title: Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis.
abstract: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone (n = 15), ciprofloxacin (n = 16), levofloxacin (n = 15), or gatifloxacin (n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the cerebrospinal fluid AUC(0-24), was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College, Exhibition Road, London, United Kingdom. guy.thwaites@btinternet.com
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Tran Thi Hong
authors.initials: TT
authors.lastname: Chau
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hammel
authors.forename: M Estée
authors.initials: ME
authors.lastname: Török
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Pham Phuong
authors.initials: PP
authors.lastname: Mai
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Reynolds
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
authors.forename: Nguyen Thi
authors.initials: NT
authors.lastname: Dung
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Robert
authors.initials: R
authors.lastname: Kulawy
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D002939:Ciprofloxacin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D004977:Ethambutol / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000077734:Gatifloxacin; D006801:Humans; D007273:Injections, Intramuscular; D007538:Isoniazid / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D015242:Ofloxacin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D011718:Pyrazinamide / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D012293:Rifampin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D013307:Streptomycin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D014390:Tuberculosis, Meningeal / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D024841:Fluoroquinolones; D011718:Pyrazinamide; D002939:Ciprofloxacin; D064704:Levofloxacin; D004977:Ethambutol; D015242:Ofloxacin; D000077734:Gatifloxacin; D007538:Isoniazid; D012293:Rifampin; D013307:Streptomycin