Guidelines for Treatment of Helicobacter Pylori (Printer-friendly)

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.01.2012 Guidelines for Treatment of Helicobacter Plori (printer-friendl)

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Abstract and Introduction

Abstract

Infection with Helicobacter ploriremains a major healthcare burden, with persistently high prevalence rates,

especially in less-developed countries. H. ploriinfection is causally related to non-malignant and malignant

gastroduodenal diseases, such as peptic ulcer diseases, gastric cancer and gastric mucosa-associated lymphoid

tissue lymphoma. Current international guidelines recommend a standard triple therapy as first-line therapy, including

a proton pump inhibitor and a combination of amoxicillin and clarithromycin. Standard triple therapy has shown a

decreasing efficacy over the years. The main reason is the increasing antibiotic resistance, particular to

clarithromycin ofH. ploristrains. Several new treatment options or modifications of already established regimens

have been introduced to overcome treatment failure. In this article, we intend to report the reasons for treatment

failure, and furthermore we give an overview of new treatment options as alternatives to the current treatment

regimens. Finally, the strategy for the future is considered.

Introduction

Treatment ofHelicobacter ploriinfection has become a challenge in recent years. The reasons for this are

numerous, but the increasing antibiotic resistance to H. ploriis the single most important factor. Various

mechanisms and causes besides H. ploriresistance can explain the loss of efficacy of the proton pump inhibitor

(PPI) triple regimen. These include the duration of therapy, rapid metabolization of PPI because of (CYP)2C19

polymorphisms with insufficient control of gastric pH and a consequent reduction in the antibiotic efficacy. This is of

high importance in clinical practice, because, for example Asian individuals have a higher proportion of poor

metabolizers as compared with the rest of the population(20 vs 5%). [1] Further aspects that negatively affecttreatment success are an increase in BMI and smoking.[2,3]

However, the most important reason for treatment failure remains the dramatic increase of antibiotic resistance. The

primary concern is clarithromycin resistance, which shows a good correlation between bacterial resistance to

clarithromycin and eradication failure. The critical bar for clarithromycin resistance is 1520%, at which clarithromycin

loses its efficacy as the most potent individual antibiotic in first-line treatment regimen. The prevalence ofH. plori

resistance to clarithromycin in different countries ranges from 2 up to more than 20%.[4] The variations in

clarithromycin resistance in various regions of the world are summarized in Table 1. Thus, triple therapy containing

clarithromycin without prior susceptibility testing should be abandoned when the clarithromycin resistance rate is ove

1520% in the specific region (Table 1).[5]

Gideline fo Teamen ofHelicobacter ploriin heEa and WeMichael Selgrad; Jan Bornschein; Peter Malfertheiner

Posted: 01/01/2012; Expert Rev Anti Infect Ther. 2011;9(8):581-588. 2011 Expert Reviews Ltd.

Table 1. Overview of primar clarithromcin resistances around the world.

Countr Patients (n) Year of stud Resistance rates (%) Ref.

Germany 271 19961997 3.3 [54]

Sweden 333 19982001 1.5 [55]

Italy 255 20042006 16.9 [56]

Bulgaria 828 19962004 18.4 [57]


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Poland 130 20012004 15 [58]

UK 1310 20002005 8.312.7 [59]

USA 106 20002001 12.2 [35]

Chile 50 2007 20 [60]

USA 348 19931996 12.6 [61]

China 157 2006 18.5 [62]

Japan 1257 20022005 27.7 [63]

India 67 20002001 0 [64]

Malaysia 120 20052007 3.3 [65]

South Korea 65 20032005 13.8 [66]

Taiwan 180 2009 10.6 [67]

Ethiopia 50 2004 0 [68]

China 374 20002009 37.2 [69]

Year of publication.



Germany 271 19961997 3.3 [54]

Sweden 333 19982001 1.5 [55]

Italy 255 20042006 16.9 [56]

Bulgaria 828 19962004 18.4 [57]

Poland 130 20012004 15 [58]

UK 1310 20002005 8.312.7 [59]

USA 106 20002001 12.2 [35]

Chile 50 2007 20 [60]

USA 348 19931996 12.6 [61]

China 157 2006 18.5 [62]

Japan 1257 20022005 27.7 [63]

India 67 20002001 0 [64]

Malaysia 120 20052007 3.3 [65]

South Korea 65 20032005 13.8 [66]

Taiwan 180 2009 10.6 [67]

Ethiopia 50 2004 0 [68]

China 374 20002009 37.2 [69]


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Metronidazole resistance has remained constant over the years, but also shows regional differences, with a much

higher prevalence in developing countries. It has been reported that metronidazole resistance shows a wide range

from 8 up to 80%, but this does not seem to impact on treatment results. [6,7]

Amoxicillin, rifampicin and tetracycline remain virtually unaffected by resistance problems.[8,9] However, there have

been reports showing a considerable increase in tetracycline resistance. [10] These findings underline the importanceof local measurements and monitoring of antibiotic resistance rates to adapt treatment regimens on local

requirements and resistance rates. In general, adopted treatment regimens should have been proven to have an

efficacy of more than 90% eradication success in the specific region.

The current challenge in H. ploritreatment is therefore, as mentioned previously, to overcome clarithromycin

resistance. Various methods have been proposed to solve this challenge: extension of the duration of PPI

clarithromycin-based triple therapies; sequential therapy; quadruple therapies; and levofloxacin as a substitute to

clarithromycin in PPI triple therapies.

Standard PPI Triple Therapies & Etension of the Length of PPI-based Triple Therapies

Extended 14-day triple therapy has been proposed to overcome the decreasing eradication rates that are achieved

with 7-day triple therapy. However, the increased length of therapy only results in a modest or insignificant rate of

treatment success. With the exception of some studies from the USA, the 14-day regimen only confers a limited

advantage. A recent meta-analysis including 21 studies from all over the world compared 7- and 14-day treatments.

This meta-analysis yielded relative risks (RRs) for eradication of 1.05 (95% CI: 1.011.10) for 7-day compared with

10-day triple therapy and 1.07 (95% CI: 1.021.12) for 7-day compared with 14-day therapy. The eradication rates

were 73 and 78%, respectively. Comparing 7-day and 10-day therapy, the eradication rates were 77 and 81%,

respectively. Taken together, the extension of the PPI-clarithromycin based triple therapy to 14 days slightly improves

the eradication success and can be considered in specific clinical situations. [11] Finally, a recent meta-analysis

including 26 studies was presented at the Digestive Disease Week 2010. This study has yielded very similar results,

with a RR of 0.79 (95% CI: 0.710.89; p < 0.0001) for 14-day therapy with an improvement of eradication rates of

approximately 6%. A similar benefit was seen with 10 days of treatment compared with 7 days (RR: 0.84; 95% CI:

0.730.96; p = 0.01). The improvement of cure rates for 10 days of triple therapy was 4%. [12]

The extension of length of therapy may not be cost effective and concerns need to be raised about decreased

compliance and the possibility of more side effects.[11,13,14] However, none of the meta-analyses found significant

differences regarding the rate of side effects with the different durations.

Sequential & Concomitant Therap

The sequential therapy originally introduced and extensively studied in Italy has constantly demonstrated highereradication rates than the conventional triple therapy. Sequential treatment is a new quadruple therapy, consisting of

10-day treatment in which a PPI plus amoxicillin is given for 5 days followed by a PPI plus clarithromycin and a

nitroimidazole (metronidazole or tinidazole) for another 5 days. Interestingly, this approach of the sequential therapy

may even work in areas of high clarithromycin resistance. Within the first 5 days of therapy, clarithromycin-resistant

strains get eradicated by PPIamoxicillin therapy, and in the remaining 5 days the remnant strains are eliminated by

the triple therapy. The sequential therapy has now been evaluated in various randomized trials and therapeutic

success was confirmed overall with respect to the standard triple therapy. [15] This regimen provides high eradication

rates (>90%) in various countries and continents around the world, although not always in controlled trials. [16]

However, it must be noted that it may not work in all geographic areas as a recent, not fully published trial from Korea

found no superiority of the sequential therapy compared with standard triple therapies. This may be related to higher



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rates of dual resistance in this area. Furthermore, previous studies demonstrated significantly lower eradication rates

with the metronidazole-based regimen compared with the tinidazole-based regimen.[17]

Recently, the 10-day sequential therapy has shown eradication rates of approximately 80% in areas with a high

prevalence of clarithromycin resistant strains.[18] A recent study from Thailand showed similar results.[19]

Interestingly, the increase of therapy duration from 10 to 14 days does not seem to improve the eradication rates. [20]

To date, the sequential therapy is a promising therapeutic approach, but for a general recommendation of sequential

therapy or its quadruple variation as a first-line treatment, studies from multicenter, multiregion randomized trials are

needed.

A simplification of the sequential therapy represents the so-called concomitant therapy. Concomitant therapy is a

quadruple regimen that contains all four compounds of the sequential regimen and all medications are given together.

Interestingly, this therapy regimen was equal to sequential therapy in one study. [21] Several studies in various

countries have proven its efficacy with eradication rates above 90%. [20,22] With application of this regimen the

treatment could even be shortened to 5 days.[23]

Quadruple Therap

The original quadruple therapy based on omeprazole, bismuth subcitrate, metronidazole and tetracycline has beenproven to be superior to standard triple therapy.[24,25] Bismuth-containing quadruple therapy should be considered as

the best first-line empirical treatment in areas of high clarithromycin resistance.[5]

The efficacy of the quadruple therapy as first-line therapy has been proven very recently in a randomized, open-label,

noninferiority, Phase III trial. In this study, 10 days of treatment with omeprazole plus a single three-in-one capsule

containing bismuth subcitrate potassium, metronidazole and tetracycline (quadruple therapy) has been compared

with 7 days of omeprazole, amoxicillin and clarithromycin (standard therapy). The quadruple therapy yielded higher

eradication rates compared with standard triple therapy.[26] Eradication rates were 80% in the quadruple therapy

group versus 55% in the standard therapy group. Interestingly, the study further demonstrated that the efficacy of the

quadruple therapy does not seem to be affected by either metronidazole or clarithromycin resistance. Importantly, the

safety and tolerability of the quadruple therapy was similar to standard therapy. Thus, it has to be concluded thatquadruple therapy should be considered as the first-line therapy in areas with a high prevalence of clarithromycin-

resistant H. ploristrains.

It should be noted that the galenic formulation of three drugs with antibacterial activity provides more consistent

results[2426] than the loose combination of these drugs used in several other studies. [27] A new quadruple regimen

adding bismuth potassium citrate to the standard triple therapy, including PPI, clarithromycin and amoxicillin, has

been introduced by a Chinese study. This therapy seemed to be more efficient than PPI triple therapy, and combined

with the addition of bismuth and prolongation of the treatment from 7 to 14 days allowed it to overcome clarithromycin

resistance in 84% of the patients.[28]

An important indication for the bismuth-containing quadruple therapy is its use as an empirical second-line therapyafter failure of PPI, clarithromycin-based triple therapy. Several studies have proven the efficacy of quadruple therapy

as second-line and/or salvage therapy, with eradication rates constantly higher than 80%.[29,30] The main problem of

the quadruple regimen is the administration of four drugs in a complex scheme and possibly decreased compliance.

Furthermore, bismuth salts are not available in some countries, such as Japan, Australia and some European

countries. The reason for this is the claim of side effects associated with the medication. But these adverse events do

not occur commonly and it can be stated that bismuth for the treatment ofH. ploriis safe and well tolerated.[5]

Quinolones (Levofloacin/Moifloacin) as a Substitute for Clarithromcin in PPI Triple

Therapies


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The increasing prevalence of clarithromycin resistance as mentioned previously has prompted authors to incorporate

levofloxacin in triple therapy. The efficacy of levofloxacin-based triple therapy has been proven in a meta-analysis

comparing this regimen with quadruple therapy as salvage therapy. The overall eradication rate with the levofloxacin

regimen was 81 versus 70% with the quadruple combination (odds ratio: 1.80; 95% CI: 0.943.46). This meta-

analysis also revealed fewer side effects and adverse events using levofloxacin-based triple therapy. In a recent

crossover study, levofloxacin-based and clarithromycin-based triple therapies were compared as first- and second-line

treatments forH. ploriinfection. Clarithromycin-based triple therapy (PPI-AC) achieved a higher eradication rate than

levofloxacin-based triple therapy (PPI-AL) as the first-line treatment (87.4% PPI-AC vs 80.1% PPI-AL). However, in

patients who experienced failure with the standard triple as first-line therapy, PPI-AL was superior as the second-linetherapy when compared with PPI-AC as second-line therapy. [31]

This study underlined the importance that the antibiotics that are currently used as rescue medications (i.e.,

levofloxacin) cannot randomly be replaced and selected as first-line treatment. After the failure of recommended first-

line therapies, PPI-AL can be recommended. However, rising rates of levofloxacin resistance should be taken into

account and it has to be noted that quinolone resistance is often associated with resistances to metronidazole and

clarithromycin.

Another opportunity for the application of levofloxacin in the eradication therapy has been demonstrated by a recent

study from Romano and colleagues.[18] In their trial, levofloxacin was applied as a substitute for clarithromycin in the

known sequential therapy regimen. A total of 375 therapy-naive patients were included in the study and randomizedto either 'classical' sequential therapy or sequential regimen containing levofloxacin instead of clarithromycin. The

eradication rates were 96.0% (95% CI: 90.998.7%) with levofloxacin 250 mg twice-daily sequential therapy, 96.8%

(95% CI: 92.099.1%) with levofloxacin 500 mg twice-daily sequential therapy, compared with 80.8% (95% CI: 72.8

87.3%) with clarithromycin sequential therapy in the intention-to-treat analysis. The authors suggested that

levofloxacin-containing sequential therapy is a therapy option as a first-line regimen in areas with clarithromycin

resistance rates of more than 15%. But it must be noted that in this study, a low levofloxacin resistance rate of 3.7%

was observed and many countries all over the world have levofloxacin resistance rates of approximately 15% or

higher. Thus, the eradication rates observed in the study by Romano et al. seem to be difficult to replicate in areas

with a high levofloxacin resistance rate.[32,33]

More recently, data is accumulating on the efficacy and tolerability of moxifloxacin-based regimens in the use ofH.

plorieradication therapy. Nista and colleagues demonstrated eradication rates of up to 92% in the moxifloxacin-

based triple regimens compared with a maximum effect of 79% in the clarithromycin-based regimens. [34] However,

the first clinical trials evaluating the efficacy of moxifloacin were performed approximately 10 years ago, when

resistance rates were reported to be approximately 6% in the general population. A recent study from Korea has

reported a steady increase from 5.6% in 2004 up to 28.2% in 2008, with the need to optimize dosage and duration of

treatment.[35] Treatment for 10 days should be preferred over a 7-day course, and there is evidence that a dose of 800

mg per day is superior to the 400 mg standard dose. [36,37] Today, moxifloxacin-based triple therapy takes its role as

an efficient and well-tolerable second-line treatment, especially when compared with bismuth-containing quadruple

therapy.[38,39]

After the failure of second-line therapies, rescue therapy should be guided by antimicrobial resistance testing

whenever possible, as recommended in the current European guidelines. [5]

Epert Commentar

H. ploriinfection remains one of the most challenging infectious diseases of the world causing high morbidity and

mortality. The prevalence of the infection varies greatly between developing and industrialized countries, as well as

between different geographic locations.[4042] Over the past years several guidelines have formulated

recommendations for treatment indications and different treatment regimens for various clinical scenarios caused by

H. plori.[5,4348] The indications for the initiation ofH. plorieradication therapy do not vary a lot in different


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guidelines and are summarized according to the Maastricht III consensus report in Table 2.

The problem that we are currently facing is that successful eradication using a standard triple regimen recommendedas the first-line regimen is often not achieved. The reason for the different eradication success rates in different areas

of the world can be attributed mainly to H. ploriresistance, which shows great variety even within individual

societies. H. ploriresistance is considered to be the most important factor for treatment failure.

Over the last decade, H. plorieradication rates have declined consistently and even with the recommended

regimens, H. ploritreatment failure is often seen in approximately 20% or more of patients, which is not an

acceptable rate.[4,49] The current standard triple therapy as recommended forH. plorieradication by different clinical

societies and their guidelines based on a PPI combined with clarithromycin and amoxicillin and/or metronidazole

continues to be the first-line option around the globe (Table 3), but faces increasing rates of failure.[5,4348]

Table 2. Recommendations for Helicobacter plorieradication according to the results of the

Maastricht III consensus conference.

Recommendation forHelicobacter plorieradicationLevel of

evidence

Grade of

recommendation

Duodenal/gastric ulcer (active or not, including complicated peptic ulcer

disease)1a A

MALToma 1c A

Atrophic gastritis 2a B

After gastric cancer resection 3b B

First-degree relatives of patients with gastric cancer 3b B

Appropriate in case of investigated nonulcer dyspepsia 1a A

Helicobacter ploritest and treat in case of uninvestigated dyspepsia (except

for regions with low H. ploriprevalence)1a A

Valuable option in chronic NSAID users but insufficient to prevent NSAID-

related ulcer disease completely1b A

H. ploritest and treat in case of unexplained iron deficiency anemia n.m. n.m.

H. ploritest and treat in case of idiopathic thrombocytopenic purpura n.m. n.m.

MALToma: Mucosa-associated lymphoid tissue lymphoma; n.m.: Not mentioned.

Recommendations taken from [10].

Table 3. Standard Helicobacter plorieradication therapies and alternative treatment regimens asrecommended b different clinical societies and their guidelines.

Stud (ear) RegionFirst-line

regimen

Duration

of

treatment

(das)

Special aspectsAlternative first-line

regimenRef.

PPI (standard

dose b.i.d.)

ClarithromycinIn populations with

less than 1520%


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Malfertheiner

e al. (2007)

Europe

(Maastricht

III)

(500 mg

b.i.d.)

Amoxicillin

(1000 mg

b.i.d.) or

metronidazole

(400 mg

b.i.d.)

714

clarithromycin

resistance.

Amoxicillin can be

replaced by

metronidazole if less

than 40% resistance

Bismuth-containing quadruple

therapy (PPI, bismuth,

tetracycline, metronidazole;

1014 days)

[5]

Fock e al.

(2009)

Asia-

Pacific

region

PPI (standarddose b.i.d.)

Clarithromycin

(500 mg

b.i.d.)

Amoxicillin

(1000 mg

b.i.d.) or

metronidazole

(400 mg

b.i.d.)

7

Depending on

regional resistance

levels, either

clarithromycin or

amoxicillin can be

replaced by

metronidazole



tetracycline, metronidazole)

[48]

Chey e al.

(2007)USA

PPI (standard

dose b.i.d.)

Clarithromycin

(500 mg

b.i.d.)

Amoxicillin

(1000 mg

b.i.d.) or

metronidazole

(500 mg

b.i.d.)

1014

Replacement of

amoxicillin by

metronidazole with

respect to local

resistance rates and

individual allergic

predisposition




1014 days)

[46]

Bourke/Jones

e al. (2005)Canada

PPI

Clarithromycin

Amoxicillin

14

In populations with

less than 1520%

clarithromycin

resistance.

Amoxicillin can be

replaced by

metronidazole if less

than 40% resistance




1014 days)

[44]

Asaka e al.

(2010) Japan

PPI (standard

dose b.i.d.)

Clarithromycin

(200400 mg

b.i.d.)

Amoxicillin

(750 mg

b.i.d.)

7

Metronidazole-

containing triple

therapy is not

recommended as

first-line treatment

Sequential therapy is

discussed as option of choice

(days 15: PPI + amoxicillin;

day 610: PPI +

clarithromycin + 5-

nitroimidazole)

[43]

PPI (standard

dose b.i.d.)


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Five-ear View

The challenge for future therapeutic options remains to facilitate the compliance of drug intake and to overcome

antibiotic resistance. The frequent use of antibiotics and their frequent overuse has lead to a steadily increasing rate

of antimicrobial resistance. The best strategy to face antimicrobial resistance is to use a proven antibiotic regimen

with the right dosage and treatment duration. Antibiotic resistance-based selection of therapy should be used in

areas known to already have a prevalence of strains resistant to currently used antibiotics. Although standard triple

therapy does not significantly benefit from the prolongation of treatment duration, prolonged therapy beyond 7 days is

crucial for the efficacy of quadruple therapy and of all rescue therapies. In the case ofH. plori, overcoming

clarithromycin-resistance is the main challenge. Clarithromycin-resistance varies throughout the world, and the

highest rates are found in Southern Europe, Southern America, some parts of the USA, Japan and China (Table 1).

Therefore, the development of new molecular tests that allow the easy detection and monitoring of the antibiotic

resistance in various geographical areas will become essential for a timely change in the first-line treatment choices

and local adaptation of treatment regimens in the various regions.[50]

Fischbach et

al. (2009)Germany

Clarithromycin

(500 mg

b.i.d.)

Amoxicillin

(1000 mg

b.i.d.) or

metronidazole

(400 mg

b.i.d.)

(at least)

7

Metronidazole should

be preferred over

amoxicillin if

resistance rates are

less than 40% for the

reason of better

tolerability and

efficacy



tetracycline, metronidazole)

or sequential therapy (days

15: PPI + amoxicillin; days

610: PPI + clarithromycin +

imidazole-derivative)

[47]

b.i.d.: Twice daily; PPI: Proton pump inhibitor.



Germany 271 19961997 3.3 [54]

Sweden 333 19982001 1.5 [55]

Italy 255 20042006 16.9 [56]

Bulgaria 828 19962004 18.4 [57]

Poland 130 20012004 15 [58]

UK 1310 20002005 8.312.7 [59]

USA 106 20002001 12.2 [35]

Chile 50 2007 20 [60]

USA 348 19931996 12.6 [61]

China 157 2006 18.5 [62]

Japan 1257 20022005 27.7 [63]

India 67 20002001 0 [64]

Malaysia 120 20052007 3.3 [65]

South Korea 65 20032005 13.8 [66]


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A safe and effective vaccine against H. plorifor a prophylactic or even therapeutic use is badly needed. A vaccine forprimary prevention would solve most of the current problems. Despite the large body of evidence in the animal setting

that vaccination against H. ploriis achievable, so far very few clinical studies have been carried out. Clinical studies

have failed to succeed for different reasons. Most of the protective H. plori-derived antigens have already been

administered to humans and have proven their safety and immunogenicity. [5153] This suggests that H. plori

vaccination is feasible and Phase II and III trials with candidate vaccines are eagerly awaited.

Sidebar

Ke Issues

Helicobacter ploriprevalence shows a wide range, with rates of 80% in developing countries.The infection with H. ploricauses high morbidity and mortality worldwide.

Current treatment regimens show decreasing eradication rates.

The main reason for failure of eradication is H. ploriresistant strains.

New treatment options include: extension of the length of proton pump inhibitor-based triple therapies,

sequential therapy, quadruple therapy, levofloxacin-based triple or quadruple therapy.

The challenge and goal for the future is the development of a safe and effective vaccine.

Taiwan 180 2009 10.6 [67]

Ethiopia 50 2004 0 [68]

China 374 20002009 37.2 [69]


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This study aimed to asses the efficacy of a levofloxacin-based regimen as the first-line treatment and a

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Financial & compe ing inee dicloe

Peter Malfertheiner has af f iliations w ith Aptalis, Novartis Vaccine and Nycomed. The authors have no other relevant affiliations or f inancial

involvement w ith any organization or entity w ith a financial interest in or f inancial conf lict w ith the subject matter or materials discussed in

the manuscript apart from those disclosed.No w riting assistance w as utilized in the production of this manuscr ipt.

Expert Rev Anti Infec t Ther. 2011;9(8):581-588. 2011 Expert Review s Ltd.

Papers of special note have been highlighted as:

of interest

of considerable interest

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