Skip to main content
SpringerLink
Log in

Fluoroquinolones in the treatment of meningitis

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

The continuous increase of resistant pathogens causing meningitis has limited the efficacy of standard therapeutic regimens. Due to their excellent activity in vitro and their good penetration into the cerebrospinal fluid (CSF), fluoroquinolones appear promising for the treatment of meningitis caused by gram-negative microorganisms, ie, Neisseria meningitidis and nosocomial gram-negative bacilli. The newer fluoroquinolones (moxifloxacin, gemifloxacin, gatifloxacin, and garenoxacin) have excellent activity against gram-positive microorganisms. Studies in animal models and limited clinical data indicate that they may play a future role in the treatment of pneumococcal meningitis. Analysis of pharmacodynamic parameters suggests that CSF concentrations that produce a Cpeak/minimal bactericidal concentration (MBC) ratio of at least 5 and concentrations above the MBC during the entire dosing interval are a prerequisite for maximal bactericidal activity in meningitis. Of interest, newer fluoroquinolones act synergistically with vancomycin and β-lactam antibiotics (ceftriaxone, cefotaxime, meropenem) against penicillin-resistant pneumococci in experimental rabbit meningitis, potentially providing a new therapeutic strategy. Clinical trials are needed to further explore the usefulness of quinolones as single agents or in combination with other drugs in the therapy of pneumococcal meningitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Tunkel AR, Scheld WM: Treatment of bacterial meningitis. Curr Infect Dis Rep 2002, 4:6–16. This state-of-the-art review provides an excellent overview of the newest therapeutic modalities of bacterial meningitis.

    Google Scholar 

  2. de Gans J, van de Beek D: Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002, 347:1549–1556. This prospective randomized study shows the benefit of addition of dexamethasone to the standard regimen in bacterial meningitis in adults.

    Article  PubMed  Google Scholar 

  3. Cabellos C, Martinez-Lacasa J, Martos A, et al.: Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis. Antimicrob Agents Chemother 1995, 39:2158–2160.

    PubMed  CAS  Google Scholar 

  4. Novak R, Henriques B, Charpentier E, et al.: Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 1999, 399:590–593.

    Article  PubMed  CAS  Google Scholar 

  5. McCullers JA, English BK, Novak R: Isolation and characterization of vancomycin-tolerant Streptococcus pneumoniae from cerebrospinal fluid of a patient who developed recrudescent meningitis. J Infect Dis 2000, 181:369–373.

    Article  PubMed  CAS  Google Scholar 

  6. Neu HC: Major advances in antibacterial quinolone therapy. Adv Pharmacol 1994, 29:227–262.

    Article  Google Scholar 

  7. Gootz TD, Brighty KE: Fluoroquinolone antibacterials: SAR, mechanism of action, resistance and clinical aspects. Med Res Rev 1996, 16:433–436.

    Article  PubMed  CAS  Google Scholar 

  8. Domagala JM, Hanna LD, Heifetz CL, et al.: New structureactivity relationships of the quinolone antibacterials using the target enzyme: the development and application of a DNA gyrase assay. J Med Chem 1986, 29:394–404.

    Article  PubMed  CAS  Google Scholar 

  9. Wolfson JS, Hooper DC: The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 1985, 28:581–586.

    PubMed  CAS  Google Scholar 

  10. Culberston TP, Domagala JM, Hagen SE, et al.: Structureactivity relationship of the quinolone antibacterials: the nature of the C7-side chain. In International Telesymposium on Quinolones. Edited by Fernandes PB, Barcelona: JR Prous Science Publishers; 1989:47–71.

    Google Scholar 

  11. Kato J, Nishimura Y, Niki H, et al.: New topoisomerase essential for chromosome segregation in E. coli. Cell 1990, 63:393–404.

    Article  PubMed  CAS  Google Scholar 

  12. Menzel R, Gelbert M: Regulation of genes for E. coli DNA gyrase: homeostatic control of DNA supercoiling. Cell 1987, 34:105–113.

    Article  Google Scholar 

  13. Gellert M, Mizuuchi D, O’Dea MH, et al.: Nalidixic acid resistance. A second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci U S A 1977, 74:4772–4776.

    Article  PubMed  CAS  Google Scholar 

  14. Sugino A, Peebles CL, Kruezer KN, Cozzarelli NR: Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc Natl Acad Sci U S A 1977, 74:4767–4771.

    Article  PubMed  CAS  Google Scholar 

  15. Huang WM: Bacterial diversity based on type II DNA topoisomerase genes. Ann Rev Genet 1996, 30:79–107.

    Article  PubMed  CAS  Google Scholar 

  16. Peng H, Marians K: E. coli topoisomerase IV: purification, characterization, subunit structure and subunit interactions. J Biol Chem 1991, 268:24481–24490.

    Google Scholar 

  17. Marians KJ: Replications fork progression. In E. coli and Salmonella Cellular and Molecular Biology. Edited by Neidhart FC, Washington DC: American Society of Microbiology; 1996:749–763.

    Google Scholar 

  18. Shen L, Pernet AG: Mechanism of inhibition of DNA gyrase by analogs of nalidixic acid: the target of the drugs is DNA. Proc Natl Acd Sci U S A 1985, 82:307–311.

    Article  CAS  Google Scholar 

  19. Khodursky AB, Cozzarelli NR: The mechanisms of inhibition of topoisomerase IV by quinolone antibacterials. J Biol Chem 1998, 273:27668–27677.

    Article  PubMed  CAS  Google Scholar 

  20. Anderson VE, Gootz TD, Osheroff N: Topoisomerase IV catalysis and the mechanism of quinolone action. J Biol Chem 1998, 273:17879–17885.

    Article  PubMed  CAS  Google Scholar 

  21. Wolfson JS, Hooper DC: The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 1985, 28:581–586.

    PubMed  CAS  Google Scholar 

  22. Eliopoulos GM: In vitro activity of new quinolone antimicrobial agents. In Microbiology-1986. Edited by Leive L. Washington DC: American Society for Microbiology; 1986:219–221.

    Google Scholar 

  23. Wiedemann B, Grimm H: Susceptibility to antibiotics: species incidence and trends. In Antibiotics in Laboratory Medicine. Edited by Lorian V. Baltimore: Williams & Wilkins; 1996:900–1168.

    Google Scholar 

  24. Morisini MI, Loza E, Almaraz F, et al.: In vitro activity of garenoxacin (BMS-284756) against prospectively collected Spanish pneumoniae isolates S. [abstract E-62.] Paper presented at 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego. September 27–30, 2002.

  25. Jones RN, Mutnick A, Biedenbach D: Garenoxacin (BMS 284756) activity against 8686 S. pneumoniae (SPN) including tentative susceptibility testing criteria [abstract E-58]. Paper presented at 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego. September 27–30, 2002.

  26. Kelly LM, Smith K, Jacobs M, Appelbaum P: Anti-pneumococcal activity of a new quinolone, DK-507k, compared to eleven other agents by MIC methodology [abstract E-572]. Paper presented at 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego. September 27–30, 2002.

  27. Ling G, Patel M, Bupte S, et al.: Time kill analysis of the antipneumococcal activity of two new quinolones, WCK 771A and WCK 919, compared to five other quinolones [abstract F-559]. Paper presented at 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego. September 27–30, 2002.

  28. Ho PL, Que TL, Tsang DN, et al.: Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999, 43:1310–1313. This paper is an important epidemiologic study revealing the increase in quinolone-resistant pneumococci.

    PubMed  CAS  Google Scholar 

  29. Pestova E, Beyer R, Ciancotto NP, et al.: Contribution of topoisomerase IV and gyrase mutations in Streptococcus pneumoniae to resistance to novel fluoroquinolones. Antimicrob Agents Chemother 1999, 43:2000–2004.

    PubMed  CAS  Google Scholar 

  30. Vasquez J, de la Fuente L, Gimenez MJ, et al.: In vitro activity of gemifloxacin and 13 other antimicrobials against 400 Spanish isolates of Neisseria meningitidis collected between 1998–1999 [abstract 132]. Paper presented at 3rd European Congress of Chemotherapy. Madrid. May 7-10, 2000.

  31. Blondeau JM, Yaschuk Y: In vitro activities of ciprofloxacin, cefotaxime, ceftriaxone, chloramphenicol and rifampicin against fully susceptible and moderately penicillin-resistant Neisseria meningitidis. Antimicrob Agents Chemother 1995, 39:2577–25769.

    PubMed  CAS  Google Scholar 

  32. Richter SS, Gordon KA, Rhomberg PR, et al.: Neisseria meningitidis with decreased susceptibility to penicillin: Report from Sentry antimicrobial surveillance program, North America, 1998–1999. Diag Microb Infect Dis 2001, 41:83–88.

    Article  CAS  Google Scholar 

  33. Schultz TR, Tapsall JW, White PA, Newton PJ: An invasive isolate of Neisseria meningitidis showing decreased susceptibility to quinolones. Antimicrob Agents Chemother 2000, 44:1166.

    Google Scholar 

  34. Garcia-Garrote F, Cercenado E, Martin-Pedroviejo J, et al.: Comparative in vitro activity of the new quinolone gemifloxacin (SB-265805) with other fluoroquinolones against respiratory tract pathogens. J Antimicrob Chemother 2001, 47:681–684.

    Article  PubMed  CAS  Google Scholar 

  35. Biedenbach DJ, Jones RN, Pfaller MA, The Sentry Participant Groups (Americas and Europe): Activity of BMS 284756 against 2681 recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis: report from the Sentry Antimicrobial Surveillance program (2000) in Europe, Canada and the United States. Diagn Microb Infect Dis 2001, 39:245–250.

    Article  CAS  Google Scholar 

  36. Tanaka M, Yamazaki E, Megumi, et al.: In vitro antibacterial activities of DQ-113, a potent quinolone-against clinical isolates. Antimicrob Agents Chemother 2002, 46:904–908.

    Article  PubMed  CAS  Google Scholar 

  37. Marco F, Garcia-de-Lomas J, Garcia-Rey C, et al., and the Spanish Surveillance Group for Respiratory Pathogens: Antimicrobial susceptibility of 1730 Haemophilus influenzae respiratory tract isolates in Spain in 1998–1999. Antimicrob Agents Chemother 2001, 45:3226–3228.

    Article  PubMed  CAS  Google Scholar 

  38. Montanari MP, Mingoia M, Marchetti F, Varaldo PE: In vitro activity of levofloxacin against gram-positive bacteria. Chemotherapy 1999, 45:411–417.

    Article  PubMed  CAS  Google Scholar 

  39. Hoogkamp-Korstanje JAA, Reolofs-Willemse J: Comparative in vitro activity of moxifloxacin against Gram-positive clinical isolates. J Antimicrob Chemother 2000, 45:31–39.

    Article  PubMed  CAS  Google Scholar 

  40. Rolston KVI, Frisbee-Hume S, LeBlanc BM, et al.: Antimicrobial activity of a novel des-fluoro(6) quinolone, garenoxacin (BMS-284756), compared to other quinolones, against clinical isolates from cancer patients. Diag Microbiol Infect Dis 2002, 44:187–194.

    Article  CAS  Google Scholar 

  41. Michelet C, Avril JL, Arvieux C, et al.: Comparative activities of new fluoroquinolones, alone and in combination with amoxicillin, trimethoprim-sulfamethoxale, or rifampicin, against intracellular Listeria monocytogenes. Antimicrob Agents Chemother 1997, 41:60–65.

    PubMed  CAS  Google Scholar 

  42. Cherubin CE, Stratton CW: Assessment of the bactericidal activity of sparfloxacin, ofloxaxin, levofloxacin, and other fluoroquinolones compared with selected agents of proven efficacy against Listeria monocytogenes. Diagn Microbiol Infect Dis 1994, 20:21–25.

    Article  PubMed  CAS  Google Scholar 

  43. Lutsar I, McCracken G, Friedland IR: Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 1998, 27:1117–1129. This outstanding paper reviews the pharmacodynamic parameters of antibiotics used in the treatment of bacterial meningitis.

    PubMed  CAS  Google Scholar 

  44. Kim MK, Nightingale CH: Pharmacokinetics and pharmacodynamics of the fluoroquinolones. In The Quinolones. Edited by Andriole VT. San Diego: Academic Press; 2000:169–202. This review presents a detailed overview of pharmacokinetic and pharmacodynamic aspects of fluoroquinolones.

    Google Scholar 

  45. Dudley MN: Pharmacodynamics of antibiotics with special reference to the fluoroquinolones. Am J Med 1991, 91(Suppl 6a):45S-50S.

    Article  PubMed  CAS  Google Scholar 

  46. Kim YS, Liu Q, Chow LL, et al.: Trovafloxacin in treatment of rabbits with experimental meningitis caused by high-level resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 1997, 41:1186–1189.

    PubMed  CAS  Google Scholar 

  47. Rodriguez-Cerrato V, Ghaffar F, Saavedra J, et al.: BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 2001, 45:3098–3103.

    Article  PubMed  CAS  Google Scholar 

  48. Rodriguez-Cerrato V, McCopig CC, Michelow IC, et al.: Pharmacodynamics and bactericidal activity of moxifloxacin in experimental Escherichia coli meningitis. Antimicrob Agents Chemother 2001, 45:3092–3097.

    Article  PubMed  CAS  Google Scholar 

  49. Lutsar I, Friedland I, Wubbel L, et al.: Pharmacodynamics of gatifloxacin in cerebrospinal fluid in experimental cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 1998, 42:2650–2655.

    PubMed  CAS  Google Scholar 

  50. Meng X, Pei Y, Nightingale CH, et al.: Determination of the in vivo post-antibiotic effect of ciprofloxacin and rifampicin. J Antimicrob Chemother 1995, 36:987–996.

    Article  PubMed  CAS  Google Scholar 

  51. Firsov AA, Shevchenko AA, Vostrov SN, Zinner SH: Inter- and intraquinolone predictors of antimicrobial effect in an in vitro dynamic model: new insights into a widely used concept. Antimicrob Agents Chemother 1998, 42:659–665.

    PubMed  CAS  Google Scholar 

  52. Hopkins S, Williams D, Dunne M, et al.: A randomized controlled trial of oral or iv trovafloxacin versus ceftriaxone in the treatment of epidemic meningococcal meningitis. Paper presented at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC. September 15–18, 1996.

  53. Saez-Lorenz X, McCoig C, Feris J, et al.: Quinolone treatment for pediatric bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin J Pediatr Infect Dis 2002, 21:14–22. This prospective multicenter study demonstrates that trovafloxacin monotherapy is comparable to the standard regimen in bacterial meningitis.

    Article  Google Scholar 

  54. Krcmery V, Filka J, Uher J, et al.: Ciprofloxacin in treatment of nosocomial meningitis in neonates and in infants: report of 12 cases and review. Diag Microbiol Infect Dis 1999, 35:75–80.

    Article  CAS  Google Scholar 

  55. Millar MR, Bransby-Zachary MA, Tompkins DS, et al.: Ciprofloxacin for Pseudomonas aeruginosa meningitis. Lancet 1986, 1:1325.

    Article  PubMed  CAS  Google Scholar 

  56. Bhutta Z, Faroqui B, Sturm W: Eradication of a multiple drug resistant Salmonella paratyphi A causing meningitis with ciprofloxacin. J Infect Dis 1992, 25:215–219.

    CAS  Google Scholar 

  57. Green SD, Ilunga F, Cheesbrough JS, et al.: The treatment of neonatal meningitis due to Gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid. J Infect Dis 1993, 26:253–256.

    CAS  Google Scholar 

  58. Lipman J, Allworth A, Walis SC: Cerebrospinal penetration of high doses of intravenous ciprofloxacin in meningitis. Clin Infect Dis 2000, 31:1331–1133.

    Article  Google Scholar 

  59. Schmidt H, Dalhoff A, Stuertz K, et al.: Moxifloxacin in the therapy of experimental pneumococcal meningitis. Antimicrob Agents Chemother 1998, 42:1397–1401.

    PubMed  CAS  Google Scholar 

  60. Ostergaard C, Sorensen TK, Knudsen JD, et al.: Evaluation of moxifloxacin, a new 8-methoxyquinolone for treatment of meningitis caused by a penicillin-resistant pneumococcus in rabbits. Antimicrob Agents Chemother 1998, 39:593–597.

    Google Scholar 

  61. Perrig M, Acosta F, Cottagnoud M, et al.: Efficacy of gatifloxacin alone and in combination with cefepime against penicillinresistant Streptococcus pneumoniae in a rabbit meningitis model and in vitro. J Antimicrob Chemother 2001, 47:701–704.

    Article  PubMed  CAS  Google Scholar 

  62. Smirnov A, Wellmer A, Gerber J, et al.: Gemifloxacin is effective in experimental pneumococcal meningitis. Antimicrob Agents Chemother 2000, 44:767–770.

    Article  PubMed  CAS  Google Scholar 

  63. Cottagnoud P, Acosta F, Cottagnoud M, et al.: Gemifloxacin is efficacious against penicillin-resistant and quinoloneresistant pneumococci in experimental meningitis. Antimicrob Agents Chemother 2002, 46:1607–1609.

    Article  PubMed  CAS  Google Scholar 

  64. Gerber CM, Tovar L, Cottagnoud M, et al.: Grepafloxacin against penicillin-resistant pneumococci in the rabbit meningitis model. J Antimicrob Chemother 2000, 46:249–243.

    Article  PubMed  CAS  Google Scholar 

  65. Rodriguez-Cerrato V, Ghaffar F, Saavedra J, et al.: BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 2001, 45:3098–3103.

    Article  PubMed  CAS  Google Scholar 

  66. Takahata M, Yamada H, Morita T, et al.: Evaluation of T-3811ME (BMS-284756), a new des-F(6)-quinolone, for treatment of meningitis caused by penicillin-resistant Streptococcus pneumoniae in rabbits. Antimicrob Agents Chemother 2002, 46:1760–1765.

    Article  PubMed  CAS  Google Scholar 

  67. Cottagnoud P, Acosta F, Cottagnoud M, et al.: Efficacies of BMS 284756 against penicillin-sensitive, penicillin-resistant, and quinolone-resistant pneumococci in experimental meningitis. Antimicrob Agents Chemother 2002, 46:184–187.

    Article  PubMed  CAS  Google Scholar 

  68. Rodriguez-Cerrato V, McCoig C, Saavedra J, et al.: Garenoxacin (BMS-284756) and moxifloxacin in experimental meningitis caused by vancomycin-tolerant pneumococci. Antimicrob Agents Chemother 2003, 47:211–215.

    Article  PubMed  CAS  Google Scholar 

  69. Rodoni D, Haenni F, Gerber CM, et al.: Trovafloxacin in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model. Antimicrob Agents Chemother 1999, 43:963–965.

    PubMed  CAS  Google Scholar 

  70. Cottagnoud P, Acosta F, Cottagnoud M, et al.: Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro. Antimicrob Agents Chemother 2000, 44:2179–2181.

    Article  PubMed  CAS  Google Scholar 

  71. Flatz L, Cottagnoud M, Acosta F, et al.: Ceftriaxone acts synergistically with levofloxacin against penicillin resistant pneumococci in experimental meningitis and reduces levofloxacin-induced resistance in vitro. Paper presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego. September 27–30, 2002.

  72. Michelet C, Leib SL, Bentue-Ferrer D, et al.: Comparative efficacies of antibiotics in a rat model of meningoencephalitis due to Listeria monocytogenes. Antimicrob Agents Chemother 1999, 43:1651–1656.

    PubMed  CAS  Google Scholar 

  73. van Deuren M, Brandzaeg P, van der Meer JW: Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 2000, 13:144–166.

    Article  PubMed  CAS  Google Scholar 

  74. Philips A, King A, Shannon K: Comparative in-vitro properties of the quinolones. In The Quinolones. Edited by Andriole VT. San Diego: Academic Press; 2002:99–137. This review presents an excellent summary of the in vitro activity of quinolones.

    Google Scholar 

  75. Bauernfeind A: Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother 1997, 40:639–651.

    Article  PubMed  CAS  Google Scholar 

  76. Tunkel AR: Bacterial meningitis. Philadelphia: Lippincott Williams & Wilkins; 2001. This outstanding book reviews all aspects of bacterial meningitis including epidemiology, pathophysiology, diagnosis, and treatment.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Inselspital, Freiburgstrasse, 3010, Bern, Switzerland

    Philippe Cottagnoud MD

Authors
  1. Philippe Cottagnoud MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin G. Täuber MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cottagnoud, P., Täuber, M.G. Fluoroquinolones in the treatment of meningitis. Curr Infect Dis Rep 5, 329–336 (2003). https://doi.org/10.1007/s11908-003-0011-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-003-0011-0

Keywords

Search

Navigation