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

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.

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Pharmacodynamics of Fluconazole in a Murine Model of Systemic Candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.5.1105 ◽

1998 ◽

Vol 42 (5) ◽

pp. 1105-1109 ◽

Cited By ~ 113

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00180-20 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 3

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.

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1395. Defining the Magnitude of AUC:MIC Driver for Efficacy of the β-Lactamase Inhibitor VNRX-5133 When Combined with Cefepime Against KPC- and VIM/NDM-Producing Enterobacteriaceae and P. aeruginosa

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1226 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S429-S429 ◽

Cited By ~ 2

Author(s):

Denis Daigle ◽

Salvador Vernacchio ◽

Luigi Xerri ◽

Daniel Pevear

Keyword(s):

In Vitro Studies ◽

Dose Fractionation ◽

Infection Model ◽

Type Model ◽

E Coli ◽

Dose Ranging ◽

New Generation ◽

Lactamase Inhibitor

Abstract Background VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) in clinical development with cefepime for treatment of infections caused by ESBL- and carbapenemase producing Enterobacteriaceae and P. aeruginosa. It is a new generation broad-spectrum BLI with direct inhibitory activity against serine-active site and emerging metallo-β-lactamases (e.g., VIM/NDM). In previous in vivo and in vitro studies, the PK-PD driver of efficacy of VNRX-5133 was defined as AUC:MIC. Described herein are in vitro studies to assess the magnitude of VNRX-5133 exposure (AUC:MIC) required to restore efficacy of cefepime against a broad collection of KPC- and VIM/NDM-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA) clinical isolates. Methods Dose-fractionation studies, consisting of four VNRX-5133 exposures fractionated into regimens administered every 4, 8, 12 and 24 hours, were performed in an in vitro infection model with simulated 2 g q8h dosing of cefepime against NDM-1 producing E. coli. A Hill-type model described the relationship between change in log10 CFU at 24 hours and VNRX-5133 exposure (AUC:MIC), where cefepime MIC was determined with 4 µg/mL VNRX-5133. To evaluate variability of efficacy enabled by VNRX-5133 between isolates as well as between Serine-BL and Metallo-BL producers, dose-ranging studies were completed for eight isolates (seven ENT and one PSA) producing KPC or VIM/NDM metallo-β-lactamases. Results The PK-PD exposure parameter AUC:MIC accurately described the efficacy of VNRX-5133 in rescuing cefepime activity against KPC and VIM/NDM carbapenemase-producing isolates of ENT and PSA. The AUC:MIC ratios associated with net bacterial stasis, 1-, and 2-log10 reductions in bacterial burden from baseline were 6.1, 18.4 and 45, respectively, for a collection of five VIM/NDM- and three KPC-producing isolates with cefepime MICs ranging from 4–8 µg/mL with no significant differences observed between Ser-BL and MBL producers. Conclusion These data confirm the equivalent in vitro activity of cefepime/VNRX-5133 against organisms producing serine- and metallo-β-lactamases and provides an initial PK-PD target for VNRX-5133 efficacy when used in combination with cefepime for the treatment of ESBL- and carbapenemase-producing ENT and PSA infections. Disclosures D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. S. Vernacchio, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee, Salary.

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Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03706-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 790-795 ◽

Cited By ~ 25

Author(s):

Eleftheria Mavridou ◽

Ria J. B. Melchers ◽

Anita C. H. A. M. van Mil ◽

E. Mangin ◽

Mary R. Motyl ◽

...

Keyword(s):

Dose Fractionation ◽

Maximum Effect ◽

Significant Activity ◽

Beta Lactamase ◽

Time Curve ◽

Unbound Fraction ◽

Content Type ◽

Concentration Time ◽

Lactamase Inhibitor

ABSTRACTMK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producingPseudomonas aeruginosaandKlebsiella pneumoniaestrains to determine its effectin vitroandin vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits forT>MICand area under the concentration-time curve (AUC)/MIC were comparable (R2of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activityin vivoand results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01517-20 ◽

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05005-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 258-270 ◽

Cited By ~ 51

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05382-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1578-1583 ◽

Cited By ~ 14

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.

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Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in anIn VitroInfection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02943-15 ◽

2016 ◽

Vol 60 (7) ◽

pp. 3891-3896 ◽

Cited By ~ 8

Author(s):

Brian D. VanScoy ◽

Michael Trang ◽

Jennifer McCauley ◽

Haley Conde ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Antimicrobial Agents ◽

Dose Fractionation ◽

Infection Model ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Wide Range ◽

Dosing Regimens ◽

Lactamase Inhibitor

ABSTRACTThe usefulness of β-lactam antimicrobial agents is threatened as never before by β-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum β-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartmentin vitroinfection model to determine the exposure measure for CB-618, a novel β-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel includedEnterobacteriaceaeclinical isolates, which collectively produced a wide range of β-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challengeKlebsiella pneumoniaeisolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0–24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0–24(r2= 0.835) andCmax(r2= 0.826). Using the CB-618 AUC0–24indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10CFU/ml at 24 h and CB-618 AUC0–24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0–24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.5.1700-1706.2003 ◽

2003 ◽

Vol 47 (5) ◽

pp. 1700-1706 ◽

Cited By ~ 56

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.

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

10.1101/2021.12.14.472732 ◽

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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