Drug Safety

, Volume 12, Issue 3, pp 183–195 | Cite as

Antibiotic-Induced Release of Endotoxin

A Therapeutic Paradox
  • James Hurley
Review Article Drug Experience


There is clear experimental evidence that antibiotics increase the bioavailability of endotoxin from Gram-negative bacteria. In this review, data for 2 variables, level of endotoxin and level of bacteria, at the time point closest to 2 hours post-antibiotic exposure were abstracted as a change from baseline readings from each available study, to enable presentation in a graphical overview. This overview indicates that the phenomenon is not limited to β-lactam agents nor is it apparent only for the more rapidly bactericidal agents. However, evidence that this phenomenon is of clinical importance is scant.

With the Jarisch-Herxheimer reaction (JHR), there is clear evidence for an acute deterioration with the initiation of antibiotic therapy and yet uncertainty as to the nature of the bacterial mediator(s) of this reaction. There is no evidence to support the commonly stated concern that therapy with antibiotics with a more rapid bactericidal action may result in the sudden lysis of bacteria with the release of cell wall components and cause a deterioration that might be avoidable through the use of antibiotics with a slower time course of action.


Adis International Limited Ceftriaxone Imipenem Bacterial Meningitis Lactam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A nasty shock from antibiotics? Lancet 1985; 2: 594Google Scholar
  2. 2.
    Hurley JC. Antibiotic-induced release of endotoxin: a reappraisal. Clin Infect Dis 1992; 15: 840–54PubMedCrossRefGoogle Scholar
  3. 3.
    Bone RC, Balk RA, Cerra FB, et al. ACCP/SCCM consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644–55PubMedCrossRefGoogle Scholar
  4. 4.
    Hurley JC. Reappraisal of the role of endotoxin in the sepsis syndrome. Lancet 1993; 341: 1133–5PubMedCrossRefGoogle Scholar
  5. 5.
    Brandtzaeg P, Kierulf P, Gaustad P, et al. Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 1989; 159: 195–204PubMedCrossRefGoogle Scholar
  6. 6.
    van Deventer SJH, Büller HR, ten Cate JW, et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520–6PubMedGoogle Scholar
  7. 7.
    Hurley JC. Endotoxemia, methods for detection and clinical correlates. Clin Microbiol Rev. 1995; 8 (2): In pressGoogle Scholar
  8. 8.
    Cohen J, McConnell JS. Release of endotoxin from bacteria exposed to ciprofloxacin and its prevention with polymyxin B. Eur J Clin Microbiol Infect Dis 1986; 5: 13–7CrossRefGoogle Scholar
  9. 9.
    Dofferhoff ASM, Nijland JH, de Vries-Hospers HG, et al. Effects of different types and combinations of antimicrobial agents on endotoxin release from gram negative bacteria: an in vitro and in vivo study. Scand J Infect Dis 1991; 23: 745–54PubMedCrossRefGoogle Scholar
  10. 10.
    Mellado MC, Rodriguez-Contreras R, Mariscal A, et al. Effect of penicillin and chloramphenicol on the growth and endotoxin release by N. meningitidis. Epidemiol Infect 1991; 106: 283–8PubMedCrossRefGoogle Scholar
  11. 11.
    Jackson JJ, Kropp H. Beta-lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime. J Infect Dis 1992; 165: 1033–41PubMedCrossRefGoogle Scholar
  12. 12.
    Bingen E, Goury V, Bennani H, et al. Bactericidal activity of beta-lactams against Haemophilus influenzae: effect on endotoxin release. J Antimicrob Chemother 1992; 30: 165–72PubMedCrossRefGoogle Scholar
  13. 13.
    Van Den Berg C, De Neeling AJ, Schot CS, et al. Delayed antibiotic-induced lysis of Escherichia coli in vitro is correlated with enhancement of LPS release. Scand J Infect Dis 1992; 24: 619–27CrossRefGoogle Scholar
  14. 14.
    Mertsola J, Kennedy WA, Waagner D, et al. Endotoxin concentrations in cerebrospinal fluid correlate with clinical severity and neurological outcome of Haemophilus influenzae type B meningitis. Am J Dis Child 1991; 145: 1099–103PubMedGoogle Scholar
  15. 15.
    Nelson DS, Kuppermann N, Saladino RA, et al. A randomized trial of a recombinant endotoxin neutralizing protein versus a monoclonal antibody to endotoxin for the treatment of E. coli sepsis in a rat model [abstract 1043]. Pediatr Res 1993; 33: 177ACrossRefGoogle Scholar
  16. 16.
    Tsukada K, Katoh H, Shiojima M, et al. Mortality rate and bacteremia, endotoxin, and endothelin-1 levels in antibiotic therapy for E. coli septic peritonitis. APMIS 1993; 101: 97–100PubMedCrossRefGoogle Scholar
  17. 17.
    Friedland IR, Jafari H, Ehrett S, et al. Comparison of endotoxin release by different antimicrobial agents and the effects on inflammation in experimental Escherichia coli meningitis. J Infect Dis 1993; 168: 657–62PubMedCrossRefGoogle Scholar
  18. 18.
    Arditi M, Kabat W, Yogev R. Antibiotic-induced bacterial killing stimulates tumor necrosis factor-alpha release in whole blood. J Infect Dis 1993; 167: 240–4PubMedCrossRefGoogle Scholar
  19. 19.
    Andersen BM, Solberg O. The endotoxin-liberating effect of antibiotics on meningococci in vitro. Acta Pathol Microbiol Scand 1980; 88 Sect. B: 231–6Google Scholar
  20. 20.
    Dofferhoff ASM, Esselink MT, de Vries-Hospers HG, et al. The release of endotoxin from antibiotic treated Escherichia coli and the production of tumour necrosis factor by human monocytes. J Antimicrob Chemother 1993; 31: 373–84PubMedCrossRefGoogle Scholar
  21. 21.
    Arditi M, Abies L, Yogev R. Cerebrospinal fluid endotoxin levels in children with H. influenzae meningitis before and after administration of intravenous ceftriaxone. J Infect Dis 1989; 160: 1005–11PubMedCrossRefGoogle Scholar
  22. 22.
    Shenep JL, Flynn PM, Barrett FF, et al. Serial quantitation of endotoxaemia and bacteraemia during therapy for Gram-negative bacterial sepsis. J Infect Dis 1988; 157: 565–8PubMedCrossRefGoogle Scholar
  23. 23.
    Evans ME, Pollack M. Effect of antibiotic class and concentration on the release of lipopolysaccharide from Escherichia coli. J Infect Dis 1993; 167: 1336–43PubMedCrossRefGoogle Scholar
  24. 24.
    Stratton CW, Cooksey RC. Susceptibility tests: special tests. In: Balows A, Hausler WJ, Hermann KL, et al., editors. Manual of clinical microbiology. 5th ed. Washington, DC: American Society for Microbiology, 1991: 1153–65Google Scholar
  25. 25.
    Russell RRB. Free endotoxin — a review. Microbios Lett 1976; 2: 125–35Google Scholar
  26. 26.
    Hurley JC. Cerebrospinal fluid endotoxin levels with ceftriaxone therapy for Haemophilus influenzae meningitis [letter]. J Infect Dis 1990; 162: 991PubMedCrossRefGoogle Scholar
  27. 27.
    van Deventer SJH, Büller HR, ten Cate JW, et al. Endotoxaemia: an early predictor of septicaemia in febrile patients. Lancet 1988; 1: 605–8PubMedCrossRefGoogle Scholar
  28. 28.
    Natanson C, Danner RL, Reilly JM, et al. Antibiotics versus cardiovascular support in a canine model of human septic shock. Am J Physiology 1990; 259: H1440–7Google Scholar
  29. 29.
    Täuber MG, Shibl AM, Hackbarth CJ, et al. Antibiotic therapy, endotoxin concentration in cerebrospinal fluid, and brain edema in experimental Escherichia coli meningitis in rabbits. J Infect Dis 1987; 156: 456–62PubMedCrossRefGoogle Scholar
  30. 30.
    Eng RHK, Smith SM, Fan-Havard P, et al. Effect of antibiotics on endotoxin release from gram negative bacteria. Diagn Microbiol Infect Dis 1993; 16: 185–9PubMedCrossRefGoogle Scholar
  31. 31.
    Hozbor D, Rodriguez ME, Samo A, et al. Release of lipopolysaccharide during Bordetella pertussis growth. Res Microbiol 1993; 144: 201–9PubMedCrossRefGoogle Scholar
  32. 32.
    Hurley JC, Louis WJ, Tosolini FA, et al. Antibiotic-induced release of endotoxin in chronically bacteriuric patients. Antimicrob Agents Chemother 1991; 35: 2388–94PubMedCrossRefGoogle Scholar
  33. 33.
    Mohler J, Fantin B, Mainardi JL, et al. Influence of antimicrobial therapy on kinetics of tumour necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae. Antimicrob Agents Chemother 1994; 38: 1017–22PubMedCrossRefGoogle Scholar
  34. 34.
    Burroughs M, Prasad S, Cabellos C, et al. The biological activities of peptidoglycan in experimental Haemophilus influenzae meningitis. J Infect Dis 1993; 167: 464–8PubMedCrossRefGoogle Scholar
  35. 35.
    Mattsby-Baltzer I, Lindgren K, Lindholm B, et al. Endotoxin shedding by enterobacteria: free and cell bound endotoxin differ in Limulus activity. Infect Immun 1991; 59: 689–95PubMedGoogle Scholar
  36. 36.
    Burroughs M, Cabellos C, Prasad S, et al. Bacterial components and the pathophysiology of injury to the blood-brain barrier: does cell wall add to the effects of endotoxin in Gram-negative meningitis? J Infect Dis 1992; 165 (Suppl. 1): S82–5PubMedCrossRefGoogle Scholar
  37. 37.
    Simon DM, Koenig G, Trenholme GM. Differences in release of tumor necrosis factor from THP-1 cells stimulated by filtrates of antibiotic-killed Escherichia coli. J Infect Dis 1991; 164: 800–2PubMedCrossRefGoogle Scholar
  38. 38.
    Crosby HA, Bion JF, Penn CW, et al. Antibiotic induced release of endotoxin form bacteria in vitro. J Med Microbiol 1994; 40: 23–40PubMedCrossRefGoogle Scholar
  39. 39.
    Hanberger H, Nilsson LE, Nilsson M, et al. Post-antibiotic effect of beta-lactam antibiotics on gram-negative bacteria in relation to morphology, initial killing and MIC. Eur J Clin Microbiol Infect Dis 1991; 10: 927–34PubMedCrossRefGoogle Scholar
  40. 40.
    Nelson D, Delahooke TES, Poxton IR. Influence of sub-inhibitory levels of antibiotics on expression of Escherichia coli lipopolysaccharide and binding of anti-lipopolysaccharide monoclonal antibodies. J Med Microbiol 1993; 39: 100–6PubMedCrossRefGoogle Scholar
  41. 41.
    Raponi G, Lun MT, Lorino G, et al. Reactivity and protective capacity of a polyclonal antiserum derived from mice immunized with antibiotic exposed Escherichia coli. J Antimicrob Chemother 1993; 31: 117–28PubMedCrossRefGoogle Scholar
  42. 42.
    Siegel SA, Evans ME, Pollack M, et al. Antibiotics enhance binding by human lipid A-reactive monoclonal antibody HA-1A to smooth gram negative bacteria. Infect Immun 1993; 61: 512–9PubMedGoogle Scholar
  43. 43.
    Almdahl SM, Osterud B. Effect of antibiotics on gram negative sepsis in the rat. Lack of endotoxin burst. Acta Chirurg Scand 1987; 153: 283–6Google Scholar
  44. 44.
    Klein VR, Cox SM, Mitchell MD, et al. The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol 1990; 75: 375–80PubMedGoogle Scholar
  45. 45.
    Loveday C, Bingham JS. Changes in circulating immune complexes during the Jarisch-Herxheimer reaction in secondary syphilis. Eur J Clin Microbiol Infect Dis 1993; 12: 185–91PubMedCrossRefGoogle Scholar
  46. 46.
    Horton JM, Blaser MJ. The spectrum of relapsing fever in the Rocky Mountains. Arch Intern Med 1985; 145: 871–5PubMedCrossRefGoogle Scholar
  47. 47.
    Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med 1992; 117: 273–80PubMedGoogle Scholar
  48. 48.
    Galloway RE, Levin J, Butler T, et al. Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrentis infection. Am J Med 1977; 63: 933–8PubMedCrossRefGoogle Scholar
  49. 49.
    Negussie Y, Remick DG, DeForge LE, et al. Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer reaction of relapsing fever. J Exp Med 1992; 175: 1207–12PubMedCrossRefGoogle Scholar
  50. 50.
    Bryceson ADM, Cooper KE, Warrell DA, et al. Studies on the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxin. Clin Sci 1972; 43: 343–54PubMedGoogle Scholar
  51. 51.
    Gelfand JA, Elin RJ, Berry FW, et al. Endotoxemia associated with the Jarisch-Herxheimer reaction. N Engl J Med 1976; 295: 211–3PubMedCrossRefGoogle Scholar
  52. 52.
    Wright DJM. Reaction following treatment of murine borreliosis and Shwartzman type reaction with borrelial sonicates. Parasite Immunol 1980; 2: 201–21PubMedCrossRefGoogle Scholar
  53. 53.
    Young EJ, Weingarten NM, Baughn RE, et al. Studies on the pathogenesis of the Jarisch-Herxheimer reaction: development of an animal model and evidence against a role for classic endotoxin. J Infect Dis 1982; 146: 606–15PubMedCrossRefGoogle Scholar
  54. 54.
    Hardy Jr PH, Levin J. Lack of endotoxin in Borrelia hispanica and Treponema pallidum. Proc Soc Exp Biol Med 1983; 174: 47–52PubMedGoogle Scholar
  55. 55.
    Shenep JL, Feldman S, Thorton D. Evaluation for endotoxemia in patients receiving penicillin therapy for secondary syphilis. JAMA 1986; 256: 388–90PubMedCrossRefGoogle Scholar
  56. 56.
    Radolf JD, Norgard MV, Brandt ME, et al. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis: analysis using a CAT reporter construct. J Immunol 1991; 147: 1968–74PubMedGoogle Scholar
  57. 57.
    Habicht GS. Cytokines in Borrelia burgdorferi infection. In: Schutzer SE, editor. Lyme disease: molecular and immunological approaches. Cold Spring Harbor Laboratory Press, 1992: 149-67Google Scholar
  58. 58.
    Tatro JB, Romero LI, Beasley D, et al. Borrelia burgdorferi and Escherichia coli lipopolysaccharides induce nitric oxide and interleukin-6 production in cultured rat brain cells. J Infect Dis 1994; 169: 1014–22PubMedCrossRefGoogle Scholar
  59. 59.
    Warrell RP Jr. Tumor lysis syndrome. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 4th ed. Philadelpia: JB Lippincott and Company, 1993: 2135Google Scholar
  60. 60.
    Graham JM, Oshiro BT, Blanco JD, et al. Uterine contractions after antibiotic therapy for pyelonephritis in pregnancy. Am J Obstet Gynecol 1993; 168: 577–80PubMedGoogle Scholar
  61. 61.
    Lehner PJ, Davies KA, Walport MJ, et al. Meningococcal septicaemia in a C6-deficient patient and effects of plasma transfusion on lipopolysaccharide release. Lancet 1992; 340: 1379–81PubMedCrossRefGoogle Scholar
  62. 62.
    Engebrestsen LF, Kierulf P, Brandtzaeg P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res 1986; 42: 713–6CrossRefGoogle Scholar
  63. 63.
    Harthug S, Bjorvatn B, Osterud B. Quantitation of endotoxin in blood from patients with meningococcal disease using a limulus lysate test in combination with chromogenic substrate. Infection 1983; 11: 192–5PubMedCrossRefGoogle Scholar
  64. 64.
    Andersen BM, Solberg O. Endotoxin liberation and invasivity of Neisseria meningitidis. Scand J Infect Dis 1984; 16: 247–54PubMedCrossRefGoogle Scholar
  65. 65.
    Mellado MC, Rodriguez-Contreras R, Fernandez-Crehuet M, et al. Endotoxin liberation by strains of N. meningitidis isolated from patients and healthy carriers. Epidemiol Infect 1991; 106: 289–95PubMedCrossRefGoogle Scholar
  66. 66.
    Brandtzaeg P, Bryn K, Kierulf P, et al. Meningococcal endotoxin in lethal septic shock plasma studied by gas chromatography, mass-spectrometry, ultracentrifugation, and electron microscopy. J Clin Invest 1992; 89: 816–23PubMedCrossRefGoogle Scholar
  67. 67.
    Hurley JC. Concordance of endotoxemia with gram negative bacteremia in patients with gram negative sepsis: a meta-analysis. J Clin Microbiol 1994; 32: 2120–7PubMedGoogle Scholar
  68. 68.
    Danner RL, Natanson C, Elin RJ, et al. Pseudomonas aeruginosa compared with Escherichia coli produces less endotoxemia but more cardiovascular dysfunction and mortality in a canine model of septic shock. Chest 1990; 98: 1480–7PubMedCrossRefGoogle Scholar
  69. 69.
    Cross AS, Opal SM, Sadoff JC, et al. Choice of bacteria in animal models of sepsis. Infect Immun 1993; 61: 2741–7PubMedGoogle Scholar
  70. 70.
    Rijkels DF. Louse-borne relapsing fever in Ethiopia. Trop Geogr Med 1971; 23: 335–40PubMedGoogle Scholar
  71. 71.
    Knaack RH, Wright LJ, Leithead CS, et al. Penicillin versus tetracycline in the treatment of louse borne relapsing fever. Ethiop Med J 1972; 10: 15–22PubMedGoogle Scholar
  72. 72.
    Butler T, Jones PK, Wallace CK. Borrelia recurrentis infection: single-dose antibiotic regimens and management of the Jarisch-Herxheimer reaction. J Infect Dis 1978; 137: 573–7PubMedCrossRefGoogle Scholar
  73. 73.
    Warrell DA, Perine PL, Krause DW, et al. Pathophysiology and immunology of the Jarisch-Herxheimer-like reaction in louse-borne relapsing fever: comparison of tetracycline and slow-release penicillin. J Infect Dis 1983; 147: 898–909PubMedCrossRefGoogle Scholar
  74. 74.
    Gebrehiwot T, Fiseha A. Tetracycline versus penicillin in the treatment of louse-borne relapsing fever. Ethiop Med J 1992; 30: 175–81PubMedGoogle Scholar
  75. 75.
    Sande MA. Antibiotic therapy of bacterial meningitis: lessons wes’ve learned. Am J Med 1981; 71: 507–10PubMedCrossRefGoogle Scholar
  76. 76.
    Lepper MH, Dowling HF Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin: studies including observations on an apparent antagonism between penicillin and aureomycin. Arch Intern Med 1951; 88: 489–94CrossRefGoogle Scholar
  77. 77.
    Schaad UB, Suter S, Gianella-Borradori A, et al. A comparison of ceftriaxone and cefuroxime for the treatment of bacterial meningitis in children. N Engl J Med 1990; 322: 141–7PubMedCrossRefGoogle Scholar
  78. 78.
    Peltola H, Anttila M, Renkonen OV, et al. Randomised comparison of chloramphenicol, ampicillin, cefotaxime, and ceftriaxone for childhood bacterial meningitis. Lancet 1989; 1: 1281–7PubMedCrossRefGoogle Scholar
  79. 79.
    Islam A, Butler T, Kabir I, et al. Treatment of typhoid fever with ceftriaxone for 5 days or chloramphenicol for 14 days: a randomized clinical trial. Antimicrob Agents Chemother 1993; 37: 1572–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • James Hurley
    • 1
  1. 1.Division of Infectious DiseasesChildrens’s Hospital and Medical CenterSeattleUSA

Personalised recommendations