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Leading articles cefetamet pivoxfl. In 17th International Congress of Chemotherapy. Berlin 1991. Abstract 1331. Cefixtme and cefdinir Neu, H. C, Saha, G. & Chin, N-X. (1989). Comparative in vitro activity and 0-lactamase stability of FK482, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 33, 1795-800. Verghese, A., Roberson, D., Kalbfleisch, J. H. & Sarubbi, F. (1990). Randomized comparative study of cefixime versus cephakxin in acute bacterial exacerbations of chronic bronchitis. Antimicrobial Agents and Chemotherapy 34, 1041-4. Ceftibuten Wise, R., Andrews, J. M.( Ashby, J. P. & Thornber, D. (1990). Ceftibuten—tn-vitro activity against respiratory pathogens, /Mactamase stability and mechanism of action. Journal of Antimicrobial Chemotherapy 26, 209-13.
Antibiotics in the treatment of peptic ulcer disease R. WISE Department of Microbiology. Dudley Road Hospital. A Rip van Winkle gastroenterologist, who Birmingham B18 7QH. UK went to sleep ten years ago, and woke up in
1992 would probably be confused. He would have no difficulty in treating duodenal ulcer and would recognize most of the drugs Reading list currently available. The logic behind proton Cefuroxime axetU Harding, S. M., Williams, P. E O. & Ayrton, J. pump inhibitors would be self-evident, but the (1984). Pharmacology of cefuroxime as the 1- suggestion that antibiotics could have a role in acetoxyethyi etter in volunteers. Antimicrobial peptic ulceration would seem completely alien. Agents and Chemotherapy 25, 78-82. Helicobacter pylori was first described eight Davies, B. I., Maeien, F. P. V. & Teengs, J. P. years ago (Warren & Marshall, 1983) and has (1987). Cefuroxime axetil in acute purulent been through several name changes and a lot exacerbations of chronic bronchitis. Infection 15, of controversy in the interim. Most 253-6. gastroenterologists would now accept that it is Cefpodoxbne Wise, R., Andrews, J. M., Ashby, J. P. & Thomber, the most important cause of Type B gastritis. D. (1990). The in-vitro activity of cefpodoxime: a Its association with duodenal ulcer is likewise comparison with other oral cephalosporins. extremely strong, with the majority of studies Journal of Antimicrobial Chemotherapy 25, suggesting that 80%-100% of affected patients 541-50. are colonized. Whether H. pylori initiates Wise, R. (1990). The phannacokinetict of the oral ulceration, or is merely an epiphenomenon is cephalosporins—a review. Journal of Anti- still disputed. It has been recognized for many microbial Chemotherapy 26, Suppl. E, 13-20. years that duodenal ulcer relapse occurs in Cefprozll the majority of patients treated with all Chin, N-X. & Neu, H. C. (1987). Comparative antibacterial activity of a new oral cephalosporin drugs currently available. Tripotassium BMY-28I00. Antimicrobial Agents and dicitratobismuthate (TDB; De-Nol), may delay relapse by several months (Martin et al., Chemotherapy 31, 480-3. 1981), but the majority of patients will Cefetamel Koup, J. R., Dubach, U. C , Brandt, R., Wys*. R. & nevertheless experience a recurrence of their Sloeckd, K. (1988). Pharmacokinetict of uker within one year. Over the past four years, cefetamet (Ro 15-8074) and cefetamet pivoxil however, a number of workers have suggested (Ro 15-8075) after intravenous and oral doses in that eradication of H. pylori significantly humans. Antimicrobial Agents and Chemotherapyreduces the rate -of duodenal ulcer relapse. 32, 573-9. It is important to define the term KissUng, M., Chadbourne, U., Zappdini, M. & Fernex, M. (1991). Overall evaluation of 'eradication', in the context of H. pylori. A
Downloaded from http://jac.oxfordjournals.org/ by guest on April 18, 2015
was being treated since many studies appear to have inappropriate pathogens for the particular infection. There is also a suspicion with most of these agents that adverse events—admittedly of a relatively minor nature—are common. Gastrointestinal side effects are the most frequently reported and often seen in more than 10% of patients. Pseudomembranous colitis appears rare—but we need to be alert to that possibility if these agents became widely used in community practice. No one could describe these new agents as 'exciting' (an over used word in the pharmaceutical industry). They offer modest but distinct advantages over the earlier agents and, with some exceptions, will probably replace them in the therapy of respiratory tract infections, including those in children. We need new agents to treat community-acquired respiratory infections. Let us hope the new oral cephalosporins will be a viable option.
Leading articles
be achieved in approximately 30% of patients (Marshall et al., 1988), but some authors have found much lower rates (Rauws & Tytgat 1989). Combination therapy has provided the best results to date. Eradication rates vary from 40% with TDB and amoxycillin (Rauws et al., 1988), to 80% with metronidazole and TDB (Weil et al., 1990). Triple therapy does even better and 96% of patients will eradicate the organism with a TDB, metronidazole and tetracydine combination (George et al., 1990). Replacing tetracycline with amoxycillin also appears to be effective. Whilst the number of agents combined has risen, the duration • of treatment has progressively fallen. Certainly four week courses are as effective as tight week, and two weeks of therapy may be as good as four. The situation may be analogous to that found with Mycobacterium tuberculosis, where triple therapy not only increased the chances of having two active drugs at the outset but also reduced the acquisition of resistance and improved the activity of the individual agents. The improvement in eradication rates have profound implications for the treatment of duodenal ulcer. To date seven studies (Coghlan et al., 1987; Lambert, et al., 1987; Marshall et al., 1988; Smith et al., 1988; George et al., 1990; Patchett et al., 1990; Rauws & Tytgat 1990) have been published which all reach the same conclusion. In patients who remain positive for H. pylori the duodenal ulcer relapse rate is 70%-80% per pnnirm In those in whom the organism is eradicated, the rate is only 10%-20% per annum. Moreover, reacquisition of H. pylori appears to predict ulcer, relapse. If further studies confirm these findings then the implications for gastroenterology are considerable. There are, however, problems with all of the papers to date. The number of patients is quite small, especially in the earlier studies. A more recent study from George et al. (1990) is particularly important AD the patients had received at least one tight week course of H2-blocker-therapy and been found to relapse. Many had taken multiple courses. Eighty-one patients were then treated with a further four weeks of dmetidine, and endoscoped as they relapsed symptotnatically. All had either failed to heal, or relapsed by ten months. They were then treated with a four week course of TDB with tetracycline 500 mg qds for four weeks and metronidazole 800 mg bd for ten days. Ninety-six per cent of patients remained
Downloaded from http://jac.oxfordjournals.org/ by guest on April 18, 2015
number of antimicrobials appear to be very effective against the organism if biopsies are taken a few days after treatment However, in the majority of cases bacteria reappear within a few weeks and are usually the same strains that were present before treatment 'Early relapsers' are, therefore, usually treatment failures. On the other hand, patients who remain negative for H. pylori 28 days or more after therapy will often remain so in the long term. Those who subsequently become positive again are usually infected with different strains (Langenberg et al., 1986). An unwritten convention has gradually emerged to restrict the term 'eradication' to patients whose biopsies, or urea breath test are negative at least four weeks after the completion of therapy (Bell, 1991). Patients tested earlier than this are probably best described as having 'cleared' the. organism, , although in my opinion it is better to give precise details of the treatment and the timing of assessment than to rely on semantics. In the laboratory H. pylori a sensitive to a wide range of antimicrobials, including penicillins, most cephalosporins, gentamicin, nitrofurantoin, the macrolides, tetracyclines, nitroimidazoles, and the quinolones (McNulty & Dent, 1988). All appear to have achievable MICs, but all have failed in vivo when used alone. Amoxycillin (Glupczynski et al., 1988) and nitrofurantoin (Gihnan et al., 1987) can achieve transient clearance rates of 80% immediately after treatment but all patients have relapsed by four weeks. Metronidazole and tinidazole resistant strains occur when used as single agents (Goodwin et al., 1988). A variety of factors probably contribute to the disappointing outcome of monotherapy. Erythromycin and dprofloxadn lose some of their activity at pH values less than 5-5. Erythromycin may also fail to achieve adequate concentrations within the gastric mucous (McNulty et al., 1988). In contrast the same investigators found that dprofloxadn was actively concentrated in the mucosa, but it is still ineffective in vivo. Acquired resistance to quinolones has been demonstrated in H. pylori after ofloxadn therapy (Glupczynski et al., 1987), and probably also occurs after dprofloxadn. Thus a variety of mechanisms contribute to the failure of single agent regimens. Even TDB appears less successful than was originally thought H. pylori recurs surprisingly quickly after TDB, often within 24-48 h as assessed by the urea breath test (Logan et al., 1991). At best eradication will
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Leading articles ulcer relapse is maintenance therapy with one of the H2-blockers which have been shown to reduce ulcer recurrence by approximately twothirds. It is not entirely dear whether ulcer complications are also reduced, and long-term treatment with current H2-blockers involves considerable expense (Howden, 1988). On the positive side H2-blockers have proved to be remarkably safe, and are well tolerated by most patients, with satisfactory rates of compliance. In contrast triple therapy regimens have been reported to cause nausea and upper gastrointestinal upset in some patients, whilst a small number have developed Clostridium difficile diarrhoea. Some of these problems may be overcome by using shorter courses of treatment, provided that their efficacy is confirmed. The high eradication rates seen in research studies may be more difficult to achieve in the setting of the typical gastroenterology clinic, particularly if compliance is a problem. Undoubtedly more large scale studies, analysed on an 'intention to treat' basis, are required to confirm the current optimistic findings. The potential advantages of eradicating H. pylori are obvious. If the ulcer diathesis really is 'cured' by eradication therapy then patients should have no more symptoms than normal controls. None of the drugs in current regimens is expensive and triple therapy will cost only a fraction of one year's maintenance with H2-blockers. No study to date has directly compared maintenance therapy with anti-helicobacter treatment What are the indications for treatment at present? Purists would probably say none, outside the context of clinical trials. Many gastroenterologists are, however, already using triple therapy, although mainly in a sporadic way. Certainly patients who have already had numerous courses of conventional ulcer therapy and who keep relapsing, or face possible surgery, have little to lose by being given triple therapy. Similarly so called 'resistant' ulcers that will not heal on normal treatment should be considered for eradication therapy. Great discretion must be shown with gastric ulcer. There are no good data on H. pylori and relapse and the worry about missing an early gastric carcinoma must still make surgery first choice for relapsing or resistant gastric ulcers. What about first presentations of duodenal ulcer? Most cases are probably seen by general practioners and many younger patients will be given H2-blockers before any form of investigation has been carried out Many will
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negative for H. pylori at four weeks and were then followed over the ensuing year. Two patients became positive for H. pylori and developed duodenitis but not ulceration. The others remained negative for H. pylori and none suffered a relapse of their duodenal ulcer. Although smaller numbers of patients have been followed up for two or more years, the findings remain the same. Those who are negative for H. pylori remain free from ulceration. One can criticize the data on a number of points. Firstly, it is well known that duodenal ulcer may relapse asymptomatically and it may be that a number of relapses have been missed. It would, however, seem highly improbable that all patients negative for H. pylori could remain ulcer free at repeat endoscopy, especially as they had all been documented to have had symptomatic relapse before entry into the study. Alternatively, the study might in some subtle way have picked a group of patients who were destined to go into longterm remission. Again this seems unlikely as they were selected on the basis of at least one documented relapse after H2-blocker therapy. More importantly it could be the use of TDB that reduces the tendency to relapse quite independently of H. pylori status. This seems doubtful because no TDB treatment study has ever achieved a comparable degree of success in preventing relapse. Rauws & Tytgat (1990) have reported a trial in which two patient groups both received TDB. One group also received antibiotics in addition to TDB. Ulcer relapse related solely to the H. pylori status in each group. Those receiving triple therapy were more likely to eradicate H. pylori and were much less likely to relapse. The most important factor in- preventing duodenal ulcer relapse appears to be the eradication of H. pylori rather than the regimen used. The situation regarding gastric ulcer is less clear. It is less frequently associated with H. pylori although when other factors such as non-steroidal anti-inflammatory drugs and carcinoma are excluded, some groups (Rauws & Tytgat, 1989) report rates similar to those for duodenal ulcer. Less information is available on the effects of H. pylori eradication, although one paper suggests that the temporary suppression of H. pylori with ce&rime may delay relapse (Tatsuta et al., 1990). In gummary, therefore, the evidence to date suggests that eradication of H. pylori may have a role in preventing ulcer relapse. The conventional approach to frequent duodenal
T«Hting articles
al., 1990). The epidemiology of H. pylori and duodenal ulcer display a number of incongruous features. For example, the prevalence of H. pylori appears to rise through life, certainly until middle age, and the sex distribution is equal. Duodenal ulcer is more common in males, but the incidence in elderly women is increasing. Both aspects are difficult to reconcile. It is premature, and certainly an over simplification, to describe H. pylori as 'the' cause of peptic ulcer. The Rip van Winkle gastroenterologLst might remain sceptical and could be excused for being confused. But surely his interest would be aroused when he became acquainted with the facts? A. W. McKINLAY Gastrointestinal and Liter Service. Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB, UK
References Bell, G. D. (1991). Anti-Helicobacter pylori therapy: clearance, elimination, or eradication? Lancet 337, 310-1. Coghlan, J. G., Guligan, D., Humphries H., McKenna, D., Dootey, C , Sweeney, E. el al. (1987). Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up itudy. Lancet U, 1109-11. George, L. L., Borody, T. J.F Andrew!, P., Devine, M., Moore-Jones, D., Walton, M. et al. (1990). Cure of duodenal ulcer after eradication of H. pylori. Medical Journal of Australia 153,145-9. Oilman, R., Leon-Barua, R., Ramirez-Ramos, A., Morgan, D., Recavarron, S., Spirt, W. et al. (1987). Efficacy of nitrofurans in the treatment of antral gastritis associated with Campylobacter pyhrUtU. Gastroenterology 92, 1405. Glupczynski, Y., Burette, A., Labbe, M., Deprez, C , De Reuck, M. & Deltenre, M. (1988). Campylobacter pylori-associated gastritis: a double-Wind placebo-controlled trial with amoxycillin. American Journal of Gastroenterology 83,365-72. Glupczynski, Y., Labbe, M., Burette, A., Dehnee, M., Avesani, V. & Brock, C. (1987). Treatment failure of ofloxacin in Campylobacter pylori infection. Lancet i, 1096. Goodwin, C. S., Marshall, B. J., Blincow, E D., Wilson, D. H., Blackboum, S. & Phillips, M. (1988). Prevention of nitroimidazole rrtittancc in Campylobacter pylori by coadministration of colloidal bismuth subcitrate: clinical and in-vitro studies Journal of Clinical Pathology 41, 207-10. Howden, C. W. (1988). Maintenance treatment with H2 receptor antagonists in patients with peptic uker disease: rarely justified in terms of cost or patient benefit British Medical Journal 297, 1393-4.
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respond entirely satisfactorily, will have infrequent problems and will continue to be managed appropriately with H2-blocker therapy. Those with frequent symptomatic recurrence, or whose ulcers prove resistant to H2-blockers should be considered for eradication therapy. It must be appreciated that the issue is still very contentious in gastroenterological circles, and -more longterm data are needed. Until more precise criteria emerge it would, seem sensible to confirm both the presence of active duodenal ulceration, and the H. pylori status before embarking on antibacterial treatment Some authors have suggested that positive serology for H. pylori and a reasonable history might be enough to warrant therapy but in my opinion a more precise diagnosis should be reached, and in this respect endoscopy is the best approach. This also allows H. pylori infection to be confirmed by either culture, histology or the biopsy urease test before treatment There must be reservations at present about recommending triple therapy for all duodenal ulcer patients. The organism can become resistant to metronidazole relatively easily (Goodwin et al., 1988), and whilst this might be considered of little consequence in an organism sensitive to a wide range of antimicrobials, in the case of H. pylori only a limited number of regimens work in clinical practice. In addition to TDB the best combinations all feature a nitroimidazole drug, and at present there are no data about which regimens should be used for resistant organisms. The first attempt at antihelicobacter treatment may, therefore, be the one most likely to succeed. The H2-blockers are probably the most thoroughly researched of all the ulcer healing agents, and more data are required comparing them with H. pylori therapy, before they are displaced from their primary position in duodenal ulcer therapy. Should microbiologists carry out routine sensitivity testing? This would seem sensible in treatment failures, or in areas where metronidazole resistance is common. No uniformly accepted methods of sensitivity testing, or definitions of resistance currently exist, a matter which will now have to be addressed. The current lack of alternative drug regimens is also worrying and there is still much scope for laboratory and clinical research. The evidence Unking H. pylori and duodenal ulcer recurrence is becoming more impressive, but numerous problems remain (McKinlay et
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Leading articles Patchett, S., O'Riordan, T , Leen, E., Keane, C. & O'Morain, C. (1990). A prospective study of Helicobacter pylori eradication in duodenal ulcer. Gastroenterology 98, A104. Rauws, E. A. J., Langenberg, W., Houthoff, H. J., Zanen, H. C. & Tytgat, G. N. J. (1988). Campylobacter pylorittts-atsoaaXtA chronic active antral gastritis. A prospective study of its prevalence and the effects of antibacterial and antiuker treatment. Gastroenterology 94, 33-40. Rauws, E. A. J. &. Tytgat, G. N. J. (1989). Campylobacter pylori W. C. den Ouden BV, Amsterdam. Rauws, E A . J . 4 Tytgat, G. N. J. (1990). Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 335, 1233-5. Smith, A. C, Price, A. B., Borriello, P. & Levi, A. J. (1988). A comparison of ranitidine and tripotattium dicitratobumuth (TDB) in relapse rates of duodenal ulcer. The role of Campylobacter pylori. Gut 29, A711. Tatsuta, M., Ishikawa, H., Iishi, H., Okuda, S. & Yokota, Y. (1990). Reduction of gastric ulcer recurrence after suppression of Helicobacter pylori by cefixime. Gut 31, 973-6. Warren, J. R. & Marshall, B. J. (1983). Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet i, 1273—5. WeiL J., Bell, G. D., Powell, K., Morden, A., Harrison, G., Gant, P. W. et al. (1990). Helicobacter pylori infection treated with a tripotassium dicitrato bismuthate and metronidazole combination. Alimentary Pharmacology and Therapeutics 4, 651-7.
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Lambert, J. R., Borromeo, M., JCorman, M. G., Hansky, J. & Eaves, E. I t (1987). Effect of colloidal bismuth (De-Nol) on healing and relapse of duodenal uken—role of Campylobaeter pylorUUs. Gastroenterology 92, 1489. Langenberg, W., Rauwt, E. A. J., Widjojokusumo, A., Tytgat, O. N. J. A Zanen, H. C. (1986). Identification of Campylobaeter pyloridis isolates by restriction endonudease DNA analysis. Journal of Clinical Microbiology 24, 414-7. Logan, R. P. H., Poison, R. J., Baron, J. H. & Misiewfcz, J. J. (1991). Follow-up after antiHelicobacter pylori treatment Lancet 337, 562-3. Marshall, B. J., Goodwin, C. S., Warren, J. R., Murray, R., Blincow, E. .D., Blackbourn, S. J. el al. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobaeter. pylori. Lancet tt. 1437-42. Martin, D. F., Hollanders, D., May S. J., Ravenscroft, M. M., Tweedle, D. E. F. & Miller, J. P. (1981). Difference is relapse rates of duodenal ulcer after hmiing with cunetidine or tripotassium dkitrato bismuthate. Lancet i, 7-10. McKinlay, A. W., Upadhyay, R^ Gemmell, C. G. & Russell, R. I. (1990). Helicobacter pylori: bridging the credibility gap. Gut 31, 940-5. McNulty, C. A. M. & Dent, J. C. (1988). Susceptibility of clinical isolates of Campylobaeter pylori to twenty-one antimicrobial agents. European Journal of Clinical Microbiology & Infectious Diseases 7, 566-9. McNulty, C. A. M., Dent, J. C , Ford, O. AL. & Wilkinson, S. P. (1988). Inhibitory antimicrobial concentrations against Campylobaeter pylori in gastric mucosa. Journal of Antimicrobial Chemotherapy 22, 729-38.
Leading articles cefetamet pivoxfl. In 17th International Congress of Chemotherapy. Berlin 1991. Abstract 1331. Cefixtme and cefdinir Neu, H. C, Saha, G. & Chin, N-X. (1989). Comparative in vitro activity and 0-lactamase stability of FK482, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 33, 1795-800. Verghese, A., Roberson, D., Kalbfleisch, J. H. & Sarubbi, F. (1990). Randomized comparative study of cefixime versus cephakxin in acute bacterial exacerbations of chronic bronchitis. Antimicrobial Agents and Chemotherapy 34, 1041-4. Ceftibuten Wise, R., Andrews, J. M.( Ashby, J. P. & Thornber, D. (1990). Ceftibuten—tn-vitro activity against respiratory pathogens, /Mactamase stability and mechanism of action. Journal of Antimicrobial Chemotherapy 26, 209-13.
Antibiotics in the treatment of peptic ulcer disease R. WISE Department of Microbiology. Dudley Road Hospital. A Rip van Winkle gastroenterologist, who Birmingham B18 7QH. UK went to sleep ten years ago, and woke up in
1992 would probably be confused. He would have no difficulty in treating duodenal ulcer and would recognize most of the drugs Reading list currently available. The logic behind proton Cefuroxime axetU Harding, S. M., Williams, P. E O. & Ayrton, J. pump inhibitors would be self-evident, but the (1984). Pharmacology of cefuroxime as the 1- suggestion that antibiotics could have a role in acetoxyethyi etter in volunteers. Antimicrobial peptic ulceration would seem completely alien. Agents and Chemotherapy 25, 78-82. Helicobacter pylori was first described eight Davies, B. I., Maeien, F. P. V. & Teengs, J. P. years ago (Warren & Marshall, 1983) and has (1987). Cefuroxime axetil in acute purulent been through several name changes and a lot exacerbations of chronic bronchitis. Infection 15, of controversy in the interim. Most 253-6. gastroenterologists would now accept that it is Cefpodoxbne Wise, R., Andrews, J. M., Ashby, J. P. & Thomber, the most important cause of Type B gastritis. D. (1990). The in-vitro activity of cefpodoxime: a Its association with duodenal ulcer is likewise comparison with other oral cephalosporins. extremely strong, with the majority of studies Journal of Antimicrobial Chemotherapy 25, suggesting that 80%-100% of affected patients 541-50. are colonized. Whether H. pylori initiates Wise, R. (1990). The phannacokinetict of the oral ulceration, or is merely an epiphenomenon is cephalosporins—a review. Journal of Anti- still disputed. It has been recognized for many microbial Chemotherapy 26, Suppl. E, 13-20. years that duodenal ulcer relapse occurs in Cefprozll the majority of patients treated with all Chin, N-X. & Neu, H. C. (1987). Comparative antibacterial activity of a new oral cephalosporin drugs currently available. Tripotassium BMY-28I00. Antimicrobial Agents and dicitratobismuthate (TDB; De-Nol), may delay relapse by several months (Martin et al., Chemotherapy 31, 480-3. 1981), but the majority of patients will Cefetamel Koup, J. R., Dubach, U. C , Brandt, R., Wys*. R. & nevertheless experience a recurrence of their Sloeckd, K. (1988). Pharmacokinetict of uker within one year. Over the past four years, cefetamet (Ro 15-8074) and cefetamet pivoxil however, a number of workers have suggested (Ro 15-8075) after intravenous and oral doses in that eradication of H. pylori significantly humans. Antimicrobial Agents and Chemotherapyreduces the rate -of duodenal ulcer relapse. 32, 573-9. It is important to define the term KissUng, M., Chadbourne, U., Zappdini, M. & Fernex, M. (1991). Overall evaluation of 'eradication', in the context of H. pylori. A
Downloaded from http://jac.oxfordjournals.org/ by guest on April 18, 2015
was being treated since many studies appear to have inappropriate pathogens for the particular infection. There is also a suspicion with most of these agents that adverse events—admittedly of a relatively minor nature—are common. Gastrointestinal side effects are the most frequently reported and often seen in more than 10% of patients. Pseudomembranous colitis appears rare—but we need to be alert to that possibility if these agents became widely used in community practice. No one could describe these new agents as 'exciting' (an over used word in the pharmaceutical industry). They offer modest but distinct advantages over the earlier agents and, with some exceptions, will probably replace them in the therapy of respiratory tract infections, including those in children. We need new agents to treat community-acquired respiratory infections. Let us hope the new oral cephalosporins will be a viable option.
Leading articles
be achieved in approximately 30% of patients (Marshall et al., 1988), but some authors have found much lower rates (Rauws & Tytgat 1989). Combination therapy has provided the best results to date. Eradication rates vary from 40% with TDB and amoxycillin (Rauws et al., 1988), to 80% with metronidazole and TDB (Weil et al., 1990). Triple therapy does even better and 96% of patients will eradicate the organism with a TDB, metronidazole and tetracydine combination (George et al., 1990). Replacing tetracycline with amoxycillin also appears to be effective. Whilst the number of agents combined has risen, the duration • of treatment has progressively fallen. Certainly four week courses are as effective as tight week, and two weeks of therapy may be as good as four. The situation may be analogous to that found with Mycobacterium tuberculosis, where triple therapy not only increased the chances of having two active drugs at the outset but also reduced the acquisition of resistance and improved the activity of the individual agents. The improvement in eradication rates have profound implications for the treatment of duodenal ulcer. To date seven studies (Coghlan et al., 1987; Lambert, et al., 1987; Marshall et al., 1988; Smith et al., 1988; George et al., 1990; Patchett et al., 1990; Rauws & Tytgat 1990) have been published which all reach the same conclusion. In patients who remain positive for H. pylori the duodenal ulcer relapse rate is 70%-80% per pnnirm In those in whom the organism is eradicated, the rate is only 10%-20% per annum. Moreover, reacquisition of H. pylori appears to predict ulcer, relapse. If further studies confirm these findings then the implications for gastroenterology are considerable. There are, however, problems with all of the papers to date. The number of patients is quite small, especially in the earlier studies. A more recent study from George et al. (1990) is particularly important AD the patients had received at least one tight week course of H2-blocker-therapy and been found to relapse. Many had taken multiple courses. Eighty-one patients were then treated with a further four weeks of dmetidine, and endoscoped as they relapsed symptotnatically. All had either failed to heal, or relapsed by ten months. They were then treated with a four week course of TDB with tetracycline 500 mg qds for four weeks and metronidazole 800 mg bd for ten days. Ninety-six per cent of patients remained
Downloaded from http://jac.oxfordjournals.org/ by guest on April 18, 2015
number of antimicrobials appear to be very effective against the organism if biopsies are taken a few days after treatment However, in the majority of cases bacteria reappear within a few weeks and are usually the same strains that were present before treatment 'Early relapsers' are, therefore, usually treatment failures. On the other hand, patients who remain negative for H. pylori 28 days or more after therapy will often remain so in the long term. Those who subsequently become positive again are usually infected with different strains (Langenberg et al., 1986). An unwritten convention has gradually emerged to restrict the term 'eradication' to patients whose biopsies, or urea breath test are negative at least four weeks after the completion of therapy (Bell, 1991). Patients tested earlier than this are probably best described as having 'cleared' the. organism, , although in my opinion it is better to give precise details of the treatment and the timing of assessment than to rely on semantics. In the laboratory H. pylori a sensitive to a wide range of antimicrobials, including penicillins, most cephalosporins, gentamicin, nitrofurantoin, the macrolides, tetracyclines, nitroimidazoles, and the quinolones (McNulty & Dent, 1988). All appear to have achievable MICs, but all have failed in vivo when used alone. Amoxycillin (Glupczynski et al., 1988) and nitrofurantoin (Gihnan et al., 1987) can achieve transient clearance rates of 80% immediately after treatment but all patients have relapsed by four weeks. Metronidazole and tinidazole resistant strains occur when used as single agents (Goodwin et al., 1988). A variety of factors probably contribute to the disappointing outcome of monotherapy. Erythromycin and dprofloxadn lose some of their activity at pH values less than 5-5. Erythromycin may also fail to achieve adequate concentrations within the gastric mucous (McNulty et al., 1988). In contrast the same investigators found that dprofloxadn was actively concentrated in the mucosa, but it is still ineffective in vivo. Acquired resistance to quinolones has been demonstrated in H. pylori after ofloxadn therapy (Glupczynski et al., 1987), and probably also occurs after dprofloxadn. Thus a variety of mechanisms contribute to the failure of single agent regimens. Even TDB appears less successful than was originally thought H. pylori recurs surprisingly quickly after TDB, often within 24-48 h as assessed by the urea breath test (Logan et al., 1991). At best eradication will
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Leading articles ulcer relapse is maintenance therapy with one of the H2-blockers which have been shown to reduce ulcer recurrence by approximately twothirds. It is not entirely dear whether ulcer complications are also reduced, and long-term treatment with current H2-blockers involves considerable expense (Howden, 1988). On the positive side H2-blockers have proved to be remarkably safe, and are well tolerated by most patients, with satisfactory rates of compliance. In contrast triple therapy regimens have been reported to cause nausea and upper gastrointestinal upset in some patients, whilst a small number have developed Clostridium difficile diarrhoea. Some of these problems may be overcome by using shorter courses of treatment, provided that their efficacy is confirmed. The high eradication rates seen in research studies may be more difficult to achieve in the setting of the typical gastroenterology clinic, particularly if compliance is a problem. Undoubtedly more large scale studies, analysed on an 'intention to treat' basis, are required to confirm the current optimistic findings. The potential advantages of eradicating H. pylori are obvious. If the ulcer diathesis really is 'cured' by eradication therapy then patients should have no more symptoms than normal controls. None of the drugs in current regimens is expensive and triple therapy will cost only a fraction of one year's maintenance with H2-blockers. No study to date has directly compared maintenance therapy with anti-helicobacter treatment What are the indications for treatment at present? Purists would probably say none, outside the context of clinical trials. Many gastroenterologists are, however, already using triple therapy, although mainly in a sporadic way. Certainly patients who have already had numerous courses of conventional ulcer therapy and who keep relapsing, or face possible surgery, have little to lose by being given triple therapy. Similarly so called 'resistant' ulcers that will not heal on normal treatment should be considered for eradication therapy. Great discretion must be shown with gastric ulcer. There are no good data on H. pylori and relapse and the worry about missing an early gastric carcinoma must still make surgery first choice for relapsing or resistant gastric ulcers. What about first presentations of duodenal ulcer? Most cases are probably seen by general practioners and many younger patients will be given H2-blockers before any form of investigation has been carried out Many will
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negative for H. pylori at four weeks and were then followed over the ensuing year. Two patients became positive for H. pylori and developed duodenitis but not ulceration. The others remained negative for H. pylori and none suffered a relapse of their duodenal ulcer. Although smaller numbers of patients have been followed up for two or more years, the findings remain the same. Those who are negative for H. pylori remain free from ulceration. One can criticize the data on a number of points. Firstly, it is well known that duodenal ulcer may relapse asymptomatically and it may be that a number of relapses have been missed. It would, however, seem highly improbable that all patients negative for H. pylori could remain ulcer free at repeat endoscopy, especially as they had all been documented to have had symptomatic relapse before entry into the study. Alternatively, the study might in some subtle way have picked a group of patients who were destined to go into longterm remission. Again this seems unlikely as they were selected on the basis of at least one documented relapse after H2-blocker therapy. More importantly it could be the use of TDB that reduces the tendency to relapse quite independently of H. pylori status. This seems doubtful because no TDB treatment study has ever achieved a comparable degree of success in preventing relapse. Rauws & Tytgat (1990) have reported a trial in which two patient groups both received TDB. One group also received antibiotics in addition to TDB. Ulcer relapse related solely to the H. pylori status in each group. Those receiving triple therapy were more likely to eradicate H. pylori and were much less likely to relapse. The most important factor in- preventing duodenal ulcer relapse appears to be the eradication of H. pylori rather than the regimen used. The situation regarding gastric ulcer is less clear. It is less frequently associated with H. pylori although when other factors such as non-steroidal anti-inflammatory drugs and carcinoma are excluded, some groups (Rauws & Tytgat, 1989) report rates similar to those for duodenal ulcer. Less information is available on the effects of H. pylori eradication, although one paper suggests that the temporary suppression of H. pylori with ce&rime may delay relapse (Tatsuta et al., 1990). In gummary, therefore, the evidence to date suggests that eradication of H. pylori may have a role in preventing ulcer relapse. The conventional approach to frequent duodenal
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al., 1990). The epidemiology of H. pylori and duodenal ulcer display a number of incongruous features. For example, the prevalence of H. pylori appears to rise through life, certainly until middle age, and the sex distribution is equal. Duodenal ulcer is more common in males, but the incidence in elderly women is increasing. Both aspects are difficult to reconcile. It is premature, and certainly an over simplification, to describe H. pylori as 'the' cause of peptic ulcer. The Rip van Winkle gastroenterologLst might remain sceptical and could be excused for being confused. But surely his interest would be aroused when he became acquainted with the facts? A. W. McKINLAY Gastrointestinal and Liter Service. Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB, UK
References Bell, G. D. (1991). Anti-Helicobacter pylori therapy: clearance, elimination, or eradication? Lancet 337, 310-1. Coghlan, J. G., Guligan, D., Humphries H., McKenna, D., Dootey, C , Sweeney, E. el al. (1987). Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up itudy. Lancet U, 1109-11. George, L. L., Borody, T. J.F Andrew!, P., Devine, M., Moore-Jones, D., Walton, M. et al. (1990). Cure of duodenal ulcer after eradication of H. pylori. Medical Journal of Australia 153,145-9. Oilman, R., Leon-Barua, R., Ramirez-Ramos, A., Morgan, D., Recavarron, S., Spirt, W. et al. (1987). Efficacy of nitrofurans in the treatment of antral gastritis associated with Campylobacter pyhrUtU. Gastroenterology 92, 1405. Glupczynski, Y., Burette, A., Labbe, M., Deprez, C , De Reuck, M. & Deltenre, M. (1988). Campylobacter pylori-associated gastritis: a double-Wind placebo-controlled trial with amoxycillin. American Journal of Gastroenterology 83,365-72. Glupczynski, Y., Labbe, M., Burette, A., Dehnee, M., Avesani, V. & Brock, C. (1987). Treatment failure of ofloxacin in Campylobacter pylori infection. Lancet i, 1096. Goodwin, C. S., Marshall, B. J., Blincow, E D., Wilson, D. H., Blackboum, S. & Phillips, M. (1988). Prevention of nitroimidazole rrtittancc in Campylobacter pylori by coadministration of colloidal bismuth subcitrate: clinical and in-vitro studies Journal of Clinical Pathology 41, 207-10. Howden, C. W. (1988). Maintenance treatment with H2 receptor antagonists in patients with peptic uker disease: rarely justified in terms of cost or patient benefit British Medical Journal 297, 1393-4.
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respond entirely satisfactorily, will have infrequent problems and will continue to be managed appropriately with H2-blocker therapy. Those with frequent symptomatic recurrence, or whose ulcers prove resistant to H2-blockers should be considered for eradication therapy. It must be appreciated that the issue is still very contentious in gastroenterological circles, and -more longterm data are needed. Until more precise criteria emerge it would, seem sensible to confirm both the presence of active duodenal ulceration, and the H. pylori status before embarking on antibacterial treatment Some authors have suggested that positive serology for H. pylori and a reasonable history might be enough to warrant therapy but in my opinion a more precise diagnosis should be reached, and in this respect endoscopy is the best approach. This also allows H. pylori infection to be confirmed by either culture, histology or the biopsy urease test before treatment There must be reservations at present about recommending triple therapy for all duodenal ulcer patients. The organism can become resistant to metronidazole relatively easily (Goodwin et al., 1988), and whilst this might be considered of little consequence in an organism sensitive to a wide range of antimicrobials, in the case of H. pylori only a limited number of regimens work in clinical practice. In addition to TDB the best combinations all feature a nitroimidazole drug, and at present there are no data about which regimens should be used for resistant organisms. The first attempt at antihelicobacter treatment may, therefore, be the one most likely to succeed. The H2-blockers are probably the most thoroughly researched of all the ulcer healing agents, and more data are required comparing them with H. pylori therapy, before they are displaced from their primary position in duodenal ulcer therapy. Should microbiologists carry out routine sensitivity testing? This would seem sensible in treatment failures, or in areas where metronidazole resistance is common. No uniformly accepted methods of sensitivity testing, or definitions of resistance currently exist, a matter which will now have to be addressed. The current lack of alternative drug regimens is also worrying and there is still much scope for laboratory and clinical research. The evidence Unking H. pylori and duodenal ulcer recurrence is becoming more impressive, but numerous problems remain (McKinlay et
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Leading articles Patchett, S., O'Riordan, T , Leen, E., Keane, C. & O'Morain, C. (1990). A prospective study of Helicobacter pylori eradication in duodenal ulcer. Gastroenterology 98, A104. Rauws, E. A. J., Langenberg, W., Houthoff, H. J., Zanen, H. C. & Tytgat, G. N. J. (1988). Campylobacter pylorittts-atsoaaXtA chronic active antral gastritis. A prospective study of its prevalence and the effects of antibacterial and antiuker treatment. Gastroenterology 94, 33-40. Rauws, E. A. J. &. Tytgat, G. N. J. (1989). Campylobacter pylori W. C. den Ouden BV, Amsterdam. Rauws, E A . J . 4 Tytgat, G. N. J. (1990). Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 335, 1233-5. Smith, A. C, Price, A. B., Borriello, P. & Levi, A. J. (1988). A comparison of ranitidine and tripotattium dicitratobumuth (TDB) in relapse rates of duodenal ulcer. The role of Campylobacter pylori. Gut 29, A711. Tatsuta, M., Ishikawa, H., Iishi, H., Okuda, S. & Yokota, Y. (1990). Reduction of gastric ulcer recurrence after suppression of Helicobacter pylori by cefixime. Gut 31, 973-6. Warren, J. R. & Marshall, B. J. (1983). Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet i, 1273—5. WeiL J., Bell, G. D., Powell, K., Morden, A., Harrison, G., Gant, P. W. et al. (1990). Helicobacter pylori infection treated with a tripotassium dicitrato bismuthate and metronidazole combination. Alimentary Pharmacology and Therapeutics 4, 651-7.
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Lambert, J. R., Borromeo, M., JCorman, M. G., Hansky, J. & Eaves, E. I t (1987). Effect of colloidal bismuth (De-Nol) on healing and relapse of duodenal uken—role of Campylobaeter pylorUUs. Gastroenterology 92, 1489. Langenberg, W., Rauwt, E. A. J., Widjojokusumo, A., Tytgat, O. N. J. A Zanen, H. C. (1986). Identification of Campylobaeter pyloridis isolates by restriction endonudease DNA analysis. Journal of Clinical Microbiology 24, 414-7. Logan, R. P. H., Poison, R. J., Baron, J. H. & Misiewfcz, J. J. (1991). Follow-up after antiHelicobacter pylori treatment Lancet 337, 562-3. Marshall, B. J., Goodwin, C. S., Warren, J. R., Murray, R., Blincow, E. .D., Blackbourn, S. J. el al. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobaeter. pylori. Lancet tt. 1437-42. Martin, D. F., Hollanders, D., May S. J., Ravenscroft, M. M., Tweedle, D. E. F. & Miller, J. P. (1981). Difference is relapse rates of duodenal ulcer after hmiing with cunetidine or tripotassium dkitrato bismuthate. Lancet i, 7-10. McKinlay, A. W., Upadhyay, R^ Gemmell, C. G. & Russell, R. I. (1990). Helicobacter pylori: bridging the credibility gap. Gut 31, 940-5. McNulty, C. A. M. & Dent, J. C. (1988). Susceptibility of clinical isolates of Campylobaeter pylori to twenty-one antimicrobial agents. European Journal of Clinical Microbiology & Infectious Diseases 7, 566-9. McNulty, C. A. M., Dent, J. C , Ford, O. AL. & Wilkinson, S. P. (1988). Inhibitory antimicrobial concentrations against Campylobaeter pylori in gastric mucosa. Journal of Antimicrobial Chemotherapy 22, 729-38.
