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Performance of the Oxoid M.I.C.Evaluator™ Strips compared with the Etest® assay and BSAC agar dilution

Objectives The Oxoid M.I.C.Evaluator™ (M.I.C.E™; Thermo Fisher Scientific) comprises an antibiotic gradient on a plastic support. We compared its performance with Etest®—a similar product—using BSAC agar dilution as a reference. Methods Parallel MIC tests were performed by M.I.C.Evaluator, Etest and agar dilution on Iso-Sensitest™ agar. In total, 9354 organism/strip combinations were tested by each method, using 1017 bacteria representing clinically important fastidious and non-fastidious species. Results Essential agreement of strip MIC values (±1 doubling dilution) with the agar dilution reference, with off-scale results excluded, was 89.9% for M.I.C.Evaluator versus 89.5% for Etest (P > 0.05). These proportions were similar, at 89.5% and 89.3% (P > 0.05), respectively, if off-scale values were counted as agreeing if they could agree (e.g. a strip MIC >32 mg/L and an agar dilution MIC of 128 mg/L). For both strips, agreement with agar dilution was best for non-fastidious genera, Moraxella, Listeria, Pasteurella and Campylobacter spp. and weaker for streptococci, anaerobes, Neisseria spp. and, especially, Haemophilus influenzae. Many ‘disagreements’, especially for H. influenzae, concerned organisms unequivocally resistant by all methods (e.g. ampicillin MIC 256 mg/L by agar dilution, 16 or 32 mg/L by both strips); nevertheless both strips underestimated imipenem MICs for Proteus. There was no difference between the two strip types in the proportion of agreements with agar dilution (P > 0.05); nevertheless their results agreed better with each other than with agar dilution (P < 0.01). Conclusions The M.I.C.Evaluator performed almost identically to the Etest, giving good agreement with BSAC agar dilution.


Introduction
Discs and automated systems with truncated MIC ranges are adequate for most routine susceptibility testing, but precise MIC determinations are needed in difficult settings, such as endocarditis and pneumococcal meningitis. MICs are also needed to guide the treatment of infections caused by multiresistant pathogens, where pharmacodynamically based dose adjustment may be sought. Finally, MICs are needed for organisms or antibiotic/organism combinations where disc testing is demonstrably unreliable, e.g. anaerobes, penicillin against most a-haemolytic streptococci except pneumococci, and glycopeptides against Staphylococcus aureus, where diffusion tests fail to discriminate strains with vancomycin MICs of 8 mg/L, 1 let alone those with the small reductions in susceptibility (MICs 2 -4 mg/L) now being associated with poor clinical outcomes. 2 Classical MIC determinations on agar or in broth are routinely performed by specialist centres, but are inconvenient for diagnostic laboratories, where only a few isolates require these investigations and where the range of drugs to be tested varies with each isolate. Rather, diagnostic laboratories find it more convenient to perform their few MIC tests using pre-formed antibiotic gradients, such as Etest w (AB bioMérieux, Marcy l'Étoile, France). These are versatile and give results in good agreement with the CLSI broth microdilution method, against which they are calibrated. 3 Their agreement with other methods, such as that of the BSAC is less well validated, but is asserted to be acceptable by the BSAC. 4 The Oxoid M.I.C.Evaluator TM Strip (Thermo Fisher Scientific, Basingstoke, UK) is a new gradient strip for MIC determinations, asserted by the manufacturer to be suitable for use on Iso-Sensitest agar as well as Mueller -Hinton agar. We compared its performance with that of the Etest Strip and the BSAC agar dilution methods.

Bacteria
The same 1017 bacterial strains and antibiotics were tested using M.I.C.Evaluator Strips, Etests and the BSAC agar dilution method, with a total of 9354 antibiotic/strain combinations. The organisms were recent clinical isolates, selected to represent a wide range of species and susceptibilities, as summarized in Table 1

Susceptibility tests
Tests with both the M.I.C.Evaluator and Etest Strips were performed on Iso-Sensitest agar (Thermo Fisher Scientific) with the supplements, incubation periods and conditions specified in the BSAC agar dilution method, except that: (i) based on advice for Etests, p-nitrophenyl glycerol was omitted from the media for strip tests with Proteeae, whereas it was included, at 50 mg/L, as an anti-swarming agent in agar dilution MIC determinations; and (ii) based on the package insert for the M.I.C.Evaluator Strips, Iso-Sensitest agar was used throughout for tests with imipenem, although the BSAC advocates Mueller-Hinton agar for this and other carbapenems. Oxacillin strips were tested on Mueller-Hinton agar supplemented with 2% NaCl as per the BSAC agar dilution method.
For all isolates the inocula for strip tests were matched to a 0.5 McFarland standard. Results were read in accordance with the manufacturers' directions, which are essentially identical for both strip products. For bactericidal antibiotics, the MIC was taken as the point of termination of all growth; for bacteriostatic agents as the point of 80% inhibition. In those cases where growth terminated between two points on the strip scale, the MIC was rounded to the higher value. The following strip types were used: 0.002 -32 mg strips of ciprofloxacin, cefotaxime, imipenem, levofloxacin and penicillin G; 0.015 -256 mg strips of amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, erythromycin, gentamicin, linezolid, metronidazole, oxacillin, penicillin G, tetracycline and vancomycin; and 0.06-1024 mg strips of gentamicin. Storage was at 2-88C for the M.I.C.Evaluator Strips and 2208C for Etests. Boxes were allowed to equilibrate at room temperature for at least 1 h before opening.
Agar dilution MICs were determined by the BSAC method, as current in 2007, 5 on oblong 12×8 cm plates, inoculated using a 96-point inoculator. Results were read with an automated optical reader (Perceptive Instruments, Haverhill, UK) and were manually corrected as necessary. 'Potential agreement' was defined as the percentage of cases where the MIC result by the test method was within one doubling dilution of the reference method or was off-scale by one method and potentially in agreement with the reference method (e.g. .32 mg/L by one method and 256 mg/L by the other). Either essential or potential agreement could appear higher because the denominators and the numerators both varied between the two measurements. Correlation between MICs by different methods was calculated using log 2 MICs, with off-scale values excluded. Comparisons of performance were by x 2 test.

Results and discussion
Performance of M.I.C.Evaluator and Etest Strips versus BSAC agar dilution A total of 1017 isolates and 18 strip types were tested, with 77 antibiotic/organism combinations represented. Essential agreement was achieved for 89.9% of tests with the M.I.C.Evaluator versus 89.5% for the Etest (P .0.05) (Tables 2 and 3); potential agreement was achieved in 89.5% for the M.I.C.Evaluator versus 89.3% for the Etest (P .0.05) ( Tables 4 and 5). The proportions of strip-type/organism combinations for which various target levels of agreement with the agar dilution reference (≥95%, ≥90% ≥85% etc.) was achieved did not differ significantly between the two strip types (P .0.05) irrespective of the target criterion selected (Table 6).
It should be added that these 'global' agreement rates included antibiotic/organism combinations, e.g. cefotaxime and oxacillin against MRSA and benzylpenicillin against penicillinaseproducing S. aureus, where MICs are notoriously fickle and would not ordinarily be determined. Agreement in these cases was poorer than for most other agents tested against staphylococci, and global agreement rates rose if they were excluded from the analysis (Tables 2 and 4).
Even for antibiotic/organism combinations where essential agreement was ,90%, the results of the strip tests mostly correlated well with BSAC agar dilution (Tables 7 and 8). Exceptions, with poorer correlation (r ≤ 0.7), were: (i) imipenem against Enterobacteriaceae, where a distortion arose owing to the behaviour of Proteeae, as described below; (ii) cases where high-drug-content strips were tested against species groups where low-content strips were more appropriate, as with cefotaxime against Neisseria spp.; and (iii)-most especially- (Tables  7 and 8), cases where MICs by the reference method were clustered over four or fewer drug dilutions, i.e. over a scarcely wider collective range than the +1 doubling dilution range conventionally accepted as experimental variation when the MIC for a single organism is repeatedly determined by the same method.
In general, agreement between the two strip tests and the BSAC reference method was best for non-fastidious organisms, including staphylococci, enterococci, Enterobacteriaceae and non-fermenters, and for members of the genera Moraxella, Listeria, Pasteurella and Campylobacter (Tables 2 -5). For these organisms, and taking all antibiotics combined, there was .89% essential agreement with the BSAC reference for the  Poorer potential than essential agreement (see Table 2) for levofloxacin versus staphylococci reflects 25 isolates with MICs of 16 mg/L by agar dilution, but .32 mg/L by both strip methods.
b Only E. faecalis tested.  Evaluator ampicillin strips against H. influenzae, though taking CLSI broth microdilution as a reference, and found 90% agreement (+1 doubling dilution) for ampicillin-susceptible isolates and those with b-lactamase-negative ampicillin resistance, versus only 65%-75% for those with b-lactamase. Tests with penicillin against streptococci also deserve comment, being another case where gradient MIC test strips are particularly useful-e.g. for pneumococci with borderline resistance and for endocarditis isolates-but where agreement appeared rather low, at 62%-68%. These figures, however, exaggerate the 'disagreements', which largely concerned b-haemolytic streptococci with penicillin MICs of ≤0.008 mg/L by agar dilution and 0.023 (rounded to 0.03) mg/L by the strip methods-a difference of no practical consequence. Penicillin MICs by Etest and M.I.C.Evaluator Strips for pneumococci with agar dilution MICs from 0.12 to 2 mg/L are shown in Table 9, indicating perfect essential agreement for the two high-content strips, though rather poorer for the low-content M.I.C.Evaluator Strip.
Agreement rates for Enterobacteriaceae were poorer with imipenem than with other strip types. This was largely owing to the strips giving 8-fold lower imipenem MICs for Proteus spp.   Mushtaq et al.
Agreement was far better for other species, as shown by the geometric mean MIC values (Table 10); these are a valid summary parameter since the MICs were normally distributed and unimodal within each species. It is possible that higher MICs by agar dilution for Proteeae reflected the inclusion of p-nitrophenyl glycerol to prevent swarming, but we can find no published assertion that this compound interferes with the activity of imipenem; moreover, broth dilution MICs, e.g. by the CLSI method, are similarly high for Proteus spp. with no anti-swarming agent present. 7 An alternative explanation, perhaps more likely, is simply that in seeking to ignore swarming into the zone of inhibition, the recorder tends to underestimate the real MICs.
Other specific concerns could be identified, e.g. there were 19 enterococci with gentamicin MICs of 256-512 mg/L, counting as high-level resistant by BSAC criteria, but nine of these gave MICs ≤128 mg/L by Etest, counting as susceptible, and five did so by M.I.C.Evaluator. Only 2/34 enterococci with gentamicin MICs of ≥1024 mg/L gave MICs ≤128 mg/L by the strip methods, each of them with both products, whilst 2/51 enterococci with a gentamicin MIC ≤128 mg/L by agar dilution appeared resistant, with MICs ≥256 mg/L in strip tests, one with the Etest only and one with both products.

Agreement between M.I.C.Evaluator and Etest Strip results
Concordance between the M.I.C.Evaluator Strip and Etest Strip results was excellent, with .95% potential agreement (+1 dilution) for 54 of 77 strip/organism combinations and 90% -95% for another 12 (Table 11). These proportions are significantly better than between either strip type and agar dilution (P,0.01, x 2 test; compare Table 6). The only antibiotic/organism combinations with ,85% agreement between the two strips were amoxicillin/clavulanic acid against both Enterobacteriaceae (70.6%) and Haemophilus spp. (81.3%) and both ampicillin and amoxicillin against Haemophilus spp. (67.4% and 68.1%, respectively). In the case of ampicillin and amoxicillin, virtually

Conclusions
Etests are in widespread use for custom MIC determinations in diagnostic laboratories. They have been calibrated to give equivalent MICs to those found by CLSI methodology using Mueller -Hinton agar, and there is a voluminous literature to support their accuracy when used in this manner. 3 The manufacturer (AB Biodisk at the time of this study, now bioMérieux) does not advocate their use on other media, and there are no substantial performance studies on Iso-Sensitest agar, which is the standard medium for the BSAC dilution method. The BSAC nevertheless states that, in general, Etests can be used on Iso-Sensitest agar, with BSAC/EUCAST breakpoints, so long as inocula equivalent to a 0.5 McFarland are used. 4 The M.I.C.Evaluator Strip has been developed as an alternative strip-based MIC method, which the manufacturer indicates to be suitable for use on either Mueller -Hinton or Iso-Sensitest agar. As with the Etest Strip, it comprises a laminated plastic support carrying a double series of antibiotic-impregnated droplets of diminishing content. Once placed on agar, the strip rapidly releases the antibiotic, delivering a stable gradient. After incubation, the MIC can be read off against a printed scale. The present data show that, used on Iso-Sensitest agar, both M.I.C.Evaluator and Etest Strips gave essentially equivalent results to one another and acceptable agreement with BSAC agar dilution. Mushtaq et al.