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. 2009 Nov 2;54(1):565–569. doi: 10.1128/AAC.01004-09

Hydrolysis and Inhibition Profiles of β-Lactamases from Molecular Classes A to D with Doripenem, Imipenem, and Meropenem▿

Anne Marie Queenan 1,*, Wenchi Shang 1, Robert Flamm 1, Karen Bush 1,†
PMCID: PMC2798497  PMID: 19884379

Abstract

The stability of doripenem to hydrolysis by β-lactamases from molecular classes A to D was compared to the stability for imipenem and meropenem. Doripenem was stable to hydrolysis by extended-spectrum β-lactamases and AmpC type β-lactamases and demonstrated high affinity for the AmpC enzymes. For the serine carbapenemases SME-3 and KPC-2 and metallo-β-lactamases IMP-1 and VIM-2, doripenem hydrolysis was generally 2- to 150-fold slower than imipenem hydrolysis. SPM-1 hydrolyzed meropenem and doripenem fourfold faster than imipenem.

Doripenem is a parenteral carbapenem with broad-spectrum activity against many aerobic and anaerobic pathogens. Doripenem MICs against gram-negative clinical isolates are frequently ≤0.5 μg/ml, even in Enterobacteriaceae expressing extended-spectrum β-lactamases (ESBLs) or overproduced AmpC (7, 12, 14). Resistance to doripenem and other carbapenems is observed in isolates producing metallo-β-lactamases (MBLs) or class A or class D carbapenemases (12, 13). In this study, we evaluated the hydrolysis of doripenem by a spectrum of β-lactamases from almost every functional group (3) and compared the doripenem kinetic profiles to those obtained for imipenem and meropenem.

(These data were presented in part as poster P909 at the 18th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, Spain, 2008.)

The broth microdilution methodology was used to determine MICs (6). Doripenem was from Shionogi & Co., Ltd. (Hyogo, Japan). Benzylpenicillin and cephaloridine were from Sigma (St. Louis, MO). Ceftazidime, imipenem, and meropenem were from U.S. Pharmacopeia (Rockville, MD).

MICs are shown in Table 1 for the strains used as sources of β-lactamases. The carbapenem MICs for isolates producing broad-spectrum, extended-spectrum, and AmpC β-lactamases were ≤2 μg/ml across the represented bacteria. Doripenem and meropenem MICs for the non-carbapenemase-producing isolates were generally four- to eightfold lower than those obtained for imipenem. Reduced susceptibility was apparent in isolates that expressed β-lactamases with known carbapenem hydrolysis profiles.

TABLE 1.

MICs for strains expressing characterized β-lactamasesb

Species Strain no. Distinguishing characteristic β-Lactamase Molecular classa Functional groupa MIC (μg/ml)
 Reference or source
IPM MEM DOR CAZ
E. coli ATCC 25922 Wild type ND NA NA 0.12 0.03 0.03 0.25 ATCC
DH5-α/pBR322 β-Lactamase positive TEM-1c A 2b 0.25 0.03 0.06 0.5 New England Biolabs
OC 11732 ESBL CTX-M-15 A 2be 0.25 0.03 0.06 32 17
OC 6697 Plasmid AmpC CMY-2 C 1 0.5 0.06 0.06 >128 1
Klebsiella pneumoniae OC 15263 Wild type, basal SHV-1c A 2b 0.5 0.03 0.06 0.12 This study
OC 4238 overexpressed SHV-1 A 2b 0.25 0.03 0.06 2 15
OC 4094d ESBL TEM-26c A 2be 0.5 0.06 0.12 >256 15
OC 5367 Carbapenemase KPC-2c A 2f 16 16 8 32 21
Klebsiella oxytoca OC 4076 Wild type K1 A 2b 0.25 0.06 0.06 1 2
Serratia marcescens OC 7555 Wild type, basal C 1 0.25 0.03 0.06 0.5 16
OC 7554 Carbapenemase SME-3c A 2f >256 128 128 0.5 16
E. cloacae OC 4080 Overexpressed AmpC C 1 1 0.25 0.25 32 4
P. aeruginosa ATCC 27853 Wild type, basal AmpC C 1 2 0.5 0.5 2 ATCC
OC 4352 Overexpressed AmpC C 1 2 0.5 0.5 32 15
OC 13996 Carbapenemase IMP-1 B 3 >256 >256 >256 >256 8
OC 7052e Carbapenemase VIM-2e B 3 64 32 32 64 10
OC 12115 Carbapenemase SPM-1 B 3 >256 >256 >256 >256 This study
OC 4083 Oxacillinase OXA-10c D 2d 1 2 2 >4 15
A. baumannii OC 16708 Wild type ND ND 0.25 0.25 0.25 4 This study
OC 11738 Carbapenemase OXA-23 D 2d 64 64 32 >256 This study
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a

Classification as in reference 3.

b

ND, not detected; NA, not applicable; IPM, imipenem; MEM, meropenem; DOR, doripenem; CAZ, ceftazidime.

c

Coding region for the β-lactamase was cloned from this plasmid or strain into the pET24a expression vector.

d

OC 4094 is also expressed as a chromosomal SHV β-lactamase.

e

Coding region for VIM-2 was cloned into the pET29a expression vector. OC 7052 also expressed as an uncharacterized pI-7.5 β-lactamase.

To compare the hydrolytic profiles of doripenem, imipenem, and meropenem, enzymes from freeze-thaw lysates were purified from lysates to >90% homogeneity by fast protein liquid chromatography, except for the OXA enzymes (∼50% purity) (15). Proteins were separated on Superdex 100 gel filtration and HiTrap SP cation- and Q anion-exchange columns (GE Healthcare, Piscataway, NJ). Columns and buffers were chosen based on the β-lactamase isoelectric point. Purity was assessed on NuPAGE 10% BT gels stained with colloidal blue (Invitrogen, Carlsbad, CA), and for protein quantitation, we used the Micro BCA assay (Pierce, Rockford, IL).

Initial hydrolysis rates were measured at 25°C in 50 mM phosphate buffer (pH 7.0) by using a Shimadzu UV-1601 spectrophotometer (15, 18). Reactions with MBLs contained 50 μM ZnCl2, and those with OXA enzymes contained 10 mM NaHCO3. Km and Vmax calculations used the Hanes plot. For Pseudomonas aeruginosa AmpC and CMY-2, hydrolysis was too slow to determine Km; a 50% inhibitory concentration obtained graphically using nitrocefin as a substrate was used to determine apparent Ki values (5). Extinction coefficients were as follows: Δɛ295 = 11,500 M−1 cm−1 for imipenem, Δɛ297 = 10,940 M−1 cm−1 for meropenem, and Δɛ297 = 11,460 M−1 cm−1 for doripenem. In general, substrates were tested on at least two separate days with variations of ≤20% of the average value reported in the tables.

Hydrolysis rates, Km values, and hydrolytic efficiencies of noncarbapenemases are shown in Table 2. The class A β-lactamases from gram-negative bacteria included TEM-1 and SHV-1 (broad-spectrum β-lactamases), and CTX-M-15, K1, and TEM-26 (ESBLs). The class C β-lactamases were represented by chromosomal AmpC enzymes from Enterobacter cloacae and P. aeruginosa and a plasmid-mediated AmpC enzyme, CMY-2. The OXA-10 (PSE-2) enzyme represented a class D noncarbapenemase. OXA-10 and OXA-23 were obtained at ∼50% purity; therefore, Vmax values are listed in Table 2 instead of kcat values. The kcat values and hydrolytic efficiencies for the carbapenems were generally at least 2 orders of magnitude lower than those for the standard substrates, benzylpenicillin or cephaloridine. Km or Ki values were in the low micromolar or nanomolar range for CMY-2 and the AmpC enzyme of P. aeruginosa, indicating high carbapenem affinity of AmpC type β-lactamases. However, hydrolysis was very inefficient due to the low kcat values. The kcat values for imipenem ranged from 0.002 s−1 for the TEM-26 enzyme to 0.2 s−1 for CTX-M-15. Regardless of β-lactamase class, doripenem and meropenem kcat values were often at least 10-fold lower than imipenem hydrolysis rates for the enzymes exhibiting measurable hydrolysis (Table 2).

TABLE 2.

Hydrolysis parameters for β-lactamases with low or undetectable carbapenemase activitya

β-Lactamase Substrate kcat (s−1) Km (μM) kcat/Km (s−1 μM−1) Relative kcat Relative kcat/Km
TEM-1 Cephaloridine 980 560 1.8 100 100
Benzylpenicillin 1,200 12 100.0 120 5,600
Imipenem 0.0095 7.2 0.0013 0.00097 0.072
Meropenem 0.00023b 15 0.000015 0.000023 0.00083
Doripenem 0.00021 5.4 0.000039 0.000021 0.0022
Ceftazidime 0.0023 200 0.000012 0.00023 0.00067
SHV-1 Cephaloridine 410 160 2.6 100 100
Benzylpenicillin 1,100 16 69 270 2,700
Imipenem 0.054 23 0.0024 0.013 0.092
Meropenem 0.0017 4.2 0.00040 0.00041 0.015
Doripenem 0.0030 4.3 0.00070 0.00073 0.027
Ceftazidime 0.010 500 0.00002 0.0024 0.00077
CTX-M-15 Cephaloridine 190 39 4.9 100 100
Benzylpenicillin 47 8.7c 5.4 25 110
Imipenem 0.17 120 0.0014 0.090 0.029
Meropenem 0.0042 11d 0.00038 0.0022 0.0078
Doripenem 0.0018 7.1 0.00025 0.00095 0.0051
Ceftazidime 4.4 240 0.018 2.3 0.37
K1 Cephaloridine 490 110 4.5 100 100
Benzylpenicillin 800 40 20 160 440
Imipenem 0.091 51 0.0018 0.019 0.040
Meropenem 0.0096 90 0.00011 0.0020 0.0024
Doripenem 0.0068 45 0.00015 0.0014 0.0033
Ceftazidime 0.013 140 0.000093 0.0027 0.0021
TEM-26 Cephaloridine 37 66 0.56 100 100
Benzylpenicillin 76 5.0 15 210 2,700
Imipenem 0.0024 14 0.00017 0.0065 0.030
Meropenem 0.00039 8.8 0.000044 0.0011 0.0079
Doripenem 0.00037 8.0 0.000046 0.0010 0.0082
Ceftazidime 95 130 0.73 260 130
CMY-2 Cephaloridine 710 290 2.4 100 100
Benzylpenicillin 22 2.2 10 3.1 420
Nitrocefin 1,700 40 43 240 1,800
Imipenem ≤0.031e 0.31f 0.10 0.0044 4.2
Meropenem 0.000081e 0.060f 0.0014 0.000011 0.058
Doripenem 0.000072e 0.0046f 0.016 0.000010 0.67
Ceftazidime 0.0035 4.5 0.00078 0.00049 0.033
AmpC of P. aeruginosa Cephaloridine 96 350 0.27 100 100
Benzylpenicillin 44 14 3.1 46 1,100
Nitrocefin 150 31 4.8 160 1,800
Imipenem ≤0.03e 1.6f ≤0.019 ≤0.031 ≤7.0
Meropenem ≤0.006e 1.4f ≤0.0043 ≤0.0063 ≤1.6
Doripenem ≤0.006e 1.8f ≤0.0033 ≤0.0063 ≤1.2
Ceftazidime ≤0.010e 8.0f ≤0.0013 ≤0.010 ≤0.48
AmpC of E. cloacae Cephaloridine 2,500g 330 7.6 100 100
Benzylpenicillin 32 4.7 6.8 1.3 89
Imipenem 0.012 24 0.00050 0.00048 0.0066
Meropenem 0.00031 9.8h 0.000032 0.000012 0.00042
Doripenem 0.00043 9.6 0.000045 0.000017 0.00059
Ceftazidime 0.021 2.9 0.0072 0.00084 0.095
OXA-10i Cephaloridine 16 200 0.080 100 100
Benzylpenicillin 86 7.9 11 540 14,000
Imipenem ≤0.014 ND ND ≤0.088 ND
Meropenem ≤0.0050 ND ND ≤0.031 ND
Doripenem ≤0.0073 ND ND ≤0.046 ND
Ceftazidime ≤0.0095 ND ND ≤0.059 ND
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a

Standard deviations were ≤20%, except as noted. Some parameters for selected β-lactamases and comparator substrates were presented as part of a previous study (15). ND, not determined; hydrolysis was too slow to obtain reliable initial rates.

b

Standard deviation, 0.00005 s−1.

c

Standard deviation, 3.1 μM.

d

Standard deviation, 4.3 μM.

e

Estimated Vmax based on two times the maximum hydrolysis rate observed.

f

Apparent Ki reported as determined by competitive inhibition of 20 μM nitrocefin.

g

Standard deviation, 560 s−1.

h

Standard deviation, 3.0 μM.

i

Enzyme preparation was ∼50% pure; therefore kcat was not calculated. Vmax is shown in nmol substrate hydrolyzed/min/μg protein; Vmax/Km is presented in place of kcat/Km.

Table 3 shows the kinetic parameters for enzymes with carbapenemase activity. Serine carbapenemases of functional group 2f were represented by the prevalent KPC-2 enzyme and the uncommon SME-3 β-lactamase. Both enzymes demonstrated similar kcat values for doripenem and meropenem, ranging from 0.55 s−1 to 3.6 s−1, while the imipenem kcat values were at least ninefold higher for KPC-2 and 100-fold higher for SME-3. Hydrolytic efficiencies for all three carbapenems were similar for the KPC-2 enzyme, whereas the hydrolytic efficiencies for doripenem and meropenem with the SME-3 carbapenemase were 10 to 20% of the rates observed with imipenem and cephaloridine.

TABLE 3.

Hydrolysis parameters for carbapenemasesa

β-Lactamase Substrate kcat (s−1) Km (μM) kcat/Km (s−1 μM−1) Relative kcat Relative kcat/Km
KPC-2 Cephaloridine 390 510 0.76 100 100
Benzylpenicillin 60 30 2.0 15 260
Imipenem 31 90 0.34 7.9 45
Meropenem 3.6 13 0.28 0.92 37
Doripenem 0.55 1.6b 0.34 0.14 45
Ceftazidime 0.38 230 0.0017 0.097 0.22
SME-3 Cephaloridine 1,200 400 3.0 100 100
Benzylpenicillin 8.8 2.2c 4.0 0.73 130
Imipenem 370d 150e 2.5 31 83
Meropenem 3.2 5.8 0.55 0.27 18
Doripenem 2.5 8.2f 0.30 0.21 10
Ceftazidime 0.16g 170h 0.00094 0.013 0.031
VIM-2 Cephaloridine 120 1,400 0.086 100 100
Benzylpenicillin 73 150 0.49 61 570
Imipenem 20 60 0.33 17 380
Meropenem 2.1 40 0.053 1.8 62
Doripenem 2.4 83 0.029 2.0 34
Ceftazidime 0.23 150 0.0015 0.19 1.7
IMP-1 Cephaloridine 270 21 13 100 100
Benzylpenicillin 1,400 550 2.5 520 19
Imipenem 190 33 5.8 70 45
Meropenem 26 6.5 4.0 9.6 31
Doripenem 110 30 3.7 41 28
Ceftazidime 37 50 0.74 14 5.7
SPM-1 Cephaloridine 120 9.6 13 100 100
Benzylpenicillin 240 27 8.9 200 68
Imipenem 45 82 0.55 38 4.2
Meropenem 170 130 1.3 140 10
Doripenem 170 110 1.5 140 12
Ceftazidime 77 120 0.64 64 4.9
OXA-23i Cephaloridine 450 1,300 0.35 100 100
Benzylpenicillin 530 13 41 120 12,000
Imipenemj 2.1, 0.92 42, 1.3k 0.05, 0.71 0.47, 0.20 14,200
Meropenem 0.13l 2.5 0.052 0.029 14.9
Doripenem 0.20 1.8 0.11 0.044 31
Ceftazidime ≤0.0042 ND ND ≤0.00093 ND
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a

Standard deviations were ≤20%, except as noted. Some parameters for selected β-lactamases and comparator substrates were presented as part of a previous study (15). ND, not determined; hydrolysis was too slow for Km determination.

b

Standard deviation, 0.5 μM.

c

Standard deviation, 0.8 μM.

d

Standard deviation, 80 s−1.

e

Standard deviation, 49 μM.

f

Standard deviation, 4.7 μM.

g

Standard deviation, 0.04 s−1.

h

Standard deviation, 40 μM.

i

Enzyme preparation was ∼50% pure; therefore, kcat was not calculated. Vmax is shown in nmol substrate hydrolyzed/min/μg protein. Vmax/Km is presented in place of kcat/Km.

j

Biphasic kinetics were observed for imipenem; the data are for the initial fast phase, followed by the slower second phase.

k

Standard deviation, 0.9 μM.

l

Standard deviation, 0.032 nmol/min/μg protein.

The class B MBLs were represented by IMP-1, VIM-2, and SPM-1. The IMP-1 and SPM-1 MBLs demonstrated robust hydrolysis of the carbapenems, with kcat values ranging from 26 to 190 s−1. Hydrolysis by VIM-2 was slower, with carbapenem kcat values of 2 to 20 s−1. For both IMP and VIM, imipenem was the most labile substrate, but the pattern was reversed for SPM, for which doripenem and meropenem were hydrolyzed approximately fourfold faster than was imipenem. Hydrolysis of meropenem was previously observed to be faster than that of imipenem in kinetic studies of SPM-1 (11). The IMP-1 enzyme demonstrated the most efficient hydrolysis, with kcat/Km values that were 2.5- to 11-fold higher than the values obtained for SPM-1 and 18- to 128-fold higher than those obtained for VIM-2.

The OXA-type carbapenemases were represented by OXA-23, one of the most prevalent OXA carbapenemases found in Acinetobacter baumannii (19). These enzymes typically demonstrate weak hydrolysis of imipenem and meropenem (20); supporting these observations, OXA-23 had very low relative Vmax values for all the carbapenems compared to those for penicillin, the preferred substrate. Although biphasic, or burst, kinetics are published for some substrates with oxacillinases (9), only imipenem demonstrated this behavior in our study.

In summary, doripenem was stable to hydrolysis by many β-lactamases of classes A, C, and D, including ESBLs, with high affinity demonstrated for the AmpC cephalosporinases. As expected, the class B metallo-β-lactamases, and the serine carbapenemases of classes A and D, demonstrated hydrolysis of all the carbapenems tested. For these enzymes, with the exception of SPM-1, doripenem and meropenem were hydrolyzed more slowly than was imipenem. These data are consistent with the potent microbiological activity observed with doripenem, especially against most gram-negative aerobic pathogens.

Acknowledgments

We thank S. Crespo-Carbone for the purification of the P99 β-lactamase and G. M. Rossolini for the IMP-1 strain. A.M.Q. thanks C. B. Origlio for helpful discussions.

We are current and past employees of Johnson & Johnson Pharmaceutical Research and Development, L.L.C.

Footnotes

▿

Published ahead of print on 2 November 2009.

REFERENCES

  • 1.Bauernfeind, A., I. Stemplinger, R. Jungwirth, and H. Giamarellou. 1996. Characterization of the plasmidic β-lactamase CMY-2, which is responsible for cephamycin resistance. Antimicrob. Agents Chemother. 40:221-224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bush, K., J. S. Freudenberger, and R. B. Sykes. 1982. Interaction of azthreonam and related monobactams with β-lactamases from gram-negative bacteria. Antimicrob. Agents Chemother. 22:414-420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Bush, K., G. A. Jacoby, and A. A. Medeiros. 1995. A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob. Agents Chemother. 39:1211-1233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Bush, K., S. K. Tanaka, D. P. Bonner, and R. B. Sykes. 1985. Resistance caused by decreased penetration of β-lactam antibiotics into Enterobacter cloacae. Antimicrob. Agents Chemother. 27:555-560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Cheng, Y., and W. H. Prusoff. 1973. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22:3099-3108. [DOI] [PubMed] [Google Scholar]
  • 6.CLSI. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A7; seventh edition. Clinical and Laboratory Standards Institute, Wayne, PA.
  • 7.Ge, Y., M. A. Wikler, D. F. Sahm, R. S. Blosser-Middleton, and J. A. Karlowsky. 2004. In vitro antimicrobial activity of doripenem, a new carbapenem. Antimicrob. Agents Chemother. 48:1384-1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Laraki, N., N. Franceschini, G. M. Rossolini, P. Santucci, C. Meunier, E. de Pauw, G. Amicosante, J. M. Frere, and M. Galleni. 1999. Biochemical characterization of the Pseudomonas aeruginosa 101/1477 metallo-β-lactamase IMP-1 produced by Escherichia coli. Antimicrob. Agents Chemother. 43:902-906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Ledent, P., X. Raquet, B. Joris, J. Van Beeumen, and J. M. Frere. 1993. A comparative study of class-D β-lactamases. Biochemical J. 292:555-562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Lolans, K., A. M. Queenan, K. Bush, A. Sahud, and J. P. Quinn. 2005. First nosocomial outbreak of Pseudomonas aeruginosa producing an integron-borne metallo-β-lactamase (VIM-2) in the United States. Antimicrob. Agents Chemother. 49:3538-3540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Murphy, T. A., A. M. Simm, M. A. Toleman, R. N. Jones, and T. R. Walsh. 2003. Biochemical characterization of the acquired metallo-β-lactamase SPM-1 from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 47:582-587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mushtaq, S., Y. Ge, and D. M. Livermore. 2004. Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized β-lactamases. Antimicrob. Agents Chemother. 48:1313-1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mushtaq, S., Y. Ge, and D. M. Livermore. 2004. Doripenem versus Pseudomonas aeruginosa in vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential. Antimicrob. Agents Chemother. 48:3086-3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Pillar, C. M., M. K. Torres, N. P. Brown, D. Shah, and D. F. Sahm. 2008. In vitro activity of doripenem, a carbapenem for the treatment of challenging infections caused by gram-negative bacteria, against recent clinical isolates from the United States. Antimicrob. Agents Chemother. 52:4388-4399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Queenan, A. M., W. Shang, M. Kania, M. G. P. Page, and K. Bush. 2007. Interactions of ceftobiprole with β-lactamases from molecular classes A to D. Antimicrob. Agents Chemother. 51:3089-3095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Queenan, A. M., W. Shang, P. Schreckenberger, K. Lolans, K. Bush, and J. Quinn. 2006. SME-3, a novel member of the Serratia marcescens SME family of carbapenem-hydrolyzing β-lactamases. Antimicrob. Agents Chemother. 50:3485-3487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Soge, O. O., A. M. Queenan, K. K. Ojo, B. A. Adeniyi, and M. C. Roberts. 2006. CTX-M-15 extended-spectrum β-lactamase from Nigerian Klebsiella pneumoniae. J. Antimicrob. Chemother. 57:24-30. [DOI] [PubMed] [Google Scholar]
  • 18.Sykes, R. B., D. P. Bonner, K. Bush, and N. H. Georgopapadakou. 1982. Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria. Antimicrob. Agents Chemother. 21:85-92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Walsh, T. R. 2008. Clinically significant carbapenemases: an update. Curr. Opin. Infect. Dis. 21:367-371. [DOI] [PubMed] [Google Scholar]
  • 20.Walther-Rasmussen, J., and N. Hoiby. 2006. OXA-type carbapenemases. J. Antimicrob. Chemother. 57:373-383. [DOI] [PubMed] [Google Scholar]
  • 21.Yigit, H., A. M. Queenan, J. K. Rasheed, J. W. Biddle, A. Domenech-Sanchez, S. Alberti, K. Bush, and F. C. Tenover. 2003. Carbapenem-resistant strain of Klebsiella oxytoca harboring carbapenem-hydrolyzing β-lactamase KPC-2. Antimicrob. Agents Chemother. 47:3881-3889. [DOI] [PMC free article] [PubMed] [Google Scholar]

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