Jamese Hilliard - Academia.edu (original) (raw)

Papers by Jamese Hilliard

Antimicrobial agents and chemotherapy, Jan 11, 2016

Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacteria... more Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as it occurs in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI, and showed that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimics the severe infections that occur in humans, including the large central dermonecrotic core surrounded...

ABSTRACT Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was... more ABSTRACT Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared to meropenem/cilastatin (MEM), and piperacillin/tazobactam (TZP) in a Pseudomonas aeruginosa murine skin and soft-tissue infection model. Methods: Female Skh-1 immunocompromised mice were infected subcutaneously (sc) with Pseudomonas aeruginosa (PA) OC 4351 (wild type with an inducible Amp C β-lactamase) or PA OC 4354 (constitutive Amp C production) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion were determined. Results: In infections with the wild type strain, DOR resulted in improved killing over MEM by 0.5 to 0.7 log CFU/g skin tissue at doses of 6.2 to 100 mg/kg/day. Bacterial killing with DOR was also greater than MEM in PA 4354 by 0.4 to 1.3 log CFU/g skin tissue at doses of 1.6, 6.2 and 100 mg/kg. A similar reduction in CFU was noted for both drugs at a dose of 25 mg/kg/day. No decreases in the number of bacteria of either strain were observed with TZP treatment. DOR was also more effective in reducing the lesion volume at the infection site. In PA 4351 infections, DOR treatment resulted in a 7.2 to 8.4% greater reduction in lesion volume than MEM in a dose range of 6.2 to 100 mg/kg/day. Against PA 4354, DOR treatment resulted in a 14 to 29% greater reduction in lesion volume than MEM at doses of 1.6 to 100 mg/kg/day. Δ Log CFU/g Skin (from infecting inoculum) PA 4351 PA 4351 PA 4351 PA 4354 PA 4354 PA 4354 Dose (mg/kg/day) DOR MEM TZP DPR MEM TZP 0 1.5 1.5 1.5 1.5 1.5 1.5 1.6 0.3 0.2 1.7 -0.1 0.7 1.9 6.2 -0.4 0.2 2.0 -0.8 0.5 2.0 25 -1.2 -0.9 2.0 -0.9 -1.1 1.7 100 -1.5 -1.0 2.2 -1.5 -1.1 1.8 Conclusion: In a skin and soft-tissue infection model against PA 4351 and PA 4354, equivalent doses of DOR resulted in greater bacterial killing and smaller lesion volume than MEM or PIP.

Antimicrobial Agents and Chemotherapy, Apr 1, 2009

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against... more RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibioticsusceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two-to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log 10 at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log 10 (MSSA) and 2 log 10 (CA-MRSA). In the pneumococcal model, RWJ-416457 was two-to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC 24 ) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC 24 /MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

Bioorganic Medicinal Chemistry Letters, Dec 15, 2006

A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate fo... more A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core. The best members of this series display in vitro and in vivo activity comparable to telithromycin. Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.

ABSTRACT Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigationa... more ABSTRACT Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-spectrum cephalosporin with anti-MRSA activity, was compared to cefazolin (CFZ), vancomycin (VAN), and linezolid (LZD) in a murine skin and soft-tissue infection model. Methods: Female Skh-1 mice were infected subcutaneously (sc) with S. aureus Smith (MSSA), or methicillin-resistant S. aureus OC 8525 (MRSA) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion was determined. Results: In MSSA, BPR achieved a >1.7 log reduction in CFU/g skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. This reduction was only achieved with CFZ at doses of 25 and 100 mg/kg/day and VAN at 100 mg/kg/day. At doses lower than 100 mg/kg/day, no reduction in bacterial burden was noted with VAN or LZD. In MRSA infections, BPR showed similar or improved reduction in bacterial load at doses of 1.6 to 100 mg/kg/day over CFZ, VAN, and LZD. BPR was also more effective in reducing the lesion volume at the infection site compared to CFZ, LZD, and VAN in MSSA and MRSA infections with the exception of the 100 mg/kg/day dose of VAN. Δ Log CFU/g Skin (from infecting inoculum) MSSA MSSA MSSA MSSA MRSA MRSA MRSA MRSA Dose (mg/kg/day) BPR CFZ VAN LZD BPR CFZ VAN LZD 0 1.6 1.6 1.6 1.6 0.8 0.8 0.8 0.8 1.6 -1.0 0.9 1.5 1.4 0.3 0.8 1.5 0.4 6.2 -1.7 -0.6 1.6 0.6 -0.8 0.6 1.2 0 25 -2.0 -1.7 0.2 0.1 -1.3 -0.3 -0.7 -0.4 100 -1.7 -1.9 -3.1 -0.4 -1.4 -0.9 -1.4 -0.4 Conclusion: In a murine skin and soft-tissue infection model against MRSA, equivalent doses of BPR compared to CFZ, LZD, or VAN resulted in equal or greater killing activity. In this MSSA infection model, BPR at low doses was more effective than CFZ, LZD, or VAN.

ABSTRACT Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigati... more ABSTRACT Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broad-spectrum cephalosporin with anti-MRSA and Gram-negative activity. The efficacy of this agent against P. aeruginosa was examined in two murine infection models. Methods: The neutropenic mouse thigh model was used to evaluate the BPR efficacy. Mice were made neutropenic with 2 ip injections of cyclophosphamide given 96 and 24 h prior to infection (150 and 100 mg/kg respectively). Animals were subsequently infected intramuscularly 5 x 105 CFU of P. aeruginosa OC4351, and dosed subcutaneously (sc) 1 and 3 h post-infection with ceftobiprole (BPR), Ceftazidime (CAZ), or Meropenem/cilastatin (MEM) (1:1ratio ). The bacterial load of the thigh muscle was determined 24-h post-infection. Efficacy was also evaluated in a lethal systemic infection model. Mice (n=24 in 3 experiments) were infected i.p. with P. aeruginosa OC4351 and dosed sc 1 and 3 h post-infection with BPR or CAZ. . The percent survival at 24 h was examined. Results: The results of treatment in the neutropenic thigh model, expressed as the change in log CFU (from infecting inoculum), and the % survival in the systemic infection model are shown in the table below: Δ log CFU % Survival (24 h) Total Dose (mg/kg/day) BPR CAZ MEM Total Dose (mg/kg/day) BPR CAZ 0 0.75 0.75 0.75 0 3.3 3.3 3.125 -2.3 -0.07 -1.6 2.5 66.7 8.3 6.25 -3.2 -0.12 -2.4 5 95.8 12.5 12.5 -3.4 -0.53 -3.1 10 100 25 25 -3.6 -0.29 -3.4 20 100 37.5 50 -4.7 -2. 9 -3.9 40 100 58.3 Conclusion: Ceftobiprole was more efficacious than CAZ and at least as potent as MEM against Pseudomonas aeruginosa in the neutropenic thigh model. Ceftobiprole demonstrated superior activity compared to CAZ in this murine systemic infection model.

Eur J Med Chem, 1999

Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibi... more Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibitors of bacterial DNA-gyrase and mammalian topoisomerase II. Structure activity relationships of the compounds against each of the enzymes are discussed.

Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared... more Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared to meropenem/cilastatin (MEM), and piperacillin/tazobactam (TZP) in a Pseudomonas aeruginosa murine skin and soft-tissue infection model. Methods: Female Skh-1 immunocompromised mice were infected subcutaneously (sc) with Pseudomonas aeruginosa (PA) OC 4351 (wild type with an inducible Amp C β-lactamase) or PA OC 4354 (constitutive Amp C production) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion were determined. Results: In infections with the wild type strain, DOR resulted in improved killing over MEM by 0.5 to 0.7 log CFU/g skin tissue at doses of 6.2 to 100 mg/kg/day. Bacterial killing with DOR was also greater than MEM in PA 4354 by 0.4 to 1.3 log CFU/g skin tissue at doses of 1.6, 6.2 and 100 mg/kg. ...

Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-s... more Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-spectrum cephalosporin with anti-MRSA activity, was compared to cefazolin (CFZ), vancomycin (VAN), and linezolid (LZD) in a murine skin and soft-tissue infection model. Methods: Female Skh-1 mice were infected subcutaneously (sc) with S. aureus Smith (MSSA), or methicillin-resistant S. aureus OC 8525 (MRSA) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion was determined. Results: In MSSA, BPR achieved a >1.7 log reduction in CFU/g skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. This reduction was only achieved with CFZ at doses of 25 and 100 mg/kg/day and VAN at 100 mg/kg/day. At doses lower than 100 mg/kg/day, no reduction in bacterial burden was noted with VAN or LZD. In MR...

Background: Doripenem (DOR) is a carbapenem with potent broad spectrum activity including resista... more Background: Doripenem (DOR) is a carbapenem with potent broad spectrum activity including resistant gram-negative pathogens. As the increasing incidence of ESBL-producing gram-negative rods is a concern, the efficacy of DOR, imipenem (IPM) and meropenem (MEM) were evaluated in a murine lower respiratory infection model with an ESBL-producing (TEM-26) Klebsiella pneumoniae isolate. Methods: Mice were infected intranasally and dosed subcutaneously (sc) with 250 mg/kg DOR, IPM or MEM, given in divided doses q3h on day 0, followed by divided doses of 200 mg/kg on days 1 and 2. IPM and MEM were co-administered with cilastatin (1:1 ratio). Efficacy was assessed as a change in the bacterial burden in the lung. Lung sections were stained with Hematoxylin-Eosin to assess changes in lung pathology. Results: The change in log CFU (from untreated controls) after treatment are shown in the table below: Δ log CFU from untreated controls Time (h) DOR MEM IPM 0 0.00 0.00 0.00 1.5 0.10 0.10 0.18 6 -...

Background: Ceftobiprole (BPR) is a broad-spectrum investigational cephalosporin with in vitro an... more Background: Ceftobiprole (BPR) is a broad-spectrum investigational cephalosporin with in vitro and in vivo activity against gram-negative rods and gram-positive cocci, including methicillin-resistant S. aureus and Streptococcus pneumoniae. The efficacy of BPR, ceftriaxone (CRO) and penicillin (PEN) were evaluated in a murine lower respiratory infection model against four strains of S. pneumoniae. Methods: Mice were infected intranasally with four penicillin-susceptible strains of S. pneumoniae and dosed subcutaneously with BPR, CRO or PEN 18 and 24 h post-infection. Mortality was monitored for 48 h, and an ED50 (the dose resulting in 50% survival) was determined using the logistic function of the SAS statistical suite. Results: MIC values for all three drugs were similar, as seen in the Table. Based on ED50 values, BPR exhibited 11- to 50-fold greater efficacy than PEN against all strains and had similar or 4-fold greater efficacy than CRO. Strain Drug MIC (μg/ml) ED50 (mg/kg/day) (...

Background: Doripenem is an investigational carbapenem with potent activity against gram-negative... more Background: Doripenem is an investigational carbapenem with potent activity against gram-negative organisms including Pseudomonas aeruginosa. The activity of this agent was examined in a murine systemic infection model with three P. aeruginosa strains. Methods: In vivo efficacy in lethal systemic models was evaluated using the Syn-Phar P. aeruginosa strains OC4351, OC4352 and OC4354 [these strains were selected on ceftazidime (CAZ)] Six-week old female C3H- HeJ mice were infected intraperitoneally (ip) and dosed subcutaneously (sc) one and three h post-infection with doripenem (DOR), imipenem (IPM) or meropenem (MEM). Mice were monitored for 72 h and the number of surviving animals was used to determine the ED50 (the dose resulting in the survival of 50% of the mice). Results: MIC and ED50 values are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day) 4351 DOR 0.25 1.5 IPM 1 2.8 MEM 0.12 2.2 CAZ 1 >20 4352 DOR 0.25 1.1 IPM 1 2.3 MEM 0.25 1.1 CAZ 32 >20 4354 DOR ...

Background: Ceftobiprole (BPR) is an investigational anti-MRSA broad-spectrum cephalosporin with ... more Background: Ceftobiprole (BPR) is an investigational anti-MRSA broad-spectrum cephalosporin with activity against both gram-positive and gram-negative organisms. The activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was examined in a murine systemic infection model with E. coli, including two β-lactamase containing strains. Methods: In vivo efficacy in a lethal systemic model was evaluated using wild-type E. coli, or the isogenic E. coli isolates producing TEM-1 β-lactamase or the ACT-1 cephalosporinases. Mice were infected intraperiotoneally and dosed subcutaneously one and three h post-infection, with ceftobiprole (BPR), ceftazidime (CAZ), cefepime (FEP), imipenem-cilastatin (IPM) or meropenem-cilastatin (MEM). Results: ED50 (the dose resulting in the survival of 50% of the mice) and MIC values are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day ) 9040 BPR 0.03 0.5 (WT) CAZ 0.06 10.7 FEP <0.03 4.6 IPM 0.5 4.8 MEM 0.06 1.6 4367 BPR ...

Background: Doripenem (DOR) is an investigational carbapenem with a molecular structure that conf... more Background: Doripenem (DOR) is an investigational carbapenem with a molecular structure that confers β-lactamase stability and resistance to inactivation by human renal dehydropeptidases. The activity of this agent was examined in a murine systemic infection model with E. coli, including two β-lactamase containing strains. Methods: In vivo efficacy in lethal systemic models was evaluated using wild-type E. coli, or the isogenic strains containing TEM-1 or ACT-1 β-lactamases. Six-week old female Swiss-Webster mice were infected intraperitoneally (ip) and dosed subcutaneously (sc) one and three h post-infection with doripenem (DOR), ceftazidime (CAZ), cefepime (FEP), imipenem-cilastatin (IPM) or meropenem-cilastatin (MEM) Mortality was monitored for 3 days and the number of surviving animals was used to determine the ED50 (the dose resulting in the survival of 50% of the mice). Results: ED50 values and MIC’s are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day) 9040 D...

Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broa... more Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broad-spectrum cephalosporin with anti-MRSA and Gram-negative activity. The efficacy of this agent against P. aeruginosa was examined in two murine infection models. Methods: The neutropenic mouse thigh model was used to evaluate the BPR efficacy. Mice were made neutropenic with 2 ip injections of cyclophosphamide given 96 and 24 h prior to infection (150 and 100 mg/kg respectively). Animals were subsequently infected intramuscularly 5 x 105 CFU of P. aeruginosa OC4351, and dosed subcutaneously (sc) 1 and 3 h post-infection with ceftobiprole (BPR), Ceftazidime (CAZ), or Meropenem/cilastatin (MEM) (1:1ratio ). The bacterial load of the thigh muscle was determined 24-h post-infection. Efficacy was also evaluated in a lethal systemic infection model. Mice (n=24 in 3 experiments) were infected i.p. with P. aeruginosa OC4351 and dosed sc 1 and 3 h post-infection with BPR or CAZ. . The percent sur...

Background: Ceftobiprole medocaril (BPR) is an investigational broad-spectrum anti-MRSA cephalosp... more Background: Ceftobiprole medocaril (BPR) is an investigational broad-spectrum anti-MRSA cephalosporin. The activity of this agent was examined in two murine infection models. Methods: In vivo efficacy in lethal systemic models was evaluated using S. aureus Smith (MSSA), or a community acquired methicillin-resistant S. aureus (CA-MRSA). Mice were infected (ip) and dosed subcutaneously (sc) one and three h post-infection with ceftobiprole (BPR), cefazolin (CFZ), vancomycin (VAN) or linezolid (LNZ). Results: ED50 (the dose resulting in the survival of 50% of the mice) values and the corresponding fiducial limits are shown in the table below: ED50 in mg/kg/day Compound Route MSSA CA-MRSA BPR SC 0.19 (0.07-0.29) 4.9 (3.8-6.3) CFZ SC 0.37 (0.19-0.55) 21.9 (14.1-45.8) LNZ SC 7 (5.4-9.1) 3.7 (1.7-5.7) VAN SC 1.7 (0.9-2.9) 12.1 (10.1-14.6) In lethal systemic infection models, BPR was 2-fold more potent than CFZ, 9-fold more potent than VAN and 35-fold more potent than LNZ against MSSA. Again...

Antimicrobial agents and chemotherapy, Jan 11, 2016

Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacteria... more Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as it occurs in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI, and showed that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimics the severe infections that occur in humans, including the large central dermonecrotic core surrounded...

ABSTRACT Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was... more ABSTRACT Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared to meropenem/cilastatin (MEM), and piperacillin/tazobactam (TZP) in a Pseudomonas aeruginosa murine skin and soft-tissue infection model. Methods: Female Skh-1 immunocompromised mice were infected subcutaneously (sc) with Pseudomonas aeruginosa (PA) OC 4351 (wild type with an inducible Amp C β-lactamase) or PA OC 4354 (constitutive Amp C production) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion were determined. Results: In infections with the wild type strain, DOR resulted in improved killing over MEM by 0.5 to 0.7 log CFU/g skin tissue at doses of 6.2 to 100 mg/kg/day. Bacterial killing with DOR was also greater than MEM in PA 4354 by 0.4 to 1.3 log CFU/g skin tissue at doses of 1.6, 6.2 and 100 mg/kg. A similar reduction in CFU was noted for both drugs at a dose of 25 mg/kg/day. No decreases in the number of bacteria of either strain were observed with TZP treatment. DOR was also more effective in reducing the lesion volume at the infection site. In PA 4351 infections, DOR treatment resulted in a 7.2 to 8.4% greater reduction in lesion volume than MEM in a dose range of 6.2 to 100 mg/kg/day. Against PA 4354, DOR treatment resulted in a 14 to 29% greater reduction in lesion volume than MEM at doses of 1.6 to 100 mg/kg/day. Δ Log CFU/g Skin (from infecting inoculum) PA 4351 PA 4351 PA 4351 PA 4354 PA 4354 PA 4354 Dose (mg/kg/day) DOR MEM TZP DPR MEM TZP 0 1.5 1.5 1.5 1.5 1.5 1.5 1.6 0.3 0.2 1.7 -0.1 0.7 1.9 6.2 -0.4 0.2 2.0 -0.8 0.5 2.0 25 -1.2 -0.9 2.0 -0.9 -1.1 1.7 100 -1.5 -1.0 2.2 -1.5 -1.1 1.8 Conclusion: In a skin and soft-tissue infection model against PA 4351 and PA 4354, equivalent doses of DOR resulted in greater bacterial killing and smaller lesion volume than MEM or PIP.

Antimicrobial Agents and Chemotherapy, Apr 1, 2009

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against... more RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibioticsusceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two-to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log 10 at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log 10 (MSSA) and 2 log 10 (CA-MRSA). In the pneumococcal model, RWJ-416457 was two-to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC 24 ) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC 24 /MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.

Bioorganic Medicinal Chemistry Letters, Dec 15, 2006

A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate fo... more A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core. The best members of this series display in vitro and in vivo activity comparable to telithromycin. Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.

ABSTRACT Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigationa... more ABSTRACT Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-spectrum cephalosporin with anti-MRSA activity, was compared to cefazolin (CFZ), vancomycin (VAN), and linezolid (LZD) in a murine skin and soft-tissue infection model. Methods: Female Skh-1 mice were infected subcutaneously (sc) with S. aureus Smith (MSSA), or methicillin-resistant S. aureus OC 8525 (MRSA) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion was determined. Results: In MSSA, BPR achieved a &gt;1.7 log reduction in CFU/g skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. This reduction was only achieved with CFZ at doses of 25 and 100 mg/kg/day and VAN at 100 mg/kg/day. At doses lower than 100 mg/kg/day, no reduction in bacterial burden was noted with VAN or LZD. In MRSA infections, BPR showed similar or improved reduction in bacterial load at doses of 1.6 to 100 mg/kg/day over CFZ, VAN, and LZD. BPR was also more effective in reducing the lesion volume at the infection site compared to CFZ, LZD, and VAN in MSSA and MRSA infections with the exception of the 100 mg/kg/day dose of VAN. Δ Log CFU/g Skin (from infecting inoculum) MSSA MSSA MSSA MSSA MRSA MRSA MRSA MRSA Dose (mg/kg/day) BPR CFZ VAN LZD BPR CFZ VAN LZD 0 1.6 1.6 1.6 1.6 0.8 0.8 0.8 0.8 1.6 -1.0 0.9 1.5 1.4 0.3 0.8 1.5 0.4 6.2 -1.7 -0.6 1.6 0.6 -0.8 0.6 1.2 0 25 -2.0 -1.7 0.2 0.1 -1.3 -0.3 -0.7 -0.4 100 -1.7 -1.9 -3.1 -0.4 -1.4 -0.9 -1.4 -0.4 Conclusion: In a murine skin and soft-tissue infection model against MRSA, equivalent doses of BPR compared to CFZ, LZD, or VAN resulted in equal or greater killing activity. In this MSSA infection model, BPR at low doses was more effective than CFZ, LZD, or VAN.

ABSTRACT Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigati... more ABSTRACT Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broad-spectrum cephalosporin with anti-MRSA and Gram-negative activity. The efficacy of this agent against P. aeruginosa was examined in two murine infection models. Methods: The neutropenic mouse thigh model was used to evaluate the BPR efficacy. Mice were made neutropenic with 2 ip injections of cyclophosphamide given 96 and 24 h prior to infection (150 and 100 mg/kg respectively). Animals were subsequently infected intramuscularly 5 x 105 CFU of P. aeruginosa OC4351, and dosed subcutaneously (sc) 1 and 3 h post-infection with ceftobiprole (BPR), Ceftazidime (CAZ), or Meropenem/cilastatin (MEM) (1:1ratio ). The bacterial load of the thigh muscle was determined 24-h post-infection. Efficacy was also evaluated in a lethal systemic infection model. Mice (n=24 in 3 experiments) were infected i.p. with P. aeruginosa OC4351 and dosed sc 1 and 3 h post-infection with BPR or CAZ. . The percent survival at 24 h was examined. Results: The results of treatment in the neutropenic thigh model, expressed as the change in log CFU (from infecting inoculum), and the % survival in the systemic infection model are shown in the table below: Δ log CFU % Survival (24 h) Total Dose (mg/kg/day) BPR CAZ MEM Total Dose (mg/kg/day) BPR CAZ 0 0.75 0.75 0.75 0 3.3 3.3 3.125 -2.3 -0.07 -1.6 2.5 66.7 8.3 6.25 -3.2 -0.12 -2.4 5 95.8 12.5 12.5 -3.4 -0.53 -3.1 10 100 25 25 -3.6 -0.29 -3.4 20 100 37.5 50 -4.7 -2. 9 -3.9 40 100 58.3 Conclusion: Ceftobiprole was more efficacious than CAZ and at least as potent as MEM against Pseudomonas aeruginosa in the neutropenic thigh model. Ceftobiprole demonstrated superior activity compared to CAZ in this murine systemic infection model.

Eur J Med Chem, 1999

Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibi... more Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibitors of bacterial DNA-gyrase and mammalian topoisomerase II. Structure activity relationships of the compounds against each of the enzymes are discussed.

Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared... more Background: Doripenem (DOR), an investigational broad-spectrum parenteral carbapenem was compared to meropenem/cilastatin (MEM), and piperacillin/tazobactam (TZP) in a Pseudomonas aeruginosa murine skin and soft-tissue infection model. Methods: Female Skh-1 immunocompromised mice were infected subcutaneously (sc) with Pseudomonas aeruginosa (PA) OC 4351 (wild type with an inducible Amp C β-lactamase) or PA OC 4354 (constitutive Amp C production) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion were determined. Results: In infections with the wild type strain, DOR resulted in improved killing over MEM by 0.5 to 0.7 log CFU/g skin tissue at doses of 6.2 to 100 mg/kg/day. Bacterial killing with DOR was also greater than MEM in PA 4354 by 0.4 to 1.3 log CFU/g skin tissue at doses of 1.6, 6.2 and 100 mg/kg. ...

Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-s... more Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-spectrum cephalosporin with anti-MRSA activity, was compared to cefazolin (CFZ), vancomycin (VAN), and linezolid (LZD) in a murine skin and soft-tissue infection model. Methods: Female Skh-1 mice were infected subcutaneously (sc) with S. aureus Smith (MSSA), or methicillin-resistant S. aureus OC 8525 (MRSA) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion was determined. Results: In MSSA, BPR achieved a >1.7 log reduction in CFU/g skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. This reduction was only achieved with CFZ at doses of 25 and 100 mg/kg/day and VAN at 100 mg/kg/day. At doses lower than 100 mg/kg/day, no reduction in bacterial burden was noted with VAN or LZD. In MR...

Background: Doripenem (DOR) is a carbapenem with potent broad spectrum activity including resista... more Background: Doripenem (DOR) is a carbapenem with potent broad spectrum activity including resistant gram-negative pathogens. As the increasing incidence of ESBL-producing gram-negative rods is a concern, the efficacy of DOR, imipenem (IPM) and meropenem (MEM) were evaluated in a murine lower respiratory infection model with an ESBL-producing (TEM-26) Klebsiella pneumoniae isolate. Methods: Mice were infected intranasally and dosed subcutaneously (sc) with 250 mg/kg DOR, IPM or MEM, given in divided doses q3h on day 0, followed by divided doses of 200 mg/kg on days 1 and 2. IPM and MEM were co-administered with cilastatin (1:1 ratio). Efficacy was assessed as a change in the bacterial burden in the lung. Lung sections were stained with Hematoxylin-Eosin to assess changes in lung pathology. Results: The change in log CFU (from untreated controls) after treatment are shown in the table below: Δ log CFU from untreated controls Time (h) DOR MEM IPM 0 0.00 0.00 0.00 1.5 0.10 0.10 0.18 6 -...

Background: Ceftobiprole (BPR) is a broad-spectrum investigational cephalosporin with in vitro an... more Background: Ceftobiprole (BPR) is a broad-spectrum investigational cephalosporin with in vitro and in vivo activity against gram-negative rods and gram-positive cocci, including methicillin-resistant S. aureus and Streptococcus pneumoniae. The efficacy of BPR, ceftriaxone (CRO) and penicillin (PEN) were evaluated in a murine lower respiratory infection model against four strains of S. pneumoniae. Methods: Mice were infected intranasally with four penicillin-susceptible strains of S. pneumoniae and dosed subcutaneously with BPR, CRO or PEN 18 and 24 h post-infection. Mortality was monitored for 48 h, and an ED50 (the dose resulting in 50% survival) was determined using the logistic function of the SAS statistical suite. Results: MIC values for all three drugs were similar, as seen in the Table. Based on ED50 values, BPR exhibited 11- to 50-fold greater efficacy than PEN against all strains and had similar or 4-fold greater efficacy than CRO. Strain Drug MIC (μg/ml) ED50 (mg/kg/day) (...

Background: Doripenem is an investigational carbapenem with potent activity against gram-negative... more Background: Doripenem is an investigational carbapenem with potent activity against gram-negative organisms including Pseudomonas aeruginosa. The activity of this agent was examined in a murine systemic infection model with three P. aeruginosa strains. Methods: In vivo efficacy in lethal systemic models was evaluated using the Syn-Phar P. aeruginosa strains OC4351, OC4352 and OC4354 [these strains were selected on ceftazidime (CAZ)] Six-week old female C3H- HeJ mice were infected intraperitoneally (ip) and dosed subcutaneously (sc) one and three h post-infection with doripenem (DOR), imipenem (IPM) or meropenem (MEM). Mice were monitored for 72 h and the number of surviving animals was used to determine the ED50 (the dose resulting in the survival of 50% of the mice). Results: MIC and ED50 values are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day) 4351 DOR 0.25 1.5 IPM 1 2.8 MEM 0.12 2.2 CAZ 1 >20 4352 DOR 0.25 1.1 IPM 1 2.3 MEM 0.25 1.1 CAZ 32 >20 4354 DOR ...

Background: Ceftobiprole (BPR) is an investigational anti-MRSA broad-spectrum cephalosporin with ... more Background: Ceftobiprole (BPR) is an investigational anti-MRSA broad-spectrum cephalosporin with activity against both gram-positive and gram-negative organisms. The activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was examined in a murine systemic infection model with E. coli, including two β-lactamase containing strains. Methods: In vivo efficacy in a lethal systemic model was evaluated using wild-type E. coli, or the isogenic E. coli isolates producing TEM-1 β-lactamase or the ACT-1 cephalosporinases. Mice were infected intraperiotoneally and dosed subcutaneously one and three h post-infection, with ceftobiprole (BPR), ceftazidime (CAZ), cefepime (FEP), imipenem-cilastatin (IPM) or meropenem-cilastatin (MEM). Results: ED50 (the dose resulting in the survival of 50% of the mice) and MIC values are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day ) 9040 BPR 0.03 0.5 (WT) CAZ 0.06 10.7 FEP <0.03 4.6 IPM 0.5 4.8 MEM 0.06 1.6 4367 BPR ...

Background: Doripenem (DOR) is an investigational carbapenem with a molecular structure that conf... more Background: Doripenem (DOR) is an investigational carbapenem with a molecular structure that confers β-lactamase stability and resistance to inactivation by human renal dehydropeptidases. The activity of this agent was examined in a murine systemic infection model with E. coli, including two β-lactamase containing strains. Methods: In vivo efficacy in lethal systemic models was evaluated using wild-type E. coli, or the isogenic strains containing TEM-1 or ACT-1 β-lactamases. Six-week old female Swiss-Webster mice were infected intraperitoneally (ip) and dosed subcutaneously (sc) one and three h post-infection with doripenem (DOR), ceftazidime (CAZ), cefepime (FEP), imipenem-cilastatin (IPM) or meropenem-cilastatin (MEM) Mortality was monitored for 3 days and the number of surviving animals was used to determine the ED50 (the dose resulting in the survival of 50% of the mice). Results: ED50 values and MIC’s are shown in the table below: Strain Drug MIC (μg/ml) ED50 (mg/kg/day) 9040 D...

Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broa... more Background: Ceftobiprole medocaril (BPR), the prodrug of ceftobiprole, is an investigational broad-spectrum cephalosporin with anti-MRSA and Gram-negative activity. The efficacy of this agent against P. aeruginosa was examined in two murine infection models. Methods: The neutropenic mouse thigh model was used to evaluate the BPR efficacy. Mice were made neutropenic with 2 ip injections of cyclophosphamide given 96 and 24 h prior to infection (150 and 100 mg/kg respectively). Animals were subsequently infected intramuscularly 5 x 105 CFU of P. aeruginosa OC4351, and dosed subcutaneously (sc) 1 and 3 h post-infection with ceftobiprole (BPR), Ceftazidime (CAZ), or Meropenem/cilastatin (MEM) (1:1ratio ). The bacterial load of the thigh muscle was determined 24-h post-infection. Efficacy was also evaluated in a lethal systemic infection model. Mice (n=24 in 3 experiments) were infected i.p. with P. aeruginosa OC4351 and dosed sc 1 and 3 h post-infection with BPR or CAZ. . The percent sur...

Background: Ceftobiprole medocaril (BPR) is an investigational broad-spectrum anti-MRSA cephalosp... more Background: Ceftobiprole medocaril (BPR) is an investigational broad-spectrum anti-MRSA cephalosporin. The activity of this agent was examined in two murine infection models. Methods: In vivo efficacy in lethal systemic models was evaluated using S. aureus Smith (MSSA), or a community acquired methicillin-resistant S. aureus (CA-MRSA). Mice were infected (ip) and dosed subcutaneously (sc) one and three h post-infection with ceftobiprole (BPR), cefazolin (CFZ), vancomycin (VAN) or linezolid (LNZ). Results: ED50 (the dose resulting in the survival of 50% of the mice) values and the corresponding fiducial limits are shown in the table below: ED50 in mg/kg/day Compound Route MSSA CA-MRSA BPR SC 0.19 (0.07-0.29) 4.9 (3.8-6.3) CFZ SC 0.37 (0.19-0.55) 21.9 (14.1-45.8) LNZ SC 7 (5.4-9.1) 3.7 (1.7-5.7) VAN SC 1.7 (0.9-2.9) 12.1 (10.1-14.6) In lethal systemic infection models, BPR was 2-fold more potent than CFZ, 9-fold more potent than VAN and 35-fold more potent than LNZ against MSSA. Again...