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 In VivoPharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus

2016 ◽  
Vol 60 (6) ◽  
pp. 3626-3632 ◽  
Author(s):  
A. J. Lepak ◽  
P. Seiler ◽  
J. P. Surivet ◽  
D. Ritz ◽  
C. Kohl ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Dose Range ◽  
Free Drug ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Time Curve ◽  
Content Type ◽  
Phenotypic Resistance

ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistantStaphylococcus aureusand penicillin- and fluoroquinolone-resistantStreptococcus pneumoniae. We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10S. aureusandS. pneumoniaeisolates with phenotypic resistance to beta-lactams and fluoroquinolones. Thein vitroactivities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 107.4to 108CFU/thigh at the start of therapy with ACT-387042 and 106.7to 108.3CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R2, 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 againstS. aureusandS. pneumoniaewere 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 againstS. aureusandS. pneumoniaewere 69 and 25, respectively. The stasis PD targets were significantly lower forS. pneumoniae(P< 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

scholarly journals Posaconazole Pharmacodynamic Target Determination against Wild-Type andCyp51Mutant Isolates of Aspergillus fumigatus in anIn VivoModel of Invasive Pulmonary Aspergillosis

2012 ◽  
Vol 57 (1) ◽  
pp. 579-585 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jaimie VanHecker ◽  
David R. Andes
Keyword(s):  
Dose Range ◽  
Invasive Pulmonary Aspergillosis ◽  
Free Drug ◽  
Lung Homogenate ◽  
Study Endpoint ◽  
Pharmacokinetic Data ◽  
Wild Type ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10A. fumigatusisolates, including 4Cyp51wild-type isolates and 6 isolates carryingCyp51mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 ± 0.19 log10Aspergillusconidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log10CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ± 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ± 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.

scholarly journals Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

2012 ◽  
Vol 56 (11) ◽  
pp. 5916-5922 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Solen Pichereau ◽  
William A. Craig ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Active Form ◽  
Maximum Effect ◽  
Time Curve ◽  
Content Type ◽  
Dosing Regimens ◽  
Staphylococcus Aureus Pneumonia ◽  
Unit Reduction

ABSTRACTTedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potentStaphylococcus aureusactivity. The current studies characterized and compared thein vivopharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptibleS. aureus(MSSA) and methicillin-resistantS. aureus(MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates ofS. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log10CFU/lungs, which increased to 7.92 ± 1.02 log10CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (Emax) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.

scholarly journals Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Catharine C. Bulik ◽  
Ólanrewaju O. Okusanya ◽  
Elizabeth A. Lakota ◽  
Alan Forrest ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Drug Plasma ◽  
Infection Models

ABSTRACT Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log10 CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (C max) to the MIC (C max/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r 2 = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

scholarly journals Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model against Staphylococcus aureus and Streptococcus pneumoniae

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Qingmei Liu ◽  
Ping Wang ◽  
Yanli Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Rational Design ◽  
Dose Range ◽  
Free Drug ◽  
Pharmacokinetic Parameters ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT KBP-7072 is a novel aminomethylcycline antibiotic in clinical development for community-acquired pneumonia. The goal of present studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter magnitude correlated with efficacy in the murine pneumonia infection model against Staphylococcus aureus and Streptococcus pneumoniae. KBP-7072 pharmacokinetic measurements were performed in plasma and epithelial lining fluid (ELF) at 4-fold-increasing doses from 1 to 256 mg/kg of body weight subcutaneously. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 82% to 238% comparing ELF drug concentrations to plasma free drug concentrations. Twenty-four-hour dose-ranging efficacy studies were then performed in the neutropenic murine pneumonia model against 5 S. aureus (3 methicillin-resistant and 2 methicillin-susceptible) and 6 S. pneumoniae (2 Tetr and 2 Penr) strains. KBP-7072 demonstrated potent in vivo activity resulting in a 3- to 5-log10 kill in CFU burden compared to the start of therapy for all strains. The PK/PD index area under the concentration-time curve (AUC)/MIC corelated well with efficacy (R2, 0.80 to 0.89). Net stasis was achieved at plasma 24-h free drug AUC/MIC values of 1.13 and 1.41 (24-h ELF AUC/MIC values of 2.01 and 2.50) for S. aureus and S. pneumoniae, respectively. A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 2.59 and 5.67 (24-h ELF AUC/MIC values of 4.22 and 10.08) for S. aureus and S. pneumoniae, respectively. A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 7.16 and 31.14 (24-h ELF AUC/MIC values of 8.37 and 42.92) for S. aureus and S. pneumoniae, respectively. The results of these experiments will aid in the rational design of dose-finding studies for KBP-7072 in patients with community-acquired bacterial pneumonia (CAP).

scholarly journals In VivoActivity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

2014 ◽  
Vol 58 (10) ◽  
pp. 5943-5946 ◽  
Author(s):  
Qi Shan ◽  
Chaoping Liang ◽  
Jing Wang ◽  
Jufeng Li ◽  
Zhenling Zeng
Keyword(s):  
Escherichia Coli ◽  
Dose Range ◽  
Serum Levels ◽  
Free Drug ◽  
Dose Fractionation ◽  
Maximum Effect ◽  
Time Curve ◽  
Content Type ◽  
E Coli ◽  
Liquid Chromatography Tandem Mass

ABSTRACTCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such asEscherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT>MIC) was the PK-PD index that best correlated with efficacy (R2= 73% forE. coli, compared with 13% for the maximum concentration of the free drug in serum [fCmax]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC0-24]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additionalE. coliisolates. A sigmoid maximum-effect (Emax) model was used to estimate the magnitudes of the %fT>MICassociated with net bacterial stasis, a 1-log10CFU reduction from baseline, and a 2-log10CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused byE. coli.

scholarly journals In VivoPharmacokinetics and Pharmacodynamics of the Lantibiotic NAI-107 in a Neutropenic Murine Thigh Infection Model

2014 ◽  
Vol 59 (2) ◽  
pp. 1258-1264 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
William A. Craig ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Dose Fractionation ◽  
Coefficient Of Determination ◽  
Maximum Effect ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Response Curves ◽  
Time Curve ◽  
Content Type

ABSTRACTNAI-107 is a novel lantibiotic compound with potentin vitroactivity against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA). The purpose of this study was to examine the activity of NAI-107 againstS. aureusstrains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose fractionation included total doses ranging from 1.56 to 400 mg/kg/72 h, divided into 1, 2, 3, or 6 doses. Studies of treatment effects against 9S. aureusstrains (4 methicillin-susceptibleStaphylococcus aureus[MSSA] and 5 MRSA) using a 12-h dosing interval and total dose range of 1.56 to 400 mg/kg/72 h were also performed. A maximum effect (Emax) model was used to determine the pharmacokinetic/pharmacodynamic (PK/PD) index that best described the dose-response data and to estimate the doses required to achieve a net bacteriostatic dose (SD) and a 1-log reduction in CFU/thigh. The pharmacokinetic studies demonstrated an area under the concentration-time curve (AUC) range of 26.8 to 276 mg · h/liter and half-lives of 4.2 to 8.2 h. MICs ranged from 0.125 to 0.5 μg/ml. The 2 highest single doses produced more than a 2-log kill and prolonged postantibiotic effects (PAEs) ranging from 36 to >72 h. The dose fractionation-response curves were similar, and the AUC/MIC ratio was the most predictive PD index (AUC/MIC, coefficient of determination [R2] = 0.89; maximum concentration of drug in serum [Cmax]/MIC,R2= 0.79; time [T] > MIC,R2= 0.63). A ≥2-log kill was observed against all 9S. aureusstrains. The total drug 24-h AUC/MIC values associated with stasis and a 1-log kill for the 9S. aureusstrains were 371 ± 130 and 510 ± 227, respectively. NAI-107 demonstrated concentration-dependent killing and prolonged PAEs. The AUC/MIC ratio was the predictive PD index. Extensive killing was observed forS. aureusorganisms, independent of the MRSA status. The AUC/MIC target should be useful for the design of clinical dosing regimens.

scholarly journals Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

2006 ◽  
Vol 50 (4) ◽  
pp. 1376-1383 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Beta Lactam ◽  
Gram Negative ◽  
Infection Models

ABSTRACT PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either S. pneumoniae or E. coli. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (R 2 = 84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug %T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of S. pneumoniae, four isolates of S. aureus, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log10 CFU/thigh. MICs ranged from 0.008 to 1 μg/ml. Mean free-drug %T>MICs ± the standard deviation associated with the static effect endpoint for S. pneumoniae, S. aureus, and gram-negative isolates were 39 ± 9, 26 ± 8, and 32 ± 6, respectively. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.

scholarly journals In Vivo Pharmacodynamics of Ceftobiprole against Multiple Bacterial Pathogens in Murine Thigh and Lung Infection Models

2008 ◽  
Vol 52 (10) ◽  
pp. 3492-3496 ◽  
Author(s):  
W. A. Craig ◽  
D. R. Andes
Keyword(s):  
Serum Levels ◽  
Lung Infection ◽  
Lung Model ◽  
Dose Fractionation ◽  
Time Curve ◽  
Gram Negative ◽  
Infection Models ◽  
Bactericidal Activities

ABSTRACT Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log10 kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 μg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new β-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

scholarly journals Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (11) ◽  
pp. 5325-5330 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Antoine Deslandes ◽  
Astrid Rey ◽  
Laurent Fraisse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Maximum Effect ◽  
Peptide Antibiotic ◽  
Time Curve ◽  
Cationic Antimicrobial Peptide ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

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