scholarly journals Use of anInVitroPharmacodynamic Model To Derive a Moxifloxacin Regimen That Optimizes Kill ofYersinia pestisand Prevents Emergence of Resistance

2010 ◽  
Vol 55 (2) ◽  
pp. 822-830 ◽  
Author(s):  
A. Louie ◽  
H. S. Heine ◽  
B. VanScoy ◽  
A. Eichas ◽  
K. Files ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Dose Range ◽  
Human Infection ◽  
Pharmacodynamic Model ◽  
Dose Fractionation ◽  
Time Curve ◽  
Infection Models ◽  
Animal Infection ◽  
Emergence Of Resistance

ABSTRACTYersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the “gold standards” for the treatment of plague. However, streptomycin is not available in many countries, andY. pestisisolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity againstY. pestisinin vitroand animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted forY. pestisin anin vitropharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing ofY. pestisand with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptibleY. pestis, while theCmax(maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due toY. pestisin 99.8% of subjects and would prevent resistance amplification. We conclude that in anin vitropharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment ofY. pestisinfections in humans. Studies of moxifloxacin in animal models of plague are warranted.

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 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 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 Isoniazid Pharmacokinetics-Pharmacodynamics in an Aerosol Infection Model of Tuberculosis

2004 ◽  
Vol 48 (8) ◽  
pp. 2951-2957 ◽  
Author(s):  
Ramesh Jayaram ◽  
Radha. K. Shandil ◽  
Sheshagiri Gaonkar ◽  
Parvinder Kaur ◽  
B. L. Suresh ◽  
...  
Keyword(s):  
Dose Fractionation ◽  
Maximum Effect ◽  
Infection Model ◽  
Limited Data ◽  
Time Curve ◽  
Bactericidal Efficacy ◽  
Infection Models ◽  
Bactericidal Activities ◽  
Aerosol Infection

ABSTRACT Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r 2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r 2 = 0.73).

scholarly journals Activity of Colistin against Heteroresistant Acinetobacter baumannii and Emergence of Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2007 ◽  
Vol 51 (9) ◽  
pp. 3413-3415 ◽  
Author(s):  
Chun-Hong Tan ◽  
Jian Li ◽  
Roger L. Nation
Keyword(s):  
Continuous Infusion ◽  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Growth Control ◽  
Pharmacodynamic Model ◽  
Bacterial Density ◽  
Control Population ◽  
Emergence Of Resistance

ABSTRACT Three clinically relevant intermittent regimens, and a continuous infusion, of colistin were simulated in an in vitro pharmacokinetic/pharmacodynamic model against two colistin-heteroresistant strains of Acinetobacter baumannii. Extensive initial killing was followed by regrowth as early as 6 h later; bacterial density in the 24- to 72-h period was within 1 log10 CFU/ml of growth control. Population analysis profiles revealed extensive emergence of resistant subpopulations regardless of the colistin regimen.

scholarly journals 682. In Vivo Pharmacodynamics of VNRX-7145 in the Neutropenic Murine Thigh Infection Model When Administered in Combination with Humanized Exposures of Twice Daily Ceftibuten (CTB) Against Serine β-Lactamase-Producing Enterobacteriaceae (SBL-EB)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S311-S311 ◽  
Author(s):  
Lindsay M Avery ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Complicated Urinary Tract Infection ◽  
Dose Fractionation ◽  
Intrinsic Activity ◽  
Infection Model ◽  
Bacterial Burden ◽  
Dose Ratio ◽  
Time Curve ◽  
In Vitro Susceptibility

Abstract Background There is a pressing need for development of oral antibiotics with activity against SBL-EB, particularly carbapenemase-producers, for use in the community or as step-down therapy for complicated urinary tract infection. VNRX-7145 is a novel boronic acid-based SBL inhibitor with no intrinsic activity that was designed as an orally bioavailable prodrug. The active moiety (VNRX-5236) is known to restore in vitro susceptibility to (CTB), an oral cephalosporin, among CTB-resistant SBL-EB. Methods CTB-resistant SBL-EB (N = 21) with CTB MICs ≥32 µg/mL and CTB/VNRX-5236 MIC range 0.12–2 µg/mL (VNRX-5236 fixed at 4 µg/mL) were evaluated. Carbapenemases were produced by 9 strains (4 OXA, 5 KPC). Bacterial suspensions (~107 CFU/mL) were used to inoculate the thighs of neutropenic mice. A human-simulated regimen of ceftibuten (CTB HSR) equivalent to a 400 mg q12h dosage was developed in infected mice. In dose ranging studies, groups of 3 animals each received the CTB HSR as monotherapy or combined with escalating VNRX-5236 exposures (CTB:VNRX-5236 dose ratios ranging from 10:1 to 1:4). Efficacy was assessed as the change in log10 CFU/thigh at 24 hours from 0 hour burden. With previous in vivo dose fractionation studies indicating the free area under the VNRX-5236 concentration–time curve to MIC ratio (fAUC0-24/MIC) as the PK/PD driver of efficacy, the Hill equation was used to estimate the magnitude required to achieve a static endpoint. Results Compared with 0 hour controls (mean log10 CFU/thigh, 5.7 ± 0.3), the bacterial burden for all isolates increased in saline-dosed controls and CTB HSR groups by 3.1 ± 0.8 and 2.5 ± 0.8 log10 CFU/thigh, respectively. The addition of VNRX-5236 resulted in bacterial stasis in 20/21 strains; the mean reduction in bacterial burden with the 1:1 CTB:VNRX-5236 dose ratio was −0.2 ± 0.7 log10 CFU/thigh. A composite assessment of exposure-responses indicated a fAUC0-24/MIC of 9.0 (R2 = 0.70) was associated with stasis. Conclusion Against CTB-resistant SBL-EB, inclusive of OXA-48- and KPC-producing strains, VNRX-5236 potentiated the in vivo activity of the CTB human-simulated exposure. The identified fAUC0-24/MIC target associated with bacterial stasis should be considered when selecting VNRX-7145 doses for clinical studies. Disclosures All authors: No reported disclosures.

scholarly journals Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

2004 ◽  
Vol 48 (3) ◽  
pp. 946-953 ◽  
Author(s):  
Boubakar B. Ba ◽  
Hala Feghali ◽  
Corinne Arpin ◽  
Marie-Claude Saux ◽  
Claudine Quentin
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Combined Therapy ◽  
Bacterial Count ◽  
Repeated Administration ◽  
Pharmacodynamic Model ◽  
Cross Resistance ◽  
Bacterial Cells ◽  
Time Curve ◽  
Resistant Mutants

ABSTRACT A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h. Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 μg/ml, respectively). The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs. The surviving bacterial cells were quinolone-resistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics. Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s). C max/MIC and area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin. Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC0-48, 342.3 to 401.3 versus 295.2 to 378.7 h × log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC0-48, 40.4 to 101.1 versus 72.9 to 144.7 h × log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S. maltophilia. However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S. maltophilia infections.

scholarly journals Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

2008 ◽  
Vol 53 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Fenglei Huang ◽  
Kristin Drda ◽  
Thomas R. MacGregor ◽  
Joseph Scherer ◽  
Lois Rowland ◽  
...  
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Dose Range ◽  
Dose Interval ◽  
Phase Ii Trials ◽  
Time Curve ◽  
Minimum Concentration ◽  
Oral Dosing ◽  
Repeated Dosing

ABSTRACT The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

scholarly journals Bactericidal Effect and Pharmacodynamics of Cethromycin (ABT-773) in a Murine Pneumococcal Pneumonia Model

2002 ◽  
Vol 46 (10) ◽  
pp. 3185-3192 ◽  
Author(s):  
Myo-Kyoung Kim ◽  
Wen Zhou ◽  
Pamela R. Tessier ◽  
Dawei Xuan ◽  
Min Ye ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Drug Exposure ◽  
Bactericidal Effect ◽  
Free Drug ◽  
Bacterial Density ◽  
Maximum Effect ◽  
Time Curve ◽  
Initiation Of Therapy

ABSTRACT Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 107 to 108 CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality (n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log10 CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log10 CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log10 CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect (E max) model revealed that the maximum concentration of free drug in serum (C max free)/MIC and the area under the free drug concentration-time curve (AUCfree)/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUCfree/MIC of 50 or C max free/MIC of 1 results in bacteriostatic effects, while higher values (twofold) maximize survival.

scholarly journals Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional time-kill method.

1997 ◽  
Vol 41 (11) ◽  
pp. 2527-2532 ◽  
Author(s):  
M Manduru ◽  
L B Mihm ◽  
R L White ◽  
L V Friedrich ◽  
P A Flume ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Drug Exposure ◽  
Growth Conditions ◽  
Pharmacodynamic Model ◽  
Drug Concentrations ◽  
Bactericidal Activities ◽  
Time Kill ◽  
In Vivo Pharmacokinetics

Bactericidal activity, historically assessed by in vitro tests which employ fixed drug concentrations, may also be evaluated in in vitro pharmacodynamic models in which in vivo pharmacokinetics and bacterial growth conditions can be simulated. However, systematic comparisons between the two methods are lacking. We evaluated the bactericidal activities of ceftazidime, at two different concentration/MIC ratios (C/MICs), against 10 clinical isolates of Pseudomonas aeruginosa in a two-compartment model with continuous-infusion conditions and a 2-h half-life. These values were compared to those determined by traditional 24-h time-kill (TTK) methods at the same C/MICs. Bactericidal activities were compared by using area under the colony count-time curves. Antibiotic exposure (area under the drug concentration-time curve) was also evaluated. Although bactericidal activity appeared greater by the TTK method (P = 0.05), when it was normalized for drug exposure, these differences disappeared (P = 0.2). This disparity was likely due to differences in drug exposure in the TTK method and in the peripheral compartment of the model (site of bacteria) over the first 8 h of the experiment, during which the antibiotic accumulated to target concentrations. This suggests that the bactericidal effects with constant antibiotic concentrations are similar in the two methods; however, this may not hold true with fluctuating drug concentrations. Further, results from the pharmacodynamic model may theoretically be more relevant, as in vivo pharmacokinetics and bacterial growth conditions call be more faithfully simulated.

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