DRUG RESISTANCE IN HELICOBACTER PYLORI

Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics.

Conclusion

This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.

HEADINGS
Helicobacter pylori; Microbial drug resistance; Point mutation

Region	Phenotypic (n)	Genotypic (n)	Agreement between the two methods	Kappa index	Reference
Brazil	20/202	18/202	90%	0.94 *	Magalhães et al.⁵²52. Magalhães PP, Queiroz DM, Barbosa DV, Rocha GA, Mendes EN, Santos A, et al. Helicobacter pylori primary resistance to metronidazole and clarithromycin in Brazil. Antimicrob Agents Chemother. 2002;46:2021-3.⁾
Brazil	12/45	12/45	100%	1 *	Garcia et al.²⁷27. Garcia M, Raymond J, Garnier M, Cremniter J, Burucoa C. Distribution of Spontaneous gyrA Mutations in 97 Fluoroquinolone- Resistant Helicobacter pylori Isolates Collected in France. Antimicrobial Agents and Chemotherapy. 2012;56:550-1.⁾
Brazil	24/114	27/114	97%	0.92 *	Lins et al.⁴⁹49. Lins AK, Lima RA, Magalhães M. Clarithromycin-resistant Helicobacter pylori in Recife, Brazil, directly identified from gastric biopsies by polymerase chain reaction. Arq Gastroenterol. 2010;47:379-82.⁾
Spain	42/118	34/118	81%	0.84 *	Agudo et al.²2. Agudo S, Perez-Perez G, Alarcón T, Lopez-Brea M. High Prevalence of Clarithromycin-Resistant Helicobacter pylori Strains and Risk Factors Associated with Resistance in Madrid, Spain. J Clin Microbiol. 2010;48:3703-7.⁾
France	24/229	24/229	100%	1 *	Burucoa et al.¹²12. Burucoa C, Garnier M, Silvain C, Fauchere JL. Quadruplex real-time PCR assay using allele-specific scorpion primers for detection of mutations conferring clarithromycin resistance to Helicobacter pylori. J Clin Microbiol. 2008;46:2320-6.⁾
France	10/59	11/59	98%	0.94 *	Lascols et al.⁴⁷47. Lascols C, Lamarque D, Costa JM, Copie-Bergman C, Le Glaunec JM, Deforges L, et al. Fast and Accurate Quantitative Detection of Helicobacter pylori and Identification of Clarithromycin Resistance Mutations in H. pylori Isolates from Gastric Biopsy Specimens by Real-Time PCR. J Clin Microbiol. 2003;41:4573-7.⁾
Iran	32/147	31/147	97%	0.98 *	Abadi et al.¹1. Abadi AT, Taghvaei T, Ghasemzadeh A, Mobarez AM. High Frequency of A2143G Mutation in Clarithromycin-Resistant Helicobacter pylori Isolates Recovered from Dyspeptic Patients in Iran. J Gastroenterol. 2011;17:396-9.⁾

Area	Year	Nº Patient	Clarithromycin		Amoxicillin	Metronidazole	Levofloxacin	Reference
		H. pylori positive	Phenotypic	Genotypic
SP	2000	90	7%(6/90) (b)	NA	29%(26/90) (e)	42%(38/90) (e)	NA	Mendonça et al.⁵⁷57. Mendonça S, Ecclissato C, Sartori MS, Godoy AP, Guerzoni RA, Degger M, et al. Prevalence of Helicobacter pylori resistance to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone in Brazil. Helicobacter. 2000;5:79-83.⁾
MG	2002	202	9.8%(20/202) (c)	90.0% (18/20) A2142G/A2143G A2142G: 16.7% (3/18), A2143G: 66.6% (12/18), A2142G +A2143G: 16.7%(3/18)	NA	53%(107/202) (e)	NA	Magalhães et al.⁵²52. Magalhães PP, Queiroz DM, Barbosa DV, Rocha GA, Mendes EN, Santos A, et al. Helicobacter pylori primary resistance to metronidazole and clarithromycin in Brazil. Antimicrob Agents Chemother. 2002;46:2021-3.
SP	2003	52	(c)	94.2% (49/52) A2142G/A2143G A2142G: 87.7%(43/49) A2143G:12.3%(6/49)	NA	NA	NA	Ribeiro et al.⁷⁵75. Ribeiro ML, Vitiello L, Miranda MCB, Benvengo YH, Godoy APO, Mendonca S, et al. Mutations in the 23S rRNA gene are associated with clarithromycin resistance in Helicobacter pylori isolates in Brazil. Ann Clin Microbiol Antimicrob. 2003;2:1-4.⁾
SP	2003	138	16%(23/138) (c)	NA	38%(54/138) (e)	55%(75/138) (e)	NA	Godoy et al.²⁸28. Godoy AP, Ribeiro ML, Benvengo YH, Vitiello L, Miranda Mde C, Mendonca S, et al. Analysis of antimicrobial susceptibility and virulence factors in Helicobacter pylori clinical isolates. BMC Gastroenterol 2003;3:1-6.⁾
SP	2008-2009	45	27%(12/45) (b)	100%(12/12) A2142G/A2143G A2143G: 67% (8/12) A2142G:33%(4/12)	4%(2/45) (d)	13%(6/45) (d)	NA	Garcia e al.²⁶26. Garcia GT, Aranda KR, Goncalves ME, Cardoso SR, Iriya K, Silva NP, et al. High prevalence of clarithromycin resistance and cagA, vacA, iceA2, and babA2 genotypes of Helicobacter pylori in Brazilian children. J Clin Microbiol. 2010;48:4266-8.⁾
AM	2007-2008	41	NA	75.6% (31/41) 23S rRNA A2143G (3.3%), T2182C (12.9%), G2224A (6.45%), T2215C (61.3%) A2192G (3.3%), G2204C (6.4%), T2221C (6.4%)	NA	NA	NA	Barile et al.⁶6. Barile KAS, Silva ALC, Xavier JNX, Assumpção MB, Corvelo TCO. Characterization of 23S rRNA domain V mutations in gastric biopsy patients from the eastern Amazon. Mem Inst Oswaldo Cruz. 2010;105:314-7.⁾
SP	2011	39	8%(3/39) (b)	NA	0% (0/39) (a)	51%(20/39) (e)	23%(9/39) (b)	Eisig et al.²²22. Eisig JN, Silva FM, Barbuti RC, Navarro-Rodriguez T, Moraes-Filho JP, Pedrazzoli Jr J. Helicobacter pylori antibiotic resistance in Brazil: clarithromycin is still a good option. Arq Gastroenterol. 2011;48:261-4.⁾
SP	2003-2006	488	NA	2.5% (12/488) A2143G/A2142G A2142G: 25%(3/12) A2143G:58.3%(7/12) A2143G + A2142G: 8.7% (1/12)	NA	NA	NA	Suzuki et al.⁹⁰90. Suzuki RB, Almeida CM, Speranca MA: Absence of Helicobacter pylori high tetracycline resistant 16S rDNA AGA926-928TTC genotype in gastric biopsy specimens from dyspeptic patients of a city in the interior of Sao Paulo, Brazil. BMC Gastroenterol. 2012;12:1-5.⁾
RS	2011-2012	54	11.1% (6/54) (b)	NA	1.9%(1/54) (b)	NA	NA	Picoli et al.⁷¹71. Picoli SU, Mazzoleni LE, Fernández H, DE Bona LR, Neuhauss E, Longo L &Prolla JC. Resistance to amoxicillin, clarithromycin and ciprofloxacin of Helicobacter pylori isolated from southern Brazil patients. Rev. Inst. Med. Trop. Sao Paul. 2014;56:197-200.⁾

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[1] Correspondence: Júlia Silveira Vianna. Núcleo de Pesquisas em Microbiologia Médica, Universidade Federal do Rio Grande. Rua General Osório, s/n, Rio Grande, RS, Brasil. E-mail: jusvianna@hotmail.com