scholarly journals Impact of High-Inoculum Staphylococcus aureus on the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model

2004 ◽  
Vol 48 (12) ◽  
pp. 4665-4672 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
Bacteriostatic Activity ◽  
High Inoculum ◽  
Dosing Regimens ◽  
The Impact

ABSTRACT We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 ± 1.1, 3.28 ± 0.4, and 3.34 ± 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 ± 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.

scholarly journals Short-Course Gentamicin in Combination with Daptomycin or Vancomycin against Staphylococcus aureus in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2005 ◽  
Vol 49 (7) ◽  
pp. 2735-2745 ◽  
Author(s):  
Brian T. Tsuji ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Single High Dose ◽  
Short Course ◽  
Dosing Regimens ◽  
Combination Regimens ◽  
The Impact

ABSTRACT The ability to maximize bactericidal activity while minimizing toxicity is a therapeutic goal in the treatment of infective endocarditis. We evaluated the impact of administering short-course regimens of gentamicin in combination with daptomycin or vancomycin against one methicillin-susceptible (MSSA 1199) and one methicillin-resistant (MRSA 494) Staphylococcus aureus isolate using an in vitro pharmacodynamic model with simulated endocardial vegetations over 96 h. Human therapeutic dosing regimens for daptomycin (6 and 8 mg/kg of body weight), vancomycin, and gentamicin were simulated. Short-course combination regimens involving gentamicin were administered either as a single 5-mg/kg dose or three 1-mg/kg doses for only the first 24 h and compared to the regimens administered for the full 96-h duration. For all experiments, physiologic conditions of albumin, calcium, and pH were simulated. Both regimens of daptomycin achieved 99.9% kill by 32 h and maintained bactericidal activity against both isolates, which was significantly different from vancomycin, which displayed bacteriostatic activity (P < 0.05). The effects of all short-course regimens of gentamicin were equal to those of the full-duration regimens in combination with daptomycin. Adding three doses of gentamicin (1 mg/kg) to daptomycin resulted in enhancement and bactericidal activity at 24 h against both MRSA and MSSA. The addition of a single dose of gentamicin (5 mg/kg) enhanced or improved the activity of daptomycin and resulted in early bactericidal activity at 4 h against both isolates. The addition of three doses of gentamicin (1 mg/kg) did not improve the activity of vancomycin. However, the addition of a single 5-mg/kg dose of gentamicin to vancomycin resulted in early enhancement at 4 h and 99.9% kill at 32 h for MRSA. These results suggest that a single high dose of gentamicin in combination with daptomycin or vancomycin may be of utility to maximize synergistic and bactericidal activity and minimize toxicity. Further investigation is warranted.

scholarly journals Impact of Inoculum Size and Heterogeneous Vancomycin-Intermediate Staphylococcus aureus (hVISA) on Vancomycin Activity and Emergence of VISA in an In Vitro Pharmacodynamic Model

2008 ◽  
Vol 53 (2) ◽  
pp. 805-807 ◽  
Author(s):  
Warren E. Rose ◽  
Steven N. Leonard ◽  
Kerri L. Rossi ◽  
Glenn W. Kaatz ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Bacterial Load ◽  
Inoculum Size ◽  
Pharmacodynamic Model ◽  
High Inoculum ◽  
High Bacterial Load

ABSTRACT The activity of vancomycin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and non-hVISA isolates, using an in vitro pharmacodynamic model, was reduced in the presence of a high inoculum amount (108 CFU/ml). A high bacterial load of >105 CFU/ml persisted for all strains with doses up to 5 g every 12 h against high inoculum amounts. No change in the vancomycin MIC was detected in any isolate at a moderate inoculum amount (106 CFU/ml), and bactericidal activity occurred only against the non-hVISA isolate (time to 99% kill, 7.5 h; P = 0.001).

scholarly journals Bactericidal Activities of Daptomycin, Quinupristin-Dalfopristin, and Linezolid against Vancomycin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2003 ◽  
Vol 47 (12) ◽  
pp. 3960-3963 ◽  
Author(s):  
Raymond Cha ◽  
William J. Brown ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
High Inoculum ◽  
Vancomycin Resistant ◽  
Bactericidal Activities ◽  
Treatment Alternatives

ABSTRACT In search of treatment alternatives against vancomycin-resistant S. aureus (VRSA), an in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein and a high inoculum was used to simulate daptomycin, linezolid, quinupristin-dalfopristin, and vancomycin against the Michigan VRSA strain. Daptomycin and quinupristin-dalfopristin exhibited the greatest bacterial reductions, and all tested agents except vancomycin exhibited bactericidal activity against the VRSA.

scholarly journals Evaluation of Daptomycin Pharmacodynamics and Resistance at Various Dosage Regimens against Staphylococcus aureus Isolates with Reduced Susceptibilities to Daptomycin in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2008 ◽  
Vol 52 (9) ◽  
pp. 3061-3067 ◽  
Author(s):  
Warren E. Rose ◽  
Steven N. Leonard ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Bactericidal Activity ◽  
Treatment Options ◽  
High Dose ◽  
Poor Treatment ◽  
Dosing Regimens ◽  
Vitro Model ◽  
The Impact

ABSTRACT The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard- and high-dose daptomycin in combination with gentamicin or rifampin against daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the daptomycin-susceptible strains. Concentration-dependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose daptomycin. These results suggest that high-dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.

scholarly journals Impact of Enterococcus faecalis on the Bactericidal Activities of Arbekacin, Daptomycin, Linezolid, and Tigecycline against Methicillin-Resistant Staphylococcus aureus in a Mixed-Pathogen Pharmacodynamic Model

2006 ◽  
Vol 50 (4) ◽  
pp. 1298-1303 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Michael J. Rybak ◽  
Kimberly D. Leuthner ◽  
Judy N. Chin
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Enterococcus Faecalis ◽  
Bactericidal Activity ◽  
Inhibitory Effect ◽  
Pharmacodynamic Model ◽  
Methicillin Resistant ◽  
Development Of Resistance ◽  
The Impact

ABSTRACT We inoculated an in vitro pharmacodynamic model simultaneously with clinical isolates of methicillin-resistant Staphylococcus aureus and an enterocin-producing enterococcus (vancomycin-resistant Enterococcus faecalis, ampicillin susceptible) at 7 log10 CFU/ml to examine enterocin effects and antimicrobial activity on staphylococci. The investigated antimicrobial regimens were 100 mg arbekacin every 12 h (q12h), 6 mg daptomycin per kg of body weight/day, 600 mg linezolid q12h, and 100 mg tigecycline q24h alone and in combination (daptomycin, linezolid, and tigecycline) with arbekacin. Simulations were performed in triplicate; bacterial quantification occurred over 48 h, and development of resistance was evaluated throughout. When we evaluated the impact of antimicrobial activity against S. aureus alone, daptomycin demonstrated bactericidal activity (≥3 log10 CFU/ml kill), whereas arbekacin, linezolid, and tigecycline displayed bacteriostatic activities (<3 log10 CFU/ml kill). In the mixed-pathogen model, early and distinctive stunting of S. aureus growth was noted (1.5 log CFU/ml difference) in the presence of enterocin-producing E. faecalis compared to growth controls run individually (P = 0.02). Most noteworthy was that in the presence of enterocin-producing E. faecalis, bactericidal activity was observed with arbekacin and tigecycline and with the addition of arbekacin to linezolid. Antagonism was noted for the combination of tigecycline and arbekacin against S. aureus in the presence of enterocin-producing E. faecalis. Our research demonstrates that the inhibitory effect of E. faecalis contributed significantly to its overall antimicrobial impact on S. aureus. This contribution was enhanced or improved compared to the activity of each antimicrobial alone. Further research is warranted to determine the impact of polymicrobial infections on antimicrobial activity.

Nemonoxacin enhances antibacterial activity and anti-resistant mutation ability of vancomycin against methicillin-resistant Staphylococcus aureus in an in vitro dynamic pharmacokinetic/pharmacodynamic model

2021 ◽  
Author(s):  
Junchen Huang ◽  
Siwei Guo ◽  
Xin Li ◽  
Fang Yuan ◽  
You Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
Methicillin Resistant ◽  
Mutant Prevention Concentration ◽  
Mrsa Infection ◽  
Independent Risk Factors ◽  
Resistant Mutation

Reduced susceptibility and emergence of resistance to vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) have led to the development of various vancomycin based combinations. Nemonoxacin is a novel nonfluorinated quinolone with antibacterial activity against MRSA. The present study aimed to investigate the effects of nemonoxacin on antibacterial activity and the anti-resistant mutation ability of vancomycin for MRSA and explore whether quinolone resistance genes are associated with a reduction in the vancomycin minimal inhibitory concentration (MIC) and mutant prevention concentration (MPC) when combined with nemonoxacin. Four isolates, all with a vancomycin MIC of 2 μg/mL, were used in a modified in vitro dynamic pharmacokinetic/pharmacodynamic model to investigate the effects of nemonoxacin on antibacterial activity (M04, M23 and M24) and anti-resistant mutation ability (M04, M23 and M25, all with MPC ≥19.2 μg/mL) of vancomycin. The mutation sites of gyrA , gyrB , parC , and parE of 55 clinical MRSA isolates were sequenced. We observed that in M04 and M23, the combination of vancomycin (1g q12h) and nemonoxacin (0.5g qd) showed a synergistic bactericidal activity and resistance enrichment suppression. All clinical isolates resistant to nemonoxacin harbored gyrA (S84→L) mutation; gyrA (S84→L) and parC (E84→K) mutations were the two independent risk factors for the unchanged vancomycin MPC in combination. Nemonoxacin enhances the bactericidal activity and suppresses resistance enrichment ability of vancomycin against MRSA with a MIC of 2 μg/mL. Our in vitro data support the combination of nemonoxacin and vancomycin for the treatment of MRSA infection with a high MIC.

scholarly journals Dalbavancin, Vancomycin and Daptomycin Alone and in Combination with Cefazolin against Resistant Phenotypes of Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 696 ◽  
Author(s):  
Jacinda C. Abdul-Mutakabbir ◽  
Razieh Kebriaei ◽  
Kyle C. Stamper ◽  
Zain Sheikh ◽  
Philip T. Maassen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Inhibitory Concentration ◽  
Pharmacodynamic Model ◽  
In Vitro Tests ◽  
Beta Lactam ◽  
Fold Reduction ◽  
The One ◽  
Time Kill

The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p < 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.

scholarly journals Attenuated Vancomycin Bactericidal Activity against Staphylococcus aureus hemB Mutants Expressing the Small-Colony-Variant Phenotype

2008 ◽  
Vol 52 (4) ◽  
pp. 1533-1537 ◽  
Author(s):  
Brian T. Tsuji ◽  
Christof von Eiff ◽  
Pamela A. Kelchlin ◽  
Alan Forrest ◽  
Patrick F. Smith
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
Small Colony Variant ◽  
Variant Phenotype ◽  
Small Colony ◽  
Bactericidal Activities

ABSTRACT The in vitro bactericidal activities of vancomycin against Staphylococcus aureus hemB mutants displaying the small-colony-variant phenotype and their parental strains were evaluated. Vancomycin killing activities against hemB mutants were markedly attenuated, demonstrating approximately 50% less effect, a result which was well described by a Hill-type pharmacodynamic model.

scholarly journals Evaluation of Telavancin Activity versus Daptomycin and Vancomycin against Daptomycin-Nonsusceptible Staphylococcus aureus in anIn VitroPharmacokinetic/Pharmacodynamic Model

2011 ◽  
Vol 56 (2) ◽  
pp. 955-959 ◽  
Author(s):  
Molly E. Steed ◽  
Céline Vidaillac ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
Content Type ◽  
Initial Inoculum ◽  
Bactericidal Activities ◽  
Post Hoc ◽  
Dual Mechanism ◽  
Better Than

ABSTRACTDaptomycin-nonsusceptible (DNS)Staphylococcus aureusstrains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNSS. aureusstrains, CB1814, R6212, and SA-684, were evaluated in anin vitropharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 108.5CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter;t1/2, 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter;t1/2, 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter;t1/2, 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey'spost hoctest. Bactericidal activity was defined as a ≥3-log10CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; −4.31 log10CFU/g), SA-684 (56 to 120 h; −3.06 log10CFU/g), and CB1814 (48 to 120 h; −4.9 log10CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P< 0.05). Telavancin displayed bactericidal activityin vitroagainst DNSS. aureusisolates.

scholarly journals Daptomycin Activity against Staphylococcus aureus following Vancomycin Exposure in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2007 ◽  
Vol 52 (3) ◽  
pp. 831-836 ◽  
Author(s):  
Warren E. Rose ◽  
Steven N. Leonard ◽  
George Sakoulas ◽  
Glenn W. Kaatz ◽  
Marcus J. Zervos ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Clinical Significance ◽  
Bactericidal Activity ◽  
Serial Passage ◽  
Pharmacodynamic Model ◽  
Clinical Isolates ◽  
Mssa Isolate

ABSTRACT Recently, the emergence of reduced susceptibility to daptomycin has been linked to the reduced vancomycin susceptibility that occurs after vancomycin exposure in Staphylococcus aureus in vivo and in vitro. This study evaluated this propensity in clinical isolates of S. aureus using an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations over 8 days. Five clinical isolates (four methicillin-resistant S. aureus isolates and one methicillin-susceptible S. aureus [MSSA] isolate), all of which were reported to have become nonsusceptible to daptomycin, were evaluated. The following regimens were evaluated: vancomycin 1 g every 12 h for 4 days followed by daptomycin 6 mg/kg of body weight daily for 4 days and daptomycin 6 mg/kg daily for 8 days. If nonsusceptibility was detected, the following regimens were evaluated: no treatment for 4 days followed by daptomycin 6 mg/kg daily for 4 days, vancomycin 1 g every 12 h for 4 days followed by daptomycin 10 mg/kg daily for 4 days, and daptomycin 10 mg/kg daily for 8 days. The emergence of daptomycin nonsusceptibility (12- to 16-fold MIC increase) was detected only with the MSSA isolate with daptomycin 6 mg/kg daily for 4 days after vancomycin exposure. However, the bactericidal activity of daptomycin was maintained and the MIC increases of these isolates, which had no mprF or yycG mutations, were unstable to serial passage on antibiotic-free agar. Subsequent regimens did not demonstrate nonsusceptibility to daptomycin. These findings suggest that reduced daptomycin susceptibility can be a strain-specific and unstable event. Further evaluation of the susceptibility relationship between daptomycin and vancomycin is necessary to understand the factors involved and their clinical significance.

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