MPC-Based Prediction of Anti-Mutant Effectiveness of Antibiotic Combinations: In Vitro Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

To explore whether combined treatments with daptomycin and gentamicin can prevent the development of Staphylococcus aureus resistance, and whether the possible restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicin-resistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model. The MPCs of the antibiotics in the combination were determined at concentration ratios equal to the ratios of 24 h areas, under the concentration–time curve (AUCs) of the antibiotics, as simulated in pharmacodynamic experiments. The MPCs of both daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the time when antibiotic concentrations were above the MPC (T>MPC). The increases in T>MPCs were concurrent with increases of the anti-mutant effects of the combined antibiotics. When anti-mutant effects of the antibiotics in single and combined treatments were plotted against the T>MPCs, significant sigmoid relationships were obtained. These findings suggest that (1) daptomycin–gentamicin combinations prevent the development of S. aureus resistance to each antibiotic; (2) the anti-mutant effects of antibiotic combinations can be predicted using MPCs determined at pharmacokinetic-based antibiotic concentration ratios; (3) T>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations.

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Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.7.2642-2647.2005 ◽

2005 ◽

Vol 49 (7) ◽

pp. 2642-2647 ◽

Cited By ~ 16

Author(s):

Alexander A. Firsov ◽

Irene Y. Lubenko ◽

Sergey N. Vostrov ◽

Yury A. Portnoy ◽

Stephen H. Zinner

Keyword(s):

In Vitro Model ◽

Therapeutic Potential ◽

Area Under The Curve ◽

Antimicrobial Effect ◽

Clinical Isolates ◽

Clinical Settings ◽

Time Curve ◽

Concentration Time ◽

Vitro Model

ABSTRACT Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC50 or the MIC90 and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (IE ) was associated with each quinolone. Based on the IE -log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUCthers), the AUCther/MIC50 ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUCther/MIC50 to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.7.2136-2140.2001 ◽

2001 ◽

Vol 45 (7) ◽

pp. 2136-2140 ◽

Cited By ~ 15

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.

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Verification of a Novel Approach to Predicting Effects of Antibiotic Combinations: In Vitro Dynamic Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

Antibiotics ◽

10.3390/antibiotics9090538 ◽

2020 ◽

Vol 9 (9) ◽

pp. 538

Author(s):

Maria V. Golikova ◽

Elena N. Strukova ◽

Yury A. Portnoy ◽

Stephen H. Zinner ◽

Alexander A. Firsov

Keyword(s):

Staphylococcus Aureus ◽

Dynamic Model ◽

Antimicrobial Effect ◽

Aureus Strain ◽

Combined Treatments ◽

Antibacterial Effects ◽

Multiple Dosing ◽

Time Curve ◽

Concentration Ratios

To explore whether susceptibility testing with antibiotic combinations at pharmacokinetically derived concentration ratios is predictive of the antimicrobial effect, a Staphylococcus aureus strain was exposed to daptomycin and gentamicin alone or in combination in multiple dosing experiments. The susceptibility of the S. aureus strain to daptomycin and gentamicin in combination was tested at concentration ratios equal to the ratios of 24 h areas under the concentration–time curve (AUC24s) of antibiotics simulated in an in vitro dynamic model in five-day treatments. The MICs of daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the antibiotic AUC24/MIC ratios and the antibacterial effects. Effects of single and combined treatments were plotted against the AUC24/MIC ratios of daptomycin or gentamicin, and a significant sigmoid relationship was obtained. Similarly, when the effects of single and combined treatments were related to the total exposure of both drugs (the sum of AUC24/MIC ratios (∑AUC24/MIC)), a significant sigmoid relationship was obtained. These findings suggest that (1) the effects of antibiotic combinations can be predicted by AUC24/MICs using MICs of each antibacterial determined at pharmacokinetically derived concentration ratios; (2) ∑AUC24/MIC is a reliable predictor of the antibacterial effects of antibiotic combinations.

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Linezolid-daptomycin combinations against total and resistant Staphylococcus aureus populations: in vitro model studies

10.26226/morressier.5f4ccc57648d3d8b3f362c1a ◽

2020 ◽

Author(s):

Kamilla Alieva ◽

Maria Golikova

Keyword(s):

Staphylococcus Aureus ◽

In Vitro Model ◽

Model Studies ◽

Vitro Model

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Influence of biofilm removal from the tooth-restoration interface on the progression of secondary caries lesions: a preliminary in vitro model study

Biofouling ◽

10.1080/08927014.2020.1870219 ◽

2021 ◽

pp. 1-12

Author(s):

Cácia Signori ◽

Tamires Timm Maske ◽

Vitor Henrique Digmayer Romero ◽

Maximiliano Sérgio Cenci

Keyword(s):

In Vitro Model ◽

Secondary Caries ◽

Model Study ◽

Biofilm Removal ◽

Vitro Model ◽

Caries Lesions

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Effect of fluoride-releasing restorative materials on bacteria-induced pH fall at the bacteria–material interface: An in vitro model study

Journal of Dentistry ◽

10.1016/j.jdent.2013.11.006 ◽

2014 ◽

Vol 42 (1) ◽

pp. 15-20 ◽

Cited By ~ 22

Author(s):

Gen Mayanagi ◽

Koei Igarashi ◽

Jumpei Washio ◽

Hitomi Domon-Tawaraya ◽

Nobuhiro Takahashi

Keyword(s):

In Vitro Model ◽

Material Interface ◽

Model Study ◽

Restorative Materials ◽

Vitro Model

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Potential of Raloxifene in reversing osteoarthritis-like alterations in rat chondrocytes: An in vitro model study

Journal of Biosciences ◽

10.1007/s12038-012-9282-7 ◽

2012 ◽

Vol 38 (1) ◽

pp. 135-147 ◽

Cited By ~ 14

Author(s):

Aysegul Kavas ◽

Seda Tuncay Cagatay ◽

Sreeparna Banerjee ◽

Dilek Keskin ◽

Aysen Tezcaner

Keyword(s):

In Vitro Model ◽

Model Study ◽

Vitro Model

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Dose ranging and fractionation of intravenous ciprofloxacin against Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of infection.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.37.9.1756 ◽

1993 ◽

Vol 37 (9) ◽

pp. 1756-1763 ◽

Cited By ~ 42

Author(s):

C R Marchbanks ◽

J R McKiel ◽

D H Gilbert ◽

N J Robillard ◽

B Painter ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

In Vitro Model ◽

Dose Ranging ◽

Vitro Model ◽

And Staphylococcus Aureus

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Studies in Cranial Suture Biology: In Vitro Cranial Suture Fusion

The Cleft Palate-Craniofacial Journal ◽

10.1597/1545-1569_1996_033_0150_sicsbv_2.3.co_2 ◽

1996 ◽

Vol 33 (2) ◽

pp. 150-156 ◽

Cited By ~ 22

Author(s):

James P. Bradley ◽

Jamie P. Levine ◽

Christopher Blewett ◽

Thomas Krummel ◽

Joseph G. Mccarthy ◽

...

Keyword(s):

Organ Culture ◽

In Vitro Model ◽

In Vitro Study ◽

Cranial Base ◽

Cranial Suture ◽

Model Study ◽

Suture Fusion ◽

Vitro Model

The biology underlying craniosynostosis remains unknown. Previous studies have shown that the underlying dura mater, not the suture itself, signals a suture to fuse. The purpose of this study was to develop an in vitro model for cranial-suture fusion that would still allow for suture-dura interaction, but without the influence of tensional forces transmitted from the cranial base. This was accomplished by demonstrating that the posterior frontal mouse cranial suture, known to be the only cranial suture that fuses in vivo, fuses when plated with its dura in an organ-culture system. In such an organ-culture system, the sutures are free from both the influence of dural forces transmitted from the cranial base and from hormonal influences only available in a perfused system. For the cranial-suture fusion in vitro model study, the sagittal sutures (controls that remain patent in vivo) and posterior frontal sutures (that fuse in vivo) with the underlying dura were excised from 24-day-old euthanized mice, cut into 5 × 4 × 2-mm specimens, and cultured in a chemically defined, serum-free media. One hundred sutures were harvested at the day of sacrifice, then every 2 days thereafter until 30 days in culture, stained with H & E, and analyzed. A subsequent cranial-suture without dura in vitro study was performed in a similar fashion to the first study, but only the calvariae with the posterior frontal or sagittal sutures (without the underlying dura) were cultured. Results from the cranial-suture fusion in vitro model study showed that all sagittal sutures placed in organ culture with the underlying dura remained patent. More importantly, the posterior frontal sutures with the underlying dura, which were plated-down as patent at 24 days of age, demonstrated fusion after various growth periods in organ culture. In vitro posterior frontal mouse-suture fusion occurred in an anterior-to-posterior direction but in a delayed fashion, 4 to 7 days later than in vivo posterior frontal mouse-suture fusion. In contrast, the subsequent cranial-suture without dura in vitro study showed patency of all sutures, including the posterior frontal suture. These data from in vitro experiments indicate that: (1) mouse calvariae, sutures, and the underlying dura survive and grow in organ-culture systems for 30 days; (2) the local dura, free from external influences transmitted from the cranial base and hormones from distant sites, influences the cells of its overlying suture to cause fusion; and (3) without dura influence, all in vitro cranial sutures remained patent. By first identifying the factors involved in dural-suture signaling and then regulating these factors and their receptors, the biologic basis of suture fusion and craniosynostosis may be unraveled and used in the future to manipulate pathologic (premature) suture fusion.

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