scholarly journals In Vivo Efficacy and Pharmacokinetics of AC98-6446, a Novel Cyclic Glycopeptide, in Experimental Infection Models

2004 ◽  
Vol 48 (5) ◽  
pp. 1708-1712 ◽  
Author(s):  
William J. Weiss ◽  
Timothy Murphy ◽  
Eileen Lenoy ◽  
Mairead Young
Keyword(s):  
Bacterial Load ◽  
Staphylococcal Infection ◽  
Gram Positive ◽  
Time Curve ◽  
In Vivo Efficacy ◽  
Naturally Occurring ◽  
Infection Models ◽  
Semisynthetic Derivative

ABSTRACT AC98-6446 is a novel semisynthetic derivative of a natural product related to the mannopeptimycins produced by Streptomyces hygroscopicus. Naturally occurring esterified mannopeptimycins exhibited excellent in vitro activity but only moderate in vivo efficacy against staphylococcal infection. The in vivo efficacy and pharmacokinetics of AC98-6446 were investigated in murine acute lethal, bacterial thigh and rat endocarditis infections. Pharmacokinetics were performed in mice, rats, monkeys, and dogs. Acute lethal infections were performed with several gram-positive isolates: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant staphylococci), vancomycin-resistant Enterococcus faecalis, and penicillin-susceptible and -resistant Streptococcus pneumoniae. The 50% effective dose for all isolates tested ranged from 0.05 to 0.39 mg/kg of body weight after intravenous (i.v.) administration. Vancomycin was more than fivefold less efficacious against all of these same infections. Results of the thigh infection with S. aureus showed a static dose for AC98-6446 of 0.4 mg/kg by i.v. administration. Reduction of counts in the thigh of >2 log10 CFU were achieved with doses of 1 mg/kg. i.v. administration of 3 mg/kg twice a day for 3 days resulted in a >3 log10 reduction in bacterial counts of vancomycin-susceptible and -resistant E. faecalis in a rat endocarditis model. Pharmacokinetics of AC98-6446 showed an increase in exposure (area under the concentration-time curve) from mouse to dog species. The i.v. half-life (t 1/2) increased threefold between rodents and the higher species dosed. Efficacy of AC98-6446 has been demonstrated in several models of infection with resistant gram-positive pathogens. This glycopeptide exhibited bactericidal activity in these models, resulting in efficacy at low doses with reduction in bacterial load.

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 In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

2005 ◽  
Vol 49 (6) ◽  
pp. 2498-2500 ◽  
Author(s):  
Eun Jeong Yoon ◽  
Yeong Woo Jo ◽  
Sung Hak Choi ◽  
Tae Ho Lee ◽  
Jae Keol Rhee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Infection Models ◽  
Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

scholarly journals Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

2010 ◽  
Vol 54 (12) ◽  
pp. 5115-5119 ◽  
Author(s):  
Jared L. Crandon ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Load ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Vancomycin Mics ◽  
Mrsa Strains

ABSTRACT Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log10 CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

scholarly journals Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

2011 ◽  
Vol 55 (4) ◽  
pp. 1671-1676 ◽  
Author(s):  
Daniela Jabés ◽  
Cristina Brunati ◽  
GianPaolo Candiani ◽  
Simona Riva ◽  
Gabriella Romanó ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Load ◽  
Severe Infection ◽  
Multidrug Resistant ◽  
Minimal Bactericidal Concentration ◽  
Gram Positive ◽  
Immunocompetent Mice ◽  
Dose Proportional

ABSTRACTNAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA), glycopeptide-intermediateS. aureus(GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate thein vivoefficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediateStreptococcus pneumoniaestrain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED50) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). Inthe granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log10-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observedin vitrowas thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

scholarly journals Pharmacodynamics of Telavancin (TD-6424), a Novel Bactericidal Agent, against Gram-Positive Bacteria

2004 ◽  
Vol 48 (8) ◽  
pp. 3043-3050 ◽  
Author(s):  
Sharath S. Hegde ◽  
Noe Reyes ◽  
Tania Wiens ◽  
Nicole Vanasse ◽  
Robert Skinner ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Time Curve ◽  
Once Daily ◽  
Gram Positive Bacteria ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Dose Dependent

ABSTRACT Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.

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 In Vivo Pharmacodynamics of New Lipopeptide MX-2401

2010 ◽  
Vol 54 (12) ◽  
pp. 5092-5098 ◽  
Author(s):  
W. A. Craig ◽  
D. R. Andes ◽  
T. Stamstad
Keyword(s):  
Methicillin Resistance ◽  
White Blood Cells ◽  
Free Drug ◽  
Dose Fractionation ◽  
Gram Positive ◽  
Time Curve ◽  
Antibiotic Resistant ◽  
Gram Positive Bacteria ◽  
Infection Models

ABSTRACT MX-2401 is a novel lipopeptide (amphomycin analog) with a broad-spectrum bactericidal activity against Gram-positive organisms. We used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic/pharmacodynamic (PK/PD) activities of MX-2401. The compound (2.5 to 40 mg/kg of body weight) demonstrated linear PK characterized by an area under the concentration-time curve (AUC) of 228 to 3,265 μg·h/ml and half-lives of 5.7 to 8.8 h. MICs ranged from 0.25 to 2 μg/ml. The in vivo postantibiotic effect was prolonged (8.5 h with Staphylococcus aureus and 10.3 to 12.3 with Streptococcus pneumoniae). MX-2401 exhibited dose-dependent in vivo activity against various strains of S. pneumoniae and S. aureus; penicillin and macrolide resistance in the pneumococci and methicillin resistance in the staphylococci had no impact on the antimicrobial activity of the drug. To determine which PK/PD index correlated best with MX-2401 activity, dose fractionation studies over a 72-hour period were performed. The maximum concentration of drug in serum divided by the MIC (C max/MIC) correlated best with the efficacy for both S. aureus and S. pneumoniae. Static doses required free-drug C max/MIC values of 0.683 to 1.06. Free-drug 72-h AUC/MIC values for the static dose were in the range of 7.49 to 32.3 and were less than expected. The drug showed modest enhancement in activity in the presence of white blood cells (1.7- to 3.4-fold). The potency of the drug in the lung was only marginally lower than in the thigh (1.3- to 1.9-fold). Based on its PK/PD profile, MX-2401 appears to be a promising new lipopeptide agent for treatment of infections by Gram-positive bacteria, including those induced by antibiotic-resistant pathogens.

scholarly journals Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent

2001 ◽  
Vol 45 (11) ◽  
pp. 3113-3121 ◽  
Author(s):  
Domingo Gargallo-Viola ◽  
Santiago Ferrer ◽  
Encarna Tudela ◽  
Marta Robert ◽  
Ramon Coll ◽  
...  
Keyword(s):  
Horse Serum ◽  
Enteric Bacteria ◽  
In Vivo Studies ◽  
Urine Ph ◽  
Gram Positive ◽  
Time Curve ◽  
Experimental Infections ◽  
Quinolinecarboxylic Acid

ABSTRACT E-4767 {(−)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4- oxo-3-quinolinecarboxylic acid} and E-5065 [(−)-7-(3-amino-1-azetidinyl)-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid] are two new chlorofluoroquinolones with an azetidine moiety at position 7. Their in vitro activities were evaluated in comparison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against gram-positive organisms, E-4767 and E-5065 were, in general, eight- and fourfold more active than tosufloxacin, which is the most potent of the reference compounds. E-4767 and E-5065 were also more potent than the reference compounds against all species of enteric bacteria tested. The MICs of E-4767 and E-5065 at which 90% of the isolates tested were inhibited (MIC90s) were 0.007 to 0.5 μg/ml and 0.03 to 2 μg/ml, respectively, for gram-positive organisms and ≤0.003 to 0.06 μg/ml and 0.007 to 0.12 μg/ml, respectively, for members of the familyEnterobacteriaceae except Serratia marcescens and Providencia spp. (MIC90s of E-4767 and E-5065 for these species were ≤0.5 μg/ml and ≤2 μg/ml, respectively). For Pseudomonas aeruginosa both compounds had a MIC90 of 0.5 μg/ml. E-4767 and E-5065 were 356- and 32-fold more potent than ciprofloxacin against Bacteroides spp., and their MIC90s for Clostridium spp. were 0.25 and 0.5 μg/ml, respectively. Both products showed a remarkable reduction of activity when the pH was below 4.8 and, in general, were less active in the presence of 5 or 10 mM Mg2+. The presence of horse serum or human urine (pH 7.2) decreased the activity of E-4767 and E-5065 only two- to fourfold more than the activity observed in broth. After an oral dose of 50 mg/kg of body weight, the maximum levels in serum (the maximum concentration of drug in serum was reached 30 min postadministration) of E-4767 and E-5065 were approximately threefold higher than that of ciprofloxacin. The area under the concentration-time curve from 0 to 4 h for ciprofloxacin was about two- and fourfold lower than that for E-4767 and E-5065, respectively. These two new chlorofluoroquinolones were as effective as or more effective than ciprofloxacin against all experimental infections evaluated, not only against gram-negative bacteria, such asEscherichia coli or P.aeruginosa, but also against gram-positive pathogens, such as Staphylococcus aureus or Streptococcus pneumoniae. E-4767 was the most effective compound, with a 50% effective dose (ED50) of ≤17 mg/kg for all strains tested except ciprofloxacin-resistant S. aureusstrains. The ED50 of E-4767 for these strains was ≤47.5 mg/kg. Against gram-positive experimental infections, the ED50 values of E-4767 were 3- to 14-fold lower than those of E-5065 and up to 25 times lower than those of ciprofloxacin.

scholarly journals Efficacy of Delafloxacin against the Biothreat Pathogen Burkholderia pseudomallei

2021 ◽  
Author(s):  
Sandra McCurdy ◽  
Erin Duffy ◽  
Mark Hickman ◽  
Stephanie Halasohoris ◽  
Steven D. Zumbrun
Keyword(s):  
Burkholderia Pseudomallei ◽  
Eradication Therapy ◽  
Tolerability Profile ◽  
Postexposure Prophylaxis ◽  
In Vivo Efficacy ◽  
Infection Models ◽  
Dosing Regimens ◽  
Mouse Model Of Infection

The in vitro activity and in vivo efficacy of delafloxacin were evaluated against the causative pathogen of melioidosis, Burkholderia pseudomallei . Delafloxacin MICs were determined by broth microdilution according to CLSI guidelines for 30 isolates of B. pseudomallei . The in vivo efficacy of delafloxacin was studied at a range of doses in a postexposure prophylaxis (PEP) murine model of melioidosis. Delafloxacin was active in vitro against B. pseudomallei (MIC 90 1 μg/mL). When the mice were dosed with 50 mg/kg and 80 mg/kg delafloxacin at both 16 and 24 hours, higher survival was observed (90-100% survival) compared to the 30 mg/kg dosed mice (70% survival). All delafloxacin-treated cohorts contained no detectable B. pseudomallei in the spleens at the end of the study. This contrasts with ceftazidime 16- and 24-hours administration, which had 40% and 20% survival, respectively. Complete clearance of infection was observed for most but not all surviving cohorts administered ceftazidime. In the mouse model of infection, comparison of survival curves for delafloxacin and ceftazidime treated animals at treatment start times of 16 and 24 hours were statistically significant (p values < 0.0001). Estimated daily delafloxacin exposures in the B. pseudomallei murine aerosol study were similar to daily human exposures with the approved BID IV (300 mg) or oral (450 mg) dosing regimens. Based on its in vitro and in vivo activity, its safety and tolerability profile, delafloxacin may offer an attractive treatment option as PEP or eradication therapy for B. pseudomallei . Evaluation in other in vivo infection models for B. pseudomallei should be considered.

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