Download PDF
Thromb Haemost 1994; 71(06): 768-772
DOI: 10.1055/s-0038-1642520
Review Article
Schattauer GmbH Stuttgart

Combination of Antibiotic Treatment with the Thrombin Inhibitor Recombinant Hirudin for the Therapy of Experimental Klebsiella pneumoniae Sepsis

Gerhard Dickneite
The Research Laboratories of Behringwerke AG, Marburg, Germany
,
Jörg Czech
The Research Laboratories of Behringwerke AG, Marburg, Germany
› Author Affiliations
Further Information

Publication History

Received: 02 December 1993

Accepted after revision: 14 February 1994

Publication Date:
09 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Rats which were infected with the gramnegative pathogen Klebsiella pneumoniae develop disseminated intravascular coagulation (DIC), multi-organ failure (MOF) and finally die in a septic shock. We investigated the therapeutic effect of antibiotic (tobramycin) treatment combined with the infusion of the highly specific thrombin inhibitor rec. hirudin. Although administration of 2 mg/kg tobramycin alone leads to a decrease of the bacterial burden, DIC could not be prevented. Infusion of rec. hirudin (0.25 mg/kg x h) for 4 h (start of treatment 1 h post infection), in addition to a bolus administration of tobramycin, led to an amelioration of DIC parameters as fibrinogen, thrombin-antithrombin complex (TAT) and platelets. Serum transaminase levels (GOT, GPT) as a marker of MOF were significantly improved by rec. hirudin, the T50 value increased from 17 h in the tobramycin group to 42 h in the tobramycin + rec. hirudin giuup, muilality rates were 90% or 60%, respectively. Combination of heparin (10011/kg x h) and tobramycin was not effective on survival.

 

  • References

  • 1 Weinstein L. Gram-Negative Bacterial Infections: A Look at the Past, a View of the Present, and a Glance at the Future. Rev Infect Dis 1985; 7 (Suppl. 4) S538-S44
    CrossrefPubMedGoogle Scholar
  • 2 Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cimnion RE, Ognibene FP. Septic Shock in Humans: Advances in the Understanding of Pathogenesis, Cardiovascular Dysfunction, and Therapy. Ann Intern Med 1990; 113: 227-42
    CrossrefPubMedGoogle Scholar
  • 3 Young LS, Martin WJ, Meyer RD, Weinstein RJ, Anderson ET. Gram-Negative Rod Bacteremia; Microbiologic, Immunologic, and Therapeutic Considerations. Ann Intern Med 1977; 86: 456-71
    CrossrefPubMedGoogle Scholar
  • 4 Rosenthal EJK. Septikamie-Erreger 1983-1985. Dt Med Wochenschr 1986; 111: 1874-80
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Corrigan JJ, Walker LR, May N. Changes in the blood coagulation system associated with septicemia. N Engl J Med 1968; 279: 851-6
    CrossrefPubMedGoogle Scholar
  • 6 Mason JW, Kleeberg U, Dolan P, Colman RW. Plasma Kallikrein and Hageman Factor in Gram-Negative Bacteremia. Ann Intern Med 1970; 73: 545-51
    CrossrefPubMedGoogle Scholar
  • 7 Blick RL, Scates SM. Disseminated intravascular coagulation. Lab Med 1992; 23: 161-5
    CrossrefPubMedGoogle Scholar
  • 8 Bone RC. Sepsis and Coagulation: An important link. Chest 1992; 101: 594-6
    CrossrefPubMedGoogle Scholar
  • 9 Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 1974; 140: 797-811
    CrossrefPubMedGoogle Scholar
  • 10 Deventer SJHvan, Biiller HR, Cate JWten, Aarden LA, Hack E, Sturk A. Experimental Endotoxemia in Humans: Analysis of Cytokine Release and Coagulation, Fibrinolytic, and Complement Pathways. Blood 1990; 76: 2520-6
    PubMedGoogle Scholar
  • 11 Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, Meer JWMvan der, Endres S, Lonnemann G, Corsetti J, Chernow B, Wilmore DW, Wolff SM, Burke JF, Dinarello CA. Circulating Interleukin-1 and Tumor Necrosis Factor in Septic Shock and Experimental Endotoxin Fever. J Infect Dis 1990; 161: 79-84
    CrossrefPubMedGoogle Scholar
  • 12 Tracey KJ. Trends in Shock Research: Tumor Necrosis Factor (Cachectin) in the Biology of Septic Shock Syndrome. Circ Shock 1991; 35: 123-8
    PubMedGoogle Scholar
  • 13 Poll Tvan der. Cytokines and their inhibition in septicaemia: The role of three major cytokines in the pathogenesis of septicaemia. Br J Intens Care, March 1992: 99-110
    Google Scholar
  • 14 Hack CE, Hart M, Strack van Schijndel RJM, Eerenberg AJM, Huijens JH, Thijs LG, Aarden LA. Interleukin-8 in Sepsis: Relation to Shock and Inflammatory Mediators. Infect Immun 1992; 60: 2835-42
    PubMedGoogle Scholar
  • 15 Fenton JW. II. Thrombin. Ann NY Acad Sci 1986; 485: 5-15
    CrossrefPubMedGoogle Scholar
  • 16 Markwardt F. Die Isolierung und chemische Charakterisierung des Hirudins. Hoppe-Seyler’s. Z Physiol Chemie 1957; 308: 147-56
    CrossrefPubMedGoogle Scholar
  • 17 Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986; 25: 4622-8
    CrossrefPubMedGoogle Scholar
  • 18 Grütter MG, Priestle JP, Rahuel J, Grossenbacher H, Bode W, Hofsteenge J, Stone SR. Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 1990; 9: 2361-5
    PubMedGoogle Scholar
  • 19 Just M, Tripier D, Seiffge D. Antithrombotic Effects of Recombinant Hirudin in Different Animal Models. Haemostasis 1991; 21 (Suppl) 80-7
    PubMedGoogle Scholar
  • 20 Imura Y, Stassen JM, Collen D. Comparative Antithrombotic Effects of Heparin, Recombinant Hirudin and Argatroban in a Hamster Femoral Vein Platelet-Rich Mural Thrombosis Model. J Pharmacol Exp Ther 1992; 261: 895-8
    PubMedGoogle Scholar
  • 21 Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V. Effects of Thrombin Inhibition of the Development of Acute Platelet-Thrombus Deposition During Angioplasty in Pigs: Heparin Versus Recombinant Hirudin, a Specific Thrombin Inhibitor. Circulation 1989; 79: 657-65
    CrossrefPubMedGoogle Scholar
  • 22 Doutremepuich C, Deharo E, Guyot M, Lalanne MC, Walenga J, Fareed J. Antithrombotic activity of recombinant hirudin in the rat: a comparative study with heparin. Thromb Res 1989; 54: 435-45
    CrossrefPubMedGoogle Scholar
  • 23 Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, Hanson SR, Harker LA. Hirudin Interruption of Heparin-Resistant Arterial Thrombus Formation in Baboons. Blood 1991; 77: 1006-12
    PubMedGoogle Scholar
  • 24 Gray E, Watton J, Cesmeli S, Barrowcliffe TW, Thomas DP. Experimental Studies on a Recombinant Hirudin, CGP 39393. Thromb Haemost 1991; 65: 355-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Agnelli G, Pascucci C, Cosmi B, Nenci GG. Effects of Hirudin and Heparin on the Binding of New Fibrin to the Thrombus in t-PA Treated Rabbits. Thromb Haemost 1991; 66: 592-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Kaiser B, Simon A, Markwardt F. Antithrombotic Effects of Recombinant Hirudin in Experimental Angioplasty and Intravascular Thrombolysis. Thromb Haemost 1990; 63: 44-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Walenga JM, Bakhos M, Messmore HL, Koza M, Wallock M, Orfei E, Fareed J, Pifarre R. Comparison of recombinant hirudin and heparin as an anticoagulant in a cardiopulmonary bypass model. Blood Coagul Fibrinolysis 1991; 2: 105-11
    CrossrefPubMedGoogle Scholar
  • 28 Markwardt F, Nowak G, Bucha E. Hirudin as Anticoagulant in Experimental Hemodialysis. Haemostasis 1991; 21 (Suppl) 149-55
    PubMedGoogle Scholar
  • 29 Hoffmann H, Siebeck M, Spannagl M, Weis M, Geiger R, Jochum M, Fritz H. Effect of Recombinant Hirudin, a Specific Inhibitor of Thrombin on Endotoxin-induced Intravascular Coagulation and Acute Lung Injury in Pigs. Am Rev Respir Dis 1990; 142: 782-8
    CrossrefPubMedGoogle Scholar
  • 30 Ishikawa A, Hafter R, Seemiiller U, Gokel JM, Graeff H. The effect of hirudin on endotoxin induced disseminated intravascular coagulation (DIG). Thromb Res 1980; 19: 351-8
    CrossrefPubMedGoogle Scholar
  • 31 Dickneite G, Czech J, Keuper H. Formation of fibrin-monomers in experi mental disseminated intravascular coagulation and its inhibition by recombinant hirudin. Circ Shock 1994. in press
    Google Scholar
  • 32 Markwardt F, Nowak G, Hoffmann J. Comparative Studies on Thrombin Inhibitors in Experimental Microthrombosis. Thromb Haemost 1983; 49: 235-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Hauptmann J, Briiggener E. Influence of Hirudin on the Consumption of Antithrombin III in Experimental DIC. Folia Haematol, Leipzig 1988; 115: 83-7
    PubMedGoogle Scholar
  • 34 Hauptmann J, Briiggener E, Markwardt F. Effect of Heparin, Hirudin, and a Synthetic Thrombin Inhibitor on Antithrombin III in Thrombin-Induced Disseminated Intravascular Coagulation in Rats. Haemostasis 1987; 17: 321-8
    PubMedGoogle Scholar
  • 35 Freund M, Cazenave JP, Courtney M, Degryse E, Roitsch C, Bernat A, Delebassee D, Defreyn G, Maffrand JP. Inhibition by Recombinant Hirudins of Experimental Venous Thrombosis and Disseminated Intravascular Coagulation Induced by Tissue Factor in Rats. Thromb Haemost 1990; 63: 187-92
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Grießbach U, Stiirzebecher J, Markwardt F. Brief Communication: Assay of hirudin in plasma using a chromogenic thrombin substrate. Thromb Res 1985; 37: 347-50
    CrossrefPubMedGoogle Scholar
  • 37 Kawabata S, Miura T, Morita T, Kato H, Fujikawa K, Iwanaga S, Takada S, Kimura T, Sakakibara S. Highly sensitive peptide-4-methylcoumaryl-7-amide substrates for blood-clotting proteases and trypsin. Fur J Biochem 1988; 172: 17-25
    PubMedGoogle Scholar
  • 38 Nowak G, Markwardt F. Hirudin in Disseminated Intravascular Coagulation. Haemostasis 1991; 21 (Suppl. 1) 142-8
    PubMedGoogle Scholar
  • 39 Dickneite G, Paques EP. Reduction of mortality with antithrombin III in septicemic rats: A study on Klebsiella pneumoniae induced sepsis. Thromb Haemost 1993; 69: 98-102
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Hurley JC. Antibiotic-Induced Release of Endotoxin: A Release of Endotoxin: A Reappraisal. Clin Infect Dis 1992; 15: 840-54
    CrossrefPubMedGoogle Scholar
  • 41 Effeney DJ, Blaisdell FW, McIntyre KE, Graziano CJ. The relationship between sepsis and disseminated intravascular coagulation. J Trauma 1978; 18: 689-95
    CrossrefPubMedGoogle Scholar
  • 42 Witte J, Jochum M, Scherer R, Schramm W, Hochstrasser K, Fritz H. Disturbances of Selected Plasma Proteins in Hyperdynamic Septic Shock. Intensive Care Med 1982; 8: 215-22
    CrossrefPubMedGoogle Scholar
  • 43 Coughlin SR, Vu TKH, Hung DT, Wheaton VI. Characterization of a Functional Thrombin Receptor; Issues and Opportunities. J Clin Invest 1992; 89: 351-5
    CrossrefPubMedGoogle Scholar
  • 44 Markwardt F, Kaiser B, Nowak G. Studies on antithrombotic effects of recombinant hirudin. Thromb Res 1989; 54: 377-88
    CrossrefPubMedGoogle Scholar
  • 45 Hoffmann A, Markwardt F. Inhibition of the Thrombin-Platelet Reaction by Hirudin. Haemostasis 1984; 14: 164-9
    PubMedGoogle Scholar
  • 46 Lämmle B, Tran TH, Ritz R, Duckert F. Plasma prekallikrein, factor XII, antithrombin III Cl-inhibitor and alplia2-macroglobulin in critically ill patients with suspected disseminated intravascular coagulation (DIC). Am J Clin Pathol 1984; 82: 396-404
    CrossrefPubMedGoogle Scholar