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Antibiotic-induced Sepsis Amr Badreldin Hamdy MD FCCP
Objective <ul><li>Define  sepsis  and antibiotic induced sepsis. </li></ul><ul><li>Highlight possible  mechanisms  of anti...
<ul><li>Sepsis  originally meant  putrefaction , a decomposition of organic matter by bacteria and fungi. </li></ul>
<ul><li>Sepsis  has now come to be recognized as the  systemic response to infection . </li></ul>
<ul><li>In  sepsis  there is an  exaggerated  stimulation of the  normal  host responses to the invading pathogen, leading...
<ul><li>Sepsis  is defined as a condition with  fever ,  tachycardia ,  tachypnea  and  leukocytosis  or  leukopenia  caus...
<ul><li>Sepsis  is severe inflammatory response syndrome  (SIRS)  with a  presumed  or  confirmed  infectious process. </l...
<ul><li>Severe sepsis  is sepsis with  signs of  at least  one acute organ dysfunction: </li></ul><ul><li>Respiratory  </l...
<ul><li>When  hypotension  persists  despite  adequate fluid resuscitation and hypo-perfusion or organ dysfunction is pres...
<ul><li>The term  SIRS  describes patients who exhibit a  sepsis-like syndrome , but who are  not   infected . It may be p...
<ul><li>Circulating  endotoxin  can induce an overwhelming inflammatory host response (= systemic inflammatory   response ...
<ul><li>Endotoxin  stimulates reactions such as the release of  cytokines  and  arachidonic acid  from  monocytes  ,  neut...
<ul><li>A number of in vitro and in vivo studies have shown an increase in  endotoxin  release  after exposure to antibiot...
<ul><li>In patients with  uncomplicated  gram –ve infections, antibiotic-induced  endotoxin  release is most probably of l...
<ul><li>Endotoxin  has been associated with a  myriad of diseases and syndromes:   complications associated with   trauma ...
<ul><li>Gram-ve bacteria  all contain  LPS  as their  major pathogenic   determinant. </li></ul><ul><li>Gram+ve bacteria  ...
<ul><li>Lipopolysacharides  play a pivotal role in the  pathomechanism  of  sepsis. </li></ul>
<ul><li>Bacteria  are the  most common agents  causing  septic   shock  but  fungi , mainly  candida albicans , as well as...
<ul><li>It is well known that bacterial products, like  endotoxin  from the gm-ve and  exotoxins  from the gm+ve bacteria,...
<ul><li>Among bacterial agents  E.coli ,  group beta streptococci  and  Listeria  predominate in the  neonates , whereas  ...
<ul><li>Since the 1980s there has been a  resurgence  of severe  group A   streptococcal  infections with rapid progressio...
<ul><li>Septic shock  in  elderly  patients  is more frequently caused by  gm-ve bacteria  from the  gastrointestinal,   u...
<ul><li>The term  endotoxin  refers to  biological activity  of the lipopolysacharide molecule ( LPS ) in the cell wall of...
<ul><li>Endotoxins  are  complex LPS , major  cell wall components  in all gm-ve bacteria.  Lipopolysaccharide  has two re...
<ul><li>Once in the circulation, the  lipid A  moiety of  endotoxin  prompts the release of  endogenous mediators  such as...
<ul><li>Endotoxin  release from the bacterial wall  occurs mainly  as a consequence of  death   and  lysis  of the cell  a...
<ul><li>Once released,  endotoxin  binds to several  receptors  and  carrier proteins , the most important being the  LPS ...
<ul><li>Gram+ve bacteria  like  staphylococci  and  streptococci  produce  exotoxins  with varying biological activities t...
<ul><li>In similarity to  endotoxin , the  exotoxins  stimulate  monocytes  and  macrophages  to release  TNF  and other  ...
<ul><li>The release of  exotoxins , many of which are  superantigens , by gm+ve bacteria  activates T-cells , resulting in...
<ul><li>In general,  bactericidal  antibiotics  liberate initially more   endotoxin  than  bacteriostatic  antibiotics, an...
<ul><li>Penicillin-binding proteins   (PBP ) are  enzymes  that are located in the bacterial cell wall and  responsible fo...
<ul><li>Beta-lactam antibiotics with affinity for  PBP1 , lead to  rapid killing without additional release   of   endotox...
<ul><li>Binding to  PBP3 , causes  selective inhibition   of  septation  and  continuing   bacterial   elongation  with  f...
<ul><li>Examples of antibiotics that are  selective for PBP1  of E.coli are  cephaloridine  and  cefsulodin. </li></ul>
<ul><li>Ceftazidime , at high concentrations binds to  PBP1 . </li></ul>
<ul><li>Antibiotics  selective  for  PBP2  are  mecillinam ,  clavulanic acid , and  imipenem , and  carbapenem . </li></ul>
<ul><li>Cefuroxime ,  cefotaxime, piperacillin  ,  mezlocillin  and  aztreonam  bind to  PBP3  and are associated with  an...
<ul><li>Antibiotics  selective  for  PBP3  at low concentrations are  cephalexin ,  cefotaxime ,  ceftazidime , and  cefur...
<ul><li>The  quinolones  inhibit protein synthesis via  inhibition of   bacterial DNA synthesis , but they have been assoc...
<ul><li>Aminoglycosides  inhibit protein synthesis, which results in rapid killing  without  excessive  endotoxin  release...
<ul><li>It is probably an advantage to add an  aminoglycoside  to the  beta-lactam  antibiotic for the treatment of  sever...
<ul><li>Imipenem  and  aminoglycosides  seem to be antibiotics with only  modest  endotoxin-liberating  abilities. Thus th...
Conclusion
<ul><li>The choice of antibiotic  class  and  dose  may important in the severely ill septic patient in whom additional to...
<ul><li>Cefuroxime ,  netilmicin  and  ciprofloxacin  may be administered safely at  early stages of sepsis . </li></ul>
<ul><li>Polymyxin B,   gentamicin ,  amikacin ,  tobramycin  can neutralize the effect of  endotoxin . </li></ul>
AMT selective for PBP1 and 2 <ul><li>Cephalorlidine </li></ul><ul><li>Cefsulodin </li></ul><ul><li>Ceftazidime (HC). </li>...
AMT selective for PBP3 <ul><li>Cefuroxime </li></ul><ul><li>Cefotaxime </li></ul><ul><li>Piperacillin </li></ul><ul><li>Me...
<ul><li>One should  start  with a  low   dose  of antibiotic ( hit gently ) instead of  hit   vigorously . </li></ul>
References
<ul><li>Editorial: Definition of Sepsis: Not quite time to dump SIRS?  Critical Care Med . 30(3):706 (2002). </li></ul><ul...
<ul><li>Hjerdt-Goscindki Gunilla: Antibiotic-induced Bacterial Toxin Release-Inhibition by Protein Synthesis Inhibitors. C...
<ul><li>Perduis GE et al.: Antimicrobial induced Endotoxaemia in patients with sepsis in the field of acute pyelonephritis...
<ul><li>Van Amersfoot ES et al: Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock.  Micro...
Thank  You
 
 
 
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Antibiotic Induced Sepsis

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Transcript of "Antibiotic Induced Sepsis"

  1. 1. Antibiotic-induced Sepsis Amr Badreldin Hamdy MD FCCP
  2. 2. Objective <ul><li>Define sepsis and antibiotic induced sepsis. </li></ul><ul><li>Highlight possible mechanisms of antibiotic induced sepsis. </li></ul><ul><li>How to avoid the condition. </li></ul>
  3. 3. <ul><li>Sepsis originally meant putrefaction , a decomposition of organic matter by bacteria and fungi. </li></ul>
  4. 4. <ul><li>Sepsis has now come to be recognized as the systemic response to infection . </li></ul>
  5. 5. <ul><li>In sepsis there is an exaggerated stimulation of the normal host responses to the invading pathogen, leading to a widespread release of inflammatory mediators and vasodilatation. </li></ul>
  6. 6. <ul><li>Sepsis is defined as a condition with fever , tachycardia , tachypnea and leukocytosis or leukopenia caused by infection. </li></ul>
  7. 7. <ul><li>Sepsis is severe inflammatory response syndrome (SIRS) with a presumed or confirmed infectious process. </li></ul>
  8. 8. <ul><li>Severe sepsis is sepsis with signs of at least one acute organ dysfunction: </li></ul><ul><li>Respiratory </li></ul><ul><li>CVS </li></ul><ul><li>Renal and hepatic </li></ul><ul><li>Hematologic </li></ul><ul><li>CNS </li></ul><ul><li>Unexplained metabolic acidosis. </li></ul>
  9. 9. <ul><li>When hypotension persists despite adequate fluid resuscitation and hypo-perfusion or organ dysfunction is present the term septic shock is used. </li></ul>
  10. 10. <ul><li>The term SIRS describes patients who exhibit a sepsis-like syndrome , but who are not infected . It may be precipitated by insults such as pancreatitis , burns or trauma , in addition to many conditions which are less common. </li></ul>
  11. 11. <ul><li>Circulating endotoxin can induce an overwhelming inflammatory host response (= systemic inflammatory response or sepsis cascade ) </li></ul>
  12. 12. <ul><li>Endotoxin stimulates reactions such as the release of cytokines and arachidonic acid from monocytes , neutrophils, and vascular endothelial cells . </li></ul>
  13. 13. <ul><li>A number of in vitro and in vivo studies have shown an increase in endotoxin release after exposure to antibiotics. </li></ul>
  14. 14. <ul><li>In patients with uncomplicated gram –ve infections, antibiotic-induced endotoxin release is most probably of limited value. </li></ul><ul><li>In patients with progressing severe sepsis or who have developed septic shock , an additional dose of endotoxin may be deleterious. </li></ul>
  15. 15. <ul><li>Endotoxin has been associated with a myriad of diseases and syndromes: complications associated with trauma , burns and invasive surgery , as well as organ-specific illnesses such as cystic fibrosis, inflammatory bowel disease, liver disease, kidney dialysis complications, asthma and autoimmune diseases. </li></ul>
  16. 16. <ul><li>Gram-ve bacteria all contain LPS as their major pathogenic determinant. </li></ul><ul><li>Gram+ve bacteria contain a number of immunogenic cell wall components besides the highly deleterious exotoxins . </li></ul>
  17. 17. <ul><li>Lipopolysacharides play a pivotal role in the pathomechanism of sepsis. </li></ul>
  18. 18. <ul><li>Bacteria are the most common agents causing septic shock but fungi , mainly candida albicans , as well as parasites and viruses may be responsible in rare cases. </li></ul>
  19. 19. <ul><li>It is well known that bacterial products, like endotoxin from the gm-ve and exotoxins from the gm+ve bacteria, in different ways initiate the inflammatory host response in sepsis and that this may further progress to severe sepsis and septic shock . </li></ul>
  20. 20. <ul><li>Among bacterial agents E.coli , group beta streptococci and Listeria predominate in the neonates , whereas pneumococci , meningococci and S.aureus are the most common causative agents in children and young adults . </li></ul>
  21. 21. <ul><li>Since the 1980s there has been a resurgence of severe group A streptococcal infections with rapid progression to toxic shock in patients of all ages , also including otherwise healthy young persons. </li></ul>
  22. 22. <ul><li>Septic shock in elderly patients is more frequently caused by gm-ve bacteria from the gastrointestinal, urinary and respiratory tracts . </li></ul>
  23. 23. <ul><li>The term endotoxin refers to biological activity of the lipopolysacharide molecule ( LPS ) in the cell wall of the gram negative bacteria . </li></ul>
  24. 24. <ul><li>Endotoxins are complex LPS , major cell wall components in all gm-ve bacteria. Lipopolysaccharide has two regions: polysaccharide and lipid A . </li></ul><ul><li>Lipid A , highly conserved across bacterial families, is the primary toxic component. </li></ul>
  25. 25. <ul><li>Once in the circulation, the lipid A moiety of endotoxin prompts the release of endogenous mediators such as TNF@, IL-1 , IL-6 and other cytokines. </li></ul>
  26. 26. <ul><li>Endotoxin release from the bacterial wall occurs mainly as a consequence of death and lysis of the cell and of growth by cell division . When the endotoxin is released and appears as free endotoxin , its biological activity increases considerably as compared with the bacterial cell-bound endotoxin. </li></ul>
  27. 27. <ul><li>Once released, endotoxin binds to several receptors and carrier proteins , the most important being the LPS binding protein (LBS). </li></ul>
  28. 28. <ul><li>Gram+ve bacteria like staphylococci and streptococci produce exotoxins with varying biological activities that can be released without bacterial growth or lysis. </li></ul>
  29. 29. <ul><li>In similarity to endotoxin , the exotoxins stimulate monocytes and macrophages to release TNF and other cytokines . In addition, they have super antigenic properties, meaning that they are mitogenic for certain T-cell subsets but do not require processing by antigen presenting cells. </li></ul>
  30. 30. <ul><li>The release of exotoxins , many of which are superantigens , by gm+ve bacteria activates T-cells , resulting in a different cellular response and different cytokine profile, with relatively low levels of TNF@, IL-1, and IL-6 and increased levels of IL-8 . </li></ul>
  31. 31. <ul><li>In general, bactericidal antibiotics liberate initially more endotoxin than bacteriostatic antibiotics, and antibiotics active on the cell wall , such as penicillins and cephalosporins , release more endotoxn than antibiotics with other modes of action, such as protein synthesis inhibitors . </li></ul>
  32. 32. <ul><li>Penicillin-binding proteins (PBP ) are enzymes that are located in the bacterial cell wall and responsible for the cell wall synthesis . They are also the primary targets for the beta-lactam antibiotics and, depending on the affinity to these PBPs, varying amounts of endotoxins are liberated from the gm-ve bacteria at exposure to these antibiotics . </li></ul>
  33. 33. <ul><li>Beta-lactam antibiotics with affinity for PBP1 , lead to rapid killing without additional release of endotoxin whereas antibiotics with selective affinity for PBP2 , lead to conversion of the bacteria to round cells, spheroplasts , with loss of viability but without cell wall destruction and excessive endotoxin release. </li></ul>
  34. 34. <ul><li>Binding to PBP3 , causes selective inhibition of septation and continuing bacterial elongation with formation of long filaments and a subsequent increased endotoxin production. Thus, the release of high amounts of endotoxin is mainly associated with PBP3 binding . </li></ul>
  35. 35. <ul><li>Examples of antibiotics that are selective for PBP1 of E.coli are cephaloridine and cefsulodin. </li></ul>
  36. 36. <ul><li>Ceftazidime , at high concentrations binds to PBP1 . </li></ul>
  37. 37. <ul><li>Antibiotics selective for PBP2 are mecillinam , clavulanic acid , and imipenem , and carbapenem . </li></ul>
  38. 38. <ul><li>Cefuroxime , cefotaxime, piperacillin , mezlocillin and aztreonam bind to PBP3 and are associated with antibiotic-induced endotoxin release. </li></ul>
  39. 39. <ul><li>Antibiotics selective for PBP3 at low concentrations are cephalexin , cefotaxime , ceftazidime , and cefuroxime , and meropenem . </li></ul>
  40. 40. <ul><li>The quinolones inhibit protein synthesis via inhibition of bacterial DNA synthesis , but they have been associated with a substantial endotoxin release. </li></ul>
  41. 41. <ul><li>Aminoglycosides inhibit protein synthesis, which results in rapid killing without excessive endotoxin release. They may even reduce the endotoxin liberation induced by beta-lactam antibiotics. </li></ul>
  42. 42. <ul><li>It is probably an advantage to add an aminoglycoside to the beta-lactam antibiotic for the treatment of severe infections such as progressing severe sepsis and septic shock. </li></ul>
  43. 43. <ul><li>Imipenem and aminoglycosides seem to be antibiotics with only modest endotoxin-liberating abilities. Thus they can be added to beta-lactams. </li></ul>
  44. 44. Conclusion
  45. 45. <ul><li>The choice of antibiotic class and dose may important in the severely ill septic patient in whom additional toxin release could be deleterious. </li></ul>
  46. 46. <ul><li>Cefuroxime , netilmicin and ciprofloxacin may be administered safely at early stages of sepsis . </li></ul>
  47. 47. <ul><li>Polymyxin B, gentamicin , amikacin , tobramycin can neutralize the effect of endotoxin . </li></ul>
  48. 48. AMT selective for PBP1 and 2 <ul><li>Cephalorlidine </li></ul><ul><li>Cefsulodin </li></ul><ul><li>Ceftazidime (HC). </li></ul><ul><li>Carbapenems </li></ul><ul><li>Mecillinam </li></ul><ul><li>Clavulanic acid </li></ul><ul><li>Imipenem </li></ul><ul><li>Aminoglycoside </li></ul>
  49. 49. AMT selective for PBP3 <ul><li>Cefuroxime </li></ul><ul><li>Cefotaxime </li></ul><ul><li>Piperacillin </li></ul><ul><li>Mezlocillin </li></ul><ul><li>Cephaloxin </li></ul><ul><li>Ceftazidime </li></ul><ul><li>Meropenem </li></ul><ul><li>Quinolones </li></ul>
  50. 50. <ul><li>One should start with a low dose of antibiotic ( hit gently ) instead of hit vigorously . </li></ul>
  51. 51. References
  52. 52. <ul><li>Editorial: Definition of Sepsis: Not quite time to dump SIRS? Critical Care Med . 30(3):706 (2002). </li></ul><ul><li>Prins JM et al.: Clinical Relevance of Antibiotic-induced Endotoxin Release. Antimicrobial Agents and Chemotherapy . </li></ul><ul><li>38:1211 (1994). </li></ul>
  53. 53. <ul><li>Hjerdt-Goscindki Gunilla: Antibiotic-induced Bacterial Toxin Release-Inhibition by Protein Synthesis Inhibitors. Comprehensive Summaries of Uppsala Dissertation from the Faculty of Medicine 1292. ACTA UNIVERSITATIS UPSALIENSIS. </li></ul>
  54. 54. <ul><li>Perduis GE et al.: Antimicrobial induced Endotoxaemia in patients with sepsis in the field of acute pyelonephritis. Journal of Postgraduate Medicine. 49(2):114 (2003). </li></ul>
  55. 55. <ul><li>Van Amersfoot ES et al: Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock. Microbiology Review . 7:379 (2003). </li></ul><ul><li>Silverman MH and Ostro MJ: Bacterial Endotoxin in Human Disease. </li></ul>
  56. 56. Thank You
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