Metronidazole & CSF
A Medline Literature Survey "metronidazole AND csf"
Date: April 19, 2000
1: Clin Pharmacokinet 1998 Sep;35(3):223-46
Pharmacokinetic optimisation of the treatment of bacterial central nervous
Nau R, Sorgel F, Prange HW
Department of Neurology, University of Gottingen, Germany. firstname.lastname@example.org
Central nervous system (CNS) infections caused by bacteria with reduced
sensitivity to antibacterials are an increasing worldwide challenge. In
successfully treating these infections the following conditions should be
Strategies to achieve optimum antibacterial concentrations in the
presence of minor disturbances of the blood-CSF and blood-brain barrier include,
- Antibacterials do not distribute homogeneously in the central
Even within the CSF, after intravenous administration, a ventriculo-lumbar
concentration gradient is often observed.
- cerebrospinal fluid (CSF),
- extracellular space of the
- intracellular space of the neurons,
- glial cells and
- Valid parameters of drug entry
into the CSF are
Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2
beta in serum.
- the CSF: serum concentration ratio in steady state and
- the CSF:
serum ratio of the area under the concentration-time curves (AUCCSF/AUCS).
- For most antibacterials,
With an intact blood-CSF and blood-brain barrier, the entry of
- molecular weight
- serum protein binding determine the drug entry into the CSF and brain
The minimum CSF concentration: MIC ratio ensuring successful therapy
- hydrophilic antibacterials
CNS compartments is poor and increases during meningeal inflammation.
- beta-lactam antibacterials,
are less dependent on the function of the blood-CSF and
- rifampicin (rifampin) and
- Determination of the minimal inhibitory concentrations
(MIC) of the causative organism is necessary for optimisation of treatment.
- For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are
Antibacterials which do not
interfere with bacterial cell wall synthesis
- the increased use of low toxicity antibacterials (e.g., beta-lactam
- the use of moderately lipophilic compounds, and
- the combination of
intravenous and intraventricular administration.
Conclusive evidence of the reduction of neuronal damage by this approach,
however, is lacking.
- delay and/or decrease the
liberation of proinflammatory bacterial products,
- delay or inhibit tumour
necrosis factor release, and
- may reduce brain oedema in experimental meningitis.
PMID: 9784935, UI: 99001114
5: Neurochirurgie 1993;39(6):380-4
[Comparative pharmacokinetics of antibiotics in blood, csf and brain].
[Article in French]
Redondo A, Tessier C, Branger C, Rey A
Service de Neurochirurgie, Hopital Beaujon, Clichy.
The knowledge of the antibiotic's cerebral diffusion is essential to define a of
neurosurgical antibioprophylaxis' strategy. Without references in the medical
world-literature, we have decided to compare the pharmacological kinetics in
of common used
molecules in neurosurgery that is to say:
- the cerebrospinal fluid and
- the sound cerebral tissue
The results show that
- metronidazole and
- the cerebral levels of
are rapidly high with an extended duration (> 10
times the M.I.C. of the sensitive bacteriae),
- metronidazole and
- but the tissue penetration of
amoxicillin is hazardous and short-duration for cefamandole (undosable after 3
PMID: 7936050, UI: 95021985
6: Am J Vet Res 1992 Oct;53(10):1807-12
Pharmacokinetics of metronidazole and its concentration in body fluids and
endometrial tissues of mares.
Specht TE, Brown MP, Gronwall RR, Rib WJ, Houston AE
Department of Large Animal Clinical Sciences, College of Veterinary Medicine,
University of Florida, Gainesville FL 32610-0136.
- Serum concentrations of metronidazole were determined in 6 healthy adult mares
after a single IV injection of metronidazole (15 mg/kg of body weight).
- The mean
elimination rate (K) was 0.23 h-1, and the mean elimination half-life (t1/2) was
- The apparent volume of distribution at steady state was 0.69 L/kg,
- the clearance was 168 ml/h/kg.
- Each mare was then given a loading dose (15
mg/kg) of metronidazole at time 0, followed by 4 maintenance doses (7.5 mg/kg, q
6 h) by nasogastric tube.
Metronidazole concentrations were measured in serial
samples of serum, synovia, peritoneal fluid, and urine.
concentrations in CSF and endometrial tissues were measured after the fourth
- The highest mean concentration in serum was 13.9 +/- 2.18
micrograms/ml at 40 minutes after the loading dose (time 0).
- The highest mean
synovial and peritoneal fluid concentrations were 8.9 +/- 1.31 micrograms/ml and
12.8 +/- 3.21 micrograms/ml, respectively, 2 hours after the loading dose.
lowest mean trough concentration in urine was 32 micrograms/ml.
concentration of metronidazole in CSF was 4.3 +/- 2.51 micrograms/ml and the
mean concentration in endometrial tissues was 0.9 +/- 0.48 micrograms/g at 3
hours after the fourth maintenance dose.
- Two mares hospitalized for treatment of
bacterial pleuropneumonia were given metronidazole (15.0 mg/kg, PO, initially
then 7.5 mg/kg, PO, q 6 h), while concurrently receiving gentamicin, potassium
penicillin, and flunixin meglumine IV. Metronidazole pharmacokinetics and serum
concentrations in the sick mares were similar to those obtained in the healthy
PMID: 1456525, UI: 93089616
7: Infect Dis Clin North Am 1989 Sep;3(3):553-70
Use of antibacterial agents in infections of the central nervous system.
Thea D, Barza M
Division of Geographic Medicine and Infectious Diseases, New England Medical
Center, Boston, Massachusetts.
The movement of drugs from the systemic circulation into the central nervous
system is restricted by several factors, including
functions of the blood-brain and blood-CSF barriers and of the active transport
system are reduced but not abolished by inflammation.
- the blood-brain and
- an active transport system that affects primarily the beta-lactam
- the high degree of serum protein binding of certain agents.
For most antimicrobial
agents, the major determinant of passage aside from serum protein binding is the
degree of lipid-solubility of the drug.
Knowledge of the relative capacity of
various drugs to penetrate the central nervous system after systemic
administration may help the physician to choose an optimum regimen for the
treatment of bacterial meningitis and brain abscess.
- The beta-lactam and aminoglycoside
antibiotics and vancomycin penetrate the central nervous system relatively
- chloramphenicol, metronidazole, the fluoroquinolones and
trimethoprim-sulfamethoxazole fare better.
PMID: 2671139, UI: 89360464
8: J Am Vet Med Assoc 1989 Aug 1;195(3):365-8
Central nervous system toxicosis associated with metronidazole treatment of
dogs: five cases (1984-1987).
Dow SW, LeCouteur RA, Poss ML, Beadleston D
Department of Clinical Sciences, College of Veterinary Medicine and Biomedical
Sciences, Colorado State University, Fort Collins 80523.
Metronidazole, administered to 5 dogs for periods ranging from 3 to 14 days, was
associated with acute development of CNS dysfunction. Metronidazole dosage
ranged from 67.3 to 129.0 mg/kg of body weight/d. Clinical signs of toxicosis
began with anorexia and intermittent vomiting and progressed rapidly to include
pronounced, generalized ataxia and vertical, positional nystagmus. These signs
were consistent with lesions of the vestibular nuclei and/or cerebellum. High
CSF protein content was detected in 2 of 3 dogs from which CSF was collected.
Two dogs were euthanatized because of severe neurologic dysfunction. Three dogs
improved slowly and recovered completely over several months. These findings
suggest that currently recommended dosages of metronidazole may be too high for
PMID: 2768064, UI: 89358863
11: Mikrobiyol Bul 1984 Oct;18(4):208-12
[A cerebellar abscess caused by anaerobic and aerobic (mixed) microorganisms].
[Article in Turkish]
Tokatli A, Kanra G, Ayhan Z, Kocoglu T, Secmeer G, Oran O
A 15 year old boy was admitted to hospital with five days history of fever,
headache, vomiting and otorrhea. Findings on physical examination included high
fever, purulent drainage from right ear, nuchal rigidity, Brudzinski's and
Kernig's signs. Laboratory finding was polymorphonuclear leukocytosis.
Computerized tomography (CT) of his brain was normal. A lumbar puncture
disclosed purulent CSF. Chloramphenicol and Penicillin G were given
intravenously as treatment for the meningitis. After five days of this therapy
he continued to be febrile and nuchal rigidity, Brudzinski's and Kerning's signs
increased. The second CT demonstrated the presence of an abscess in the
cerebellum. The abscess was aspirated during mastoidectomy. In the cultures of
the aspiration material Bacteroides species and gram positive micrococci grew
out. Metronidazole, 500 mg qid per oral, was added to the therapy. During
treatment, his condition was evaluated with serial computerized tomography scans
of his brain and these studies showed progressive decrease in the size of the
lesion. Metronidazole and antibiotics therapies were continued 45 days. The
patient made an uneventful recovery.
PMID: 6513826, UI: 85085643
12: Arzneimittelforschung 1984;34(7):830-1
[Metronidazole concentration of the cerebrospinal fluid from slightly inflamed
[Article in German]
Hoffmann HG, Forster D, Muirhead B
The concentrations of metronidazole (Clont i.v.) in the cerebrospinal fluid were
measured in 12 patients with viral meningitis or subsiding bacterial meningitis
after a single infusion of 500 mg lasting 20 min.
- 1 h after infusion the
CSF-concentrations were between 2.3 micrograms/ml and 7.4 micrograms/ml and
- 2 h
after infusion between 6.5 micrograms/ml and 8.6 micrograms/ml.
- They attained
45,9% respectively 75,9% of the corresponding serum concentrations.
- Because the
minimal inhibitory concentrations of the most important obligate anaerobic
gram-negative bacteria are attained, it appears that metronidazole can be used
for the treatment of bacterial meningitis caused by these pathogens.
PMID: 6541920, UI: 85046676
13: J Neurosurg 1983 Nov;59(5):735-44
Current concepts of bacterial infections of the central nervous system.
Bacterial meningitis and bacterial brain abscess.
Investigative work continues to provide guidance toward more rational management
of bacterial meningitis and bacterial brain abscess. An increased understanding
of the host's response in cases of bacterial meningitis has established that
diffusibility of an antibiotic into the cerebrospinal fluid (CSF) is necessary,
but is not sufficient for microbial cure. The antibiotic must also have a
bactericidal effect on the pathogen. Meningitis after neurosurgery may be caused
by Gram-negative aerobic bacilli. In some of these cases the newer cephalosporin
antibiotics may be a useful advance. Meningitis complicating ventricular CSF
shunts presents a paradigm for the problem of eradicating foreign body-related
infections. Studies of the interaction of the host, the organism, and the shunt
material offer some explanation for the limited efficacy of antibiotics observed
in this setting. There have been advances in microbial definition of bacterial
brain abscess. The identification of Bacteroides fragilis as a pathogen in
certain brain abscesses has established a role for a newly available antibiotic,
metronidazole. The study of the pathological distinction between cerebritis and
frank abscess is clarifying two clinical characteristics of brain abscess: the
limited success of antibiotic treatment and the increase in intracranial
pressure. Computerized tomography has offered a valuable clinical "look" at
brain abscesses; however, there are still problems in correlating the scan
images with the evolving pathological process.
PMID: 6352873, UI: 84009954
14: Pharmacotherapy 1982 Nov-Dec;2(6):384-7
Mental confusion in a patient treated with metronidazole--a
Schentag JJ, Ziemniak JA, Greco JM, Rainstein M, Buckley RJ
We report a case of serious mental confusion, hallucinations, and agitation in a
65 year old man, occurring in close relationship to the intravenous
administration of metronidazole. The patient was treated twice, but at different
dosages. The confusion and hallucinations occurred at the recommended daily dose
of 2.0 g, but did not return at a daily dose of 500 mg. Metronidazole serum
concentrations were obtained throughout both courses of therapy; CSF and tissue
concentrations were obtained at autopsy. The mental confusion was associated
with peak serum concentrations of approximately 40 micrograms/ml. Symptoms
resolved within 24-48 hr after stopping metronidazole, and resolution was
consistent with a metronidazole half life of 14 hr. We conclude that
metronidazole can be associated with a dose- and serum concentration-related
mental confusion state, and that this side effect appears completely reversible
upon discontinuing the drug.
PMID: 7167392, UI: 83169180
15: Drug Intell Clin Pharm 1981 Nov;15(11):838-46
Metronidazole (Flagyl IV, Searle).
Stranz MH, Bradley WE
Metronidazole is a narrow spectrum antibiotic with undoubted efficacy against
common anaerobic bacteria; resistance is unusual. Therapeutic concentrations of
the drug are attained throughout most body compartments after either oral or
intravenous administration. The limited side effects of metronidazole are
generally tolerable, transient, or reversible. Clinically, metronidazole is as
effective as clindamycin and probably chloramphenicol against anaerobes. It has
a definite advantage over clindamycin in CNS infections since clindamycin does
not penetrate the CSF well. Metronidazole has no irreversible hematologic
toxicities, nor has pseudomembranous colitis been definitely attributed to
intravenous use of the drug. Metronidazole may replace chloramphenicol for use
in anaerobic infections since it lacks the predictable hematologic toxicity of
the latter drug. It should also be useful in patients who fail to respond to
clindamycin or who develop pseudomembranous colitis while receiving clindamycin.
Problems with metronidazole include a complicated preparation procedure, and the
high cost of the drug.
The single major drawback to the use of metronidazole is
uncertainty about its carcinogenic potential in humans. Metronidazole is
carcinogenic in animals and mutagenic in vitro, but has not increased the
incidence of cancer in humans followed for relatively short periods. Thus, the
risk appears to be small. Still, the question will not be resolved for years
because of the long latency periods involved in carcinogenesis. Until that time,
metronidazole should be used conservatively.
PMID: 7028437, UI: 82050195
16: Am J Med Sci 1980 Nov-Dec;280(3):143-9
Metronidazole treatment of Bacteroides fragilis infections.
Melo JC, Raff MJ, Wunderlich HF, Chun CH, Summersgill JT, Varghese R
Seven patients with Bacteroides fragilis infections were treated with
intravenous and/or oral metronidazole. Infections treated included endocarditis,
osteomyelitis, lung abscess, empyema, peritonitis, septicemia, and pelvic
infection. Some patients had failed to respond to therapy with chloramphenicol
or clindamycin or both. Metronidazole was used alone or in combination with
to therapy with metronidazole was considered to be excellent. The only serious
side effect noted was hypotension, which occurred in the last patient. Therapy
was discontinued, and therefore therapeutic results could not be evaluated.
Metronidazole appears to be a safe and effective agent in the treatment of B
- Serum levels of metronidazole several times in excess of the
minimal inhibitory concentrations for the organisms were easily achieved and
one patient the CSF metronidazole level was equal to that of the serum.
PMID: 7457495, UI: 81106690
17: Infection 1980;8(3):101-3
Cerebrospinal fluid concentrations of metronidazole, tinidazole and ornidazole
Jokipii AM, Jokipii L
The penetration of metronidazole, tinidazole and ornidazole into the
cerebrospinal fluid (CSF) of rabbits was determined using a bioassay based on
the antibacterial activity of the drugs.
- After an intravenous dose of 50 mg, the
CSF levels of each drug exceeded previously reported minimum bactericidal
concentrations against Bacteriodes fragilis.
- Low serum levels of each drug,
produced by intramuscular administration of low doses, resulted in CSF/serum
ratios ranging from 0.63--0.73.
PMID: 7419273, UI: 81025595