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Department of Gastroenterology and Public Health Laboratory Service, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, UK
Correspondence Ewen A. B. Cameron camerone99{at}aol.com
Received October 6, 2003
Accepted January 27, 2004
Helicobacter pylori infection causes a number of gastrointestinal diseases and its current treatment is based on multidrug regimes including acid suppression and antimicrobials. The success of these regimes is determined by a number of factors including antibiotic resistance, which varies widely but is an increasing problem. Local data are important in establishing the most cost-effective eradication regime. Data have been collected prospectively on antibiotic resistance at Ipswich Hospital (Suffolk, UK) in all consecutive isolates of H. pylori from 1991 to 2001. The success of regimes consisting of a proton pump inhibitor, amoxycillin and metronidazole (PPI/A/M) has also been evaluated in patients found positive on serological testing in primary care using urea breath testing. Overall, metronidazole resistance was found in 31.7 % of isolates and clarithromycin resistance in 5.3 %. A significant increase in metronidazole resistance from 29.1 to 37.0 % (P = 0.022) and a decrease in clarithromycin resistance from 10.3 to 3.8 % (P = 0.014) was seen over the study period. Metronidazole resistance was significantly more common in women (P < 0.001) and young patients (P < 0.001). Eradication with PPI/A/M was successful in 89.9 % of patients and did not change significantly over the study period. Eradication rates were lower in young patients (P < 0.001). Whilst metronidazole resistance is increasing in Suffolk, this does not seem to have a significant effect on eradication rates. Metronidazole-based regimes are still effective first-line treatments in most patients.
Present address: Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich NR4 7UZ, UK.
Present address: School of Computing Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Abbreviations: PPI/A/M, proton pump inhibitor, amoxycillin and metronidazole; PPI/A/C, proton pump inhibitor, amoxycillin and clarithromycin.
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INTRODUCTION |
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 TOP INTRODUCTION METHODSRESULTS AND DISCUSSIONREFERENCES |
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The treatment of H. pylori infection usually relies on the simultaneous administration of various combinations of drugs. Most commonly, an acid suppressor (usually a proton pump inhibitor) is prescribed in combination with two antibiotics (usually from amoxycillin, metronidazole and clarithromycin). The success of eradication depends on a number of factors, including antibiotic resistance (Jenks, 2002).
The level of antibiotic resistance amongst H. pylori strains varies markedly even within Western Europe. Rates of metronidazole resistance range from 15.9 % (France) to 41.9 % (Norway), whilst clarithromycin resistance is seen in between 1 % (Norway) and 5 % of isolates (UK and Ireland) (Megraud et al., 1999). As a result, local sensitivity data aid the choice of eradication regime.
Ipswich Hospital is a district general hospital in Suffolk (East Anglian region of England) that has been involved in the study of H. pylori infection since shortly after its discovery, including the development of the C14 urea breath test (Bell et al., 1987) as a means of monitoring the success of various candidate eradication regimes and monitoring reinfection/recrudescence rates, as well as the development of histological stains for identification of the organism (Trowell et al., 1987). We have prospectively collected data on antibiotic sensitivity of H. pylori isolates since 1991. Our local dyspepsia guidelines recommend first-line treatment of infection, in the absence of antibiotic sensitivities, with a 1 week course of omeprazole 40 mg o.d., amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. We have examined the changing pattern of resistance to metronidazole since 1991 and to clarithromycin since 1995 and its variation with age and sex. We have also examined the effect of time, age and sex on the eradication rate with triple therapy regimes consisting of a proton pump inhibitor, amoxycillin and metronidazole (PPI/A/M) or clarithromycin (PPI/A/C) since 1994.
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METHODS |
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TOPINTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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Efficacy of H. pylori eradication.
Data were prospectively collected for all consecutive serology positive patients referred for urea breath testing to confirm successful eradication of H. pylori after treatment with either PPI/A/M or PPI/A/C, including demographic data and the result of urea breath testing.
Statistical analysis was performed using the SPSS version 9.0 statistics package. Comparisons between groups were performed using Pearson's chi-squared test and, when appropriate, Fisher's exact test. Statistical significance was set at the 5 % level. Where more than one factor was significantly associated with resistance, multiple logistic regression with forward stepwise selection was performed to ensure the independence of factors associated with antibiotic resistance.
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RESULTS AND DISCUSSION |
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TOPINTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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40 years old than in patients >40 (P < 0.001) (Table 1). Multiple logistic regression with forward stepwise selection confirmed both youth (odds ratio 2.02; 95 % confidence interval 1.37–2.92; P = 0.0004) and the female sex (odds ratio 1.70; 95 % confidence interval 1.33–2.16; P < 0.0001) to be independently associated with the risk of metronidazole resistance.
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Susceptibility to clarithromycin was tested in 388 isolates between 1995 and 2001, 5.4 % (3.1–7.5 %) of which were resistant. Clarithromycin resistance fell significantly between 1995–1998 (9.3 %, 3.8–14.9 %) and 1999–2001 (3.8 %, 1.6–6.0 %) (P = 0.014). There was no significant association between the presence of clarithromycin resistance and either age or sex (Table 1).
Although available in our hospital since 1987, a urea breath test service was only made generally available to all local general practitioners in 1994 to allow confirmation of eradication in patients found to be positive for H. pylori on serological testing. Testing utilized urea labelled with either C13 or C14 as described previously (Bell & Weil, 1992; Logan, 1992). Between 1994 and 2001, 706 patients were referred for urea breath testing by their general practitioners following a course of eradication therapy with a PPI/A/M triple therapy regime. The overall eradication rate was 89.9 % (87.7–92.2 %), with no statistically significant change in eradication rate with time. Whilst the eradication rate was significantly lower in patients 40 years old than in those older (P < 0.001), there was no difference between men and women (Table 2). During the same time period, 63 patients were referred following a course of eradication therapy with PPI/A/C. The eradication rate in these patients was 92.1 % (85.4–98.7 %) with no statistically significant difference in eradication rates compared with patients treated with PPI/A/M (P = 0.589).
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This study provides important information with regards to changing patterns of antibiotic resistance in H. pylori infection in Suffolk. There has been a slow but steady rise in metronidazole resistance without an accompanying rise in clarithromycin resistance. Recent data from Nottingham and Dublin suggest rates of resistance of 26.6 % to metronidazole and 5 % to clarithromycin (Megraud et al., 1999). Numbers from these two centres were, however, small (60 patients overall) and limited to patients with duodenal ulcer disease. The large number of our own isolates (1263) from all disease processes and the duration of our study provide valuable information that can be applied to all patients with H. pylori infection.
As previously documented, we found higher rates of metronidazole resistance amongst women (Weil et al., 1990; Wolle et al., 2002; Osato et al., 2001; Meyer et al., 2002), a phenomenon thought to occur as a result of metronidazole use in the treatment of gynaecological infections. Previous reports have also suggested higher rates of metronidazole resistance in younger patients (Mollison et al., 2000), but this is far from being a consistent finding (Osato et al., 2001). When deciding on the choice of eradication regime in patients without the use of sensitivity data, it is important to be able to identify subgroups of patients at high risk of antibiotic resistance. Continued use of metronidazole in eradication regimes in the absence of sensitivity data might seem counter-intuitive; however, increasing rates of clarithromycin resistance are being seen around the world (Cabrita et al., 2000; Megraud, 1998). The avoidance of widespread use of clarithromycin in the treatment of H. pylori infection may help to prevent this rise in resistant organisms.
Recently, a consensus has been reached on the methods that are to be used in the testing for antibiotic susceptibility in H. pylori (McNulty et al., 2002). We recognize the limitations of the disc diffusion method we have used. However, whilst some cases of low-level resistance may have been missed, this would not have affected the overall trend observed. In addition, it is important that we have used the same method throughout the study period, allowing direct comparison across time periods.
Despite increasing levels of metronidazole resistance, no effect was seen on eradication rates amongst patients treated with PPI/A/M. Importantly, these cases were not treated as part of a clinical trial and, as such, are representative of the real situation in clinical practice. The patient group studied was selected as it represents a sample of the local population in whom identification of H. pylori infection was made without the use of culture and sensitivity testing. This ensured that eradication rates were not falsely elevated by selection of patients with metronidazole-susceptible isolates. In fact, as one would expect urea breath testing to be performed more often in patients with ongoing symptoms after therapy than in those with symptom resolution, this group probably contained a slight excess of treatment failures and, as a result, metronidazole resistance.
Whilst it is possible that some of the cases of H. pylori infection identified with serological testing might have been false positives, the rate of successful eradication was similar to that found locally in clinical trials (Bell et al., 1995) and no significant difference was seen with PPI/A/C regimes. False positives would have been expected in similar proportions of both groups. The much smaller number of patients treated with PPI/A/C reflected the local recommendation to use omeprazole, amoxycillin and metronidazole as a first-line regime.
It is not clear why increasing rates of metronidazole resistance had little impact on eradication rates. High eradication rates with metronidazole-containing regimes have been seen despite in vitro metronidazole resistance in H. pylori isolates (Megraud et al., 1999; Graham et al., 1996), and this may occur due to differences between in vitro and in vivo susceptibility (Jenks, 2002). The reason for the fall in rates of clarithromycin resistance over the study period is also not obvious. The small number of isolates tested between 1995 and 1998 and the fact that not all isolates were routinely tested over this time period may have contributed to this finding. Between 1995 and 1998, clarithromycin resistance was utilized as a research tool on isolates from one consultant's endoscopy lists. Whilst this led to smaller numbers of isolates being tested during this time period, the cases on these lists were not specially selected and, as a result, should have been representative of all isolates.
The population in Suffolk may not be entirely representative of other populations within the UK. The ethnic minority population in Suffolk is considerably smaller than the national mean, with 97.2 % of the local population being white (http://www.statistics.gov.uk/census2001/), potentially affecting the generalizability of the results to areas with different ethnic characteristics.
Clarithromycin-containing regimes are currently recommended in the UK by the Primary Care Society for Gastroenterology (http://www.pcsg.org.uk/) and the British Society of Gastroenterology (http://www.bsg.org.uk/clinical_prac/guidelines/dyspepsia.htm) in the first-line treatment of H. pylori infection. However, whilst overall eradication rates with PPI/A/M remain approximately 90 % [a figure comparable to that previously reported in open and double-blind studies in Suffolk (Bell et al., 1995)], the use of amoxycillin and metronidazole as first-line eradication therapy in combination with a proton pump inhibitor seems reasonable for the majority of patients. This approach may help to reduce the spread of clarithromycin resistance and is considerably cheaper. The current cost of a 1 week course of clarithromycin 500 mg b.d. is £24.74, compared with £3.50 for metronidazole 500 mg t.d.s. (http://www.bnf.org). Avoidance of metronidazole-containing regimes in subgroups of patients with high rates of metronidazole resistance (such as young women and certain ethnic groups) in whom sensitivity testing has not been performed is, however, probably indicated. Whilst most centres utilize direct urease tests for the identification of H. pylori in gastric biopsies, we have continued to culture the organism in Ipswich directly. This continued surveillance of antibiotic sensitivity will be vital in directing future eradication therapy.
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