Center for Research in Anti-Infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
Received 10 March 2004; returned 18 April 2004; revised 12 May 2004; accepted 18 May 2004
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Abstract |
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Methods: Susceptibilities of bacteria chosen for their varying levels of resistance to the comparator agents were determined by NCCLS microdilution methodology.
Results: CS-023 exhibited activity comparable to that of imipenem against most Gram-positive isolates, but was 8-fold more potent against oxacillin-resistant staphylococci. It was comparable to meropenem against most Gram-negative isolates, but was 4- to 8-fold more potent against five isolates of meropenem-resistant Pseudomonas aeruginosa.
Conclusions: If tissue and body fluid concentrations >8 mg/L can safely be achieved, further studies of CS-023 are warranted to determine its clinical efficacy.
Keywords: carbapenems , ß-lactams , imipenem , meropenem
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Introduction |
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Materials and methods |
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The isolates were chosen to include bacteria with varying levels of resistance to the comparator agents. They were selected from clinical isolates submitted to Creighton University by 29 US clinical microbiology laboratories in 14 states during the period December 2000 to December 2001. They were not randomly selected. The NCCLS control strains yielded in-range results for the comparator agents. The strains were (with CS-023 MIC ranges in parentheses): Escherichia coli ATCC 25922 (0.0080.03 mg/L), Enterococcus faecalis ATCC 29212 (0.251 mg/L), Haemophilus influenzae ATCC 49247 (0.0040.06 mg/L), H. influenzae ATCC 49766 (0.03 mg/L), P. aeruginosa ATCC 27853 (0.120.5 mg/L), S. aureus ATCC 29213 (0.12 mg/L) and Streptococcus pneumoniae ATCC 49619 (0.015 mg/L).
Susceptibility testing
MICs were determined by NCCLS microdilution methodology.7 Oxacillin and penicillin G were also tested to provide phenotypic typing of staphylococci and streptococci. Sankyo Co. Ltd, Tokyo, Japan, provided CS-023 laboratory powder and the manufacturers of the comparator antibiotics provided their antibiotic powders to TREK Diagnostic Systems, Inc, Westlake, OH, USA, for incorporation into frozen microdilution panels.
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Results and discussion |
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None of the agents was very potent against the Enterococcus spp. Levofloxacin was the most potent agent against both Enterococcus faecalis and Enterococcus faecium with respective MIC50 values of 1 and 2 mg/L. CS-023 was highly potent against all Streptococcus spp. except penicillin-intermediate and -resistant S. pneumoniae. For penicillin-intermediate S. pneumoniae, the carbapenem MIC90 values were 0.12 mg/L (CS-023 and imipenem) and 0.25 mg/L (meropenem), compared with 1 mg/L of ceftriaxone and levofloxacin. For penicillin-resistant S. pneumoniae, MIC90 values were 1, 0.5, 2, 1 and 4 mg/L of CS-023, imipenem, meropenem, levofloxacin and ceftriaxone, respectively.
CS-023 was highly potent against ß-lactamase-positive or -negative Moraxella catarrhalis and H. influenzae, inhibiting all isolates of these species at 0.008 and 0.06 mg/L, respectively. Against M. catarrhalis, CS-023 and meropenem were similar in potency and at least 8- to 16-fold more potent than imipenem. Against H. influenzae CS-023 was 2-fold more potent than meropenem and 16- to 32-fold more potent than imipenem.
CS-023 was highly potent against most isolates of Enterobacteriaceae, some of which were highly resistant to the study agents. CS-023 inhibited all isolates of E. coli, Shigella, Salmonella and Klebsiella oxytoca at 0.06 mg/L. The comparator carbapenems were also highly active against these isolates with meropenem being comparable to CS-023 and imipenem being 4- to 8-fold less active. The production of ESBLs and hyper-production of chromosomal or plasmid-mediated AmpC ß-lactamases by some E. coli isolates is reflected by the high ceftriaxone MIC90 and MIC upper range values of 8 and >32 mg/L, respectively. Isolates with reduced carbapenem susceptibility occurred among Citrobacter freundii, K. pneumoniae, Enterobacter spp., Serratia marcescens, Proteus spp., Morganella morganii, and Providencia spp. For these organisms the highest MIC90 values were 1 mg/L of CS-023, 2 mg/L of meropenem and 8 mg/L of imipenem (Table 1). Most of these isolates were highly susceptible to CS-023 as indicated by the low MIC50 values of 0.015 mg/L for K. pneumoniae and E. cloacae, 0.03 mg/L for C. freundii and E. aerogenes, 0.06 mg/L for S. marcescens, 0.12 for Providencia spp., 0.25 mg/L for Proteus mirabilis and Proteus vulgaris, and 0.5 mg/L for M. morganii.
Against P. aeruginosa, CS-023 (MIC90 8 mg/L) was equivalent to twofold more potent overall than meropenem (MIC90 16 mg/L), 4- to 8-fold more potent than imipenem (MIC90 32 mg/L) and at least 4-fold more potent than levofloxacin (MIC90 >32 mg/L). This species was notable for the heterogeneity of its isolates in susceptibility to the carbapenems. Five isolates were meropenem resistant. CS-023 was 4- to 8-fold more potent than meropenem against these. For one isolate the CS-023 and meropenem MICs were 4 and 32 mg/L, respectively. For three other isolates the respective MICs of CS-023 and meropenem were 4 and 16 mg/L, and for the fifth isolate CS-023 and meropenem MICs were 8 and 32 mg/L. (None of these isolates was susceptible to imipenem.) Similar activity against meropenem-resistant P. aeruginosa isolates has also been reported for some other investigational carbapenems.9
None of the carbapenems was highly potent against Burkholderia cepacia or Stenotrophomonas maltophilia, or against some isolates of Acinetobacter baumannii. For A. baumannii, the respective MIC50 and MIC90 values were 0.25 and 1 mg/L for imipenem, 0.5 and 1 mg/L for meropenem, and 2 and 4 mg/L for CS-023.
Overall, CS-023 is a novel carbapenem with potent in vitro activity against a wide range of Gram-positive and Gram-negative pathogens. Its most novel antibacterial attributes are its enhanced potency against oxacillin-resistant staphylococci and meropenem-resistant P. aeruginosa. However, since only five meropenem-resistant isolates of P. aeruginosa were studied, it is important that more isolates with this phenotype be tested. The broad spectrum of in vitro activity of CS-023 suggests potential for therapy of a wide range of infections, including polymicrobial infections involving oxacillin-resistant staphylococci and P. aeruginosa. It will therefore be of considerable interest to determine whether its in vitro activity translates into clinical efficacy. If tissue and body fluid concentrations >8 mg/L can be safely achieved in infected patients, further studies are warranted to determine its clinical efficacy.
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Acknowledgements |
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Footnotes |
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References |
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