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. 1983 Mar;71(3):411–419. doi: 10.1172/JCI110785

Bactericidal versus Bacteriostatic Antibiotic Therapy of Experimental Pneumococcal Meningitis in Rabbits

W Michael Scheld 1, Merle A Sande 2
PMCID: PMC436888  PMID: 6826714

Abstract

A rabbit model of pneumococcal meningitis was used to examine the importance of bactericidal vs. bacteriostatic antimicrobial agents in the therapy of meningitis 112 animals were infected with one of two strains of type III Streptococcus pneumoniae. Both strains were exquisitely sensitive to ampicillin, minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)<0.125 μg/ml. The activity of chloramphenicol against the two strains varied: strain1—MIC 2 μg/ml, MBC 16 μg/ml; strain2—MIC 1 μg/ml, MBC 2 μg/ml. Animals were treated with either ampicillin or chloramphenicol in dosages that achieved a peak bactericidal effect in cerebrospinal fluid (CSF) for ampicillin against both strains. Two different dosages were used for chloramphenicol. The first dosage achieved a peak CSF concentration of 4.4±1.1 μg/ml that produced a bacteriostatic effect against strain1 and bactericidal effect against strain2. The second dosage achieved a bactericidal effect against both strains (mean peak CSF concentration 30.0 μg/ml). All animals were treated intramuscularly three times a day for 5 d. CSF was sampled daily and 3 d after discontinuation of therapy for quantitative bacterial cultures. Results demonstrate that only antimicrobial therapy that achieved a bactericidal effect in CSF was associated with cure. Over 90% of animals treated with one of the bactericidal regimens (i.e., animals in which the bacterial counts in CSF dropped >5 log10 colony-forming units [cfu]/ ml after 48 h) had sterile CSF after 5 d of treatment. On the other hand, the regimen that achieved bacteriostatic concentrations (CSF drug concentrations between the MIC and MBC) produced a drop of 2.4 log10 cfu/ml by 48 h; however, none of the animals that survived had sterile CSF after 5 d. These studies clearly demonstrate in a strictly controlled manner that maximally effective antimicrobial therapy of experimental pneumococcal meningitis depends on achieving a bactericidal effect in CSF.

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Selected References

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  1. Agbayani M. M., Braun J., Chang C. T., Glass L., Evans H. E. Effect of CSF on bacterial growth. Arch Neurol. 1981 Jan;38(1):43–45. doi: 10.1001/archneur.1981.00510010069012. [DOI] [PubMed] [Google Scholar]
  2. Baird D. R., Whittle H. C., Greenwood B. M. Mortality from pneumococcal meningitis. Lancet. 1976 Dec 18;2(7999):1344–1346. doi: 10.1016/s0140-6736(76)91985-1. [DOI] [PubMed] [Google Scholar]
  3. Bannatyne R. M., Cheung R. Chloramphenicol bioassay. Antimicrob Agents Chemother. 1979 Jul;16(1):43–45. doi: 10.1128/aac.16.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beam T. R., Jr, Allen J. C. Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges. Antimicrob Agents Chemother. 1977 Dec;12(6):710–716. doi: 10.1128/aac.12.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beam T. R. Vancomycin therapy of experimental pneumococcal meningitis caused by penicillin-sensitive and resistant strains. J Antimicrob Chemother. 1981 Jan;7(1):89–99. doi: 10.1093/jac/7.1.89. [DOI] [PubMed] [Google Scholar]
  6. Bernhardt L. L., Simberkoff M. S., Rahal J. J., Jr Deficient cerebrospinal fluid opsonization in experimental Escherichia coli meningitis. Infect Immun. 1981 Apr;32(1):411–413. doi: 10.1128/iai.32.1.411-413.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cherubin C. E., Marr J. S., Sierra M. F., Becker S. Listeria and gram-negative bacillary meningitis in New York City, 1972-1979. Frequent causes of meningitis in adults. Am J Med. 1981 Aug;71(2):199–209. doi: 10.1016/0002-9343(81)90106-6. [DOI] [PubMed] [Google Scholar]
  8. Chow H. S., Sarpel S. C., Epstein R. B. Pathophysiology of Candida albicans meningitis in normal, neutropenic, and granulocyte transfused dogs. Blood. 1980 Apr;55(4):546–551. [PubMed] [Google Scholar]
  9. Dacey R. G., Sande M. A. Effect of probenecid on cerebrospinal fluid concentrations of penicillin and cephalosporin derivatives. Antimicrob Agents Chemother. 1974 Oct;6(4):437–441. doi: 10.1128/aac.6.4.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feldman W. E. Concentrations of bacteria in cerebrospinal fluid of patients with bacterial meningitis. J Pediatr. 1976 Apr;88(4 Pt 1):549–552. doi: 10.1016/s0022-3476(76)80003-0. [DOI] [PubMed] [Google Scholar]
  11. Feldman W. E. Relation of concentrations of bacteria and bacterial antigen in cerebrospinal fluid to prognosis in patients with bacterial meningitis. N Engl J Med. 1977 Feb 24;296(8):433–435. doi: 10.1056/NEJM197702242960806. [DOI] [PubMed] [Google Scholar]
  12. Giampaolo C., Scheld M., Boyd J., Savory J., Sande M., Wills M. Leukocyte and bacterial interrelationships in experimental meningitis. Ann Neurol. 1981 Apr;9(4):328–333. doi: 10.1002/ana.410090403. [DOI] [PubMed] [Google Scholar]
  13. Greenwood B. M. Chemotactic activity of cerebrospinal fluid in pyogenic meningitis. J Clin Pathol. 1978 Mar;31(3):213–216. doi: 10.1136/jcp.31.3.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Griffin D. E. Immunoglobulins in the cerebrospinal fluid: changes during acute viral encephalitis in mice. J Immunol. 1981 Jan;126(1):27–31. [PubMed] [Google Scholar]
  15. Guckian J. C., Christensen G. D., Fine D. P. The role of opsonins in recovery from experimental pneumococcal pneumonia. J Infect Dis. 1980 Aug;142(2):175–190. doi: 10.1093/infdis/142.2.175. [DOI] [PubMed] [Google Scholar]
  16. Haeney M. R., Thompson R. A., Faulkner J., Mackintosh P., Ball A. P. Recurrent bacterial meningitis in patients with genetic defects of terminal complement components. Clin Exp Immunol. 1980 Apr;40(1):16–24. [PMC free article] [PubMed] [Google Scholar]
  17. Hodges G. R., Perkins R. L. Acute bacterial meningitis: an analysis of factors influencing prognosis. Am J Med Sci. 1975 Nov-Dec;270(3):427–440. doi: 10.1097/00000441-197511000-00003. [DOI] [PubMed] [Google Scholar]
  18. Hosea S. W., Brown E. J., Frank M. M. The critical role of complement in experimental pneumococcal sepsis. J Infect Dis. 1980 Dec;142(6):903–909. doi: 10.1093/infdis/142.6.903. [DOI] [PubMed] [Google Scholar]
  19. Kinnman J., Link H., Frydén A. Characterization of antibody activity in oligoclonal immunoglobulin G synthesized within the central nervous system in a patient with tuberculous meningitis. J Clin Microbiol. 1981 Jan;13(1):30–35. doi: 10.1128/jcm.13.1.30-35.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Klastersky J., Cappel R., Daneau D. Clinical significance of in vitro synergism between antibiotics in gram-negative infections. Antimicrob Agents Chemother. 1972 Dec;2(6):470–475. doi: 10.1128/aac.2.6.470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. LEPPER M. H., DOWLING H. F. Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin; studies including observations on an apparent antagonism between penicillin and aureomycin. AMA Arch Intern Med. 1951 Oct;88(4):489–494. doi: 10.1001/archinte.1951.03810100073006. [DOI] [PubMed] [Google Scholar]
  22. Lietman P. S., White T. J., Shaw W. V. Chloramphenicol: an enzymological microassay. Antimicrob Agents Chemother. 1976 Aug;10(2):347–353. doi: 10.1128/aac.10.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nolan C. M., Monson T. P., Ulmer W. C., Jr Rosaramicin versus penicillin G in experimental Pneumococcal meningitis. Antimicrob Agents Chemother. 1979 Dec;16(6):776–780. doi: 10.1128/aac.16.6.776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. O'Donoghue J. M., Schweid A. I., Beaty H. N. Experimental pneumococcal meningitis I: a rabbit model. Proc Soc Exp Biol Med. 1974 Jun;146(2):571–574. doi: 10.3181/00379727-146-38149. [DOI] [PubMed] [Google Scholar]
  25. RISCHBIETH R. H. Pneumonococcal meningitis-a killing disease. Med J Aust. 1960 Apr 9;47(1):578–581. [PubMed] [Google Scholar]
  26. Sande M. A. Antibiotic therapy of bacterial meningitis: lessons we've learned. Am J Med. 1981 Oct;71(4):507–510. doi: 10.1016/0002-9343(81)90191-1. [DOI] [PubMed] [Google Scholar]
  27. Sande M. A., Courtney K. B. Nafcillin-gentamicin synergism in experimental staphylococcal endocarditis. J Lab Clin Med. 1976 Jul;88(1):118–124. [PubMed] [Google Scholar]
  28. Sande M. A., Korzeniowski O. M., Allegro G. M., Brennan R. O., Zak O., Scheld W. M. Intermittent or continuous therapy of experimental meningitis due to Streptococcus pneumoniae in rabbits: preliminary observations on the postantibiotic effect in vivo. Rev Infect Dis. 1981 Jan-Feb;3(1):98–109. doi: 10.1093/clinids/3.1.98. [DOI] [PubMed] [Google Scholar]
  29. Sande M. A., Scheld W. M. Combination antibiotic therapy of bacterial endocarditis. Ann Intern Med. 1980 Mar;92(3):390–395. doi: 10.7326/0003-4819-92-3-390. [DOI] [PubMed] [Google Scholar]
  30. Sande M. A., Sherertz R. J., Zak O., Strausbaugh L. J. Cephalosporin antibiotics in therapy of experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis in rabbits. J Infect Dis. 1978 May;137 (Suppl):S161–S168. doi: 10.1093/infdis/137.supplement.s161. [DOI] [PubMed] [Google Scholar]
  31. Schaad U. B., McCracken G. H., Jr, Loock C. A., Thomas M. L. Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime, cefoperazone, and rocephin in experimental bacterial meningitis. J Infect Dis. 1981 Feb;143(2):156–163. doi: 10.1093/infdis/143.2.156. [DOI] [PubMed] [Google Scholar]
  32. Schaad U. B., McCracken G. H., Jr, Loock C. A., Thomas M. L. Pharmacokinetics and bacteriological efficacy of moxalactam (LY127935), netilmicin, and ampicillin in experimental gram-negative enteric bacillary meningitis. Antimicrob Agents Chemother. 1980 Mar;17(3):406–411. doi: 10.1128/aac.17.3.406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Scheld W. M., Brodeur J. P., Sande M. A., Alliegro G. M. Comparison of cefoperazone with penicillin, ampicillin, gentamicin, and chloramphenicol in the therapy of experimental meningitis. Antimicrob Agents Chemother. 1982 Oct;22(4):652–656. doi: 10.1128/aac.22.4.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Scheld W. M., Dacey R. G., Winn H. R., Welsh J. E., Jane J. A., Sande M. A. Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. J Clin Invest. 1980 Aug;66(2):243–253. doi: 10.1172/JCI109850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Scheld W. M., Fink F. N., Fletcher D. D., Sande M. A. Mecillinam-ampicillin synergism in experimental Enterobacteriaceae meningitis. Antimicrob Agents Chemother. 1979 Sep;16(3):271–276. doi: 10.1128/aac.16.3.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scheld W. M., Fletcher D. D., Fink F. N., Sande M. A. Response to therapy in an experimental rabbit model of meningitis due to Listeria monocytogenes. J Infect Dis. 1979 Sep;140(3):287–294. doi: 10.1093/infdis/140.3.287. [DOI] [PubMed] [Google Scholar]
  37. Scheld W. M., Park T. S., Dacey R. G., Winn H. R., Jane J. A., Sande M. A. Clearance of bacteria from cerebrospinal fluid to blood in experimental meningitis. Infect Immun. 1979 Apr;24(1):102–105. doi: 10.1128/iai.24.1.102-105.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Scheld W. M. Pathophysiological correlates in bacterial meningitis. J Infect. 1981 Mar;3(1 Suppl):5–19. doi: 10.1016/s0163-4453(81)80003-5. [DOI] [PubMed] [Google Scholar]
  39. Simberkoff M. S., Moldover N. H., Rahal J., Jr Absence of detectable bactericidal and opsonic activities in normal and infected human cerebrospinal fluids. A regional host defense deficiency. J Lab Clin Med. 1980 Mar;95(3):362–372. [PubMed] [Google Scholar]
  40. Strausbaugh L. J., Mandaleris C. D., Sande M. A. Comparison of four aminoglycoside antibiotics in the therapy of experimental E. coli meningitis. J Lab Clin Med. 1977 Apr;89(4):692–701. [PubMed] [Google Scholar]
  41. Strausbaugh L. J., Sande M. A. Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits. J Infect Dis. 1978 Mar;137(3):251–260. doi: 10.1093/infdis/137.3.251. [DOI] [PubMed] [Google Scholar]
  42. Veeder M. H., Folds J. D., Yount W. J., Lee T. J. Recurrent bacterial meningitis associated with C8 and IgA deficiency. J Infect Dis. 1981 Nov;144(5):399–402. doi: 10.1093/infdis/144.5.399. [DOI] [PubMed] [Google Scholar]
  43. Whittle H. C., Greenwood B. M. Cerebrospinal fluid immunoglobulins and complement in meningococcal meningitis. J Clin Pathol. 1977 Aug;30(8):720–722. doi: 10.1136/jcp.30.8.720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wyler D. J., Wasserman S. I., Karchmer A. W. Substances which modulate leukocyte migration are present in CSF during meningitis. Ann Neurol. 1979 Apr;5(4):322–326. doi: 10.1002/ana.410050403. [DOI] [PubMed] [Google Scholar]

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