TABLE 1.

CSF penetration and clinical use of different classes of antibioticsa

Compound (reference[s] for CSF penetration)AUCCSF/AUCSbRelationship of CSF concn to MIC with usual dosesCompound(s) with broad clinical experience for CNS infectionsDescription
Uninflamed or mildly inflamed meningesStrong meningeal inflammation
Penicillins Penicillin (46, 107, 108, 194, 246) 0.02 0.2 CSF concn with uninflamed meninges close to the MICs for moderately susceptible bacteriaPenicillin G, ampicillin, amoxicillinLow toxicity; daily dose can be increased up to 15-20 g (ampicillin)
    Nafcillin (164)
    Cloxacillin (46, 217)0.0087
    Amoxicillin (18, 35)0.058
    Ampicillin (35, 46, 72)
    Mezlocillin (94)
    Piperacillin (51, 168)0.0340.32
β-Lactamase inhibitors 0.07 0.1 CSF concn with inflamed and uninflamed meninges below the concn used in vitro for susceptibility testing (1-4 mg/liter)SulbactamLittle experience with in vivo activity in meningitis in humans; high-dose sulbactam (up to 8 g/day) was used successfully to treat Acinetobacter meningitis
    Clavulanate (18)0.0370.084
    Sulbactam (72)
    Tazobactam (168)0.106
Cephalosporins 0.007-0.1 0.15 CSF concn with uninflamed meninges close to the MICs of moderately susceptible bacteria; because of binding to plasma proteins, AUC ratio for ceftriaxone is approx 1 order of magnitude lower than that of cefotaximeCefazolin, cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpiromeLow toxicity; daily dose can be increased up to 12-24 g (cefotaxime)
    Cefazolin (111)
    Cephaloridine (46)
    Cefuroxime (112, 229)
    Cefotaxime (96, 175, 194, 195, 230)0.120.04, 0.17
    Ceftriaxone (47, 118, 141, 162, 175, 195, 236)0.007
    Ceftazidime (24, 70, 83, 156, 160, 172, 265)0.057
    Cefixime (165)
    Cefepime (213)0.103
    Cefpirome (73, 181, 262)0.145, 0.31
Carbapenems 0.2 0.3 CSF concn with uninflamed meninges close to the MICs for moderately susceptible bacteriaMeropenemMeropenem meningitis dose of 6 g/day; high proconvulsive activity of imipenem
    Imipenem (15, 155, 263)0.14
    Meropenem (34, 41, 142, 170)0.047, 0.21, 0.250.39
Aminoglycosides 0.2 Not availableCSF concn with uninflamed meninges close to the MICs for moderately susceptible bacteriaGentamicin, amikacinHigh toxicity precludes strong increase of the daily dose; consider intrathecal application
    Gentamicin (28, 46)
    Netilmicin (29, 55, 177)0.24
    Amikacin (26, 76)
Fluoroquinolones 0.3-0.7 0.7-0.9 CSF concn above the MIC for susceptible bacteria with uninflamed and inflamed meningesCiprofloxacin, (lev)ofloxacin, moxifloxacinEffective compounds with favorable CNS pharmacokinetics; suitable therapy for susceptible bacteria (Gram-negative aerobic bacilli, L.monocytogenes)
    Ciprofloxacin (173, 261)0.24, 0.430.92
    Ofloxacin (169)0.62
    Levofloxacin (189, 223)0.71
    Moxifloxacin (4, 5, 105)0.460.79 (0.71-0.94)
Chloramphenicol (46, 74, 270)0.6-0.70.6-0.7CSF concn above the MIC for susceptible bacteria with uninflamed and inflamed meningesChloramphenicolBacteriostatic, risk of aplastic anemia; reserve antibiotic
Macrolides (98)Despite adequate CSF concn, bacteriostatic against S. pneumoniaeErythromycin, clarithromycinCase reports suggest effectiveness in CNS infections caused by Mycoplasma, Chlamydia, and Legionella spp.
    Clarithromycin (137)Not available0.18
TetracyclinesRatios of individual CSF and serum samples suggest AUC ratio ∼0.2Ratios of individual CSF and serum samples suggest AUC ratio ∼0.2CSF concn close to the MIC for susceptible bacteriaDoxycyclineDocumented effectiveness for neuroborreliosis, -brucellosis, and -syphilis
    Doxycycline (56, 107, 108, 269)
Fosfomycin (75, 115, 193)0.18 (0.09-0.27)Not availableCSF concn above the MIC for susceptible pathogens with both inflamed and uninflamed meningesFosfomycinReserve antibiotic for S. aureus and P. aeruginosa CNS infections
Linezolid (20, 252)0.9 (0.8-1)Not availableCSF concn above the MIC for susceptible pathogens with both inflamed and uninflamed meningesLinezolidReserve antibiotic for S. aureus and Enterococcus sp. CNS infections
Metronidazole (93, 101, 258)Not available0.87CSF concn above the MIC for susceptible pathogens with both inflamed and uninflamed meningesMetronidazoleStandard therapy for CNS infections by anaerobic bacteria
RifamycinsCSF concn above the MIC for susceptible pathogens with both inflamed and uninflamed meningesRifampinStandard therapy of tuberculous meningitis; favorable clinical experience with S. aureus and S. pneumoniae CNS infections
    Rifampin (52, 62, 89, 106, 150, 163, 174)0.22Not available
Trimethoprim and sulfamethoxazole (57, 125, 257)With high doses, CSF concn above the MIC for susceptible pathogens with both inflamed andCotrimoxazoleReserve antibiotic for L. monocytogenes and T. gondii CNS
    Trimethoprim0.180.42-0.51    uninflamed meninges    infections
    Sulfamethoxazole0.120.24-0.30
GlycopeptidesWith uninflamed meninges, CSF concn below or close to the MICs forsusceptible bacteriaVancomycinStandard therapy for CNS infections by methicillin-resistant S. aureus and multiresistant S. pneumoniae; high CSF-to-serum ratios were determined during continuous infusion of a high vancomycin dose (60 mg/kg/day) (2); other reports suggested lower CSF penetration
    Vancomycin (2, 31, 65, 192, 205)0.18, 0.140.30 (0.29-0.48)
Antituberculosis drugsNot availableAlthough AUC ratios are not available for all compounds, isoniazide, pyrazinamide, and ethionamide readily enter the CSF; streptomycin behaves like other aminoglycosidesIsoniazide, pyrazinamide, ethambutol, streptomycinLimited data suggest moderate CSF penetration of ethambutol
    Isoniazid (53, 54, 62, 106, 228)0.86 (0.78-1.17)
    Pyrazinamide (54, 106)
    Ethambutol (25, 85)
    Streptomycin (62, 106)
    Ethionamide (62)
Antiherpesvirus nucleoside analoguesNot availableCSF concn above the IC of susceptible viruses with both inflamed and uninflamed meningesAcyclovir, ganciclovirHigh-dose intravenous acyclovir and ganciclovir are the treatment of choice for CNS infections by herpesviruses
    Acyclovir (134)0.31
    Valacyclovir (135)0.19
    Ganciclovir
Foscarnet (90, 199, 231)0.27, 0.430.23, 0.66CSF concn above the IC of susceptible viruses with both inflamed and uninflamed meningesFoscarnetReserve compound for cytomegalovirus CNS infections
Antiretroviral drugsNot availableCSF penetration depends strongly on the compound studied; based on animal exptl and clinical data, zidovudine, abacavir, stavudine, amprenavir-ritonavir, fosamprenavir-ritonavir, indinavir-ritonavir, and lopinavir-ritonavir are considered to reach an effective CNS concn (121, 241, 264)Zidovudine, abacavir, delavirdine, nevirapine, ritonavir-lamivudine, delavirdine, nevirapine, boostered amprenavir, indinavir, or lopinavirEffective concn in the CNS probably prevents dementia and development of resistant mutants
    Abacavir (12, 146, 249)0.35
    Lamivudine (12, 71, 249)
    Stavudine (12, 71, 88, 249)
    Zidovudine (12, 71, 209, 249)0.75
    Efavirenz (12, 238)
    Nevirapine (12, 249)
    Amprenavir (212)
    Atazanavir (250)
    Darunavir (267)
    Indinavir (12, 86, 122, 140)0.06-0.15
    Lopinavir (30, 268)0.29
    Ritonavir (12, 114)
    Saquinavir (12, 114)
    Raltegravir (266)
    Enfuvirtide (248)
    Maraviroc (248)
Antifungal drugsNot availableFluconazole, flucytosine, and voriconazole readily enter the CSF in the absence and presence of meningeal inflammation and reach therapeutic levels; with both conventional and liposomal amphotericin B, CSF concentrations are lowFluconazole, flucytosine, voriconazole, amphotericin BStandard therapy (amphotericin B, flucytosine, and fluconazole for Cryptococcus neoformans and Candida albicans; voriconazole for Aspergillus spp.) for CNS mycoses; consider intrathecal therapy with amphotericin B
    Flucytosine (23)0.74
    Fluconazole (16, 138, 148, 242)0.86 (0.74-0.89)
    Voriconazole (48, 63, 133)0.46
    Itraconazole (97)
    Posaconazole (210)
    Amphotericin B (110, 127)Low
    Micafungin (185)
Antiparasitic drugsNot availableAlbendazole penetrates the central nervous compartments more readily than praziquantel; high-dose sulfadiazine and pyrimethamine result in effective CSF concn in humansAlbendazole, sulfadiazine, pyrimethamineAlbendazole is the therapy of choice in neurocysticercosis; the combination of pyrimethamine and sulfadiazine is standard therapy for cerebral toxoplasmosis
    Albendazole (103, 157, 237)0.38, 0.43
    Praziquantel (103, 186)0.24
    Sulfadiazine (3, 19)0.27-0.33
    Dapsone (77, 206)
    Pyrimethamine (147, 260)
Intraventricular therapy ≫1 ≫1 High CSF concn with uninflamed and inflamed meninges; with large and/or hydrophilic compounds, which do not readily cross the blood-CSF barrier, the relatively low CSF turnover rate in humans allows once-daily dosingOption when i.v. administration will not lead to CSF concn above the MIC for the causative organism
    Colistin (100, 139, 272)
    Gentamicin (113, 200, 256)
    Netilmicin (55)
    Vancomycin (191, 192, 204)
    Daptomycin (64)
    Amphotericin B (14)
  • a For detailed pharmacokinetic data, see Tables S1.1 to S1.4 and S2 in the supplemental material. The statements on CSF concentrations are based only on dosing regimens usually employed for CNS infections (243) (Table S1).

  • b Boldface type indicates estimates of CSF penetration of the antibiotic class based on available data.