Download Antibiotic distribution into the CNS

Antibiotics and the
CNS
M Armstrong
Antibiotic penetration into the
CNS
• Pharmacokinetic data concerning the entry
of drugs into the CSF is incomplete
-Physical barrier: blood-CSF barrier (or
blood brain)
-Enzymatic blood-brain barrier
Different CNS compartments
Distribution of drugs within the CNS is not uniform (think CSF,
extracellular and intracellular spaces within the brain and spinal cord)
-most drugs achieve higher concentrations in the lumbar CSF vs
ventricular CSF
However no diffusional barrier exists between the interstitial space of
the nervous system and the CSF
In theory there should be good correlation between CSF levels and
interstitial levels
But…CSF is in constant flux from extracellular fluid (1/3rd of CSF
originates from the extracellular space of neurons) to the “CSF space”
and then into the venous system
The majority of anti-infections that have reached steady state
concentrations in the CSF, have levels substantially lower than the
corresponding plasma concentration
-AUCcsf/AUCs or the steady state concentration of CSF drug
concentration to serum drug concentration is the most accurate
parameter characterizing drug penetration into the CSF
Additional host factors such as meningeal inflammation* and age as
well as physicochemical properties of drugs are also important
*drug concentrations measured in the absence of meningeal
inflammation represent the minimal concentrations that can be
encountered in early or resolving CNS infection
Physicochemical properties
Molecular size:
The smaller the better for CNS penetration
Lipophilicity:
The more lipophilic usually the better- although very
lipophilic molecules are often highly protein bound or bind
to lipid membranes. Diffusion can also be pH dependent
Plasma protein binding:
Generally increased binding results in less penetration into
the CNS
Physicochemical properties
Active transport systems:
Variable effect on different drugs but usually active
transport is out of the CNS (P-glycoprotein, Oat3, PEPT2)
Upregulation of active transport system can occur
Metabolism within the CNS:
Certain drugs are more susceptible then others
e.g. the choroid plexus are able to metabolize
phenobarbital, dexamethasone and cephalothin
Meningeal inflammation
Results in blood brain barrier becoming “leaky” as
tight junctions break down
CSF outflow resistance also increases, leading to
moderate CSF production and absorption rate
Active transport mechanisms can also be inhibited
Beta-Lactams
400 Da, 0-95% plasma protein binding
In absence of meningeal inflammation penetration
is usually poor (AUCcsf/AUCs around 0.15)
High doses can be tolerated, which can get over
the issue of poor penetration
*but can decrease the seizure threshold
Potential issues with PK differences in BL-BLI
combinations in CNS infection
Aminoglycosides
400 Da, hydrophilic, low plasma protein binding
CSF penetration considered poor, however is not
lower then that of beta-lactams and other
hydrophilic antibiotics of a similar mass
Therapeutic index is low- ? Role of intrathecal
administration
Fluroquinolones
300 Da, Moderately lipophilic, low binding to plasma
proteins (20-40%)
Penetration into CSF in non-inflamed meninges much
higher than for beta-lactams
Utility in treating gram negative aerobic bacilli and TB
Not feasible in treating other pathogens such as
Streptococcus pneumonia because activity to low and
unable to increase dose significantly because of relative
high CNS toxicity
Chloramphenicol
Small molecule, active against a wide range of bacteria
Readily enters the CSF
Previous extensive use to treat meningitis
Lawyers’ limit its use (in industrialized countries)
Macrolides
Highly lipophilic, 750 Da, high affinity for P-gp
Limited CNS penetration
Role is limited to CNS infections 2nd to Mycoplasma sp.
And Legionella pneumophila encephalitis
Tetracyclines and Tigecycline
Doxycycline is lipophilic, with protein binding over 80%
CNS penetration 0.2 in absence and presence of
inflammation of meninges (usually dose 400mg per day)
Not inferior to Ceftriaxone in treating neuroborreliosis. Can
be used for neurobrucellosis and even neurosyphilis
Tigecycline – CNS penetration 0.1 in uninflamed meninges
Fosfomycin
138 Da, hydrophilic, not protein bound
Enters CNS more readily then beta-lactams
Use in Europe of intravenous fosfomycin in treating some
CNS infection by multi-resistant bacteria
Oxazolidinones
Linezolid is amphiphilic and has a CNS penetration ration
of close to 1
Although primary bacteriostatic, potential utility in gram
positive CNS infection by resistant organisms
Metronidazole and Clindamycin
Metronidazole: small, lipophilic molecule
-Good penetration into CSF and absesses
Clindamycin: 425 Da, with poor CNS penetration, but can
be used in high doses potentially
Rifamycins
Lipophilic, > 800 Da, protein binding around 80%
Moderate CNS penetration, with CNS concentrations often
independent of the state of the blood-CSF barrier
Side effects of limit use for CNS infection
Sulfonamides and Trimethoprim
Small lipophilic molecules
Good CNS penetration, higher then that of betalactams
Not so dependent of meningeal inflammation
Use in certain infections- Listeria sp, Nocardia sp,
Stenotropomonas, toxoplasmosis
Bone marrow toxicity may complicate use
Glycopeptides
Hydrophilic antibiotics with high mass (over 1400 Da)
Protein binding <50% for vancomycin, >90% for teicoplanin
Patients with inflamed meninges usually optain good
therapy levels in CSF
Concurrent dexamethasone may reduce CSF levels
(? Use ceftriaxone and rifampicin instead of vanc in empiric
meningitis therapy)
Toxicity can limit dose increases
Daptomycin and fusidic acid
While daptomycin only has 6% CNS penetration, has
previously been used to treat MRSA meningitis with
success
Fusidic acid has poor CNS penetration
Colistin
Poor CNS penetration
Used in carbapenem resistant Acinetobacter sp CNS
infection
Can use intra-thecally
Anti-tuberculosis drugs
Pyrazinamide and isoniazid are moderately lipophilic and
small molecules and have good CNS penetration
Other first line agents have poor penetration
Moxifloxacin is a useful alternative
Anti-herpes virus drugs
Moderate for oral administration
CSF penetration of ganciclovir 0.155 in non-inflamed
meninges (similar to acyclovir)
Antiretrovirals
HIV encephalitis does not have a significant effect
on the blood-CSF/blood brain barrier
Wide variation in compounds studied, but
generally PI’s have poorer CNS penetration (often
ligands of P-gp)
CNS penetration-effectiveness (CPE) index
-zidovudine (0.75), abacavir (0.35), delavirdine,
nevirapine, indinavir, lopinavir
Antifungals
Amphotericin (all formulations), has poor CNS penetration
-although still often used for CNS disease
-intrathecal administration possible
5-Flucytosine has good CNS penetration (0.75)
Echinocandins have poor CNS penetration
Azoles- voriconazole (0.46) and fluconazole are the best
Antiparasitics
Pyrimethamine (cerebral toxoplasmosis), has CSF
levels about 10-25% of serum levels
Atorvaquone has no studies but has had some
clinical success
Albendazole has good CNS penetration, compared
to Praziquantel
Reference
Nau et al. Penetration of Drugs through the
Blood-Cerebrospinal Fluid/Blood Brain
Barrier for Treatment of Central Nervous
System Infections. Clin. Microbiol. Rev.
2010, 23(4):858-883.