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 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 Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

2006 ◽  
Vol 50 (11) ◽  
pp. 3763-3769 ◽  
Author(s):  
Reiko Sato ◽  
Yusuke Tanigawara ◽  
Mitsuo Kaku ◽  
Naoki Aikawa ◽  
Kihachiro Shimizu
Keyword(s):  
Staphylococcus Aureus ◽  
Logistic Regression ◽  
Clinical Cure ◽  
Preceding Paper ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Efficacy Analysis ◽  
The Individual

ABSTRACT Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (C max), AUC/MIC, C max/MIC, and trough concentration (C min) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The C max, C min, and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the C max of arbekacin was increased, with an odds ratio of 6.7 for a change in C max from 7.9 to 12.5 μg/ml (P = 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed C min and AUC as risk factors of nephrotoxicity (P < 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the C min values were 1, 2, and 5 μg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

scholarly journals In Vivo Pharmacodynamics of Omadacycline against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Infection Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Concentration Time ◽  
Mrsa Strains

ABSTRACT Omadacycline is a novel aminomethylcycline antibiotic with potent activity against Staphylococcus aureus, including methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). We investigated the pharmacodynamic activity of omadacycline against 10 MSSA/MRSA strains in a neutropenic murine thigh model. The median 24-h area under the concentration-time curve (AUC)/MIC values associated with net stasis and 1-log kill were 21.9 and 57.7, respectively.

scholarly journals Tolerance and Pharmacokinetic Interactions of Rifabutin and Clarithromycin in Human Immunodeficiency Virus-Infected Volunteers

1998 ◽  
Vol 42 (3) ◽  
pp. 631-639 ◽  
Author(s):  
Richard Hafner ◽  
James Bethel ◽  
Maureen Power ◽  
Bernard Landry ◽  
Mary Banach ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Single Agent ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Interactions ◽  
Immunodeficiency Virus ◽  
Gastrointestinal Adverse Events

ABSTRACT This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically stable human immunodeficiency virus-infected volunteers with CD4 counts of <200 cells/mm3. Thirty-four subjects were randomized equally to either regimen A or regimen B. On days 1 to 14, subjects assigned to regimen A received clarithromycin and subjects assigned to regimen B received rifabutin, and then both groups received both drugs on days 15 to 42. Of the 14 regimen A and the 15 regimen B subjects who started combination therapy, 1 subject in each group prematurely discontinued therapy due to toxicity, but 19 of 29 subjects reported nausea, vomiting, and/or diarrhea. Pharmacokinetic analysis included data for 11 regimen A and 14 regimen B subjects. Steady-state pharmacokinetic parameters for single-agent therapy (day 14) and combination therapy (day 42) were compared. Regimen A resulted in a mean decrease of 44% (P = 0.003) in the clarithromycin area under the plasma concentration-time curve (AUC), while there was a mean increase of 57% (P = 0.004) in the AUC of the clarithromycin metabolite 14-OH-clarithromycin. Regimen B resulted in a mean increase of 99% (P = 0.001) in the rifabutin AUC and a mean increase of 375% (P < 0.001) in the AUC of the rifabutin metabolite 25-O-desacetyl-rifabutin. The usefulness of this combination for prophylaxis of Mycobacterium avium infections is limited by frequent gastrointestinal adverse events. Coadministration of clarithromycin and rifabutin results in significant bidirectional pharmacokinetic interactions. The resulting increase in rifabutin levels may explain the increased frequency of uveitis observed with concomitant use of these drugs.

scholarly journals Preferential Emergence of Reduced Vancomycin Susceptibility in Health Care-Associated Methicillin-Resistant Staphylococcus aureus Isolates during Continuous-Infusion Vancomycin Therapy in anIn VitroDynamic Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3627-3630 ◽  
Author(s):  
Sheryl Zelenitsky ◽  
Noha Alkurdi ◽  
Zhanni Weber ◽  
Robert Ariano ◽  
George Zhanel
Keyword(s):  
Health Care ◽  
Staphylococcus Aureus ◽  
Continuous Infusion ◽  
Total Serum ◽  
Vancomycin Therapy ◽  
Time Curve ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Concentration Time

ABSTRACTBacterial killing and the development of reduced vancomycin susceptibility during continuous-infusion vancomycin (CIV) therapy were dependent on the area under the concentration-time curve over 24 h divided by the MIC (ƒAUC24/MIC), with values of ≥240 (equivalent total serum AUC24/MICs of ≥480) being bactericidal and suppressing emerging resistance in methicillin-resistantStaphylococcus aureus(MRSA). Also, vancomycin therapy was less likely to be bactericidal and 4.4 times more likely to lead to reduced vancomycin susceptibility in health care-associated MRSA than in community-associated MRSA.

scholarly journals Efficacies of Ceftobiprole Medocaril and Comparators in a Rabbit Model of Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus

2008 ◽  
Vol 52 (5) ◽  
pp. 1618-1622 ◽  
Author(s):  
Li-Yan Yin ◽  
Jason H. Calhoun ◽  
Jacob K. Thomas ◽  
Stuart Shapiro ◽  
Anne Schmitt-Hoffmann
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Matrix ◽  
Rabbit Model ◽  
Subcutaneous Administration ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Concentration Time ◽  
New Zealand White Rabbits ◽  
Serum Trough ◽  
The Mean

ABSTRACT The pharmacokinetics and distribution into bone tissue of ceftobiprole in uninfected New Zealand White rabbits were determined after subcutaneous administration of the prodrug ceftobiprole medocaril. Serum exposure (maximum concentration of the drug in serum, trough concentration, area under the concentration-time curve) to ceftobiprole at 20 and 80 mg/kg was dose proportional, and there was no accumulation of ceftobiprole following repeated (every 6 h [q6h]) injections of the antibiotic. Ceftobiprole titers in the tibial matrix and marrow were 3.2 ± 1.3 μg/g and 11.2 ± 6.5 μg/g, respectively, in uninfected animals treated with 20 mg/kg of the antibiotic and 13.4 ± 7.3 μg/g and 66.3 ± 43.2 μg/g, respectively, in uninfected animals treated with 80 mg/kg of the antibiotic. No differences in ceftobiprole titers were observed between right and left tibiae for either bone matrix or marrow. The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg administered subcutaneously [s.c.] q6h), vancomycin (30 mg/kg administered s.c. q12h), or linezolid (60 mg/kg administered orally q8h) were compared, using a rabbit model of methicillin-resistant Staphylococcus aureus tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from vancomycin- or linezolid-treated animals had bacterial titers below the level of detection; the mean titers of ceftobiprole were 3 to 5 times higher in infected left tibiae than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis in this rabbit model.

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