scholarly journals Pharmacodynamics of Fluconazole in a Murine Model of Systemic Candidiasis

1998 ◽  
Vol 42 (5) ◽  
pp. 1105-1109 ◽  
Author(s):  
Arnold Louie ◽  
George L. Drusano ◽  
Partha Banerjee ◽  
Qing-Feng Liu ◽  
Weiguo Liu ◽  
...  
Keyword(s):  
Total Dose ◽  
Murine Model ◽  
Dose Fractionation ◽  
Maximal Effect ◽  
Systemic Candidiasis ◽  
Pharmacodynamic Parameter ◽  
Dose Response Relationship ◽  
Time Curve ◽  
Dose Ranging ◽  
Fractionation Schedules

ABSTRACT In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicansinfections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (E max) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (C max) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicansisolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

scholarly journals Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity

2005 ◽  
Vol 49 (12) ◽  
pp. 5058-5068 ◽  
Author(s):  
Arnold Louie ◽  
Mark Deziel ◽  
Weiguo Liu ◽  
Michael F. Drusano ◽  
Tawanda Gumbo ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Murine Model ◽  
Dose Fractionation ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Systemic Candidiasis ◽  
Serum Concentrations ◽  
Pharmacodynamic Parameter ◽  
Concentration Time ◽  
Drug Concentrations

ABSTRACT Pharmacokinetic and pharmacodynamic studies were conducted in a murine model of systemic candidiasis to determine the pharmacodynamic parameter linked with caspofungin efficacy. Additional studies defined the importance of persistent tissue drug concentrations to treatment outcome. The pharmacokinetics of caspofungin were determined in the serum and kidneys of infected mice over 96 h. Population pharmacokinetic analysis demonstrated a serum terminal half-life (t 1/2) for caspofungin of 20.2 h when only serum concentrations were considered, but the terminal t 1/2 increased to 59.2 h when serum and kidney concentration-time data were comodeled. In dose-range studies, the dose-response effect was well described by an inhibitory sigmoid curve for the exposure-effect killing caused by the drug (r 2 > 0.96; P ≪ 0.001). In dose-fractionation studies, fungal counts in kidneys were not statistically different for total doses given as one, two, or four equally divided doses over 96 h, indicating that the area under the concentration-time curve/MIC is the pharmacodynamic parameter that predicts caspofungin efficacy in our infection model. In a separate study, mice infected with Candida albicans 24 h after serum concentrations of caspofungin fell below the MIC for the fungal isolate had significant reductions in fungal densities in their kidneys compared with the growth of fungi in the kidneys of untreated controls (P = 0.005). This in vivo biological assay demonstrates that therapeutic concentrations of caspofungin persist at the site of infection in kidney tissue well after serum concentrations fall below the MIC, underscoring the primacy of caspofungin levels in tissues on determining treatment outcome.

scholarly journals Pharmacodynamics of the Novel Metallo-β-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Shampa Das ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Nicola Farrington ◽  
Adam Kirby ◽  
...  
Keyword(s):  
Zinc Ion ◽  
Dose Fractionation ◽  
Maximal Effect ◽  
The Novel ◽  
Time Curve ◽  
3 Dimensional ◽  
Combined Use ◽  
Dose Ranging ◽  
Pharmacodynamic Data ◽  
Lactamase Inhibitor

ABSTRACT Enterobacteriaceae that produce metallo-β-lactamases (MBLs) are an emerging threat to public health. The metallo-β-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner β-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae. Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

scholarly journals Pharmacodynamic Evaluation of MRX-8, a Novel Polymyxin, in the Neutropenic Mouse Thigh and Lung Infection Models against Gram-Negative Pathogens

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Alexander J. Lepak ◽  
Wen Wang ◽  
David R. Andes
Keyword(s):  
Polymyxin B ◽  
Lung Model ◽  
Dose Fractionation ◽  
Time Curve ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Infection Models ◽  
Dose Ranging

ABSTRACT MRX-8 is a novel polymyxin analogue in development for the treatment of infections caused by Gram-negative pathogens, including those resistant to other antibiotic classes. In the present study, we examined the pharmacodynamic activity of MRX-8 against a variety of common Gram-negative pathogens in the neutropenic mouse thigh and lung models. Additionally, we examined polymyxin B (PMB) as a comparator. Plasma pharmacokinetics of MRX-8 and PMB were linear over a broad dosing range of 0.156 to 10 mg/kg of body weight and had similar AUC0–∞ (area under the drug concentration-time curve from 0 h to infinity) exposures of MRX-8, 0.22 to 12.64 mg · h/liter, and PMB, 0.12 to 13.22 mg · h/liter. Dose fractionation was performed for MRX-8 using a single Escherichia coli isolate, and the results demonstrated that both Cmax (maximum concentration of drug in serum)/MIC and AUC/MIC ratios were strongly associated with efficacy. In the thigh model, dose-ranging studies included strains of E. coli (n = 3), Pseudomonas aeruginosa (n = 2), Klebsiella pneumoniae (n = 3), and Acinetobacter baumannii (n = 1). Both MRX-8 and PMB exhibited increased effects with increasing doses. MRX-8 and PMB free AUC/MIC exposures for net stasis were similar for E. coli and K. pneumoniae at 20 to 30. Notably, for P. aeruginosa and A. baumannii, the free AUC/MIC ratio for stasis was numerically much smaller for MRX-8 at 6 to 8 than for PMB at 16 to 37. In the lung model, MRX-8 was also more effective than PMB when dosed to achieve similar free-drug AUC exposures over the study period. MRX-8 is a promising novel polymyxin analogue with in vivo activity against many different clinically relevant species in both the mouse thigh and lung models.

scholarly journals Pharmacodynamics of β-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of β-Lactamases

2011 ◽  
Vol 56 (1) ◽  
pp. 258-270 ◽  
Author(s):  
Arnold Louie ◽  
Mariana Castanheira ◽  
Weiguo Liu ◽  
Caroline Grasso ◽  
Ronald N. Jones ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Cell ◽  
Dose Fractionation ◽  
Infection Model ◽  
Dosing Regimen ◽  
Time Curve ◽  
Content Type ◽  
Cell Kill ◽  
Successful Clinical Outcome ◽  
Dose Ranging

ABSTRACTNew broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of β-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined β-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains ofKlebsiella pneumoniaeand one isolate ofEnterobacter cloacae. K. pneumoniae27-908M carried KPC-2, SHV-27, and TEM-1 β-lactamases. Its isogenic mutant,K. pneumoniae4207J, was “cured” of the plasmid expressing the KPC-2 enzyme.K. pneumoniae24-1318A carried a CTX-M-15 enzyme, andE. cloacae2-77C expressed a stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that “time > threshold” was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.

scholarly journals Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis

2000 ◽  
Vol 44 (9) ◽  
pp. 2333-2340 ◽  
Author(s):  
P. Aviles ◽  
C. Falcoz ◽  
R. San Roman ◽  
D. Gargallo-Viola
Keyword(s):  
Murine Model ◽  
Therapeutic Efficacy ◽  
Elongation Factor ◽  
Systemic Candidiasis ◽  
Dose Selection ◽  
Time Curve ◽  
Animal Therapy ◽  
Kaplan Meier ◽  
Drug Concentrations

ABSTRACT Sordarins are a new class of antifungal agents which selectively inhibit fungal protein synthesis (FPS) by impairing the function of elongation factor 2. The present study investigates possible correlations between sordarin pharmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose selection in the first study of efficacy in humans. A significant correlation between PK parameters and the in vivo activity of GM 237354, taken as a representative FPS inhibitor, was demonstrated in a murine model of lethal systemic candidiasis. Area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C max) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in healthy animals (no significant PK changes with infection were observed for other sordarin derivatives). These results have been used to simulate PK profiles obtained after several doses and/or schedules in animal therapy. A PK-pharmacodynamic (PD) parameter such as the time that serum drug concentrations remain above the MIC (t> MIC) was also determined. Treatment efficacies were evaluated in terms of the area under the survival time curve (AUSTC), using Kaplan-Meier survival analysis and in terms of kidney fungal burden (log CFU/gram) after s.c. doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg). The results show all treatments to significantly prolong survival versus that of infected and nontreated controls (P < 0.05). Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but notC max or t > MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC50 (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 μg · h/ml (total concentrations) for AUSTC and kidney burden using a sigmoidE max and an inhibitory sigmoidE max PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 μg · h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.

scholarly journals Pharmacodynamics of TD-1792, a Novel Glycopeptide-Cephalosporin Heterodimer Antibiotic Used against Gram-Positive Bacteria, in a Neutropenic Murine Thigh Model

2011 ◽  
Vol 56 (3) ◽  
pp. 1578-1583 ◽  
Author(s):  
Sharath S. Hegde ◽  
Olanrewaju O. Okusanya ◽  
Robert Skinner ◽  
Jeng-Pyng Shaw ◽  
Glenmar Obedencio ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Single Dose ◽  
Dose Fractionation ◽  
Maximum Plasma ◽  
Maximal Effect ◽  
Bacterial Burden ◽  
Total Drug ◽  
Gram Positive ◽  
Time Curve ◽  
Content Type

ABSTRACTTD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organismsin vitro. The present studies evaluated thein vivopharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains ofStaphylococcus aureusandStaphylococcus epidermidis(MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains ofStreptococcus pneumoniae(PSSP),Streptococcus pyogenes, and vancomycin-intermediate-susceptibleStaphylococcus aureus(VISA). In single-dose efficacy studies, the 1-log10CFU kill effective dose (ED1-log kill) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log10CFU/g from pretreatment values. AgainstS. aureusATCC 33591 (MRSA), the total 24-h log10stasis dose (EDstasis) and ED1-logkilldoses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r2= 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio;r2= 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC;r2= 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log10CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.

scholarly journals Pharmacokinetics and Pharmacodynamics of ASP2151, a Helicase-Primase Inhibitor, in a Murine Model of Herpes Simplex Virus Infection

2012 ◽  
Vol 57 (3) ◽  
pp. 1339-1346 ◽  
Author(s):  
Kiyomitsu Katsumata ◽  
Koji Chono ◽  
Kota Kato ◽  
Yoshiaki Ohtsu ◽  
Shoji Takakura ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Murine Model ◽  
Limit Of Detection ◽  
Dose Fractionation ◽  
Time Curve ◽  
Varicella Zoster ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus. Here, to determine and analyze the correlation between the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of ASP2151, we examined the PD profile of ASP2151 usingin vitroplaque reduction assay and a murine model of HSV-1 infection. ASP2151 inhibited thein vitroreplication of HSV-1 with a mean 50% effective concentration (EC50) of 14 ng/ml. In the cutaneously HSV-1-infected mouse model, ASP2151 dose dependently suppressed intradermal HSV-1 growth, with the effect reaching a plateau at a dose of 30 mg/kg of body weight/day. The dose fractionation study showed that intradermal HSV-1 titers were below the detection limit in mice treated with ASP2151 at 100 mg/kg/day divided into two daily doses and at 30 or 100 mg/kg/day divided into three daily doses. The intradermal HSV-1 titer correlated with the maximum concentration of drug in serum (Cmax), the area under the concentration-time curve over 24 h (AUC24h), and the time during which the concentration of ASP2151 in plasma was above 100 ng/ml (T>100). The continuous infusion of ASP2151 effectively decreased intradermal HSV-1 titers below the limit of detection in mice in which the ASP2151 concentration in plasma reached 79 to 145 ng/ml. Our findings suggest that the antiviral efficacy of ASP2151 is most closely associated with the PK parameterT>100in HSV-1-infected mice. Based on these results, we propose that a plasma ASP2151 concentration exceeding 100 ng/ml for 21 to 24 h per day provides the maximum efficacy in HSV-1-infected mice.

scholarly journals Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-β-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Adam Johnson ◽  
Laura McEntee ◽  
Nicola Farrington ◽  
Ruwanthi Kolamunnage-Dona ◽  
Samantha Franzoni ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Drug Exposure ◽  
Antimicrobial Effect ◽  
Therapeutic Options ◽  
Dose Fractionation ◽  
Maximal Effect ◽  
The Novel ◽  
Time Curve ◽  
Content Type ◽  
Extended Spectrum

ABSTRACT Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

scholarly journals Pharmacodynamics of Oritavancin (LY333328) in a Neutropenic-Mouse Thigh Model of Staphylococcus aureus Infection

2003 ◽  
Vol 47 (5) ◽  
pp. 1700-1706 ◽  
Author(s):  
Carole J. Boylan ◽  
Kristina Campanale ◽  
Philip W. Iversen ◽  
Diane L. Phillips ◽  
Michael L. Zeckel ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Peak Plasma ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Maximum Effect ◽  
Maximal Effect ◽  
Time Curve ◽  
Bacterial Killing ◽  
Dosing Strategies

ABSTRACT The pharmacokinetics and pharmacodynamics of oritavancin (LY333328), a glycopeptide antibiotic with concentration-dependent bactericidal activity against gram-positive pathogens, in a neutropenic-mouse thigh model of Staphylococcus aureus infection were studied. Plasma radioequivalent concentrations of oritavancin were determined by using [14C]oritavancin at doses ranging from 0.5 to 20 mg/kg of body weight. Peak plasma radioequivalent concentrations after an intravenous dose were 7.27, 12.56, 69.29, and 228.83 μg/ml for doses of 0.5, 1, 5, and 20 mg/kg, respectively. The maximum concentration of drug in serum (C max) and the area under the concentration-time curve (AUC) increased linearly in proportion to the dose. Neither infection nor neutropenia was seen to affect the pharmacokinetics of oritavancin. Intravenous administration resulted in much higher concentrations in plasma than the concentrations obtained with subcutaneous administration. Single-dose dose-ranging studies suggested a sigmoid maximum effect (E max) dose-response relationship, with a maximal effect evident at single doses exceeding 2 mg/kg. The oritavancin dose (stasis dose) that resulted in a 24-h colony count similar to the pretreatment count was 1.53 (standard error [SE], 0.35) mg/kg. The single oritavancin dose that resulted in 50% of maximal bacterial killing (ED50) was 0.95 (SE, 0.20) mg/kg. Dose fractionation studies suggested that single doses of 0.5, 1, 2, 4, and 16 mg/kg appeared to have greater bactericidal efficacy than the same total dose subdivided and administered multiple times during the 24-h treatment period. When using an inhibitory E max model, C max appears to correlate better with bactericidal activity than do the time during which the concentration in plasma exceeds the MIC (T>MIC) and AUC. These data suggest that optimal oritavancin dosing strategies will require regimens that favor high C max concentrations rather than long periods during which unbound concentrations in plasma exceed the MIC.

Pharmacokinetics and Pharmacodynamics of Vancomycin derivative LYSC98 in a Murine Thigh Infection Model against Staphylococcus aureus

2021 ◽  
Author(s):  
Peng He ◽  
Xin Li ◽  
Xiaohan Guo ◽  
Xingchen Bian ◽  
Meiqing Feng
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Dose Fractionation ◽  
Infection Model ◽  
Maximum Plasma ◽  
Time Curve ◽  
Elimination Half ◽  
Dose Ranging ◽  
Plasma Pharmacokinetics

LYSC98 is a vancomycin derivative used for gram-positive bacterial infections therapy. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of LYSC98 against Staphylococcus aureus using a murine thigh infection model. Three Staphylococcus aureus strains were utilized. Single-dose plasma pharmacokinetics of LYSC98 were determined in infected mice after the tail vein injection of 2, 4, and 8mg/kg. The results showed maximum plasma concentration (Cmax) 11466.67 -48866.67 ng/mL, area under the concentration-time curve from 0 to 24 h(AUC0-24) 14788.42 -91885.93 ng/mL·h, and elimination half-life(T1/2) 1.70-2.64 h, respectively. The Cmax (R2 0.9994) and AUC0-24 (R2 0.981) were positively correlated with the dose of LYSC98 in the range of 2-8 mg/kg. Dose fractionation studies using total doses of 2 to 8 mg/kg administered with q6h, q8h, q12h, and q24h were performed to evaluate the correlation of different PK/PD indices with efficacy. Sigmoid model analysis showed Cmax/MIC (R2 0.8941) was the best PK/PD index to predict the efficacy of LYSC98. In the dose ranging studies, two Methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used to infect the mice and 2-fold-increasing doses (1 to 16 mg/kg) of LYSC98 were administered. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. The results of this study showed LYSC98 a promising antibiotic with in vivo potency against MRSA, and will help in the dose design of phase one study for LYSC98.

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