Abstract
The susceptibility of 513 clinical isolates to doripenem was determined by broth microdilution, agar dilution, and Etest. Overall agreements for Etest and agar dilution MIC values compared to reference broth microdilution at ±1 log2 dilution were 88% and 94%, respectively. Etest MIC values demonstrated 98% agreement within ±2 log2 dilutions compared to the reference broth microdilution method.
Doripenem is a broad-spectrum carbapenem recently approved in the United States for complicated intra-abdominal and complicated urinary tract infections, including pyelonephritis, and in Europe for the same two indications and for nosocomial pneumonia, including ventilator-associated pneumonia. Doripenem has been shown to have in vitro activity against nonfermentative Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp., Enterobacteriaceae, and Gram-positive cocci (except for Enterococcus faecium and methicillin-resistant staphylococci) (3, 7, 8, 9). MIC susceptibility testing for doripenem as for other agents can be performed by a variety of test methodologies, such as broth microdilution (BMD), agar dilution, and Etest. As laboratories may use any one or multiple methods, it is of interest to know how MIC results for a drug will compare across methods. In this study the in vitro activity of doripenem against relevant Gram-negative and Gram-positive pathogens was determined by three MIC methods: broth microdilution or the standard reference method, agar dilution, and Etest. The BMD MICs were compared to results from agar dilution and Etest.
(This work was presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007 [1].)
Recent clinical isolates (n = 513) were studied from eight major organism groups based on the current groupings in the Clinical and Laboratory Standards Institute (CLSI) M100 supplement (6). The organism groups were Staphylococcus spp., Streptococcus pneumoniae, Streptococcus beta-hemolytic group, Streptococcus viridans group, Enterococcus spp., Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp. The appropriate CLSI quality control (QC) strains Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, S. pneumoniae ATCC 49619, Escherichia coli ATCC 25922, and P. aeruginosa ATCC 27853 were evaluated concurrently with every test.
Broth microdilution MIC testing followed CLSI methodology (4, 5) using cation-adjusted Mueller-Hinton (MH) broth (Sensititre; Trek Diagnostic Systems, Cleveland, OH) with or without the addition of 3% lysed horse blood (Hardy Diagnostics, Santa Maria, CA). Custom susceptibility panels in the frozen format were obtained from Trek Diagnostic Systems (Cleveland, OH).
Agar dilution MIC testing was performed on MH II agar (BD BBL, Sparks, MD) according to CLSI methodology (4, 5). Organisms were inoculated onto 100-mm agar plates prepared on the day of testing with a replicator (Craft Machine Inc., Chester, PA) that delivered 2 μl per spot. For streptococci other than S. pneumoniae, MH agar was supplemented with 5% sheep blood (Hardy Diagnostics, Santa Maria, CA).
MIC testing by the doripenem Etest (AB Biodisk, Solna, Sweden) was performed and results were interpreted according to the manufacturer's instructions. MH II agar plates (BD BBL, Sparks, MD) and plates of MH with 5% sheep blood agar (BD BBL, Sparks, MD) were used. Etest MICs were rounded up to the nearest 2-fold dilution in a standard MIC test, and these values were used in comparisons between the Etest and the reference BMD method.
MIC values for isolates to doripenem were generated by BMD, agar dilution, and Etest methods. Agar dilution MICs were not determined for S. pneumoniae, since agar dilution is not a recommended reference method for this organism. The MIC results from agar dilution and Etest were compared to those from the standard reference BMD MIC method. For all isolates, the comparator carbapenem class agent, meropenem, was tested in parallel with doripenem. In testing of the appropriate CLSI QC strains, both doripenem and meropenem performed within acceptable CLSI QC limits (data not shown).
The distribution of doripenem MIC values against Gram-negative and Gram-positive clinical isolates is shown in Table 1. The isolates were chosen to provide a range of MIC values and were not selected at random. Thus, the number of resistant isolates is higher than those that would be found in a random population. The percentages of doripenem-susceptible clinical isolates were 98% (98/100) for Enterobacteriaceae, 80% (64/80) for P. aeruginosa, and 55% (11/20) for Acinetobacter baumannii based on FDA breakpoints. Of the viridans group streptococci, seven isolates were identified as Streptococcus anginosus group, and of these seven isolates 100% were doripenem susceptible. The FDA susceptible MIC breakpoints for doripenem are ≤0.5 μg/ml for Enterobacteriaceae, ≤2 μg/ml for P. aeruginosa, ≤1 μg/ml for A. baumannii, and ≤0.12 μg/ml for S. anginosus group. At this time, susceptible breakpoints for doripenem have not been determined for the other organism groups.
TABLE 1.
Doripenem MIC distributions determined by broth microdilution MIC method
| Organism (description)a | No. of isolates |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | With doripenem MIC (μg/ml): |
||||||||||||
| ≤0.015 | 0.03 | 0.06 | 0.13 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | ||
| Gram negative | |||||||||||||
| Enterobacteriaceaeb (18 ESBL+) | 100 | 14 | 44 | 11 | 16 | 10 | 3 | 2 | |||||
| Non-Enterobacteriaceae | 100 | 2 | 4 | 16 | 21 | 14 | 12 | 9 | 8 | 5 | 4 | 5 | |
| Pseudomonas aeruginosa | 80 | 1 | 4 | 15 | 17 | 11 | 10 | 6 | 7 | 4 | 1 | 4 | |
| Acinetobacter baumannii (10 MDR) | 20 | 1 | 1 | 4 | 3 | 2 | 3 | 1 | 1 | 3 | 1 | ||
| Gram positive | |||||||||||||
| Enterococcus spp.c | 49 | 15 | 21 | 5 | 1 | 7 | |||||||
| Staphylococcus spp. | 100 | 13 | 35 | 7 | 6 | 16 | 7 | 3 | 3 | 2 | 3 | 3 | 2 |
| S. aureus (26 MR, 35 MS) | 61 | 9 | 23 | 5 | 3 | 10 | 5 | 2 | 1 | 2 | 1 | ||
| CoNS (20 MR, 19 MS)d | 39 | 4 | 12 | 2 | 3 | 6 | 2 | 3 | 1 | 1 | 3 | 1 | 1 |
| Streptococcus spp., not S. pneumoniae | 61 | 43 | 9 | 3 | 2 | 2 | 2 | ||||||
| Streptococcus spp., beta-hemolytic groupe | 39 | 35 | 4 | ||||||||||
| Streptococcus spp., viridans groupf | 22 | 8 | 5 | 3 | 2 | 2 | 2 | ||||||
| Streptococcus pneumoniae | 103 | 39 | 8 | 12 | 4 | 7 | 25 | 7 | 1 | ||||
ESBL+, extended-spectrum β-lactamase positive; MDR, multidrug resistant; MR, methicillin resistant; MS, methicillin susceptible; CoNS, coagulase-negative staphylococci.
Enterobacteriaceae included Citrobacter braakii, n = 2; Citrobacter freundii, n = 6; Enterobacter cloacae, n = 10; Enterobacter sakazakii, n = 2; Escherichia coli, n = 31; Hafnia alvei, n = 1; Klebsiella oxytoca, n = 7; Klebsiella pneumoniae, n = 14; Morganella morganii, n = 9; Proteus mirabilis, n = 10; Proteus penneri, n = 2; Proteus vulgaris, n = 2; and Serratia marcescens, n = 4.
Enterococci included Enterococcus faecalis, n = 39, and Enterococcus faecium, n = 10, including 1 vancomycin-resistant strain.
Coagulase-negative staphylococci included Staphylococcus capitis, n = 1; Staphylococcus epidermidis, n = 24; Staphylococcus haemolyticus, n = 9; Staphylococcus hominis, n = 3; Staphylococcus saprophyticus, n = 1; and Staphylococcus simulans, n = 1.
Streptococcus beta-hemolytic group included Streptococcus agalactiae, n = 21, and Streptococcus pyogenes, n = 18.
Streptococcus viridans group included S. anginosus, n = 2; Streptococcus bovis, n = 1; Streptococcus constellatus, n = 5; Streptococcus mitis, n = 3; Streptococcus oralis, n = 3; Streptococcus salivarius, n = 1; and Streptococcus viridans group, n = 7.
The BMD, agar dilution, and Etest doripenem MIC values are summarized in Table 2. Among the Gram-negative isolates, all methods yielded a doripenem MIC90 for Enterobacteriaceae of 0.25 μg/ml. For P. aeruginosa the BMD and Etest MIC90s were 8 μg/ml and the agar dilution MIC90 was 4 μg/ml for doripenem. For A. baumannii, the BMD, Etest, and agar dilution MIC90 values were 16, >32, and 8 μg/ml, respectively.
TABLE 2.
Doripenem MICs determined by various susceptibility methods
| Organism group (n) | MIC determination method | MIC (μg/ml) |
% susceptiblea | |||
|---|---|---|---|---|---|---|
| Range | MIC50 | MIC90 | Mode | |||
| Enterobacteriaceae (100) | BMD | ≤0.015-1 | 0.03 | 0.25 | 0.03 | 98 |
| Agar Db,c | 0.015-1 | 0.06 | 0.25 | 0.03 | 99 | |
| Etest | 0.015-1 | 0.06 | 0.25 | 0.06 | 99 | |
| Non-Enterobacteriaceae (100) | BMD | 0.03->16 | 0.5 | 8 | 0.25 | — |
| Agar D | 0.015->16 | 0.5 | 8 | 0.25 | — | |
| Etest | 0.03->32 | 0.5 | 32 | 0.25 | — | |
| P. aeruginosa (80) | BMD | 0.03->16 | 0.5 | 8 | 0.25 | 80 |
| Agar D | 0.06->16 | 0.5 | 4 | 0.25 | 80 | |
| Etest | 0.06->32 | 0.25 | 8 | 0.25 | 78.8 | |
| A. baumannii (20) | BMD | 0.03->16 | 1 | 16 | 0.25 | 55 |
| Agar D | 0.015-8 | 2 | 8 | 2 | 40 | |
| Etest | 0.03->32 | 2 | >32 | 2 | 40 | |
| Enterococcus spp. (49) | BMD | 2->16 | 4 | >16 | 4 | — |
| Agar D | 1->16 | 4 | >16 | 2 | — | |
| Etest | 0.5->32 | 4 | >32 | 4 | — | |
| Staphylococcus spp. (100) | BMD | ≤0.015->16 | 0.06 | 2 | 0.03 | — |
| Agar De | ≤0.015->16 | 0.06 | 2 | 0.03 | — | |
| Etest | 0.004->32 | 0.125 | 4 | 0.06 | — | |
| S. aureus (61) | BMD | ≤0.015->16 | 0.03 | 0.5 | 0.03 | — |
| Agar D | 0.03-16 | 0.03 | 2 | 0.03 | — | |
| Etest | 0.03->32 | 0.125 | 2 | 0.06 | — | |
| CoNSd (39) | BMD | ≤0.015->16 | 0.125 | 8 | 0.03 | — |
| Agar D | ≤0.015->16 | 0.06 | 2 | 0.03 | — | |
| Etest | 0.004->32 | 0.125 | 4 | 0.06 | — | |
| Streptococcus spp., other than S. pneumoniae (61) | BMD | ≤0.015-4 | ≤0.015 | 0.06 | ≤0.015 | — |
| Agar D | ≤0.008-4 | 0.015 | 0.06 | ≤0.008 | — | |
| Etest | 0.002-2 | 0.03 | 0.125 | 0.03 | — | |
| Beta-hemolytic group (39) | BMD | ≤0.015-0.03 | ≤0.015 | ≤0.015 | ≤0.015 | — |
| Agar D | ≤0.008-0.03 | 0.015 | 0.015 | ≤0.008 | — | |
| Etest | 0.002-0.125 | 0.03 | 0.03 | 0.03 | — | |
| Viridans group (22) | BMD | ≤0.015-4 | 0.03 | 0.25 | ≤0.015 | — |
| Agar D | ≤0.008-4 | 0.06 | 0.25 | 0.06 | — | |
| Etest | 0.008-2 | 0.06 | 0.25 | 0.06 | — | |
| Streptococcus pneumoniae (103) | BMD | ≤0.015-2 | 0.06 | 0.5 | ≤0.015 | — |
| Etest | 0.008-1 | 0.06 | 1 | 0.008 | — | |
Doripenem FDA susceptible breakpoints: Enterobacteriaceae, ≤0.5 μg/ml; P. aeruginosa, ≤2 μg/ml; A. baumannii, ≤1 μg/ml. —, doripenem FDA breakpoints have not yet been determined for these organism groups.
Agar D, agar dilution.
The number of Enterobacteriaceae tested by agar dilution was 98.
CoNS, coagulase-negative staphylococci.
The number of staphylococci tested by agar dilution was 97, including 60 S. aureus isolates and 37 coagulase-negative staphylococci.
Against 49 enterococci, the MIC50 and MIC90 were 4 and ≥16 μg/ml, respectively, by all three methods. For all staphylococci, the doripenem MIC90s were 2 μg/ml by BMD and agar dilution and 4 μg/ml by Etest. The S. pneumoniae doripenem MIC90 was 0.5 μg/ml by BMD and 2-fold higher by Etest. The MIC90 for beta-hemolytic streptococci was ≤0.015 μg/ml by BMD and agar dilution and 0.03 μg/ml by Etest; for viridans group streptococci the MIC90 was 0.25 μg/ml for all test methods.
As doripenem has only susceptible FDA breakpoints, an analysis of very major test errors was conducted for organisms that were defined as nonsusceptible by the reference method, BMD, and categorized as susceptible by agar dilution or Etest. Major errors were determined for organisms that were susceptible by BMD and nonsusceptible by agar dilution or Etest. For the Enterobacteriaceae group, there was one very major error for both agar dilution and Etest methods. Among the P. aeruginosa isolates tested, there was one major error by Etest. For A. baumannii, there were three major errors by both agar dilution and Etest methods.
Doripenem MICs for 60% (59/98) of the Enterobacteriaceae, 55% (44/80) of the P. aeruginosa isolates, and 40% (8/20) of the A. baumannii isolates tested were identical for BMD and agar dilution within each group. Among the Gram-positive isolates tested, 50.7% (105/207) had identical MIC results for BMD and agar dilution (Table 3). Etest and BMD tests had a lower percentage of identical MIC results for many of the organism groups, especially the Enterobacteriaceae, staphylococci, and non-S. pneumoniae isolates. Etest and BMD MICs were identical for only 28% (28/100) of the Enterobacteriaceae, 45% (36/80) of P. aeruginosa isolates, 45% (9/20) of A. baumannii isolates, and 48.1% (150/312) of the Gram-positive isolates tested (Table 4).
TABLE 3.
Distribution of doripenem log2 dilution differences between agar dilution and BMD methods
| Organism group | No. of isolates |
% agreement |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total | With log2 dilution differencea: |
|||||||||
| −2 | −1 | 0 | 1 | 2 | ≥3 | Same | ±1 | ±2 | ||
| Enterobacteriaceae | 98 | 18 | 59 | 19 | 1 | 1 | 60.2 | 96.8 | 99.0 | |
| Non-Enterobacteriaceae | 100 | 5 | 15 | 52 | 26 | 2 | 52.0 | 93.0 | 98.0 | |
| P. aeruginosa | 80 | 3 | 11 | 44 | 22 | 55.0 | 96.3 | 100.0 | ||
| A. baumannii | 20 | 2 | 4 | 8 | 4 | 2 | 40.0 | 80.0 | 90.0 | |
| Enterococcus spp. | 49 | 3 | 16 | 24 | 6 | 49.0 | 93.9 | 100.0 | ||
| Staphylococcus spp. | 97 | 7 | 12 | 40 | 32 | 6 | 41.2 | 86.6 | 100.0 | |
| S. aureus | 60 | 1 | 8 | 23 | 22 | 6 | 38.3 | 88.3 | 100.0 | |
| CoNSb | 37 | 6 | 4 | 17 | 10 | 45.9 | 83.8 | 100.0 | ||
| Streptococcus spp., not S. pneumoniae | 61 | 8 | 41 | 11 | 1 | 67.2 | 98.4 | 100.0 | ||
| Streptococcus spp., beta-hemolytic group | 39 | 3 | 33 | 3 | 84.6 | 100.0 | 100.0 | |||
| Streptococcus spp., viridans group | 22 | 5 | 8 | 8 | 1 | 36.4 | 95.5 | 100.0 | ||
| Total | 405 | 15 | 69 | 216 | 94 | 8 | 3 | 53.3 | 93.6 | 99.3 |
Negative number, agar dilution result was lower than BMD result. Positive number, agar dilution result was higher than the BMD result.
CoNS, coagulase-negative staphylococci.
TABLE 4.
Distribution of doripenem log2 dilution differences between Etest and BMD reference methods
| Organism group | No. of isolates |
% agreement |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | With log2 dilution differencea: |
||||||||||
| ≤−3 | −2 | −1 | 0 | 1 | 2 | ≥3 | Same | ±1 | ±2 | ||
| Enterobacteriaceae | 100 | 1 | 7 | 28 | 57 | 7 | 28.0 | 92.0 | 100.0 | ||
| Non-Enterobacteriaceae | 100 | 1 | 27 | 45 | 19 | 6 | 2 | 45.0 | 91.0 | 98.0 | |
| P. aeruginosa | 80 | 1 | 26 | 36 | 13 | 4 | 45.0 | 93.8 | 100.0 | ||
| A. baumannii | 20 | 1 | 9 | 6 | 2 | 2 | 45.0 | 80.0 | 90.0 | ||
| Enterococcus spp. | 49 | 1 | 8 | 26 | 13 | 1 | 53.1 | 95.9 | 98.0 | ||
| Staphylococcus spp. | 100 | 2 | 3 | 16 | 45 | 29 | 5 | 16.0 | 64.0 | 95.0 | |
| S. aureus | 61 | 7 | 27 | 24 | 3 | 11.5 | 55.7 | 95.1 | |||
| CoNSb | 39 | 2 | 3 | 9 | 18 | 5 | 2 | 23.1 | 76.9 | 94.9 | |
| Streptococcus spp., not S. pneumoniae | 60 | 4 | 30 | 20 | 5 | 1 | 50.0 | 90.0 | 98.3 | ||
| Streptococcus spp., beta-hemolytic group | 39 | 22 | 16 | 1 | 56.4 | 97.4 | 97.4 | ||||
| Streptococcus spp., viridans group | 21 | 4 | 8 | 4 | 5 | 38.1 | 76.2 | 100.0 | |||
| Streptococcus pneumoniae | 103 | 6 | 78 | 19 | 75.7 | 100.0 | 100.0 | ||||
| Total | 512 | 1 | 4 | 55 | 223 | 173 | 48 | 8 | 43.6 | 88.1 | 98.2 |
Negative number, Etest result was lower than BMD result. Positive number, Etest result was higher than the BMD result.
CoNS, coagulase-negative staphylococci.
Comparison of doripenem agar dilution MIC results to Etest MIC values (Table 5) showed >92% essential agreement (within ±1 log2 dilution) for Enterobacteriaceae, P. aeruginosa, enterococci, and streptococci that were not S. pneumoniae. A. baumannii and staphylococci demonstrated lower essential agreements (within ±1 log2 dilution) of 60% and 84.5% for doripenem agar dilution MIC and Etest MIC comparisons, respectively.
TABLE 5.
Distribution of doripenem log2 dilution differences between Etest and agar dilution methods
| Organism group | No. of isolates |
% agreement |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | With log2 dilution differencea: |
||||||||||
| ≤−3 | −2 | −1 | 0 | 1 | 2 | ≥3 | Same | ±1 | ±2 | ||
| Enterobacteriaceae | 98 | 4 | 40 | 49 | 5 | 40.8 | 94.9 | 100.0 | |||
| Nonfermenters | 100 | 3 | 3 | 26 | 50 | 8 | 5 | 5 | 50.0 | 84.0 | 92.0 |
| P. aeruginosa | 80 | 2 | 2 | 26 | 39 | 7 | 3 | 1 | 32.5 | 90.0 | 96.3 |
| A. baumannii | 20 | 1 | 1 | 11 | 1 | 2 | 4 | 55.0 | 60.0 | 75.0 | |
| Enterococcus spp. | 49 | 1 | 5 | 19 | 22 | 1 | 1 | 38.8 | 93.9 | 95.9 | |
| Staphylococcus spp. | 97 | 1 | 25 | 56 | 13 | 2 | 25.8 | 84.5 | 97.9 | ||
| S. aureus | 60 | 14 | 38 | 8 | 23.3 | 86.7 | 100.0 | ||||
| CoNSb | 37 | 1 | 11 | 18 | 5 | 2 | 29.7 | 81.1 | 94.6 | ||
| Streptococcus spp., not S. pneumoniae | 60 | 1 | 37 | 18 | 3 | 1 | 61.7 | 93.3 | 98.3 | ||
| Beta-hemolytic group | 39 | 23 | 13 | 2 | 1 | 59.0 | 92.3 | 97.4 | |||
| Viridans group | 21 | 1 | 14 | 5 | 1 | 66.7 | 95.2 | 100.0 | |||
| Total | 404 | 4 | 3 | 37 | 171 | 153 | 27 | 9 | 42.3 | 89.4 | 96.8 |
Negative number, Etest result was lower than agar dilution result. Positive number, Etest result was higher than the agar dilution result.
CoNS, coagulase-negative staphylococci.
The essential agreement (within ±1 log2 dilution) of doripenem BMD results for all organisms tested compared to agar dilution MICs was 93.6%, and that compared to Etest MICs was 88.1%. A. baumannii and staphylococci demonstrated slightly lower essential agreements (within ±1 log2 dilution) of 80% and 86.6% by agar dilution and 80% and 64% by Etest, respectively (Tables 3 and 4). A. baumannii and staphylococci also demonstrated lower essential agreement when Etest results were compared to agar dilution MICs. Organism groups with >93% essential agreement (within ±1 log2 dilution) of doripenem BMD and agar dilution MICs were Enterobacteriaceae, P. aeruginosa, enterococci, and viridans group streptococci, and the group with 100% essential agreement (within ±1 log2 dilution) was beta-hemolytic streptococci. In comparing doripenem BMD to Etest, organism groups with >92% essential agreement (within ±1 log2 dilution) of doripenem BMD and agar dilution MICs were Enterobacteriaceae, P. aeruginosa, enterococci, and beta-hemolytic streptococci, and S. pneumoniae showed 100% essential agreement (within ±1 log2 dilution). Within ±2 log2 dilutions, the agreements of BMD results for all organisms tested compared to agar dilution and to Etest were 99.3% and 98.2%, respectively.
As commercial methods for susceptibility testing of doripenem are becoming more available, it is important to know how results determined by alternate methods compare to the standard reference method, BMD. This study demonstrated that agar dilution MICs were comparable to BMD MICs with ≥93% essential agreement and that 99% were within ±2 log2 dilutions. By Etest, most MICs, including the MIC mode and MIC90 values for all organisms examined, tended to be 1 log2 dilution higher than the BMD values. This trend was also observed in a previous study with P. aeruginosa isolates at or near the doripenem breakpoint (2 μg/ml) (2).
In this study, the Etest method performed comparably to the standard reference methods with >96% of the doripenem MICs within ±2 log2 dilutions of the BMD and agar dilution methods. Given the overall comparability of these three methods, laboratories should be comfortable in using their method of choice for MIC testing of doripenem. However, it should be recognized that there may be inherent, although sometimes subtle, differences that may occur in MIC testing, depending on the method chosen.
Acknowledgments
We thank Ellyn Wira, Ashok Vasant, and Heather Krause from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., for their technical contributions to the susceptibility data.
Footnotes
Published ahead of print on 30 June 2010.
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