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Penetration and activity of antibiotics in brain

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Article in Journal of the College of Physicians and Surgeons--Pakistan: JCPSP April 2005
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UPDATE
PENETRATION AND ACTIVITY OF ANTIBIOTICS IN
BRAIN ABSCESS
Muhammad W. Raza, Amjad Shad,* Steve J Pedler** and Karamat A. Karamat***
A BSTRACT
Penetration of antimicrobial agents into the cerebrospinal fluid is dependent on numerous factors, including their
serum protein binding, molecular size and lipid solubility, and degree of local inflammation. The choice of an
appropriate agent is further complicated by diverse bacterial flora involved in brain abscess, local resistant patterns
and activity of the drug in abscess environment. This update examines the conventional and newer agents in the
above context for their role in the management of brain abscess.
KEY WORDS: Brain abscess. Bacterial infections.
Blood brain barrier.
INTRODUCTION
Treatment of infections in the central nervous system (CNS) is
complicated due to different permeability of various
antibiotics across the blood-cerebrospinal fluid (CSF)-barrier
(B-CSF-B) and the blood-brain-barrier (BBB). In patients with
brain abscesses, the therapy can be further complicated due to
limited penetration of antibiotics into the abscess cavity. Other
pharmacokinetic and pharmacodynamic properties of the
antibacterial agents also affect their preference in treating
infection in CNS. The choice of antibiotics for empirical
therapy may be facilitated by the knowledge of location of the
abscess in the brain, which may not be accessible for
microbiological testing. The microbial flora colonising or
infecting the extracerebral structure(s) near to the site of the
abscess are likely to be involved in its pathogenesis.1 This
update reviews the use of conventional antibacterial agents
following more experience and data on their use and some of
the newer agents.
BARRIERS TO THE PASSAGE OF DRUGS INTO THE
BRAIN
The CNS is normally protected from free exposure to
administered drugs due to a unique functional and
morphological nature of brain capillaries.2 Agents are tested
for their ability to cross these barriers to avoid toxicity to the
CNS, and to measure their efficacy in treating CNS conditions.
The CSF compartment is protected by B-CSF-B and in health
the B-CSF-B permits the entry of simple, small molecules but
the passage of more complex drugs is very limited. Inflamed
Department of Microbiology/Virology/Public Health, Health Protection Agency,
Newcastle General Hospital, Newcastle, UK
* Department of Neurosurgery, Wallsgrave Hospital, Coventry UK, CV2 2DX.
** Department of Microbiology, Royal Victoria Infirmary, Newcastle UK, NE1 4LP.
***National Institute of Health, Islamabad.
Correspondence: Dr. Muhammad W. Raza, 7 Willerby Drive, Whitebridge
Park, Newcastle NE3 5LL, UK. E-mail: mraza7@hotmail.com
Received October 13, 2004 ; accepted February 13, 2005.
JCPSP 2005, Vol. 15 (3): 165-167
Antibiotics. Nervous system. Blood cerebrospinal fluid.
meninges, however, enhance their entry into the CSF. This
could be due to acidosis in the CSF compartment, which
results in an increase in the plasma-CSF pH gradient that
facilitates the entry of the agents ionised at normal pH, e.g., b-
lactams.3 Adjuvant therapy with anti-inflammatory agents
might hinder the passage of drugs, particularly larger
molecules, e.g., vancomycin, across the barriers.4 Lipid
solubility of drugs, e.g., fluoroquinolones, also facilitates drug
delivery to this compartment.5 Only the fraction of the drug
free in serum, and not bound to serum proteins, is available
for crossing the barrier.6 Most drugs are removed from the
CSF compartment by active, energy-dependent mechanisms
that are inhibited during meningitis.7 Hydrophilic drugs, e.g.,
b-lactams, have longer half life in CSF compared with serum,
allowing longer dosing intervals.5
Brain parenchyma is protected from free exposure to drugs by
BBB. Distribution of antibiotics in the interstitial space of the
brain is dependent on both the BBB and B-CSF-B. The BBB is
important in delivery of drugs to brain parenchyma in cases of
metabolic or parenchymal brain disease and in areas of the
brain with cerebritis and abscess. It has been shown that
passage of antibiotics across the BBB is enhanced in the areas
of brain affected by inflammation.8 Interstitial space in the
brain is contiguous with the CSF compartment and there is no
anatomical CSF-brain barrier. Drugs delivered directly to the
CSF do not, however, effectively penetrate brain tissue
possibly due to tortuous nature of the interstitial space in the
brain.9
ANTIBIOTICS IN CNS INFECTIONS
Choice of antibiotic in the treatment of infection in CNS
depends upon the availability of the antibiotic in the brain
tissue, abscess fluid or CSF. Table I summarises the
conventional antibiotics that can appear in therapeutic
concentrations in the CSF compartment and abscess fluid.
165
Muhammad W. Raza, Amjad Shad, Steve J Pedler and Karamat A. Karamat

Table I: Activity of conventional antibiotics in the CNS. over the barriers, and length of treatment is usually guided
empirically by the progress in the individual cases. Most
Antibiotic Level in abscess fluid CSF level Reference
studies recommend 4-6 weeks treatment with appropriate
Penicillin Therapeutic with high 10
dose regimen antibiotics in brain abscess.1 The choice between medical
Sub-therapeutic with
management with or without surgical intervention depends,
usual doses Therapeutic** 4 among the other factors, on the initial size of abscess.
Amoxycillin/Amoxycillin Abscesses smaller than 1.7 cm (range, 0.82.5 cm) have been
+clavulanic acid NA Therapeutic** 11 successfully treated with antibiotics alone, while medical
Flucloxacillin Therapeutic NA 12 treatment alone cannot be relied upon when the size is larger
Imipenem Therapeutic Therapeutic 13 (4.2 cm, range 2.0-6.0).30
Cefotaxime Therapeutic Therapeutic 14
There are two possible routes for the bacteria to cause brain
Cefuroxime NA Low*** 15
abscesses: contiguous spread from the carrier sites in the nose
Ceftazidime NA Therapeutic** 16
and throat, sometimes facilitated by local trauma; and
Other b lactams Sub-optimal NA 10
metastatic seeding during bacteremia. While a local extension
Aztreonam NA Therapeutic 17 of infection usually results in a single abscess with
Chloramphenicol* Erratic Therapeutic** 10 polymicrobial flora, bacteremia might be complicated with
Fosfomycin Therapeutic Therapeutic 10 multiple abscesses involving only one type of organism.
Aminoglycosides Poor NA 10
Due to uncertainty about the issue of bioavailability in the
Erythromycin NA Therapeutic** 19
CNS, cases of brain abscess might be preferably treated with
Clindamycin Therapeutic/Low Therapeutic** 20
multiple intravenous antibiotics, combined wherever possible
Fusidic acid Therapeutic 9
with intraventricular antibiotics delivered through an EVD
Low Low 21
inserted to control the CSF pressure or for drainage of pus. We
Vancomycin Therapeutic Therapeutic** 22
support the view that insertion of an EVD solely for antibiotic
Trimethoprim+
Sulfamethoxazole* Therapeutic Therapeutic 23
therapy might be justified in cases where the organisms are
sensitive only to antibiotics with poor CNS penetration and an
Rifampicin Therapeutic Therapeutic 24
increase in the antibiotic dose is precluded by its toxicity, or
Metronidazole* Therapeutic NA 25
NA, reliable data not available; * Lipid-soluble; ** therapeutic levels are achieved only with a
where iv therapy alone has not been clinically effective or has
barrier disorder; *** The authors argue against the use of cefuroxime in neurosurgical not sterilised the CSF compartment.
prophylaxis.
Duration of therapy depends upon the size and site and
NEW OR EXPERIMENTAL ANTIBACTERIAL AGENTS number of abscesses, the organisms involved and availability
of bactericidal agents with appropriate CSF penetration. In
Linezolid belongs to a novel group called oxazolidinones, most cases, 8-12 weeks therapy is required.3 1 The progress
which act in inhibiting the initiation of bacterial protein needed to be closely monitored with inflammatory markers,
synthesis. Linezolid has been licensed in the UK for the repeated scanning, if necessary, and for adverse drug effects.
treatment of pneumonia and skin and soft tissue infections.
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