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. 2017 Mar 8;2017(3):CD012588. doi: 10.1002/14651858.CD012588

Proton pump inhibitor‐ and fluoroquinolone‐based triple therapies for Helicobacter pylori eradication

Luís Eduardo S Fontes 1,✉, Ana Luiza C Martimbianco 2, Christieny Chaipp Mochdece 3, Rachel Riera 2
PMCID: PMC6464356

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of proton pump inhibitor (PPI)‐ and fluoroquinolone‐based triple therapies for H. pylori eradication.

Background

Description of the condition

Helicobacter pylori (H. pylori) is responsible for one of the most common chronic infections in humans. This pathogen reaches the gastric cavity by either oral‐oral or fecal‐oral transmission (Dunn 1997; Momtaz 2012), and penetrates the mucus layer and adheres to epithelial cells. It lives as a planktonic microorganism or, most commonly, by forming a biofilm community to protect itself from the acidic environment adjacent to the mucus layer. Some virulence factors of H. pylori are essential to its pathogenicity, including urease synthesis, flagella, enzymes (lipases and proteases), as well as adhesin and toxins (cytotoxin‐associated gene A (CagA) and vacuolating cytotoxin A (VacA)) (Kao 2016). Adhered to epithelial cells, H. pylori leads to chronic inflammation of the gastric mucosa and may cause chronic gastritis, atrophy, intestinal metaplasia, dysplasia, and neoplasm.

Diagnosis of H. pylori infection is confirmed by a positive result in the urea breath test, serology, stool antigen test, endoscopic biopsy with rapid urease reaction, histology, or in vitro cell culture. Chronic H. pylori infection is associated with development of atrophic gastritis, mucosal‐associated lymphoid tissue (MALT) lymphoma, peptic ulcer disease, gastric cancer, functional dyspepsia (Kuipers 1997; Malfertheiner 2009; Zhao 2014), as well as other non‐gastric conditions such as idiopathic thrombocytopenic purpura (Stasi 2009), and idiopathic iron deficiency anemia (Chaabane 2011).

Prevalence varies worldwide and is higher in developing countries, probably due to poor sanitary issues (Hunt 2011). An estimated 50% or more of the world's population is infected, but only about 20% of these people will develop symptoms (Venerito 2013).

See Appendix 1 for a glossary of terms.

Description of the intervention

Current options to treat H. pylori infection are proton pump inhibitor (PPI) triple therapy, bismuth quadruple therapy, sequential therapy, concomitant therapy, hybrid therapy, and levofloxacin‐based regimens (Malfertheiner 2012).

Fluoroquinolones are derived from nalidixic acid and are the only class of antibiotic that inhibit bacterial DNA synthesis by blocking the enzymes gyrase and topoisomerase IV, which are essential for bacterial DNA replication. At peak concentration, they have bactericidal effects. After an oral dose, absorption varies depending on the class of drug (Sharma 2009). Newer classes have a better bioavailability profile compared with ciprofloxacin. They have good penetration into various tissues and fluids (except for the central nervous system) and are eliminated by the kidneys and liver (Sharma 2009).

Levofloxacin (the main representative of the fluoroquinolones) reaches a mean peak plasma concentration (Cmax) of 2.8 mg/L within one to two hours after oral administration of 250 mg and 5.2 mg/L after oral administration of 500 mg. Absorption is rapid and almost complete with extensive, large distribution throughout tissues, as described above (Sharma 2009). The plasma half‐life ranges from six to eight hours in people who have normal renal function and 80% of the drug is eliminated unchanged in urine. Drug interactions are observed with aluminium‐containing and magnesium‐containing antacids and ferrous sulfates, which results in decreased absorption. Also, cimetidine and probenecid increase the half‐life of levofloxacin by altering renal clearance. Theophylline, warfarin, ranitidine, digoxin, cyclosporin, zidovudine, and sucralfate are other drugs that have a minor interaction risk (Fish 1997).

In vitro susceptibility tests have shown that fluoroquinolones are effective against H. pylori (Glupczynski 1988; McNulty 1985).

Fluoroquinolones are a promising antibiotic option to include in regimens intended to treat people with H. pylori infections, especially levofloxacin‐based protocols that have emerged in first, second, and third‐line regimens to treat H. pylori (Rispo 2014).

How the intervention might work

Classic triple therapy with a PPI plus amoxicillin and clarithromycin or metronidazole remains the most used regimen. However, increased development of clarithromycin resistance has led to unacceptable H. pylori eradication rates (Megraud 2013). In some regions of the world, resistance rates have achieved levels as high as 30% (Rispo 2014). Since the first reports of alarming clarithromycin resistance rates and treatment failure, newer regimens have emerged that use new combinations of antibiotics.

Cammarota and colleagues used levofloxacin in association with rabeprazole and clarithromycin in a trial conducted in Italy. This trial showed an H. pylori infection eradication rate of 84% after first‐line therapy (Cammarota 2004).

After this trial, several others studies tested the efficacy of fluoroquinolones in first‐line therapy, with conflicting results (Castro‐Fernández 2009; Chen 2014; Cuadrado‐Lavín 2012; Rakici 2014a; Rakici 2014b; Telaku 2013; Ye 2014). The differences in results were explained by variations in fluoroquinolone resistance rates according to the region of the world in which these studies were performed. Xiao and colleagues published one systematic review and meta‐analysis to evaluate the efficacy and safety of levofloxacin‐based triple therapy (LbTT) in first‐line treatment of H. pylori and included nine randomized controlled trials (RCTs). The LbTT eradication rate was slightly superior to standard clarithromycin‐based triple therapy (80.2% versus 77.4%; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.94 to 1.13). No significant difference was found in the rates of adverse events between the two groups. In the Asian subgroup, seven‐day standard therapy was superior to seven‐day LbTT (RR 0.91, 95% CI 0.86 to 0.97) (Xiao 2014).

The second‐line approach using fluoroquinolones as a PPI triple therapy regimen is the most acceptable according to literature data. Gisbert 2006a published a systematic review and meta‐analysis that included 14 studies with 977 participants. They highlighted the better efficacy and safety of fluoroquinolone‐based regimens compared with quadruple bismuth regimens. Di Caro 2012 performed a meta‐analysis comparing LbTT with standard quadruple therapy that included 14 trials and 677 participants. This review showed an eradication rate of 76.5% in the LbTT group and 67.4% in the quadruple therapy group. Although many other studies have reached similar results in favor of LbTT, fluoroquinolone‐resistance patterns in some regions of the world should not be ignored. Moon 2013 compared LbTT with quadruple therapy in the second‐line treatment of H. pylori in two centers in Korea. Successful eradication was obtained in 84.2% of participants treated with quadruple therapy versus 67.9% in the LbTT group, according to intention‐to‐treat (ITT) analysis. Based on current evidence, Statement 14 of the Maastricht IV Consensus recommends the use of either bismuth‐contained quadruple therapy or LbTT after initial treatment failure (Malfertheiner 2012).

Third‐line therapy for H. pylori must be based on in vitro cell culture. However, some studies examined empirical regimens for eradication of H. pylori after one or two precedent tentatives. Gisbert and colleagues published a study in which 100 participants received LbTT after two precedent treatments for H. pylori eradication. The per‐protocol eradication rate was 66% and the ITT rate was 60% (Gisbert 2006c). A Spanish study with 40 participants compared third‐line therapy with LbTT with rifabutin‐based triple therapy. At the end of the study, per‐protocol and ITT eradication rates were 81% and 85% in LbTT group respectively, versus 45% and 45% in the rifabutin group (Gisbert 2006b). However, again the regional pattern of drug susceptibility might be an important issue. Jeong 2012 conducted a trial that compared levofloxacin with rifabutin in triple therapy regimens in South Korea, with a better eradication rate in the rifabutin group (71.4% versus 57.1%).

Thus, eradication of H. pylori might work by preventing the development of some conditions and resolving (or at least improving) other clinically important diseases worldwide.

Why it is important to do this review

Eradication of H. pylori is an important public health priority worldwide. Since the infection is associated with conditions that have a high impact on morbidity, mortality, public health costs, and people's quality of life, it is critical to achieve higher cure rates and avoid a rise in antibiotic resistance.

There are many regimens to treat H. pylori infection, although there is some controversy about which is best. Clarithromycin‐based triple therapy seems to be the initial choice in areas with low resistance to clarithromycin, while bismuth regimens are useful in areas of high resistance (Malfertheiner 2012).

Some studies have shown that fluoroquinolone‐based triple therapy may be effective as either a first, second, or third‐line therapy to eradicate H. pylori (Rispo 2014). However, increasing quinolone resistance (currently about 40% in America, 20% in Europe, and 10% in Asia) has limited this approach, especially when used as a first‐line regimen (De Francesco 2010). Increasing quinolone resistance will jeopardize the future use of fluoroquinolone‐based triple therapy.

This Cochrane review will focus on first, second, and third‐line fluoroquinolone‐based PPI triple therapy regimens that consist of each of the three following drugs.

  • One PPI (omeprazole, lansoprazole, esomeprazole, rabeprazole, or pantoprazole).

  • One fluoroquinolone (sitafloxacin, levofloxacin, ofloxacin, moxifloxacin, ciprofloxacin, or norfloxacin).

  • Any antibiotic.

We will conduct this systematic review to compare fluoroquinolone‐based triple therapies. We will also explore uncertainty that arises from conflicting results in different studies on this subject, according to their efficacy and safety profile.

Objectives

To assess the effectiveness and safety of proton pump inhibitor (PPI)‐ and fluoroquinolone‐based triple therapies for H. pylori eradication.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs). We will include studies reported as full‐text articles, published as abstracts only, and unpublished data, regardless of language or date of publication.

We will exclude cluster‐randomized and cross‐over design studies, and studies that used fluoroquinolones as part of a quadruple or sequential therapy.

Types of participants

We will include trials that enrolled adults (over 16 years old) that had a diagnosis of H. pylori infection, confirmed by urea breath test, stool antigen test, validated immunoglobulin G (IgG) serology, endoscopic biopsies with rapid urease reaction, histology, or in vitro cell culture.

Types of interventions

We will include trials that compare the following.

  • First‐line PPI‐ and fluoroquinolone‐based triple therapies versus any treatment without quinolones.

  • Second‐line PPI‐ and fluoroquinolone‐based triple therapies versus any treatment without quinolones.

  • Third‐line PPI‐ and fluoroquinolone‐based triple therapies versus any treatment without quinolones.

We will exclude the following trials.

  • Trials in which duration of treatment was below seven days and above 14 days.

  • Trials that test gatifloxacin, temifloxacin, or trovafloxacin, since these drugs are no longer approved for clinical use because of toxicity issues.

Types of outcome measures

We will include studies that assessed at least one of the following outcomes.

Primary outcomes

  • Proportion of participants with successful H. pylori eradication (intention‐to‐treat (ITT) analysis). We will define eradication as a negative test for H. pylori at the latest available time point, but at least four weeks after treatment (Malfertheiner 2012). Negative results will be confirmed by urea breath test, stool antigen test, endoscopic biopsies with rapid urease reaction, or histology.

  • Proportion of participants who experienced a serious adverse event (those that are immediately life‐threatening, or resulted in hospitalization, incapacity, malignant disease, or death)

Secondary outcomes

  • Proportion of participants with successful H. pylori eradication (per protocol analysis). We will define eradication as above.

  • Proportion of participants who experienced any non‐serious adverse event. These will include gastrointestinal, cutaneous, neurological, toxic, and other non‐serious adverse events. We will extract information regarding the reporting of side effects and adverse events as absolute numbers and types of events, proportions of participants, and interference in compliance.

  • Number of withdrawals due to adverse events.

Search methods for identification of studies

Electronic searches

We will conduct a literature search to identify all published and unpublished RCTs. The literature search will identify potential studies in all languages. We will translate the non‐English language papers and fully assess them for potential inclusion in the review as necessary.

We will search the following electronic databases for identifying potential studies.

  • Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2).

  • MEDLINE (1966 to present) (Appendix 3).

  • Embase (1988 to present) (Appendix 4).

  • CINAHL (1982 to present).

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references.  We will contact authors of identified trials and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field.

We will search for errata or retractions from eligible trials on www.ncbi.nlm.nih.gov/pubmed and will report the date we perform this in the review.

Grey literature databases
Clinical trials registers/trial result registers

We will also search the following clinical trial registers and trial result registers.

Data collection and analysis

Selection of studies

Two review authors (LESF and CCM) will independently screen titles and abstracts for inclusion based on all the potential studies we identify as a result of the search. We will code studies as either 'retrieve' (eligible or potentially eligible, or unclear) or 'do not retrieve'. We will obtain the full‐text study reports/publications of studies coded 'retrieve'. Two review authors (LESF and CCM) will independently screen the full‐text article(s) and identify studies for inclusion, as well as identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author (RR). We will exclude duplicates and collate multiple reports of the same study, so that each study, rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and list the excluded full‐text articles and their reasons for exclusion in a 'Characteristics of excluded studies' table.

Data extraction and management

We will use a standard data collection form for study characteristics and outcome data, which we will pilot on at least one study that meets the inclusion criteria of the review. Two review authors (LESF and CCM) will extract study characteristics from included studies. We will extract the following study characteristics.

  • Methods: study design, total study duration, number of study centres and location, study setting, withdrawals, date of study.

  • Participants: number of participants (N), mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, exclusion criteria.

  • Interventions: intervention, comparison, concomitant medications, excluded medications.

  • Outcomes: primary and secondary outcomes specified and collected, time points reported.

  • Notes: funding for trial, notable conflicts of interest of trial authors.

Two review authors (LESF and CCM) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if the study authors reported outcome data in an unusable way. We will resolve disagreements by consensus or by involving a third review author (RR). One review author (LESF) will copy the data from the data collection form into the Review Manager 5 (RevMan 5) file (Review Manager 2014). We will double check that LESF has entered the data correctly by comparing the study reports with how the data are presented in the systematic review. A second review author will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (LESF and ALCM) will independently assess the risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving a third review author (RR). We will assess the risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We will assess each potential source of bias as either at high, low, or unclear risk of bias and will provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' tables. We will summarize the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary, e.g. for unblinded outcome assessment, the risk of bias for all‐cause mortality may be very different than a patient‐reported pain scale. Where information on the risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the review.

Measures of treatment effect

We will analyze dichotomous data as a risk ratio (RR) with 95% confidence intervals (CIs).

We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense.

Where a single trial reports multiple trial arms, we will only include the relevant trial arms. If we must enter two comparisons (e.g. drug A versus placebo and drug B versus placebo) into the same meta‐analysis, we will halve the control group to avoid double counting.

Unit of analysis issues

The unit of analysis will be the individual, and will collect and analyze a single measurement of each outcome for each participant.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data when possible (e.g. when we identify a study as an abstract only). If we cannot find the study authors, we intend to deal with missing participants using an ITT analysis, assuming that missing participants have failed treatment.

Assessment of heterogeneity

We will investigate heterogeneity using the Chi2 test and we will use I2 statistic to estimate its magnitude. We will consider an I2 statistic value of greater than 50% to indicate substantial heterogeneity (Higgins 2011). We will explore potential reasons for heterogeneity by checking clinical and methodological differences. If we identify substantial heterogeneity, we will explore it using pre‐specified subgroup analysis.

We will explore statistical diversity by estimates of treatment effect through forest plots created in RevMan 5 (Review Manager 2014).

Assessment of reporting biases

We will attempt to contact study authors and ask them to provide missing outcome data. When this is not possible and we think the missing data may introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. 

If we are able to pool 10 or more trials, we will create and examine a funnel plot to explore possible publication biases.

Data synthesis

When participants, interventions, comparisons, and outcomes are sufficiently similar to make clinical sense, we will combine the results from similar studies by undertaking a meta‐analysis and using RevMan 5 (Review Manager 2014). We will use a random‐effects model by default. We will conduct sensitivity analyses for primary outcomes using a fixed‐effect model to testing the robustness of our findings. In case of divergence between the two models, we will present both results; otherwise, we will present only results from the random‐effects model (Higgins 2003).

'Summary of findings' table

We will create a 'Summary of findings' table using all pre‐planned outcomes. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence as it relates to the studies that contribute data to the meta‐analyses for the pre‐specified outcomes. We will use methods and recommendations described in Chapter 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Schünemann 2011), as well as GRADEpro software (GRADEpro GDT 2014). We will justify all decisions to downgrade or upgrade the quality of the evidence using footnotes and will make comments to aid the reader's understanding of the review where necessary. We will consider whether there is any additional outcome information that we were unable to incorporate into the meta‐analyses, note this in the comments, and state if it supports or contradicts the information from the meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We plan to perform the following subgroup analyses.

  • Trials that tested fluoroquinolone‐based triple therapy as a first‐line therapy.

  • Trials that tested fluoroquinolone‐based triple therapy as a second‐line therapy.

  • Trials that tested fluoroquinolone‐based triple therapy as a third‐line therapy.

  • Efficacy according to antibiotic resistances when available.

We will use the following outcome in subgroup analysis.

  • Successful eradication rate (ITT analysis).

Sensitivity analysis

For the primary outcome, we will perform the following sensitivity analyses to assess the robustness of our conclusions.

  • Excluding studies with high risk of bias (those we classify as at high risk of bias in at least one of these criteria: randomization, allocation concealment, and blinding) versus studies with unclear or low risk of bias.

  • Using a random‐effects model, instead of a fixed‐effect model.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of the included studies. We will discuss implications for research, which will give the reader a clear sense of where the focus of any future research in the area should be and what the remaining uncertainties are.

Acknowledgements

We acknowledge the help and support of the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group. We also thank the following editors and peer referees who provided comments that improved the protocol: Sarah Rhodes (Editor), Marilyn Walsh, Xavier Calvet, an anonymous clinical reviewer, and Javier Gisbert (Editor), as well as to Deirdre P Walshe for copy editing the protocol.

The Methods section of this protocol is based on a standard template used by the Cochrane UGPD Group.

Appendices

Appendix 1. Glossary of terms

Atrophic gastritis: a pre‐malignant type of gastritis characterized by atrophy of gastric glands.

Faecal‐oral transmission: transmission characterized by oral ingestion of water or food that is contaminated with faeces.

Idiopathic: relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown.

Oral‐oral transmission: transmission achieved by oral contact with the oral secretion of another person (e.g. saliva, vomiting).

Pathogen: a microorganism that can cause disease.

Appendix 2. CENTRAL search strategy

1 MeSH descriptor: [Helicobacter] explode all trees

2 MeSH descriptor: [Helicobacter Infections] explode all trees

3 helicobacter or pylori or pyloridis or "HP" or Campylobacter:ti,ab,kw (Word variations have been searched)

4 #1 or #2 or #3

5 MeSH descriptor: [Proton Pump Inhibitors] explode all trees

6 proton near/2 pump near/2 inhibitor*:ti,ab,kw (Word variations have been searched)

7 PPI or PPIs:ti,ab,kw (Word variations have been searched)

8 omeprazole or h 16868 or h 168 68 or losec or omeprazon or prilosec or rapinex or zegerid or zoltum:ti,ab,kw (Word variations have been searched)

9 lansoprazole or lansoprazol or ag 1749 or agopton or bamalite or banilux or laprazol or lansol or lansox or lanzo or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton:ti,ab,kw (Word variations have been searched)

10 dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194*:ti,ab,kw (Word variations have been searched)

11 pantoprazole or anagastra or by 1023 or controloc or eupantol or inipom or inipomp or pantecta or pantoloc or pantozol or protium or protonix or rifun or skf‐96022 or skf96022 or somac or ulcotenal or zurcal or zurcazol:ti,ab,kw (Word variations have been searched)

12 rabeprazole or aciphex or dexrabeprazole or e 3810 or e3810 or ly‐307640 or ly307640 or pariet or pariprazole or rabec or rabeloc:ti,ab,kw (Word variations have been searched)

13 esomeprazole or nexium:ti,ab,kw (Word variations have been searched)

14 tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865" or TU 199 or benatoprazole:ti,ab,kw (Word variations have been searched)

15 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14

16 #4 and #15

17 MeSH descriptor: [Quinolones] explode all trees

18 quinolone or quinolones or fluoroquinolone or fluoroquinolones:ti,ab,kw (Word variations have been searched)

19 levofloxacin or aeroquin or cravit or dr 3355 or dr3355 or elequine or floxacin or hr 355 or hr355 or Levaquin or levokacin or mp 376 or mp376 or quinsair or quixin or rwj 25213 or rwj25213 or tavanic:ti,ab,kw (Word variations have been searched)

20 ofloxacin or ofloxacine or akilen or audret or bactocin or bioquil or dl 8280 or dl8280 or dr 3354 or dr3354 or eukinoft or exocin or exocine or flobacin or floxal or floxedol or floxil or floxin or floxstat or gyroflox or hoe 280 or hoe280 or medofloxin or medofloxine or monoflocet or monoox or ocuflox or oflocet or oflocin or oflodinex or oflogen or oflohexal or oflox or ofloxamed or ofloxin or ofus or orf28489 or orf 28489 or ottoflox or oxacid or oxatrex or praxin or "pt 01" or pt01 or quinofree or rg 191 or rg191 ru 43280 or ru43280 or surnox or tabrin or taravid or tarivid or taroflox or trafloxal or tructum or urotarivid or zanocin:ti,ab,kw (Word variations have been searched)

21 norfloxacin or "am 0715" or am 715 or am0715 or "m.k. 0366" or "mk 0366" or mk 366 or mk0366 or mk366 or noroxin or amicrobin or baccidal or barazan or chibroxin or chibroxine or chibroxol or esclebin or fulgram or gonorcin or lexinor or myfloxin or nalion or noracin or norbactin or norxacin or oranor or sebercim or uroctal or uroxacin or utinor or zoroxin:ti,ab,kw (Word variations have been searched)

22 enoxacin or at 2266 or at2266 or ci 919 or ci919 or enoxin or enoxor or pd 107779 or pd107779 or penetrex or bactidan or comprecin or enoram or enoxabid or enoxen or flumark or gyramid or rb 1620 or rb1620:ti,ab,kw (Word variations have been searched)

23 ciprofloxacin or "bay 09867" or bay09867 or ciprinol or Cipro or bay 9867 or bay o 9867 or bay o9867 or bay q 3939 or bay q3939 or bay9867 or baycip or cetraxal or ciflox or cifran or ciloxan or ciloxin or ciplox or ciprobay or ciprobid or ciproflox or ciprolet or ciprolkan or ciproxan or ciproxin or ciproxina or ciproxine or citopcin or cyprobay or flociprin or otiprio or proquin or proxacin or quintor or rigoran or sarf or septocipro or unex or uniflox or uroxin:ti,ab,kw (Word variations have been searched)

24 Pefloxacin or "2589 r.b." or abactal or abaktal or am 725 or am725 or eu 5306 or eu5306 or peflacin or peflacine or pefloxacine or peflox or pefloxacin or rb 1589 or rb1589:ti,ab,kw (Word variations have been searched)

25 sitafloxacin or du 6856 or du 6857 or du 6858 or du 6859 or du 6859a or du6856 or du6857 or du6858 or du6859 or du6859a or gracevit:ti,ab,kw (Word variations have been searched)

26 moxifloxacin or actira or avalox or avelox or bacterol or bay 12 8039 or bay 128039 or bay128039 or moxeza or octegra or proflox or vigamox:ti,ab,kw (Word variations have been searched)

27 #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26

28 #16 and #27

Appendix 3. MEDLINE search strategy

1 exp helicobacter/

2 exp Helicobacter Infections/

3 (helicobacter or pylori or pyloridis or "HP" or Campylobacter).mp.

4 or/1‐3

5 exp Proton Pump Inhibitors/

6 (proton adj2 pump adj2 inhibitor*).mp.

7 (PPI or PPIs).mp.

8 (omeprazole or h 16868 or h 168 68 or losec or omeprazon or prilosec or rapinex or zegerid or zoltum).mp.

9 (lansoprazole or lansoprazol or ag 1749 or agopton or bamalite or banilux or laprazol or lansol or lansox or lanzo or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).mp.

10 (dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194* or dexrabeprazole).mp.

11 (pantoprazole or anagastra or by 1023 or controloc or eupantol or inipom or inipomp or pantecta or pantoloc or pantozol or protium or protonix or rifun or skf‐96022 or skf96022 or somac or ulcotenal or zurcal or zurcazol).mp.

12 (rabeprazole or aciphex or dexrabeprazole or e 3810 or e3810 or ly‐307640 or ly307640 or pariet or pariprazole or rabec or rabeloc).mp.

13 (esomeprazole or nexium).mp.

14 (tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865" or TU 199 or benatoprazole).mp.

15 or/5‐14

16 4 and 15

17 exp quinolones/

18 (quinolone or quinolones or fluoroquinolone or fluoroquinolones).mp.

19 (levofloxacin or aeroquin or cravit or dr 3355 or dr3355 or elequine or floxacin or hr 355 or hr355 or Levaquin or levokacin or mp 376 or mp376 or quinsair or quixin or rwj 25213 or rwj25213 or tavanic).mp.

20 (ofloxacin or ofloxacine or akilen or audret or bactocin or bioquil or dl 8280 or dl8280 or dr 3354 or dr3354 or eukinoft or exocin or exocine or flobacin or floxal or floxedol or floxil or floxin or floxstat or gyroflox or hoe 280 or hoe280 or medofloxin or medofloxine or monoflocet or monoox or ocuflox or oflocet or oflocin or oflodinex or oflogen or oflohexal or oflox or ofloxamed or ofloxin or ofus or orf28489 or orf 28489 or ottoflox or oxacid or oxatrex or praxin or "pt 01" or pt01 or quinofree or rg 191 or rg191 ru 43280 or ru43280 or surnox or tabrin or taravid or tarivid or taroflox or trafloxal or tructum or urotarivid or zanocin).mp.

21 (norfloxacin or "am 0715" or am 715 or am0715 or "m.k. 0366" or "mk 0366" or mk 366 or mk0366 or mk366 or noroxin or amicrobin or baccidal or barazan or chibroxin or chibroxine or chibroxol or esclebin or fulgram or gonorcin or lexinor or myfloxin or nalion or noracin or norbactin or norxacin or oranor or sebercim or uroctal or uroxacin or utinor or zoroxin).mp.

22 (enoxacin or at 2266 or at2266 or ci 919 or ci919 or enoxin or enoxor or pd 107779 or pd107779 or penetrex or bactidan or comprecin or enoram or enoxabid or enoxen or flumark or gyramid or rb 1620 or rb1620).mp.

23 (ciprofloxacin or "bay 09867" or bay09867 or ciprinol or Cipro or bay 9867 or bay o 9867 or bay o9867 or bay q 3939 or bay q3939 or bay9867 or baycip or cetraxal or ciflox or cifran or ciloxan or ciloxin or ciplox or ciprobay or ciprobid or ciproflox or ciprolet or ciprolkan or ciproxan or ciproxin or ciproxina or ciproxine or citopcin or cyprobay or flociprin or otiprio or proquin or proxacin or quintor or rigoran or sarf or septocipro or unex or uniflox or uroxin).mp.

24 (Pefloxacin or "2589 r.b." or abactal or abaktal or am 725 or am725 or eu 5306 or eu5306 or peflacin or peflacine or pefloxacine or peflox or pefloxacin or rb 1589 or rb1589).mp.

25 (sitafloxacin or du 6856 or du 6857 or du 6858 or du 6859 or du 6859a or du6856 or du6857 or du6858 or du6859 or du6859a or gracevit).mp.

26 (moxifloxacin or actira or avalox or avelox or bacterol or bay 12 8039 or bay 128039 or bay128039 or moxeza or octegra or proflox or vigamox).mp.

27 or/17‐26

28 16 and 27

29 randomized controlled trial.pt.

30 controlled clinical trial.pt.

31 placebo.ab.

32 random$.mp.

33 trial.ab.

34 groups.ab.

35 drug therapy.fs.

36 or/29‐35

37 exp animals/ not exp humans/

38 36 not 37

39 28 and 38

Appendix 4. Embase search strategy

1 exp Helicobacter/

2 exp Helicobacter infection/

3 (helicobacter or pylori or pyloridis or "HP" or Campylobacter).mp.

4 or/1‐3

5 exp proton pump inhibitor/

6 (proton adj2 pump adj2 inhibitor*).mp.

7 (PPI or PPIs).mp.

8 (omeprazole or h 16868 or h 168 68 or losec or omeprazon or prilosec or rapinex or zegerid or zoltum).mp.

9 (lansoprazole or lansoprazol or ag 1749 or agopton or bamalite or banilux or laprazol or lansol or lansox or lanzo or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).mp.

10 (dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194*).mp.

11 (pantoprazole or anagastra or by 1023 or controloc or eupantol or inipom or inipomp or pantecta or pantoloc or pantozol or protium or protonix or rifun or skf‐96022 or skf96022 or somac or ulcotenal or zurcal or zurcazol).mp.

12 (rabeprazole or aciphex or dexrabeprazole or e 3810 or e3810 or ly‐307640 or ly307640 or pariet or pariprazole or rabec or rabeloc).mp.

13 (esomeprazole or nexium).mp.

14 (tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865" or TU 199 or benatoprazole).mp.

15 or/5‐14

16 4 and 15

17 exp quinoline derivative/ or exp quinoline derived antiinfective agent/

18 (quinolone or quinolones or fluoroquinolone or fluoroquinolones).mp.

19 (levofloxacin or aeroquin or cravit or dr 3355 or dr3355 or elequine or floxacin or hr 355 or hr355 or Levaquin or levokacin or mp 376 or mp376 or quinsair or quixin or rwj 25213 or rwj25213 or tavanic).mp.

20 (ofloxacin or ofloxacine or akilen or audret or bactocin or bioquil or dl 8280 or dl8280 or dr 3354 or dr3354 or eukinoft or exocin or exocine or flobacin or floxal or floxedol or floxil or floxin or floxstat or gyroflox or hoe 280 or hoe280 or medofloxin or medofloxine or monoflocet or monoox or ocuflox or oflocet or oflocin or oflodinex or oflogen or oflohexal or oflox or ofloxamed or ofloxin or ofus or orf28489 or orf 28489 or ottoflox or oxacid or oxatrex or praxin or "pt 01" or pt01 or quinofree or rg 191 or rg191 ru 43280 or ru43280 or surnox or tabrin or taravid or tarivid or taroflox or trafloxal or tructum or urotarivid or zanocin).mp.

21 (norfloxacin or "am 0715" or am 715 or am0715 or "m.k. 0366" or "mk 0366" or mk 366 or mk0366 or mk366 or noroxin or amicrobin or baccidal or barazan or chibroxin or chibroxine or chibroxol or esclebin or fulgram or gonorcin or lexinor or myfloxin or nalion or noracin or norbactin or norxacin or oranor or sebercim or uroctal or uroxacin or utinor or zoroxin).mp.

22 (enoxacin or at 2266 or at2266 or ci 919 or ci919 or enoxin or enoxor or pd 107779 or pd107779 or penetrex or bactidan or comprecin or enoram or enoxabid or enoxen or flumark or gyramid or rb 1620 or rb1620).mp.

23 (ciprofloxacin or "bay 09867" or bay09867 or ciprinol or Cipro or bay 9867 or bay o 9867 or bay o9867 or bay q 3939 or bay q3939 or bay9867 or baycip or cetraxal or ciflox or cifran or ciloxan or ciloxin or ciplox or ciprobay or ciprobid or ciproflox or ciprolet or ciprolkan or ciproxan or ciproxin or ciproxina or ciproxine or citopcin or cyprobay or flociprin or otiprio or proquin or proxacin or quintor or rigoran or sarf or septocipro or unex or uniflox or uroxin).mp.

24 (Pefloxacin or "2589 r.b." or abactal or abaktal or am 725 or am725 or eu 5306 or eu5306 or peflacin or peflacine or pefloxacine or peflox or pefloxacin or rb 1589 or rb1589).mp.

25 (sitafloxacin or du 6856 or du 6857 or du 6858 or du 6859 or du 6859a or du6856 or du6857 or du6858 or du6859 or du6859a or gracevit).mp.

26 (moxifloxacin or actira or avalox or avelox or bacterol or bay 12 8039 or bay 128039 or bay128039 or moxeza or octegra or proflox or vigamox).mp.

27 or/17‐26

28 16 and 27

29 random*.mp.

30 clinical trial*.mp.

31 blind*.mp.

32 placebo*.mp.

33 double‐blind:.mp.

34 exp health care quality/

35 or/29‐34

36 exp animal/ not human/

37 35 not 36

38 28 and 37

Contributions of authors

LESF conceived the protocol, secured funding for the protocol, and performed previous work that was the foundation for this protocol.

LESF, CCM, ALCM, and RR designed the protocol.

LESF and RR co‐ordinated and wrote the protocol.

The Cochrane UGPD Group designed the search strategies.

RR provided general advice on the protocol.

Sources of support

Internal sources

  • Petropolis Medical School, Brazil.

    Provided logistical support and time to develop the protocol.

  • Cochrane Brazil, Brazil.

    Provided methodological expertise through systematic review workshops.

External sources

  • No sources of support supplied

Declarations of interest

LESF: no known conflicts of interest.

ALM: no known conflicts of interest.

CCM: no known conflicts of interest.

RR: no known conflicts of interest.

New

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