Bismuth-based Therapy for H. Pylori Eradication in Children
Bismuth-based Therapy for H. Pylori Eradication in Children
Background Because of the decrease in the Helicobacter pylori eradication rate after standard triple therapy with a proton pump inhibitor and two antibiotics, bismuth-based therapy has recently been recommended as alternate first-line regimen in children.
Aim To comprehensively review the clinical, pharmacologic and microbiologic properties of bismuth salts, and to summarise the evidence for the therapeutic efficacy of bismuth-based therapy for H. pylori eradication in children.
Methods Bibliographical searches were performed in MEDLINE. Results on the efficacy of bismuth-containing regimens on H. pylori eradication were combined using the inverse variance method.
Results Bismuth monotherapy showed a very low efficacy. Overall, the mean eradication rate with bismuth-based dual therapy was 68% (95% CI, 60–76%) (intention-to-treat analysis-ITT) and 73% (95% CI, 64–81%) (per protocol-PP). In case series, the overall percentages of children with successful eradication for triple therapy containing bismuth were 82% (95% CI, 76–88%) and 86% (95% CI, 80–92%) according to ITT and PP respectively. In comparative studies, H. pylori eradication rates ranged between 69% and 85% according to ITT and between 74% and 96% PP. Side effects included dark stools, urine discoloration, black tongue, burning tongue, and marked darkness of the gums.
Conclusions The evidence in favour of bismuth compounds for treating infected children is still not clear. Well-designed, randomised, multi-centre studies of H. pylori eradication trials in children comparing bismuth-based triple therapy with the best available recommended first-line therapies are needed. The evidence obtained from audited case series that produce an eradication rate of >95% on PP analysis should also be considered.
Helicobacter pylori is the source of a highly prevalent, serious and chronic infection that has been associated causally with a diverse spectrum of gastrointestinal disorders including chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. In both developed and developing countries, H. pylori is most frequently acquired during childhood, and is associated with family size, clustering in families, low socioeconomic status and low level of education. In general, it is hypothesised that spontaneous eradication of H. pylori infection is extremely rare.
The combination of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole) has been the recommended first-line therapy since the first published guidelines for H. pylori infection in children. In recent years, the success of eradication therapies has declined, in part due to the development of H. pylori resistant strains. Several studies have documented high resistance rates to clarithromycin and metronidazole in paediatric and adult populations. In Europe, Koletzko et al. showed that primary resistance to clarithromycin and metronidazole was present in 20% and 23% of H. pylori strains respectively, while secondary resistance in 42% and 35% of the strains recovered after at least one failed treatment for H. pylori. The use of clarithromycin for other indications, mainly for respiratory tract infections, seemed to be the major risk factor for development of primary resistance to this drug. On the other hand, the only risk factor for primary metronidazole resistance was the immigration from a non-European country. In fact, the authors showed that children born in Asia, Africa or the Middle East had a 2.4 times higher risk for primary metronidazole resistance than patients of the same age and gender born in Europe. Iterative metronidazole treatments for parasitic or diarrhoeal diseases in children originating from Africa and Asia may be incriminated in the increased primary resistance rates of metronidazole recorded in these paediatric populations. A prospective US multicentre study in adults and children also documented similar high clarithromycin resistance rates.
Declining eradication rates with standard triple regimens have led to the development of alternate treatment options. Recently, ESPGHAN and NASPGHAN jointly renewed clinical guidelines for H. pylori infection in children using a standardised evidence based approach. Bismuth-based triple therapy or sequential therapy was recommended as alternate first-line regimens. Quadruple therapy with PPI, metronidazole, amoxicillin, and bismuth was also suggested as second-line therapy or salvage therapy in the absence of primary culture and sensitivity testing.
In this article, we comprehensively review, from a paediatric point of view, the literature on the clinical, pharmacologic, and microbiologic properties of bismuth salts. We also summarise the therapeutic efficacy of bismuth-based triple and quadruple therapy for eradication of H. pylori on the basis of evidence from case studies, and comparative (randomised and nonrandomised) studies.
Abstract and Introduction
Abstract
Background Because of the decrease in the Helicobacter pylori eradication rate after standard triple therapy with a proton pump inhibitor and two antibiotics, bismuth-based therapy has recently been recommended as alternate first-line regimen in children.
Aim To comprehensively review the clinical, pharmacologic and microbiologic properties of bismuth salts, and to summarise the evidence for the therapeutic efficacy of bismuth-based therapy for H. pylori eradication in children.
Methods Bibliographical searches were performed in MEDLINE. Results on the efficacy of bismuth-containing regimens on H. pylori eradication were combined using the inverse variance method.
Results Bismuth monotherapy showed a very low efficacy. Overall, the mean eradication rate with bismuth-based dual therapy was 68% (95% CI, 60–76%) (intention-to-treat analysis-ITT) and 73% (95% CI, 64–81%) (per protocol-PP). In case series, the overall percentages of children with successful eradication for triple therapy containing bismuth were 82% (95% CI, 76–88%) and 86% (95% CI, 80–92%) according to ITT and PP respectively. In comparative studies, H. pylori eradication rates ranged between 69% and 85% according to ITT and between 74% and 96% PP. Side effects included dark stools, urine discoloration, black tongue, burning tongue, and marked darkness of the gums.
Conclusions The evidence in favour of bismuth compounds for treating infected children is still not clear. Well-designed, randomised, multi-centre studies of H. pylori eradication trials in children comparing bismuth-based triple therapy with the best available recommended first-line therapies are needed. The evidence obtained from audited case series that produce an eradication rate of >95% on PP analysis should also be considered.
Introduction
Helicobacter pylori is the source of a highly prevalent, serious and chronic infection that has been associated causally with a diverse spectrum of gastrointestinal disorders including chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. In both developed and developing countries, H. pylori is most frequently acquired during childhood, and is associated with family size, clustering in families, low socioeconomic status and low level of education. In general, it is hypothesised that spontaneous eradication of H. pylori infection is extremely rare.
The combination of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole) has been the recommended first-line therapy since the first published guidelines for H. pylori infection in children. In recent years, the success of eradication therapies has declined, in part due to the development of H. pylori resistant strains. Several studies have documented high resistance rates to clarithromycin and metronidazole in paediatric and adult populations. In Europe, Koletzko et al. showed that primary resistance to clarithromycin and metronidazole was present in 20% and 23% of H. pylori strains respectively, while secondary resistance in 42% and 35% of the strains recovered after at least one failed treatment for H. pylori. The use of clarithromycin for other indications, mainly for respiratory tract infections, seemed to be the major risk factor for development of primary resistance to this drug. On the other hand, the only risk factor for primary metronidazole resistance was the immigration from a non-European country. In fact, the authors showed that children born in Asia, Africa or the Middle East had a 2.4 times higher risk for primary metronidazole resistance than patients of the same age and gender born in Europe. Iterative metronidazole treatments for parasitic or diarrhoeal diseases in children originating from Africa and Asia may be incriminated in the increased primary resistance rates of metronidazole recorded in these paediatric populations. A prospective US multicentre study in adults and children also documented similar high clarithromycin resistance rates.
Declining eradication rates with standard triple regimens have led to the development of alternate treatment options. Recently, ESPGHAN and NASPGHAN jointly renewed clinical guidelines for H. pylori infection in children using a standardised evidence based approach. Bismuth-based triple therapy or sequential therapy was recommended as alternate first-line regimens. Quadruple therapy with PPI, metronidazole, amoxicillin, and bismuth was also suggested as second-line therapy or salvage therapy in the absence of primary culture and sensitivity testing.
In this article, we comprehensively review, from a paediatric point of view, the literature on the clinical, pharmacologic, and microbiologic properties of bismuth salts. We also summarise the therapeutic efficacy of bismuth-based triple and quadruple therapy for eradication of H. pylori on the basis of evidence from case studies, and comparative (randomised and nonrandomised) studies.