fibrin and Pneumococcal-Infections

Topics: Adolescent; Adrenal Glands; Adult; Aged; Blood Coagulation Disorders; Child; Female; Fibrin; Hemorrhagic Disorders; Heparin; Humans; Kidney; Male; Meningitis; Middle Aged; Pneumococcal Infections; Sepsis; Splenectomy; Splenic Diseases; Thrombosis; Waterhouse-Friderichsen Syndrome

Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.. By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis.. In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis.. COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18).. Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk.

Topics: Case-Control Studies; COVID-19; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Intensive Care Units; Pneumococcal Infections; Thrombosis

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-resistant Streptococcus 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 10(6) 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.

Topics: Anti-Infective Agents; Blood Coagulation; Ciprofloxacin; Fibrin; Fluoroquinolones; Gatifloxacin; Humans; Levofloxacin; Microbial Sensitivity Tests; Naphthyridines; Ofloxacin; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae

Using a clinical pneumococcal strain for which MICs were 4, 2, and 32 mg/liter for penicillin, amoxicillin, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and their combinations in the treatment of prolonged (48-h) experimental fibrin clot infection in rabbits. Treatments were as follows: amoxicillin IV at 20 mg/kg of body weight in one dose (Amo20), 50 mg/kg in one dose (Amo50), or two doses 6 h apart (Amo20 x 2 and Amo50 x 2); fosfomycin IV at a fixed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apart (Fos50 x 2); or the combinations of amoxicillin and fosfomycin with the same schedules. Maximum concentrations in clots were 2.03 +/- 1.02 and 2.13 +/- 0.33 mg/liter for Amo20 regimens, 3.7 +/- 1.9 and 4 +/- 1.3 mg/liter for Amo50 regimens, and 24 +/- 7 and 40 +/- 8 mg/liter for fosfomycin regimens, respectively. The mean half-lives of elimination from clots were between 2 and 3 h for amoxicillin regimens and between 5 and 7 h for fosfomycin. We observed the highest bacterial reductions (log10 CFU/gram) for Amo50 in two divided doses with or without fosfomycin. A significantly higher bacterial reduction than that with each monotherapy was observed when Amo20 was combined with fosfomycin in either one dose or two doses 6 h apart (0.16 +/- 0.8 and 1.64 +/- 1.6 log10 CFU/g for Amo20 in one and two doses, respectively, and 0.93 +/- 0.81 and 0.61 +/- 0.56 log10 CFU/g for fosfomycin in one and two doses, respectively, versus 3.46 +/- 1.26 and 3.16 +/- 1.31 log10 CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]). A time-dependent effect was observed with amoxicillin regimens. The time of regrowth was significantly delayed when amoxicillin was combined with fosfomycin. By using a multivariate analysis, we demonstrated that the most important parameter correlated to efficacy of the combination amoxicillin-fosfomycin was the length of the period during which the concentration of amoxicillin remained above the MIC. We demonstrated that the in vivo efficacy of the combination of amoxicillin and fosfomycin gave higher antibacterial effect than each monotherapy.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Drug Therapy, Combination; Fibrin; Fosfomycin; Half-Life; Humans; Penicillin Resistance; Penicillins; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae

We studied the antipneumococcal efficacy of cefotaxime and vancomycin alone and a combination of cefotaxime with various dosages of vancomycin in the treatment of prolonged (48 h) experimental fibrin clot infections in rabbits. A clinical pneumococcal strain for which MICs were 2, 0.5 and 0.5 mg/L of penicillin, cefotaxime and vancomycin respectively, was used in this study. Cefotaxime was given iv at a fixed dose of 50 mg/kg and vancomycin iv at 1, 2.5, 5, 10 or 20 mg/kg. Maximal concentrations in clots were (mean +/- S.D.): 2.1 +/- 0.9, 1.1 +/- 0.4, 1.9 +/- 1, 2.3 +/- 1.5, 3.6 +/- 0.4 and 4 +/- 0.3 mg/g, respectively. The mean half-lives of elimination from clots were 2.2 h for cefotaxime and 7 h for vancomycin. We observed the highest bacterial reductions for the highest doses of vancomycin with or without cefotaxime. The combination of intermediate doses of vancomycin with cefotaxime led to higher antibacterial effects than either monotherapy. The low dose of vancomycin gave no significant additional effect compared with cefotaxime alone. The times of regrowth were similar for cefotaxime and cefotaxime-vancomycin 1, and also for vancomycin 10 and vancomycin 20 with or without cefotaxime but were significantly delayed for the combination cefotaxime-vancomycin 2.5 and cefotaxime-vancomycin 5 as compared with vancomycin 2.5 and vancomycin 5. By using a multivariate analysis, we demonstrated that the most important parameters were Cmax (r = 0.43) and AUC (r = 0.58) for cefotaxime alone and Cmax (r = 0.70) for vancomycin alone; none of the tested parameters was found to be significantly correlated with the efficacy of the combinations of cefotaxime and vancomycin. From these findings, and under the experimental conditions used (i.e., relatively low concentrations of cefotaxime), we demonstrated that the in-vivo antibacterial efficacy of the combination of cefotaxime and vancomycin was higher than each monotherapy when the local concentrations of vancomycin were at least 1.9 mg/L.

Topics: Analysis of Variance; Animals; Cefotaxime; Disease Models, Animal; Drug Therapy, Combination; Fibrin; Half-Life; Microbial Sensitivity Tests; Penicillin Resistance; Pneumococcal Infections; Rabbits; Thrombosis; Treatment Outcome; Vancomycin

The effect of immunization with whole organisms on the development of Streptococcus pneumoniae endocarditis was examined by in vivo and in vitro methods. Immunization protected rabbits from pneumococcal endocarditis when the in vivo catheterization model was used. The inoculum size that caused endocarditis in 50% of the unimmunized rabbits was 1.1 X 10(5) colony-forming units, whereas 1.2 X 10(7) colony-forming units were required for infecting 50% of the immunized rabbits (P less than 0.001). Investigations were carried out to determine the mechanism which enabled immunization to prevent the development of pneumococcal endocarditis; they indicated that a reduction in bacterial adherence could not explain this phenomenon. In vitro studies showed that subagglutinating quantities of antibody increased the adherence (P less than 0.05) of pneumococci to rabbit aortic valve cusps. The adherence ratio of pneumococci to fibrin-platelet clots was at least doubled by the presence of subagglutinating dilutions of immune sera (P less than 0.001). Further studies showed that immunoglobulin G in the immune sera accounted for this increased in vitro adherence. However, further in vivo studies showed that immunized rabbits were able to clear live pneumococci from their bloodstreams within 4.5 h, whereas unimmunized rabbits failed to clear the organism within 24 h.

Topics: Adhesiveness; Animals; Aortic Valve; Blood Platelets; Endocarditis, Bacterial; Fibrin; Immune Sera; Immunization; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae

Topics: Adult; Animals; Blood Urea Nitrogen; Creatinine; Disseminated Intravascular Coagulation; Female; Fibrin; Glomerulonephritis; Humans; Hyalin; Kidney; Kidney Glomerulus; Lung; Male; Middle Aged; Pneumococcal Infections; Pneumonia, Pneumococcal; Proteinuria; Rats; Sepsis; Streptococcus pneumoniae; Thrombosis; Uremia