With very few exceptions, the most common adverse events associated with antibiotics used to treat H. pylori infection are gastrointestinal in origin (for example: nausea, dysgeusia, dyspepsia/abdominal pain, diarrhea). As such, we have not listed adverse events for most of the therapies. Where unusual adverse events can occur with a specific therapy, we have tried to point that out.
The previous ACG guideline from 2007 recommended 14 days of treatment with a PPI, clarithromycin, and amoxicillin (clarithromycin-based triple therapy) or—in patients with an allergy to penicillin—metronidazole as an alternative to amoxicillin. At that time, eradication rates for clarithromycin triple therapy were reported to be 70–85% and were highly influenced by the underlying rate of clarithromycin resistance (26). However, there has been growing concern regarding the efficacy of clarithromycin triple therapy. Key questions which were considered while preparing this document included the expected eradication rate of clarithromycin triple therapy in North America, the most appropriate duration of therapy, and whether eradication rates have been dropping over time.
There are data from other parts of the world to suggest that eradication rates for clarithromycin triple therapy are below 80% (103). In preparing this updated guideline, we identified all randomized, controlled trials conducted in the United States or Canada which have assessed the efficacy of this regimen since 2000 (100, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119). Consistent with other meta-analyses, eradication rates with 7 or 10 days of clarithromycin triple therapy in studies from the US or Canada were indeed below 80%. Eradication rates with 14 days of triple therapy were higher, but only two study arms with 195 subjects were included. This finding is consistent with the most recent and most complete meta-analysis or the world’s literature on this topic which was published by the Cochrane Collaboration (120). For clarithromycin triple therapy, higher eradication rates were reported with 14 vs. 7 days of treatment (34 studies, RR 0.65, 95% CI 0.57–0.75; NNT 12, 95% CI 9–16), and with 14 vs. 10 days (10 studies, RR 0.69, 95% CI 0.52–0.91). Based upon the available data, when triple therapy is utilized in North America, it should be given for 14 days.
The lack of recent RCT data on clarithromycin triple therapy makes it difficult to confidently report on temporal trends in eradication rates. To address this issue, we conducted a retrospective analysis of eradication rates for clarithromycin triple therapy at the University of Michigan from 2001–15. Data was divided into 5-year blocks and eradication rates for 10–14 days of triple therapy when given first-line were calculated. In 662 patients, the overall eradication rate was 79.5% (95% CI 77.2–82.4%) with no significant difference in eradication rates for the 3, 5-year blocks (Figure 2, unpublished data).
The impact of clarithromycin resistance on the efficacy of clarithromycin triple therapy is well documented. A 2010 meta-analysis reported an eradication rate of 22% for clarithromycin-resistant H. pylori strains compared with 90% for clarithromycin-sensitive strains (121). As such, clarithromycin triple therapy should not be utilized in areas where the rate of clarithromycin resistance is known to be high. The Maastricht/Florence Consensus document published in 2012 recommended against using triple therapy when the rate of underlying clarithromycin resistance exceeds 15–20% (55). Although current large scale data on H. pylori antibiotic resistance in North America are unavailable, recent data from Houston suggest that clarithromycin resistance rates may now fall within that range (122). In the absence of local or even regional H. pylori antibiotic resistance data, it is very important to ask patients about previous exposure to antibiotics for any reason, particularly macrolides and fluoroquinolones, as this provides a proxy for underlying H. pylori antibiotic resistance (123, 124). A recent study confirmed an association between number of previous antibiotic exposures and an increasing risk for antibiotic resistance (125). Similarly, duration of previous macrolide therapy for greater than 2 weeks is also associated with a greater risk of treatment failure with clarithromycin triple therapy (126).
Based upon the available data, we conclude that clarithromycin triple therapy consisting of a PPI, clarithromycin, and amoxicillin or metronidazole for 14 days remains a first-line treatment option in regions where H. pylori clarithromycin resistance is known to be low. In regions where clarithromycin resistance exceeds 15%, as may well be the case in many parts of North America, clarithromycin triple therapy should be avoided. All patients should be asked about previous macrolide exposure for any reason. In those with previous macrolide exposure, clarithromycin triple therapy should be avoided.
The previous ACG guideline also endorsed the use of 10–14 days of bismuth quadruple therapy composed of a PPI or histamine-2 receptor antagonist, bismuth, metronidazole, and tetracycline. There is very limited data on the efficacy or comparative effectiveness of bismuth quadruple therapy in North America. A literature search identified only two RCTs which included a bismuth quadruple therapy arm (n=172). The mean eradication rate with this regimen given for 10 days was 91% (95% CI; 81–98%).
A meta-analysis of studies from around the world comparing clarithromycin triple and bismuth quadruple therapies suggested that the two treatments had similar efficacy, compliance, and tolerability (121). An updated meta-analysis, which included 12 RCTs and 2753 patients, reported intention-to-treat (ITT) eradication rates of 77.6% with bismuth quadruple therapy vs. 68.9% with clarithromycin triple therapy (risk difference=0.06, 95% CI; −0.01 to 0.13). There was significant heterogeneity in the data set, in part attributable to differences in treatment duration, drug dosing, and location. Ten days of bismuth quadruple therapy was found to be more effective than 7 days of clarithromycin triple therapy. However, no significant differences in efficacy of the two regimens were identified when given for 10–14 days (127). The most recent network meta-analysis of H. pylori regimens also found that 10–14 days of bismuth quadruple therapy was superior to 7 days of clarithromycin triple therapy (85 vs. 73%, RR=1.17; 95% CI=1.12–1.21) (103). Based upon these data, a treatment duration of 10–14 days is recommended for bismuth quadruple therapy. For a time, there were supply issues with tetracycline in the United States which limited access to bismuth quadruple therapy. These issues have now been resolved.
Unlike clarithromycin triple therapy, the efficacy of bismuth quadruple therapy is not affected by clarithromycin resistance. Further, although metronidazole resistance does have an impact on the efficacy of bismuth quadruple therapy, it is not nearly as profound as that of clarithromycin resistance on clarithromycin triple therapy (127). As such, in regions where the rate of clarithromycin resistance is known to be high or if a patient has previously been treated with macrolides for any reason, bismuth quadruple therapy should be strongly considered as the initial treatment choice.
So-called “concomitant therapy” consists of a PPI, amoxicillin, clarithromycin, and a nitroimidazole (tinidazole or metronidazole) given together for 3–10 days (128). No RCTs from North America have assessed the efficacy of concomitant therapy. A meta-analysis of 19 clinical trials of concomitant therapy which included 2070 patients with H. pylori infection revealed a mean cure rate of 88% (95% CI, 85–91%). In RCTs which compared concomitant therapy (481 patients) with clarithromycin triple therapy (503 patients), the ITT cure rates were 90% and 78%, respectively (OR, 2.36; 95% CI, 1.67–3.34)(129). Nearly all of the trials evaluated were performed in Europe or Asia, with one study performed in Latin America. A recent network meta-analysis yielded very similar results (103). In a comprehensive meta-analysis of sequential therapy, no differences were found in the efficacy of sequential therapy for 10 days (81.3%, 95% CI, 74.9–87%) vs. concomitant therapy for 5–10 days (81.7%, 95% CI, 76.1–86.7%) based upon data from six studies with over 2000 patients (130).
In the meta-analysis by Gisbert, longer durations of therapy were associated with a trend toward higher cure rates (129). A recent large, multicenter, randomized trial in Latin America reported that 14 days of clarithromycin triple therapy yielded higher cure rates than 5 days of concomitant therapy (82.2 vs. 73.6%, respectively; difference=8.6%, 95% CI, 2.6–14.5%) (131) indirectly supporting a duration for concomitant therapy of at least 7 days. At present, there are no RCTs which have evaluated the efficacy of concomitant therapy for 14 days. Limited data suggest that the efficacy of concomitant therapy may be reduced in patients with clarithromycin-resistant H. pylori infection but to a lesser degree than with clarithromycin triple therapy (129). The tolerability and compliance reported in trials with concomitant therapy is similar to clarithromycin triple therapy or sequential therapy (103, 130).
Acknowledging the lack of data from North America, we conclude that concomitant therapy is a promising treatment option that has produced high cure rates in international studies but awaits validation in North America. Because concomitant therapy is at least as effective as clarithromycin triple therapy with similar tolerability, it can be considered as a recommended first-line treatment option for North America. If concomitant therapy is recommended, a duration of at least 10–14 days seems appropriate. Studies to assess whether extending the duration of concomitant therapy to 14 days results in improved eradication are eagerly awaited.
Sequential therapy, consisting of a PPI plus amoxicillin for 5 days, followed by a PPI, clarithromycin, and a nitroimidazole for an additional 5 days, was introduced in 2000 as an alternative to clarithromycin triple therapy (132). A recent systematic review and meta-analysis identified 46 RCTs including 13,532 patients which compared sequential therapy to established and newer therapies (130). The overall eradication rate for sequential therapy was 84.3% (95% CI, 82.1–86.4%). Sequential therapy was superior to 7 days of clarithromycin triple therapy (RR 1.21; 95% CI, 1.17–1.25). However, sequential therapy was only marginally superior to 10 days of clarithromycin-based triple therapy (RR, 1.11; 95% CI, 1.04–1.19) and was not superior to 14 days of clarithromycin-based triple therapy (RR, 1.00; 95% CI, 0.94–1.06) or 10–14 of bismuth quadruple therapy (RR, 1.01; 95% CI, 0.95–1.06).
The efficacy of sequential therapy is subject to significant geographic variation. Although studies from Italy have reported high eradication rates (133), a multicenter trial which enrolled 1463 adults from six Latin American countries found that 14 days of clarithromycin triple therapy yielded a higher eradication rate than 10 days of sequential therapy (82.2 vs. 76.5%, difference, 5.6%; 95% CI, –0.04% to 11.6%) (131). Another large study from Taiwan identified reduced eradication rates with sequential therapy when clarithromycin resistance was present, although to a lesser degree than with clarithromycin triple therapy. This study was also one of the first to suggest that eradication rates might be improved by extending the duration of sequential therapy to 14 days (134).
A literature search identified only two RCTs which have evaluated sequential therapy in the United States and Canada (100, 104). In an abstract presented in 2014, investigators from Dallas, Texas randomized 134 patients with H. pylori infection to 10 days of sequential therapy or clarithromycin triple therapy. No significant difference in eradication rates between the two treatments was observed (RR 0.95; 95% CI 0.79–1.15). In a second trial from Canada, 126 patients were randomized to 10 days of sequential therapy or clarithromycin triple therapy. This trial also failed to identify a significant difference in the efficacy of the two regimens (RR 0.83, 95% CI 0.62–1.06). A random effects meta-analysis of these two trials revealed a pooled RR of 0.91 (95% CI, 0.78–1.06). Tolerability and compliance with sequential therapy appear to be similar to clarithromycin triple therapy (103).
On the basis of the available data, 10 day sequential therapy appears to be a viable alternative to 14 day clarithromycin triple therapy. However, 10 day sequential therapy cannot be endorsed as superior to 14 day clarithromycin triple therapy in North America. Also, the complexity of sequential therapy detracts from its relevance as a first-line treatment option in North America. Extending sequential therapy to 14 days may improve the eradication rate but further research is necessary to confirm the encouraging preliminary results reported in other parts of the world.
Hybrid therapy represents a cross between sequential and concomitant therapies. Hybrid therapy consists of a PPI and amoxicillin for 7 days followed by another 7 days of PPI, amoxicillin, clarithromycin, and a nitroimidazole (135).
To date, there have been no RCTs which have evaluated the efficacy or tolerability of hybrid therapy in North America. Several recent meta-analyses have summarized results from RCTs conducted in other parts of the world (103, 136, 137). A meta-analysis by Wang et al. (136) identified six RCTs which assessed hybrid therapy vs. sequential and/or concomitant therapy. When data from the hybrid therapy treatment arms were pooled, the ITT eradication rate was 88.6%. This ITT eradication rate was confirmed by two other recent meta-analyses (Li 89% (95% CI, 81–94%); He 86.6% (95% CI, 82–91%)(103, 137). Hybrid therapy appears to be more effective than the 7-day clarithromycin triple therapy (89 vs. 73%, Network meta-analysis RR 1.22; 95% CI 1.11–1.29) (103). Tolerability of hybrid therapy is similar to clarithromycin triple therapy (103). Further, there appear to be no significant differences in the efficacy, tolerability, or compliance observed with hybrid, sequential, or concomitant therapies (136, 137).
Acknowledging the lack of data from North America, we conclude that a 14 day course of hybrid therapy is a promising treatment option that has produced high cure rates in international studies but awaits validation in North America. Because hybrid therapy is at least as effective as clarithromycin triple therapy with similar tolerability, it is a suggested treatment alternative to clarithromycin triple therapy. Though hybrid and concomitant therapies perform similarly in RCTs, the complexity of hybrid therapy may dampen enthusiasm for its use in clinical practice.
There are no RCTs which have assessed the efficacy of first-line levofloxacin triple therapy in North America. A meta-analysis of seven trials from other parts of the world found that levofloxacin triple therapy for 7 days and clarithromycin triple therapy for 7 days yield similar eradication rates (79 vs. 81%, respectively, risk ratio 0.97, 95% CI, 0.93–1.02) (138). Another meta-analysis which included nine studies and 2502 patients confirmed these results and identified significant regional variation in eradication rates with levofloxacin triple therapy favored in Europe and clarithromycin triple therapy favored in Asia (139). On the other hand, in the network meta-analysis by Li et al. (103), levofloxacin triple therapy for 10–14 days proved superior to clarithromycin triple therapy for 7 days (90%, 95% CI, 84–94 vs. 73%, 95% CI, 71–75%; RR 1.23, 95% CI, 1.16–1.29). Although not formally compared, the pooled eradication rate of levofloxacin triple therapy was also higher than clarithromycin triple therapy for 10–14 days (81%, 95% CI, 78–84%). Tolerability of levofloxacin triple therapy appears to be similar to clarithromycin triple therapy (103, 138).
Levofloxacin and ciprofloxacin have also been utilized in modified versions of sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5–7 days. There are no studies from North America which have evaluated the efficacy or tolerability of fluoroquinolone sequential therapy. A meta-analysis which included six trials and 738 treatment-naive patients with H. pylori infection from other parts of the world compared the efficacy of flouroquinolone sequential therapy for 10–14 days vs. clarithromycin triple therapy for 7–14 days or standard sequential therapy for 10 days. Using a random effects model, the pooled eradication rate with fluoroquinolone sequential therapy was 87.8% vs. 71.1% for clarithromycin triple and standard sequential therapies (RR 1.21, 95% CI, 1.09–1.35). A subgroup analysis demonstrated superiority of levofloxacin sequential therapy vs. clarithromycin triple therapy (83.6% vs. 64%, RR 1.32, 95% CI, 1.09–1.60) or standard sequential therapy (87.4% vs. 78.9%, RR 1.12, 95% CI, 1.04–1.21). Fluoroquinolone sequential therapy eradication rates were not sensitive to duration of therapy, choice of PPI, or fluoroquinolone dose. The incidence of total adverse events and study discontinuations was similar between groups (140).
A first-line quadruple regimen, referred to as “LOAD” consists of levofloxacin, omeprazole, nitazoxanide (Alinia), and doxycycline. In an open-label, randomized study of 270 patients conducted in the United States, LOAD given for 7 or 10 days, yielded eradication rates of 89 and 90% compared with 73% with a 10-day course of lansoprazole, amoxicillin, and clarithromycin (106). No data were provided in the manuscript regarding the impact of levofloxacin resistance on the efficacy of LOAD therapy, and additional trials using this unconventional and expensive regimen are awaited.
There is growing interest in the United Statese of probiotics as adjuvant therapy in the treatment of H. pylori infection. Emerging evidence suggests an inhibitory effect of Lactobacillus and Bifidobacterium species on H. pylori. Furthermore, these probiotic strains may also help to reduce the side effects of eradication therapies and improve compliance with therapy (143, 144).
A recent meta-analysis of 10 clinical trials of adjuvant probiotics in patients with H. pylori infection demonstrated increased cure rates with probiotic supplementation (pooled OR, 2.07; 95% CI, 1.40–3.06) (143). Probiotics also reduced the incidence of total side effects (pooled OR, 0.31; 95% CI, 0.12–0.79). However, most of these studies were performed in China, and were at high risk of bias due to lack of blinding, and inadequate concealment of allocation. Furthermore, there was great variability in the probiotics used, as well as in the treatment regimens employed. Although probiotic therapy for H. pylori infection seems promising, many important questions remain, including the optimal dose, the time of dosing (before, during, or after eradication therapy), and the duration of therapy.
A variety of other clinical variables have been suggested to play a role in the success of eradication therapy. Chief among these are cigarette smoking and diabetes mellitus which have been associated with treatment failure in separate meta-analyses (149, 150). The summary ORs for treatment failure were 1.95 for smoking and 2.19 for diabetes. However, there were only eight studies in the diabetes analysis, including four from Turkey and none from North America. It is conceivable that these results might be confounded by reduced medication adherence or greater prior antibiotic exposure leading to antibiotic resistance since neither of these analyses controlled for these important factors.
As has already been mentioned, the presence of clarithromycin resistance reduces the success of clarithromycin triple therapy by ˜50% (151, 152). Levofloxacin resistance lowers success rates of levofloxacin-containing regimens by ˜20–40%, although data addressing the clinical impact of levofloxacin resistance are very limited (154, 155). For metronidazole, where in vitro resistance to H. pylori is quite high worldwide, the effect on H. pylori eradication is less predictable. Metronidazole resistance reduces eradication rates by ˜25% in triple therapies but less so in quadruple therapies and when PPIs are included in the regimen (152). Increasing the dose and duration of metronidazole also improves outcomes in metronidazole-resistant strains, demonstrating that, unlike clarithromycin and levofloxacin, in vitro metronidazole resistance is not an absolute predictor of eradication failure (156). Indeed, multiple mechanisms of metronidazole resistance in H. pylori have been described and the definition and measurement of metronidazole resistance among H. pylori strains remain to be adequately standardized.
A multicenter European survey conducted in 2008–9, reported resistance rates of 35% for metronidazole, 17.5% for clarithromycin (double from 10 years earlier) and 14% for levofloxacin (124). Resistance was associated with outpatient use of quinolones and long-acting macrolides in individual European countries, suggesting that H. pylori antibiotic resistance is causally connected to community antibiotic utilization. Similarly, high resistance rates to clarithromycin and even higher resistance rates for metronidazole have been observed in some parts of South America (157) and most other regions of the world from which data exist (158). Generally speaking, antibiotic resistance rates have tended to increase over time (158) with rates as high as 50% for clarithromycin, 65% for metronidazole and 50% for levofloxacin reported recently in other parts of the world (158).
In comparison with the efforts of many countries to carefully sample strains and document antibiotic resistance rates in order to guide more rational treatment selection, there have been no organized attempts to track H. pylori resistance patterns in North America. The most recent US national sampling study, which included 347 strains collected from 11 hospitals during 1998–2002, reported resistance rates of 21% for metronidazole and 13% for clarithromycin (159). A decade later, among 128 cultured strains from the Houston VA Medical Center a similar 20% resistance rate for metronidazole was observed whereas resistance to clarithromycin had risen to 16% and levofloxacin resistance was at 31%. Multiple resistance was noted for 17% of strains and only half were susceptible to all five antibiotics tested (122). In an Alaskan native population sampled from 2000–8, resistance to metronidazole was 42%, clarithromycin 30% and levofloxacin 19% (141). Thus the sparse available data from North America suggest concerning rates of resistance to many of the antibiotics currently in use against H. pylori. (Table 3). This is perhaps not all that surprising given that Americans receive, on average, one outpatient antibiotic prescription per person per year, with the macrolide azithromycin the most frequently prescribed antibiotic (160). Caution should be exercised when considering the extension of this limited data set to a wider audience of people living in North America. These preliminary data emphasize the desperate need for organized surveillance of antibiotic resistance patterns in North America.
As an alternative, faster and simpler molecular methods have been developed and validated for fresh, frozen, or paraffin-embedded gastric mucosal biopsies; such testing has also been successfully applied to fecal samples, thus obviating the need for endoscopy. Molecular methods such as polymerase chain reaction or fluorescently-labeled nucleic acid hybridization can be used to identify many of the mutations known to be responsible for antibiotic resistance (161). Current testing focuses on a small number of mutations known to account for clarithromycin and levofloxacin resistance since these are currently felt to be the most important clinically. Clarithromycin resistance is usually due to point mutations in one of two sites in H. pylori’s 23S ribosomal subunit RNA, although multiple other mutations elsewhere in 23SrRNA or other genes have been more rarely implicated. Levofloxacin resistance is normally caused by one of two point mutations within DNA gyrase subunit A. On the other hand, molecular techniques are not suitable for identifying metronidazole resistance which can be due to multiple mechanisms. At present, molecular testing is not FDA- or CLIA-approved in the United States.
Usual treatment of a bacterial infection involves the selection of an antibiotic based upon the organism’s in vitro sensitivity, or at least its likely sensitivity from knowledge of local microbiological data. In contrast, the treatment of H. pylori relies upon empiric trials of antibiotic therapies. Outside of the US, the increasing difficulty in eradicating H. pylori has prompted some experts to advocate for more liberal antibiotic resistance testing, especially after one or more failed treatments and particularly when antibiotic resistance is prevalent in the population. Thus, the Maastricht guidance document has recommended clarithromycin resistance testing before prescribing clarithromycin triple therapy when clarithromycin resistance is common (as it is in many regions) and especially after a second-line treatment has failed (55).
The merits of susceptibility-based vs. empiric antibiotic treatment for first-line or subsequent therapies have been much debated. A recent meta-analysis of 12 publications favored the susceptibility-guided approach for choosing first-line therapies over standard 7–10 day triple therapy after endoscopy and culture (162). Other studies have shown a high eradication rate with susceptibility-guided second-line (163) and third-line therapies (164), but the cost-effectiveness of such strategies has not been rigorously evaluated. The need for repeat endoscopy for the sole purpose of obtaining biopsies may render this approach cost-prohibitive after failed therapy in the United States. The development of non-invasive (fecal or other) sensitivity testing could favorably alter this calculus. In the meantime, clinicians should review patient history of antibiotic use in general and assume previous exposure provides a surrogate measure of resistance to levofloxacin, clarithromycin, or metronidazole.
The arguments supporting routine post-treatment testing are intuitively obvious when there is already a clear indication for H. pylori treatment. However, the scientific evidence to support such a strategy from a cost-effectiveness viewpoint is less than robust. An exception is for bleeding peptic ulcers associated with H. pylori where modeling studies do support the cost-effectiveness of routinely testing to confirm H. pylori eradication (168, 169). In contrast, such a strategy may not be cost-effective for uncomplicated duodenal ulcers, even when eradication rates are as low as 70% (170).
A final argument in favor of post-treatment testing is to provide data on which to make rational community-based decisions. Without re-testing it is impossible to obtain information on a practitioner’s or community’s eradication success and on the need to modify antibiotic regimens.
We acknowledge that in clinical practice, circumstances may arise in which the performance of eradication testing may be impractical or deemed by the provider or patient to be unnecessary. However, in the overwhelming majority of situations where treatment for H. pylori is offered, eradication testing should be offered to the patient.
As explained elsewhere in this document, the most important determinant of the success of eradication therapy is the sensitivity or resistance of H. pylori to the antibiotics used; resistance to antibiotics is, in turn, strongly correlated to prior use of these specific antibiotics (for H. pylori or other infections) (153). This applies mainly to clarithromycin, fluoroquinolones and rifabutin (an antibiotic that is not currently used first-line) which should not be re-used empirically, because resistance to these antibiotics cannot be overcome by increasing dose, duration of treatment or frequency of administration (151, 152, 153). However, amoxicillin or tetracycline can be re-used, because resistance remains rare even after their prior use (122). In general, re-use of metronidazole should be avoided, although resistance to it can be partially overcome by increasing its dose, duration of use or frequency of administration (151, 152). Therefore, if alternative regimens are predicted to be clearly inferior, metronidazole could be re-used as a component of a 14-day course of bismuth-based quadruple therapy, especially if its previous use was brief or at a low dose. A listing of available salvage treatment options can be found in Table 3. Figure 3 provides a recommended construct to assist the choice of therapy in an individual patient with persistent H. pylori infection.
Since 2000, 30 RCTs have compared bismuth quadruple therapy with other regimens or with a bismuth quadruple regimen of different duration as salvage treatment after one or more failed eradication attempts (Supplementary Appendix 3). Of those, 23 studies included only patients who had failed a first-line treatment; of those, 20 studies included only patients who had failed clarithromycin triple regimens. The remaining three RCTs did not specify which regimens were used first-line (although in one (171), patients were specifically excluded if they had received bismuth quadruple therapy previously).
With regards to the optimal duration of the salvage bismuth quadruple therapy, the meta-analysis by Marin et al. (172) found a non-significant trend in subgroup analyses (between-study comparisons) for increasing eradication rates with longer duration of treatment from 7 days (76%) to 10 days (77%) to 14 days (82%) after failure of clarithromycin triple therapy. The systematic review conducted for this guideline identified four RCTs comparing 14-day bismuth quadruple therapy with 7-day bismuth quadruple therapy that were published since 2000, two from Asia (173, 174) and two from Europe (175, 176). Meta-analysis of these four RCTs showed a significantly higher eradication rate with 14-day bismuth quadruple therapy (RR 1.14; 95% CI 1.02–1.28). Given the above evidence and the fact that resistance to metronidazole can be partially overcome by increasing treatment duration (151, 152), it is reasonable to encourage a 14-day duration for the bismuth quadruple salvage regimen.
We found eleven RCTs, published since 2000, that had compared 14-day bismuth quadruple therapy with other regimens as salvage treatment; one was conducted in the United States (177), three in Europe (175, 176, 178) and the remaining seven in Asia (173, 179, 180, 181, 182, 183, 184). Eight of these studies only included patients who failed eradication once, after treatment with clarithromycin triple therapy. The only study from the US (177) included patients who had failed once after treatment with one of several regimens (67% of the patients had failed either bismuth quadruple therapy or ranitidine bismuth citrate, metronidazole, and tetracycline). Two studies, one from Europe (178) and one from Asia (179), included patients who had failed one or more eradication attempts with various regimens. The pooled eradication rate for 14-day bismuth quadruple therapy was 80% (95% CI 76–84%), and was significantly higher among Asian studies (82%; 77–86%) compared with European or US studies (74%; 68–81%). in the United States study (177), the overall eradication rate for 14-day bismuth quadruple therapy was 71%, but differed substantially among patients who had previously failed bismuth quadruple treatments for 7–14 days (eradication rate 53%; 28–77%) and the patients who had previously failed triple or dual clarithromycin-based treatments without bismuth (eradication rate 100%; 72–100%).
Fifteen RCTs that compared levofloxacin triple therapy with other regimens as salvage treatment have been published since 2000 (Supplementary Appendix 4). Only one of these studies assessed 14-day levofloxacin triple therapy; it was conducted in Taiwan, among 101 patients who had failed treatment with 7 day clarithromycin triple therapy, and found no difference in eradication rates between 14-day levofloxacin triple therapy (86%; 95% CI 77–96%) and 14-day bismuth quadruple (PBMT, 86%; 76–96%)(181). Four RCTs assessed the 10-day levofloxacin triple therapy regimen (176, 185, 186, 187); all were conducted in Europe and the pooled eradication rate was 84% (73–92%). Ten RCTs, seven from Asia and three from Europe, assessed the 7-day levofloxacin triple therapy regimen; the pooled eradication rate was 66% (95% CI 60–73%) with no difference between Asian and European studies. A meta-analysis of cohort studies and cohort-type data from RCTs which assessed levofloxacin triple therapy showed that the eradication rate was 76% (95% CI 72–81%) after failure of clarithromycin triple therapy among 19 studies, and 81% (95% CI 71–91%) after failure of sequential therapy among five studies (172).
Levofloxacin triple therapy also seems to be efficacious as a third-line treatment. Gisbert et al. (188) calculated a pooled eradication rate of 73% for six European cohort studies that assessed 10-day levofloxacin triple therapy in patients who had failed two previous eradication attempts (most patients had clarithromycin triple therapy as first-line and bismuth quadruple therapy as second-line).
Regarding the optimal duration of levofloxacin triple salvage treatment, subgroup analyses (between-study comparisons) from the meta-analysis conducted for this guideline (see above) showed that this regimen given for 10 or 14 days was significantly more effective than when given for 7 days. Only one RCT compared two durations for levofloxacin triple salvage treatment; Di Caro et al. (186) compared two types of 10-day and two types of 7-day PAL regimens in Italy and found significantly higher efficacy with longer duration (88% vs. 78%). This finding was confirmed by an RCT from Turkey which reported significantly higher efficacy with longer duration of PAL as first-line treatment (72% with 14-day regimen vs. 34% with 7-day regimen) (189).
The optimal dose of levofloxacin is unclear. Two RCTs that assessed different doses of levofloxacin in salvage treatments found no difference when administering 500 mg of levofloxacin once or twice daily in 7 or 10 day regimens (186, 190).
Only two RCTs that compared concomitant therapy with another regimen as salvage treatments have been published since 2000 (193, 194). Both studies included patients who had failed first-line treatment with clarithromycin triple therapy. A trial from Japan randomized 104 patients to 7-day triple therapy with a PPI, amoxicillin, and metronidazole or 7-day concomitant regimen; eradication rates were 83% (95% CI 73–93%) and 89% (80–97%), respectively (193). However, these results are not necessarily generalizable to other countries; the efficacy of metronidazole-containing regimens is particularly high in Japan, due to a relatively low resistance of H. pylori to this antibiotic, which in turn is probably due to the its restricted use nationally (195). The second trial was conducted in Korea and randomized 124 patients to bismuth quadruple therapy or concomitant therapy for 10 days. The treatments were found to be equally effective (eradication rates 92% vs. 90%) (194).
There is indirect evidence from studies on first-line treatment that concomitant therapy should have acceptable efficacy as a second-line treatment. First, it is one of the most efficacious first-line regimens (129). Second, limited data from Spain and Taiwan suggest that concomitant therapy may even remain effective in patients with dual resistance to clarithromycin and metronidazole (196, 197).
There is very little evidence on the optimal duration of salvage concomitant treatment. No RCTs have compared two concomitant regimens of different durations as salvage treatments. A systematic review that assessed the efficacy of 19 cohort studies and cohort-type data from RCTs for first-line treatment found a non-significant trend for increased efficacy with increased durations of treatment: 3 days (85%); 4 days (88%); 5 days (83%); 7 days (91%); and 10 days (90%) (129).
In current clinical practice in North America, it is uncommon for clarithromycin not to have been used first-line unless the patient had already been judged to have been at high risk for clarithromycin resistance. Theoretically, there is no evidence-based reason to avoid this regimen as a second-line treatment in such situations. That being said, the guideline committee recommends concomitant therapy over clarithromycin triple therapy when a clarithromycin containing salvage regimen is chosen.
The evidence supporting the use of clarithromycin triple therapy as a salvage regimen is limited. After 2000, three RCTs in the United States or Europe assessed triple therapy with a PPI, clarithromycin, and amoxicillin as a second-line treatment (177, 198, 199), while none assessed triple therapy replacing amoxicillin with metronidazole as a second-line treatment. In a US RCT by Magaret et al. (177), patients who had failed one of several first-line treatments for H. pylori were randomized to 14-day PAC or 14-day bismuth quadruple therapy. Although not reported in the paper, among the 32 patients who had bismuth quadruple therapy for 10–14 days or ranitidine bismuth citrate-, metronidazole, and tetracycline for 7–10 days as first-line treatment, the eradication rate was 79% (95% CI 49–95%) for clarithromycin triple therapy and 53% (28–77%) for bismuth quadruple therapy (P=NS). In the German RCT (198), all 84 patients had failed PPI, clarithromycin, and metronidazole for 7 days as first-line treatment; not surprisingly, eradication rates were inferior with 7-day clarithromycin triple therapy compared with 7-day bismuth quadruple therapy (43% (28–59%) vs. 68% (51–81%), P=0.03) and the difference was even more pronounced among the 79% of patients who had clarithromycin-resistant strains after first- line treatment. The French RCT (199), showed that among 172 patients in whom first-line clarithromycin triple therapies (clarithromycin triple therapy 87%, PPI, amoxicillin, metronidazole 7%, clarithromycin triple therapy with metronidazole 3%, H2RA, clarithromycin, and amoxicillin 3%) had failed, empiric second-line treatment with 7- or 14-day triple therapy with a PPI, clarithromycin and amoxicillin had lower eradication rates than 14-day PPI, clarithromycin, and metronidazole (47% vs. 355 vs. 63%, respectively).
As mentioned above, repeating the same triple regimen should be avoided. A meta-analysis of cohort studies and cohort-type data from RCTs showed that, among eight studies that repeated clarithromycin triple therapy as second-line treatment (after failure of the same regimen as first-line treatment), the pooled eradication rate was unacceptably low (46%; 95% CI 34–58%) (172).
Four RCTs have compared rifabutin triple therapy consisting of a PPI, rifabutin and amoxicillin against other regimens as salvage treatments (171, 202, 203, 204). Ten-day rifabutin triple regimens were assessed in only one RCT by Perri et al. in Europe among 135 patients who had failed between one and three previous treatments. Rifabutin triple therapy for 10 days with 300 mg rifabutin once daily (eradication rate 87%; 95% CI 76–96%) was significantly more efficacious than a 10-day regimen with 150 mg rifabutin once daily and 10-day bismuth-based quadruple treatment, both of which had identical eradication rates of 67% (95% CI 53–80%) (204). The other three RCTs, two from Europe (171, 203) and one from Asia (202), assessed 7-day rifabutin triple regimens with rifabutin given as 150 mg twice daily; the pooled eradication rate was 66% (45–83%), but with substantial heterogeneity among the studies. In Spain, Navarro et al. (174) found lower eradication rates for rifabutin triple therapy than the other RCTs: among 99 patients in whom clarithromycin triple therapy had failed, 7-day rifabutin triple therapy achieved an eradication rate of 44%, which was significantly lower than the eradication rate of 70% with a 7-day bismuth-based quadruple regimen.
In a meta-analysis of cohort studies and cohort-type data from RCTs that used PAR as salvage treatment, pooled eradication rates were 79% (95% CI 67–92%) as second-line, 66% (55–77%) as third-line, and 70% (60–79%) as fourth- or fifth-line (200).
There is little evidence on the optimal duration for the PAR salvage treatment. There have been no RCTs comparing different durations of treatment. Comparisons between subgroups (between-study comparisons) in meta-analyses suggest that, when PAR is used as second-line treatment, 10- to 12-day regimens achieved higher eradication rates than 7-day regimens (95 vs. 69%). It is notable that myelotoxicity which can rarely complicate treatment with rifabutin tends to occur with doses of greater than 600 mg per day or with prolonged use (200). Thus, when rifabutin triple therapy is recommended, a dose of 300 mg once daily and duration of 10 days is appropriate.
The reasons for considering high-dose dual therapy as a salvage treatment are that H. pylori rarely develops resistance to amoxicillin (122), and that the efficacy of amoxicillin increases with increasing gastric pH (205),
Since 2000, three RCTs have compared 14-day high-dose dual regimens (defined as total daily dose of amoxicillin ≥3 g, and frequency of administration ≥3/day in an attempt to avoid the low trough levels of b.i.d. amoxicillin dosing) with other regimens as salvage treatments (178, 203, 206). Two of these studies have been conducted in Germany, both by Miehlke et al. The first study included 84 patients with at least one previous treatment failure (most patients had two or more treatment failures) and compared 14-day high-dose dual therapy (omeprazole 40 mg and amoxicillin 750 mg, both given q.i.d.) with 14-day bismuth quadruple treatment. The eradication rates for the two regimens did not differ significantly (dual therapy: 76%, 95% CI: 60–88%, vs. bismuth quadruple therapy: 81%, 67–92%) (178). The second study included 145 patients with at least one previous eradication failure and dual H. pylori resistance to metronidazole and clarithromycin who were randomized to high-dose dual therapy for 14 days or rifabutin triple therapy for 7 days. No significant difference between the two regimens was identified (dual therapy: 70%, 95% CI 58–80% vs. rifabutin triple therapy: 74, 62–84%) (203). By proportion meta-analysis, the pooled eradication rate for high-dose dual salvage treatment in the European studies was 71% (63–79%). Finally, in Taiwan, Yang et al. (206) included 168 patients with one or more previous eradication failures, and reported that the eradication rate with the 14-day high-dose dual therapy (rabeprazole 20 mg and amoxicillin 750 mg, both given q.i.d.) was 89% (81–98%), which was not significantly different than with 7-day levofloxacin triple therapy (79, 67–90%), but was significantly higher than with 10-day sequential therapy (52, 38–65%). The pooled eradication rate for high-dose dual salvage therapy among all three studies was 78% (95% CI 65–89%).
Of note, three other RCTs, all from Japan, assessed a different 10- to 14-day dual salvage regimen that contained high-dose PPI (a standard dose but given q.i.d.) with standard dose amoxicillin (i.e., 500 mg q.i.d.) (207, 208, 209). The results were highly heterogeneous among these studies, with eradication rates of 0, 54, and 91%.
Sequential therapy has mainly been tested as a first-line treatment. Only two RCTs have assessed its efficacy as a salvage treatment, and the results are discouraging. One RCT, conducted in Taiwan, included 168 patients who had failed one or more previous eradication treatments; the eradication rate with 10-day sequential therapy (52%, 95% CI 38–65%) was significantly lower than with 14-day high-dose dual amoxicillin therapy (89%, 81–98%) or 7-day levofloxacin triple therapy (79, 67–90%) (206). The other RCT was conducted in Korea and included 158 patients who had failed clarithromycin triple therapy; 10-day sequential therapy was significantly inferior to 10-day bismuth-based quadruple therapy (eradication rates 57 vs. 84%) (210). Based upon the lack of North American data and discouraging data from Asia, we do not recommend sequential therapy as a salvage treatment.
We were unable to identify any RCTs that compared hybrid therapy with other regimens as salvage treatment. Therefore, there is insufficient evidence to support a recommendation for hybrid therapy as a salvage treatment.
The nitrofuran-based antimicrobial furazolidone is not currently available in the United States. There are no published studies of its use as a salvage therapy in North America. Non-randomized studies from Russia, Ireland and Australia utilizing three- and four-drug regimens, have reported ITT eradication rates ranging from 60 to 86% for furazolidone salvage regimens (211, 212, 213). The lack of RCTs reporting the comparative efficacy of furazolidone salvage therapy and its potential for harms including hypotension, urticaria, gastrointestinal symptoms, and reversible hemolysis make it impossible to recommend its use as a salvage treatment.
Amoxicillin is an important component of first-line and salvage regimens used to treat H. pylori infection. Fortunately, there are a number of evidence-based regimens that do not include amoxicillin and that can be used in patients with true allergy—most notably bismuth quadruple therapy. If a “penicillin-allergic” patient has failed 1 or 2 eradication attempts, it is then advisable to consider investigating whether or not the patient has a true penicillin allergy. Numerous studies have demonstrated that, although 5–10% of the US population state that they are “allergic” to penicillin, ˜90% of such patients have negative skin testing and can tolerate penicillin without hypersensitivity (214). Furthermore, penicillin avoidance without confirming true allergy is recognized in the United States as a public health issue, as it contributes to the overuse of non-beta-lactam containing antibiotics (http://www.choosingwisely.org/clinician-lists/american-academy-allergy-asthma-immunlogy-non-beta-lactam-antibiotics-penicillin-allergy/). Referral of these “penicillin-allergic” patients for skin testing will, therefore, result in most being found to be not truly allergic. After excluding true allergy, they can safely be prescribed amoxicillin-containing salvage regimens, as recommended for the non-allergic population.
This guideline is in overall agreement with the recently published Toronto Consensus for the treatment of H pylori infection in adults, which had a narrower focus and was restricted only to treatment options (215). Both guidelines attempt to restrict the use of clarithromycin triple therapy and strengthen the role of bismuth quadruple therapy and concomitant therapy. Both guidelines advocate for a longer duration of treatment (14 days for almost all regimens in the Toronto Consensus; 10–14 for almost all regimens in the ACG guideline). There are only a few differences between the two guidelines, occurring in areas with limited, low-quality evidence. The Toronto Consensus recommends against the use of sequential treatment (neither as a first-line therapy nor as a rescue treatment), while the ACG guideline conditionally recommends it as first-line therapy. Hybrid therapy and high-dose dual therapy are not officially endorsed by the Toronto Consensus, whereas the ACG guideline conditionally recommends them as first-line and rescue therapy respectively.
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Erik-Jan Wamsteker, MD, who served as guideline monitor for this document.
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