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 system infections.

Nau R, Sorgel F, Prange HW

Department of Neurology, University of Gottingen, Germany. rnau@gwdg.de

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 considered:

  1. Antibacterials do not distribute homogeneously in the central nervous compartments Even within the CSF, after intravenous administration, a ventriculo-lumbar concentration gradient is often observed.
  2. Valid parameters of drug entry into the CSF are
    1. the CSF: serum concentration ratio in steady state and
    2. the CSF: serum ratio of the area under the concentration-time curves (AUCCSF/AUCS).
    Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2 beta in serum.
  3. For most antibacterials, With an intact blood-CSF and blood-brain barrier, the entry of
    1. hydrophilic antibacterials
      • beta-lactam antibacterials,
      • glycopeptides
      into the CNS compartments is poor and increases during meningeal inflammation.
    2. More lipophilic compounds
      • metronidazole,
      • quinolones,
      • rifampicin (rifampin) and
      • chloramphenicol
      are less dependent on the function of the blood-CSF and blood-brain barrier.
    3. Determination of the minimal inhibitory concentrations (MIC) of the causative organism is necessary for optimisation of treatment.
    4. For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are required.
    The minimum CSF concentration: MIC ratio ensuring successful therapy is unknown.
Strategies to achieve optimum antibacterial concentrations in the presence of minor disturbances of the blood-CSF and blood-brain barrier include, Antibacterials which do not interfere with bacterial cell wall synthesis Conclusive evidence of the reduction of neuronal damage by this approach, however, is lacking.

Publication Types:

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 results show that
  1. the cerebral levels of are rapidly high with an extended duration (> 10 times the M.I.C. of the sensitive bacteriae),
  2. but the tissue penetration of amoxicillin is hazardous and short-duration for cefamandole (undosable after 3 hours).

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.
  1. Serum concentrations of metronidazole were determined in 6 healthy adult mares after a single IV injection of metronidazole (15 mg/kg of body weight).
  2. 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. RESULTS:
  3. 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 mares.

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

The functions of the blood-brain and blood-CSF barriers and of the active transport system are reduced but not abolished by inflammation.

For most antimicrobial agents, the major determinant of passage aside from serum protein binding is the degree of lipid-solubility of the drug.

  1. The beta-lactam and aminoglycoside antibiotics and vancomycin penetrate the central nervous system relatively poorly, whereas
  2. chloramphenicol, metronidazole, the fluoroquinolones and trimethoprim-sulfamethoxazole fare better.
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.

Publication Types:

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 some dogs.

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 meninges].

[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. 1 h after infusion the CSF-concentrations were between 2.3 micrograms/ml and 7.4 micrograms/ml and
  2. 2 h after infusion between 6.5 micrograms/ml and 8.6 micrograms/ml.
  3. They attained 45,9% respectively 75,9% of the corresponding serum concentrations.
  4. 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.

Garvey G

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. Publication Types:

PMID: 6352873, UI: 84009954

14: Pharmacotherapy 1982 Nov-Dec;2(6):384-7

Mental confusion in a patient treated with metronidazole--a concentration-related effect?

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.

Publication Types:

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 aminoglycosides.
  1. Serum levels of metronidazole several times in excess of the minimal inhibitory concentrations for the organisms were easily achieved and
  2. in one patient the CSF metronidazole level was equal to that of the serum.
Response 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 fragilis infections.

PMID: 7457495, UI: 81106690

17: Infection 1980;8(3):101-3

Cerebrospinal fluid concentrations of metronidazole, tinidazole and ornidazole in rabbits.

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.
  1. After an intravenous dose of 50 mg, the CSF levels of each drug exceeded previously reported minimum bactericidal concentrations against Bacteriodes fragilis.
  2. 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