Management of H. pylori Resistance

Transcription

1 Management of H. pylori Resistance Manfred Kist, Erik Glocker, Nicole Wüppenhorst, Beate Hobmaier National Reference Centre for Helicobacter pylori Institute of Medical Microbiology and Hygiene Freiburg, Germany

2 Management of disease Identify and estimate impact of the issue Analyse the problem Identify and estimate impact of specific risk factors associated with the problem Plan and launch appropriate intervention steps

3 Identify and estimate impact of the issue

4 Impact of Helicobacter pylori infection and associated diseases Up to 20 Mio individuals are infected in Germany About 20-30% suffer from complications (Peptic ulcer disease > gastric cancer > MALT lymphoma) About 50,000 of those individuals per month visit their doctor for diagnosis and treatment About 40,000 of those are diagnosed and treated for the first time and can be treated empirically according to the local primary resistance pattern About 10,000 visit their doctor after the first or repeated treatment failures For those patients the individual resistance pattern of H. pylori is of particular interest

5 Because like in other bacterial infections resistance to the antimicrobial drug in use jeopardizes therapeutic success

6 Dore MP, Leandro G, Realdi G, Sepulveda AR, Graham DY (2000) Effect of pretreatment antibiotic resistance to metronidazole and clarithromycin on outcome of Helicobacter pylori therapy: a meta-analytical approach. Dig Dis Sci 45: Metaanalysis Metronidazole 3594 pts; 2334 Mtz R; 1160 Mtz S Loss of therapeutical success rate: 37,7 % (29,6 45,7) P < 0,001 Clarithromycin 501 pts; 468 Cla S; 33 Cla R Loss of therapeutical success rate : 55 % (33 78) In conclusion, metronidazole and clarithromycin pretreatment resistant H. pylori are the main factors responsible for treatmant failure. If H.pylori antibiotic resistance continues to increase, pretherapy antibiotic sensitivity testing might become necessary in many regions

7 Analyse the problem

8 Development of Resistance in Campylobacter in Helicobacter animals Antibiosis Antibiosis environment Development of antimicrobial resistance in H. pylori is mostly and nearly exclusively an individual issue

9 That means Because the primary resistance of H. pylori in the infected population is not expected to be prone to a relevant impact of exogenous factors Development of resistance must be controlled by an appropriate clinical management of the individual patient

10 Identify and estimate impact of specific risk factors associated with the problem

11 ResiNet Sentinel Network of Microbiological Centres for Surveillance of H. pylori Resistance Prevalence of Resistance Trends Risk Factors NRZ Candidates Active since 08/2001 Situation December 2006

12 RKI Berlin ResiNet Meetings of Study Centres BMG NRC for Helicobacter Freiburg Project Board ResiNet - RKI / BMG - Scientific societies (DGVS / DGHM / BÄMI) - WEBSITE 16 Microbiological Study Centres - Plenary Meetings open for Gastroenterologists and Microbiologists Gastroenterological Sentinel Practises ResiNet Structure

13 What is Special about ResiNet Data are collected systematically and prospectively Study weeks : assigned gastroenterologists enrol patients consecutively during defined weeks All patients willing to participate and having a positive rapid urease test (60 min) in a gastric biopsy are included in the study No further selection for patients e. g. for treatment failures clinical and epidemiological data are collected prospectively Methods are standardized and quality-controlled All study centres use identical culture media lots during identical study weeks All study centres use identical standardised operating procedures provided by the NRC All study centres use identical Quality Control Strains Study data are not comparable with data raised from routine diagnostic laboratories

14 Representative resistance data can not be raised from routine laboratory investigations 80,00% 60,00% 40,00% 20,00% 39,40% 21,76% 15,30% 3,41% 15,53% 64,17% 60,92% (N=274) 37,26% 10,74% 16,92% 0,00% Isolates from Study (n=850) Isolates from Routine (n=2532) MZ CLA MZ/CLA MZ/CLA/CIP CIP

15 Resistance Patterns are Different in Isolates from Different Gender 50,00% 40,00% n.s. * * ** *** **** p < 0,000 p = 0,001 p = 0,002 p = 0,018 30,00% 20,00% ** * 10,00% 0,00% *** **** ** *** **** <= 30 yrs. > 30 yrs female male MZ CLA MZ/CLA MZ/CLA/CIP CIP

16 Repeated Empirical Treatment Renders Strains Resistant 100,00% 80,00% 60,00% 40,00% 20,00% 0,00% * * ** *** **** ***** ** p < 0,001 p < 0,001 p < 0,001 p < 0,001 p < 0,05 ***** **** *** * ** **** *** not pre-treated pre-treated once repeatedly pretreated pts * ** *** ***** **** MZ CLA MZ/CLA MZ/CLA/CIP CIP

17 Pre-treatment regimes including metronidazole are significantly associated with resistance 100,00% 80,00% 60,00% * ** *** **** ***** p < 0,001 p < 0,001 p < 0,001 p < 0,001 p < 0,003 ** ** ** *** 40,00% 20,00% * * *** **** ***** **** ***** 0,00% all pre-treated pts (n=149) Pre-treatment w/o MZ (n=61) Pre-treatment with MZ (n=88) MZ CLA MZ/CLA MZ/CLA/CIP CIP

18 Summary of ResiNet data representative resistance data, due to the selection bias, can not be raised from routine laboratory investigations systematic and prospective collection of data is essential for resistance surveillance studies primary resistance is lower in male individuals empirical treatment renders strains resistant, already after the first treatment failure

19 Plan and launch appropriate intervention steps

20 What is proposed by the International Maastricht Consensus 2005? (Gut published online 17 Jan 2007) PPI-clarithromycin-amoxicillin or metronidazole remains first choice in populations with less than 15-20% clarithromycin resistance, otherwise test for sensitivity before use PPI-clarithromycin-metronidazole remains first choice in populations with less than 40% metronidazole resistance, otherwise do not use Second choice (after treatment failure): Bismuth based quadruple therapies Rescue treatment (3 rd choice) based on antimicrobial susceptibility testing

21 The treatment regime proposed by the International Maastricht Consensus 2005, which recommends sensitivity testing not before the second treatment failure is not endorsed by our ResiNet data! ResiNet clearly shows that already after the first treatment failure resistant isolates exceed 40%, which in accordance to the Maastricht Consensus would clearly require treatment based on sensitivity testing already at this early time point!

22 To conclude: Primary resistance in Hp-isolates is moderate in Germany. This allows empirical treatment in patients which have not been treated before, and applies for about 80% of all Hp infected patients seeing their doctors. Resistance to clarithromycin and metronidazole with proportions exceeding 50% are definitely associated with the first treatment failure According to these results, culture, sensitivity testing, and sensitivity based treatment are in contrast to Maastricht 2005 obviously indicated after the first treatment failure

23 This essential amendment should be recognized in the upcoming German National S3 Guideline on Management of H. pylori infection and peptic ulcer disease which is actually in preparation