Abstract
This study examined the antimicrobial susceptibility of invasive meningococcal disease (IMD)–associated Neisseria meningitidis recovered in the Republic of Ireland between 1996 and 2016. In total, 1359 isolates representing over one-third of all laboratory-confirmed cases of IMD diagnosed each epidemiological year (EY; July 1–June 30) were analysed. All isolates were susceptible to ciprofloxacin, rifampicin and cefotaxime and 74% and 87% were susceptible to sulphonamide and penicillin, respectively. The proportion of isolates exhibiting reduced susceptibility to penicillin increased significantly during the study with no evidence of major clonal expansion or horizontal spread of a specific penA allele. Greater diversity observed among recently recovered meningococci and specifically among isolates exhibiting reduced penicillin susceptibility contributed to the overall increase in penA allele diversity throughout. The emergence and dissemination of strains with phenotypic and genotypic reduced susceptibility to penicillin increase the need for continued surveillance of antimicrobial susceptibility of meningococci in the Republic of Ireland especially in view of the recommendation of penicillin G as empiric treatment of choice for pre-hospital management.
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References
Halperin SA, Bettinger JA, Greenwood B, Harrison LH, Jelfs J, Ladhani SN, McIntyre P, Ramsay ME, Sáfadi MAP (2012) The changing and dynamic epidemiology of meningococcal disease. Vaccine. 30(Suppl 2):B26–B36. https://doi.org/10.1016/j.vaccine.2011.12.032
Sadarangani M, Pollard AJ (2016) Can we control all-cause meningococcal disease in Europe? Clin Microbiol Infect 22:S103–S112. https://doi.org/10.1016/j.cmi.2016.03.006
Health Protection Surveillance Centre (2012) Guidelines for the early clinical and public health management of bacterial meningitis (including meningococcal disease ). Report of Scientific Advisory Committee of HPSC:1–122
Jorgensen JH, Crawford SA, Fiebelkorn KR (2005) Susceptibility of Neisseria meningitidis to 16 antimicrobial agents and characterization of resistance mechanisms affecting some agents. J Clin Microbiol 43:3162–3171. https://doi.org/10.1128/JCM.43.7.3162-3171.2005
Taha M, Vázquez JA, Hong E, Bennett DE, Bertrand S, Bukovski S, Cafferkey MT, Carion F, Christensen JJ, Diggle M, Edwards G, Enríquez R, Fazio C, Frosch M, Heuberger S, Hoffmann S, Jolley KA, Kadlubowski M, Kechrid A, Kesanopoulos K, Kriz P, Lambertsen L, Levenet I, Musilek M, Paragi M, Saguer A, Skoczyńska A, Stefanelli P, Thulin S, Tzanakaki G, Unemo M, Vogel U, Zarantonelli ML (2007) Target gene sequencing to characterize the penicillin G susceptibility of Neisseria meningitidis. Antimicrobial Agents and Chemotherapy 51:2784–2792. https://doi.org/10.1128/AAC.00412-07
Taha M, Hedberg ST, Szatanik M, Hong E, Ruckly C, Abad R, Bertrand S, Carion F, Claus H, Corso A, Enríquez R, Heuberger S, Hryniewicz W, Jolley KA, Kriz P, Mollerach M, Musilek M, Neri A, Olcén P, Pana M, Skoczynska A, Pereira CS, Stefanelli P, Tzanakaki G, Unemo M, Vázquez JA, Vogel U, Wasko I Multicenter study for defining the breakpoint for rifampin resistance in Neisseria meningitidis by rpoB sequencing. Antimicrobial Agents and Chemotherapy 54(2010):3651–3658. https://doi.org/10.1128/AAC.00315-10
Hong E, Thulin Hedberg S, Abad R, Fazio C, Enríquez R, Deghmane A-EA-E, Jolley KA, Stefanelli P, Unemo M, Vázquez JA, Veyrier FJ, Taha M-K (2013) Target gene sequencing to define the susceptibility of Neisseria meningitidis to ciprofloxacin. Antimicrob Agents Chemother 57:1961–1964. https://doi.org/10.1128/AAC.02184-12
B.H. Harcourt, R. Anderson, H.M. Wu, A.C. Cohn, J.R. MacNeil, T.H. Taylor, X. Wang, T.A. Clark, N.E. Messonnier, L.W. Mayer, Population-based surveillance of Neisseria meningitidis antimicrobial resistance in the United States., Open Forum Infectious Diseases. 2 (2015) ofv117. https://doi.org/10.1093/ofid/ofv117
Deghmane A-E, Hong E, Taha M-K (2017) Emergence of meningococci with reduced susceptibility to third-generation cephalosporins. J Antimicrob Chemother 72:95–98. https://doi.org/10.1093/jac/dkw400
Tóth Á, Berta B, Tirczka T, Jekkel C, Ábrahám A, Prohászka Z, Bognár Z, Erdősi T (2017) First description of a rifampicin-resistant Neisseria meningitidis serogroup Y strain causing recurrent invasive meningococcal disease in Hungary. Acta Microbiol Immunol Hung 64:1–7. https://doi.org/10.1556/030.64.2017.006
Hong E, Deghmane A-E, Taha M-K (2018) Acquisition of Beta-Lactamase by Neisseria meningitidis through possible horizontal gene transfer. Antimicrob Agents Chemother 62:e00831–e00818. https://doi.org/10.1128/AAC.00831-18
Y. Zouheir, T. Atany, N. Boudebouch, Emergence and spread of resistant N. meningitidis implicated in invasive meningococcal diseases during the past decade (2008–2017), The J Antibiot 72 (2019) 185–188. https://doi.org/10.1038/s41429-018-0125-0
Bennett DE, Cafferkey MT (2003) PCR and restriction endonuclease assay for detection of a novel mutation associated with sulfonamide resistance in Neisseria meningitidis. Antimicrob Agents Chemother 47:3336–3338. https://doi.org/10.1128/AAC.47.10.3336-3338.2003
Nadel S (2016) Treatment of meningococcal disease. The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine 59:S21–S28. https://doi.org/10.1016/j.jadohealth.2016.04.013
European Centre for Disease Control, Surveillance of invasive bacterial diseases, in Europe 2012, 2015. https://doi.org/10.2900/2884
Bertrand S, Carion F, Wintjens R, Mathys V, Vanhoof R (2012) Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates in Belgium from 2000 to 2010: increasing prevalence of penicillin nonsusceptibility. Antimicrob Agents Chemother 56:2268–2272. https://doi.org/10.1128/AAC.06310-11
Bijlsma MW, Bekker V, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A (2014) Epidemiology of invasive meningococcal disease in the Netherlands, 1960-2012: an analysis of national surveillance data. Lancet Infect Dis 14:805–812. https://doi.org/10.1016/S1473-3099(14)70806-0
Brown EM, Fisman DN, Drews SJ, Dolman S, Rawte P, Brown S, Jamieson F (2010) Epidemiology of invasive meningococcal disease with decreased susceptibility to penicillin in Ontario, Canada, 2000 to 2006. Antimicrob Agents Chemother 54:1016–1021. https://doi.org/10.1128/AAC.01077-09
Hedberg ST, Fredlund H, Nicolas P, Caugant DA, Olcén P, Unemo M (2009) Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives. Antimicrob Agents Chemother 53:1561–1566. https://doi.org/10.1128/AAC.00994-08
Skoczyńska A, Waśko I, Kuch A, Kadłubowski M, Gołębiewska A, Foryś M, Markowska M, Ronkiewicz P, Wasiak K, Kozińska A, Matynia B, Hryniewicz W (2013) A decade of invasive meningococcal disease surveillance in Poland. PLoS One 8:e71943. https://doi.org/10.1371/journal.pone.0071943
Mowlaboccus S, Jolley KA, Bray JE, Pang S, Lee YT, Bew JD, Speers DJ, Keil AD, Coombs GW, Kahler CM (2017) Clonal expansion of new penicillin-resistant clade of Neisseria meningitidis serogroup W clonal complex 11, Australia. Emerg Infect Dis 23. https://doi.org/10.3201/eid2308.170259
Zapun A, Morlot C, Taha MK (2016) Resistance to β-lactams in neisseria ssp due to chromosomally encoded penicillin-binding proteins. Antibiotics (Basel, Switzerland) 5:35–47. https://doi.org/10.3390/antibiotics5040035
Zalmanovici Trestioreanu A, Fraser A, Gafter-Gvili A, Paul M, Leibovici L, Cochrane Acute Respiratory Infections Group (2013) Antibiotics for preventing meningococcal infections. Cochrane Database Syst Rev 2013(10):CD004785. https://doi.org/10.1002/14651858.CD004785.pub5
Lahra MM, Enriquez RP (2016) Australian meningococcal surveillance programme annual report, 2014. Communicable Diseases Intelligence Quarterly Report 40:E221–E228
Bennett DE, O’Lorcain P, Morgan S, Cotter S, Cafferkey M, Cunney R (2019) Epidemiology of two decades of invasive meningococcal disease in the Republic of Ireland: an analysis of national surveillance data on laboratory-confirmed cases from 1996 to 2016. Epidemiol Infect 147:e142. https://doi.org/10.1017/s0950268819000396
Bennett DE, Meyler KL, Cafferkey MT, Cunney RJ (2020) Diversity of meningococci associated with invasive meningococcal disease in the Republic of Ireland over a 19 year period, 1996-2015. PLoS One 15:e0228629. https://doi.org/10.1371/journal.pone.0228629
Bennett DE, Cafferkey MT (2006) Consecutive use of two multiplex PCR-based assays for simultaneous identification and determination of capsular status of nine common Neisseria meningitidis serogroups associated with invasive disease. J Clin Microbiol 44:1127–1131. https://doi.org/10.1128/JCM.44.3.1127-1131.2006
Bennett DE, Mulhall RM, Cafferkey MT (2004) PCR-based assay for detection of Neisseria meningitidis capsular serogroups 29E, X, and Z. J Clin Microbiol 42:1764–1765. https://doi.org/10.1128/JCM.42.4.1764-1765.2004
Trotter CL, Fox AJ, Ramsay ME, Sadler F, Gray SJ, Mallard RH, Kaczmarski EB (2002) Fatal outcome from meningocccal disease - an association with meningococcal phenotype but not with reduced susceptibility to benzylpenicillin. J.Med.Microbiol. 51:855–860
Gray SJ, Trotter CL, Ramsay ME, Guiver M, Fox AJ, Borrow R, Mallard RH, Kaczmarski EB (2006) Epidemiology of meningococcal disease in England and Wales 1993/94 to 2003/04: contribution and experiences of the meningococcal reference unit. J Med Microbiol 55:887–896. https://doi.org/10.1099/jmm.0.46288-0
Vázquez JA, Arreaza L, Block C, Ehrhard I, Gray SJ, Heuberger S, Hoffmann S, Kriz P, Nicolas P, Olcen P, Skoczynska A, Spanjaard L, Stefanelli P, Taha M, Tzanakaki G (2003) Interlaboratory comparison of agar dilution and Etest methods for determining the MICs of antibiotics used in management of Neisseria meningitidis infections. Antimicrob Agents Chemother 47:3430–3434. https://doi.org/10.1128/AAC.47.11.3430-3434.2003
Vázquez JA (2007) Resistance testing of meningococci: the recommendations of the European monitoring group on meningococci. FEMS Microbiol Rev 31:97–100. https://doi.org/10.1111/j.1574-6976.2006.00050.x
Thulin S, Olcén P, Fredlund H, Unemo M (2006) Total variation in the penA gene of Neisseria meningitidis: correlation between susceptibility to beta-lactam antibiotics and penA gene heterogeneity. Antimicrob Agents Chemother 50:3317–3324. https://doi.org/10.1128/AAC.00353-06
Belkacem N, Hong E, Antunes A, Terrade A, Deghmane A-EE, Taha M (2016) Use of animal models to support revising meningococcal breakpoints of beta-lactams. Antimicrob Agents Chemother 60:4023–4027. https://doi.org/10.1128/AAC.00378-16
Maiden MCJ, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, Zhang Q, Zhou J, Zurth K, Caugant DA, Feavers IM, Achtman M, Spratt BG (1998) Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95:3140–3145
Bennett DE, Cafferkey MT (2003) Multilocus restriction typing: a tool for Neisseria meningitidis strain discrimination. J Med Microbiol 52:781–787. https://doi.org/10.1099/jmm.0.05225-0
Spratt BG, Zhang QY, Jones DM, Hutchison A, Brannigan JA, Dowson CG (1989) Recruitment of a penicillin-binding protein gene from Neisseria flavescens during the emergence of penicillin resistance in Neisseria meningitidis. Proc Natl Acad Sci U S A 86:8988–8992. https://doi.org/10.1073/pnas.86.22.8988
Arnaud-Haond S, Duarte CM, Alberto F, Serrão EA (2007) Standardizing methods to address clonality in population studies. Mol Ecol 16:5115–5139. https://doi.org/10.1111/j.1365-294X.2007.03535.x
Grünwald NNJ, Goodwin SSB, Milgroom MG, Fry WE (2003) Analysis of genotypic diversity data for populations of microorganisms. Phytopathology. 93:738–746. https://doi.org/10.1094/PHYTO.2003.93.6.738
Hedberg ST, Olcén P, Fredlund H, Unemo M (2010) Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden---the meningococcal population remains susceptible. Scand J Infect Dis 42:61–64. https://doi.org/10.3109/00365540903292682
du Plessis M, de Gouveia L, Skosana H, Thomas J, Blumberg L, Klugman KP, von Gottberg A (2010) Invasive Neisseria meningitidis with decreased susceptibility to fluoroquinolones in South Africa, 2009. J Antimicrob Chemother 65:2258–2260. https://doi.org/10.1093/jac/dkq291
I. Mounchetrou Njoya, A.-E. Deghmane, M. Taha, H. Isnard, I. Parent du Chatelet, A cluster of meningococcal disease caused by rifampicin-resistant C meningococci in France, April 2012., Euro Surveillance : Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin 17 (2012) 1–3
Zhu B, Fan Y, Xu Z, Xu L, Du P, Gao Y, Shao Z (2014) Genetic diversity and clonal characteristics of ciprofloxacin-resistant meningococcal strains in China. J Med Microbiol 63:1411–1418. https://doi.org/10.1099/jmm.0.078600-0
Unemo M, Shafer WM (2014) Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 27:587–613. https://doi.org/10.1128/CMR.00010-14
Jolley KA, Maiden MCJ (2010) BIGSdb: scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 11:595. https://doi.org/10.1186/1471-2105-11-595
Acknowledgements
This work was presented in part at the 8th meeting of European Monitoring Group on Meningococci, 7–10 September 2005, Dublin (Abstract O5.3).
We would like to thank Piaras O’Lorcain for statistical support, Robert Mulhall and Richard Drew for helpful discussions and the staff of all the Clinical Microbiology Departments in hospitals in the Republic of Ireland for provision of the isolates used in this study.
We also acknowledge Steve Gray and staff (Meningococcal Reference Unit, Manchester, M13 9WL, U.K.) for performing isolate susceptibility testing prior to EY2006/2007, and Muhamed-Kheir Taha and Eva Hong (Neisseria Unit and the French National Reference Center for Meningococci, Institut Pasteur, Paris, France) curators of the penA allele database for allele assignment. This publication made use of the Neisseria Multi Locus Sequence Typing website (http://pubmlst.org/ neisseria/) developed by Keith Jolley and sited at the University of Oxford [45]. The development of Neisseria Multi Locus Sequence Typing website is supported by the Wellcome Trust and the European Union.
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This study was conducted as part of our routine work and was partially supported by a grant from the Irish Health Research Board (RP180/2001).
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D.E.B performed the molecular work, curated and analysed the data and was the main author of the manuscript. K.L.M performed the antimicrobial susceptibility testing and was a major contributor to the manuscript. M.T.C established the Irish Meningitis and Sepsis Reference Laboratory. M.T.C and R.J.C were involved in the design and supervision of the study. All authors participated in the drafting of the manuscript as well as read and approved the final manuscript.
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N. meningitidis isolates were received as part of routine activity of the IMSRL for performing national surveillance of invasive meningococcal disease in the Republic of Ireland and were analysed anonymously.
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Bennett, D.E., Meyler, K.L., Cafferkey, M.T. et al. Antibiotic susceptibility and molecular analysis of invasive Neisseria meningitidis recovered in the Republic of Ireland, 1996 to 2016. Eur J Clin Microbiol Infect Dis 40, 1127–1136 (2021). https://doi.org/10.1007/s10096-020-04114-0
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DOI: https://doi.org/10.1007/s10096-020-04114-0