Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived

Ijeoma N. Okoliegbe* (Corresponding Author), Karolin Hijazi, Kim Cooper, Corinne Ironside, Ian M Gould

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
3 Downloads (Pure)


The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest methoddependent synergism for isolates, with ceftazidime susceptibility after increased exposure. Theresults show that when interpretative criteria are considered, gradient diffusion (especiallyMIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa
Original languageEnglish
Article number967
Number of pages12
Issue number8
Early online date12 Aug 2021
Publication statusPublished - 12 Aug 2021

Bibliographical note

Funding: This research was funded by the NHS Grampian Endowment fund, grant number EA9431, and the NHS Grampian Clinical Microbiology Fund (NHS Grampian Endowment Funds, Registered Charity Number SC017296).
Acknowledgments: The authors would like to thank the laboratories and clinicians who use the Cystic Fibrosis Susceptibility Testing Service. CFASS is an adult patient-testing facility, funded by the National Services Division of the Common Services Agency of the Scottish Executive.


  • antimicrobials
  • ceftazidime
  • combination antimicrobial susceptibility testing
  • gradient diffusion
  • Pseudomonas aeruginosa
  • synergy testing
  • tobramycin


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