciprofloxacin, rifampicin and tetracycline was tested by using the Etest® method according to a protocol described previously.2 The isolate showed susceptibility to amoxicillin (0.016 mg/L) and rifampicin (0.38 mg/L), but resistance to metronidazole (256 mg/L), clarithromycin (256 mg/L) and quinolones (32 mg/L) and reduced susceptibility to tetracycline (1 mg/L). The Etest® result for tetracycline was confirmed using the agar dilution technique, for which an MIC of 8 mg/L was obtained, thereby supporting the reduced susceptibility to tetracycline. The isolate harboured an A2143G mutation in the 23S gene and an A272G mutation in the gyrA gene, confirming the clarithromycin- and quinolone-resistant phenotype. Since mutations affecting the nucleotides 926–928 in the 16S rRNA genes (rrnA and rrnB) are one of the most extensively studied mechanisms conferring resistance or reduced susceptibility to tetracycline in H. pylori, we sequenced these genes and detected a homozygous nucleotide exchange at position 926 (A926T) resulting in an altered TGA triplet. H. pylori isolates exhibiting a triple nucleotide exchange at this site (AGA926-928TTC) were associated with increased MICs of tetracycline (
4 mg/L) and thus considered as the clinically most relevant strains.3,4 Recently, single or double nucleotide substitutions were also shown to confer resistance to tetracycline in H. pylori clinical isolates.4 The isolation of tetracycline-resistant H. pylori strains in treatment failure cases points to negative consequences of tetracycline resistance on the clinical outcome in H. pylori eradication.5,6 However, tetracycline resistance is rarely seen, which hampers the performance of studies to evaluate its impact on treatment success.
In the current case, we recommended the gastroenterologist to apply a rescue regimen including amoxicillin (1 g, twice daily), rifabutin (150 mg, twice daily) and a proton pump inhibitor (standard dose, twice daily). Testing for successful eradication by urea breath test or stool antigen test was advised, but unfortunately no data are yet available.
In order to avoid treatment failures and to reduce costs, we recommend antimicrobial susceptibility testing after the first unsuccessful H. pylori eradication therapy or in patients who have already received multiple antibiotic treatments due to unrelated bacterial infections. Furthermore, the presented case underlines the need for regular surveillance studies in order to detect antibiotic resistance of H. pylori and to define relevant risk factors for resistance development.
Transparency declarations
None to declare.
Acknowledgements
We thank Dr G. Mueller and Dr K.-P. Schneider, Trier, Germany, for co-operation and clinical information, Marianne Vetter-Knoll for excellent technical assistance and Dr Stephen Batsford and Dr Christian Bogdan as well for critical reading of the manuscript. This work was supported by the Robert-Koch-Institut by a grant to M. Kist (1369-239) of the German Ministry of Health.
References
1
Suerbaum S and Michetti P. (2002) Helicobacter pylori infection. N Engl J Med 347:1175–86.
2 Glupczynski Y, Mégraud F, Lopez-Brea M, et al. (2001) European multicentre survey of in vitro antimicrobial resistance in Helicobacter pylori. Eur J Clin Microbiol Infect Dis 20:820–3.[CrossRef][Web of Science][Medline]
3
Lawson AJ, Elviss NC, Owen RJ. (2005) Real-time PCR detection and frequency of 16S rDNA mutations associated with resistance and reduced susceptibility to tetracycline in Helicobacter pylori from England and Wales. J Antimicrob Chemother 56:282–6.
4
Wu JY, Kim JJ, Reddy R, et al. (2005) Tetracycline-resistant clinical isolates with and without mutations in 16S rRNA-encoding genes. Antimicrob Agents Chemother 49:578–83.
5
Trieber CA and Taylor DE. (2002) Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J Bacteriol 184:2131–40.
6
Gerrits MM, De Zoete MR, Arents NL, et al. (2002) 16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori. Antimicrob Agents Chemother 46:2996–3000.
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