Helicobacter pylori eradication and reinfection

clear reticulocyte response (up to 3-4%) was also seen. Folic acid was subsequently tapered weekly by 1 mg to 1 mg daily. Since the initiation of folate, no transfusions have been required, and no side-effects have been noted. Folic-acid deficiency may result from various causes including dietary deficiency, alcoholism and cirrhosis, a

drug-induced malabsorption, usually leads to an anaemia with megaloblastic changes.’ In our case, no underlying cause could be identified, and bone-marrow samples showed no morphological evidence of megaloblastic anaemia. We propose that our patient developed, perhaps by somatic mutation or an unknown metabolic inhibitor, an acquired defect of folate uptake and/or use in erythroid precursor cells. Although the possibility of a spontaneous remission’ cannot be excluded, the timing of recovery in relation to vitamin administration (figure) strongly suggests a causal relation. Our experience should encourage further attempts of high-dose folate administration in similar cases.

congenital

pregnancy,

deficiency,

or

intestinal diseases, and

post-treatment. As the figure shows, when we arbitrarily divide the anti-helicobacter regimens into those with an eradication rate of <20%, 20-40%, 40-60%, and >80% we find that the 6-month "reinfection" rate is inversely the eradication rate. The same correlated with metronidazole-containing regimen given to patients in different countries could thus give not only widely varying eradication rates but also very different rates of reinfection/late recrudescence, depending on the prevalence of metronidazole-resistant strains in that population. We will need to see data from larger numbers of patients with metronidazole-resistant strains before abandoning our less complex, well tolerated, and probably equally effective one week regimens,2,3 and we are not yet persuaded that such eradication therapy has been successful in patients whose ulcers have previously bled unless we have a diagnostic test of cure such as a breath test, before discontinuing maintenance acid-lowering therapy.

Guido Gothoni, Matti Vuoristo, *Kimmo Kontula

*G D Bell, K U Powell *Department of Medicine, Ipswich Hospital, Ipswich,

Dextra Medical Center, Helsinki; and *Department of Medicine, University of Helsinki, FIN-00290 Helsinki, Finland

1

1

Dessypris EN. The biology of pure red cell aplasia.

Semin Hematol

1991; 28: 275-84. 2 3

4

Marmont AM. Therapy of pure red cell aplasia. Semin Hematol 1991; 28: 285-97. Branda RF, Moldow CF, MacArthur Jr, et al. Folate-induced remission in aplastic anemia with familial defect of cellular folate uptake. N Engl J Med 1978; 298: 469-75. Lee GR. Megaloblastic and nonmegaloblastic macrocytic anemias. In: Lee GR, Bitnell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe’s clinical hematology, 9th ed. Philadelphia: Lea & Febiger, 1993.

Helicobacter pylori eradication and reinfection SiR-de Boer and colleagues’ study (April 1, p 817) of one week of quadruple therapy for Helicobacter pylori in patients with duodenal ulcer disease records an impressive eradication rate of 98-1% but the conclusion that the therapy would "obviate the need for a diagnostic test of cure in compliant patients" is premature. The success rate of any H pylori-eradication regimen containing metronidazole is critically dependent on the frequency of metronidazole sensitivity in the population treated. In de Boer and colleagues’ study from the Netherlands, the frequency of H pylori metronidazole resistance was only 7-7% compared with 20% in Suffolk (UK) and 37-90% in different ethnic groups in London (UK).’ We have followed up 1182 H pylori positive patients in whom we had apparently achieved successful eradication, as indicated by a negative "C-urea breath test at least one month post-treatment. We observed 57 "reinfections" of which 45 had occurred by 6 months

Figure: Effect of eradication rate at 1 month post-treatment in subsequent reinfection at 6 months (r=0.97) 1646

2

3

Suffolk IP4 5PD, UK

Banatvala N, Davies GR, Abdi Y, et al. High prevalence of Helicobacter pylori metronidazole resistance in migrants to east London: relation with previous nitroimidazole exposure and gastroduodenal disease. Gut

1994; 35: 1562-66. Bell GD, Powell KU, Burridge SM, et al. Rapid eradication of Helicobacter pylori in ulcer disease. Aliment Pharmacol Therap 1995; 9: 41-46. Powell KU, Bell GD, Bowden A, Trowell JE, Jones PH. One week Helicobacter pylori eradication therapy with omeprazole, clarithromycin and metronidazole is as effective as two week therapy. Br J Clin Res 1995; 6: 85-90.

conclude that their short-term is the best treatment choice for H pylori quadruple regimen associated ulcers. In our opinion, this suggestion is countered by evidence of success with simpler regimens. For instance, the efficacy (90-95% eradication) of low-dose 1-week triple therapy with omeprazole, clarithromycin, and a nitroimidazole is well-documented.I,2 The results with this combination are similar to those achieved by de Boer and colleagues but the triple regimen is simpler and has fewer side-effects. Two recent trials3’ have even shown that H pylori-associated ulcers can be cured with only 1 week of the traditional triple therapy without any control of acid secretion. In another study’ the Dutch group recommended 1 week of standard triple therapy plus ranitidine or cimetidine as first-line anti-H pylori treatment in a compliant population of peptic-ulcer patients. They achieved an eradication rate of 95%, a result comparable with that now reported for the same regimen but containing omeprazole instead of an H2 blocker. Again, there is published evidence that eradication rates of 89-100% can be obtained with simpler triple regimens (two antimicrobials plus ranitidine). The similar results that de Boer and colleagues have achieved with two quadruple regimens, one containing omeprazole and the other ranitidine, prompts the question: is the eradication rate of H pylori infection with two or three antimicrobials really affected by concomitant acid suppression? If it is, the more profound and prolonged acidinhibitory effects of omeprazole should produce better results, but no large difference has emerged. If a direct comparison of two identical antibacterial regimens plus ranitidine or omeprazole were to show that eradication rates do not differ, that finding would greatly reduce the role of acid suppression in the eradication of H pylori. The relevance of ranitidine or omeprazole would then be restricted to the speed of control of the patient’s symptoms. We agree with Harris and Misiewicz (March 25, p 806) on the need to educate primary care physicians in the

SIR-de Boer and

colleagues

disorders that will benefit from H pylori eradication but first the best combination among double, triple, and quadruple regimens has to be identified and the role of acid suppression in respect of the antibiotic action against H pylori must be clarified. *Vincenzo Savarino, Guido Celle

Giuseppe Sandro Mela, Sergio Vigneri,

*Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy; and Institute of Internal Medicine and Geriatrics, University of Palermo

In the past year we have seen in our of recurrence of bleeding from duodenal hospital ulcer several months after eradication therapy’ with 2 weeks of daily omeprazole (20 mg/day), colloidal bismuth subcitrate (120 mgX4), tetracycline hydrochloride (500 mgX4), and metronidazole (250 mgX3). In neither case was control of eradication (or of healing) done and H pylori was confirmed at endoscopy during the recurrent bleeding

remains

mandatory.

two cases

episode. Furthermore, in studies

Bazzoli F, Zagari RM, Fossi S, et al. Short-term low-dose tnple therapy for the eradication of Helicobacter pylori. Eur J Gastroenterol Hepatol 1994; 6: 773-77. Goddard A, Logan R. One-week low-dose triple therapy: new standards for Helicobacter pylori treatment. Eur J Gastroenterol Hepatol

1

2

on

a clinical setting, in contrast to controlled selected patients, compliance is very difficult to

measure.

*F Gomollón, E Bajador, *Hospital Miguel Servet, Zaragoza 50009, Spain

1995; 7: 1-3.

Hosking SW, Ling TKW, Chung SCS, et al. Duodenal ulcer healing by eradication of H pylori without anti-acid treatment: randomised

3

controlled trial. Lancet 1994; 343: 508-10. Sung JJY, Chung SCS, Ling TKW, et al. Antibacterial treatment of gastric ulcers associated with Helicobacter pylori. N Engl J Med 1995; 332: 139-42. de Boer WA, Driessen WMM, Potters HVPJ, Tytgat GNJ. Randomized study comparing 1 and 2 weeks of quadruple therapy for eradicating H pylori. Am J Gastroenterol 1994; 89: 1993-97.

4

5

1

2 3

203-07.

4

eradication rates achieved by de Boer and colleagues by a combination of bismuth, tetracycline, and metronidazole alone (83-3%) or with omeprazole (98-1%) fit well with published data. In our meta-analysis (unpublished) we found eradication rates of 83-6% (n=1762) and 94-6% (n=372) (p<001), respectively. However, we disagree with the conclusion that acid inhibition may potentiate the H pylori-eradicating efficacy of bismuth in this regimen. We found that omeprazole pretreatment enhanced bismuth absorption’ but decreased eradication potential when compared with bismuth alone, to a rate similar to that achieved with omeprazole monotherapy.2 The value of bismuth in combination with omeprazole is doubtful in our view. Furthermore bismuth is not necessary in a new, SIR-The

promising consisting

(eradication rate 90-95%) triple therapy, of and clarithromicin, omeprazole, metronidazole.’ A comparative trial with tetracycline instead of clarithromicin would be of great interest. *G Treiber, O Klotz Departments of *Gastroenterology and Clinical Pharmacology, Robert-BoschHospital, D-70376 Stuttgart, Germany

1

2

3

Treiber G, Walker S, Klotz U. Omeprazole induced increase in the absorption of bismuth (Bi) from tripotassium dicitrato bismuthate. Clin Pharmacol Ther 1994; 55: 486-91. Treiber G, Walker S, Fritz P, et al. Two different therapeutic regimens to attempt Helicobacter pylori eradication. Acta Gastroenterol Belg 1993; 56: 146 (abstr). Bazzoli F, Zagari RM, Fossi S, et al. Efficacy and tolerability of a short term, low dose triple therapy for eradication of Helicobacter pylori. Am J Gastroenterol 1994; 89: 1364 (abstr 317).

SIR-While uncontrolled studies suggest that the natural

history of peptic ulcer is clearly modified (for the better) by curing H pylori infection’ we should not forget that complications from peptic ulcer are common, sometimes appear years later, and can be independent of H pylori infection (eg, those related to non-steroidal antiinflammatory drugs).°3 We do agree with de Boer and colleagues, that, if their excellent results are confirmed in other geographical settings, omission of a diagnostic test of cure would be adequate policy in uncomplicated duodenal ulcer patients. However, in bleeding ulcer patients or in those with gastric or refractory duodenal ulcers, a diagnostic test of cure, and in some cases even of healing of the ulcer, I

Labenz J, Börsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J Gastroenterol 1994; 89: 1785-88. Lindell G, Celebioglu F, von Holstein S, Graffner H. On the natural history of peptic ulcer. Scand J Gastroenterol 1994; 29: 979-82. Kim JG, Graham DY. Helicobacter pylon infection and development of gastric or duodenal ulcers m patients receiving chronic NSAID therapy: the Misoprostol Study Group. Am J Gastroenterol 1994; 89: de Boer WA, Driessen WMM, Potters HVPJ, Tytgat G. Randomized study comparing 1 and 2 weeks of quadruple therapy for eradicating Helicobacter pylori. Am J Gastroenterol 1994; 89: 1993-97.

Authors’reply SiR-Testing for cure is indicated only if it enables the physician to identify correctly those patients in whom H pylori infection persists. However, apart from endoscopy with multiple biopsy, there is no non-invasive alternative to for cure that can achieve 100% accuracy. Problems with false negatives and false positives will, therefore, remain. If pretest likelihood of cure is above 95%, as it seems to be for quadruple therapy, a diagnostic test can yield little and it is hard to identify patients who need further anti-H pylori

test

treatment.

Urea breath testing can distinguish those with infection from those without but it is insufficiently validated posttreatment, where it is much harder to distinguish patients with a limited residual bacterial load 4 weeks after antibiotic therapy from those in whom H pylori has been eradicated. Slomiansky et al reported 88% sensitivity and 94% specificity for the "C-urea breath test after therapy’ wheras the 14C test with a single 40 min breath sample in our hands has a sensitivity of 92% and a specificity of only 74% when compared with endoscopy (unpublished). Bell et al claim much higher sensitivity (99-3%) and specificity (96-2%) for their 14C-urea breath test in which an integrated area under the curve from breath samples collected over 2 h is calculatedEven an adequate diagnostic test will have a low negative predictive value when the prevalence of H pylori infection is high, as it will be after ineffective therapy. Therefore more false-negative results will be recorded after inadequate therapy. Bell’s conclusion that late recrudescence occurs more often after ineffective therapy seems to us a misrepresentation of their data; the recrudescence rate is not affected by the treatment itself but merely reflects the fact that the urea breath test has inadequate negative predictive value when used after a treatment with limited efficacy. The issue raised by Savarino et al-Hreceptor antagonist or proton-pump inhibitor to enhance triple therapy-was discussed in our article. The fact that in another study of 7day triple therapy without an antisecretory drug a cure rate of over 90% was reported is not an argument against our results because the studies were not a head-to-head comparison under the same study design using the same 1647

Our randomised population. comparison demonstrated that omeprazole does increase efficacy when it is added to triple therapy. Treiber and Klotz confirm our hypothesis that bismuth absorption increases when combined with omeprazole, but their conclusion that this decreases the eradication potential is illogical. Bismuth mainly enhances the bactericidal effect of metronidazole. If a higher concentration of bismuth is achieved in the gastric mucosa the bactericidal potential of the antibiotics will probably be enhanced as well. A combination of omeprazole, tetracycline, and metronidazole cured only 25 out of 43 patients, illustrating the essential role of bismuth in quadruple therapy.3 Bell and Savarino favour omeprazole plus two antibiotics but few studies have been published in full (amoxycillin plus a nitroimidazole or clarithromycin, or clarithromycin plus a nitroimidazole). These regimens do have a simpler dosing schedule but resistance to metronidazole and/or can be induced and a clarithromycin regimen containing a nitroimidazole will probably not differ in side-effect profile from our quadruple therapy. We can only know how sideeffects truly differ when therapies are compared in the same population with the same randomised study design.’ Moreover, these new regimens usually have success rates in the 80-95% range whereas quadruple therapy has the potential to cure over 95%,5 that result being confirmed in a population with 26-7% pretreatment metronidazole resistance. We stand by our claim that quadruple therapy is the best regimen. Treiber and colleagues’ unpublished meta-analysis apparently confirms our data. Quadruple therapy may well become the "gold standard" with which new treatments need to be compared.

patient

*Wink de Boer, Sint Anna Ziekenhuis, Guido

Tytgat

*Sint Anna Ziekenhuis, 5340BE Oss, Netherlands; and Academic Medical Center, Amsterdam, Netherlands

1

2

3

4

5

Slomiansky A, Schubert T, Cutler AF. [13C] Urea breath test to confirm eradication of Helicobacter pylori. Am J Gastroenterol 1995;

90: 224-26. Bell GD, Powell KU, Bumdge SM, et al. Reinfection or recrudescence after apparently successful eradication of Helicobacter pylori infection: implications for treatments of patients with duodenal ulcer disease. Q J Med 1993; 86: 375-82. McCarthy CJ, Collins R, Beattie S, Hamilton H, O’Morain C. Treatment of Helicobacter pylori-associated duodenal ulcer with omeprazole plus antibiotics. Aliment Pharmacol Ther 1993; 7: 463-65. de Boer WA, Tytgat CNJ. Review. The best therapy for Helicobacter pylori infection: should efficacy or side effect profile determine our choice? Scand J Gastroenterol 1995; 30: 401-07. Borody TJ, Andrews P, Shortis NP, Hyland L. 7 day therapy for Helicobacter pylori. Gastroenterology 1995; 108: A6.

Figure:

Reasons for

use

of alcohol swabs

survey to see how well the policy has been adopted. Our survey focused on the number of users and the reasons for

their use. We surveyed 90 staff including consultants, doctors of different grades, medical students, nursing sisters, nurses, and technical staff. Different numbers were surveyed in each group for practical reasons. 78% of the sample surveyed used alcohol swabs. 60-78% of the medical staff used swabs whereas 80-95% of the nursing and technical staff used them. The highest proportion of users were nurses. The reasons given for the use of swabs (see figure) were similar in all the groups surveyed. The most common reason was for sterilisation, which is unfounded. The next most common reason was that use of swabs stems from routine teaching and practice, which is clearly unscientific. The most surprising response was given by those users who stated that they did not know why they used the swabs. When a procedure has been shown to have no scientific foundation and might be a potential hazard, it should be discontinued. To persist with this archaic ritual is illogical and reflects the difficulty in altering long-standing routine practices. Modern medicine should reflect the appliance of science and therefore we recommend that the routine use of alcohol swabs be abandoned. .

Jennifer Liauw, *G J Archer Department of Medicine, Stepping Hill Hospital, Stockport SK2 7JE, UK

1 2 3

Malathi I, Millar MR, Leeming JP, Hedges A, Marlow N. Skin disinfection in preterm infants. Arch Dis Child 1993; 69: 312-16. Lewis MJ. Skin preparation before injection. Nursing Times 1975; 71: 786-87. Dann TC. Routine skin preparation before injection: an unnecessary procedure. Lancet 1969; ii: 96-97.

Swabaholics? S!R—There has long been controversy surrounding the use of alcohol-soaked swabs. They have been shown to be of no value for sterilising the skin when used routinely to swab the area for a few seconds before venepuncture.’°2 Similar studies have shown that giving injections without skin preparation does not cause local or systemic infections.3 The swabs are also a potential health hazard because they are frequently used to stem the bleeding point, allowing the patient’s blood to soak through the wafer-thin pads onto the user’s fingers. It is perplexing to find that most healthcare professionals continue to use the swab even though swabbing for a few seconds has no useful function. 8 eight years ago, our local hospital began a policy to get rid of this useless practice. 8 years on we have carried out a 1648

CORRECTIONS Impaired olfactory function in Parkinson’s disease-In this letter by Lehrner and colleagues (April 22, p 1054), the last line of the second paragraph should have read: "Results are expressed as the binding ratio striatum minus cerebellum/cerebellum (specific/nonspecific binding)". The minus sign of the correlation coefficient in the first sentence of the fourth paragraph was also omitted.

dehydroepiandrosterone-In this Commentary byHerbert 1193), paragraph three, line nineteen, should have read have not proved successful".

The age of

(May 13, "...

p

Fatal complication of desmopressin-In this letter by Hartmann and Reinhart (May 20, p 1302), the second sentence of the fourth paragraph should have read "We used a test dose (0-4 )g/kg) corresponding to a total of 34-4 )J.g in 80 mL saline 0-9% intravenously over 35 min".