Meningitis cerebrospinal fluid penetration

GaiUard J et al. Cerebrospinal fluid penetration of amikacin in children with community-acquired bacterial meningitis. Antimicrob Agents Chemother 1995 39 253-255. 

In patients with meningitis, levofloxacin penetration in cerebrospinal fluid and the liquor-to-plasma ratio was assessed at 2 hours after dosing in five patients with spontaneous acute bacterial meningitis. Cerebrospinal fluid levofloxacin concentration at 2 hours after dosing was 2.0 pg/ml, and the liquor-to-plasma ratio at 2 hours after dosing was 0.35 (1). 

Scotton PG, Pea F, Giobbia M, Baraldo M, VagUa A, Furlanut M. Cerebrospinal fluid penetration of levofloxacin in patients with spontaneous acute bacterial meningitis. Qin Infect Dis 2001 33(9) el09-ll. 

Jimenez-Mejias ME, Pichardo-Guerrero C, Marquez-Rivas FJ, Martin-Lozano D, Prados T, Pachon J. Cerebrospinal fluid penetration and pharmacokinetic/phar-macodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter bau-mannii meningitis. Eur J CUn Microbiol Infect Dis 2002 21(3) 212-14. 

Lipman J, Allworth A, Wallis SC. Cerebrospinal fluid penetration of high doses of intravenous ciprofloxacin in meningitis. Clin Infect Dis 2000 31 1131-1133. 

The importance of tissue penetration varies with the site of infection. The CNS is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in cerebrospinal fluid should either be avoided or instilled directly when treating meningitis. 

The degree of penetration of the aminoglycosides into cerebrospinal fluid is proportional to the degree of inflammation of the meninges. However, aminoglycosides are best combined with the (3-lactams or other antibiotics in the treatment of meningitis. 

The tetracyclines are distributed throughout body tissues and fluids in concentrations that reflect the lipid solubility of each individual agent. Minocycline and doxycycline are the most lipid soluble, while oxytetracy-chne is the least hpid soluble. The tetracyclines penetrate (but somewhat unpredictably) the uninflamed meninges and cross the placental barrier. Peak serum levels are reached approximately 2 hours after oral administration cerebrospinal fluid (CSF) levels are only one-fourth those of plasma. 

Drug concentrations in pleural fluid, peritoneal fluid, synovial fluid, aqueous humor, and vitreous humor approach two-thirds of the serum concentration when local inflammation is present. Meningeal and am-niotic fluid penetration, with or without local inflammation, is uniformly poor. Measurement of serum, urine, or cerebrospinal fluid drug levels has not been used clinically. 

Reductions in renal and hepatic function do not alter plasma drug concentrations, and ketoconazole is not removed by hemodialysis or peritoneal dialysis. Penetration into cerebrospinal fluid is negligible, so that ketoconazole is ineffective in the treatment of fungal meningitis. Since only small amounts of active drug appear in the urine, ketoconazole is not effective in the treatment of Candida cystitis. 

Most antimicrobial agents are well distributed to most body tissues and fluids. Penetration into the cerebrospinal fluid is an exception. Most do not penetrate uninflamed meninges to an appreciable extent. In the presence of meningitis, however, the cerebrospinal fluid concentrations of many antimicrobials increase (Table 51-6). 

Blood-brain barrier Treatment of central nervous system infections, such as meningitis, depends on the ability of a drug to penetrate into the cerebrospinal fluid (CSF). The blood-brain barrier (see p. 8) ordinarily excludes many antibiotics. However, inflammation facilitates penetration and allows sufficient levels of many (but not all) antibiotics to enter the CSF. [Note For cure of meningitis, it is important that a bactericidal rather than a bacteriostatic effect is achieved in the CSF. Yet, this is not without its problems, since rapid bacteriolysis in the infected CSF will liberate high concentrations of bacterial cell walls and lipopolysaccharide that can exacerbate the inflammation. This has led to the use of adjunctive (simultaneous administration of) corticosteroids, which diminish the inflammatory process and neurologic sequelae.]... 

Distribution All of these antibiotics distribute very well into body fluids. However, adequate therapeutic levels in the cerebrospinal fluid (CSF), regardless of inflammation, are achieved only with the third generation cephalosporins (for example, ceftriaxone or cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by Haemophilus influenzae). Cefazolin (se FA zo lin) finds application in orthopedic surgery because of its activity against penicillinase-producing Staphylococcus aureus, its half-life and its ability to penetrate bone. 

Distribution All of the aminoglycosides have similar pharmacokinetic properties. Levels achieved in most tissues are low, and penetration into most body fluids is variable. Concentrations in cerebrospinal fluid are inadequate even when the meninges are inflamed. Except for neomycin, the aminoglycosides may be administered intrathecally. High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear, which may account for their nephrotoxic and ototoxic potential. All cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. 

The importance of tissue penetration varies with the site of infection. The CNS is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in cerebrospinal fluid should either be avoided or instilled directly when treating meningitis. Apart from the bloodstream, other body fluids where drug concentration data are clinically relevant include urine, synovial fluid, and peritoneal fluid. Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For... 

Tuberculous Meningitis and Extrapulmonary Disease In general, INH, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid readily. Patients with CNS TB are often treated for longer periods (9 to 12 months). Extrapulmonary TB of the soft tissues can be treated with conventional regimens. TB of the bone is typically treated for 9 months, occasionally with surgical debridement. 

The skull and vertebrae protect the CNS from blunt or penetrating trauma (Fig. 105-1). The brain is suspended in these structures by cerebrospinal fluid (CSF) and is surroimded by the meninges. The meninges are made up of three separate membranes dura mater, arachnoid, and pia mater. Dura mater, or pachymeninges, lies directly beneath and is adherent to the skuU. The other two membranes are referred to collectively as leptomeninges. Pia mater lies directly over brain tissue. Arachnoid, the middle layer, lies between the dura mater and the pia mater. The subarachnoid space, located between the arachnoid and the pia mater, is the conduit for CSF. By definition, meningitis refers to inflammation of the subarachnoid space or spinal fluid, whereas encephalitis is an inflammation of the brain... 

Cerebrospinal Fluid PeniciUin does not readily enter the CSF but penetrates more easily with meningeal inflammation. The concentration attained usuaUy reaches 5% of the value in plasma and thus is therapeutically effective against susceptible microorganisms. Penicilhn and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. In uremia, other organic acids compete with penicillin for secretion the drug occasionally reaches toxic CNS concentrations that can produce convulsions. 

ABSORPTION, DISTRIBUTION, AND EXCRETION Isoniazid is readily absorbed after oral or parenteral administration. Isoniazid diffuses readily into aU body fluids and cells. The drug achieves significant quantities in pleural and ascitic fluids concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the plasma. Isoniazid penetrates well into caseous material and persists in therapeutic concentrations. 

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