Treatment for Helicobacter infection in New Zealand a discussion document

Treatment for Helicobacter infection in New Zealand

A discussion document

Associate Professor Alan Fraser, University of Auckland

Losec HP (formerly Klacid HP7) has been the cornerstone of treatment for Helicobacter for the last 10 years. The recent withdrawal of Losec HP7 will have some consequences for treatment. The combination of omeprazole, clarithromycin and amoxicillin together as a pack has enhanced compliance and has been easy to prescribe. Giving treatment as separate items with endorsement required for clarithromycin will enable the treatment to continue to be available but may require some education of GP’s to ensure consistent prescribing and good patient compliance. Substitution of metronidazole for amoxicillin will continue as before for penicillin-sensitive patients.

The issue which has been developing over time is what to do with treatment failures. The success rate for the current combination in New Zealand is assumed to be over 85% but there is no local data. It is likely that the success rates are gradually decreasing as macrolide resistance becomes more prevalent. There is some cross-resistance to clarithromycin from the use of other macrolides. We do not know if increasing resistance to clarithromycin is an issue in New Zealand

Therefore there are significant numbers of patients who have failed eradication treatment. The majority are “failed treatments” are never diagnosed because follow-up is usually limited (no routine use of breath tests or faecal antigen tests) and mostly this is not a major clinical issue as only a small proportion of those treated have significant disease (i.e peptic ulcer disease) with a risk of future complications.

However there are patients who need to have effective second-line treatment. The options have been limited but the preferred strategy has been quadruple treatment - De-Nol tabs 2 bd, tetracycline HCl 500mg qid, omeprazole 20mg bd and metronidazole 400mg tds - usually for 7 days (some have advocated treatment for 14 days although reasonable evidence that 7 days is sufficient). Use of quadruple therapy with a PPI, bismuth, tetracycline and metronidazole is recommended by the updated Maastricht Consensus Report (Malfertheiner et al. 2007)

This was difficult treatment to prescribe, and consequently patient compliance was probably low and there were significant side-effects. Compliance is complicated by the differing dose frequencies and differing timing with meals required. Despite these difficulties there was some good success – reported eradication rates 60-75%.

The problem now is the withdrawal of bismuth treatments from the market - this includes DeNoltabs and also ranitidine bismuth citrate (RBC). An another problem in New Zealand is the lack of availability of tetracycline HCl. There is reasonable data to suggest that doxycycline and minocycline are ineffective substitutes in Helicobacter treatment.

In designing a treatment strategy for Helicobacter the focus should not be just on primary therapy, but on the overall plan for treatment of failures and the final (overall) eradication rate that is achieved. After failure of a combination of PPI, amoxicillin and clarithromycin, a theoretically correct alternative would be the use, as second option, of other PPI-based triple therapy including amoxicillin (that does not induce resistance) and metronidazole (an antibiotic not used in the first trial). However in practice this approach (as second-line treatment has proven to be disappointing (approx 50% eradication rate). Failures to treatment may be over-represented by people who have problems with compliance and it is not reasonable to expect someone to take multiple courses of different antibiotic combinations. Therefore the second-line treatment needs to have good efficacy and equal simplicity to the first treatment.

Levofloxacin-based 'rescue' therapy appears to be the best second-line strategy, representing a good alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure – this treatment has higher efficacy, simplicity of use (better compliance) and less adverse effects.

Levofloxacin is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. Levofloxacin has, in vitro, remarkable activity against H. pylori and primary resistance is relatively infrequent (when compared with metronidazole or clarithromycin). A recent in vitro study also showed a synergistic effect of quinolone anti-microbial agents and PPIs on strains of H. pylori. Levofloxacin (in vitro) retains its activity when H. pylori strains are resistant to clarithromycin and metronidazole. These favorable results have been confirmed in vivo, indicating that most of the patients with both metronidazole and clarithromycin resistance are cured with the levofloxacin-based regimen. A combination of a PPI, amoxicillin and levofloxacin, as first-line regimen, has mean eradication rates of about 90%. For patients with one previous eradication failure, H. pylori cures rates range from 60% to 94%. A recent systematic review showed a mean eradication rate with levofloxacin-based 'rescue' regimens (combined with amoxicillin and a PPI in most studies) of 80%, which represents a relatively high figure when considering 'rescue' therapy will have have eradication rates lower than first-line treatments.

A systematic review found higher H. pylori cure rates with 10-day than with 7-day regimens with the levofloxacin-amoxicillin-PPI combination in particular (80% versus 68%), suggesting that the longer (10-day) therapeutic scheme should be chosen. The daily dose is still unclear but 500mg daily may be as effective as 500mg bd.

Two recent meta-analyses have suggested that after H. pylori eradication failure, levofloxacin-based 'rescue' regimen is more effective than the generally recommended quadruple treatment. Levofloxacin is generally well tolerated, and most adverse events associated with its use are mild to moderate in severity and transient. The most frequent adverse effects affect the gastrointestinal tract. Occasional cases of tendinitis and tendon rupture have been reported in the literature with levofloxacin therapy. However, data derived from more than 15 million prescriptions in the US indicated the rate is fewer than 4 per million prescriptions. Adverse effects were reported, overall, by 18% of the patients treated with levofloxacin-based therapies, and these adverse effects were severe (defined so by the authors or explaining treatment discontinuation) in only 3% of the cases. The incidence of adverse effects was not different when levofloxacin-amoxicillin-PPI was administered for 7 or 10 days

Resistance to quinolones is easily acquired, and in countries with a high consumption of these drugs, the resistance rate is increasing and is already relatively high. The presence of levofloxacin resistance will significantly reduce the eradication rate following a therapy with this antibiotic. Therefore, levofloxacin should be reserved for 'rescue' treatment to avoid the increase of the resistance phenomenon.

Proposal

Levofloxacin should be available under special authority for use by gastroenterologists as second-line treatment for H.pylori infection. The recommended dose would be 500mg daily in combination with omeprazole 20mg bd and amoxicillin 1g bd.

The success of quinolone -based treatment for Helicobacter will depend on the rate of primary resistance to quinolones in New Zealand.



Meta-analysis - favours levofloxacin-based treatment over quadruple treatment

References

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Appendix:
Table from Di Caro, S. Digestive & Liver Diseases. 2009; 41: 480

Levofloxacin-based second-line therapies for H. pylori eradication. L: levofloxacin; A: amoxicillin; T: tinidazole; M: metronidazole; Ri: rifabutin; Az: azithromycin; E: esomeprazole; R: rabeprazole; O: omperazole; La: lansoprazole; P: pantoprazole. OD: once daily; BD: twice daily; ITT: intention-to-treat eradication rate.

Studies	Scheme	Patients	ITT (%)
Gisbert et al	LAO (10 days; L: 500 mg BD)	150	81
Gisbert et al.	LAO (10 days; L: 500 mg BD)	300	77
Cheng et al.	LALa (7 days; L: 500 mg OD/BD)	124	79/80.6
Wong et al.	LRiR-LALa (7 days; L: 500 mg OD)	53/53	91/57
Lee et al.	LAE (10 days; L: 500 mg OD)	105	91.4
Kang et al.	LAzO (7 days; L: 500 mg BD)	29	65.5
Giannini et al.	LTR (4/7 days; L: 500 mg BD)	85	83/84
Matsumoto et al.	LALa (7 days; L: 300 mg BD)	30	70
Bilardi et al.	LAP (10 days; L: 250 mg BD)	44	70
Watanabe et al.	LALa (7 days; L: 200 mg OD)	33	69.7
Perri et al.	LAP (7 days; L: 500 mg OD)	60	63
Nista et al	LAR-LTR (10 days; L: 500 mg OD)	140	94

Full-size table