Hypersensitivity reaction to omeprazole in a patient treated for Helicobacter pylori

Introduction

Helicobacter pylori infection remains one of the most common bacterial infections in humans [Pounder and Ng, 1995; Cave, 1996]. These infections can cause gastritis, peptic ulcer disease, and gastric adenocarcinoma [Peterson et al. 2000]. Standard eradication regimens include combinations of antibiotics and antisecretory agents such as proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) [Chey and Wong, 2007]. PPIs have been used more commonly over H2RAs due to more effective acid suppression and antibacterial effects [Stoschus et al. 1996; McGowan et al. 1994; Gisbert et al. 2003]. We report the case of a H. pylori-positive patient who developed a hypersensitivity reaction to omeprazole therapy. The patient was subsequently treated with a triple therapy regimen that included pantoprazole without incident.

Case report

A 37-year-old woman with a medical history significant for alcoholic hepatitis presented with a chief complaint of ongoing nausea for several weeks. The patient had stopped drinking alcohol 12 weeks prior. Her medication regimen included furosemide 20 mg PO twice daily, spironolactone 50 mg PO daily, and tramadol 50 mg PO every 6 hours as needed. The patient also had six rods of retained levonorgestrel hormonal contraceptive. On the day of presentation, her liver function tests were within normal limits (total bilirubin 1.2 mg/dl, alkaline phosphatase 123 U/l, aspartate aminotransferase 34 U/l, alanine aminotransferase 26 U/l), as were her lipase (169 pg/ml) and serum creatinine (0.6 mg/dl) levels.

A serum H. pylori antibody test was ordered and the patient was treated with omeprazole 20 mg PO twice daily for the nausea and high pretest probability of H. pylori infection. The next day, serology testing confirmed a positive H. pylori test. Five days later, the patient reported an all-over urticarial rash. The patient confirmed taking the omeprazole twice daily for 3 days, discontinuing the drug on day 4, and on day 6 the rash had resolved. The precise day of therapy on which the rash appeared is unknown.

The patient was challenged with pantoprazole 40 mg PO twice daily (in addition to amoxicillin and clarithromycin) for 14 days. The patient completed her 14 day course of triple therapy and was continued on pantoprazole for ongoing gastroesophageal reflux disease (GERD) symptoms with no adverse reactions.

Based on the Naranjo Adverse Drug Reaction Probability Scale, the hypersensitivity to omeprazole was probable (score = 6; Table 1) [Naranjo et al. 1981].

Table 1.

Naranjo Adverse Drug Reaction Probability Scale results.

Criterion	Yes	No	Do not know or not applicable
Are there previous conclusive reports on this reaction?	+1	0	0
Did the adverse event occur after the suspected drug was administered?	+2	–1	0
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0
Did the adverse reaction reappear when the drug was readministered?	+2	–1	0
Are there alternative causes (other than the drug) that could have on their own caused the reaction?	–1	+2	0
Did the reaction reappear when a placebo was given?	–1	+1	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0
Total Score: 6

Note: Bold text indicates the score applicable to the case described.

Information from Naranjo et al. [1981].

Discussion

Treatment of H. pylori involves bacterial eradication and gastric ulcer healing with antibiotics and a PPI [Chey and Wong, 2007]. While PPIs are generally well-tolerated, PPI-induced hypersensitivity reactions can occur. These include urticaria, angioedema, anaphylaxis, cytopenia, vasculitis, acute allergic interstitial nephritis, contact dermatitis, drug rash with eosinophilia and systemic symptoms, Stevens–Johnson syndrome, and toxic epidermal necrolysis [Bose et al. 2013; Chang, 2012; Sobrevia Elfau et al. 2010].

Patients with PPI-related hypersensitivity fit into one of three categories: (1) hypersensitive to all PPIs; (2) selectively hypersensitive to PPIs, or (3) hypersensitive to one PPI and tolerant of all others (Table 2) [Sobrevia Elfau et al. 2010]. Category 1 may be explained by structural similarities as all commercially available PPIs are modified benzimidazoles with a shared pyridine ring. In category 2, selective hypersensitivity may occur based on the presence of side chain substitution on the PPI. The third category describes patients who exhibit hypersensitivity to a single PPI and are tolerant of all others [Sobrevia Elfau et al. 2010; Garrido Fernández et al. 2008; Özdemir et al. 2013].

Table 2.

Proton-pump inhibitor (PPI) cross-reactivity patterns.

Pattern	Description
1	Allergy to a single PPI with cross-reactivity to all PPIs
2	Allergy to two PPIs with tolerance of two alternative PPIs
3	Allergy to a single PPI with tolerance of all alternative PPIs

Information from Sobrevia Elfau et al. [2010].

In this case, the patient developed a hypersensitivity to omeprazole and tolerated pantoprazole. It is unknown whether the patient is intolerant of any other PPIs and therefore fits either category 2 or 3 (Table 2). Omeprazole and pantoprazole both contain substitutions in their benzimidazole rings but have slightly different pyridine rings (Figure 1) [AstraZeneca, 2013; Wyeth, 2013]. Omeprazole has a methoxy chain and pantoprazole a difluoromethoxy chain in their respective benzimidazole rings and omeprazole has two methyl and one methoxy groups in its pyridine ring while pantoprazole has two methoxy groups in this ring [Sobrevia Elfau et al. 2010; Garrido Fernández et al. 2008; Özdemir et al. 2013; AstraZeneca, 2013; Wyeth, 2013]. These variations in ring substitutions may explain why our patient reacted to omeprazole but not to pantoprazole despite both having predominantly substituted benzimidazole rings.

Figure 1.

Omeprazole and pantoprazole structural formulas with highlighted differences.

Alternative eradication regimens involve the use of quadruple therapy containing an H2RA [Chey and Wong, 2007]. One first-line regimen for H. pylori eradication includes bismuth subsalicylate 525 mg PO 4 times daily, metronidazole 250 mg PO 4 times daily, and tetracycline 500 mg PO 4 times daily for 2 weeks plus ranitidine 150 mg PO BID for 4 weeks. This regimen has a 75–90% eradication success rate, which is similar to clarithromycin-based triple therapy [Chey and Wong, 2007]. However, this regimen has several potential disadvantages, including decreased efficacy due to use of an H2RA, large pill burden with frequent dosing, and perceived increase in adverse effects [Chey and Wong, 2007; Fischbach et al. 2004].

In patients with a severe PPI allergy who require a PPI for treatment, PPI desensitization can be performed. One case report describes a 44-year-old male with symptomatic H. pylori gastritis who failed triple therapy twice and manifested an anaphylactic reaction to omeprazole during the third round. He underwent oral omeprazole desensitization in the inpatient setting, starting with 0.001 mg of omeprazole with a doubling of each dose given at 20-minute intervals. The final dose of 16 mg occurred after 5.6 hours of therapy, with a cumulative exposure of 32.6 mg. The patient was successfully treated with omeprazole 20 mg PO BID following the desensitization [Confino-Cohen and Goldberg, 2006]. Based on the cost and complexity of inpatient PPI desensitization, this option may be less desirable than treating a PPI-allergic patient with an H2RA instead.

Conclusion

A patient with H. pylori experienced a hypersensitivity reaction to omeprazole and was successfully treated with triple therapy that included amoxicillin, clarithromycin, and pantoprazole without incident. Because PPI use is so prevalent, hypersensitivity reactions to PPIs are not uncommon and yet cross-reactivity among members of the drug class is not clear. A patient may tolerate an alternative PPI or may be allergic to the entire drug class, in which case a different antisecretory agent would be warranted.