In Vivo
 Pharmacodynamic Activity of Tomopenem (formerly CS-023) against
 Pseudomonas aeruginosa
 and Methicillin-Resistant
 Staphylococcus aureus
 in a Murine Thigh Infection Model

The antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistant Staphylococcus aureus (MRSA) were compared in an in vivo mouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. The differences in CFU after 24 h of treatment were compared between control and treatment groups. Vehicle-dosed control groups increased in bacterial density an average of 1.1 logs. All treatments reduced the bacterial density at 24 h with an average of 1.2, 1.6, and 0.1 logs for TZD, linezolid, and vancomycin, respectively. The efficacy of TZD versus linezolid regimens against the three MRSA isolates was not statistically different (P > 0.05), although both treatments were significantly different from controls. In contrast, the vancomycin regimen was significantly different from TZD against one MRSA isolate and from linezolid against all isolates. The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model. Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated (CA) and health care-associated (HA) strains, continue to dominate the infectious disease landscape. MRSA strains USA100, USA300, and USA400 are increasingly more resistant to antimicrobials and are spread over the United States and globally (3,10,13,23,27). As this species continues to adapt, the treatment of both CA-MRSA and HA-MRSA pneumonia has become more difficult (27,33). Tedizolid phosphate (TZD; formerly torezolid phosphate) is a novel oxazolidinone antibiotic that is under investigation in phase III trials for acute bacterial skin and skin structure infections (ABSSSI) and has proven to be a powerful new agent against Gram-positive pathogens, including MRSA, Streptococcus pneumonia, and enterococci (2, 29). TZD is a prodrug antibiotic that is rapidly converted in vivo to the microbiologically active moiety tedizolid, also known as TR-700. Human pharmacokinetic studies of tedizolid showed improved pharmacokinetic results compared to those of linezolid and support a once-daily dose of 200 mg (25, 29). Additionally, tedizolid was shown to have in vivo efficacy in a pneumonia model of infection (26).In this current study, the epithelial lining fluid (ELF) profile observed after the administration of 200 mg tedizolid every...

Section: Discussionmentioning

confidence: 99%

Comparative In Vivo Efficacies of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid, and Vancomycin for Methicillin-Resistant Staphylococcus aureus in a Mouse Pneumonia Model

Tessier

Keel²,

Hagihara

et al. 2012

“…(1, 15, 17, 19), but also depends on the bacterial strain being tested (13). The TϾMIC for bactericidal effects are larger; a TϾMIC of 30 to 55% is required for a 2-log-unit reduction in viable bacterial counts (15,17), and the maximum effect for some strains may require a TϾMIC of Ͼ60% (14,15). The relationships between carbapenem TϾMICs and antibacterial effect are less clear for S. aureus, including MRSA strains.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Razupenem (PZ601) Studied in an In Vitro Pharmacokinetic Model of Infection

MacGowan

Noel

Tomaselli

et al. 2011

) and five strains of Enterobacteriaceae (three Escherichia coli strains [two containing extended-spectrum ␤-lactamases {ESBLs}] and two Enterobacter sp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 g/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2؋ MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 g/ml) and at 120 h with strain 27706 (MIC, 1.5 g/ml). Against E. coli and Enterobacter spp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 g/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except for Enterobacter strain 34425 (MIC, 6.0 g/ml), where colonies were recovered from media containing 2؋, 4؋, and 8؋ MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% ؎ 1.4%, and that for a 1-log-unit reduction in count was 12.5% ؎ 5.8%. Population profiles indicated growth on 2؋ MIC recovery medium at fT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments with Enterobacteriaceae, the fT>MIC for a 24-h bacteriostatic effect was 34.2% ؎ 7.6% and that for a 1-log-unit reduction in count was 42.5% ؎ 7.8%. Population analysis profiles indicated growth on recovery media with 2؋, 4؋, and 8؋ MIC at fT>MICs in the range of 1 to 69% but rarely at values of >70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of <3.0 g/ml and Enterobacteriaceae with MICs of <0.4 g/ml. fT>MIC targets of >35% for MRSA and >70% for Enterobacteriaceae should provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.Razupenem (also called SM-216601, SMP601, PZ601, and PTZ601) is a developmental 1␤-methyl carbapenem with in vitro potency against a broad range of Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and extended-spectrum ␤-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. (16, 10). The razupenem MIC 90 s (g/ml) for methicillin-sensitive S. aureus (MSSA), MRSA, and penicillin-resistant S. pneumoniae are Յ0.06, 2, and 0.25 g/ml, respectively, and the MIC 90 s for E. coli, Klebsiella pneumoniae, and Enterobacter cloacae are 0.5, 0.2, and 8 g/ml, respectively. Serratia marcescens, Pseudomonas aeruginosa, and Bacteroides fragilis all have MIC 90 of Ն16 g/ml (18). The model MICs for razupenem against ESBLproducin...

“…In the previous PK-PD analysis, we also showed that the efficacy of tomopenem was driven by T MIC and the magnitude required for the static effect was comparable to that of MEM, almost 30 f%T MIC (23). There is a difference in the dosing regimen of 4 to 90 mg/kg/dose and 50 to 800 mg/kg/dose between this study and the previous PK-PD analysis; however, pharmacodynamic profiles that correlated with the efficacy of tomopenem were shown to be almost the same in both studies.…”

mentioning

confidence: 57%

“…The values of the volume of distribution in the central compartment (V 1 ) and the constants k 10 , k 12 , and k 21 were determined by use of a 2-compartment intravenous infusion, no lag time, and the 1st-order elimination model using WinNonlin professional software (version 4.0.1; Pharsight Corp.). Murine pharmacokinetic parameters for tomopenem and MEM were calculated using plasma concentrations of the same infection model at 50 mg/kg (23). The values of the volume of distribution (V), k 01 , and k 10 were determined by 1-compartment oral administration and no lag time using the same software.…”

Section: Methodsmentioning

confidence: 99%

“…In this model, tomopenem showed good in vivo efficacy against not only P. aeruginosa but also MRSA and is expected to be effective at over 40 f%T MIC , which is obtained at an MIC of Յ8 g/ml for 750 mg TID and an MIC of Յ16 g/ml for 1,500 mg TID. Our previous study also showed that there is no difference between the target values for P. aeruginosa and MRSA (23). From the in vitro study, tomopenem showed strong bactericidal activity and a postantibiotic effect against MRSA similar to those against P. aeruginosa (13,26).…”

mentioning

confidence: 86%

See 1 more Smart Citation

Efficacy of Human-Simulated Exposures of Tomopenem (Formerly CS-023) in a Murine Model of Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infection

Sugihara

Tateda

Yamamura

et al. 2011

Self Cite

Tomopenem (formerly CS-023) is a novel carbapenem with improved activity against diverse hospital pathogens, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), and has a half-life about twice longer than the half-lives of other carbapenems such as imipenem and meropenem. Our objective in this study was to estimate the efficacy of tomopenem in humans by human-simulated exposures in a neutropenic murine thigh infection model against 9 clinical isolates of P. aeruginosa with MICs of 4 to 32 g/ml and 9 clinical isolates of MRSA with MICs of 4 to 16 g/ml. Human-simulated dosing regimens in neutropenic mice were designed to approximate the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%T MIC ) observed with tomopenem at 750 and 1,500 mg given as a 0.5-h infusion three times a day (TID) in humans. As reported previously, there was no difference between the target values of P. aeruginosa and MRSA required for efficacy (K. Sugihara et al., Antimicrob. Agents Chemother. 54:5298-5302, 2010). Tomopenem at 750 mg showed bactericidal or bacteriostatic effects against 10 of 11 strains of P. aeruginosa and MRSA with MICs of <8 g/ml (f%T MIC > 41), and tomopenem at 1,500 mg showed bactericidal effects against 16 of 17 strains of P. aeruginosa and MRSA with MICs of <16 g/ml (f%T MIC > 43). Meropenem at 1,000 mg TID was tested for comparison purposes and showed bactericidal or bacteriostatic effects against 3 of 4 strains of P. aeruginosa with MICs of <4 g/ml (f%T MIC > 33). From these results, tomopenem is expected to be effective with an f%T MIC of over 40 against P. aeruginosa and MRSA strains with MICs of <8 g/ml at doses of 750 mg TID and strains with MICs of <16 g/ml at doses of 1,500 mg TID.