In Vivo Activity of the Pyrrolopyrazolyl-Substituted Oxazolidinone RWJ-416457

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c Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

Section: Discussionmentioning

confidence: 86%

Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Hilliard¹,

Datta²,

Tkaczyk³

et al. 2015

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“…The animals received ceftobiprole medocaril, cefazolin, vancomycin, or linezolid 1, 3, 25, and 27 h postinfection at a dose of 1.6, 6.2, 25, or 100 mg/kg/day. All drugs were delivered subcutaneously except for linezolid, which was given orally because of the equivalent bioavailability of linezolid (subcutaneous versus oral) against MSSA and MRSA in a mouse septicemia model (31).…”

Section: Methodsmentioning

confidence: 99%

In Vivo Activity of Ceftobiprole in Murine Skin Infections Due to Staphylococcus aureus and Pseudomonas aeruginosa

Fernandez

Hilliard

Abbanat

et al. 2010

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In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8-and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC ␤-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

“…To study the comparative efficacies of JNJ-Q2, moxifloxacin, and gemifloxacin in a murine lower respiratory tract infection model (14,16), female CF-1 mice were briefly anesthetized with isoflurane and infected by placing 50 l of S. pneumoniae ATCC 6301 (approximately 1 ϫ 10 8 CFU/mouse) at the tip of the nares and allowing the mouse to inhale the inoculum. Mice were then treated subcutaneously or orally once at 24 h postinfection, and mortality was monitored over 2 days.…”

mentioning

confidence: 99%

“…To study the comparative efficacies of JNJ-Q2, linezolid, and vancomycin against S. aureus in an acute skin infection model (13,14,16), female SKH1 mice were anesthetized with isoflurane and given a 0.2-ml subcutaneous (s.c.) injection of a Cytodex bead inoculum containing S. aureus (CA-MRSA OC 8525) (approximately 7 ϫ 10 6 CFU/mouse flank) on the left and right flanks. Animals received JNJ-Q2, linezolid, or vancomycin at 1, 3, 25, and 27 h postinfection at a dose of 1.6, 6.2, 25, or 100 mg/kg of body weight/day.…”

mentioning

confidence: 99%

“…To study the comparative efficacies of JNJ-Q2, ciprofloxacin, moxifloxacin, and gemifloxacin in the mouse septicemia model (14,16) CFU/mouse, 10ϫ to 100ϫ the LD 50 ) and then treated either subcutaneously or orally for 1 h (JNJ-Q2) or 1 and 3 h (comparators) postinfection, and mortality was monitored for 3 days. The dosing regimen (once a day [QD] versus twice a day [BID]) was determined from pilot studies conducted in the mouse septicemia model (data not shown).…”

mentioning

confidence: 99%

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Efficacy of a New Fluoroquinolone, JNJ-Q2, in Murine Models of Staphylococcus aureus and Streptococcus pneumoniae Skin, Respiratory, and Systemic Infections

Fernandez¹,

Hilliard²,

Morrow³

et al. 2011

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The in vivo efficacy of JNJ-Q2, a new broad-spectrum fluoroquinolone (FQ), was evaluated in a murine septicemia model with methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) and in a Streptococcus pneumoniae lower respiratory tract infection model. JNJ-Q2 and comparators were also evaluated in an acute murine skin infection model using a community-acquired MRSA strain and in an established skin infection (ESI) model using a hospital-acquired strain, for which the selection of resistant mutants was also determined. JNJ-Q2 demonstrated activity in the MSSA septicemia model that was comparable to that moxifloxacin (JNJ-Q2 50% effective dose [ED 50 Successive improvements in the spectrum and antimicrobial potency of agents in the fluoroquinolone class have resulted in widespread clinical utility of these agents, and the activities of levofloxacin and moxifloxacin against Gram-positive pathogens, particularly Streptococcus pneumoniae, have contributed to the adoption of these agents for the empirical treatment of respiratory tract infections in the community setting. Although fluoroquinolone resistance in S. pneumoniae remains low, with the rate of levofloxacin resistance in U.S. isolates typically reported at less than 1% (12), the rate of fluoroquinolone resistance has, in selected populations or geographic regions, been reported to be greater than 10% (1). In association with the introduction of the seven-valent pneumococcal vaccine (PCV7), an increased prevalence in non-PCV7 serotypes has been observed (11, 12), including several predominant fluoroquinolone-resistant and multidrug-resistant clones (4, 10). Several of the marketed fluoroquinolone agents also display in vitro activity against Staphylococcus aureus isolates and have been used successfully to treat staphylococcal infections (31), although none of these marketed agents are approved for the treatment of methicillin-resistant S. aureus (MRSA) infections. MRSA has become an increasingly important pathogen in community infections (19), and the increased incidence of infection is associated with elevated resistance, with levofloxacin resistance observed in 70% of recent U.S. clinical MRSA isolates (18). Community staphylococcal isolates typically express elevated levels of several virulence determinants, which are associated with increased virulence in murine models of bacteremia and skin abscess infection (20). Efficacy in murine models of MRSA infection is a key attribute for new antibacterial agents targeted for the treatment of staphylococcal infections, including MRSA infections in the community setting. Several investigational fluoroquinolones active against MRSA (2,5,15,17,32) are reported to be the subject of ongoing clinical studies that are investigating their efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by MRSA. The development of new fluoroquinolone agents retaining activity against multidrug-resistant S. pneumoniae isolates and displaying potent a...