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J Antimicrob Chemother 2011; 66: 2308 – 2311doi:10.1093/jac/dkr293 Advance Access publication 15 July 2011 Primary antibiotic resistance of Helicobacter pylori strains isolated from Portuguese children: a prospective multicentre study Mo´nica Oleastro 1*, Jose´ Cabral 2, Paulo Magalha˜es Ramalho 3,4, Piedade Sande Lemos 5, Eleonora Paixa˜o 6, Joa˜o Benoliel 1, Andrea Santos 1 and Ana Isabel Lopes 3,4 1Departamento de Doenc¸as Infecciosas, Instituto Nacional Sau´de Dr Ricardo Jorge, Lisboa, Portugal; 2Unidade de GastrenterologiaInfantil, Centro Hospitalar Lisboa Central, Lisboa, Portugal; 3Unidade de Gastrenterologia Pedia´trica, Hospital Universita´rio de SantaMaria, Lisboa, Portugal; 4Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; 5Unidade de Gastrenterologia Pedia´trica, Hospital Fernando da Fonseca, Lisboa, Portugal; 6Departamento de Epidemiologia, Instituto Nacional Sau´de Dr Ricardo Jorge, *Corresponding author. Tel: +351-217-508-179/217-519-231; Fax: +351-217-526-400; E-mail: [email protected] Received 28 March 2011; returned 6 May 2011; revised 9 June 2011; accepted 21 June 2011 Objectives: The aim of this study was to prospectively assess the pattern of evolution of primary resistance toantibiotics in Helicobacter pylori strains isolated from Portuguese children over a 10 year period (2000– 09).
Methods: A total of 1115 H. pylori strains were tested for antibiotic susceptibility to clarithromycin, metronida- zole, amoxicillin, ciprofloxacin and tetracycline.
Results: H. pylori strains were isolated from children and adolescents [ages 4 months –18 years (mean age10.17+4.03 years)], comprising 562 (50.4%) boys and 553 (49.6%) girls. Overall, the primary resistance ratewas 34.7% to clarithromycin, 13.9% to metronidazole and 4.6% to ciprofloxacin, while 6.9% were resistantto two of these antibiotics simultaneously. Resistance to amoxicillin and to tetracycline was not detected. Ingeneral, the resistance rate was not associated with gender or the children’s age. European ethnicity, whencompared with an African background, was associated with clarithromycin resistance [P ¼ 0.002; odds ratio(OR) ¼ 0.30; 95% confidence interval (CI) 0.14–0.66], while the inverse situation was observed for metronida-zole (P,0.001; OR ¼ 3.50; 95% CI 1.90– 6.45). No significant temporal trend was noticed for resistance to clar-ithromycin and metronidazole, whereas ciprofloxacin and double-resistance rates have significantly increasedover time (P ¼ 0.004 and P ¼ 0.05, respectively).
Conclusions: The primary resistance rate of H. pylori strains isolated from Portuguese children to the commonlyused anti-H. pylori antibiotics used is high. Additionally, the increasing trend of ciprofloxacin-resistant anddouble-resistant strains may compromise H. pylori eradication in a high-prevalence population.
Keywords: H. pylori, temporal trend, Portugal The most common first-line regimen for the eradication of H. pylori consists of a combination of clarithromycin or metroni- Helicobacter pylori colonizes the human gastric mucosa of more dazole, with amoxicillin, plus a proton pump inhibitor (PPI). Pro- than 50% of the world’s population, with infection always elicit- ing an acute immune response that fails, however, in achieving fluoroquinolones, tetracyclines or rifamycin-based therapies.
spontaneous eradicaThe lifelong persistence of this infec- Considering both the large percentage of the infected population tion may result in the development of non-ulcer dyspepsia and the high and increasing rates of antibiotic resistance (NUD), which may further progress to severe gastric diseases, reported worldwide, the issue of treatment is thus currently such as peptic ulcer disease (PUD) and two forms of gastric unsolved and particularly problematic.
cancer [adenocarcinoma and mucosa-associated lymphoid The actual prevalence of H. pylori antibiotic resistance among children in Portugal is not known. The present study aimed to # The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [email protected] Primary H. pylori resistance in Portuguese children prospectively assess the pattern of evolution of primary resist- ance to antibiotics in H. pylori strains isolated from Portuguese Overall, the primary resistance rate of H. pylori was 34.7% children over a 10 year period (2000– 09), as well as identify (n¼ 387) to clarithromycin (median MIC 0.016 mg/L, range 0.016– 256), 13.9% (n¼ 155) to metronidazole (median MIC0.25 mg/L, range 0.016– 256) and 4.6% (n¼ 51) to ciprofloxacin.
Simultaneous resistance to two of these antibiotics occurred in6.9% (n¼ 76) of the isolates, of which 72.4% (n ¼55) were resist- ant to both clarithromycin and metronidazole, 23.7% (n¼ 18) to From January 2000 to December 2009, a total of 1115 H. pylori strains both clarithromycin and ciprofloxacin, and 3.9% (n¼ 3) to metro- were prospectively isolated from Portuguese children and adolescents nidazole and ciprofloxacin. One strain was simultaneously resist- attending the three Paediatric Gastroenterology Units in the Lisbon ant to these three antibiotics. Resistance to amoxicillin (median area for severe and/or recurrent upper gastrointestinal symptoms sug- MIC 0.016 mg/L, range 0.016–0.5) and tetracycline was not gestive of organic disease and considered sufficiently relevant to justify an upper endoscopy and antibiotic treatment. Demographic and clinical No overall significant trend for resistance to clarithromycin or data were collected retrospectively. None of the patients had been metronidazole was noticed. Indeed, considering three time treated for H. pylori infection before endoscopy. Clinical strains were cul- periods, 2000 –02 (n¼ 191), 2003 –05 (n¼ 320) and 2006–09 tured from a pool of colonies from antral biopsy specimens.
(n¼ 604), a stationary trend could be observed for both these antibiotics (Table although between 2000 –02 and 2003 – 05, a significant decrease in the metronidazole resistance ratewas observed (P ¼0.037) (Table ). The clarithromycin and Susceptibility testing was performed using Etest (bioMe´rieux, Marcy metronidazole MIC values were also stable throughout the l’E´toile, France) for clarithromycin, metronidazole and amoxicillin, and time period studied (data not shown).
by disc diffusion (Oxoid, Hampshire, UK) for ciprofloxacin and tetracycline.
In contrast, the resistance rate to ciprofloxacin has been signifi- The MIC breakpoints used were ≥1 mg/L for clarithromycin, .8 mg/L for cantly rising over time, particularly during the period 2006 –09 metronidazole and .0.5 mg/L for amoxicillin, according to previous refer- (P ¼ 0.004), and the same scenario has been observed for the By disc diffusion, strains were classified as resistant if growth inhi-bition zones were ,20 mm for ciprofloxacin (5 mg) and ,17 mm for double-resistant strains (P ¼ 0.050) (Figure ).
tetracycline (30 mg) [Comite´ de l’Antibiogramme de la Socie´te´ Franc¸aise The univariate analysis showed that, overall, there was no de Microbiologie, Recommendations 2010 (Edition de Janvier 2010), association of resistance to clarithromycin, metronidazole or ciprofloxacin with children’s gender or disease outcome(Table except that metronidazole resistance was morecommon in older children (group aged 11–18 years), particularly when comparing with the youngest children (13.7% versus 9.9%, Statistical analysis was performed with the statistical package PASW respectively; P ¼0.051; OR ¼1.76; 95% CI 1.00 –3.10). Resistance Statistics version 18.01 (IBM SPSS Statistics, release 18.0, July 2009).
to clarithromycin was associated with European ethnicity, when Pearson’s x2 test and 95% confidence intervals (CIs) were used. Identifi- compared with an African background (37.0% versus 15.1%, cation of variables associated with H. pylori antibiotic resistance was per- respectively; P ¼ 0.002; OR¼ 0.30; 95% CI 0.14– 0.66), while, formed by univariate logistic regression and confirmed by multiple inversely, resistance to metronidazole was more common logistic regression analysis. The level of significance was set at 5%.
among African children (35.8% versus 13.8%, respectively;P,0.001; OR¼ 3.50; 95% CI 1.90–6.45). No significantly related factors were related to ciprofloxacin and double resist-ance (Table ). All the associations found were confirmed by multiple logistic regression analysis (data not shown).
Within a 10 year observation period, 1115 H. pylori strains were iso-lated from children and adolescents, ages 4 months –18 years (mean age 10.17+4.03 years), comprising 562 (50.4%) boysand 553 (49.6%) girls. Children were stratified into three age The present study, concerning primary resistance to antibiotics of groups: 0 –5 years (163, 14.6%); 6 –10 years (430, 38.6%); and H. pylori strains isolated between 2000 and 2009 from 1115 11 –18 years (522, 46.8%). Information on ethnicity was available Portuguese children, shows that the overall resistance rate for 615 (55.2%) children, with the following distribution: 554 remains high, in particular to clarithromycin (34.7%). These (90.1%) European [mostly Portuguese (98%)], 53 (8.6%) African data are corroborated by a recent European multicentre study and 8 (1.3%) Asian or Caucasian/European. According to clinical on antibiotic resistance of H. pylori strains showing that children outcome, most of the children (96%, n¼ 1069) presented with from south Europe presented a significant risk for primary clari- NUD (comprising severe recurrent abdominal pain, reflux-like dys- thromycin resistance, which is likely a consequence of a recog- pepsia, vomiting, coeliac disease and unexplained refractory side- nized overuse in the past and the persistent use nowadays of ropenic anaemia) and 4.0% (n¼ 44) had PUD. This latter condition macrolides for the treatment of upper respiratory tract infections was significantly more common in older children [5.4% versus in those In our study, the only factor associated with 2.8%; P ¼ 0.021; odds ratio (OR) ¼2.12; 95% CI 1.13 –3.99] and clarithromycin resistance was European ethnicity, compared with also in boys (63.6% versus 36.4%; P¼ 0.025; OR¼ 2.04; 95% CI an African background, as shown in previous studies.– The high H. pylori clarithromycin primary resistance recently reported in Table 1. Univariate analysis of factors associated with H. pylori primary resistance to clarithromycin, metronidazole and ciprofloxacin amongpaediatric patients aP value obtained by univariate logistic model.
Statistically significant P values (,0.05) are highlighted in bold.
Figure 1. Temporal trend for H. pylori resistance to ciprofloxacin and to two of the antibiotics simultaneously (clarithromycin, metronidazole orciprofloxacin), considering three time periods: 2000–02 (00–02, n ¼191), 2003–05 (03– 05, n¼320) and 2006–09 (06– 09, n¼604).
children from several European countries, as well as from other The metronidazole primary resistant rate observed in our parts of the developed world, emphasizes that this is a study (13.9%) was about 2-fold lower than the average rate reported for European childr– This discrepancy may be Primary H. pylori resistance in Portuguese children only partially explained by the lower percentage of children withAfrican ethnicity (8.6%) than that reported in other studies. This result also contrasts with the high primary resistance seen This work was partially supported by the BNP Paribas patronage.
among Portuguese adults (32.3%),and likely reflects differ-ences in metronidazole consumption according to the patient’sage. Indeed, the lack of a metronidazole paediatric formulation in Portugal may discourage parents to treat their children, result-ing in less exposure to this antibiotic.
The high rate of metronidazole resistance detected in our study among African children (35.8%) is in agreement withother reports and consistent with its extensive use for treating parasitic diseases in tropical countries.Metronidazole resistance 1 Robinson K, Argent R, Atherton J. The inflammatory and immune was also associated with older age, which has not been com- monly reported. Indeed, association with age has been described for clarithromycin, but in the opposite sense, i.e. associated with 2 Kusters J, van Vliet A, Kuipers E. Pathogenesis of Helicobacter pylori younger age,although in our study, as well as in other studies, infection. Clin Microbiol Rev 2006; 19: 449– 90.
3 De Francesco V, Giorgio F, Hassan C et al. Worldwide H. pylori antibiotic Data on H. pylori quinolone resistance in children is scarce.
resistance: a systematic review. J Gastrointestin Liver Dis 2010; 19: Nevertheless, the global primary resistance rate to ciprofloxacin observed in our study (4.6%) was higher than that reported in 4 Koletzko S, Richy F, Bontems P et al. Prospective multicentre study on children from Spain (ciprofloxacin, 2/66, 3.6%) or Austria (levo- antibiotic resistance of Helicobacter pylori strains obtained from floxacin, 0%).Moreover, it has been increasing at an alarming children living in Europe. Gut 2006; 55: 1711– 6.
rate over time, reaching almost 7% in the last period studied 5 Kalach N, Serhal L, Asmar E et al. Helicobacter pylori primary resistant (2006 –09). These results are consistent with data on quinolone strains over 11 years in French children. Diagn Microbiol Infect Dis 2007; consumption among 25 European countries, showing that southern countries presented the highest outpatient use of qui- 6 Ve´csei A, Kipet A, Innerhofer A et al. Time trends of Helicobacter pylori nolones, with Portugal occupying the first plac resistance to antibiotics in children living in Vienna, Austria. Helicobacter In conclusion, this is the first H. pylori antibiotic resistance multicentre study ever conducted in Portugal, comprising a 7 Agudo S, Alarco´n T, Cibrelus L et al. High percentage of clarithromycin large number of infected children. We emphasize the findings and metronidazole resistance in Helicobacter pylori clinical isolates of high primary resistance rates to the antibiotics most com- obtained from Spanish children. Rev Esp Quimioter 2009; 22: 88 –92.
monly used in the first-line H. pylori eradication treatment 8 Cabrita J, Oleastro M, Matos R et al. Features and trends in Helicobacter schemas, with a negative clinical impact in the management pylori antibiotic resistance in Lisbon area, Portugal (1990–1999).
of this infection. Furthermore, the increasing detection rate of J Antimicrob Chemother 2000; 46: 1029– 31.
ciprofloxacin and double-resistant strains over time warrants 9 Ferech M, Coenen S, Malhotra-Kumar S et al. European Surveillance of specific attention and continued surveillance, as it may compro- Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe.
mise the efficacy of second-line schemas in the paediatric age J Antimicrob Chemother 2006; 58: 423–7.
group, representing a serious public health problem in popu- 10 Oleastro M, Pelerito A, Nogueira P et al. Prevalence and incidence of lations with a high prevalence of H. pylori infection, such as the Helicobacter pylori infection in a healthy pediatric population in the Lisbon area. Helicobacter 2011; in press.


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