scholarly journals In Vivo Pharmacodynamic Characterization of a Novel Plectasin Antibiotic, NZ2114, in a Murine Infection Model

2009 ◽  
Vol 53 (7) ◽  
pp. 3003-3009 ◽  
Author(s):  
D. Andes ◽  
W. Craig ◽  
L. A. Nielsen ◽  
H. H. Kristensen
Keyword(s):  
Single Dose ◽  
Time Course ◽  
Day Treatment ◽  
Dose Range ◽  
Infection Model ◽  
Time Curve ◽  
Dose Time ◽  
Dosing Regimens ◽  
Drug Resistant Strains

ABSTRACT NZ2114 is a novel plectasin derivative with potent activity against gram-positive bacteria, including multiply drug-resistant strains. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of NZ2114 and determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy. Serum drug levels following administration of three fourfold-escalating single-dose levels of NZ2114 were measured by microbiologic assay. Single-dose time-kill studies following doses of 10, 40, and 160 mg/kg of body weight demonstrated concentration-dependent killing over the dose range (0.5 to 3.7 log10 CFU/thigh) and prolonged postantibiotic effects (3 to 15 h) against both Staphylococcus aureus and Streptococcus pneumoniae. Mice had 106.3 to 106.8 CFU/thigh of strains of S. pneumoniae or S. aureus at the start of therapy when treated for 24 h with 0.625 to 160 mg/kg/day of NZ2114 fractionated for 4-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD index best correlated with microbiologic efficacy. Efficacies of NZ2114 were similar among the dosing intervals (P = 0.99 to 1.0), and regression with the 24-h area under the concentration-time curve (AUC)/MIC index was strong (R 2, 0.90) for both S. aureus and S. pneumoniae. The maximum concentration of drug in serum/MIC index regression was also strong for S. pneumoniae (R 2, 0.96). Studies to identify the PD target for NZ2114 utilized eight S. pneumoniae and six S. aureus isolates and an every-6-h regimen of drug (0.156 to 160 mg/kg/day). Treatment against S. pneumoniae required approximately twofold-less drug for efficacy in relationship to the MIC than did treatment against S. aureus. The free drug 24-h AUCs/MICs necessary to produce a stasis effect were 12.3 ± 6.7 and 28.5 ± 11.1 for S. pneumoniae and S. aureus, respectively. The 24-h AUC/MIC associated with a 1-log killing endpoint was only 1.6-fold greater than that needed for stasis. Resistance to other antimicrobial classes did not impact the magnitude of the PD target required for efficacy. The PD target in this model should be considered in the design of clinical trials with this novel antibiotic.

scholarly journals Pharmacodynamics of the New Des-F(6)-Quinolone Garenoxacin in a Murine Thigh Infection Model

2003 ◽  
Vol 47 (12) ◽  
pp. 3935-3941 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Time Course ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Strain Atcc ◽  
Time Curve ◽  
Gram Negative ◽  
Percent Time ◽  
Dosing Regimens ◽  
Resistant Strains

ABSTRACT Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 106.5 to 106.7 CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R 2= 71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]).In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 105.9 to 107.2 CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4μ g/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios ± standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 ± 18, 81± 37, and 33 ± 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.

scholarly journals In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model

2007 ◽  
Vol 52 (2) ◽  
pp. 539-550 ◽  
Author(s):  
D. Andes ◽  
D. J. Diekema ◽  
M. A. Pfaller ◽  
R. A. Prince ◽  
K. Marchillo ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Time Course ◽  
Dose Range ◽  
Treatment Success ◽  
In Vivo Studies ◽  
Serum Drug Concentration ◽  
Time Curve ◽  
Maximum Serum ◽  
Dosing Regimens

ABSTRACT Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC0-24] to the MIC, and the ratio of the maximum serum drug concentration [C max] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max/MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max/MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 μg/ml) to determine if similar C max/MIC and AUC0-24/MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.

scholarly journals Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.

1997 ◽  
Vol 41 (4) ◽  
pp. 823-826 ◽  
Author(s):  
Y Q Xiong ◽  
J Caillon ◽  
M F Kergueris ◽  
H Drugeon ◽  
D Baron ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Single Dose ◽  
Ex Vivo ◽  
Day Treatment ◽  
Total Daily Dose ◽  
Once Daily ◽  
Adaptive Resistance ◽  
Dosing Regimens

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.

scholarly journals Pharmacokinetic Data Are Predictive ofIn VivoEfficacy for Cefixime and Ceftriaxone against Susceptible and ResistantNeisseria gonorrhoeaeStrains in the Gonorrhea Mouse Model

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Kristie L. Connolly ◽  
Ann E. Eakin ◽  
Carolina Gomez ◽  
Blaire L. Osborn ◽  
Magnus Unemo ◽  
...  
Keyword(s):  
Single Dose ◽  
Mouse Model ◽  
Infection Model ◽  
Pharmacokinetic Data ◽  
Drug Resistant ◽  
Genital Tract Infection ◽  
Clear Dose Response ◽  
Dosing Regimens ◽  
Strain Fa1090

ABSTRACTThere is a pressing need for drug development for gonorrhea. Here we describe a pharmacokinetic (PK)/pharmacodynamic (PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. The PK determined in uninfected mice displayed a clear dose-response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESC-susceptible (ESCs) strain FA1090 were 5 mg/kg of body weight (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (the time that the free drug concentration remains above the MIC [fTMIC]) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against ESC-resistant (ESCr) strain H041. However, fractionation (three times a day every 8 h [TIDq8h]) of a 120-mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to the findings for gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤50% of mice, with the therapeutic times estimated from single-dose PK data being 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships observed in mice reflected those observed in humans, within vivoefficacy against an ESCsstrain requiring doses that yielded anfTMICin excess of 20 to 24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCrstrain and were useful in designing effective dosing regimens.

scholarly journals In VivoPharmacodynamics of Torezolid Phosphate (TR-701), a New Oxazolidinone Antibiotic, against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Strains in a Mouse Thigh Infection Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3453-3460 ◽  
Author(s):  
Arnold Louie ◽  
Weiguo Liu ◽  
Robert Kulawy ◽  
G. L. Drusano
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTTorezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potentin vitroactivity against Gram-positive bacteria, including methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) againstS. aureusis incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model ofS. aureusinfection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA,in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.

scholarly journals Pharmacodynamics of the New Fluoroquinolone Gatifloxacin in Murine Thigh and Lung Infection Models

2002 ◽  
Vol 46 (6) ◽  
pp. 1665-1670 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Time Course ◽  
Peak Level ◽  
Lung Infection ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Infection Models ◽  
The Family ◽  
Multiple Pathogens

ABSTRACT Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 106.5 to 107.4 CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log10 numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R 2 = 90 to 94% for the three organisms, whereas R 2 = 70 to 81% for peak level/MIC and R 2 = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 106.5 to 107.4 CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 108.3 CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 μg/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean ± standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 ± 21, 52 ± 20, and 36 ± 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection.

scholarly journals Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

2012 ◽  
Vol 56 (11) ◽  
pp. 5916-5922 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Solen Pichereau ◽  
William A. Craig ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Active Form ◽  
Maximum Effect ◽  
Time Curve ◽  
Content Type ◽  
Dosing Regimens ◽  
Staphylococcus Aureus Pneumonia ◽  
Unit Reduction

ABSTRACTTedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potentStaphylococcus aureusactivity. The current studies characterized and compared thein vivopharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptibleS. aureus(MSSA) and methicillin-resistantS. aureus(MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates ofS. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log10CFU/lungs, which increased to 7.92 ± 1.02 log10CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (Emax) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.

scholarly journals Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models

2006 ◽  
Vol 50 (1) ◽  
pp. 243-249 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Time Course ◽  
Lung Infection ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Strain Atcc ◽  
Beta Lactam ◽  
Time Curve ◽  
Infection Models ◽  
Resistant Strains

ABSTRACT XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 106.8 to 108.4 CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and −1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 106.1 to 107.8 CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 μg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs ± standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 ± 10 and 31 ± 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.

scholarly journals Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

2021 ◽  
Vol 12 ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Roger L. Nation
Keyword(s):  
Time Course ◽  
Biological Fluids ◽  
Total Daily Dose ◽  
Infection Model ◽  
Full Time ◽  
Time Curve ◽  
Antibiotic Development ◽  
New Antibiotics

Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids. This enabled the linking of antibacterial response at a single time point in an animal or in vitro infection model with one of three summary pharmacokinetic (PK) measures of in vivo exposure to the antibiotic. The summary PK exposure measures were normalised to the minimum inhibitory concentration (MIC), an in vitro measure of the pharmacodynamic (PD) potency of the drug. The three PK-PD indices (ratio of maximum concentration to MIC, ratio of area under the concentration-time curve to MIC, time concentration is above MIC) have been used extensively since the 1980s. While these MIC-based summary PK-PD metrics have undoubtedly facilitated the development of new antibiotics and the clinical application of both new and old antibiotics, it is increasingly recognised that they have a number of substantial limitations. In this article we use a historical perspective to review the origins of the three traditional PK-PD indices before exploring in detail their limitations and the implications arising from those limitations. Finally, in the interests of improving antibiotic development and dosing in patients, we consider a model-based approach of linking the full time-course of antibiotic concentrations with that of the antibacterial response. Such an approach enables incorporation of other factors that can influence treatment outcome in patients and has the potential to drive model-informed precision dosing of antibiotics into the future.

scholarly journals Activity of Amoxicillin-Clavulanate against Penicillin-Resistant Streptococcus pneumoniae in an Experimental Respiratory Infection Model in Rats

1998 ◽  
Vol 42 (4) ◽  
pp. 813-817 ◽  
Author(s):  
Gillian M. Smith ◽  
Brian Slocombe ◽  
Karen H. Abbott ◽  
Linda W. Mizen
Keyword(s):  
Streptococcus Pneumoniae ◽  
Infection Model ◽  
Time Curve ◽  
Penicillin Binding Proteins ◽  
Amoxicillin Clavulanate ◽  
Potassium Clavulanate ◽  
Differential Binding ◽  
High Doses ◽  
Oral Doses

ABSTRACT High doses of amoxicillin, equivalent to those produced by 500- and 750-mg oral doses in humans (area under the plasma concentration-time curve), were effective against a penicillin-resistant strain ofStreptococcus pneumoniae in an experimental respiratory tract infection in immunocompromised rats; this superior activity confirms the results of previous studies. An unexpected enhancement of amoxicillin’s antibacterial activity in vivo against penicillin-resistant and -susceptible S. pneumoniaestrains was observed when subtherapeutic doses of amoxicillin were coadministered with the β-lactamase inhibitor potassium clavulanate. The reason for this enhancement was unclear since these organisms do not produce β-lactamase. The differential binding of clavulanic acid and amoxicillin to penicillin-binding proteins may have contributed to the observed effects.

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