Abstract
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 method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.
Highlights
In CF patient management, there is the continuous emergence of multi-/pan-drugresistant (MDR/PDR) strains, especially Pseudomonas aeruginosa, due to the prolonged and frequent administration of antimicrobial agents that are used in the treatment of pulmonary exacerbations [1,2,4,5]
There is a dearth of evidence on the best antimicrobial combination that will give a positive outcome [4,6,7,13] in clinical management, as the response of P. aeruginosa to various antimicrobial combinations has been shown to be unpredictable [11]
Kidd et al [14] reported that disk and gradient diffusion tests are mostly used in clinical microbiology laboratories, due to their low cost and ease of performance, while dilution tests are commonly employed in research and reference laboratory settings
Summary
37.14% (n = 26/70) and 52.86% (n = 37/70) absol agreement was observed for tobramycin and ceftazidime, respectively. When w3eoaf 1n2alyzed synergy gradient MIC values for agreement with the checkerboard assay, Figure 1 show that there was a reduced essential agreement, in the proportions of isolates ctohmerbeiwnastiaonredMucICeds ewssietnhtinal a≤g1retewmoe-nfto,lidn tdhieluptrioopno,rtfionrsbooftihsoltaotbesrafomr ycocminbiannadtiocneftazidi WMhICilse wsiimthiinla≤r 1retdwuoc-ftoioldndsilwuteiroen,ofborsebrovthedtofborarmayllcitnobanradmceyfctainzidgirmaed.ieWnhtidleifsfimusiilaorn metho threeduMctIioCn:sMwICeremobestehrovded dfoermalol ntosbtrraamteydcinthgeradleiaenstt d(i~ff2u0s%io)n mreedthuocdtiso, nthecMomICp:MarIeCd with cmfhoerectchkeofetdrabzdoiedamimroden.astsrsaateydftohrecleeaftsat z(~id20im%)er.eduction compared with the checkerboard assay. FICI and SBPI of P. aeruginosa Isolate Synergy Testing. NInwcointhtratsht,ethceomcompapraartaotirveshanoawlyesdis a decre f6owog0rfr%haSibdlBeoiiePntdnIhcitrvredteachialftuefsoueevMssieow(rIFnlCaaigmy:sMu(ero4teIh7bC.o20sd)e6(s%sr1.hv7,Toe.n1hwd4e=e%cud5r0,soa)isnnnpsgr=miondec1thrtu2heec)aoesdadcenr(ti8odhn.se8sdt2mh%iemro,espnectr.tt=ohopo3vo7dre)trpi(olr4ano5yd.o7u(f18cie%.s5do7,lta%hntee,sl=nefao3s=rt26ai)n.l)lcImrtnehaersecteeho, ondtrsa,swt, comparative analysis of SBPI values (Figure 2) showed an increase in the proportion isolates for all three gradient diffusion methods. Observed FICI and SBPI proportions in study isolates. Okoliegbe 1,2,*, Karolin Hijazi 2, Kim Cooper 1, Corinne Ironside 1 and Ian M. Gould 1 1,2,*, Karolin Hijazi 2, Kim Cooper 1, Corinne Ironside 1 and Ian M.
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