Helicobacter pylori positive Peptic Ulcer

Disease: Antibiotic resistance to first line

therapy
David Wang, Pharm.D. Candidate

Introduction
Helicobacter pylori is a gram-negative bacterium that was first identified in 1982. Since that

time, several studies and surveys have demonstrated the importance of H. pylori as one of the

major etiological factors in chronic gastritis, peptic ulcer disease (PUD), and stomach cancer.

(Table 1)1,2 H. pylori is considered the most common chronic infection worldwide and in the

United States it is estimated the percentage of the population infected by this bacteria is 30-40%.2

In the United States alone, it is estimated that PUD affects > 6 million people every year and data

from the Nationwide Inpatient Sample database shows that there were a total of 1,453,892

hospitalizations for PUD from 1998-2005.3,4 Sandler et al., the estimated US economic burden

of PUD was greater than 3.1 billion dollars in 1998 costs. This was the 4th highest total for

gastrointestinal diseases in their study, behind only gastroesophageal reflux disease (GERD),

gallbladder disease, and colorectal cancer.5

Table 1. Rates of H. pylori incidence in gastric disease states.2

Duodenal Ulcer Gastric ulcer Dyspepsia Gastric Cancer
% of Incidence 50-75% 65-95% 20-60% 70-90%

Studies performed after the discovery of H. pylori as a causative agent of PUD have shown that

the eradication of the infection leads to ulcer healing, a decrease in recurrence, and greater

symptom relief.5 Before the advent of antibiotics in the eradication of H. pylori, treatment

options were limited to lifestyle changes, long-term acid suppression and vagotomy. Sonnenberg
et al., evaluated the costs of each of these treatment options and showed that antibiotic treatment

was the most cost effective option for treating PUD. (Table 2)6

Table 2. Cost evaluation of PUD treatments6

Antibiotic Therapy Long-term acid Ulcer Surgery (selective
suppression vagotomy)
Costs in 1993 dollars $995 $11, 186a $17,661a
a Figures have been extrapolated out to 15 years of therapy due to the lack of eradication with the treatment.

Presently, the consensus treatment for H. pylori positive PUD is triple therapy with two

antibiotics and a proton pump inhibitor.1,7 However, there is a risk to antibiotic usage; the

selection and spread of resistant strains of H. pylori. Recent studies have shown that the first line

antibiotics clarithromycin, metronidazole, and amoxicillin have experienced a drop in efficacy

due to the emergence of resistant strains of bacteria.8, 9, 10 The purpose of this article is to review

possible mechanisms of resistance to the first line antibiotics, rates of incidence of resistant H.

pylori strains, and recommendations for treatment in resistant infections.

Treatment Regimens: Guideline recommendations

Both the European Helicobacter Pylori Study Group (EHPS) and American College of

Gastroenterology (ACG) have released updated guidelines on the treatment of H. pylori.1,7 The

EHPS and the ACG first line therapy recommendations include clarithromycin (500mg twice

daily), a PPI (standard dosing), and amoxicillin (1 gram twice daily), or the same combination

with a substitution of amoxicillin with metronidazole (400 or 500 mg twice daily). 1,7 The EHPS

makes mention that these regimens should only be used if known population resistance of

clarithromycin is less than 15-20%.7 The ACG states that clinicians should be aware that

resistance could be a problem and cites Vakil et al., whose multicenter study of 3, 7, and 10 day

triple therapy showed that none of the first-line antibiotic regimens achieved greater than 78%

eradication rates.11 See Table 3 for common treatment regimens and associated patient cost.
Table 3. Common Treatment Regimens for Helicobacter pylori Eradication12
Regimen Duration Estimated total regimen cost to
patienta
Omeprazole (Prilosec®), 20 mg
twice daily, plus amoxicillin
(Amoxil®), 1 g twice daily, plus 14 days $150.64
clarithromycin (Biaxin®), 500 mg
twice daily
Lansoprazole (Prevacid®), 30 mg
twice daily, plus amoxicillin, 1 g
10 to 14 days $141.80-170.52
twice daily, plus clarithromycin, 500
mg twice daily
Omeprazole (Prilosec®), 20 mg
twice daily, plus metronidazole
(Flagyl®), 500 mg twice daily, plus 14 days $132.96
clarithromycin (Biaxin®), 500 mg
twice daily
Bismuth subsalicylate (Pepto-
Bismol®), 525 mg four times daily,
plus metronidazole (Flagyl®), 250
14 days (additional 14 days of H2
mg four times daily, plus $41.72
blocker treatment only)
tetracycline (Sumycin®), 500 mg
four times daily, plus histamine H2
blocker
a. Costs obtain from www.drugstore.com on 9/18/2010, generics used when available; ranitidine was used as the H2 blocker
of choice.

Mechanism of Resistance: Clarithromycin, Metronidazole, and Amoxicillin

Clarithromycin:

Resistance to clarithromycin is an important consideration due to its inclusion as a major

component of the first line treatment regimens.13 The mechanism of action for clarithromycin

resistance in H. pylori is associated with three point mutations in the 23s rRNA gene.14 These

point mutations are A2143G, A2142G, and A2142C. Each of these mutations can cause

conformational changes in the peptidyl transferase loop of domain V of the 23s ribosomal RNA,

causing a decrease in the binding affinity of clarithromycin to bacterial ribosomes.15 This

resistance is selected with through increased antibiotic use and is subsequently passed along via

vertical transmission to bacterial progeny.

Metronidazole:

Metronidazole resistance is a much larger concern in developing countries due to its availability

over the counter, inexpensiveness, and its usage to treat parasitic infections indigenous to the

local areas. Some studies have shown that resistance to metronidazole can be above 90% in these

countries.13 The basis of resistance for metronidazole is the lack of its activation inside the H.

pylori bacteria into its active reduced form.16 There is some evidence that shows metronidazole

resistance may be combated by longer durations and the usage of higher doses.1,7

Amoxicillin:

Presently it is considered that resistance to amoxicillin is negligible with no appreciable effect on

eradication rates.1,7 However, there are newer studies showing that amoxicillin resistant strains

are on the rise and could soon be a major factor in treatment decisions of H. pylori infections. 17

DeLoney et al., evaluated a selected strain of amoxicillin resistant H. pylori where distinct two

mechanisms of resistance were identified. This particular strain overcame amoxicillin’s effects

through altered penicillin binding proteins and what the authors state as either a diffusion barrier

or efflux pump mechanism limiting the amount of amoxicillin allowed into the cell.18

Studies on resistance rates of H. pylori to antibiotics:

Please refer to Table 4, for a summary of antibiotic resistant H. pylori prevalence for the US and

worldwide.

Table 4. Comparison of primary resistance prevalence in different parts of the world.21

Country Years Type # Clarithromycin Metronidazole Amoxicillin Reference

of strains Resistance (%) Resistance (%) Resistance
Study tested (%)

Germany 95-00 MonoC 1644 2.2 26.2 0 Wolle22

 Italy 98-02 MonoC 406 23.4 36.7 0.2 Torachio23

Spain 95-98 MonoC 235 12.9 23.5 0 Cuchi Burgos24

United 95-98 MonoC 843 3.9 36 0.4 Teare25

Kingdom

Mexico 95-97 MonoC 144 25 76.3 0 Torres26

USA* 93-99 MultiC 3439 10.6 21.6 0.08 Osato19

USA* 93-99 MultiC 3624 10.1 36.9 1.4 Meyer20

Iran 02 BiC 203 9.8 53 ND Mohammadi27

Hong 97-01 MonoC 991 4.5 2.9 0.3 Ling28

Kong

Japan 95-00 MonoC 593 11 9 0.3 Perez Aldana29

Korea 94-99 BiC 456 5.9 40.6 0 Kim30

Singapor 93-96 MonoC 459 ND 62.7 ND Teo31

e

New 93-98 MonoC 225 6.8 32 ND Fraser32

Zealand

*Denotes studies discussed in text., ND = Not Determined

Pattern of Primary Resistance to Metronidazole or Clarithromycin

In a study by Osato et al, the frequency of primary claritrhromycin and metronidazole resistance

among H. pylori isolated from patients enrolled in 17 US-based antibiotic treatment trials

between 1993 and 1999 was reviewed in relation to patient age, sex, and region of the United

States.19 The database consisted of 3439 samples of which prevalence rates of clarithromycin and

metronidazole resistance were calculated for the total isolates. Over the 7 years rates of

resistance to clarithromycin varied among the years of evaluation (χ2 = 12.855; P=.05) with a

combined overall prevalence of 11.1% and a range from 6.1% to 14.5%. Metronidazole

resistance differed based upon which test method was used, E-test or agar dilution. For the E-

test metronidazole prevalence was 39% versus 25.2% as determined with the agar dilution
methods (P<.001). In the study women were more likely than men to have a metronidazole-

resistant strain (63% vs 35.1%, respectively, as determined by E-test [P=.01] and 34.7% vs

22.6%, respectively, as determined by agar dilution [P=.03]). Comparatively women were also

more likely to have clarithromycin resistant strains as well, but the difference (14.1% to 9.7%)

was not statistically significant (P=.06). Age also played a factor in resistance determination

with those over 70 years of age showing lower resistance than those people aged between 20 and

70. Metronidazole resistance increased to 50% in the middle-aged population than dropped to

31% after the age of 70 years (P=.05) and those over 70 were also less likely to be

clarithromycin resistant as well (P<.05). As for regional differences, there was some variation

but nothing that was statistically significant (P>.20). The most important outcome of this study

for this article was the observed metronidazole resistance prevalence of 35% and clarithromycin

resistance prevalence of 11%.

Risk Factors for Helicobacter pylori Resistance in the United States: The Surveillance of H.

pylori Antimicrobial Resistance Partnership (SHARP) Study, 1993–1999

In a meta-analysis by Meyer et al, patient-level data was used to estimate the prevalence of H.

pylori resistance to antimicrobials in the United States, to characterize risk factors associated

with resistance, and to explore association between drug utilization and antimicrobial resistance

over time.20 Data was gathered from 20 nationwide H. pylori eradication trials in the United

States between the years of 1993 to 1999. Meta-analysis of this information was used to

combine information about the relationship between H. pylori resistance and eight risk factors,

geographic location, age, sex, year of enrollment, ethnicity, ulcer status, test method, and study.

In the analysis overall clarithromycin-resistance prevalence was 10.1% (95% CI, 9.1% to 11.1%)

with significant variation attributed to geographic region (P = 0.014), age (P < 0.001), sex (P <
0.001), year of enrollment (P = 0.003), ulcer status (P < 0.001), and study (P = 0.004).

Clarithromycin resistant H. pylori was more likely in the mid-Atlantic and northeastern regions

of the US, older patients, women, and patients with an inactive ulcer. Overall metronidazole

resistance was 36.9% (CI, 35.1% to 38.7%) with significant variation attributed to geographic

region (P = 0.042), age (P = 0.002), sex (P < 0.001), ethnicity (P < 0.001), ulcer status (P <

0.001), test method (P < 0.001), and study (P < 0.001). Metronidazole resistance was higher in

the southeastern United States, in females, those of Asian ethnicity, those enrolled in earlier

years, and in those where E-test was used. Amoxicillin resistance was significantly variable

between studies (P=0.002). The level of prevalence was low overall and none of the covariates

were significantly associated with increased amoxicillin resistance. The authors also investigated

the occurrence of H. pylori with resistance to both clarithromycin and metronidazole.

Approximately 3.9% (CI, 3.2% to 4.7%) of the tested isolates were positive for dual resistance.

Dual resistance was significantly variable with sex (P < 0.001), age (P = 0.001), year (P = 0.094),

ethnicity (P = 0.03), and study (P = 0.069). Higher levels were found in women, those aged

greater than 40, and those of Asian ethnicity. In the discussion the authors make an observation

that pretreatment antimicrobial resistance of H. pylori has been found to have a negative impact

on treatment efficacy with clarithromycin being the most compromising of the studied

resistances. The clarithromycin resistance affects dual therapy (95.1% failure rate) more so than

triple therapy (68.6% failure rate), but does lead to the need of salvage therapy in those

individuals. Metronidazole resistance is associated with a reduction of efficacy of approximately

37.7% in triple therapy regimens but quadruple-therapy regimens (PPI, bismuth, tetracycline,

and metronidazole) were equally effective in treating both metronidazole-susceptive and

metronidazoale-resistant strains (92%, range 63%-100%), if given for longer than 7 days.
Treatment for Resistant H. pylori Infections.

With the decreasing eradication rates of clarithromycin based therapy in the United States, there

is an emerging need for therapies to address those with primary resistance and patients who fail

their initial therapy regimens.13 The ACG recommends that initial clarithromycin based triple

therapy should be given for 14 days to achieve greater than 80% eradication rate, which 3, 7, and

10 day durations do not achieve.1 In the occurrence of persistent H. pylori infection, effort should

be made to avoid the usage of any antibiotics that the patient may have previously taken,

including macrolides, quinolones, and nitroimidazoles due to the high likely hood of pressure

selection of resistant strains by exposure.21

FDA approved second line therapy includes a 10-14 day quadruple regimen of bismuth, a PPI,

tetracycline, and metronidazole (regimen is also approved as an alternate 1st line therapy). The

disadvantage with this regimen is the daily pill burden, up to 18 pills a day, and the four times

daily dosing frequency.1 A number studies have tested alternative salvage therapies that have not

received US approval. Perri et al, used 10 day course of rifabutin 150mg/300mg once daily,

pantoprazole 40 mg twice daily, and amoxicillin 1g twice daily to achieve an eradication rate of

87% in resistant H. pylori infections.33 Another study used a 10 day regimen of panatoprazole

40mg, amoxicillin 1g, and levofloxacin 250mg, all given twice daily which yielded a 70%

eradication rate in resistant H. pylori infections.34 Thirdly, a sequential therapy lasting 10 days,

involving a PPI (standard dose twice daily) and amoxicillin (1g twice daily) for 5 days followed

by 5 days of a PPI (standard dose twice daily), clarithromycin (500mg twice daily), and

tinidazole (500mg twice daily) achieved an 89% eradication rate in patients with documented

clarithromycin resistance.35
Summary

Almost three decades have passed since Helicobacter pylori was discovered and implicated as a

major causative factor of peptic ulcer disease. Through antibiotic selective pressure and vertical

transmission of resistance mutations, H. pylori has gradually blunted the efficacy of first line

triple therapy to a point where persistent infections have become almost a 1 in 5 occurrence.

Antibiotic therapy is still the most cost effective treatment for H. pylori positive PUD, however

FDA approved second line therapies are limited by decreased eradication levels and high pill

burdens. There is however promising alternatives with initial results that show good eradication

levels against resistant H. pylori infections. Therefore with conscious usage of therapies,

clinicians can still effect a cure for PUD.

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