scholarly journals Activity of Telavancin against Staphylococcus aureus Strains with Various Vancomycin Susceptibilities in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

2009 ◽  
Vol 53 (7) ◽  
pp. 2928-2933 ◽  
Author(s):  
Steven N. Leonard ◽  
Céline Vidaillac ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
In Vitro Model ◽  
Therapeutic Potential ◽  
Population Analysis ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Vitro Model

ABSTRACT We investigated the activity of telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 ± 0.5 for MRSA 494, 2.8 ± 0.3 for MSSA 1199, 4.2 ± 0.2 for hGISA 1629, and 4.1 ± 0.3 for GISA NJ 992. Combinations of telavancin with gentamicin significantly enhanced killing compared to telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in telavancin susceptibilities were observed. These results suggest that telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.

scholarly journals Synergistic Killing of Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula by Colistin Combined with Doripenem in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2011 ◽  
Vol 55 (12) ◽  
pp. 5685-5695 ◽  
Author(s):  
Phillip J. Bergen ◽  
Brian T. Tsuji ◽  
Jurgen B. Bulitta ◽  
Alan Forrest ◽  
Jovan Jacob ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Limit Of Detection ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Content Type ◽  
High Inoculum

ABSTRACTCombination therapy may be required for multidrug-resistant (MDR)Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDRP. aeruginosa. Studies were conducted in a one-compartmentin vitropharmacokinetic/pharmacodynamic model for 96 h at two inocula (∼106and ∼108CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 106- and 108-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.

scholarly journals The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in anIn VitroPharmacokinetic/Pharmacodynamic Model

2012 ◽  
Vol 56 (10) ◽  
pp. 5103-5112 ◽  
Author(s):  
Zakuan Z. Deris ◽  
Heidi H. Yu ◽  
Kathryn Davis ◽  
Rachel L. Soon ◽  
Jovan Jacob ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Resistant Isolate ◽  
Colistin Resistance ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTMultidrug-resistant (MDR)Klebsiella pneumoniaemay require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDRK. pneumoniaeand emergence of colistin resistance. A one-compartmentin vitropharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106and ∼108CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [Cmax] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 106-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 108-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (Cmax, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.

scholarly journals Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

2006 ◽  
Vol 50 (6) ◽  
pp. 1931-1936 ◽  
Author(s):  
Boubakar B. Ba ◽  
Corinne Arpin ◽  
Céline Vidaillac ◽  
Arnaud Chausse ◽  
Marie-Claude Saux ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Goodness Of Fit ◽  
Reference Strain ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Β Phase ◽  
Ciprofloxacin Resistance ◽  
Total Elimination ◽  
Gram Positive Cocci

ABSTRACT Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 μg/ml, respectively), its efflux mutant SA-1 (16 and 0.5 μg/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 μg/ml), Sa2667 (4 and 0.5 μg/ml), and Sa2669 (16 and 1 μg/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 μg/ml, respectively, and the corresponding half-life at β-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: −2.18 at the 1-h time point [t 1] and −6.80 at t 24 and t 48; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h × log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4- to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).

scholarly journals Beneficial Influence of Platelets on Antibiotic Efficacy in an In Vitro Model of Staphylococcus aureus-Induced Endocarditis

2004 ◽  
Vol 48 (7) ◽  
pp. 2551-2557 ◽  
Author(s):  
Renee-Claude Mercier ◽  
Robert M. Dietz ◽  
Jory L. Mazzola ◽  
Arnold S. Bayer ◽  
Michael R. Yeaman
Keyword(s):  
Staphylococcus Aureus ◽  
In Vitro Model ◽  
Antimicrobial Effect ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Activated Platelets ◽  
Vitro Model ◽  
Antibiotic Efficacy ◽  
Chamber Fluid

ABSTRACT Platelets contribute to antimicrobial host defense against infective endocarditis (IE) by releasing platelet microbicidal proteins (PMPs). We investigated the influence of thrombin-stimulated human platelets on the evolution of simulated IE in the presence and absence of vancomycin or nafcillin. Staphylococcus aureus strains differing in intrinsic susceptibility to PMPs or antibiotics were studied: ISP479C (thrombin-induced PMP-1 [tPMP-1] susceptible; nafcillin and vancomycin susceptible), ISP479R (tPMP-1 resistant; nafcillin and vancomycin susceptible), and GISA-NJ (tPMP-1 intermediate-susceptible; vancomycin intermediate-susceptible). Platelets were introduced and thrombin activated within the in vitro IE model 30 min prior to inoculation with S. aureus. At 0 to 24 h postinoculation, bacterial densities in chamber fluid and simulated endocardial vegetations (SEVs) were quantified and compared among groups. Activated platelets alone, or in combination with antibiotics, inhibited the proliferation of ISP479C in chamber fluid or SEVs over the initial 4-h period (P < 0.05 versus controls). Moreover, nafcillin-containing regimens exerted inhibitory effects beyond 4 h against ISP479C in both model phases. By comparison, activated platelets inhibited GISA-NJ proliferation in SEVs but not in chamber fluid. The combination of platelets plus nafcillin or vancomycin significantly inhibited proliferation of the GISA-NJ strain in SEVs compared to the effect of platelets or antibiotics alone (P < 0.05). In contrast, platelets did not significantly alter the antistaphylococcal efficacies of nafcillin or vancomycin against ISP479R. These data support our hypothesis that a beneficial antimicrobial effect may result from the interaction among platelets, PMPs, and anti-infective agents against antibiotic-susceptible or -resistant staphylococci that exhibit a tPMP-1-susceptible or -intermediate-susceptible phenotype.

Pharmacokinetically-based prediction of the effects of antibiotic combinations on resistant Staphylococcus aureus mutants: in vitro model studies with linezolid and rifampicin

2016 ◽  
Vol 29 (4) ◽  
pp. 220-226 ◽  
Author(s):  
Alexander A. Firsov ◽  
Maria V. Golikova ◽  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Svetlana A. Dovzhenko ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Vitro Model ◽  
Model Studies ◽  
Vitro Model

scholarly journals In Vitro Evaluation of the Activities of Telavancin, Cefazolin, and Vancomycin against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus in Peritoneal Dialysate

2007 ◽  
Vol 51 (12) ◽  
pp. 4521-4524 ◽  
Author(s):  
Frances L. Clouse ◽  
Laurie B. Hovde ◽  
John C. Rotschafer
Keyword(s):  
Staphylococcus Aureus ◽  
Peritoneal Dialysis ◽  
In Vitro Model ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Dialysis Fluid ◽  
Methicillin Resistant ◽  
Peritoneal Dialysate ◽  
Peritoneal Dialysis Fluid ◽  
Vitro Model

ABSTRACT This study compared the ability of telavancin to the ability of cefazolin and vancomycin to eliminate staphylococci from peritoneal dialysis fluid by using a static in vitro model to simulate the conditions of peritoneal dialysis. The results showed that telavancin exhibited statistically significantly better kill (P < 0.05) against both methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

scholarly journals In VitroPharmacodynamics of Vancomycin and Cefazolin Alone and in Combination against Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 56 (1) ◽  
pp. 202-207 ◽  
Author(s):  
Mao Hagihara ◽  
Dora E. Wiskirchen ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Synergistic Effects ◽  
Bacterial Density ◽  
Bacterial Killing ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Mics ◽  
Time Kill

ABSTRACTPrevious studies employing time-kill methods have observed synergistic effects against methicillin-resistantStaphylococcus aureus(MRSA) when a β-lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. Four clinical isolates (two MRSA isolates [vancomycin MICs, 0.5 and 2.0 μg/ml], a heterogeneous vancomycin-intermediateS. aureus[hVISA] isolate [MIC, 2.0 μg/ml], and a vancomycin-intermediateS. aureus[VISA] isolate [MIC, 8.0 μg/ml]) were evaluated in anin vitropharmacodynamic model with a starting inoculum of 106or 108CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 106CFU/ml studies, combination therapy achieved greater log10CFU/ml changes than vancomycin alone at 12 h (−4.31 ± 0.58 versus −2.80 ± 0.59,P< 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ± 14) compared with vancomycin alone (148 ± 22,P= 0.017). Similar results were observed during 108CFU/ml studies, where combination therapy achieved greater log10CFU/ml changes at 12 h than vancomycin alone (−4.00 ± 0.20 versus −1.10 ± 0.04,P< 0.001) and significantly reduced the AUBC (275 ± 30 versus 429 ± 37,P< 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments.

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