Abstract
Susceptibility to piperacillin was similar to that to piperacillin-tazobactam (<1% difference) for 6,938 isolates of Enterobacter aerogenes and 13,954 isolates of Enterobacter cloacae tested using a Vitek system; for the same species, in contrast, susceptibility rates to piperacillin-tazobactam were 5.9 to 13.9% higher than to piperacillin using disk diffusion, MicroScan, and Vitek 2 testing. Unprecedented phenotypes (piperacillin susceptible and piperacillin-tazobactam intermediate; piperacillin intermediate and piperacillin-tazobactam resistant; piperacillin susceptible and piperacillin-tazobactam resistant) accounted for 6.1% of the results for E. aerogenes isolates and 6.0% of the results for E. cloacae isolates tested with the Vitek system.
Piperacillin is hydrolyzed by plasmid-mediated β-lactamases of gram-positive and gram-negative bacteria as well as by Bush group 1 chromosomal β-lactamases of gram-negative bacteria (AmpC) (2). Tazobactam inhibits most β-lactamases produced by Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, and Citrobacter koseri but not isolates of Enterobacter species, Serratia species, Citrobacter freundii, and Pseudomonas aeruginosa expressing stably derepressed AmpC β-lactamases (2, 12). Piperacillin-tazobactam demonstrates in vitro activity against isolates of Enterobacteriaceae harboring TEM or SHV β-lactamases and their derivatives, extended-spectrum β-lactamases (2, 9, 12). Piperacillin (15, 16) and tazobactam (4, 8, 9, 11, 12, 20) do not induce chromosomal AmpC β-lactamases at clinically relevant concentrations; piperacillin is also a poor selector for stably derepressed mutants (6, 11).
No published precedents or plausible mechanistic explanation exists supporting the following MIC interpretative phenotypes: the susceptible to piperacillin and intermediate or resistant to piperacillin-tazobactam phenotype and the intermediate to piperacillin and resistant to piperacillin-tazobactam phenotype. In vitro broth microdilution studies have repeatedly confirmed expected similarities and differences in susceptibilities of Enterobacteriaceae and P. aeruginosa to piperacillin and piperacillin-tazobactam on the basis of anticipated β-lactamase profiles (1, 3, 5, 7, 9, 13, 14, 17). The present study was undertaken to assess the activities of piperacillin and piperacillin-tazobactam against six species of Enterobacteriaceae and P. aeruginosa as tested by the disk diffusion method and Vitek(bioMérieux, Hazelwood, Mo.), Vitek 2 (bioMérieux), and MicroScan Walkaway (Dade Behring, West Sacramento, Calif.) systems.
The Surveillance Network (TSN) Database-USA (Focus Technologies, Herndon, Va.) was used as the source of antimicrobial susceptibility testing results for this study. TSN electronically assimilates antimicrobial susceptibility testing and patient demographic data from a network of hospitals in the United States and has been previously described (19). Laboratories are included in TSN on the basis of factors such as national accreditation, hospital bed size, patient population, geographic location, and antimicrobial susceptibility testing methods used (19). Susceptibility testing of patient isolates is conducted on site by each participating laboratory as a part of routine diagnostic testing. Only data generated using Food and Drug Administration-approved testing methods with MIC results interpreted according to National Committee for Clinical Laboratory Standards recommendations (18) are included in TSN.
The antimicrobial susceptibility testing results included in the present analysis were restricted to the 100 U.S. laboratories that participated in TSN from 1999 to 2002 and that concurrently tested piperacillin and piperacillin-tazobactam against isolates of C. koseri, Enterobacter aerogenes, Enterobacter cloacae, E. coli, Klebsiella pneumoniae, P. mirabilis, or P. aeruginosa. Laboratories included in the analysis were from all nine U.S. Bureau of the Census regions. Duplicate isolates, defined as two or more isolates (of the same species taken from the same patient in a 5-day period) with identical antibiograms, were removed from the data set. Results determined using the Vitek 2 automated system were from 2000 to 2002 only.
In comparisons of MIC interpretation categorical agreements for piperacillin and piperacillin-tazobactam, the following categorical agreements for piperacillin and piperacillin-tazobactam were considered acceptable: susceptible-susceptible,intermediate-intermediate, resistant-resistant, intermediate-susceptible, and resistant-susceptible. The acceptability of these categorical agreements was based upon previously published broth dilution data for piperacillin and piperacillin-tazobactam (1, 3, 5, 7, 9, 10, 13, 14, 17) and studies of mechanisms of resistance (2, 12). Because there is no precedent or plausible mechanistic explanation for phenotypes other than those listed, other phenotypes were considered errors and divided into two groups. A minor error was defined as an isolate of Enterobacteriaceae or P. aeruginosa testing as susceptible to piperacillin and intermediate to piperacillin-tazobactam or as intermediate to piperacillin and resistant to piperacillin-tazobactam. A major error was defined as an isolate testing as susceptible to piperacillin and resistant to piperacillin-tazobactam.
Table 1 indicates that all isolates of species tested by disk diffusion, MicroScan Walkaway, Vitek, and Vitek 2 methods were more susceptible to piperacillin-tazobactam than piperacillin, with the exception of E. aerogenes and E. cloacae isolates tested using the Vitek system. In tests using the Vitek system, differences in susceptibilities to piperacillin and piperacillin-tazobactam were 0.8 and 0.2%, respectively, for isolates of E. aerogenes and E. cloacae. E. aerogenes and E. cloacae isolates demonstrated higher rates of resistance to piperacillin than to piperacillin-tazobactam (differences in resistance were 1.0 and 2.1%, respectively). By year from 1999 to 2002, susceptibility to piperacillin and piperacillin-tazobactam differed (maximally) by 2.0% for E. aerogenes and by 2.6% for E. cloacae in tests using the Vitek system (data not shown).
TABLE 1.
Susceptibilities of clinical isolates of Enterobacteriaceae and P. aeruginosa to piperacillin and piperacillin-tazobactam as assessed by four testing methods in U.S. clinical laboratories from 1999 to 2002
| Test method | Organism (no. of isolates) | Antimicrobial | % Susceptible | % Intermediate | % Resistant |
|---|---|---|---|---|---|
| Disk diffusion | C. koseri (121) | Piperacillin | 59.5 | 29.8 | 10.7 |
| Piperacillin-tazobactam | 94.2 | 4.1 | 1.7 | ||
| E. aerogenes (412) | Piperacillin | 56.6 | 10.4 | 33.0 | |
| Piperacillin-tazobactam | 63.3 | 13.3 | 23.3 | ||
| E. cloacae (935) | Piperacillin | 42.6 | 6.6 | 50.8 | |
| Piperacillin-tazobactam | 56.5 | 8.9 | 34.7 | ||
| E. coli (5,922) | Piperacillin | 44.2 | 4.7 | 51.1 | |
| Piperacillin-tazobactam | 91.5 | 6.2 | 2.2 | ||
| K. pneumoniae (2,461) | Piperacillin | 49.4 | 25.3 | 25.3 | |
| Piperacillin-tazobactam | 87.8 | 6.9 | 5.3 | ||
| P. mirabilis (708) | Piperacillin | 72.5 | 18.6 | 8.9 | |
| Piperacillin-tazobactam | 98.9 | 0.6 | 0.6 | ||
| P. aeruginosa (20,642) | Piperacillin | 85.6 | —a | 14.5 | |
| Piperacillin-tazobactam | 88.3 | — | 11.7 | ||
| Microscan Walkaway | C. koseri (1,482) | Piperacillin | 44.7 | 32.5 | 22.8 |
| Piperacillin-tazobactam | 99.1 | 0.8 | 0.1 | ||
| E. aerogenes (3,045) | Piperacillin | 64.5 | 15.6 | 19.8 | |
| Piperacillin-tazobactam | 76.6 | 18.2 | 5.3 | ||
| E. cloacae (7,398) | Piperacillin | 63.1 | 5.5 | 31.3 | |
| Piperacillin-tazobactam | 75.5 | 10.5 | 14.0 | ||
| E. coli (46,661) | Piperacillin | 57.6 | 3.9 | 38.4 | |
| Piperacillin-tazobactam | 95.9 | 2.3 | 1.8 | ||
| K. pneumoniae (14,416) | Piperacillin | 60.7 | 12.3 | 27.0 | |
| Piperacillin-tazobactam | 90.2 | 3.1 | 6.7 | ||
| P. mirabilis (9,046) | Piperacillin | 86.3 | 2.0 | 11.7 | |
| Piperacillin-tazobactam | 99.5 | 0.3 | 0.1 | ||
| P. aeruginosa (31,944) | Piperacillin | 85.0 | — | 15.0 | |
| Piperacillin-tazobactam | 88.3 | — | 11.7 | ||
| Vitek | C. koseri (3,827) | Piperacillin | 90.8 | 4.0 | 5.3 |
| Piperacillin-tazobactam | 95.7 | 2.4 | 1.9 | ||
| E. aerogenes (6,938) | Piperacillin | 80.2 | 13.1 | 6.7 | |
| Piperacillin-tazobactam | 79.4 | 14.9 | 5.7 | ||
| E. cloacae (13,954) | Piperacillin | 70.4 | 9.0 | 20.6 | |
| Piperacillin-tazobactam | 70.2 | 11.3 | 18.5 | ||
| E. coli (162,864) | Piperacillin | 64.1 | 9.2 | 26.6 | |
| Piperacillin-tazobactam | 96.0 | 2.7 | 1.3 | ||
| K. pneumoniae (37,023) | Piperacillin | 84.4 | 4.7 | 10.9 | |
| Piperacillin-tazobactam | 90.1 | 5.3 | 4.6 | ||
| P. mirabilis (21,940) | Piperacillin | 86.8 | 3.4 | 9.8 | |
| Piperacillin-tazobactam | 96.8 | 2.0 | 1.3 | ||
| P. aeruginosa (52,311) | Piperacillin | 81.3 | — | 18.7 | |
| Piperacillin-tazobactam | 91.0 | — | 9.0 | ||
| Vitek 2b | C. koseri (589) | Piperacillin | 82.2 | 10.0 | 7.8 |
| Piperacillin-tazobactam | 96.1 | 3.2 | 0.7 | ||
| E. aerogenes (1,040) | Piperacillin | 81.2 | 13.3 | 5.6 | |
| Piperacillin-tazobactam | 87.1 | 11.9 | 1.0 | ||
| E. cloacae (2,354) | Piperacillin | 71.9 | 8.7 | 19.5 | |
| Piperacillin-tazobactam | 82.3 | 10.3 | 7.4 | ||
| E. coli (30,604) | Piperacillin | 72.3 | 13.3 | 14.4 | |
| Piperacillin-tazobactam | 99.1 | 0.6 | 0.3 | ||
| K. pneumoniae (7,202) | Piperacillin | 80.8 | 6.8 | 12.4 | |
| Piperacillin-tazobactam | 95.8 | 2.9 | 1.3 | ||
| P. mirabilis (5,557) | Piperacillin | 93.3 | 4.2 | 2.4 | |
| Piperacillin-tazobactam | 99.7 | 0.2 | 0.1 | ||
| P. aeruginosa (14,243) | Piperacillin | 88.9 | — | 11.1 | |
| Piperacillin-tazobactam | 93.1 | — | 6.9 |
Dashes indicate lack of data; an intermediate breakpoint has not been not published for piperacillin or piperacillin-tazobactam tested against isolates of P. aeruginosa (18).
Vitek 2 data were not available in 1999.
Given the absence of a difference in the susceptibilities of E. aerogenes and E. cloacae to piperacillin and piperacillin-tazobactam in tests using the Vitek system compared with the expected differences observed with the other three methods (Table 1), we investigated this observation further by determining the prevalence of minor and major errors for E. aerogenes and E. cloacae isolates in tests using the Vitek system (Table 2). A similar analysis was also conducted on Vitek 2 results as a control. Minor errors were observed for 5.8% of E. aerogenes and 5.5% of E. cloacae isolates in tests using the Vitek system. A piperacillin-susceptible and piperacillin-tazobactam-intermediate phenotype accounted for approximately two-thirds of the minor errors for both E. aerogenes and E. cloacae. Only 34.5% of piperacillin-susceptible and piperacillin-tazobactam-intermediate isolates of E. cloacae had piperacillin MICs of 16 μg/ml; the remaining isolates (65.5%) had piperacillin MICs of ≤8 μg/ml (data not shown). Similarly, among piperacillin-susceptible and piperacillin-tazobactam-intermediate isolates of E. aerogenes, 54.7% had piperacillin MICs of 16 μg/ml and 45.3% had piperacillin MICs of ≤8 μg/ml. Minor errors accounted for <1% of isolate test results for all organism-testing method combinations other than those for E. aerogenes, E. cloacae, and K. pneumoniae (1.3%) in tests using the Vitek system (data not shown). For each of the four testing methods, <0.5% of the test results for C. koseri, E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, E. aerogenes, and E. cloacae isolates showed major errors for piperacillin and piperacillin-tazobactam, with the exception of results for E. cloacae isolates tested by disk diffusion (0.5%) and P. aeruginosa isolates tested by MicroScan Walkaway (0.6%) (data not shown).
TABLE 2.
Summary of minora and majorb errors among E. aerogenes and E. cloacae isolates tested against piperacillin and piperacillin-tazobactam
| Organism | Total no. of isolates tested by Vitek | MIC interpretative phenotypec by Vitek
|
Error type; no. of isolates (%) by Vitek | Total no. of isolates tested by Vitek 2 | MIC interpretative phenotypec by Vitek 2
|
Error type; no. of isolates (%) by Vitek 2 | ||
|---|---|---|---|---|---|---|---|---|
| Piperacillin | Piperacillin- tazobactam | Piperacillin | Piperacillin- tazobactam | |||||
| E. aerogenes | 6,938 | Susceptible | Intermediate | Minor; 274 (3.9) | 1,040 | Susceptible | Intermediate | Minor; 7 (0.6) |
| Intermediate | Resistant | Minor, 132 (1.9) | Intermediate | Resistant | Minor; 5 (0.5) | |||
| Susceptible | Resistant | Major; 16 (0.2) | Susceptible | Resistant | Major; 1 (0.1) | |||
| E. cloacae | 13,954 | Susceptible | Intermediate | Minor; 522 (3.7) | 2,354 | Susceptible | Intermediate | Minor; 6 (0.2) |
| Intermediate | Resistant | Minor; 254 (1.8) | Intermediate | Resistant | Minor; 2 (0.1) | |||
| Susceptible | Resistant | Major; 59 (0.4) | Susceptible | Resistant | Major; 0 (0) | |||
A minor error was defined as an isolate testing as susceptible to piperacillin and intermediate to piperacillin-tazobactam or as intermediate to piperacillin and resistant to piperacillin-tazobactam.
A major error was defined as an isolate testing as susceptible to piperacillin and resistant to piperacillin-tazobactam.
MIC interpretative phenotypes were determined using National Committee for Clinical Laboratory Standards recommendations (18).
Table 3 depicts minor and major error rates for laboratories using the Vitek and Vitek 2 systems to test >50 isolates of E. aerogenes and E. cloacae. For E. aerogenes, 7 of 27 laboratories (25.9%) demonstrated major errors. Minor error rates exceeded 5% for 16 of 27 laboratories (59.3%); all laboratories reported at least one isolate test result with a minor error. Of the four laboratories using the Vitek 2 system to test E. aerogenes isolates, one laboratory reported a major error and two laboratories reported minor error rates of >1 to 5%. Among E. cloacae isolates tested using the Vitek system, 19 of 42 laboratories (45.2%) reported results with major errors; 23 of 42 laboratories (54.8%) had minor error rates of >5%. Out of five laboratories using the Vitek 2 system to test E. cloacae isolates, three reported at least one isolate test result with a minor error; there were no major errors reported in tests using the Vitek 2 system.
TABLE 3.
Summary of minora and majorb error rates at laboratories testing >50 isolates of E. aerogenes or E. cloacae against piperacillin and piperacillin-tazobactam by the Vitek or Vitek 2 method in 1999 to 2002
| Organism | Test method | Total no. of laboratories testing >50 isolates of an Enterobacter sp. by Vitek or Vitek 2 | Total no. of isolates tested | No. of laboratories without minor errors | No. of laboratories with minor error ratesc of:
|
No. of laboratories without major errors | No. of laboratories with major error ratesc of:
|
||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤1% | >1-5% | >5% | ≤0.5% | >0.5-1% | >1% | ||||||
| E. aerogenes | Vitek | 27 | 6,385 | 0 | 0 | 11 | 16 | 20 | 2 | 3 | 2 |
| Vitek 2 | 4 | 968 | 2 | 0 | 2 | 0 | 3 | 1 | 0 | 0 | |
| E. cloacae | Vitek | 42 | 13,813 | 1 | 0 | 18 | 23 | 23 | 5 | 7 | 7 |
| Vitek 2 | 5 | 2,299 | 2 | 3 | 0 | 0 | 5 | 0 | 0 | 0 | |
A minor error was defined as an isolate testing as susceptible to piperacillin and intermediate to piperacillin-tazobactam or as intermediate to piperacillin and resistant to piperacillin-tazobactam.
A major error was defined as an isolate testing as susceptible to piperacillin and resistant to piperacillin-tazobactam.
Some laboratories reported both minor and major errors.
The percentages of isolates susceptible to piperacillin-tazobactam are higher than those of isolates susceptible to piperacillin for E. coli, Klebsiella species, Proteus species, P. stuartii, M. morganii, and C. koseri due to the preponderance of plasmid-mediated β-lactamases in these species (1, 3, 7, 9, 13, 14, 17). Results from the present study (Table 1) confirmed the broth microdilution findings previously reported. Piperacillin-tazobactam is at least as active as piperacillin against Enterobacter species, Serratia species, C. freundii, and P. aeruginosa, given the propensity for some strains of these species to express stably derepressed AmpC β-lactamases and for many also to harbor plasmid-mediated β-lactamases (1, 3, 5, 7, 9, 10, 13, 14, 17). AmpC β-lactamases confer frank resistance to β-lactam-β-lactamase inhibitor combinations and to all β-lactams except carbapenems and fourth-generation cephalosporins (e.g., cefepime). The difference in piperacillin and piperacillin-tazobactam categorical interpretations for Enterobacter species, Serratia species, C. freundii, and P. aeruginosa observed in the present study suggests that there may be small subpopulations of organisms that either produce a class A β-lactamase or have AmpC β-lactamases that are only partially derepressed (6).
A recent study describing clinical isolates of P. aeruginosa (n = 557) reported 15% higher potency for piperacillin-tazobactam than for piperacillin, with 4% of the isolates being resistant to piperacillin and susceptible to piperacillin-tazobactam (10). The authors of that study suggested that it may no longer be appropriate to use piperacillin resistance rates to predict those of piperacillin-tazobactam and that even though the percentages of isolates that were susceptible were similar, a microbiological benefit may be observed with piperacillin-tazobactam because of its greater potency (i.e., lower MICs) (10). The present study found that only 0.1, 0.6, 0.1, and 0.3% of isolates of P. aeruginosa tested by disk diffusion (n = 20,642), MicroScan Walkaway (n = 31,944), Vitek (n = 52,311), and Vitek 2 (n = 14,243) methods had a piperacillin-susceptible and piperacillin-tazobactam-resistant phenotype (major error) (data not shown).
A previous study identified the potential for Vitek to overcall resistance to piperacillin-tazobactam relative to that to piperacillin against isolates of Enterobacter species and P. aeruginosa (G. A. Denys, P. B. Renzi, M. F. Wack, D. W. Smith, and M. B. Kays, Abstr. 102nd Gen. Meet. Am. Soc. Microbiol., abstr. C-130, p. 122-123, 2002). The authors of that study noted MICs for piperacillin-tazobactam that were two- to fourfold higher than for piperacillin for some isolates of both species but stated that this discrepancy remained widely unrecognized because it did not generally translate into differences in categorical interpretation for the two agents. The present study reported on categorical interpretation data only and found that according to tests using the Vitek system, the percentages of isolates that were resistant to piperacillin-tazobactam and susceptible to piperacillin accounted for 0.4 and 0.2% of E. aerogenes and E. cloacae isolate test results (Table 2) and 0.1% of P. aeruginosa isolate test results (data not shown). In tests using the Vitek system, minor errors (isolates testing as susceptible to piperacillin and intermediate to piperacillin-tazobactam or as intermediate to piperacillin and resistant to piperacillin-tazobactam) represented 5.8% and 5.5%, respectively, of E. aerogenes and E. cloacae test results. Minor errors were less commonly reported using the Vitek 2 system than the Vitek system for E. aerogenes (1.1%) and E. cloacae (0.3%) isolates. Given the absence of an MIC intermediate interpretative category for P. aeruginosa in tests with piperacillin and piperacillin-tazobactam (18), minor errors were not observed for this species.
Accurate in vitro susceptibility testing methods are important for optimal patient therapy, particularly for hospitalized patients. The disk diffusion method and MicroScan Walkaway, Vitek, and Vitek 2 systems appear to reliably report susceptibilities to piperacillin and piperacillin-tazobactam with low major error rates (isolates resistant to piperacillin-tazobactam and susceptible to piperacillin) in most laboratories. The Vitek system may not identify differences in susceptibility to piperacillin and piperacillin-tazobactam for some isolates of E. aerogenes and E. cloacae. Institutions (particularly those using the Vitek system) that produce laboratory results in which an isolate of Enterobacteriaceae (including Enterobacter species) or P. aeruginosa is more susceptible to piperacillin than to piperacillin-tazobactam should retest that isolate using a different method, as such a phenotype is unprecedented and without mechanistic explanation.
Acknowledgments
We thank David Styers of Focus Technologies for his technical support and the participating institutions in TSN Database-USA.
Wyeth Pharmaceuticals financially supported this study.
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