scholarly journals Efficacy of Human Simulated Exposures of Ceftaroline Administered at 600 Milligrams Every 12 Hours against Phenotypically Diverse Staphylococcus aureus Isolates

2011 ◽  
Vol 55 (9) ◽  
pp. 4028-4032 ◽  
Author(s):  
Rebecca A. Keel ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Clinical Utility ◽  
Immune Status ◽  
Bacterial Density ◽  
Immunocompetent Mouse ◽  
Content Type ◽  
Drug Concentrations ◽  
Infection Models ◽  
Model Independent ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA)Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline againstS. aureusin both the neutropenic and immunocompetent mouse thigh infection models. Twenty-sixS. aureusisolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log10CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log10CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log10CFU/ml reduction (log10CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all testedS. aureusisolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline againstS. aureus, including MRSA, with MICs of ≤4 μg/ml.

scholarly journals Efficacy of Human Simulated Exposures of Ceftaroline against Phenotypically Diverse Enterobacteriaceae Isolates

2012 ◽  
Vol 56 (5) ◽  
pp. 2576-2580 ◽  
Author(s):  
Seth T. Housman ◽  
Rebecca A. Keel ◽  
Jared L. Crandon ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Clinical Utility ◽  
Similar Efficacy ◽  
Immunocompetent Mouse ◽  
Ceftaroline Fosamil ◽  
Gram Negative ◽  
Content Type ◽  
Infection Models

ABSTRACTCeftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, includingEnterobacteriaceae, and Gram-positive pathogens, including methicillin-resistantStaphylococcus aureusand penicillin-resistantStreptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinicalEnterobacteriaceaein both neutropenic and immunocompetent mouse thigh infection models. Thirty-fiveEnterobacteriaceaeisolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and fiveEscherichia coliisolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log10CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy againstEnterobacteriaceaewith MICs of ≤1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

scholarly journals Human Simulated Studies of Aztreonam and Aztreonam-Avibactam To Evaluate Activity against Challenging Gram-Negative Organisms, Including Metallo-β-Lactamase Producers

2013 ◽  
Vol 57 (7) ◽  
pp. 3299-3306 ◽  
Author(s):  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Free Drug ◽  
Bacterial Density ◽  
Infection Model ◽  
Bacterial Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Drug Concentrations ◽  
Gram Negative Organisms ◽  
The Stability ◽  
Immunocompetent Mice

ABSTRACTSecondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-β-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14Enterobacteriaceaeand 13Pseudomonas aeruginosaisolates, of which 25 produced metallo-β-lactamases. Additionally, sixP. aeruginosaisolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of theEnterobacteriaceaebacterial isolates (aztreonam MIC, ≤32 μg/ml;fT>MIC, ≥38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥128 μg/ml;fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14Enterobacteriaceaeisolates (aztreonam-avibactam MICs, ≤16 μg/ml;fT>MIC, ≥65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity againstP. aeruginosawas noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤16 μg/ml and variable efficacy noted when the MICs were ≥32 μg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.

scholarly journals Comparative Efficacies of Human Simulated Exposures of Tedizolid and Linezolid against Staphylococcus aureus in the Murine Thigh Infection Model

2012 ◽  
Vol 56 (8) ◽  
pp. 4403-4407 ◽  
Author(s):  
R. A. Keel ◽  
P. R. Tessier ◽  
J. L. Crandon ◽  
D. P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Density ◽  
Infection Model ◽  
Immunocompetent Mouse ◽  
Time Curve ◽  
Free Concentration ◽  
Content Type ◽  
The Mean

ABSTRACTTedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhancedin vitropotency against Gram-positive pathogens, including methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA). The efficacies of human simulated exposures of tedizolid and linezolid againstS. aureusin an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 μg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similarin vivoefficacies against theS. aureusisolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused byS. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

scholarly journals ComparativeIn VivoEfficacies of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid, and Vancomycin for Methicillin-Resistant Staphylococcus aureus in a Mouse Pneumonia Model

2012 ◽  
Vol 56 (5) ◽  
pp. 2342-2346 ◽  
Author(s):  
Pamela R. Tessier ◽  
Rebecca A. Keel ◽  
Mao Hagihara ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Bacterial Density ◽  
Epithelial Lining ◽  
Control Groups ◽  
Epithelial Lining Fluid ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups

ABSTRACTThe antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistantStaphylococcus aureus(MRSA) were compared in anin vivomouse 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.

scholarly journals In VitroPharmacodynamics of Vancomycin and Cefazolin Alone and in Combination against Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 56 (1) ◽  
pp. 202-207 ◽  
Author(s):  
Mao Hagihara ◽  
Dora E. Wiskirchen ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Synergistic Effects ◽  
Bacterial Density ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Mics ◽  
Time Kill

ABSTRACTPrevious studies employing time-kill methods have observed synergistic effects against methicillin-resistantStaphylococcus aureus(MRSA) when a β-lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. Four clinical isolates (two MRSA isolates [vancomycin MICs, 0.5 and 2.0 μg/ml], a heterogeneous vancomycin-intermediateS. aureus[hVISA] isolate [MIC, 2.0 μg/ml], and a vancomycin-intermediateS. aureus[VISA] isolate [MIC, 8.0 μg/ml]) were evaluated in anin vitropharmacodynamic model with a starting inoculum of 106or 108CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 106CFU/ml studies, combination therapy achieved greater log10CFU/ml changes than vancomycin alone at 12 h (−4.31 ± 0.58 versus −2.80 ± 0.59,P< 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ± 14) compared with vancomycin alone (148 ± 22,P= 0.017). Similar results were observed during 108CFU/ml studies, where combination therapy achieved greater log10CFU/ml changes at 12 h than vancomycin alone (−4.00 ± 0.20 versus −1.10 ± 0.04,P< 0.001) and significantly reduced the AUBC (275 ± 30 versus 429 ± 37,P< 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments.

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

2014 ◽  
Vol 59 (1) ◽  
pp. 299-309 ◽  
Author(s):  
Jamese J. Hilliard ◽  
Vivekananda Datta ◽  
Christine Tkaczyk ◽  
Melissa Hamilton ◽  
Agnieszka Sadowska ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Soft Tissue ◽  
Single Agent ◽  
Alpha Toxin ◽  
Tissue Necrosis ◽  
Content Type ◽  
Infection Models ◽  
Neutralizing Monoclonal Antibody ◽  
Treatment Window

ABSTRACTAlpha-toxin (AT) is a major virulence determinant inStaphylococcus aureusskin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), preventsS. aureusdisease 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 ofS. aureusskin and soft tissue infections.

scholarly journals Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Lung Model ◽  
Maximum Effect ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Content Type ◽  
Infection Models

ABSTRACT The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.

scholarly journals Efficacy of Ceftaroline Fosamil in a Staphylococcal Murine Pneumonia Model

2012 ◽  
Vol 56 (12) ◽  
pp. 6160-6165 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Jared L. Crandon ◽  
Donald Biek ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Infection Model ◽  
Ceftaroline Fosamil ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Human Dose ◽  
Drug Concentrations ◽  
Exposure Profile ◽  
Dose Ranging ◽  
Relationship Of

ABSTRACTCeftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistantStaphylococcus aureus(MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil againstS. aureusin an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. SeventeenS. aureus(2 methicillin-susceptibleStaphylococcus aureus[MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. SerumfT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log10kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log10CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, thefT>MICs required for stasis and a 1-log10kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serumfT>MIC targets required in this lung infection model were similar to those observed with ceftaroline againstS. aureusin a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.

scholarly journals Identification of the In Vivo Pharmacokinetics and Pharmacodynamic Driver of Iclaprim

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Jee Hyun Park ◽  
William Craig ◽  
Karen Marchillo ◽  
David B. Huang ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Area Under The Curve ◽  
Infection Model ◽  
Content Type ◽  
Drug Concentrations ◽  
In Vivo Pharmacokinetics

ABSTRACT The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against Staphylococcus aureus ATCC 29213 and Staphylococcus pneumoniae ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for S. aureus ( R 2 , 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (% T >MIC) were strongly associated with effect ( R 2 , 0.86 for both parameters) for S. pneumoniae .

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