scholarly journals Studies on the ultrastructure of fibrin lacking fibrinopeptide B (beta- fibrin)

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1073-1081 ◽  
Author(s):  
MW Mosesson ◽  
JP DiOrio ◽  
MF Muller ◽  
JR Shainoff ◽  
KR Siebenlist ◽  
...  
Keyword(s):  
Fibrin Clot ◽  
Fiber Bundles ◽  
Normal Product ◽  
Cable Network ◽  
Thick Fiber ◽  
Diminished Capacity ◽  
Mean Diameter ◽  
Alpha Beta ◽  
Self Aggregation ◽  
Fibrin Clots

Release of fibrinopeptide B from fibrinogen by copperhead venom procoagulant enzyme results in a form of fibrin (beta-fibrin) with weaker self-aggregation characteristics than the normal product (alpha beta-fibrin) produced by release of fibrinopeptides A (FPA) and B (FPB) by thrombin. We investigated the ultrastructure of these two types of fibrin as well as that of beta-fibrin prepared from fibrinogen Metz (A alpha 16 Arg----Cys), a homozygous dysfibrinogenemic mutant that does not release FPA. At 14 degrees C and physiologic solvent conditions (0.15 mol/L of NaCl, 0.015 mol/L of Tris buffer pH 7.4), the turbidity (350 nm) of rapidly polymerizing alpha beta-fibrin (thrombin 1 to 2 U/mL) plateaued in less than 6 min and formed a “coarse” matrix consisting of anastomosing fiber bundles (mean diameter 92 nm). More slowly polymerizing alpha beta-fibrin (thrombin 0.01 and 0.001 U/mL) surpassed this turbidity after greater than or equal to 60 minutes and concomitantly developed a network of thicker fiber bundles (mean diameters 118 and 186 nm, respectively). Such matrices also contained networks of highly branched, twisting, “fine” fibrils (fiber diameters 7 to 30 nm) that are usually characteristic of matrices formed at high ionic strength and pH. Slowly polymerizing beta-fibrin, like slowly polymerizing alpha beta-fibrin, displayed considerable quantities of fine matrix in addition to an underlying thick cable network (mean fiber diameter 135 nm), whereas rapidly polymerizing beta-fibrin monomer was comprised almost exclusively of wide, poorly anastomosed, striated cables (mean diameter 212 nm). Metz beta-fibrin clots were more fragile than those of normal beta-fibrin and were comprised almost entirely of a fine network. Metz fibrin could be induced, however, to form thick fiber bundles (mean diameter 76 nm) in the presence of albumin at a concentration (500 mumol/L) in the physiologic range and resembled a Metz plasma fibrin clot in that regard. The diminished capacity of Metz beta-fibrin to form thick fiber bundles may be due to impaired use or occupancy of a polymerization site exposed by FPB release. Our results indicate that twisting fibrils are an inherent structural feature of all forms of assembling fibrin, and suggest that mature beta-fibrin or alpha beta-fibrin clots develop from networks of thin fibrils that have the ability to coalesce to form thicker fiber bundles.

scholarly journals Studies on the ultrastructure of fibrin lacking fibrinopeptide B (beta- fibrin)

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1073-1081 ◽  
Author(s):  
MW Mosesson ◽  
JP DiOrio ◽  
MF Muller ◽  
JR Shainoff ◽  
KR Siebenlist ◽  
...  
Keyword(s):  
Fibrin Clot ◽  
Fiber Bundles ◽  
Normal Product ◽  
Cable Network ◽  
Thick Fiber ◽  
Diminished Capacity ◽  
Mean Diameter ◽  
Alpha Beta ◽  
Self Aggregation ◽  
Fibrin Clots

Abstract Release of fibrinopeptide B from fibrinogen by copperhead venom procoagulant enzyme results in a form of fibrin (beta-fibrin) with weaker self-aggregation characteristics than the normal product (alpha beta-fibrin) produced by release of fibrinopeptides A (FPA) and B (FPB) by thrombin. We investigated the ultrastructure of these two types of fibrin as well as that of beta-fibrin prepared from fibrinogen Metz (A alpha 16 Arg----Cys), a homozygous dysfibrinogenemic mutant that does not release FPA. At 14 degrees C and physiologic solvent conditions (0.15 mol/L of NaCl, 0.015 mol/L of Tris buffer pH 7.4), the turbidity (350 nm) of rapidly polymerizing alpha beta-fibrin (thrombin 1 to 2 U/mL) plateaued in less than 6 min and formed a “coarse” matrix consisting of anastomosing fiber bundles (mean diameter 92 nm). More slowly polymerizing alpha beta-fibrin (thrombin 0.01 and 0.001 U/mL) surpassed this turbidity after greater than or equal to 60 minutes and concomitantly developed a network of thicker fiber bundles (mean diameters 118 and 186 nm, respectively). Such matrices also contained networks of highly branched, twisting, “fine” fibrils (fiber diameters 7 to 30 nm) that are usually characteristic of matrices formed at high ionic strength and pH. Slowly polymerizing beta-fibrin, like slowly polymerizing alpha beta-fibrin, displayed considerable quantities of fine matrix in addition to an underlying thick cable network (mean fiber diameter 135 nm), whereas rapidly polymerizing beta-fibrin monomer was comprised almost exclusively of wide, poorly anastomosed, striated cables (mean diameter 212 nm). Metz beta-fibrin clots were more fragile than those of normal beta-fibrin and were comprised almost entirely of a fine network. Metz fibrin could be induced, however, to form thick fiber bundles (mean diameter 76 nm) in the presence of albumin at a concentration (500 mumol/L) in the physiologic range and resembled a Metz plasma fibrin clot in that regard. The diminished capacity of Metz beta-fibrin to form thick fiber bundles may be due to impaired use or occupancy of a polymerization site exposed by FPB release. Our results indicate that twisting fibrils are an inherent structural feature of all forms of assembling fibrin, and suggest that mature beta-fibrin or alpha beta-fibrin clots develop from networks of thin fibrils that have the ability to coalesce to form thicker fiber bundles.

scholarly journals Incorporation of α2-Plasmin Inhibitor into Fibrin Clots and Its Association with the Clinical Outcome of Acute Ischemic Stroke Patients

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 347
Author(s):  
Zsuzsa Bagoly ◽  
Barbara Baráth ◽  
Rita Orbán-Kálmándi ◽  
István Szegedi ◽  
Réka Bogáti ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Intracranial Hemorrhage ◽  
Intravenous Thrombolysis ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Stroke Patients ◽  
Plasmin Inhibitor ◽  
Fibrin Clots

Cross-linking of α2-plasmin inhibitor (α2-PI) to fibrin by activated factor XIII (FXIIIa) is essential for the inhibition of fibrinolysis. Little is known about the factors modifying α2-PI incorporation into the fibrin clot and whether the extent of incorporation has clinical consequences. Herein we calculated the extent of α2-PI incorporation by measuring α2-PI antigen levels from plasma and serum obtained after clotting the plasma by thrombin and Ca2+. The modifying effect of FXIII was studied by spiking of FXIII-A-deficient plasma with purified plasma FXIII. Fibrinogen, FXIII, α2-PI incorporation, in vitro clot-lysis, soluble fibroblast activation protein and α2-PI p.Arg6Trp polymorphism were measured from samples of 57 acute ischemic stroke patients obtained before thrombolysis and of 26 healthy controls. Increasing FXIII levels even at levels above the upper limit of normal increased α2-PI incorporation into the fibrin clot. α2-PI incorporation of controls and patients with good outcomes did not differ significantly (49.4 ± 4.6% vs. 47.4 ± 6.7%, p = 1.000), however it was significantly lower in patients suffering post-lysis intracranial hemorrhage (37.3 ± 14.0%, p = 0.004). In conclusion, increased FXIII levels resulted in elevated incorporation of α2-PI into fibrin clots. In stroke patients undergoing intravenous thrombolysis treatment, α2-PI incorporation shows an association with the outcome of therapy, particularly with thrombolysis-associated intracranial hemorrhage.

scholarly journals Predictive value of C-reactive protein for radiographic spinal progression in axial spondyloarthritis in dependence on genetic determinants of fibrin clot formation and fibrinolysis

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001751
Author(s):  
Berthold Hoppe ◽  
Christian Schwedler ◽  
Hildrun Haibel ◽  
Maryna Verba ◽  
Fabian Proft ◽  
...  
Keyword(s):  
Predictive Value ◽  
Axial Spondyloarthritis ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Genetic Determinants ◽  
C Reactive Protein ◽  
Inception Cohort ◽  
Reactive Protein ◽  
A Subunit ◽  
Fibrin Clots

ObjectiveGenetic determinants of fibrin clot formation and fibrinolysis have an impact on local and systemic inflammatory response. The aim of the present study was to assess whether coagulation-related genotypes affect the predictive value of C-reactive protein (CRP) in regards of radiographic spinal progression in axial spondyloarthritis (axSpA).MethodsTwo hundred and eight patients with axSpA from the German Spondyloarthritis Inception Cohort were characterised for genotypes of α-fibrinogen, β-fibrinogen (FGB) and γ-fibrinogen, factor XIII A-subunit (F13A) and α2-antiplasmin (A2AP). The relation between CRP levels and radiographic spinal progression defined as worsening of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by ≥2 points over 2 years was assessed in dependence on the respective genetic background in logistic regression analyses.ResultsOverall, CRP was associated with mSASSS progression ≥2 points: time-averaged CRP ≥10 mg/L, OR: 3.32, 95% CI 1.35 to 8.13. After stratification for coagulation-related genotypes, CRP was strongly associated with mSASSS progression in individuals predisposed to form loose, fibrinolysis-susceptible fibrin clots (FGB rs1800790GG, OR: 6.86, 95% CI 2.08 to 22.6; A2AP 6Trp, OR: 5.86, 95% CI 1.63 to 21.0; F13A 34Leu, OR: 8.72, 95% CI 1.69 to 45.1), while in genotypes predisposing to stable fibrin clots, the association was absent or weak (FGB rs1800790A, OR: 0.83, 95% CI 0.14 to 4.84; A2AP 6Arg/Arg, OR: 1.47, 95% CI 0.35 to 6.19; F13A 34Val/Val, OR: 1.72, 95% CI 0.52 to 5.71).ConclusionsElevated CRP levels seem to be clearly associated with radiographic spinal progression only if patients are predisposed for loose fibrin clots with high susceptibility to fibrinolysis.

Down-regulation of activated factor XIII by polymorphonuclear granulocyte proteases within fibrin clot

2007 ◽  
Vol 98 (08) ◽  
pp. 359-367 ◽  
Author(s):  
Zsuzsa Bagoly ◽  
Gizella Haramura ◽  
László Muszbek
Keyword(s):  
Factor Xiii ◽  
Proteolytic Enzymes ◽  
Fibrin Clot ◽  
Cathepsin G ◽  
Proteolytic Degradation ◽  
Clotting Factors ◽  
Down Regulation ◽  
Elastase Inhibitor ◽  
Partial Protection ◽  
Fibrin Clots

SummaryActivated clotting factors are down-regulated by two major mechanisms which involve protease inhibitors or proteolytic degradation. To date, no down-regulating mechanism for activated factor XIII (FXIIIa) has been demonstrated. As the hemostatic plug contains polymorphonuclear granulocytes (PMNs) rich in proteolytic enzymes, we tested if these proteases are released in fibrin clots, and become involved in the down-regulation of FXIIIa.The supernatant of stimulated granulocytes proteolytically degraded and inactivated FXIIIa. In the fibrin clot formed from fibrinogen solution elastase, cathepsin G and matrix metalloprotease-9 (MMP-9) were released from granulocytes without any external stimulus. PMN proteases released in fibrin clot exerted a fibrinolytic effect and almost completely de-graded both FXIII subunits.The elastase inhibitor, ONO 5046, partially inhibited the proteolytic degradation of FXIII in PMNsupplemented fibrin clots. Cathepsin G and MMP-9 inhibitors provided less protection; in these cases intermediate split products accumulated.The proteolytic degradation of FXIII by PMNs was also significant when the clot was made from whole plasma. The main plasma protease inhibitor, α1-antitrypsin, provided only partial protection. In the fibrin clot which contained α1-antitrypsin FXIIIa was degraded by PMN proteases significantly faster than cross-linked fibrin.The results suggest that the degradation of FXIII subunits by the concerted action of PMN proteases released within the clot represents a novel mechanism for the down-regulation of FXIIIa.

scholarly journals Synergistic Effect of Bypassing Agents and Sequence Identical Analogue of Emicizumab and Fibrin Clot Structure in the In Vitro Model of Hemophilia A

TH Open ◽  
2020 ◽  
Vol 04 (02) ◽  
pp. e94-e103
Author(s):  
Yanan Zong ◽  
Aleksandra Antovic ◽  
Nida Mahmoud Hourani Soutari ◽  
Jovan Antovic ◽  
Iva Pruner
Keyword(s):  
In Vitro Model ◽  
Hemophilia A ◽  
Fibrin Clot ◽  
Substantial Improvement ◽  
Activated Prothrombin Complex Concentrate ◽  
Bypassing Agents ◽  
Vitro Model ◽  
Clot Structure ◽  
Fibrin Clots

AbstractDevelopment of inhibitors to factor VIII (FVIII) occurs in approximately 30% of severe hemophilia A (HA) patients. These patients are treated with bypassing agents (activated prothrombin complex concentrate [aPCC] and recombinant activated FVII-rFVIIa). Recently, a bispecific FIX/FIXa- and FX/FXa-directed antibody (emicizumab) has been approved for the treatment of HA patients with inhibitors. However, the data from clinical studies imply that coadministration of emicizumab and bypassing agents, especially aPCC, could have a thrombotic effect.This study was aimed to address the question of potential hypercoagulability of emicizumab and bypassing agents' coadministration, we have investigated fibrin clot formation and structure in the in vitro model of severe HA after adding sequence-identical analogue (SIA) of emicizumab and bypassing agents.Combined overall hemostasis potential (OHP) and fibrin clot turbidity assay was performed in FVIII-deficient plasma after addition of different concentrations of SIA, rFVIIa, and aPCC. Pooled normal plasma was used as control. The fibrin clots were analyzed by scanning electron microscopy (SEM).OHP and turbidity parameters improved with the addition of aPCC, while therapeutic concentrations of rFVIIa did not show substantial improvement. SIA alone and in combination with rFVIIa or low aPCC concentration improved OHP and turbidity parameters and stabilized fibrin network, while in combination with higher concentrations of aPCC expressed hypercoagulable pattern and generated denser clots.Our in vitro model suggests that combination of SIA and aPCC could potentially be prothrombotic, due to hypercoagulable changes in fibrin clot turbidity and morphology. Additionally, combination of SIA and rFVIIa leads to the formation of stable clots similar to normal fibrin clots.

Retraction Of Fibrin Clots By Cultured Endothelial Cells

1981 ◽  
Author(s):  
B Barbieri ◽  
G Balconi ◽  
E Dejana ◽  
M B Donati
Keyword(s):  
Endothelial Cells ◽  
Primary Cultures ◽  
Fibrin Clot ◽  
Test System ◽  
In Vitro Test ◽  
Clot Retraction ◽  
System L ◽  
Vitro Test ◽  
Fibrin Clots

The interactions between endothelial cells (EC) and fibrin are still poorly understood. We approached this problem by studying the ability of cultured EC to induce in vitro the retraction of fibrin clots. EC were obtained from bovine aorta and human umbilical veins by collagenase treatment and grown in Eagle MEM. At the time of the test the cells were harvested from the flask by a short trypsin-EDTA treatment and resuspended in tyrode solution. The test system involved incubation of the cell suspension in a water-bath at 37°C in the presence of cell-free plasma which was clotted by thrombin. The course of retraction was followed by measuring the diameter of the clot with a microcaliper. Retraction values were expressed after calculation of percent activity by an appropriate formula. EC were found to induce the retraction of the fibrin clot to an extent which increased with the time (1-24 h) and with the number of cells in the system (l-4×l06/ml f.c.). Fibrin clot retractile (FCR) activity of EC could not be detected at 22°C or in presence of Na2-EDTA or using mechanically disrupted cells. Moreover, using batroxobin instead of thrombin as a clotting agent, no retraction occurred; FCR of EC thus showed many characteristics in common with platelet- and fibroblast- induced clot retraction.FCR activity of bovine EC increased with the number of subcultures, being very low in cells harvested from primary cultures. In contrast, human EC had high activity in primary cultures. Similarly to fibroblasts, EC with higher density in culture showed lower FCR, suggesting that con-fluency inhibits the cell contractile capacity.FCR could thus represent a simple in vitro test to further characterize the biology of EC and to evaluate their role in the development of fibrin thrombi.

Reduced Fibrinolysis in the Hepatic Venous Occlusive Disease: Effect of Defibrotide on Plasmin Activity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1992-1992
Author(s):  
Cinara Echart ◽  
Cinzia Repice ◽  
Laura Ferro ◽  
Kenneth Anderson ◽  
Paul Richardson ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Clinical Studies ◽  
Fibrinolytic Activity ◽  
Fibrin Clot ◽  
Occlusive Disease ◽  
Dependent Manner ◽  
Plasmin Activity ◽  
Plasminogen Activator Inhibitor 1 ◽  
Presence And Absence ◽  
Fibrin Clots

Abstract Introduction: The fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease (VOD) after stem cells transplantation (SCT). Defibrotide (DF) is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and anti-adhesive properties. Numerous clinical studies have shown promising results with DF in the treatment of VOD, with minimal toxicity. In laboratory studies, DF has been shown to decrease plasminogen activator inhibitor-1 (PAI-1), increase tissue plasminogen activator (t-PA) levels and increase the overall plasma fibrinolytic activity in patients with VOD. Similar results have been observed in pre-clinical studies with endothelial cells stimulated by lipopolysaccharide. Plasmin is a potent and nonspecific serine protease, generated from the proenzyme plasminogen by plasminogen activators. Plasmin plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. The purpose of this study was to investigate whether DF is capable of modulating the activity of plasmin in different in vitro studies. Method: Plasmin activity was measured in the presence and absence of DF, at different concentrations, by following the cleavage of the chromogenic substrate S-2251. S-2251 contains the preferential cleavage site for plasmin and mimics the fibrin polymer substrate present in fibrin clots. In addition, we evaluated the activity of plasmin generated by t-PA and urokinase-plasminogen activation as well as the plasmin activity in plasma in the presence and absence of DF. Further, plasmin activity generated in fibrin clot plate was measured in the presence and absence of DF. Finally, the inhibition of plasmin by aminocaproic acid was tested in these systems. Results: DF increased the activity of plasmin, to hydrolyze its substrate, in a dose dependent manner. Similar concentration-dependent effects of DF were observed when plasmin was generated by t-PA or urokinase activation of plasminogen and on plasmin in plasma samples (p<0.001). In contrast, DF had no direct effect in activation of plasminogen to plasmin. We also showed that DF was able to enhance the activity of plasmin to degrade the fibrin clot formed from fibrinogen, plasminogen and thrombin (p<0.001). This effect was concentration dependent and directly correlated with the enzymatic activity of plasmin. Conclusion: The present study demonstrates that DF is capable of enhancing the activity of plasmin. The stimulation of plasmin by DF was concentration-dependent. These findings can, in part, explain the fibrinolytic activity of DF and support its effect in restoring the fibrinolytic vascular phenotype in conditions such as VOD.

scholarly journals BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

2017 ◽  
Vol 117 (02) ◽  
pp. 295-302 ◽  
Author(s):  
Katie A. Greenhalgh ◽  
Mark W. Strachan ◽  
Saad Alzahrani ◽  
Paul D. Baxter ◽  
Kristina F. Standeven ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasma Clot ◽  
Lysis Time ◽  
Increased Risk ◽  
Fibrin Network ◽  
Clot Lysis Time ◽  
Fibrin Clots

SummaryBoth type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

scholarly journals Kinetics of fibrin clot lysis

1968 ◽  
Vol 106 (1) ◽  
pp. 101-105 ◽  
Author(s):  
R. J. Merrills ◽  
J. T. B. Shaw
Keyword(s):  
Plasminogen Activator ◽  
Experimental Studies ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Lysis Time ◽  
Kinetics Of ◽  
Fibrin Clots

The principles relating the lysis times of fibrin clots to their contents of fibrin, plasminogen and plasminogen-activator were investigated. Mathematical considerations suggested that the square of the lysis time should correlate linearly with the fibrin content, and inversely with the activator and the plasminogen contents of the system. Experimental studies, during which these parameters were independently varied, showed that the predicted relationships were valid for concentrations that gave clot-lysis times in the range normally used for studies of fibrinolysis.

scholarly journals Activities of Trovafloxacin, Gatifloxacin, Clinafloxacin, Sparfloxacin, Levofloxacin, and Ciprofloxacin against Penicillin-Resistant Streptococcus pneumoniae in an In Vitro Infection Model

2000 ◽  
Vol 44 (3) ◽  
pp. 598-601 ◽  
Author(s):  
Ellie Hershberger ◽  
Michael J. Rybak
Keyword(s):  
Streptococcus Pneumoniae ◽  
Fibrin Clot ◽  
Infection Model ◽  
Significant Activity ◽  
Time Curve ◽  
Horse Blood ◽  
Bactericidal Activities ◽  
Lysed Horse Blood ◽  
Fibrin Clots

ABSTRACT We adapted an in vitro pharmacodynamic model of infection to incorporate infected fibrin clots. The bactericidal activities of various fluoroquinolones against two strains of penicillin-resistantStreptococcus pneumoniae were studied over a 48-h period. Bacteria were prepared in Muller-Hinton broth by using colonies from a 24-h tryptic soy agar plus 5% sheep blood plate and were added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 106 CFU of organism per fibrin clot. The fibrin clots were suspended into the models and removed, in triplicate, at various time points over 48 h. Control models were also conducted to characterize the growth of S. pneumoniae in the growth medium without antibiotic. Trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were administered to simulate their pharmacokinetic profiles in humans. Fibrin clot samples were also plated onto antibiotic-containing tryptic soy agar plus 5% lysed horse blood to detect resistance. The newer fluoroquinolones demonstrated better activity than ciprofloxacin against both isolates. In conclusion, the newer quinolones demonstrated significant activity against penicillin-resistant S. pneumoniae, with standard dosing resulting in area under the concentration-time curve/MIC ratios and peak concentration/MIC ratios that resulted in 99.9% killing against these isolates.

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