Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobater pylori

Review article: non-bismuth quadruple (concomitant) therapyfor eradication of Helicobater pyloriJ. P. Gisbert* & X. Calvet�

*Department of Gastroenterology,Hospital Universitario de La Princesa,Instituto de Investigacion SanitariaPrincesa (IP), and Centro de Investi-gacion Biomedica en Red de Enfer-medades Hepaticas y Digestivas(CIBEREHD), Madrid, Spain.�Department of Gastroenterology,Hospital de Sabadell, Departament deMedicina, Universitat Autonoma deBarcelona and Centro de InvestigacionBiomedica en Red de EnfermedadesHepaticas y Digestivas (CIBEREHD),Barcelona, Spain.

Correspondence to:Prof. J. P. Gisbert, Playa de Mojacar29. Urb. Bonanza, 28669 Boadilla delMonte, Madrid, Spain.E-mail: [email protected]

Publication dataSubmitted 26 April 2011First decision 22 May 2011Resubmitted 24 June 2011Accepted 26 June 2011

This uncommissioned review article wassubject to full peer-review.

SUMMARY

BackgroundTraditional standard triple therapy for Helicobacter pylori infection (PPI-clarithromycin-amoxicillin) can easily be converted to non-bismuth quadru-ple (concomitant) therapy by the addition of a nitroimidazole twice daily.

AimTo critically review evidence on the role of non-bismuth quadruple therapy(PPI-clarithromycin-amoxicillin-nitroimidazole) in the treatment ofH. pylori infection.

MethodsBibliographical searches were performed in MEDLINE and relevant congresses.

ResultsThe first randomised comparison of the non-bismuth quadruple therapyand the sequential (PPI-amoxicillin 5 days plus PPI-clarithromycin-nitroim-idazole 5 days) regimens recently concluded that both were similar in termsof efficacy and safety and that the sequential administration protocol maybe unnecessarily complex. Several randomised controlled trials (and onemeta-analysis) have demonstrated that non-bismuth quadruple therapy ismore effective than and is equally well tolerated as standard triple therapy.A meta-analysis of 15 studies (1723 patients) revealed a mean H. pyloricure rate (intention-to-treat) of 90% for non-bismuth quadruple therapy. Atendency towards better results with longer treatments (7–10 days vs. 3–5 days) has been observed, so it seems reasonable to recommend the lengthof treatment by achieving maximal cure rates (10 days). Clarithromycinresistance may reduce the efficacy of non-bismuth quadruple therapy,although the decrease in eradication rates seems to be far lower than instandard triple therapy. Experience with the non-bismuth quadruple ther-apy in patients with metronidazole-resistant strains is still very limited.

ConclusionsNon-bismuth quadruple (concomitant) therapy appears to be an effective,safe, and well-tolerated alternative to triple therapy and is less complexthan sequential therapy. Therefore, this regimen appears well suited for usein settings where the efficacy of triple therapy is unacceptably low.

Aliment Pharmacol Ther

ª 2011 Blackwell Publishing Ltd 1

doi:10.1111/j.1365-2036.2011.04770.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONHelicobacter pylori infects approximately 50% of theadult population and is associated with a wide range ofupper gastrointestinal diseases including gastritis, pepticulcer disease and gastric cancer.1 The most widely rec-ommended treatment in international guidelines for theeradication of H. pylori is the so called standard, or pro-ton pump inhibitor–based (PPI), triple therapy, whichcombines two antibiotics (clarithromycin plus amoxicillinor metronidazole) with a PPI for at least 7 days.2–6 How-ever, since the microorganism was discovered, the eradi-cation rate has fallen considerably with this regimen.7

Two recent double-blind, US multicentre studies founddisappointingly low eradication rates with standard ther-apy (77%)8, 9, and two meta-analyses including morethan 53 000 patients revealed the cure rate to be below80%.10, 11 Therefore, the ethics of continued use of stan-dard triple therapy has recently been questioned, andalternative approaches have been recommended.12

Attempts to increase the duration of triple therapy, thusprolonging exposure to antibiotics, have achieved contro-versial results, but have not generally resulted in remark-able benefits.13, 14 Consequently, new strategies toimprove first-line treatment are still urgently needed.

One recent innovation, postulated as an alternative tostandard triple therapy, is sequential treatment, whichinvolves a simple dual regimen including a PPI plus amoxi-cillin for the first 5 days followed by a triple regimenincluding a PPI, clarithromycin and tinidazole for the fol-lowing 5 days.15 Several randomised clinical trials (includ-ing pooled-data analyses and meta-analyses) havedemonstrated that a sequential regimen is more effectivethan standard triple therapy.16–20 Therefore, some guide-lines have proposed sequential therapy as an alternative tostandard triple therapy for the eradication of H. pylori.21

However, a recent update of previous meta-analyses per-formed by a Cochrane Collaboration group22 found thatthe results obtained with the sequential regimen wereclearly heterogeneous, and that eight recently publishedstudies were unable to demonstrate differences betweensequential and standard triple therapy. So, although theoverall mean eradication rate with a sequential regimen wasnearly 90%, a tendency towards lower efficacy with this reg-imen was observed in the more recent studies.23–26

Moreover, a relevant question is whether it is neces-sary to provide the drugs sequentially or if the four con-stituent components of sequential therapy can be givenconcurrently.27, 28 In other words, does sequentialadministration represent an advantage or does it maketherapy more complicated than necessary?12, 29 In this

regard, the triple combination of clarithromycin plusamoxicillin and a nitroimidazole with a PPI (but withoutbismuth) has previously been examined as a nonsequen-tial regimen, which proved efficacious. The concept of a‘‘non-bismuth quadruple regimen’’ or ‘‘concomitant’’ reg-imen (the term used hereafter) has recently resurfaced.Traditional standard triple therapy (PPI-clarithromycin-amoxicillin) can easily be converted to concomitanttherapy by the addition of 500 mg of metronidazole ortinidazole twice daily.30

The aim of the present article is to critically reviewevidence on the role of concomitant therapy in the treat-ment of H. pylori infection. We review the followingaspects: rationale for use, efficacy of the regimen and thevariables affecting it, comparison between the concomi-tant regimen and standard triple and sequential therapy,and, finally, limitations of the concomitant regimen.

SEARCH STRATEGYBibliographical searches were performed in MEDLINEup to May 2011 using the following keywords (all fields):(‘‘Helicobacter pylori’’ OR ‘‘H. pylori’’) AND [(concomi-tant OR concurrent OR quadruple OR (clarithromycinAND (amoxicillin OR amoxicillin) AND (metronidazoleOR tinidazole OR nitroimidazole)]. Articles published inany language were included. Reference lists from the tri-als selected in the electronic search were hand-searchedto identify further relevant trials. We also conducted amanual search of abstracts from the scientific meetingsof the International Workshop of the European Helico-bacter Study Group, the United European Gastroenterol-ogy Week and the American Digestive Disease Week.Abstracts of the articles selected in each of these multiplesearches were reviewed, and those meeting the inclusioncriteria were selected. References from reviews onH. pylori treatment with the concomitant regimen andfrom the works selected for the study were also examinedto identify articles meeting the inclusion criteria. In thecase of duplicate reports or studies obviously reportingresults from the same study population, only the latestpublished results were used.

RATIONALE ⁄HISTORICAL PERSPECTIVE OF THECONCOMITANT REGIMENIn 1998, two groups of investigators, one in Germanyand the other in Japan, proposed that a PPI, amoxicillin,clarithromycin and nitroimidazole be given concurrentlyas a nonsequential four-drug, three-antibiotic, non–bis-muth-containing quadruple regimen.31, 32 Despite theshort duration of therapy (5 days on average), this

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2 Aliment Pharmacol Ther

ª 2011 Blackwell Publishing Ltd

approach provided high cure rates (>90% by intention-to-treat).

The efficacy of a triple regimen (PPI, clarithromycin,and a nitroimidazole) was known to be inversely relatedto bacterial load, and higher eradication rates wereachieved in patients with a low bacterial density in thestomach.33–35 Therefore, the addition of amoxicillin low-ered bacterial load in the stomach, with the consequentimprovement in the efficacy of the short course of tripletherapy.36 In other words, concurrent administration ofthe three antibiotics as concomitant therapy proved moreefficacious than when they were administered separately.37

Proponents of sequential treatment (amoxicillin for5 days, followed up by clarithromycin plus a nitroimi-dazole for a further 5 days) argue that initial use ofamoxicillin could provide a key advantage in the eradica-tion of H. pylori 17, namely, prevention of the selectionof secondary clarithromycin resistance.38 Indeed, it isknown that bacteria can develop efflux channels for clar-ithromycin, which rapidly transfer the drug out of thebacterial cell, preventing the binding of the antibiotic tothe ribosome.39–41 It has been speculated that the disrup-tion of the cell wall caused by amoxicillin prevents thedevelopment of efflux channels by damaging the cell wallof the bacterium. In theory, this disruption could help toimprove the efficacy of clarithromycin in the secondphase of treatment.38, 42 However, the improved effectwith sequential (and concomitant) therapy – as com-pared with standard triple therapy – may not be due tosequential administration itself, but to the larger numberof antibiotics (three drugs) to which the organism isexposed or to the use of a nitroimidazole, which is notcontained in the standard triple-drug regimen.43, 44

EFFICACY OF THE CONCOMITANT REGIMEN FORERADICATION OF H. PYLORIStudies evaluating the efficacy of the concomitant regi-men are summarised in Table 1 and are representedgraphically in Figure 1.31, 32, 45–57 These studies wereperformed in different countries in Europe, Asia, andLatin America and most were randomised controlled tri-als. Similar concomitant regimens were prescribed, withonly minor modifications, namely, the PPI (omeprazole,lansoprazole, rabeprazole, or esomeprazole) and the nitro-imidazole (metronidazole or tinidazole). However, dura-tion of treatment varied markedly between 3 and10 days (see below). Our analysis of the 15 studies (1723patients) revealed a mean H. pylori cure rate (intention-to-treat) of 90% (95% confidence interval [95% CI] from86% to 93%) (Figure 2). The data were combined using

the generic inverse variance method, which involves aweighted average of the effect estimates from the individ-ual studies. The weight for each study is taken to be theinverse of the variance (one divided by the square of thestandard error) of the effect estimate. As results wereheterogeneous (P < 0.001; I2 = 81%), a random effectmodel (DerSimonian and Laird) was applied to performthe meta-analysis (using Review Manager 5.0.25, devel-oped by the Cochrane Collaboration).

From those studies, the one performed in Latin Amer-ica (including patients from Chile, Colombia, Costa Rica,Honduras, Mexico and Nicaragua) had markedly disap-pointing results, with a 74% eradication rate55; the ratesrecorded in the remaining studies were >80% and even>90%). In fact, if this study is excluded, the mean eradi-cation rate (intention-to-treat) of the remaining 14 stud-ies increases to 92%, and the inter-study heterogeneitycompletely disappears (I2 = 3%). The explanation for thisoutlier is unclear, as the study has not yet been publishedas a peer-reviewed article, and information on the antibi-otic susceptibility of H. pylori is not available in theabstract. Furthermore, even though the study lasted only5 days, other studies with the same period of administra-tion performed some years ago obtained excellent results(>90%) (see below for a more detailed discussion on theduration of treatment). We might speculate that 5-dayconcomitant regimens were effective enough a decadeago, but that increased antibiotic resistance rates haverevealed the need for longer regimens.

EFFECTS OF DIFFERENT VARIABLES ON THEEFFICACY OF CONCOMITANT THERAPYThe efficacy of the concomitant regimen on H. pylorieradication depends on several factors.

Clarithromycin resistanceResistance rates for antimicrobial agents rise with indis-criminate use, and clarithromycin resistance may be dueto the widespread use of this agent for upper respiratorytract infections.58, 59 Antimicrobial resistance is largelyresponsible for the poor eradication rates with standardtriple therapy.60–62 Culture and antimicrobial sensitivitytesting of H. pylori are not widely available and, whenthey are available, they may not produce any clear clini-cal benefit.30, 63–65 One meta-analysis reported an almost60% decline in eradication rates with standard tripletherapy if clarithromycin resistance was present.60, 66

Therefore, the use of standard triple therapy has beenrecommended only in those areas where clarithromycinresistance is lower than 15–20%.2

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Aliment Pharmacol Ther 3


Table1|S

tudies

evalua

tingtheeffic

acyof

aconcom

itant

regimen

forthetreatm

entof

Helicobacterpyloriinfection

Autho

rCou

ntry

Publication

year

Stud

yde

sign

Disease

type

The

rapy

regimen

Days*

No.

ofpa

tients

Erad

ication

rate

(%)(ITT)

Erad

ication

rate

(%)(PP)

Calvetet

al.45

Spain

2000

NC

PUD

O20

mgb.d.

+A

1gb.d.

+C

500mgb.d.

+T50

0mgb.d.

456

49

⁄56(87.5)

49

⁄54(90.7)

Catalanoet

al.46

Italy

2000

RCT

PUD

O40mgod

+A

1gb.d.

+C

500mgb.d.

+M

500mgb.d.

356

50⁄56(89.3)

50⁄54(92.6)

Chanet

al.47�

China

2001

NC

PUD,

NUD,o

thers

O20

mgb.d.

+A

20mg

⁄kg

t.d.s+C7.5mg

⁄kgt.d

.s+M

7.5mg

⁄kg5tim

esaday

733

31⁄33(94)

31⁄33(94)

Molina-Infante

etal.48

Spain

2011

NC

PUD,

NUD,o

thers

PPIb.d.

+A

1gb.d.

+C50

0mg

b.d.

+M

500mg

1081

70⁄81(86)

70⁄80(88)

Nagaharaet

al.49

Japan

2000

RCT

PUD,N

UD

R10

mgb.d.

+A

750mgb.d.

+C

200mgb.d.

+M

250mgb.d.

555

52⁄55(94.5)

52⁄53(98.1)

Nagaharaet

al.50

Japan

2001

RCT

PUD,N

UD

R20

mgb.d.

+A

750mgb.d.

+C20

0mgb.d.

+M

250mgb.d.

580

74⁄80(92.5)

74⁄79(93.7)

Nevilleet

al.51

UK

1999

RCT

PUD,

NUD,o

thers

L30

mgb.d.

+A

1gb.d.

+C

250mgb.d.

+M

400mgb.d.

556

49

⁄56(87.5)

49

⁄54(90.7)

Okada

etal.32

Japan

1998

RCT

PUD,

NUD,o

thers

O20

mgb.d.

+A

500mgt.d

.s+

R150mgb.d.

+M

250mgt.d

.s.

790

85⁄90(94.4)

85⁄88(96.6)

Okada

etal.52

Japan

1999

RCT

PUD,

NUD,o

thers

O20

mgb.d.

+A

500mgt.d

.s.+

R150mgb.d.

+M

250mgt.d

.s.

7169

155

⁄169

(92)

155

⁄163

(95)

Treibe

ret

al.31

Germany

1998

RCT

PUD,o

thers

O20

mgb.d.

+A

1gb.d.

+C

250mgb.d.

+M

400mgb.d.

546

42

⁄46(91.3)

42

⁄44(95.5)

Treibe

ret

al.(a)

53

Germany

2002

RCT

PUD,

NUD,o

thers

L30

mgb.d.

+A

1gb.d.

+C

250mgb.d.

+M

400mgb.d.

380

65⁄80(81.2)

65⁄76(85.5)

Treibe

ret

al.(b)

53

Germany

2002

RCT

PUD,

NUD,o

thers

L30

mgb.d.

+A

1gb.d.

+C

250mgb.d.

+M

400mgb.d.

583

74⁄83(89.2)

74⁄79(93.7)

Wuet

al.54

Taiwan

2010

RCT

PUD,

NUD,o

thers

E40mgb.d.

+A

1gb.d.

+C

500mgb.d.

+M

500mgb.d.

10115

107

⁄115

(93)

107

⁄115

(93)

Ferreccioet

al.55

Latin

America

2011

RCT

PUD,

NUD,o

thers

L30

mgb.d.

+A

1gb.d.

+C

500mgb.d.

+M

500mgb.d.

5488

359

⁄488

(73.6)

359

⁄456

(78.7)

Kon

gchayanu

net

al.(a)

56

Thailand

2011

RCT

NUD

R20

mgb.d.

+A

1gb.d.

+C1g

od+M

500mgt.d

.s.

550

45

⁄50(90)

45

⁄50(90)

Kon

gchayanu

net

al.(b)

56

Thailand

2011

RCT

NUD

R20

mgb.d.

+A

1gb.d.

+C1g

od+M

500mgt.d

.s.

1050

48

⁄50(96)

48

⁄50(96)




Clarithromycin resistance reduces the efficacy ofsequential therapy, although the decrease in eradicationrates was far lower than in triple therapy.15, 17–20, 43, 67

Therefore, the sequential treatment regimen may be pref-erable when the prevalence of clarithromycin-resistantH. pylori infection is high, which is the case in manydeveloped countries.43 Nevertheless, this suggestion mustbe interpreted with some caution, because the number ofclarithromycin-resistant strains effectively exposed tosequential therapy is relatively low (55 in only 4 studiesfrom which 41 ⁄ 55 [75%] were eradicated).15

This advantage of sequential therapy over standardtriple therapy (i.e. higher eradication rates amongpatients with clarithromycin resistance) also seems to beapplicable to concomitant therapy. An initial meta-analy-sis determined the effect of drug resistance on the effi-cacy of first-line treatment regimens for H. pylori andidentified the most efficacious treatments in the presenceof drug resistance; the results showed that resistance toclarithromycin or metronidazole may be overcome byusing quadruple therapies, especially those containingboth clarithromycin and metronidazole.62 The effect ofclarithromycin resistance on the efficacy of concomitantregimens was negligible, with 95% efficacy in the oneclarithromycin-sensitive arm, and 96% in the one clari-thromycin-resistant arm.62 Nevertheless, this conclusionwas based on only two studies.51, 52 In the study by Ok-ada et al.52, H. pylori was eradicated in 15 out of 16(94%) patients with roxithromycin-resistant strains andin 140 out of 147 (95%) patients with roxithromycin-sensitive strains. More recently, Wu et al.54 found no sig-nificant effect of antibiotic resistance on the efficacy ofconcomitant therapy: H. pylori was eradicated in three offour (75%) clarithromycin-resistant patients.

Although the reasons why the sequential regimen ismore effective for resistant strains need to be clarified,some hypotheses may be put forward.42 These mecha-nisms may also explain why the concomitant regimen iseffective for resistant strains. Indirect evidence support-ing an advantage of a concomitant regimen over asequential regimen comes from the recent study by Moli-na-Infante et al.48 The authors evaluated the efficacy ofempiric concomitant therapy in a geographical area (inSpain) where sequential therapy had previously provedinefficient (76% cure rate in a prior study23). Eradicationrates for the concomitant regimen were 88% by per-pro-tocol analysis and 86% by intention-to-treat analysis, andthe authors concluded that in settings with high clari-thromycin resistance (>15–20%) and documented failureof sequential therapy, concomitant therapy may achieve

Table1|C

ontin

ued

Autho

rCou

ntry

Publication

year

Stud

yde

sign

Disease

type

The

rapy

regimen

Days*

No.

ofpa

tients

Erad

ication

rate

(%)(ITT)

Erad

ication

rate

(%)(PP)

Kim

etal.57

Korea

2011

RCT

-L30

mgb.d.

+A

1gb.d.

+C

500mgb.d.

+M

500mgb.d.

5135

123

⁄135

(91.4

)123

⁄135

(91.4

)

ITT,

intention-to-treat;P

P,pe

r-protocol;R

CT,

rand

omised

controlledtrial;NC,n

on-con

trolled;

PUD,p

eptic

ulcerdisease;

NUD,n

on-ulcer

disease;

PPI,proton

pumpinhibitor(at

standard

dose);O,o

mep

razole;L

,lansoprazole;

R,rabe

prazole;

E,esom

eprazole;A

,amoxicillin;C

,clarithromycin;M

,metronidazole;T,tinidazole;

R,roxithromycin;o

d,on

cedaily;b

.d.,tw

otim

esaday;

t.d.s,three

times

aday.

*Daysof

antib

iotic

treatm

ent.

�Paed

iatric

patie

nts.




acceptable eradication rates.48 The reason for this theo-retical advantage of concomitant therapy over sequentialtherapy (which should be confirmed in randomised

controlled trials including both regimens in the samestudy) may be a lower effect of antibiotic resistance onthe eradication rate with concomitant therapy (when all

89

81

88

95 9388

91 89

74

90 9194 94

92

86

9396

0

10

20

30

40

50

60

70

80

90

100

Catala

no

Treibe

r

Calvet

Nagah

ara

Nagah

ara

Neville

Treibe

r

Treibe

r

Ferre

ccio

KimCha

n

Okada

Okada

Moli

na-In

fant

eW

u

Kongc

haya

nu

Kongc

haya

nu

Era

dica

tion

rate

(%

)

3 days 4 days 7 days 10 days

Figure 1 | Studies evaluating the efficacy (intention-to-treat) of the concomitant regimen for the treatment of H. pyloriinfection.

Study or subgroup

Calvet 2000Catalano 2000Chan 2001Ferreccio 2011Kim 2011Kongchayanun a 2011Kongchayanun b 2011Molina-Infante 2011Nagahara 2000Nagahara 2001Neville 1999Okada 1998Okada 1999Treiber 1998Treiber 2002 aTreiber 2002 bWu 2010

Total (95% CI)

Heterogeneity: τ = 0.00; χ = 85.81, df = 16 (P < 0.00001); ITest for overall effect: Z = 51.48 (P < 0.00001)

Eradication rate

0.8750.8930.9390.7360.911

0.90.96

0.8640.9450.9250.8750.9440.9170.9130.8130.892

0.93

SE

0.0440.0410.0420.02

0.0240.0420.0280.0380.0310.0290.0440.0240.0210.0420.0440.0340.024

Weight

5.1%5.3%5.3%6.9%6.6%5.3%6.3%5.6%6.1%6.3%5.1%6.6%6.8%5.3%5.1%5.9%6.6%

100.0%

IV, Random, 95% CI

0.88 [0.79, 0.96]0.89 [0.81, 0.97]0.94 [0.86, 1.02]0.74 [0.70, 0.78]0.91 [0.86, 0.96]0.90 [0.82, 0.98]0.96 [0.91, 1.01]0.86 [0.79, 0.94]0.94 [0.88, 1.01]0.93 [0.87, 0.98]0.88 [0.79, 0.96]0.94 [0.90, 0.99]0.92 [0.88, 0.96]0.91 [0.83, 1.00]0.81 [0.73, 0.90]0.89 [0.83, 0.96]0.93 [0.88, 0.98]

0.90 [0.86, 0.93]

IV, Random, 95% CI

–1 –0.5 0 0.5 1= 81%2 2 2

Figure 2 | Meta-analysis of efficacy (intention-to-treat) of studies evaluating the concomitant regimen for the treat-ment of H. pylori infection.




the three antibiotics are administered concurrently) orthe longer period of time each antibiotic is prescribed(5 days in the sequential regimen and 7–10 days in the7- to 10-day concomitant regimen).

Nitroimidazole resistanceDespite the inclusion of tinidazole, it has been sug-gested that the sequential regimen may achieve a signif-icantly higher eradication rate than the tinidazole-freestandard triple therapies.19 On the other hand, experi-ence with concomitant therapy in patients with metro-nidazole-resistant strains is still very limited. In thestudy by Neville et al.51, similar eradication rates againstboth metronidazole-sensitive (95%) and metronidazole-resistant strains (85%) were achieved with the concomi-tant regimen. Okada et al.52 found that H. pylori waseradicated in 25 of 27 (93%) patients with metronida-zole-resistant strains compared with 130 of 136 (96%)in patients with metronidazole-sensitive strains. How-ever, Treiber et al.53 observed that 5-day concomitanttreatment eradicated H. pylori in 90% of metronidazole-susceptible patients but in only 50% (8 of 16) of metro-nidazole-resistant patients. Finally, bismuth-based qua-druple therapy has been proposed as a means ofovercoming imidazole resistance, and it remains to beseen how concomitant therapy would perform in com-parison.68

Dual clarithromycin and metronidazole resistanceSequential therapy has been reported to be absolutelyineffective in patients with dual resistance (clarithro-mycin and imidazole).43 Primary dual resistance for clar-ithromycin and imidazole has been shown to produce aneradication rate of 50% (two of four) following 5 days ofconcomitant therapy53 and 75% (3 of 4) after 7 days ofconcomitant therapy.52

Comparative studies where both sequential and con-comitant regimens are administered are clearly necessary.In this respect, Wu et al. 54 compared the efficacy ofsequential and concomitant therapy and analysed theeffects of antibiotic resistance. Dual resistance did notinfluence the level of eradication in the concomitanttherapy group, but significantly affected that of thesequential therapy group. In particular, patients withdual resistance had a significantly lower eradication rateafter sequential therapy (present vs. absent: 33.3% vs.95.1%; P < 0.0001), but not after concomitant therapy(present vs. absent: 75.0% vs. 92.4%; P = 0.22; althoughthe low number of patients makes the possibility of atype II error likely).

In summary, concomitant therapy may be more suit-able than sequential therapy for patients with dual resis-tance to antibiotics. Nevertheless, one would suspect thatneither concomitant nor sequential therapy would be agood choice in the face of known dual resistance12. Inany case, these considerations are based on results fromsmall samples; therefore, more data are needed before areliable conclusion can be drawn.

Patient demographicsThe influence of age on the efficacy of concomitanttreatment is unclear. In the study by Neville et al.51, theprobability of eradication with concomitant treatmentdecreased with age, whereas in that by Treiber et al.53,younger age was associated with failure of eradication.The only study that has evaluated concomitant therapyin children showed encouraging results (94% eradicationin 33 children).47

Gender was not found to be a significant predictivefactor for the success or failure of eradication when con-comitant treatment was administered.51

Some data suggest that eradication following standardtriple therapies in patients with non-ulcer dyspepsiatends to be lower than in patients with peptic ulcer.69–71

On the contrary, cure rates with a concomitant regimenwere surprisingly higher for non-ulcer dyspepsia thanthat for ulcer patients in the study by Treiber et al.53

Concomitant treatment was not affected by smokingin one study,46 which contrasts with reports for othereradication regimens, where smoking increased the treat-ment failure rate for H. pylori eradication.72

Finally, in the meta-analysis by Essa et al.73, meta-regression analysis for treatment outcome regardingrandomised controlled trials showed that none of thevariables studied (age, gender, or endoscopy-based diag-nosis) significantly explained the variation in treatmentefficacy between concomitant and triple therapy.

H. pylori CagA statusSome authors have demonstrated the importance ofH. pylori CagA status for the efficacy of antibiotic treat-ment.74, 75 For example, Broutet et al.75 clearly statedthat the infection with cytotoxic strains is a good predic-tive marker of successful therapy. These results havebeen confirmed by Treiber et al. among ulcer patientsreceiving concomitant treatment.53

Proton pump inhibitor typeEncouraging results have been obtained with the con-comitant regimen including different PPIs (omeprazole,




lansoprazole, rabeprazole, or esomeprazole) (Table 1).These results are consistent with those obtained with thesequential regimen, with which pooled-data analyses andmeta-analyses have demonstrated that the success rateamong the different PPIs used was also similar.18, 19

Duration of treatmentNon-bismuth quadruple (concomitant) therapy was orig-inally developed in an attempt to decrease the durationof treatment for H. pylori infection. In studies performedin the late 1990s, data from Europe and Japan suggestedthat a short course of 3–5 days with three antibiotics anda PPI could achieve reasonable eradication rates.59

In their meta-analysis (nine studies), Essa et al.73

showed that, despite the very short durations of some ofthe trials, concomitant therapy yielded excellent resultsbut duration of therapy became a significant variable,with longer duration tending to produce higher eradica-tion rates.

The results of the studies included in Table 1 andFigure 1 show that, depending on the duration of treat-ment, mean H. pylori eradication rates for concomitanttreatment were 3 days (85%), 4 days (88%), 5 days (89%),7 days (93%) and 10 days (92%). Therefore, a trendtowards better results with longer treatments was observed.

The only randomised trial to date that has compared a5-day regimen of concomitant therapy with a 10-day reg-imen56 revealed a nonsignificant trend for higher curerates with the longer regimen (96% with 10 days vs. 90%with 5 days). Although the authors conclude that bothdurations were ‘‘similar’’, a type II error may not be ruledout, and this 6% difference may be clinically relevant.

The increase of eradication rates with longer regimenscould be mainly dependent on the compensation (over-coming) of resistance of metronidazole.60–62 It may be

suggested that, perhaps, using metronidazole at high dose(e.g. 500 mg t.d.s) might be another option of increasingthe cure rate, instead of prolonging treatment duration.Nevertheless, even when clarithromycin-containing stan-dard triple therapy is prescribed, prolonging exposure toantibiotics from 7 to 10–14 days may produce a slightincrease in efficacy.13, 14

The real benefit of a highly effective first-line therapyis much greater than what the raw percentage data sug-gest.76 Furthermore, outcome was better in poor PPImetabolisers, a finding that is consistent with the con-cept that concomitant therapy could be furtherimproved by modifying PPI dose and possibly durationof therapy.77 As safety is similar and the increase incosts relatively low, it seems reasonable to recommendthe length of treatment achieving maximal cure rates(10 days), even though the expected improvements willbe moderate.

COMPARISON BETWEEN THE CONCOMITANTREGIMEN AND THE STANDARD TRIPLE REGIMEN

EfficacySeveral randomised studies have confirmed the superior-ity of concomitant therapy over standard triple therapy.A recent meta-analysis73 examined nine prospective trialstreating H. pylori for up to 7 days with a concomitantregimen (PPI-macrolide-imidazole-amoxicillin). Treat-ment generally lasted 5 days (four in one study andseven in another). Overall, concomitant therapy waseffective in 90% of patients in the intention-to-treat anal-ysis and 93% in the per-protocol analysis. Pooled esti-mates of the five randomised controlled trials showedthe superiority of concomitant therapy over triple ther-apy (odds ratio of 2.86; 95% CI, 1.73–4.73).

Study or subgroup

Treiber 1998Neville 1999Nagahara 2000Catalano 2000Nagahara 2001Kim 2011

Total (95% CI)

Total eventsHeterogeneity: χ = 4.73, df = 5 (P = 0.45); ITest for overall effect: Z = 4.40 (P < 0.0001)

Events

4249525074

123

390

Total

4656555680

135

428

Events

3833404565

116

337

Total

4256505580

135

418

Weight

7.3%22.0%11.4%13.7%18.2%27.4%

100.0%

Peto, Fixed, 95% CI

1.10 [0.26, 4.69]4.24 [1.84, 9.74]

3.77 [1.19, 12.00]1.82 [0.63, 5.23]2.67 [1.07, 6.65]1.66 [0.79, 3.51]

2.40 [1.63, 3.55]

Year

199819992000200020012011

Peto odds ratio Peto odds ratioStandardConcomitantPeto, Fixed, 95% CI

0.005 0.1 1 10 200Standard therapy Concomitant therapy

= 0%22

Figure 3 | Meta-analysis comparing the efficacy of the concomitant regimen with that of standard triple therapy forthe eradication of H. pylori infection (intention-to-treat).




We recently updated these analyses with a more recentstudy57 and have performed a meta-analysis includingthe randomised controlled studies that, to date (May2011), have compared these two regimens. As summar-ised in Figure 3, 428 patients received the concomitantregimen and 418 the standard triple regimen. The formerwas more effective than the latter: 91.1% vs. 80.6% in theintention-to-treat analysis. As the results were veryhomogeneous (P = 0.45; I2 = 0%), a fixed effect model(Peto method) was used to perform the meta-analysis(Review Manager 5.0.25). The odds ratio for this com-parison was 2.4 (95% CI, 1.63–3.55) (Figure 3).

ToleranceIn the meta-analysis by Essa et al.73, no severe sideeffects were reported in any of the studies, apart fromanaphylactic reactions to medication32, 52, 53. Mild-to-moderate side effects were reported in 27–51% ofpatients treated with the concomitant regimen (com-pared with 21–48% of patients treated with triple ther-apy).73 These observations suggest that concomitant andstandard triple therapies have a similar safety profile.

COMPARISON BETWEEN CONCOMITANT ANDSEQUENTIAL REGIMENSOne potential problem with sequential therapy is itscomplexity, as it requires switching from a dual to a tri-ple therapy halfway through treatment. Therefore, trialscomparing sequential with concomitant therapy usingthe same combination of drugs are necessary. Such com-parisons would address whether or not the sequentialelement of sequential quadruple therapy is actually help-ful.29 A direct head-to-head comparison between sequen-tial and concomitant therapy would also tell us which ofthese two competitors can eventually replace the currentfirst-line triple therapies.78

In this respect, Wu et al.54 recently performed a multi-centre randomised comparison of 10-day sequential ther-apy with 10-day concomitant therapy, including 232H. pylori-infected patients from three hospitals in Taiwan.Intention-to-treat eradication rates were similar for bothregimens: 92% vs. 93%, respectively. Per-protocol curerates were exactly the same: 93% with both regimens.The frequency of adverse events was also similar (31%vs. 27%), as was adherence to therapy (96% vs. 98%).Therefore, the authors concluded that sequential andconcomitant administration of the same drugs providessimilar results in terms of efficacy and safety and that thesequential administration protocol may produce unneces-sary complexity for both patients and physicians com-

pared with concurrent prescription of all the medicationsfrom the outset.54 The study, however, was performed ina population with a very low rate of clarithromycin anddual clarithromycin-metronidazole resistance; therefore,the potential advantage of concomitant therapy in multi-resistant strains may not been adequately appreciated. Infact, the rate of antibiotic resistance in Taiwan is verylow, and excellent cure rates (almost 90%) have also beenrecently reported with standard triple therapy.79

A second randomised study has compared theconcomitant regimen (5 days) and the sequential regimen(10 days) in seven Latin American populations55 and hasreported disappointing results with both regimens (74%and 76% cure rates). By contrast, the eradication rateachieved with the standard triple therapy administeredfor 14 days was statistically higher (82%).

LIMITATIONS OF CONCOMITANT THERAPYThe results of the aforementioned studies are encourag-ing, although a number of limitations may affect thestrength of their conclusions (see below).

Old dataMany of the previously mentioned data (see Table 1) arefrom a decade ago, when the rates of clarithromycin andmetronidazole resistance were quite low.59 Consideringchanges in resistance rates, these data may not be validtoday.65 As no recent data are available from Westernpopulations with current rates of resistance, well-con-trolled studies are necessary.59 Nonetheless, the only studyrecently published in complete journal format reportedexcellent results: 93% eradication both by intention-to-treat and by per-protocol analysis with 10-day concomi-tant treatment54, suggesting that, at least with the 10-dayregimen, favourable results may still be obtained. Obvi-ously, further robust assessment across a much broaderrange of patients is required before concomitant therapycan be generally recommended in clinical practice.15

Small sample size and low quality of studiesThe sample in most studies evaluating the concomitantregimen comprises fewer than 100 patients (Table 1). Inparticular, all the individual studies included in the onlymeta-analysis published to date had a small samplesize.73 Furthermore, the quality of the studies is low inmost cases. Thus, there are no double-blind randomisedcontrolled trials with this regimen, and only two of thetrials included in the meta-analysis by Essa et al. weresingle-blinded, thus limiting the quality of the availableevidence.73




Complexity of therapyPoor adherence is the second most important reason forfailure of H. pylori eradication after antibiotic resistance.One in 10 patients on triple therapy are estimated to failto take even 60% of their medication80, a threshold atwhich significantly lower rates of eradication have beenproven.68, 81 The concomitant regimen is slightly morecomplex than standard triple therapy, because it involvesthe intake of an additional drug (twice a day). Neverthe-less, the concomitant regimen and standard triple regi-men seem to be characterised by similar adherence, atleast in clinical trials.73

Lack of validation in clinical practiceThe lower H. pylori eradication rates achieved in somestudies probably reflect the fact that they were performedunder conditions of clinical practice in a relatively unse-lected population. In this setting, higher rates of non-adherence and dropout during follow-up are to beexpected. In contrast, patients treated within the frame-work of a clinical trial may have a better clinical out-come.82 The low rate of withdrawal may not bereproducible outside the trial setting, especially if theprescribing physician does not explain the temporarynature of most side effects and the importance of com-pleting the regimen as prescribed (four drugs each time).

Insufficient information on the effects of antibioticresistanceAs most of the published studies failed to evaluate clari-thromycin and nitroimidazole resistance, available infor-mation is insufficient to truly judge this antimicrobialregimen according to its applicability in populations withhigh and ⁄ or low antimicrobial resistance.

Unsuitability for penicillin-allergic patientsH. pylori eradication is a challenge in penicillin-allergicpatients.83, 84 The concomitant regimen includes amoxi-cillin and, therefore, is not suitable for patients with pen-icillin allergy.85 However, such a limitation also appliesfor one of the standard triple therapies suggested in theEuropean guidelines (PPI-amoxicillin-clarithromycin).17

Limitation of future treatment options after failure oferadicationAll regimens require an adequate backup or rescue ther-apy.63, 64, 78 However, it remains unclear how failure ofconcomitant therapy should be managed. One potentialdisadvantage of concomitant therapy is that patients withfailed eradication would have limited options for further

treatment, because they would already have received threedifferent antibiotics: amoxicillin, clarithromycin and nitro-imidazole.16 In this respect, the first choice for eradicationtreatment should probably not be a regimen combiningclarithromycin and metronidazole.63, 78 Although this reg-imen is very effective, patients who are not cured will haveat least single, and usually double, resistance86, and fewlogical empirical treatment options are subsequently avail-able.78 Some authors have demonstrated that initial regi-mens containing both clarithromycin and nitroimidazoleare associated with significantly worse results overall, withlower eradication rates after logically chosen second-linetherapy and sensitivity-directed third-line therapy; thepoor results were due to the emergence of multiplyresistant strains, as evidenced by culture testing after thesecond failed course.87

However, the recent appearance of levofloxacin mayovercome this problem, as levofloxacin-containing rescuetherapy constitutes an encouraging empirical second-lineor even third-line strategy after multiple previous H. pylorieradication failures with key antibiotics such as amoxicillin,clarithromycin, metronidazole and tetracycline.88–90 Zulloet al. 91 recently performed a pilot study on patients whofailed sequential therapy (a regimen including the sameantibiotics as concomitant therapy). Following 10-day tri-ple therapy with a PPI, levofloxacin and amoxicillin, H.pylori infection was successfully cured in 86% of cases. Inanother study, Perna et al.92 prescribed a 10-day triple regi-men with a PPI, levofloxacin and amoxicillin in patients inwhom first treatment with either standard 10-day triple orsequential therapy (only 10 patients) had failed. H. pyloriwas eradicated in 73% of cases, although the authors do notprovide separate efficacy rates depending on the first (fail-ure) treatment. These data seem to indicate that a tripleregimen (PPI-levofloxacin-amoxicillin) is a suitableapproach for second-line treatment in patients whosesequential—and probably also concomitant therapy fails.17,

93, 94 Therefore, the concomitant regimen plus levofloxacin-containing triple therapy may be an adequate therapeuticstrategy for the management of H. pylori in clinical prac-tice. However, given the rise in resistance to this antibiotic,the prevalence in each country must be taken into account.

Finally, bismuth-based quadruple therapy (i.e. PPI,bismuth, tetracycline and nitroimidazole) could be analternative in patients whose concomitant therapy fails.Thus, the results of a recent study showed that allpatients who had failed sequential therapy (i.e. a regimenincluding the same antibiotics as the concomitant ther-apy) were able to eradicate the bacterium with bismuth-based quadruple therapy.95




Lack of comparison with bismuth-based quadrupletherapyConcomitant therapy has not been compared with bis-muth-based quadruple therapy (a PPI, bismuth salt, tetra-cycline and a nitroimidazole). Bismuth-based quadrupletherapy seems to overcome metronidazole resistance andis not influenced by macrolide resistance.96, 97 Thus, thisregimen been recommended as the treatment of choicewhen clarithromycin resistance rates are ‡15% in thecommunity.28 Nevertheless, two meta-analyses failed tofind a significant difference in success rates between bis-muth-based quadruple therapy and standard triple ther-apy, both of which were suboptimal.97, 98 The maindisadvantage of a bismuth-based quadruple regimen is itscomplexity, as it has the highest daily pill burden.78 How-ever, this drawback may be overcome, thanks to a novelsingle capsule containing bismuth, metronidazole and tetra-cycline that has recently become available.78, 99–102 Thisnew formulation can simplify the regimen to make itmore acceptable for general use.78, 99–101 However, itsprincipal disadvantage is that three capsules still need tobe taken four times daily, and a PPI needs to be takenseparately twice daily.28 A final and relevant limitation isthat bismuth salts are not available in many countries.

CONCLUSIONSStandard triple therapy is still the most widely used treat-ment in clinical practice. However, the prevalence of clar-ithromycin and metronidazole resistance has increasedsubstantially in recent years, and there has been a corre-sponding decrease in the eradication rate for H. pyloriinfection. Eradication rates are at their lowest levels sincea decade ago and are likely to fall further as antimicrobialresistance becomes more prevalent worldwide.59 It is clearthat alternative treatment regimens are urgently needed,particularly for patients with clarithromycin-resistantstrains of H. pylori.103

Sequential therapy has been proposed as an alternativeto standard triple therapy for eradication of H. pylori.However, the sequential approach, which may be morecomplicated than necessary, does not appear to offer spe-cific advantages. In fact, the first randomised comparisonof the sequential and the non-bismuth quadruple con-

comitant regimens recently concluded that sequentialand concomitant administration of the same drugs pro-vide similar results in terms of efficacy and safety.

Several randomised controlled trials (and one meta-analysis) have demonstrated that concomitant therapy ismore effective than and equally well tolerated as stan-dard triple therapy. A meta-analysis of 15 studiesrevealed a mean H. pylori cure rate of 90% for concomi-tant therapy. A tendency towards better results withlonger treatments (7–10 days vs. 3–5 days) with the con-comitant regimen has been observed, so it seems reason-able to recommend the length of treatment by achievingmaximal cure rates (10 days).

Clarithromycin resistance may reduce the efficacy ofconcomitant therapy, although the decrease in eradica-tion rates seems to be far lower than that in standardtriple therapy. Therefore, it has been suggested thatthe concomitant regimen may be preferable when theprevalence of clarithromycin-resistant H. pylori infec-tion is high, which is the case in many developedcountries. Experience with the concomitant therapy inpatients with metronidazole-resistant strains is still verylimited.

Although the aforementioned results are encouraging,a number of limitations should be taken into account: (i)much of the data previously mentioned are relatively old;(ii) the number of patients included in most studies evalu-ating the concomitant regimen is low; (iii) the concomitantregimen has not been sufficiently validated in clinical prac-tice; (iv) there is still insufficient information on the effectof antibiotic resistance on efficacy; and (v), no compari-sons with bismuth-based quadruple therapy are available.

In summary, non-bismuth quadruple concomitanttherapy appears to be an effective, safe and well-toleratedalternative to standard triple therapy and is less complexthan sequential therapy. Therefore, this regimen appearswell suited for use in settings where the efficacy of tripletherapy is unacceptably low.

ACKNOWLEDGEMENTDeclaration of personal interests: None. Declaration offunding interests: CIBEREHD is funded by the Institutode Salud Carlos III.

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Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobater pylori

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