scholarly journals Pharmacodynamics of Moxifloxacin and Levofloxacin at Simulated Epithelial Lining Fluid Drug Concentrations against Streptococcus pneumoniae

2004 ◽  
Vol 48 (4) ◽  
pp. 1215-1221 ◽  
Author(s):  
Naomi R. Florea ◽  
Pamela R. Tessier ◽  
Cuilian Zhang ◽  
Charles H. Nightingale ◽  
David P. Nicolau
Keyword(s):  
Streptococcus Pneumoniae ◽  
Fluoroquinolone Resistance ◽  
Epithelial Lining ◽  
Time Curve ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Log Reduction ◽  
Development Of Resistance ◽  
Drug Concentrations

ABSTRACT Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC, gyrA, and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.

scholarly journals Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

2002 ◽  
Vol 46 (12) ◽  
pp. 4029-4034 ◽  
Author(s):  
Ayman M. Noreddin ◽  
Danielle Roberts ◽  
Kim Nichol ◽  
Aleksandra Wierzbowski ◽  
Daryl J. Hoban ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Compartment Model ◽  
Free Drug ◽  
Pharmacodynamic Modeling ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Initial Inoculum ◽  
Drug Concentrations

ABSTRACT The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug Cp maximum of 2 μg/ml, t 1/2 of 6 h; in ELF, C ELF(total) maximum of 35μg/ml, t 1/2 of 6 h; CELF(free) maximum of 14 μg/ml, t 1/2 of 6 h). Starting inocula were 106 CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of ≥90% (AUC0-24/MIC ratio, ≥61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC0-24/MIC ratios of ≥30.5 to 38) resulted in a 1.2 to 2.0 log10 CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of ≤8% (AUC0-24/MIC ratio, ≤17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 μg/ml. However, mef(A) isolates for which MICs are ≥16 μg/ml along with erm(B) may result in bacteriological failures.

scholarly journals Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux (mefE)-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary

2005 ◽  
Vol 49 (5) ◽  
pp. 1943-1948 ◽  
Author(s):  
George G. Zhanel ◽  
Christel Johanson ◽  
Nancy Laing ◽  
Tamiko Hisanaga ◽  
Aleksandra Wierzbowski ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Area Under The Curve ◽  
Free Drug ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Initial Inoculum ◽  
Drug Concentrations ◽  
Vitro Model

ABSTRACT The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 μg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C max] in serum, 0.7 μg/ml; half-life [t 1/2], 10 h; free-drug C max in ELF, 6.0 μg/ml; t 1/2, 10 h). Starting inocula were 106 CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log10 CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C max 0.9 ± 0.08 μg/ml, area under the curve to MIC (AUC0-24 h) 6.4 ± 1.5 μg · h/ml, and t 1/2 of 10.6 ± 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C max 6.6 ± 0.8 μg/ml, AUC0-24 h 45.5 ± 5.5 μg · h/ml, and t 1/2 of 10.5 ± 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 μg/ml and 1 μg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C max/MIC ≥ 3.5 and AUC0-24 h/MIC ≥ 25 completely eradicated (≥4 log10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C max/MIC ≥ 1.8 and AUC0-24 h/MIC ≥ 12.5 were bacteriostatic (0.1 to 0.2 log10 killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C max/MIC ≥ 3.5 and AUC0-24 h/MIC ≥ 25 completely eradicated (≥4 log10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant Staphylococcus aureus (MRSA): Implications for Dosing in MRSA Pneumonia

2009 ◽  
Vol 53 (9) ◽  
pp. 3894-3901 ◽  
Author(s):  
Yoriko Harigaya ◽  
Jürgen B. Bulitta ◽  
Alan Forrest ◽  
George Sakoulas ◽  
Alan J. Lesse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pharmacodynamic Model ◽  
Type Model ◽  
High Dose ◽  
Optimal Dosage ◽  
Epithelial Lining ◽  
Time Curve ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
The Impact

ABSTRACT Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC24]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC24/MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr-functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 108 CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a ƒAUC24/MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (ƒAUC24/MIC ≤ 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (ƒAUC24/MIC ≥ 280) suppressed development of resistance. Resistant mutants amplified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model (r 2 ≥ 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (r 2 ≥ 0.965). Due to the emergence of vancomycin-intermediate resistance at a ƒAUC24/MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.

scholarly journals Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

2003 ◽  
Vol 47 (8) ◽  
pp. 2606-2614 ◽  
Author(s):  
George P. Allen ◽  
Glenn W. Kaatz ◽  
Michael J. Rybak
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pharmacodynamic Model ◽  
The Other ◽  
Time Curve ◽  
Development Of Resistance ◽  
Concentration Time ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT The differential effects of moxifloxacin and levofloxacin on the development of resistance in four Streptococcus pneumoniae isolates were examined by using an in vitro pharmacodynamic model. Therapeutic regimens (moxifloxacin: peak, 4.5 μg/ml; half-life [t 1/2], 12 h; and levofloxacin: peak, 6 μg/ml; t 1/2, 6 h) were tested against two fluoroquinolone-susceptible isolates (strains 79 and ATCC 49619) and KD2138 and KD2139 (parC and gyrA mutants, respectively, of ATCC 49619). Mutant prevention concentration (MPC)-targeted regimens with modified pharmacokinetics of each drug were simulated to match the area under the concentration-time curve (AUC) above the MPC for the two fluoroquinolones. Moxifloxacin MICs and MPCs (MIC/MPC) for isolates 79, ATCC 49619, KD2138, and KD2139, respectively, were 0.125 and 0.5, 0.125 and 0.5, 0.25 and 8, and 0.25 and 4 μg/ml. Levofloxacin MICs and MPCs for the same isolates were 1 and 4, 0.5 and 2, 1 and 64, and 0.5 and 32 μg/ml, respectively. Therapeutic levofloxacin concentrations led to isolation of mutants of ATCC 49619 (S79Y in ParC), KD2138 (S81Y in GyrA), and KD2139 (S79Y in ParC). Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates. MPC-targeted moxifloxacin (lower-than-normal peak = 0.75 to 1.5 μg/ml, administered at levofloxacin's t 1/2) caused growth of a GyrA variant (S81Y) of KD2138 and a ParC variant (S79Y) of KD2139, while no mutants of ATCC 49619 were recovered. MPC-targeted levofloxacin (higher-than-normal peak = 14.5 to 29.5 μg/ml, administered at moxifloxacin's t 1/2) against KD2138 and KD2139 did not prevent the development of the mutations observed in therapeutic regimens, but resistance in the fluoroquinolone-susceptible ATCC 49619 was no longer noted. Normalization of the respective AUC/MPC ratios of moxifloxacin and levofloxacin did not eliminate differences in resistance selectivity of the two agents in all cases. We conclude that the reduced recovery of resistant mutants of S. pneumoniae following moxifloxacin exposure compared to levofloxacin may be due to intrinsic differences between the drugs. Increasing the concentration and exposure (t 1/2) to exceed the MPC may prevent mutations from occurring in fluoroquinolone-susceptible strains. However, this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations. Further study of the MPC concept to evaluate these relationships is warranted.

scholarly journals Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

2013 ◽  
Vol 58 (1) ◽  
pp. 419-423 ◽  
Author(s):  
Odin J. Naderer ◽  
Keith A. Rodvold ◽  
Lori S. Jones ◽  
John Z. Zhu ◽  
Chester L. Bowen ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Alveolar Macrophages ◽  
Bacterial Infections ◽  
Time Course ◽  
Respiratory Pathogens ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time

ABSTRACTGSK1322322 is a potent peptide deformylase inhibitor within vitroandin vivoactivity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0–τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0–τfor ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0–τratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered atClinicalTrials.govunder registration number NCT01610388.)

scholarly journals Fluoroquinolone Resistance in Streptococcus pneumoniae: Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin

2007 ◽  
Vol 51 (4) ◽  
pp. 1315-1320 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Michael J. Rybak ◽  
Brian Tsuji ◽  
Thomas P. Lodise ◽  
Glenn W. Kaatz
Keyword(s):  
Streptococcus Pneumoniae ◽  
Sequence Analysis ◽  
Fluoroquinolone Resistance ◽  
Second Step ◽  
Wild Type ◽  
Time Curve ◽  
Resistance Development ◽  
Concentration Time ◽  
Structural Differences

ABSTRACT The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (108.5 to 109 log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and ≤60, 34 and 37, ≤82 and ≤86, and ≤24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P < 0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P < 0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin > gatifloxacin > moxifloxacin = gemifloxacin, which may be related to structural differences within the class.

scholarly journals Fluoroquinolone Resistance in Anaerobic Bacteria following Exposure to Levofloxacin, Trovafloxacin, and Sparfloxacin in an In Vitro Pharmacodynamic Model

2001 ◽  
Vol 45 (7) ◽  
pp. 2136-2140 ◽  
Author(s):  
Gigi H. Ross ◽  
David H. Wright ◽  
Laurie Baeker Hovde ◽  
Marnie L. Peterson ◽  
John C. Rotschafer
Keyword(s):  
In Vitro Model ◽  
Anaerobic Bacteria ◽  
Pharmacodynamic Model ◽  
Fluoroquinolone Resistance ◽  
Time Curve ◽  
Development Of Resistance ◽  
Concentration Time ◽  
Vitro Model

ABSTRACT This investigation explored pharmacodynamic characteristics of fluoroquinolones against Bacteroides thetaiotamicron and the potential for development of resistance. An in vitro model was used to generate kill curves with three fluoroquinolones at various area under the concentration-time curve (AUC)/MIC ratios. Concentration-independent killing was observed. Increases in MICs were noted following exposure to fluoroquinolones at AUC/MIC ratios of 6 to 14.

scholarly journals In VitroActivity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline, Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

2014 ◽  
Vol 58 (12) ◽  
pp. 7520-7526 ◽  
Author(s):  
Shawn H. MacVane ◽  
Wonhee So ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Pneumonia ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Response Change ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTStaphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment ofS. aureuspneumonia. Anin vitropharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). FourS. aureusisolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ∼106CFU/ml. Time-kill curves were constructed, and microbiological response (change in log10CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log10CFU/ml was largest for ceftaroline q8h (reductions of >3 log10CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P< 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log10CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log10CFU/ml increase). Against theseS. aureusisolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided forS. aureuspneumonia.

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