CS-023 (R-115685), a novel carbapenem with enhanced in vitro activity against oxacillin-resistant staphylococci and Pseudomonas aeruginosa

Kenneth S. Thomson* and Ellen Smith Moland

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Objective: To compare the in vitro activities of the carbapenem, CS-023, four representative ß-lactam antibiotics and levofloxacin, against 970 Gram-positive or Gram-negative US clinical isolates.

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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Currently available carbapenems are potent and clinically efficacious therapeutic agents for infections caused by a wide range of Gram-positive and Gram-negative bacteria, but lack useful activity against oxacillin-resistant staphylococci and, in some centres, are becoming less effective against Pseudomonas aeruginosa because of increasing carbapenem resistance.13 CS-023 (R-115685) is an investigational parenteral 1ß-methylcarbapenem which is more stable to hydrolysis by human renal DHP-I than meropenem or imipenem4 and is bactericidal against P. aeruginosa and methicillin-resistant Staphylococcus aureus.5 In a study with healthy male volunteers it achieved relatively high maximum plasma concentrations of 135±18 mg/L after a 2100 mg dose.6 The current study was designed to evaluate its in vitro activity against 970 recent US clinical isolates using imipenem, meropenem, ceftriaxone, levofloxacin and ampicillin as comparator agents.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Bacteria

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 (0.008–0.03 mg/L), Enterococcus faecalis ATCC 29212 (0.25–1 mg/L), Haemophilus influenzae ATCC 49247 (≤0.004–0.06 mg/L), H. influenzae ATCC 49766 (0.03 mg/L), P. aeruginosa ATCC 27853 (0.12–0.5 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.


    Results and discussion
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
The activities of the study drugs are summarized in Table 1, which shows the MIC ranges and the concentrations that inhibited 50% and 90% of isolates (MIC50 and MIC90). Overall, CS-023 exhibited activity comparable to that of imipenem against most isolates of Gram-positive pathogens, and was generally similar to meropenem against Gram-negative pathogens. These findings were consistent with and extended those of Fukuoka et al. in a study of European clinical isolates.8


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Table 1. In vitro activity (mg/L) of CS-023 and comparator agents

 
The three carbapenems were highly potent against oxacillin-susceptible staphylococci (Table 1). CS-023 inhibited all isolates at 0.5 mg/L and was intermediate in activity between imipenem (most potent) and meropenem (least potent). Against oxacillin-resistant staphylococci, CS-023 was significantly more potent overall than imipenem, meropenem or levofloxacin inhibiting all oxacillin-resistant S. aureus at 4 mg/L, compared with 32 mg/L for meropenem and >32 mg/L for imipenem and levofloxacin. Interestingly, imipenem was more potent than CS-023 against the more susceptible isolates, as indicated by a 4-fold lower MIC50. All oxacillin-resistant coagulase-negative staphylococci were inhibited by 8 mg/L of CS-023, compared with 32 mg/L of levofloxacin and >32 mg/L of meropenem and imipenem. The greater potency of CS-023 in this study against oxacillin-resistant staphylococci was similar to in vitro activities reported for some other investigational carbapenems (J-111,347, J-111,225, J-114,870, J-114,871, SM-197436, SM-232721 and SM-232724)9,10 and also to the activity of CS-023 reported against Japanese isolates.4

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.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
We thank Jennifer A. Black and Thomas J. Lockhart for their excellent technical assistance, the many microbiologists who provided the isolates used in the study, and Sankyo Co., Ltd for the grant supporting this research. This work was previously presented at the 2002 ICAAC, abstract F-325.


    Footnotes
 
* Corresponding author. Tel: +1-402-280-4096; Fax: +1-402-280-1225; Email: kstaac{at}creighton.edu


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
1 . Sanders, C. C. & Thomson, K. S. (1992). Other ß-lactam antibiotics. In Infectious Diseases, 2nd edn. (Gorbach, S., Bartlett, J. & Blacklow, N. R. Eds), pp. 197–204. W. B. Saunders Company, Philadelphia, PA, USA.

2 . Livermore, D. M., Oakton, K. J., Carter, M. W. et al. (2001). Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent ß-lactamases. Antimicrobial Agents and Chemotherapy 45, 2831–7.[Abstract/Free Full Text]

3 . Sader, H. S., Cerbara, E. F., Luz, D. et al. (1999). Evaluation of the cephalosporins, cefepime, cefpirome and ceftazidime, against clinical isolates of imipenem-resistant Pseudomonas aeruginosa. Brazilian Journal of Infectious Diseases 3, 231–7.[Medline]

4 . Kawamoto, I., Shimoji, Y., Kanno, O. et al. (2003). Synthesis and structure–activity relationships of novel parenteral carbapenems, CS-023 (R-115685) and related compounds containing an amidine moiety. Journal of Antibiotics (Tokyo) 56, 565–79.

5 . Fukuoka, T., Koga, T., Ishii, C. et al. (2002). Antibacterial activity of CS-023 against MRSA and Pseudomonas aeruginosa. In Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapyc, 22–30 September 2002, San Diego, CA, USA. Abstract F-324, p. 172. American Society for Microbiology, Washington, DC, USA.

6 . Rennecke, J., Hirota, T., Shibayama, T. et al. (2002). Safety, tolerability, and pharmacokinetics (PK) of CS-023, a new parenteral carbapenem, in healthy male volunteers. In Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, 22–30 September 2002, San Diego, CA, USA. Abstract F-327, p. 173. American Society for Microbiology, Washington, DC, USA.

7 . National Committee for Clinical Laboratory Standards (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically–Fifth Edition: Approved Standard, M7-A5. NCCLS, Wayne, PA, USA.

8 . Fukuoka, T., Puechler, K., Rennecke, J. et al. (2002). In vitro activity of CS-023 against European clinical relevant bacterial isolates. In Program and Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, 22–30 September 2002, San Diego, CA, USA. Abstract F-326, p. 172. American Society for Microbiology, Washington, DC, USA.

9 . Nagano, R., Shibata, K., Adachi, Y. et al. (2000). In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 44, 489–95.[Abstract/Free Full Text]

10 . Ueda, Y. & Sunagawa, M. (2003). In vitro and in vivo activities of novel 2-(thiazol-2-ylthio)-1beta-methylcarbapenems with potent activities against multiresistant Gram-positive bacteria. Antimicrobial Agents and Chemotherapy 47, 2471–80.[Abstract/Free Full Text]