Doripenem activity tested against a global collection of Enterobacteriaceae, including isolates resistant to other extended-spectrum agents

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Diagnostic Microbiology and Infectious Disease 63 (2009) 415 – 425 www.elsevier.com/locate/diagmicrobio

Doripenem activity tested against a global collection of Enterobacteriaceae, including isolates resistant to other extended-spectrum agents Rodrigo E. Mendesa,⁎, Paul R. Rhomberga , Jan M. Bellb , John D. Turnidgeb,c , Helio S. Sadera b

a JMI Laboratories, North Liberty, IA 52317, USA Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia c University of Adelaide, Adelaide, South Australia 5005, Australia

Abstract The emergence and rapid dissemination of extended-spectrum β-lactamase (ESBL)-producing isolates among Enterobacteriaceae coupled with increasing prevalence of stably derepressed and plasmid-borne AmpC producers have rendered broad-spectrum cephalosporins and β-lactam/β-lactamase inhibitor combinations less effective. This scenario has required the use of carbapenems for treatment of infections caused by such organisms. In this study, the in vitro activities of doripenem and comparator agents against Enterobacteriaceae, including ESBL- and AmpC-producing strains, were evaluated. A total of 36 614 isolates collected from more than 60 medical centers (2000–2007) were included and tested for susceptibility using reference methods and interpretive criteria, except for doripenem (product package insert). Overall, doripenem inhibited 98.7% of all Enterobacteriaceae tested at ≤0.5 μg/mL. ESBL rates were higher among Klebsiella pneumoniae (from 7.7% to 44.0%, varied by geographic region), followed by Escherichia coli (3.6–14.0%) and Proteus mirabilis (0.8–34.8%). Derepressed AmpC production-mediated resistance rates were highest among Enterobacter cloacae (26.6–38.7%) compared with other species and generally higher for strains isolated in the Asia-Pacific and Latin American regions. Doripenem inhibited 94.3% and 93.7% of the ESBL phenotype and derepressed AmpC isolates, respectively, and these resistances had little adverse influence on doripenem MIC50 values (nil to 2-fold increases). The observed increase in AmpC- and ESBL-producing Enterobacteriaceae necessitates a greater confidence on carbapenem empiric therapy. Doripenem could represent a valuable choice for broad-spectrum coverage of contemporary Enterobacteriaceae isolates with widespread resistance mechanisms. © 2009 Elsevier Inc. All rights reserved. Keywords: Enterobacteriaceae; Doripenem; ESBL; Resistance

1. Introduction Escherichia coli and Klebsiella pneumoniae possessing extended-spectrum Ambler class A β-lactamases (ESBL) were first described in the early 1980s, and since those early reports, the main ESBL representatives (TEM and SHV variants) have been detected worldwide (Perez et al., 2007). However, a contemporary perspective on the epidemiology of ESBL occurrences revealed the emergence and spread of CTX-M–type enzymes, which has become the most

⁎ Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: [email protected] (R.E. Mendes). 0732-8893/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.02.002

prevalent ESBL worldwide, not only in the nosocomial settings but also in the community (Canton and Coque, 2006). This scenario has been concurrent with the increase of derepressed chromosomal AmpC (Bush group 1) enzymes among Enterobacter spp., Citrobacter spp., and Serratia spp. isolates (Jones et al., 2008). The increasing prevalence of Enterobacteriaceae producing β-lactamases with carbapenemase activity (primarily KPC-2) and multidrug-resistant (MDR) nonfermentative Gram-negative bacilli has caused important changes in empiric antimicrobial therapy in the healthcare setting (Walsh, 2008). These changes have been more exacerbated in those clinical environments dealing with a high proportion of seriously ill patients (Chastre et al., 2008).

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Table 1 Activity of doripenem and comparator antimicrobial agents tested against Enterobacteriaceae clinical isolates Organism (no. tested)/ antimicrobial agent E. coli (17 841) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam K. pneumoniae (7831) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam K. oxytoca (1290) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam P. mirabilis (1895) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam P. vulgaris (182) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam E. cloacae (3564) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam

MIC (μg/mL) 50%

Percentage by categorya

Cumulative percentage inhibited at MIC 90%

≤0.5

1

2

4

8

Susceptible/resistant

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 2

≤0.06 ≤0.5 ≤0.12 ≤0.06 4 32 2 2 8

99.8 99.2 99.8 99.4 86.8 87.6 – 88.3 3.47

99.9 99.8 99.8 99.7 87.5 88.1 88.6 89.4 34.2

99.9 99.9 99.9 99.8 88.4 88.4 90.2 90.2 76.0

99.9 99.9 99.9 99.8 90.1 88.7 91.4 91.0 86.9

99.9 99.9 99.9 99.9 91.8 89.1 92.8 92.2 90.9

99.9/– 99.9/b0.1 99.9/b0.1 99.8/0.1 91.9/6.7 89.1/9.8 92.8/4.2 92.2/6.3 94.2/2.6

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 4

0.12 ≤0.5 ≤0.12 0.25 N16 N32 N16 N16 N64

96.7 93.5 96.6 95.2 70.6 70.1 – 71.3 1.5

97.3 96.8 97.1 96.1 71.4 70.4 70.3 73.5 12.6

97.7 97.6 97.7 96.8 72.3 71.0 72.2 76.0 45.6

98.4 98.1 98.0 97.3 73.8 72.1 74.4 78.5 67.0

99.1 98.5 98.5 97.9 75.3 73.5 76.9 81.3 75.0

96.7/– 98.1/1.4 98.0/1.4 96.8/2.7 75.3/21.7 73.5/21.9 76.9/18.3 81.3/14.9 80.5/13.1

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 2

≤0.06 ≤0.5 ≤0.12 ≤0.06 N16 16 2 2 N64

99.0 97.7 98.9 98.6 77.0 79.3 – 83.6 6.36

99.0 98.1 98.9 98.8 79.7 80.5 88.5 87.0 38.9

99.4 98.9 99.0 99.0 80.8 81.9 91.7 91.6 68.9

99.5 99.3 99.5 99.4 82.4 84.3 92.6 94.6 77.8

99.8 99.8 99.6 99.5 84.6 87.7 93.5 96.7 81.6

99.0/– 99.3/0.2 99.5/0.5 99.0/0.6 84.6/12.3 87.7/5.5 93.5/5.2 96.7/2.6 82.7/15.1

0.12 1 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 ≤0.5

0.25 2 ≤0.12 ≤0.06 0.25 1 ≤1 0.5 1

99.1 33.7 99.6 99.6 92.9 89.8 – 90.4 85.2

99.6 67.8 99.8 99.9 94.1 90.2 93.2 91.3 95.6

99.8 94.5 99.9 99.9 95.4 91.4 94.8 92.0 97.6

99.9 99.4 100.0 99.9 96.4 92.0 96.0 92.9 98.4

99.9 99.9 – 99.9 97.2 92.5 96.5 93.5 99.0

99.1/– 99.4/0.1 99.9/0.0 99.6/0.1 97.2/2.3 92.5/5.9 96.5/3.0 93.5/5.6 99.4/0.1

0.12 1 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 ≤0.5

0.25 2 ≤0.12 ≤0.06 ≤0.12 4 ≤1 0.25 1

100.0 18.7 99.4 99.4 98.9 64.3 – 96.7 80.8

– 61.0 99.4 99.4 98.9 69.8 97.3 99.4 98.4

– 94.5 100.0 99.4 99.5 87.4 99.5 100.0 99.4

– 100.0 – 100.0 98.5 98.4 99.5 – 100.0

– – – – 98.5 99.4 100.0 – –

100.0/– 100.0/0.0 100.0/0.0 99.4/0.0 99.5/0.0 99.5/0.0 100.0/0.0 100.0/0.0 100.0/0.0

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 4

0.12 1 ≤0.12 1 N16 N32 N16 8 N64

97.9 79.6 97.8 86.6 62.6 58.7 – 70.4 1.0

98.7 94.6 98.6 93.1 63.7 61.6 61.4 75.2 11.9

99.1 98.7 99.0 97.3 64.9 63.5 64.6 81.2 49.6

99.6 99.4 99.5 98.7 66.6 65.1 66.4 86.4 65.0

99.8 99.7 99.7 99.3 70.1 67.5 69.1 90.1 70.9

98.0/– 99.4/0.3 99.5/0.3 97.3/1.3 70.1/23.7 67.5/22.6 69.1/26.5 90.1/7.6 75.9/12.9

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Table 1 (continued) Organism (no. tested)/ antimicrobial agent E. aerogenes (932) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam C. freundii (548) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam C. koseri (251) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam S. marcescens (1813) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam M. morganii (467) Doripenem Imipenem Meropenem Ertapenem Aztreonam Ceftriaxone Ceftazidime Cefepime Piperacillin/tazobactam a

MIC (μg/mL)

Percentage by categorya

Cumulative percentage inhibited at MIC

50%

90%

≤0.5

1

≤0.06 1 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 4

0.12 2 ≤0.12 0.5 N16 32 N16 2 64

97.1 45.0 97.0 93.5 64.6 63.4 – 83.9 1.2

97.6 83.8 97.4 95.8 65.9 65.8 63.0 88.4 10.4

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 4

≤0.06 1 ≤0.12 0.25 N16 N32 N16 2 64

99.3 63.0 98.7 97.0 65.1 63.9 – 75.9 0.5

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 2

≤0.06 ≤0.5 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 8

0.12 1 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤2 ≤0.12 2 0.25 2 ≤0.12 ≤0.06 ≤0.12 ≤0.25 ≤1 ≤0.12 ≤0.5

2

4

8

Susceptible/resistant

99.0 96.7 98.2 97.0 68.1 68.0 66.6 91.8 42.4

99.7 98.0 99.5 97.4 70.6 70.7 69.3 93.6 61.8

99.8 99.2 99.7 97.8 77.0 80.9 72.6 95.9 68.8

97.1/– 98.0/0.8 99.5/0.3 97.0/2.6 77.0/12.2 80.9/8.0 72.6/21.1 95.9/2.6 76.7/5.3

99.8 96.0 99.4 98.5 66.2 65.7 62.6 85.4 11.3

100.0 99.6 99.6 99.3 67.3 67.5 66.2 90.5 49.1

– 99.8 100.0 99.8 68.4 69.0 68.2 91.6 63.1

– 99.8 – 100.0 74.1 71.2 71.0 93.2 71.7

99.3/– 99.8/0.2 100.0/0.0 99.3/0.2 74.1/16.8 71.2/14.6 71.0/23.9 93.2/5.1 77.6/8.2

99.6 98.4 99.6 100.0 95.6 96.4 – 96.4 1.2

99.6 99.2 100.0 – 96.4 96.4 96.4 96.8 11.5

100.0 99.6 – – 96.8 96.4 96.8 97.2 74.9

– 99.6 – – 96.8 96.4 96.8 98.0 87.2

– 100.0 – – 97.6 96.4 97.2 99.2 92.8

99.6/– 99.6/0.0 100.0/0.0 100.0/0.0 97.6/2.0 96.4/2.4 97.2/2.8 99.2/0.4 97.6/1.6

0.25 1 ≤0.12 0.12 4 16 ≤2 0.5 16

98.8 47.8 98.8 97.8 83.1 77.2 – 90.2 3.9

99.2 90.9 99.2 98.7 85.8 81.5 89.5 92.4 33.8

99.5 99.2 99.4 99.2 88.6 84.1 92.9 94.6 70.2

99.6 99.6 99.6 99.4 92.4 85.8 94.9 95.9 83.7

99.7 99.7 99.7 99.6 94.0 89.9 95.7 96.7 87.0

98.8/– 99.7/0.3 99.6/0.3 99.2/0.6 93.9/4.7 89.9/4.4 95.8/2.6 96.7/2.8 90.2/2.4

0.5 4 ≤0.12 ≤0.06 1 2 8 ≤0.12 2

96.8 1.7 99.8 100.0 84.8 82.2 – 94.6 73.4

100.0 15.6 99.8 – 90.4 86.5 73.0 96.6 86.3

– 70.0 100.0 – 94.2 91.2 80.3 97.4 92.7

– 98.9 – – 96.1 94.6 87.4 97.6 95.9

– 100.0 – – 97.0 95.9 90.1 97.6 97.4

96.8/– 98.9/0.0 100.0/0.0 100.0/0.0 97.0/1.7 95.9/2.6 90.1/4.3 97.6/1.9 97.9/0.9

Breakpoint criteria are those of CLSI (2008) (M100-S18) (3) or the US-FDA (Doribax™ Product Package Insert, 2007). – = no breakpoints established.

Resistances to “3rd- and 4th-generation” cephalosporins, βlactam/β-lactamase inhibitor combinations, fluoroquinolones, and aminoglycosides have also become commonplace in some geographic regions, requiring the use of carbapenems, glycylcyclines, combination therapies, or “agents of last resort”, such as the polymyxins (Sader et al., 2003).

As an antimicrobial class, carbapenems are innately stable to most β-lactamases of classes A, C, and D and are widely used therapies for serious infections involving MDR Enterobacteriaceae (including ESBL, derepressed and plasmid-borne AmpC-producing isolates), anaerobes, Pseudomonas aeruginosa, and Acinetobacter spp. (Zhanel et al., 2007). Doripenem was recently approved in Europe for

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treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) and nosocomial pneumonia (Chastre et al., 2008; Lucasti et al., 2008; Rea-Neto et al., 2008). In the United States, doripenem was approved by the US Food and Drug Administration (USFDA) with indications for cIAI and cUTI, and it is under regulatory review for nosocomial pneumonia (Doribax™ Product Package Insert, 2007). This agent has a spectrum and potency versus Gram-positive cocci most similar to that of imipenem and Gram-negative activity like that of meropenem (i.e., 2- to 4-fold greater than imipenem) (Davies et al., 2008; Doribax™ Product Package Insert, 2007; Fritsche et al., 2005; Jones et al., 2005; Mushtaq et al., 2004). The agent is generally β-lactamase stable, is resistant to inactivation by renal dehydropeptidases, and, when compared with several other antipseudomonal agents including other carbapenems, is among the lowest rates of spontaneously occurring resistance (Sakyo et al., 2006; Tanimoto et al., 2008). This report summarizes the activity of doripenem and other comparator agents used in similar clinical circumstances against a large collection of Enterobacteriaceae submitted to a longitudinal (2000–2007) international doripenem surveillance network, with emphasis on rapidly increasing and problematic resistant subsets of enteric bacilli. These results will be compared with the prior published in vitro findings. 2. Materials and methods 2.1. Bacterial strain collection A total of 36 614 consecutive nonduplicate clinical isolates of Enterobacteriaceae were submitted from more than 60 medical centers located in North America (11 485 strains, 31.4%), Latin America (5163, 14.1%), Europe (13 525, 36.9%), and Asia-Pacific region (APAC) (6441, 17.6%) as part of the Doripenem International Surveillance Network for the years 2000 through 2007. Isolates originated from patients with documented bloodstream, respiratory, skin and skin structure, and urinary tract infections, according to previously defined protocols (Fritsche et al., 2005), and included E. coli (17 841, 48.4%), K. pneumoniae (7831, 21.2%), Enterobacter cloacae (3564, 9.7%), Proteus mirabilis (1895, 5.1%), Serratia marcescens (1813, 4.9%), Klebsiella oxytoca (1290, 3.5%), Enterobacter aerogenes (932, 2.5%), Citrobacter freundii (548, 1.5%), Morganella morganii (467, 1.3%), Citrobacter koseri (251, 0.7%), and Proteus vulgaris (182, 0.5%). 2.2. Susceptibility test methods All strains were tested for susceptibility by the Clinical and Laboratory Standards Institute (CLSI, 2006) (formerly National Committee on Clinical Laboratory Standards Institute) broth microdilution method using cation-adjusted Mueller–Hinton broth in validated panels (TREK Diagnostics, Cleveland, OH) against a variety of antimicrobial agents

representing the most common classes and examples of drugs used for the empiric or directed treatment of the indicated pathogen. Interpretation of MIC results was in accordance with CLSI (2008) (M100-S18) published criteria. Doripenem MIC results were interpreted according to breakpoints for Enterobacteriaceae approved by the US-FDA (breakpoint for susceptibility at ≤0.5 μg/mL) (Doribax™ Product Package Insert, 2007). E. coli, K. pneumoniae, and P. mirabilis with elevated MIC values (≥2 μg/mL) for ceftazidime or ceftriaxone or aztreonam were classified as an ESBL phenotype. ESBL production was confirmed using the disk approximation method (Cormican et al., 1996) or Etest (AB BIODISK, Solna, Sweden) according to the manufacture's instruction. An ESBL confirmatory test was performed on strains collected during 2007 from all geographic regions except for those from the APAC region. Derepressed AmpC production among characteristic species was based on nonsusceptibility to ceftazidime (MIC, ≥16 μg/mL). Quality control (QC) strains used included E. coli ATCC 25922 and 35218 and P. aeruginosa ATCC 27853. All QC results were within CLSI (2008)-specified ranges.

3. Results The spectrum and activity of doripenem and comparator agents against Enterobacteriaceae are listed in Table 1. The carbapenems were highly active against the tested Enterobacteriaceae species in general. Aztreonam (MIC90, 4 μg/mL), ceftazidime (MIC90, 2 μg/mL), cefepime (MIC90, 2 μg/mL), and piperacillin/tazobactam (MIC90, 8 μg/mL) demonstrated good in vitro activity (susceptibility rates, N90%) against E. coli isolates (91.9–94.2% susceptible). However, piperacillin/tazobactam, aztreonam, and “3rd- and 4th-generation” cephalosporins showed limited activity against K. pneumoniae, with susceptibility rates between 73.5% and 81.3%. Overall, only the carbapenems displayed good activity against K. pneumoniae (96.7–98.1% susceptible), and doripenem or meropenem (MIC90, ≤0.12 μg/mL) were between 2- and 4-fold more active than ertapenem and imipenem (MIC90, 0.25 and 0.5 μg/mL, respectively). Aztreonam (84.6% susceptible), ceftriaxone (87.7% susceptible), and piperacillin/tazobactam (82.7% susceptible) exhibited lower susceptibility rates against a collection of K. oxytoca when compared with ceftazidime (93.5% susceptible) and cefepime (96.7% susceptible). These latler susceptibility rates were slightly inferior to those observed for the carbapenems (98.9–99.5% susceptible). Overall, the doripenem and the comparator agents tested showed good in vitro activity (susceptibility rates, N90%) against P. mirabilis, P. vulgaris, C. koseri, S. marcescens, and M. morganii. In contrast, when tested against E. cloacae, E. aerogenes, and C. freundii, only cefepime (90.1–95.9% susceptible) and carbapenems (97.0–100.0% susceptible) demonstrated acceptable activity.

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(MIC90, ≤0.06 μg/mL), P. mirabilis (MIC90, 0.25 μg/mL), P. vulgaris (MIC90, 0.25 μg/mL), C. koseri (MIC90, ≤0.06 μg/mL), and S. marcescens (MIC90, 0.25 μg/mL) regardless

When the activity of doripenem was evaluated according to the geographic region, this agent demonstrated sustained activity against E. coli (MIC90, ≤0.06 μg/mL), K. oxytoca

Table 2 Antimicrobial activity of doripenem against Enterobacteriaceae according to geographic region Organism/region (no. tested) E. coli North America (5193) Europe (7779) Latin America (2254) Asia-Pacific (2597) K. pneumoniae North America (2520) Europe (1942) Latin America (1409) Asia-Pacific (1960) K. oxytoca North America (501) Europe (546) Latin America (128) Asia-Pacific (115) P. mirabilis North America (568) Europe (684) Latin America (225) Asia-Pacific (418) P. vulgaris North America (22) Europe (103) Latin America (19) Asia-Pacific (38) E. cloacae North America (1255) Europe (1115) Latin America (562) Asia-Pacific (632) E. aerogenes North America (324) Europe (304) Latin America (154) Asia-Pacific (150) C. freundii North America (165) Europe (190) Latin America (78) Asia-Pacific (115) C. koseri North America (100) Europe (101) Latin America (13) Asia-Pacific (37) S. marcescens North America (725) Europe (503) Latin America (263) Asia-Pacific (322) M. morganii North America (112) Europe (240) Latin America (58) Asia-Pacific (57) a

MIC (μg/mL)

Percentage by categorya

Cumulative percentage inhibited at MIC

50%

90%

≤0.06 ≤0.06 ≤0.06 ≤0.06

≤0.06 ≤0.06 ≤0.06 ≤0.06

≤0.06 ≤0.06 ≤0.06 ≤0.06

≤0.5

1

2

4

8

Susceptible/resistant

99.9 99.9 99.8 99.6

99.9 99.9 99.9 99.6

99.9 99.9 99.9 99.7

99.9 100.0 100.0 99.8

100.0 – – 99.9

99.9/– 99.9/– 99.8/– 99.6/–

≤0.06 ≤0.06 0.12 0.12

95.7 96.9 96.5 98.0

95.9 97.3 97.9 98.8

96.1 97.8 98.7 99.0

96.9 98.7 99.1 99.5

98.4 99.1 99.6 99.8

95.8/– 96.9/– 96.5/– 98.0/–

≤0.06 ≤0.06 ≤0.06 ≤0.06

≤0.06 ≤0.06 ≤0.06 ≤0.06

98.4 99.8 97.7 98.3

98.6 99.8 97.7 98.3

99.4 100.0 97.7 98.3

99.6 – 98.4 98.3

99.6 – 98.4 98.3

98.4/– 99.8/– 97.7/– 98.3/–

0.12 0.12 0.12 0.25

0.25 0.25 0.25 0.25

99.3 99.3 99.6 98.3

99.8 99.7 99.6 99.0

100.0 99.8 100.0 99.5

– 99.8 – 100.0

– 99.8 – –

99.3/– 99.3/– 99.6/– 98.3/–

0.12 0.12 0.12 0.25

0.25 0.25 0.25 0.25

100.0 100.0 100.0 100.0

– – – –

– – – –

– – – –

– – – –

100.0/– 100.0/– 100.0/– 100.0/–

≤0.06 ≤0.06 ≤0.06 ≤0.06

0.12 0.12 0.25 0.25

98.7 97.1 97.3 98.6

99.0 98.1 98.9 99.0

99.3 98.6 99.8 99.4

99.8 99.1 100.0 99.8

99.8 99.5 – 99.8

98.7/– 97.1/– 97.3/– 98.6/–

≤0.06 ≤0.06 ≤0.06 ≤0.06

0.12 0.25 0.12 0.12

98.1 95.7 96.7 98.0

98.1 96.4 97.4 99.3

99.4 98.4 99.3 99.3

99.7 99.3 100.0 100.0

100.0 99.3 – –

98.1/– 95.7/– 96.8/– 98.0/–

≤0.06 ≤0.06 ≤0.06 ≤0.06

≤0.06 ≤0.06 ≤0.06 0.12

98.8 99.5 98.7 100.0

99.4 100.0 100.0 –

100.0 – – –

– – – –

– – – –

98.8/– 99.5/– 98.7/– 100.0/–

≤0.06 ≤0.06 0.06 ≤0.06

≤0.06 ≤0.06 0.06 ≤0.06

100.0 99.0 100.0 100.0

– 99.0 – –

– 100.0 – –

– – – –

– – – –

100.0/– 99.0/– 100.0/– 100.0/–

0.12 0.12 0.12 0.12

0.25 0.25 0.25 0.25

98.5 99.6 99.2 97.8

99.2 99.6 99.6 98.4

99.2 99.6 100.0 99.7

99.4 99.6 – 99.7

99.6 99.6 – 100.0

98.5/– 99.6/– 99.2/– 97.8/–

0.25 0.25 0.25 0.25

0.5 0.5 0.5 1

97.3 99.6 98.3 82.5

100.0 100.0 100.0 100.0

– – – –

– – – –

– – – –

97.3/– 99.6/– 98.3/– 82.5/–

Breakpoint criteria are those of CLSI (2008) (M100-S18) (3) or the US-FDA (Doribax™ Product Package Insert, 2007). – = no breakpoints established.

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of the origin of the isolates (Table 2). The remaining organisms, such as K. pneumoniae and E. cloacae, displayed MIC90 values 1 doubling dilution higher for those isolates recovered from Latin America (MIC90, 0.12 and 0.25 μg/ mL, respectively) and the APAC region (MIC90, 0.12 and 0.25 μg/mL, respectively) when compared with those strains from North America (MIC90, ≤0.06 and 0.12 μg/mL, respectively) and Europe (MIC90, ≤0.06 and 0.12 μg/mL, respectively). E. aerogenes isolates from Europe also showed slightly higher MIC 90 results (2-fold) when compared with those strains from the other geographic regions. In addition, doripenem had higher susceptibility rates (≥95.7% susceptible) for all isolates, except for M. morganii strains recovered from the APAC region (82.5% susceptible), although all isolates were inhibited at a doripenem MIC at ≤1 μg/mL. The rates of confirmed ESBL-producing isolates in 2007 varied widely according to the species and geographic region of isolation (Table 3). ESBL-confirmed rates were higher among K. pneumoniae, varying from 7.7% in North America to 44.0% in Latin America, compared with E. coli (3.6– 14.0%) and P. mirabilis (0.8–34.8%). Among the geographic regions where an ESBL confirmatory test was performed, ESBL rates were highest in Latin America (14.0–44.0%) and lowest in North America (0.8–7.7%) (Table 3). ESBL confirmatory testing was not performed on isolates from the APAC region, and the rates of ESBL-producing strains could not be completely assessed. However, high prevalence of strains displaying an ESBL phenotype was noted in this region, which varied from 16.7% among P. mirabilis (54 strains tested) to 43.2% among E. coli (1062 strains) and 41.7% among K. pneumoniae (893 strains) (Table 3). Although the rates of the ESBL phenotype among P. mirabilis (34.8%) and K. pneumoniae (52.9%) from Latin America were even higher when compared with those rates from the APAC region (16.7 and 41.7%, respectively), the rates of the ESBL phenotype among E. coli strains from the APAC region were particularly high (43.2%) when com-

pared with those rates from the other regions evaluated (5.7% in the United States, 9.0% in Europe, and 18.3% in Latin America). Stably derepressed expression of AmpC (nonsusceptibility to ceftazidime) also varied significantly according to the geography and organism group. Rates were highest among E. cloacae (ranging from 26.6% in North America to 38.7% in the APAC region) compared with other species and generally higher among strains from the APAC and Latin America regions (Table 3). Doripenem was very active against E. coli isolates with an ESBL phenotype (MIC90, ≤0.06 μg/mL) (Table 4), and these results were very similar to those demonstrated for meropenem (MIC90, ≤0.12 μg/mL). Higher carbapenem MIC90 results were noted (MIC90, 1–4 μg/mL) against K. pneumoniae isolates showing the ESBL phenotypes when compared with those from wild-type population (MIC90, ≤0.06 to ≤0.5 μg/mL). Overall doripenem, imipenem, and meropenem showed identical spectrums of activity (MIC90, 1 μg/mL) and were 4-fold more active than ertapenem (MIC90, 4 μg/mL) against K. pneumoniae displaying an ESBL phenotype. The MIC90 values for imipenem and meropenem against K. oxytoca with ESBL phenotypes remained unchanged when compared with their respective susceptible strains (MIC90, ≤0.5 to ≤0.12 μg/mL, respectively), whereas MIC90 values for doripenem increased 2-fold (from ≤0.06 to 0.12 μg/mL) and ertapenem increased 4-fold (from ≤0.06 to 0.25 μg/mL). Similar findings were observed for meropenem and ertapenem against P. mirabilis, which demonstrated identical MIC90 values between P. mirabilis with ESBL phenotypes and the wild-type population (MIC90, ≤0.12 to ≤0.06 μg/mL, respectively). On the other hand, MIC90 values for doripenem and ertapenem increased 2-fold (from 0.25 to 0.5 μg/mL and from 2 to 4 μg/mL, respectively) between these 2 organism populations. Doripenem and meropenem were the most active compounds tested against E. cloacae (MIC90, 0.5 μg/mL)

Table 3 Distribution of Enterobacteriaceae clinical isolates showing an ESBL phenotype (MIC values ≥2 μg/mL for aztreonam or ceftazidime or ceftriaxone), confirmed production of ESBL, and inferred AmpC cephalosporinases (ceftazidime MIC, ≥16 μg/mL) according to the species and geographic region for isolates collected in 2007 Resistance phenotype/organism ESBL E. coli K. pneumoniae P. mirabilis Stably derepressed AmpC C. freundii E. cloacae E. aerogenes M. morganii a b

Percentage of strains with an ESBL phenotype or derepressed AmpC/confirmed ESBL (total no. tested) North America 5.7/3.6 (1137) 14.4/7.7 (661) 3.3/0.8 (121) 12.8/NAb (47) 26.6/NA (334) 16.9/NA (65) 11.5/NA (26)

Europe

Latin America

9.0/7.8 (1914) 21.8/16.4 (513) 4.8/4.8 (145)

18.3/14.0 (493) 52.9/44.0 (350) 34.8/34.8 (46)

34.5/NA (55) 31.7/NA (262) 38.2/NA (68) 9.3/NA (60)

9.1/NA (11) 34.2/NA (155) 18.9/NA (37) 0.0/NA (14)

ESBL confirmatory test was not performed in the isolates from the APAC. NA = not applicable.

Asia-Pacific 43.2/–a (1208) 41.7/– (963) 16.7/– (263) 45.3/NA (53) 38.7/NA (292) 32.8/NA (61) 14.3/NA (14)

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Table 4 Activity of doripenem and comparator antimicrobial agents tested against E. coli, Klebsiella spp. and P. mirabilis displaying positive criteria for an ESBL phenotype (i.e., MIC ≥2 μg/mL for aztreonam or ceftazidime or ceftriaxone) Organism (no. tested)/ antimicrobial agent

MIC (μg/mL) 50%

90%

E. coli (ESBL phenotype, 2363) Doripenem ≤0.06 ≤0.06 Imipenem ≤0.5 ≤0.5 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 0.25 E. coli (non-ESBL phenotype, 15 478) Doripenem ≤0.06 ≤0.06 Imipenem ≤0.5 ≤0.5 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 ≤0.06 K. pneumoniae (ESBL phenotype, 2444) Doripenem ≤0.06 1 Imipenem ≤0.5 1 Meropenem ≤0.12 1 Ertapenem 0.12 4 K. pneumoniae (non-ESBL phenotype, 5387) Doripenem ≤0.06 ≤0.06 Imipenem ≤0.5 ≤0.5 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 ≤0.06 K. oxytoca (ESBL phenotype, 277) Doripenem ≤0.06 0.12 Imipenem ≤0.5 ≤0.5 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 0.25 K. oxytoca (non-ESBL phenotype, 1013) Doripenem ≤0.06 ≤0.06 Imipenem ≤0.5 ≤0.5 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 ≤0.06 P. mirabilis (ESBL phenotype, 129) Doripenem 0.25 0.5 Imipenem 2 4 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 ≤0.06 P. mirabilis (non-ESBL phenotype, 1766) Doripenem 0.12 0.25 Imipenem 1 2 Meropenem ≤0.12 ≤0.12 Ertapenem ≤0.06 ≤0.06 a

Percentage by categorya

Cumulative percentage inhibited at MIC ≤0.5

1

2

4

8

Susceptible/resistant

99.0 97.1 98.9 95.6

99.3 99.1 99.1 98.3

99.5 99.5 99.3 98.8

99.8 99.6 99.5 99.1

99.9 99.8 99.8 99.4

99.0/– 99.6/0.2 99.5/0.2 98.8/0.9

N99.9 99.6 N99.9 N99.9

100.0 N99.9 N99.9 N99.9

– N99.9 100.0 N99.9

– 100.0 – 100.0

– – –

N99.9/– 100.0/0.0 100.0/0.0 N99.9/b0.1

89.6 84.9 89.3 85.0

91.5 90.4 90.7 87.8

92.8 92.5 92.7 89.8

94.9 93.9 93.7 91.5

97.2 95.4 95.4 93.4

89.6/– 93.9/4.6 93.7/4.6 89.8/8.5

N99.9 97.4 N99.9 99.8

N99.9 99.7 N99.9 N99.9

N99.9 100.0 N99.9 N99.9

N99.9 – 100.0 N99.9

100.0 – – N99.9

N99.9/– 100.0/0.0 100.0/0.0 N99.9/b0.1

94.9 92.4 94.9 93.5

95.3 92.8 94.9 94.6

97.1 94.9 95.3 95.3

97.8 96.7 97.5 97.1

97.8 98.9 97.8 97.8

94.9/– 96.8/1.1 97.5/2.2 95.3/2.9

100.0 99.1 100.0 100.0

– 99.6 – –

– 100.0 – –

– – – –

– – – –

100.0/– 100.0/0.0 100.0/0.0 100.0/0.0

95.3 14.7 95.3 96.1

96.1 44.2 96.9 96.1

97.7 82.9 96.9 96.1

99.2 96.9 99.2 98.4

99.2 99.2 100.0 99.2

95.3/– 96.9/0.8 99.2/0.0 96.1/1.6

99.4 35.1 99.9 99.9

99.8 69.5 100.0 99.9

100.0 95.3 – 99.9

– 99.6 – 100.0

– 100.0 – –

99.4/– 99.6/0.0 100.0/0.0 99.9/0.0

Breakpoint criteria are those of CLSI (2008) (M100-S18) (3) or the US-FDA (Doribax™ Product Package Insert, 2007). – = no breakpoints established.

and E. aerogenes (MIC 90, 0.5 μg/mL), showing a stably derepressed AmpC-producing phenotype, and were from 2- to 4-fold more active than imipenem (MIC90, 1 and 2 μg/mL, respectively) and from 4- to 8-fold more active than ertapenem (MIC90, 2 and 4 μg/mL, respectively) (Table 5). Similar results were observed for doripenem and meropenem against ceftazidime-nonsusceptible C. freundii (MIC90, 0.12 μg/mL), and these agents were 4- and 8-fold more active than ertapenem (MIC90, 0.5 μg/mL) and imipenem (MIC90, 1 μg/mL), respectively. Overall, the carbapenems showed similar activity when tested against ceftazidime-susceptible and nonsusceptible C. freundii isolates, except for ertapenem that had an MIC90 value 8-

fold higher (0.5 μg/mL) when compared with the wild-type population (≤0.06 μg/mL). The carbapenems showed sustained potent antimicrobial activity against S. marcescens (MIC90, ≤0.06–1 μg/mL), including ceftazidime-nonsusceptible strains (MIC90, 0.25– 2 μg/mL). Doripenem and meropenem were the most active compounds against these isolates (MIC90, 0.5 and 0.25 μg/ mL, respectively), and imipenem was the least active carbapenem (MIC90, 2 μg/mL). The MIC90 results for the carbapenems observed against ceftazidime-nonsusceptible M. morganii were identical to those values obtained against their respective susceptible isolates. Ertapenem was the most potent agent (MIC50/90, ≤0.06/≤0.06 μg/mL) against

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Table 5 Antimicrobial activity of doripenem against Enterobacteriaceae with stably derepressed AmpC production (i.e., ceftazidime MIC, ≥16 μg/mL) isolates displaying susceptible MIC values for ceftazidime are shown for comparison purposes Organism (no. tested)/ antimicrobial agent

MIC (μg/mL) 50%

E. cloacae (derepressed AmpC, 1101) Doripenem 0.12 Imipenem ≤0.5 Meropenem ≤0.12 Ertapenem 0.5 E. cloacae (2462) Doripenem ≤0.06 Imipenem ≤0.5 Meropenem ≤0.12 Ertapenem ≤0.06 E. aerogenes (derepressed AmpC, 255) Doripenem 0.12 Imipenem ≤0.5 Meropenem ≤0.12 Ertapenem 0.25 E. aerogenes (677) Doripenem ≤0.06 Imipenem 1 Meropenem ≤0.12 Ertapenem ≤0.06 C. freundii (derepressed AmpC, 159) Doripenem ≤0.06 Imipenem ≤0.5 Meropenem ≤0.12 Ertapenem 0.12 C. freundii (389) Doripenem ≤0.06 Imipenem ≤0.5 Meropenem ≤0.12 Ertapenem ≤0.06 S. marcescens (derepressed AmpC, 77) Doripenem 0.12 Imipenem 1 Meropenem ≤0.12 Ertapenem ≤0.06 S. marcescens (1736) Doripenem 0.12 Imipenem 1 Meropenem ≤0.12 Ertapenem ≤0.06 M. morganii (derepressed AmpC, 46) Doripenem 0.5 Imipenem 2 Meropenem ≤0.12 Ertapenem ≤0.06 M. morganii (421) Doripenem 0.25 Imipenem 2 Meropenem ≤0.12 Ertapenem ≤0.06 a

Percentage by categorya

Cumulative percentage inhibited at MIC 90%

≤0.5

0.5 1 0.5 2

1

2

4

8

Susceptible/resistant

94.0 79.1 93.7 59.7

96.0 92.6 95.9 78.9

97.4 96.0 97.0 91.8

98.8 98.1 98.4 96.0

99.3 99.4 99.0 97.8

94.0/– 98.1/0.6 98.4/1.0 91.8/4.0

≤0.06 1 ≤0.12 0.12

99.8 79.7 99.6 98.7

99.9 95.4 99.8 99.5

99.9 99.9 99.9 99.7

99.9 99.9 99.9 99.9

99.9 99.9 99.9 99.9

99.8/– 99.9/0.1 N99.9/b0.1 99.7/b0.1

0.5 2 0.5 4

90.6 57.2 90.2 78.8

92.5 82.7 91.8 86.7

97.2 90.6 94.1 89.8

98.8 93.3 98.0 91.4

99.2 97.2 98.8 92.2

90.6/– 93.3/2.7 98.0/1.2 89.8/8.6

0.12 2 ≤0.12 0.12

99.6 40.3 99.6 99.1

99.6 84.2 99.6 99.3

99.7 99.0 99.7 99.7

100.0 99.7 100.0 99.7

– 100.0 – 100.0

99.6/– 99.7/0.0 100.0/0.0 99.7/0.3

0.12 1 ≤0.12 0.5

98.7 67.9 97.5 93.1

99.4 96.2 99.4 96.6

100.0 99.4 99.4 99.4

– 100.0 100.0 100.0

– – – –

98.7/– 100.0/0.0 100.0/0.0 99.4/0.0

≤0.06 1 ≤0.12 ≤0.06

99.5 60.9 99.2 98.7

100.0 95.9 99.5 99.2

– 99.7 99.7 99.2

– 99.7 100.0 99.7

– 99.7 – 100.0

99.5/– 99.7/0.3 100.0/0.0 99.2/0.3

0.5 2 0.25 1

92.2 40.3 94.8 89.5

94.8 83.1 96.1 92.1

96.1 98.7 96.1 94.7

96.1 98.7 96.1 97.4

98.7 100.0 98.7 97.4

92.2/– 98.7/0.0 96.1/1.3 94.7/2.6

0.25 1 ≤0.12 ≤0.06

99.1 48.1 99.0 98.2

99.4 91.2 99.4 99.0

99.6 99.2 99.5 99.4

99.8 99.7 99.7 99.5

99.8 99.7 99.8 99.7

99.1/– 99.7/0.3 99.7/0.2 99.4/0.5

0.5 4 0.25 ≤0.06

91.3 15.2 97.8 100.0

100.0 15.2 97.8 –

– 60.9 100.0 –

– 100.0 – –

– – – –

91.3/– 100.0/0.0 100.0/0.0 100.0/0.0

0.5 4 ≤0.12 ≤0.06

97.4 1.9 100.0 100.0

100.0 15.7 – –

– 71.0 – –

– 98.8 – –

– 100.0 – –

97.4/– 98.8/0.0 100.0/0.0 100.0/0.0

Breakpoint criteria are those of CLSI (2008) (M100-S18) (3) or the US-FDA (Doribax™ Product Package Insert, 2007). – = no breakpoints established.

M. morganii regardless of the susceptibility to ceftazidime and inhibited all isolates at ≤0.5 μg/mL, whereas the remaining carbapenems displayed MIC90 values 2- (meropenem MIC90, ≤0.12 μg/mL), 8- (doripenem MIC90, 0.5 μg/mL), and 64-fold (imipenem MIC90, 4 μg/mL) higher than ertapenem.

4. Discussion “Third-generation” cephalosporins were originally developed as β-lactam agents capable to overcome resistance caused by common β-lactamases produced by Enterobacteriaceae. When 1st introduced, cefotaxime, ceftriaxone, and

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ceftazidime were mostly stable in the presence of common β-lactamases and highly active against Enterobacteriaceae. These antimicrobial agents remained very active and effective in vivo against these isolates for many years; however, the emergence and dissemination of Enterobacteriaceae strains producing more potent β-lactamases, such as ESBL and stably derepressed AmpC, rendered these agents, as well as aztreonam and β-lactam/β-lactamase inhibitor combinations, generally ineffective (Paterson, 2006). Enterobacteriaceae producing ESBL (mainly E. coli and K. pneumoniae) have been established as major causes of hospital-acquired infections, and more recently, it emerged also in the community setting (Pitout et al., 2005). ESBLproducing organisms frequently carry genes encoding resistance to other antimicrobial classes, such as fluoroquinolones, tetracyclines, and aminoglycosides, and the therapeutic options have become markedly reduced (Canton and Coque, 2006). Enterobacteriaceae producing stably derepressed AmpC enzymes usually exhibit an MDR phenotype as well (Sader et al., 2003). Thus, the parenteral carbapenems have become the most applicable treatment of serious infections caused by ESBL and stably derepressed AmpC producers (Pitout and Laupland, 2008). Since the earliest reports on doripenem spectrum of activity, the overall MIC90 values against Enterobacteriaceae have ranged from 0.03 to 0.5 μg/mL and have resembled those of meropenem, except for M. morganii and Proteus spp., for which the doripenem MIC90 values reported have usually been slightly elevated (Fritsche et al., 2005; Ge et al., 2004; Jones et al., 2004, 2005; Pillar et al., 2008; Tsuji et al., 1998). In a recent report (Pillar et al., 2008), 99.5% of the Enterobacteriaceae strains collected during November 2005 and June 2006 from 44 hospitals across the United States were inhibited by doripenem at the US-FDA breakpoint (≤0.5 μg/mL). Results described above are very similar to those obtained during the present surveillance study report, where the MIC90 values for doripenem were between ≤0.06 and 0.5 μg/mL, and this agent inhibited at the current USFDA breakpoint (≤0.5 μg/mL), 98.7% of all tested Enterobacteriaceae isolates worldwide. The carbapenems monitored inhibited ≥99.0% of all E. coli, K. oxytoca, P. mirabilis, P. vulgaris, C. freundii, and C. koseri clinical isolates tested. Lower susceptibility rates were noted for these agents when tested against K. pneumoniae (≥96.7%) and characteristic AmpC producers, such as E. cloacae (97.3%), E. aerogenes (97.0%), S. marcescens (98.8%), and M. morganii (96.8%), and susceptibility rates of doripenem against these isolates were slightly lower than those observed for meropenem or imipenem. However, it must be considered that the lower doripenem susceptibility breakpoint for Enterobacteriaceae used here (US-FDA breakpoint ≤0.5 μg/mL) when compared with the current CLSI interpretative criteria for imipenem and meropenem (breakpoint for susceptibility ≤4 μg/mL) markedly alters perception of clinical use. Thus, the lower breakpoint value for doripenem consequently increases the number of

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nonsusceptible isolates (e.g., increased by 0.0–3.2% across all species listed in Table 1). Similar to reports from other surveillance programs or studies (Paterson, 2006; Pitout and Laupland, 2008; Pitout et al., 2005; Sader et al., 2003), the present report showed that the prevalence of Enterobacteriaceae producing βlactamases (especially ESBL and stably derepressed AmpC) remains high worldwide. Overall, the prevalence of ESBLproducing strains was extremely high among K. pneumoniae isolated in Latin America (44.0%, ESBL phenotype) and the APAC region (41.7%). In addition, the ESBL phenotype rate found among E. coli (43.2%) isolates recovered from the APAC region in this study is extremely worrisome, because it was as elevated as that observed among K. pneumoniae strains (41.7%). A recent report from the British Society for Antimicrobial Chemotherapy Bacteremia Resistance Surveillance Program (2001–2006) has revealed a dramatic increase in the resistance rates to oxyimino-cephalosporins among E. coli isolates, which matched or exceeded those of K. pneumoniae (Livermore et al., 2008). Findings of comparable ESBL rates between E. coli and K. pneumoniae were also noted in Spain, Germany, Poland, Turkey, Mexico, and Canada (Canton and Coque, 2006; Perez et al., 2007). Similar findings were also noted in nosocomial isolates from Asia (Livermore et al., 2008), and a recent study on Enterobacteriaceae isolates causing community-acquired infections in multiple medical sites in China revealed ESBL production rates of 16% and 17% among E. coli and Klebsiella spp. strains, respectively (Hawkey, 2008). The elevated rates of ESBL production among E. coli strains in the APAC region reflect dissemination of CTX-M enzymes, which have overtaken SHV and TEM variants in this bacterial population (Hawkey, 2008; Livermore et al., 2007). In the present study, doripenem inhibited 94.3% of all Enterobacteriaceae displaying an ESBL phenotype. The doripenem MIC90 values for those isolates exhibiting such a phenotype were identical or slightly higher (2-fold) than the values observed for those susceptible wild-type counterpart isolates, except for K. pneumoniae with an ESBL phenotype, for which the carbapenems MIC90 values were between 2- and 64-fold higher than their respective susceptible strains. In previous reports (Fritsche et al., 2005; Ge et al., 2004; Jones et al., 2005; Pillar et al., 2008), the doripenem MIC90 values for ESBL-producing K. pneumoniae were identical or 2-fold dilution higher (0.06–0.12 μg/mL) than those obtained for the wild-type population (0.03–0.12 μg/mL). These results show the inherent enhanced stability of carbapenems against most βlactamases of class A. However, the increased carbapenem MIC90 values for K. pneumoniae with an ESBL phenotype noted in this study relates to the occurrence of sporadic metallo-β-lactamases and mainly to the Bush group 2f carbapenemases (KPC), which has become epidemic among medical centers located at the US East Coast (data not shown) (Castanheira et al., 2008).

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Among the isolates with stably derepressed AmpC enzymes (ceftazidime-intermediate or -resistant), doripenem inhibited 93.7% at ≤0.5 μg/mL (96.1–100.0 at ≤4 μg/mL) (Table 5). In addition, doripenem MIC90 values, when tested against derepressed AmpC-producing isolates, were identical or 1 dilution higher than those of the wild-type population, except for E. aerogenes and E. cloacae that displayed doripenem MIC90 values 4- and 8-fold higher (MIC90, 0.5 μg/mL) when compared with those ceftazidimesusceptible strains (MIC90, 0.12 and ≤0.06 μg/mL). In a recent report published by Ge et al. (2004), the spectrum of activity of doripenem and comparator agents were tested against 351 Enterobacteriaceae isolates collected from US medical centers during 1999 and 2003. The spectrum of activity of doripenem for C. freundii (MIC90, 0.12 μg/mL), E. aerogenes (MIC90, 0.12 μg/mL), E. cloacae (MIC90, 0.25 μg/mL), and S. marcescens (MIC90, 0.25 μg/mL) isolates with intermediate or resistant ceftazidime MIC values was very similar to those observed in the present study, except for E. aerogenes (MIC90, 0.5 μg/mL) that showed an MIC90 value 4-fold higher than that previously described. The reasons for these higher doripenem MIC results remain unclear. In the study reported here, the increased rate of ESBL phenotypes among E. coli isolates from the APAC region and the elevated carbapenem MIC90 values against the ESBL phenotype K. pneumoniae are reasons for growing concern and confirm previous findings of the dissemination of CTXM- and KPC-like enzymes in these organism populations, respectively. Nevertheless, these data obtained from a very large global population of contemporary clinical isolates confirm previous reports showing that doripenem activity is similar to that of meropenem and superior to that of imipenem against Enterobacteriaceae (including ESBL and stably derepressed AmpC producers). In addition, the overall doripenem activity observed in this study was consistent with earlier reports, which appears to indicate no trend toward decreased carbapenem susceptibility over the monitored years. Doripenem demonstrated a favorable MIC90 potency when tested against Enterobacteriaceae clinical isolates compared with the remaining carbapenems, whereas doripenem susceptibility rates were eventually slightly offset because of the lower susceptibility breakpoints established for this drug based on the dosage of 500 mg tid (1 h infusion) when compared with those breakpoints established for imipenem and meropenem, which were based on the studied dosages of 2 to 3 g daily. In addition, previous studies have demonstrated that doripenem was well tolerated and not associated with some adverse effects noted with other carbapenems (renal toxicity and neurotoxicity), including lower rates of neurologic adverse effects when compared with imipenem or meropenem (Ge et al., 2004; Horiuchi et al., 2006; Lucasti et al., 2008). These favorable characteristics may position doripenem as an alternative choice for broad-spectrum coverage of prevalent Enterobacteriaceae

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