Tasman Medical Journal

ISSN: 2652-1881

Increasing secondary resistance to fluoroquinolones amongst Helicobacter pylori in Western Australia

Puraskar Pateria, Marcus Chin, Romilly Goodheart, Cheryll McCullough, Edward Raby, James O. Robinson and Paul R. Ingram

ABSTRACT

Background  The Australian Therapeutic Guidelines does not endorse culture and susceptibility testing prior to salvage therapy for Helicobacter pylorieradication.  We wished to determine whether this remains appropriate.

Aim  To determine the sensitivity (as minimum inhibitory concentrations, MIC) of H pylorito a range of antibiotics used in salvage therapy over time.

Methods  From 2012 to 2017, gastric or duodenal biopsy samples were obtained from 154 patients receiving H pylorieradication therapy.  MIC for amoxicillin, clarithromycin, tetracycline, metronidazole, rifampicin and levofloxacinwere measured using standard laboratory techniques.

Results  A significant increase from zero to 28% in secondary resistance to levofloxacin amongst H. pyloriin Western Australia was noted over the study period.  No corresponding trend was seen with the other antibiotics.

Conclusions  These findings suggest that selective use of culture and susceptibility testing may be warranted prior to initiating salvage therapy with levofloxacin.   Tasman Medical Journal 2020; 2: 15-19

Full Text

Introduction

The prevalence of H pylori (HP) in Australian populations varies between the non-indigenous (15.4 – 30.6%), indigenous (76%) and migrant populations (46.2 – 91%).1-3 HP eradication therapy has a role in the management of peptic ulcer disease, non-ulcer dyspepsia, gastric cancer and mucosa-associated lymphoid tissue lymphoma.4-6  Selection of first-line and salvage HP eradication therapy is guided by local surveillance studies as both primary (obtained from patients without prior HP eradication therapy) and secondary (obtained from patients with at least one course of prior HP eradication therapy) isolate resistance demonstrates significant global geographical variation.7,8 The Australian Therapeutic Guidelines endorses the combination of clarithromycin, amoxicillin and a proton pump inhibitor as first-line eradication therapy, based upon local susceptibility data. In the event of treatment failure, salvage therapies include a fluoroquinolone (most commonly levofloxacin), rifabutin-based triple therapy or tetracycline-based quadruple therapy.9 Historically low rates of resistance to all three of these classes of antimicrobials10,11 has meant salvage therapy selection has not required prior culture and susceptibility testing.4,9

We wished to determine the local (Western Australia) prevalence, including temporal trends, of secondary resistance amongst HP, and to identify host risk factors for fluoroquinolone resistance. 

Methods

We performed a prospective cohort study from 2012 to 2017.  This included all patients who had received at least one course of HP eradication therapy, and from whom a HP isolate was subsequently cultured from gastric and/or duodenal biopsy specimens.  The material was processed by the Microbiology Department of PathWest Laboratory Medicine (PathWest, Perth WA) at the Royal Perth Hospital (RPH).   RPH is a tertiary metropolitan public teaching hospital in Perth, Western Australia.

Cases were identified on the basis of the laboratory log of all isolates for which susceptibility testing was performed. Specimen processing and susceptibility testing utilised standardised laboratory methods.12  The MIC for amoxicillin, clarithromycin, tetracycline, metronidazole, rifampicin and levofloxacin were determined using Etests according to the manufacturer’s instructions (AB Biodisk, Sweden) and interpreted using European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoints.13

For patients harbouring fluoroquinolone-resistant isolates, patient demographics and details of prior HP eradication therapy were extracted retrospectively from patient medical records.  For the purposes of comparison, the same information was extracted for twice as many randomly selected patients harbouring fluoroquinolone-susceptible isolates. 

Statistics

Comparison of demographic variables between groups was assessed by chi-squared test for categorical variables. All statistical analysis was done using SPSS software (v25) and p < 0.05 was considered significantEthics approval was obtained from the East Metropolitan Health Human Research Ethics Committee.

Results

The study cohort consisted of 154 patients with a median age of 45 years (interquartile range 37-58), of whom 49% were male. Their regions of birth were Australia (n=64, 41.5%), Asia (n=63, 40.9%), Europe (n=11, 7%), Africa (n=9, 5.8%), Middle East (n=6, 3.8%) and North America (n=1, 0.6%). 

Table 1 provides the rates of HP isolates with secondary resistance to differing antimicrobial classes.  There was a significant temporal increase in resistance of HP to levofloxacin from 2012 to 2017 when expressed as the percentage of all isolates with each class of antimicrobial (p < 0.001).  As similar trend was not observed with other antimicrobial classes but a late increase in resistance for rifampicin was noted.  The MIC50 and MIC90 for levofloxacin over the study period were 0.064 and 4 microg/mL respectively.  

Rates of levofloxacin resistance were significantly higher in those born outside of Australia (20/90, 22.2 %) compared to those born within Australia (0/64, 0%; p<0.001). The countries of birth of patients with levofloxacin resistant isolates were China (7), India (3), Russia (2), Afghanistan (2), Vietnam (2), Iran (2), Korea (1) and Sudan (1).

Prior exposure to fluoroquinolones occurred in 13 (65%) of 20 patients with levofloxacin resistant isolates, compared to 5 (12.5%) of 40 patients with levofloxacin susceptible isolates (OR 15.17, 95% CI, 3.9–58.3, p<0.001).  Multivariate analysis showed that prior fluoroquinolone use and being born overseas were co-variates (p = 0.024).

Table 1: Temporal trends of percentage of Helicobacter pylori isolates with secondary resistance to differing antimicrobials.
Table 1: Temporal trends of percentage of Helicobacter pylori isolates with secondary resistance to differing antimicrobials.

Discussion

Our study demonstrates that in a collection of Western Australian HP isolates, secondary resistance to fluoroquinolones increased progressively from zero to 27.8% from 2012-2017 (Table 1). This trend may be driven by an increasing number of isolates obtained from patients born overseas.  This is a novel risk factor for fluoroquinolone-resistant Helicobactor pylori.

Systematic antimicrobial susceptibility surveillance programs exist in Australia and New Zealand for a wide variety of bacterial pathogens, however these programs do not include HP.14 We are aware of only 1 previous Australian study of secondary resistance to fluoroquinolones.15 Seven years ago, Tay et alfound a rate of secondary resistance to fluoroquinolones of 6%, but no attempt was made to examine temporal trends or risk factors for harbouring fluoroquinolone resistant isolates.

Increasing rates of fluoroquinolone resistant HP are well described overseas.10,16,17  However, in contrast to the Australian setting, this has largely been attributed to increased rates of primary resistance10 which in turn correlates with increased community consumption of fluoroquinolones.18 Due to a policy of restricted access, the Australian community experiences uniquely low usage of fluoroquinolones,14 which is reflected in a recent Australian study demonstrated nil primary fluoroquinolone resistance with HP.19

Several factors may explain increasing secondary resistance to fluoroquinolones in Australia.  Firstly, immigration to Australia from neighbouring developing countries, in which there are higher rates of fluoroquinolone resistant HP, is increasing1,15,20 and importation of fluoroquinolone resistant pathogens other than HP has previously been described.21,22  As has occurred overseas,16,18,23 increased use of fluoroquinolone-based salvage therapy is likely to be occurring in Australia as, during the study period, more recent versions of the national guidelines endorsed fluoroquinolone-based salvage regimes9 and levofloxacin availability increased.9 Following fluoroquinolone exposure, stepwise point mutations within the gyrAand gyrBregions leads to an incremental increase in fluoroquinolone MIC24 and prior fluoroquinolone therapy has previously been shown to be a risk factor for resistance to this class of antimicrobial.18,25 Prior non-fluoroquinolone therapy also been shown to be a risk factor for fluoroquinolone resistance in HP, possibly due to co-selection of fluoroquinolone resistance determinants.26

Our findings have important clinical implications.  Currently empiric fluoroquinolone-based salvage therapy without prior biopsy for culture and susceptibility testing is endorsed by the Australian Therapeutic Guidelines.9  The major determinant of successful HP eradication is the absence of pre-treatment resistance27 and a recent international consensus statement4 proposed that when clarithromycin resistance rates exceed 15-20%, this class of antimicrobial should not constitute part of empirical HP eradication therapy.  By extension, our data suggests that, for a subset of patients receiving salvage therapy, fluoroquinolone resistance may have exceeded this threshold in Western Australia.  Thus we believe there may be a role for selective culture and antimicrobial susceptibility testing to guide choice of salvage therapy.  In the context of HP demonstrating 12% secondary resistance to fluoroquinolones, a recent Italian randomised controlled trial demonstrated this strategy to be associated with significantly higher rates of HP eradication.28 It may also be more cost effective.29.30  On the basis of our and others data, patients who would benefit from this strategy could be identified based upon risk factors for fluoroquinolone resistance such as country of residence7,10,18 or birth, prior fluoroquinolone-based HP eradication therapy and increasing age.5,25

Throughout the study we demonstrated low rates of resistance to amoxicillin, indicating that it remains an appropriate component of fluoroquinolone-based salvage regimes. I n the event that non-fluoroquinolone based salvage therapy is warranted, isolates are (on the basis of our data) more likely to be susceptible to tetracycline than rifampicin, while acknowledging that rifampicin resistant does not necessarily predict rifabutin resistance.31

Our study has several other limitations.  Being a tertiary hospital laboratory, there may be a selection bias towards more resistant isolates.  HP susceptibility profiles are geographically disparate which may limit the generalisability of our data, and emphasises the need for periodic local surveillance to inform therapeutic guidelines.  We did not analyse clinical outcomes and hence we were unable determine the in vivoimpact of fluoroquinolone resistance.  We note that fluoroquinolone-based salvage therapy demonstrated 90% HP eradication success rate in the Australian context, although secondary resistance rates were not assessed.19

Conclusions

Our study demonstrates that, as with other pathogens in Australia and overseas,14 rates of antimicrobial resistance in HP continue to rise, which has implications for selection of empiric salvage therapy.  There may be an increased need for selective culture and susceptibility testing, performed on patients selected based upon risk factors such as prior fluoroquinolone therapy and country of birth. 

Conflicts of interest: None declared.
Ethical approval:Approved by East Metropolitan Health Human Research Ethics Committee.
Funding: Not required
Review: Internal review by TMJ.

Corresponding Author 
Dr Puraskar Pateria, Department of Gastroenterology, Royal Perth Hospital, PO Box X2213, Perth, WA 6847, Australia.
Email – Puraskar.Pateria@health.wa.gov.au

REFERENCES

1. Pandeya N, Whiteman DC.  Prevalence and determinants of Helicobacter pylori sero-positivity in the Australian adult community.  J Gastroenterol Hepatol. 2011; 26: 1283-9.

2. Windsor HM, Abioye-Kuteyi EA, Leber JM, Morrow SD, Bulsara MK, Marshall BJ.  Prevalence of Helicobacter pylori in Indigenous Western Australians: comparison between urban and remote rural populations.  Med J Aust 2005; 182: 210-3.

3. Moujaber T, MacIntyre CR, Backhouse J, Gidding H, Quinn H, Gilbert GL. The seroepidemiology of Helicobacter pylori infection in Australia.  Int J Inf Dis 2008; 12: 500-4.

4. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG  Clinical Guideline: Treatment of Helicobacter pylori Infection. Amer J Gastroenterol 2017; 112: 212-39.

5. Malfertheiner P, Megraud F, O’Morain CA, Gisbert JP, Kuipers EJ, Axon AT, et al.Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.  Gut 2017; 66: 6-30.

6. Nakamura S, Sugiyama T, Matsumoto T, Iijima K, Ono S, Tajika M, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan.  Gut 2012; 61: 507-13.

7. Thung I, Aramin H, Vavinskaya V, Gupta S, Park JY, Crowe SE, et al. Review article: the global emergence of Helicobacter pylori antibiotic resistance.  Alimentary Pharmacol Ther 2016; 43: 514-33.

8. Boyanova L, Gergova G, Markovska R, Kandilarov N, Davidkov L, Spassova Z, et al.Primary Helicobacter pylori resistance in elderly patients over 20 years: A Bulgarian study.  Diag Microbiol Infect Dis 2017; 88: 264-7.

9. Helicobacter pylori infection [2017 Nov]. [Internet]. Melbourne: Therapeutic Guidelines Ltd.  Available from: http://www.tg.org.au. Accessed 18 January 2018].

10.Kuo YT, Liou JM, El-Omar EM, Wu JY, Leow AHR, Goh KL, et al.  Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis.  Lancet Gastroenterology & Hepatology 2017; 2: 707-15.

11. Katelaris PH, Forbes GM, Talley NJ, Crotty B.  A randomized comparison of quadruple and triple therapies for Helicobacter pylori eradication: The QUADRATE Study.  Gastroenterol 2002; 123: 1763-9.

12. James Versalovic KCC, Guido Funke, James H Jorgensen, Marie Louise Landry, David W Warnock. Manual of Clinical Microbiology, 10th ed: 2011: ASM Press Washington USA.

13. European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diametersV8.0 (2018) www.eucast.org/ast_of_bacteria/previous_versions_of_documents/  Accessed 28/1/2020.

14. Australian Commission on Safety and Quality in Health Care. Antimicrobial Use and Resistance in Australia (AURA): 2nd Australian Report on Antimicrobial Use and Resistance in Human Health. Sydney 2017. https://www.safetyandquality.gov.au/our-work/antimicrobial-resistance/antimicrobial-use-and-resistance-australia-surveillance-system-aura/aura-2017 Accessed 28/1/2020

15. Tay CY, Windsor HM, Thirriot F, Lu W, Conway C, Perkins TT, et al.  Helicobacter pylori eradication in Western Australia using novel quadruple therapy combinations.  Alimentary Pharmacol Ther 2012; 36: 1076-83.

16. Zhang YX, Zhou LY, Song ZQ, Zhang JZ, He LH, Ding Y.  Primary antibiotic resistance of Helicobacter pylori strains isolated from patients with dyspeptic symptoms in Beijing: a prospective serial study. World J Gastroenterol 2015; 21: 2786-92.

17. Hung KH, Sheu BS, Chang WL, Wu HM, Liu CC, Wu JJ. Prevalence of primary fluoroquinolone resistance among clinical isolates of Helicobacter pylori at a University Hospital in Southern Taiwan. Helicobacter 2009; 14: 61-5.

18. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, et al.Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption.  Gut 2013; 62: 34-42.

19. Katelaris PH, Katelaris AL.  A prospective evaluation of levofloxacin-based triple therapy for refractory Helicobacter pylori infection in Australia.  Int Med J 2017; 47: 761-6.

20. Gibney KB, Mihrshahi S, Torresi J, Marshall C, Leder K, Biggs BA. The profile of health problems in African immigrants attending an infectious disease unit in Melbourne, Australia.  Amer J Trop Med Hygiene 2009; 80: 805-11.

21. Tapsall JW, Limnios EA, Murphy D. Analysis of trends in antimicrobial resistance in Neisseria gonorrhoeae isolated in Australia, 1997-2006. J Antimicrob Chemother 2008; 61: 150-5.

22. Annual Report of the Australian Gonococcal Surveillance Programme, 2009. Communicable diseases intelligence quarterly report 2010; 34(2): 89-95.See also https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-cdi3402a.htm  Accessed 28/1/2020

23. Cabrita J, Oleastro M, Matos R, Manhente A, Cabral J, Barros R, et al.Features and trends in Helicobacter pylori antibiotic resistance in Lisbon area, Portugal (1990-1999). J Antimicrob Chemother 2000; 46: 1029-31.

24. Glocker E, Stueger HP, Kist M. Quinolone resistance in Helicobacter pylori isolates in Germany. Antimicrob Agents Chemother 2007; 51: 346-9.

25. Chuah SK, Tai WC, Hsu PI, Wu DC, Wu KL, Kuo CM, et al.The efficacy of second-line anti-Helicobacter pylori therapy using an extended 14-day levofloxacin/amoxicillin/ proton-pump inhibitor treatment – a pilot study.  Helicobacter 2012; 17: 374-81.

26. Berning M, Krasz S, Miehlke S.  Should quinolones come first in Helicobacter pylori therapy?  Ther Adv Gastroenterol 2011; 4: 103-14.

27. McMahon BJ, Hennessy TW, Bensler JM, Bruden DL, Parkinson AJ, Morris JM, et al.The relationship among previous antimicrobial use, antimicrobial resistance, and treatment outcomes for Helicobacter pylori infections. Ann Int Med  2003; 139: 463-9.

28. Marzio L, Coraggio D, Capodicasa S, Grossi L, Cappello G. Role of the preliminary susceptibility testing for initial and after failed therapy of Helicobacter pylori infection with levofloxacin, amoxicillin, and esomeprazole.  Helicobacter 2006; 11: 237-42.

29. Sugimoto M, Furuta T.  Efficacy of tailored Helicobacter pylori eradication therapy based on antibiotic susceptibility and CYP2C19 genotype. World J Gastroenterol 2014; 20: 6400-11.

30. Wenzhen Y, Yumin L, Quanlin G, Kehu Y, Lei J, Donghai W, et al.  Is antimicrobial susceptibility testing necessary before first-line treatment for Helicobacter pylori infection? Meta-analysis of randomized controlled trials.  Int Med (Japan) 2010; 49: 1103-9.

31. Cavusoglu C, Karaca-Derici Y, Bilgic A. In-vitro activity of rifabutin against rifampicin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations.  Clin Microbiol Infection 2004; 10: 662-5.

Publication Categories

AUTHOR INFORMATION

Dr Puraskar Pateria

OCCUPATION
Physician
INSTITUTIONAL AFFILIATIONS
Royal Perth Hospital

Dr Marcus Chin

OCCUPATION
Gastroenterologist
INSTITUTIONAL AFFILIATIONS
Royal Perth Hospital

Dr Romilly Goodheart

OCCUPATION
RMO
INSTITUTIONAL AFFILIATIONS
Fiona Stanley Hospital

Ms Cheryll McCullough

OCCUPATION
Senior Scientist
INSTITUTIONAL AFFILIATIONS
Fiona Stanley Hospital

Dr Edward Raby

OCCUPATION
ID Physician and Microbiologist
INSTITUTIONAL AFFILIATIONS
Royal Perth Hospital

Dr James O. Robinson

OCCUPATION
ID Physician
INSTITUTIONAL AFFILIATIONS
Royal Perth Hospital

Dr Paul R. Ingram

OCCUPATION
ID Physician and Microbiologist
INSTITUTIONAL AFFILIATIONS
University of Western Australia