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JAC Advance Access published online on October 3, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn411
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model

Yoshitomo Morinaga1,2,{dagger}, Katsunori Yanagihara1,2,*,{dagger}, Shigeki Nakamura2, Kazuko Yamamoto2, Koichi Izumikawa2, Masafumi Seki2, Hiroshi Kakeya2, Yoshihiro Yamamoto2, Yasuaki Yamada1, Shigeru Kohno2 and Shimeru Kamihira1

1 Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan 2 Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

* Correspondence address. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan. Tel: +81-95-819-7418; Fax: +81-95-819-7257; E-mail: k-yanagi{at}net.nagasaki-u.ac.jp

Received 14 May 2008; returned 11 June 2008; revised 19 August 2008; accepted 6 September 2008


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Objectives: Tomopenem (CS-023) is a novel parenteral carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria, as well as potent activity against drug-resistant pathogens, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. We compared the in vivo activity of tomopenem and that of meropenem in a chronic lower respiratory infection mouse model of P. aeruginosa.

Methods: Mice with chronic airway infection by P. aeruginosa were treated with saline (as the control, twice daily), tomopenem (100 mg/kg, twice daily) or meropenem (100 mg/kg, twice daily) for 7 days. After treatment, the number of viable bacteria in lungs and histopathological findings were analysed. The pharmacokinetics of tomopenem and meropenem were also analysed after initial treatment.

Results: The number of viable bacteria in lungs treated with saline, tomopenem or meropenem was 4.21 ± 1.28, 2.91 ± 0.87 and 3.01 ± 1.00 log10 cfu/lung (mean ± SEM), respectively (P < 0.05, control versus tomopenem- or meropenem-treated groups). In the histopathological examination of lung specimens, the control group had the features of chronic bronchial infection; however, tomopenem- and meropenem-treated groups had fewer inflammatory cells compared with the control group. The pharmacokinetic parameter of % time above MIC for tomopenem and meropenem was 16% and 17% in sera and 15% and 18% in lungs, respectively.

Conclusions: Tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection by P. aeruginosa, compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious.

Key Words: chronic respiratory infections , meropenem , P. aeruginosa


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Pseudomonas aeruginosa is an important pathogen of chronic lower respiratory tract infectious diseases, such as cystic fibrosis, diffuse panbronchiolitis, chronic bronchitis and bronchiectasis. Once P. aeruginosa colonizes the lower respiratory tract, it is difficult to treat. Chronic respiratory infection causes excessive inflammation and lung tissue damage in humans. The lung function decreases gradually and exacerbations of chronic airway infections sometimes occur. These patients require treatment with antibiotics at every acute exacerbation. Although carbapenems are active against P. aeruginosa and have been used to treat acute exacerbations resulting from P. aeruginosa infection, they are also becoming less effective against P. aeruginosa. In Japan, the susceptibility rates of P. aeruginosa to imipenem have fallen from 63.8% in 1998 to 53.6% in 2003.1 Therefore, new antibacterial agents that are effective against resistant pathogens are required.

Tomopenem (CS-023) is a novel parenteral carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria, and also has potent activity against drug-resistant pathogens, including penicillin-resistant Streptococcus pneumoniae (PRSP), methicillin-resistant Staphylococcus aureus (MRSA) and imipenem-resistant P. aeruginosa in vitro.2–4 The MIC90s of tomopenem, imipenem and meropenem for the clinical isolates of P. aeruginosa in Japan are 4, 16 and 16 mg/L, respectively.3 Tomopenem has a longer half-life compared with other carbapenems except for ertapenem and characteristic high stability against human renal dehydropeptidase-I (DHP-I).5,6 In a murine pneumonia model induced by PRSP, tomopenem showed efficacy comparable with imipenem and better than meropenem in the number of viable bacteria left in the lungs.3

In the present study, we studied the efficacy of tomopenem compared with meropenem in a chronic lower respiratory tract infection model of P. aeruginosa. Furthermore, we analysed the pharmacokinetics of these agents in sera and lungs.


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Antimicrobial agents

Tomopenem was kindly provided by Daiichi Sankyo Co., Ltd (Tokyo, Japan). Meropenem was purchased from Dainippon Sumitomo Pharma Co., Ltd (Osaka, Japan). Both agents were dissolved in saline.

Laboratory animals

Male, ddY, specific pathogen-free mice (6 weeks old, body weight: 30–35 g) were purchased from Shizuoka Agricultural Cooperative Association Laboratory Animals (Shizuoka, Japan). All the animals were housed in a pathogen-free environment and received sterile food and water in the Laboratory Animal Center for Biomedical Science at Nagasaki University. The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation at our institution.

Bacterial strains

P. aeruginosa S10 strain was used in this study. This strain was clinically isolated from the sputum of patients at Nagasaki University hospital and produces biofilm formation.7 The bacteria were stored at –80°C in brain heart infusion broth (BBL Microbiology System, Cockeysville, MD, USA) supplemented with 10% (v/v) glycerol and 5% (weight/volume) skimmed milk (Yukijirushi Co., Tokyo, Japan) until use.

Antibiotic susceptibility testing

The MICs of the agents were determined by the broth dilution method with Mueller–Hinton broth (Becton Dickinson and Company, Franklin Lakes, NJ, USA). Microtitre plates containing 5.0 x 105 cfu/well were incubated with agents at 35°C for 24 h, and the lowest concentration of the agent that prevented visible growth was considered the MIC.

Experimental model of chronic respiratory infection

Disposable sterile plastic cut-down intravenous catheters with a 3 Fr. (1 mm) outer diameter (Atom Co., Tokyo, Japan) were used for intubation. The tubes were 3.0 mm in length, with a few slits made at the proximal end to prevent blockage by oral secretions. To prepare the inoculum, P. aeruginosa was cultured on a Muller–Hinton II agar plate for 24 h, then the bacteria suspended in saline, harvested by centrifugation (3000 g, 4°C, 10 min), resuspended in sterile saline and adjusted to 1–2 x 109 cfu/mL, as estimated by turbidimetry. The intubation tube was then immersed in the bacterial saline suspension for 3 days at 37°C. The bacterial count on these tubes 3 days after incubation just before intubation was 6.0 ± 0.3 (log10 cfu/mL, mean±SD, n = 9). After 3 days of incubation, the bacteria were inoculated to anaesthetized mice intratracheally. The method used for inducing infection has been described in detail previously.8 Briefly, the intubation tube harbouring the bacteria was attached to the blunted tip of the needle of an intravenous catheter (Angiocath; Becton Dickinson, Vascular Access, Sandy, UT, USA). The needle tube was inserted through the oral cavity and then advanced through the vocal cords. When the tip of the tube was in the trachea, the needle/catheter was pulled out and the outer sheath was pushed gently to place the pre-coated tube into the main bronchus.

Treatment protocol

Lower airway infection of the mice was induced with P. aeruginosa, as described above. Treatment commenced 7 days after inoculation. Tomopenem or meropenem was injected intraperitoneally into the mice twice a day (100 mg/kg). The same dosage of cilastatin (Wako Pure Chemical Industries, Ltd, Osaka, Japan), a DHP-I inhibitor, was also injected along with both agents. In the control group, saline was injected into the mice instead of tomopenem or meropenem. Eight mice were used for each group. After 7 days of treatment (14th day after inoculation), bacteriological and histological examinations were analysed in each group.

Bacteriological examinations

The mice were sacrificed by cervical dislocation on day 14 (12 h after the final treatment). The lungs were dissected under aseptic conditions and suspended in 1 mL of saline. The organs were homogenized with a homogenizer (AS One Co., Osaka, Japan), quantitatively inoculated onto Muller–Hinton II agar plates using serial dilutions and incubated at 37°C for 18 h.

Histological examinations

The mice were sacrificed by cervical dislocation on day 14 (12 h after the final treatment). The lungs were fixed in 10% buffered formalin and stained with haematoxylin–eosin.

Bioanalytical procedures

Quantification of tomopenem and meropenem in serum was performed by fully validated high-performance liquid chromatography with UV absorbance detection (UV-HPLC). The range of quantification of both agents in serum was 0.5 mg/L as the lower limit of quantification (LLOQ) up to 200 mg/L. The accuracy of the intra-assay reproducibility for tomopenem using samples spiked at concentrations of 0.5, 2, 3, 20 and 150 mg/L ranged from 98.0% to 119% at LLOQ. The intra-assay precision for tomopenem using the same samples did not exceed 4.8%. The accuracy and precision of the inter-assay reproducibility for tomopenem did not exceed 97.0% to 100% and 12.8%, respectively. Replicate analysis of meropenem did not exceed 94.0% to 97.4% for accuracy and 6.0% for precision for the intra-assay reproducibility. The inter-assay reproducibility of meropenem did not exceed 91.6% to 105% for accuracy and 11.4% for precision. No interfering peaks in the blank samples on the chromatograms were observed. The stability of the agents in frozen serum from preparation to the end of the analysis was confirmed. The UV-HPLC system used was an LC-10A system (Shimadzu Corp.) and the conditions for tomopenem were as follows: analytical column, XBridgeTM C18 (5 µm, 4.6 mmx150 mm, Waters Co.); mobile phase, 20 mM disodium hydrogenphosphate/methanol (88:12, v/v); detection wavelength, 304 nm; flow rate, 1.0 mL/min. The conditions for meropenem were as follows: analytical column, XBridgeTM C18 (5 µm, 4.6 mmx150 mm, Waters Co.); mobile phase, water/methanol/acetic acid/ammonium acetate (920:80:2:770, v/v/v/w); detection wavelength, 298 nm; flow rate, 1.0 mL/min.

Quantification of tomopenem and meropenem in lung homogenates was performed by fully validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The homogenates were added to deuterium-labelled tomopenem as the internal standard for both agents. The mixture was applied to solid-phase extract (Oasis LB 3 cc cartridge, Waters Co.), and the target agents were eluted by methanol. The extract was dried with nitrogen gas at 40°C and was reconstituted with purified water. The recovery of the extraction for tomopenem and meropenem was more than 86.5% of both agents at two concentrations. The analyses were separated using LC (Alliance 2795 Separations Module, Waters Co.) on an ODS column (Inertsil ODS-3, 2.1 mmx150 mm, 5 µm, GL Science) for a period of 8 min. Electrospray ionization tandem mass spectrometer (MicroMass Quattro II, Waters Co.) was operated in the positive time-scheduled multi-reaction monitoring mode. The monitored positive ions of tomopenem, meropenem and the internal standard were 295, 254 and 300, respectively, as the daughter ions. The range of quantification for both agents in the lung was 0.5 µg/g as the LLOQ up to 200 µg/g. The intra-assay reproducibility for tomopenem using samples spiked at 0.05, 0.15, 2.5 and 15 mg/L (final lung concentrations of 0.5, 1.5, 25 and 150 µg/g) was 96.0% to 107% for accuracy and below 3.8% for precision. The inter-assay reproducibility for tomopenem using the same samples was 98.7% to 117% at LLOQ for accuracy and below 5.5% for precision. The accuracy and precision of the intra-assay reproducibility for meropenem did not exceed 85.3% to 98.7% and 6.7%, respectively. Replicate analysis of meropenem did not exceed 90.7% to 105% for accuracy and 12.0% for precision of the inter-assay reproducibility. The stability of the agents in frozen homogenate from preparation to the end of the analysis was confirmed.

Pharmacokinetic studies

These studies were undertaken to determine the pharmacokinetic profiles of tomopenem and meropenem in a chronic lower airway mouse model of infection due to P. aeruginosa. On the seventh day after inoculation of P. aeruginosa, the mice were sacrificed by cervical dislocation at 5, 15, 30, 60, 90 and 120 min after treatment with tomopenem or meropenem at the dose of 100 mg/kg in combination with cilastatin. Three or four mice were used for each group. The blood was centrifuged and then the serum was mixed with an equal volume of MOPS buffer (pH 7.0). The lungs were homogenized using a homogenizer after addition of 2 mL of MOPS buffer (pH 7.0). The homogenate was centrifuged and then the supernatant and serum concentrations of the agents were determined by LC-MS/MS and UV-HPLC, respectively. The concentration–time profiles were analysed using WinNonlin Professional software (Version 4.0.1; Pharsight Corp.). A one-compartment oral model with the various dosages was fit to the observations. The best-fit model was determined by Akaike's information criteria. The time above MIC (%T>MIC) was calculated using SAS System Release 8.2 software (SAS Institute Inc.). The free %T>MIC (f%T>MIC) was also calculated, with the protein binding in the mouse serum of tomopenem and meropenem being 17.4% and 33.8%, respectively.9,10

Statistical analysis

The bacterial data are expressed as the mean ± SEM. Differences between the groups were examined for statistical significance by an unpaired Student's t-test. A P value of <0.05 denoted the presence of a statistically significant difference.


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In vitro susceptibility

For P. aeruginosa S10, the MICs of drugs are presented in Table 1. The MICs of tomopenem and meropenem were 1.0 and 0.5 mg/L, respectively.


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  		Table 1. MICs for Pseudomonas aeruginosa S10 strain

 
Bacteriological examination

The mean cfu ± SEM of P. aeruginosa recovered from homogenized lung tissue after treatment is shown in Figure 1. The mean numbers of viable bacteria in the lungs of the tomopenem, meropenem and control mice were 2.91 ± 0.87, 3.01 ± 1.00 and 4.21 ± 1.28 log10 cfu/lung (n = 8 each), respectively. There were no sterilized mice after treatment in each group. The number of viable bacteria in the lungs of mice treated with tomopenem or meropenem was significantly less than that in lungs of the control (P < 0.05 for each comparison). There was no statistically significant difference in the number of viable bacteria in the lungs between the tomopenem- and meropenem-treated mice (P = 0.85).


Figure 1
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  		Figure 1. Number of viable bacteria in the lungs after 7 days of treatment with tomopenem or meropenem (100 mg/kg, twice daily) and control (saline, twice daily). Data are expressed as the mean ± SEM for eight mice. Tomopenem and meropenem significantly reduced the number of viable bacteria compared with the control (P < 0.05).

 
Histopathological examination

The histopathological findings in the lung specimens from mice sacrificed 12 h after the final treatment are shown in Figure 2. In the control group, microscopic examination of the lung specimens revealed the features of chronic bronchitis. Inflammatory cells had infiltrated around the bronchi and exudates had collected in the alveolar spaces. However, both the tomopenem- and meropenem-treated groups showed fewer inflammatory cells and exudates than the control group. There were no significantly different findings between the tomopenem- and meropenem-treated groups.


Figure 2
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  		Figure 2. Histopathological examination of lung specimens. The control group showed the features of chronic bronchopneumonia; inflammatory cells had infiltrated around the bronchi and exudates had collected in the alveolar spaces. However, only few inflammatory cells were observed in both the tomopenem- and meropenem-treated groups.

 
Lung and serum concentrations of tomopenem and meropenem in mice

The levels of tomopenem and meropenem in the sera and lungs of infected mice are presented in Figure 3 (n = 3 or 4 at each point). The calculated pharmacokinetics of the agents are presented in Table 2. The half-life (t1/2) of tomopenem and meropenem was 0.197 and 0.264 h in sera and 0.343 and 0.363 h in the lungs, respectively. The %T>MIC for tomopenem and meropenem was 16% and 17% in sera and 15% and 18% in the lungs, respectively. The f%T>MIC was 16% for both agents.


Figure 3
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  		Figure 3. Pharmacokinetics of tomopenem and meropenem in serum (a) and in the lungs (b) of infected mice. Each point represents the mean ± SD for three or four mice.

 


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  		Table 2. Selected PK parameters estimated for tomopenem and meropenem in serum and in the lung

 

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In the present study, the in vivo activity of tomopenem, a new carbapenem, against P. aeruginosa was compared with that of meropenem by evaluating its bacteriological and pharmacological effects.

Among chronic airway infectious diseases such as chronic bronchitis, cystic fibrosis, diffuse panbronchiolitis and bronchiectasis, airway infection with P. aeruginosa and the accompanying inflammatory response are major clinical problems. These patients often have an acute exacerbation of P. aeruginosa infection and antibiotic chemotherapy is required at every exacerbation. While antibiotic chemotherapy has reduced the morbidity and early mortality of patients suffering from this infection, resistance to antibiotics has developed in P. aeruginosa.1 The rates of resistance to carbapenems (>8 mg/L) of P. aeruginosa are slowly increasing11–14 and treatment against P. aeruginosa infection is becoming more difficult.

Carbapenems have potent activity against Gram-positive and -negative bacteria. In addition, tomopenem has exceptional activity against MRSA and P. aeruginosa compared with imipenem and meropenem in vitro.3,4

Carbapenems are hydrolysed at the β-lactam ring by mammalian DHP-I.5,15,16 Therefore, imipenem requires the DHP-I inhibitor cilastatin when used for therapy in humans. However, 1-β-methylcarbapenems such as tomopenem, meropenem, biapenem and ertapenem show high stability in the presence of human DHP-I15 and do not require a DHP-I inhibitor. On the other hand, DHP-I activity against tomopenem and meropenem varies greatly according to the experimental animal species and organs involved.15,17 To eliminate the effect of murine DHP-I as much as possible, we treated mice with cilastatin in both the tomopenem- and meropenem-treated groups in this study.

In this study, tomopenem and meropenem significantly decreased the number of viable bacteria in lungs and dramatically improved histological findings compared with the control. In this study, because tomopenem- or meropenem-treated groups had obviously fewer inflammatory cells in the histological findings compared with the control group, we did not perform scoring. These findings suggest that tomopenem has an efficacy in treatment of chronic respiratory infection diseases of P. aeruginosa similar to that of meropenem.

The %T>MIC is an important pharmacodynamic parameter that influences the outcome of β-lactam antibiotic, including carbapenem, treatment.18 In this study, the %T>MIC for tomopenem was similar to that for meropenem in both the sera and the lungs. There was also no difference in the serum f%T>MIC. This profile is consistent with our finding that there was no significant difference in the number of viable bacteria in the lungs between these two agents. Since the antibacterial target magnitude associated with efficacy has been reported to be similar among carbapenems,19 the target value of tomopenem would be the same as that of meropenem in humans.

The half-life of a drug is another important pharmacokinetic factor because it influences the %T>MIC. Although the half-life of tomopenem in serum was a little shorter than that of meropenem in mice, it has been reported that the half-life of tomopenem is longer than that of meropenem in humans, despite similar serum protein binding.6 Shibayama et al. reported that the lack of recognition of tomopenem by renal transporters involved in uptake across the basolateral membrane is one of the reasons for its long plasma half-life in humans compared with meropenem, since no tomopenem molecules exist as an anionic form at physiological pH.20 The MICs of tomopenem for clinical isolates of P. aeruginosa showed more activity than meropenem.3 Considering the longer half-life of tomopenem, the %T>MIC for tomopenem is much higher than that for meropenem for humans. Therefore, tomopenem is strongly expected to be efficacious in treating patients with lower respiratory infection caused by P. aeruginosa.

In conclusion, tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection by P. aeruginosa compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, we expect tomopenem to be effective against chronic respiratory tract infection with P. aeruginosa.


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This study was supported by internal funding.


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None to declare.


   Footnotes
 
{dagger} These authors contributed equally to this study. Back


   Acknowledgements
 
We would like to thank T. Koga (Daiichi Sankyo Co., Ltd, Tokyo, Japan) for his assistance in the pharmacokinetic analyses.


   References
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1 . Ishii Y, Iwata M, Murakami H, et al. Annual change of susceptibility of Pseudomonas aeruginosa isolated from lower respiratory tract or urinary tract infections against antibacterial agents. Jpn J Chemother (2004) 52:256–64.

2 . Brown NP, Draghi DC, Jones ME, et al. Baseline profile of RO4908463 (CS-023) against recent isolates of target Gram-negative pathogens exhibiting lactam-resistant phenotypes from Europe (EU), 2003–2006. In: Abstracts of the Seventeenth European Congress of Clinical Microbiology and Infectious Diseases, Munich, Germany, 2007. Abstract P1663.

3 . Koga T, Abe T, Inoue H, et al. In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem. Antimicrob Agents Chemother (2005) 49:3239–50.[Abstract/Free Full Text]

4 . Thomson KS, Moland ES. CS-023 (R-115685), a novel carbapenem with enhanced in vitro activity against oxacillin-resistant staphylococci and Pseudomonas aeruginosa. J Antimicrob Chemother (2004) 54:557–62.[Abstract/Free Full Text]

5 . Kawamoto I, Shimoji Y, Kanno O, et al. Synthesis and structure–activity relationships of novel parenteral carbapenems, CS-023 (R-115685) and related compounds containing an amidine moiety. J Antibiot (Tokyo) (2003) 56:565–79.[Medline]

6 . Shibayama T, Matsushita Y, Hirota T, et al. Pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem, in healthy male Caucasian volunteers. Antimicrob Agents Chemother (2006) 50:4186–8.[Abstract/Free Full Text]

7 . Yanagihara K, Tomono K, Sawai T, et al. Combination therapy for chronic Pseudomonas aeruginosa respiratory infection associated with biofilm formation. J Antimicrob Chemother (2000) 46:69–72.[Abstract/Free Full Text]

8 . Yanagihara K, Tomono K, Sawai T, et al. Effect of clarithromycin on lymphocytes in chronic respiratory Pseudomonas aeruginosa infection. Am J Respir Crit Care Med (1997) 155:337–42.[Abstract]

9 . Shibayama T, Matsushita Y, Kurihara A, et al. Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in humans using animal data. Xenobiotica (2007) 37:91–102.[CrossRef][Web of Science][Medline]

10 . Sumita Y, Nouda H, Tada E, et al. Pharmacokinetics of meropenem, a new carbapenem antibiotic, parenterally administered to laboratory animals. Chemotherapy (Tokyo) (1992) 40(Suppl_1):123–31.

11 . Iaconis JP, Pitkin DH, Sheikh W, et al. Comparison of antibacterial activities of meropenem and six other antimicrobials against Pseudomonas aeruginosa isolates from North American studies and clinical trials. Clin Infect Dis (1997) 24(Suppl 2):S191–6.[Web of Science][Medline]

12 . Karlowsky JA, Draghi DC, Jones ME, et al. Surveillance for antimicrobial susceptibility among clinical isolates of Pseudomonas aeruginosa and Acinetobacter baumannii from hospitalized patients in the United States, 1998 to 2001. Antimicrob Agents Chemother (2003) 47:1681–8.[Abstract/Free Full Text]

13 . Jones RN, Kirby JT, Beach ML, et al. Geographic variations in activity of broad-spectrum β-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997–2000). Diagn Microbiol Infect Dis (2002) 43:239–43.[CrossRef][Web of Science][Medline]

14 . Turner PJ. Meropenem activity against European isolates: report on the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) 2006 results. Diagn Microbiol Infect Dis (2008) 60:185–92.[CrossRef][Web of Science][Medline]

15 . Fukasawa M, Sumita Y, Harabe ET, et al. Stability of meropenem and effect of 1β-methyl substitution on its stability in the presence of renal dehydropeptidase I. Antimicrob Agents Chemother (1992) 36:1577–9.[Abstract/Free Full Text]

16 . Kropp H, Sundelof JG, Hajdu R, et al. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase. Antimicrob Agents Chemother (1982) 22:62–70.[Abstract/Free Full Text]

17 . Shibayama T, Matsushita Y, Kawai K, et al. Pharmacokinetics and disposition of CS-023 (RO4908463), a novel parenteral carbapenem, in animals. Antimicrob Agents Chemother (2007) 51:257–63.[Abstract/Free Full Text]

18 . Craig WA, Ebert SC. Continuous infusion of β-lactam antibiotics. Antimicrob Agents Chemother (1992) 36:2577–83.[Free Full Text]

19 . Craig W, Ebert S, Watanabe Y. Differences in time above MIC (T>MIC) required for efficacy of β-lactams in animal infection models. In: Abstracts of the Thirty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, Louisiana, 1993. Abstract 88.

20 . Shibayama T, Sugiyama D, Kamiyama E, et al. Characterization of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem as substrates of human renal transporters. Drug Metab Pharmacokinet (2007) 22:41–7.[CrossRef][Web of Science][Medline]


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