1887

Abstract

The public health burden of infections caused by is magnified due to high rates of resistance to traditional antimicrobials. The aim of this study was to evaluate the efficacy of an alternative dual therapy comprising gentamicin and azithromycin.

The E-test method was used to determine the minimum inhibitory concentrations (MICs) of gentamicin and azithromycin individually prior to testing in combination using the cross or 90 angle formation method. A total of 70 clinical isolates of displaying varying ceftriaxone MICs along with 2 reference strains (WHO K and P) and 1 ceftriaxone-resistant QA isolate were examined. The fractional inhibitory concentration index (FICI) was calculated and the results were interpreted using the following criteria: synergy, FICI ≤0.5; indifference or additive, FICI >0.5 to ≤4.0; and antagonism, FICI >4.0.

A total of 54 (77.1 %) isolates displayed indifference, while 16 (22.9 %) demonstrated synergy. When azithromycin was tested alone, the MICs ranged from 0.016 to 2 µg ml . However, in combination with gentamicin, the mean MIC value of all isolates decreased from 0.275 µg ml to 0.090 µg ml (=0.05).When gentamicin was tested alone, the MICs ranged from 0.25 to 8 µg ml, with a mean MIC of 4.342 µg ml, whereas in combination with azithromycin it decreased significantly to 2.042 µg ml (=0.04).

No antagonism was observed in this combination, suggesting that it could be a future treatment option as we prepare for a post-cephalosporin era. However, comprehensive evaluations are warranted and recommendations should be made based on clinical trials.

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2019-04-01
2019-12-11
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References

  1. Centers for Disease Control and Prevention (CDC) Antibiotic resistance threats in the United States, 2013 2013;1–114
  2. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55:1–94
    [Google Scholar]
  3. Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 2011;55:3538–3545 [CrossRef]
    [Google Scholar]
  4. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A et al. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012;56:1273–1280 [CrossRef]
    [Google Scholar]
  5. Cámara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother 2012;67:1858–1860 [CrossRef]
    [Google Scholar]
  6. Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill 2011;16:19833
    [Google Scholar]
  7. Sood S, Mahajan N, Verma R, Kar HK, Sharma VK. Emergence of decreased susceptibility to extended-spectrum cephalosporins in Neisseria gonorrhoeae in India. Natl Med J India 2013;26:26–28
    [Google Scholar]
  8. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64:1–137
    [Google Scholar]
  9. Daly CC, Hoffman I, Hobbs M, Maida M, Zimba D et al. Development of an antimicrobial susceptibility surveillance system for Neisseria gonorrhoeae in Malawi: Comparison of methods. J ClinMicrobiol 1997;35:2985–2988
    [Google Scholar]
  10. Ministry of Health, Essential Drugs Programme Malawi standard treatment guidelines, 2nd ed. Lilongwe, Malawi: Ministry of Health; 1993
    [Google Scholar]
  11. Bala M, Singh V, Bhargava A, Kakran M, Joshi NC et al. Gentamicin susceptibility among a sample of multidrug-resistant Neisseria gonorrhoeae isolates in India. Antimicrob Agents Chemother 2016;60:7518–7521 [CrossRef]
    [Google Scholar]
  12. Jia J, Zhu F, Ma X, Cao ZW, Li Y et al. Mechanisms of drug combinations: interaction and network perspectives. Nat Rev Drug Discov 2009;8:111–128 [CrossRef]
    [Google Scholar]
  13. Singh V, Bala M, Bhargava A, Kakran M, Bhatnagar R. In vitro synergy testing of gentamicin, an old drug suggested as future treatment option for gonorrhoea, in combination with six other antimicrobials against multidrug-resistant Neisseria gonorrhoeae strains. Sex Transm Dis 2018;45:127–131 [CrossRef]
    [Google Scholar]
  14. Mahajan N, Sood S, Singh R, Kapil A, Das BK et al. Antimicrobial resistance and Neisseria gonorrhoeae multiantigen sequence typing profile of Neisseria gonorrhoeae in New Delhi, India. Sex Transm Dis 2016;43:506–516 [CrossRef]
    [Google Scholar]
  15. Laboratory Diagnosis of Gonorrhoea WHO Regional Publication, South East Asia Series No.33 Geneva: World Health Organization; 1999
  16. Bell SM, Pham JN, Carter IW, Hanrahan JK. Antibiotic susceptibility testing by the CDS method A Manual for Medical and Veterinary Laboratories , 8th ed. 2016
    [Google Scholar]
  17. White RL, Burgess DS, Manduru M, Bosso JA. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother 1996;40:1914–1918 [CrossRef]
    [Google Scholar]
  18. Bala M, Kakran M, Singh V, Sood S, Ramesh V et al. Monitoring antimicrobial resistance in Neisseria gonorrhoeae in selected countries of the WHO South-East Asia Region between 2009 and 2012: a retrospective analysis. Sex Transm Infect 2013;89:iv28–iv35 [CrossRef]
    [Google Scholar]
  19. Kerantzas CA, Jacobs WR Jr. Origins of combination therapy for tuberculosis: lessons for future antimicrobial development and application. MBio 2017;8:e01586–16 [CrossRef]
    [Google Scholar]
  20. Furuya R, Nakayama H, Kanayama A, Saika T, Iyoda T et al. In vitro synergistic effects of double combinations of β-lactams and azithromycin against clinical isolates of Neisseria gonorrhoeae. J Infect Chemother 2006;12:172–176 [CrossRef]
    [Google Scholar]
  21. Barbee LA, Soge OO, Holmes KK, Golden MR. In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae. J AntimicrobChemother 2014;69:1572–1578 [CrossRef]
    [Google Scholar]
  22. Wind CM, de Vries HJ, van Dam AP. Determination of in vitro synergy for dual antimicrobial therapy against resistant Neisseria gonorrhoeae using Etest and agar dilution. Int J Antimicrob Agents 2015;45:305–308 [CrossRef]
    [Google Scholar]
  23. Lkhamsuren E, Shultz TR, Limnios EA, Tapsall JW. The antibiotic susceptibility of Neisseria gonorrhoeae isolated in Ulaanbaatar, Mongolia. Sex Transm Infect 2001;77:218–219 [CrossRef]
    [Google Scholar]
  24. Ferreira WA, Vasconcelos WdeS, Gomes JS, Silva MdeFPda, Ferreira CM. Susceptibility of Neisseria gonorrhoeae to gentamicin, chloramphenicol and other antibiotics in Manaus, Amazon, Brazil. J Bras Doenças Sex Transm 2015;27:58–60 [CrossRef]
    [Google Scholar]
  25. Chisholm SA, Quaye N, Cole MJ, Fredlund H, Hoffmann S et al. An evaluation of gentamicin susceptibility of Neisseria gonorrhoeae isolates in Europe. J Antimicrob Chemother 2011;66:592–595 [CrossRef]
    [Google Scholar]
  26. Public Health Agency of Canada National surveillance of antimicrobial susceptibilities of Neisseria gonorrhoeae—annual summary. 2014
  27. Pereira R, Cole MJ, Ison CA. Combination therapy for gonorrhoea: in vitro synergy testing. J Antimicrob Chemother 2013;68:640–643 [CrossRef]
    [Google Scholar]
  28. Furuya R, Koga Y, Irie S, Ikeda F, Kanayama A et al. In vitro activities of antimicrobial combinations against clinical isolates of Neisseria gonorrhoeae. J Infect Chemother 2013;19:1218–1220 [CrossRef]
    [Google Scholar]
  29. Golparian D, Hadad R, Hellmark B, Fredlund H, Unemo M. P2.087  i n vitro antimicrobial synergy testing, using Etest methodology, of Neisseria gonorrhoeae for evaluation of susceptibility when using dual antimicrobial therapy?. Sex Transm Infect 2013;89:A114.3–A115 [CrossRef]
    [Google Scholar]
  30. Kirkcaldy RD, Weinstock HS, Moore PC, Philip SS, Wiesenfeld HC et al. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis 2014;59:1083–1091 [CrossRef]
    [Google Scholar]
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