scholarly journals Pharmacodynamic Profile of Tigecycline against Methicillin-Resistant Staphylococcus aureus in an Experimental Pneumonia Model

2009 ◽  
Vol 53 (12) ◽  
pp. 5060-5063 ◽  
Author(s):  
Pornpan Koomanachai ◽  
Jared L. Crandon ◽  
Mary Anne Banevicius ◽  
Li Peng ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Response Relationship ◽  
Time Curve ◽  
Free Concentration ◽  
Epithelial Lining Fluid ◽  
Exposure Response ◽  
Concentration Time ◽  
Pharmacodynamic Profile ◽  
Highly Correlated

ABSTRACT Tigecycline (TGC) is an extended-spectrum antibiotic with activity against Staphylococcus aureus, including methicillin (meticillin)-resistant S. aureus strains, which are well-recognized pathogens in nosocomial pneumonia. The objective of this study was to characterize the exposure-response relationship for TGC against S. aureus in an immunocompromised BALB/c murine pneumonia model. Six S. aureus isolates were studied, and the TGC MICs for those isolates ranged from 0.125 to 0.5 mg/liter. The pharmacokinetics (PK) of TGC in serum and bronchoalveolar lavage (BAL) fluid were evaluated, as was the level of protein binding of the compound in this murine species. Administration of TGC at 1.56 to 150 mg/kg of body weight/day in single or two to three divided doses was used in the efficacy studies. TGC displayed linear PK and had a mean half-life of 10.9 ± 2.5 h. Efficacy was highly correlated with the area under the free concentration-time curve (fAUC)/MIC (r 2 = 0.93). The 80% and 50% effective exposure indexes and the stasis exposure index were similar between the isolates (means ± standard deviations, 3.04 ± 1.12, 1.84 ± 1.3, and 1.9 ± 1.5, respectively). Maximal efficacy was predicted at a 2.85-log10-CFU reduction. TGC appeared to accumulate in the interstitial space, as the ratios of the fAUC from 0 to 8 h of epithelial lining fluid to plasma were 7.02, 15.11, and 23.95 for doses of 12.5, 25, and 50 mg/kg, respectively. TGC was highly effective in this murine pneumonia model. In light of current MIC distributions, the fAUC/MIC targets that we defined against S. aureus are readily achievable in humans given conventional doses of TGC.

scholarly journals In Vivo Pharmacodynamic Evaluation of Omadacycline against Staphylococcus aureus in the Neutropenic Mouse Pneumonia Model

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Effect ◽  
Bacterial Pneumonia ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Concentration Time ◽  
Mrsa Strains

ABSTRACT Omadacycline is an effective therapy for community-acquired bacterial pneumonia (CABP). Given its potent activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA), we sought to determine the pharmacodynamic activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with a therapeutic effect in the neutropenic mouse pneumonia model against 10 MSSA/MRSA strains. The area under the concentration-time curve (AUC)/MIC associated with 1-log kill was noted at 24-h epithelial lining fluid (ELF) and plasma AUC/MIC exposures of ∼2 (ELF range, <0.93 to 19; plasma range, <1.06 to 17) and 2-log kill was noted at 24-h ELF and plasma AUC/MIC exposures of ∼12 (ELF range, 2.5 to 130; plasma range, 3.5 to 151).

scholarly journals In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species

2010 ◽  
Vol 54 (6) ◽  
pp. 2497-2506 ◽  
Author(s):  
D. Andes ◽  
D. J. Diekema ◽  
M. A. Pfaller ◽  
J. Bohrmuller ◽  
K. Marchillo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Candida Parapsilosis ◽  
Free Drug ◽  
Response Relationship ◽  
Time Curve ◽  
Exposure Response ◽  
Concentration Time ◽  
Drug Concentrations ◽  
Good Descriptor

ABSTRACT Previous pharmacodynamic studies using in vivo candidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicans and were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosis strains with various MICs (anidulafungin, 0.015 to 4.0 μg/ml; caspofungin, 0.03 to 4.0 μg/ml; and micafungin, 0.008 to 1.0 μg/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosis required more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) were significantly lower than those for C. albicans (mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.

scholarly journals Pharmacokinetics in nonhuman primates of a prototype carbapenem active against methicillin-resistant Staphylococcus aureus.

1996 ◽  
Vol 40 (3) ◽  
pp. 795-798 ◽  
Author(s):  
J G Sundelof ◽  
R Thompson ◽  
K M White ◽  
M W Sasor ◽  
L Cama ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rhesus Monkeys ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Single Agent ◽  
Beta Phase ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Concentration Time ◽  
Carbapenem Antibiotic

Pharmacokinetic parameters were determined for imipenem-cilastatin and a carbapenem antibiotic, L-695,256, active against methicillin-resistant Staphylococcus aureus in rhesus monkeys and a chimpanzee. L-695,256 had larger areas under the concentration-time curve than imipenem-cilastatin (30 +/- 5 versus 24 +/- 1 micrograms.h/ml in the rhesus monkeys and 77 versus 60 micrograms.h/ml in the chimpanzee) and a longer half-life at beta phase (1.2 +/- 0.1 versus 0.6 +/- 0.1 h in the rhesus monkeys and 1.0 versus 0.8 h in the chimpanzee). Resistance to hydrolysis by the renal dehydropeptidase-I allowed L-695,256 to be administered as a single agent.

scholarly journals Validation of Vancomycin Area under the Concentration—Time Curve Estimation by the Bayesian Approach Using One-Point Samples for Predicting Clinical Outcomes in Patients with Methicillin-Resistant Staphylococcus aureus Infections

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 96
Author(s):  
Takashi Ueda ◽  
Yoshio Takesue ◽  
Kazuhiko Nakajima ◽  
Kaoru Ichiki ◽  
Kaori Ishikawa ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Response ◽  
Clinical Outcomes ◽  
Early Treatment ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Concentration Time ◽  
Early Treatment Response ◽  
Two Samples

Area under the concentration–time curve (AUC)-guided vancomycin treatment is associated with decreased nephrotoxicity. It is preferable to obtain two samples to estimate the AUC. This study examined the usefulness of AUC estimation via trough concentration (Cmin)-only sampling of 260 adults infected with methicillin-resistant Staphylococcus aureus (MRSA) who received vancomycin. The exact Cmin sampling time was used for Bayesian estimation. A significantly higher early treatment response was observed in patients with a day 2 AUC ≥ 400 µg·h/mL than those with <400 µg·h/mL, and a significantly higher early nephrotoxicity rate was observed in patients with a day 2 AUC ≥ 600 µg·h/mL than those with <600 µg·h/mL. These AUC cutoff values constituted independent factors for each outcome. In sub-analysis, the discrimination ability for early clinical outcomes using these AUC cutoffs was confirmed only in patients with q12 vancomycin administration. A significant difference in early treatment response using the 400 µg·h/mL cutoff was obtained only in patients with low-risk infections. The usefulness of the vancomycin AUC target to decrease nephrotoxicity while assuring clinical efficacy was even confirmed with a single Cmin measurement. However, assessment with two samples might be required in patients with q24 administration or high/moderate-risk MRSA infections.

scholarly journals Pharmacodynamic Characterization of Ceftobiprole in Experimental Pneumonia Caused by Phenotypically Diverse Staphylococcus aureus Strains

2008 ◽  
Vol 52 (7) ◽  
pp. 2389-2394 ◽  
Author(s):  
Somvadee Laohavaleeson ◽  
Pamela R. Tessier ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Phenotypic Profile ◽  
Concentration Time ◽  
Mrsa Strains ◽  
Hospital Acquired ◽  
Free Plasma

ABSTRACT Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 μg/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log10 CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED80), ED50, and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to β-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.

scholarly journals Efficacy of Telavancin (TD-6424), a Rapidly Bactericidal Lipoglycopeptide with Multiple Mechanisms of Action, in a Murine Model of Pneumonia Induced by Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (10) ◽  
pp. 4344-4346 ◽  
Author(s):  
Noe Reyes ◽  
Robert Skinner ◽  
Koné Kaniga ◽  
Kevin M. Krause ◽  
Josephine Shelton ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Murine Model ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Mechanisms Of Action ◽  
Potential Utility ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Bacterial Titer ◽  
Concentration Time

ABSTRACT The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared to that of vancomycin and linezolid against methicillin-resistant Staphylococcus aureus (MRSA) in a murine pneumonia model. Telavancin produced greater reductions in lung bacterial titer and mortality than did vancomycin and linezolid at human doses equivalent to those described by the area under the concentration-time curve. These results suggest the potential utility of telavancin for treatment of MRSA pneumonia.

scholarly journals Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. Aminoglycosides

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sandrine Marchand ◽  
Matthieu Boisson ◽  
Shachi Mehta ◽  
Christophe Adier ◽  
Olivier Mimoz ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Antimicrobial Agents ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time

ABSTRACT Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.

scholarly journals Administration of aminoglycosides to hemodialysis patients immediately before dialysis: a new dosing modality.

1997 ◽  
Vol 41 (12) ◽  
pp. 2597-2601 ◽  
Author(s):  
H Matsuo ◽  
J Hayashi ◽  
K Ono ◽  
K Andoh ◽  
Y Andoh ◽  
...  
Keyword(s):  
High Performance ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Cellulose Triacetate ◽  
The Body ◽  
High Rate ◽  
Complete Disappearance ◽  
Time Curve ◽  
Once Daily ◽  
Ethylene Vinyl Alcohol ◽  
Concentration Time

We describe a new modality for administering aminoglycosides to hemodialysis (HD) patients, namely, a modification of the once-daily regimen which consists of administering the aminoglycosides over 60 min by drip infusion just before each HD session, with a preplanned peak concentration being reached at the beginning of the session and then with a rapidly decreasing concentration being achieved by the start of HD. The area under the concentration-time curve (AUC), i.e., the accumulation of the drug in the body, is thus minimized by this modality. Arbekacin (ABK) was given at a dose of 2 mg/kg of body weight to 10 HD patients infected with methicillin-resistant Staphylococcus aureus (MRSA) for 2 weeks (six sessions in total), resulting in the complete disappearance of MRSA in 5 patients. A high rate of elimination of ABK was attained for each patient while the patient was on HD (range, 0.20 to 0.42 h-1; mean 0.28 +/- 0.08 h-1) by using high-performance dialyzers provided with membranes made of either polymethylmethacrylate, cellulose triacetate (CTA), or ethylene vinyl alcohol. The best results were obtained with the CTA membrane, as revealed by the overall mass transfer coefficient (Ko). The AUC in the simulation model for the variation in the serum ABK concentration in this modality was calculated to be 40% of that of the conventional post-HD dosing modality, suggesting that a much higher dose could be administered to HD patients who receive HD thrice weekly (4 h per session), giving, e.g., 4 mg/kg initially and before the HD sessions, when there is an interval of 68 h from HD session to HD session, and giving 2 mg/kg before the other sessions.

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