Anti-mutant efficacy of antibiotic combinations: in vitro model studies with linezolid and daptomycin

2021 ◽  
Author(s):  
Stephen H Zinner ◽  
Kamilla N Alieva ◽  
Maria V Golikova ◽  
Elena N Strukova ◽  
Yury A Portnoy ◽  
...  
Keyword(s):  
Dynamic Models ◽  
Aureus Strain ◽  
Once Daily ◽  
Model Studies ◽  
Drug Treatments ◽  
Resistant Mutants ◽  
Vitro Model ◽  
Mrsa Strains ◽  
Pharmacokinetic Simulations

Abstract Objectives To explore whether linezolid/daptomycin combinations can restrict Staphylococcus aureus resistance and if this restriction is associated with changes in the mutant prevention concentrations (MPCs) of the antibiotics in combination, the enrichment of resistant mutants was studied in an in vitro dynamic model. Methods Two MRSA strains, vancomycin-intermediate resistant ATCC 700699 and vancomycin-susceptible 2061 (both susceptible to linezolid and daptomycin), and their linezolid-resistant mutants selected by passaging on antibiotic-containing medium were used in the study. MPCs of antibiotics in combination were determined at a linezolid-to-daptomycin concentration ratio (1:2) that corresponds to the ratio of 24 h AUCs (AUC24s) actually used in the pharmacokinetic simulations. Each S. aureus strain was supplemented with respective linezolid-resistant mutants (mutation frequency 10−8) and treated with twice-daily linezolid and once-daily daptomycin, alone and in combination, simulated at therapeutic and sub-therapeutic AUC24s. Results Numbers of linezolid-resistant mutants increased at therapeutic and sub-therapeutic AUC24s, whereas daptomycin-resistant mutants were enriched only at sub-therapeutic AUC24 in single drug treatments. Linezolid/daptomycin combinations prevented the enrichment of linezolid-resistant S. aureus and restricted the enrichment of daptomycin-resistant mutants. The pronounced anti-mutant effects of the combinations were attributed to lengthening the time above MPC of both linezolid and daptomycin as their MPCs were lowered. Conclusions The present study suggests that (i) the inhibition of S. aureus resistant mutants using linezolid/daptomycin combinations can be predicted by MPCs determined at pharmacokinetically derived antibiotic concentration ratios and (ii) T>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations as studied using in vitro dynamic models.

scholarly journals Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Jordan R. Smith ◽  
Juwon Yim ◽  
Seth Rice ◽  
Kyle Stamper ◽  
Razie Kebriaei ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Treatment Options ◽  
Antagonistic Activity ◽  
Exact Nature ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vitro Model

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for health care-associated infections, and treatment options are limited. Tedizolid (TZD) is a novel oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP) has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD and DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs). TZD simulations of 200 mg once daily and DAP simulations of 6 mg/kg of body weight and 10 mg/kg once daily were tested alone and in the combinations TZD plus DAP at 6 mg/kg or DAP at 10 mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine the antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents. Against both strains 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 h. In all cases, DAP alone was statistically superior to DAP plus TZD. When the combination was stopped after 96 h, transitioning to DAP at 6 mg/kg or DAP at 10 mg/kg alone resulted in better antibacterial activity than either of the TZD-plus-DAP combinations, further demonstrating antagonistic effects. Against MRSA, we demonstrated that TZD and DAP have antagonistic activity that hinders their overall antimicrobial efficacy. The exact nature of this antagonistic relationship is still undetermined, but its presence warrants further study of the potentially harmful grouping of the two antibiotics in clinical use.

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

Epithelial-mesenchymal crosstalk in COPD: An update from in vitro model studies

2020 ◽  
Vol 125 ◽  
pp. 105775 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Tillie-Louise Hackett
Keyword(s):  
In Vitro Model ◽  
Model Studies ◽  
Vitro Model

scholarly journals Predictors of effect of ampicillin-sulbactam against TEM-1 beta-lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC.

1996 ◽  
Vol 40 (3) ◽  
pp. 734-738 ◽  
Author(s):  
A A Firsov ◽  
D Saverino ◽  
D Savarino ◽  
M Ruble ◽  
D Gilbert ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
In Vitro Model ◽  
Dynamic Models ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Time Curve ◽  
Peripheral Tissues ◽  
Vitro Model

The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 micrograms/ml) of the beta-lactamase inhibitor (MIC1). The enzyme activities (EA) and the MICs estimated at a constant ratio of ampicillin to sulbactam of 2:1 (MIC2) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were examined as alternatives to MIC1 as predictors of the antibacterial effects of this combined drug as studied in an in vitro model which simulates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hypothetical value (ABBC/ABBCmax) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBCmax, r = -0.91) and with MIC2 (r = 0.94, -0.94, and -0.95, respectively) but not with MIC1. Both EA and MIC2 can be considered reliable predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dynamic models might be useful to reexamine established susceptibility breakpoints obtained with data based on the MIC1 (MICs obtained with constant levels of beta-lactamase inhibitors). These data also suggest that quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and other beta-lactam-inhibitor combinations.

scholarly journals Using In Vitro Dynamic Models To Evaluate Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica Serovar Typhimurium

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Seung-Jin Lee ◽  
Elias Gebru Awji ◽  
Na-hye Park ◽  
Seung-Chun Park
Keyword(s):  
Salmonella Enterica ◽  
Dynamic Models ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Bacterial Killing ◽  
Mutant Prevention Concentration ◽  
Serovar Typhimurium ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR), and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug exposure were quantified. PK/PD indices associated with different levels of antibacterial activity were computed. Mechanisms of fluoroquinolone resistance were determined by analyzing target mutations in the quinolone resistance-determining regions (QRDRs) and by analyzing overexpression of efflux pumps. Maximum losses in susceptibility of fluoroquinolone-exposed S. Typhimurium occurred at a simulated AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 47 to 71. Target mutations in gyrA (S83F) and overexpression of acrAB-tolC contributed to decreased susceptibility in fluoroquinolone-exposed S. Typhimurium. The current data suggest AUC/MIC (AUC/mutant prevention concentration [MPC])-dependent selection of resistant mutants of S. Typhimurium, with AUC/MPC ratios of 69 (DIF), 62 (ENR), and 39 (MAR) being protective against selection of resistant mutants. These values could not be achieved in veterinary clinical areas under the current recommended therapeutic doses of the fluoroquinolones, suggesting the need to reassess the current dosing regimen to include both clinical efficacy and minimization of emergence of resistant bacteria.

scholarly journals Once-versus thrice-daily netilmicin combined with amoxicillin, penicillin, or vancomycin against Enterococcus faecalis in a pharmacodynamic in vitro model.

1996 ◽  
Vol 40 (10) ◽  
pp. 2258-2261 ◽  
Author(s):  
S Schwank ◽  
J Blaser
Keyword(s):  
Enterococcus Faecalis ◽  
Half Life ◽  
In Vitro Model ◽  
Bacterial Biofilm ◽  
In Vivo Studies ◽  
Bacterial Killing ◽  
Once Daily ◽  
Vitro Model

Several in vitro and in vivo studies as well as clinical trials have demonstrated that once-daily aminoglycoside regimens are as effective as or more effective than multiple daily dosings. However, the most favorable aminoglycoside dosing regimen for treating enterococcal endocarditis remains controversial. The same total dose of netilmicin was administered as once-daily (24-micrograms/ml peaks) and thrice-daily (8 micrograms/ml) regimens in a pharmacodynamic in vitro model simulating exposure of Enterococcus faecalis to human serum kinetics. Netilmicin was administered in combination with continuous infusions of amoxicillin, vancomycin, or penicillin against a bacterial biofilm adhering to glass beads. No significant differences in bacterial killing were found after 24 or 48 h between the once- and thrice-daily regimens. Additional experiments considering animal kinetics (half-life of netilmicin, 20 min) instead of human kinetics (half-life, 2.5 h) in the pharmacodynamic model also revealed similar results. The addition of netilmicin synergistically increased the activity of vancomycin (P < 0.05). In contrast, amoxicillin alone was as effective as the combination with netilmicin. Thus, it could not be established in this model that once-daily dosing of aminoglycosides is contraindicated for treating infections caused by E. faecalis.

scholarly journals In vivo and in vitro model studies on noodles prepared with antioxidant-rich pseudocereals

2019 ◽  
Vol 13 (4) ◽  
pp. 2696-2704 ◽  
Author(s):  
Attila Kiss ◽  
Krisztina Takács ◽  
András Nagy ◽  
Magdolna Nagy-Gasztonyi ◽  
Zsuzsanna Cserhalmi ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Model Studies ◽  
Vitro Model
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