Clinical Pharmacokinetics of Antibacterials in Cerebrospinal Fluid

Abstract

In the past 20 years, an increased discrepancy between new available antibacterials and the emergence of multidrug-resistant strains has been observed. This condition concerns physicians involved in the treatment of central nervous system (CNS) infections, for which clinical and microbiological success depends on the rapid achievement of bactericidal concentrations. In order to accomplish this aim, the choice of drugs is based on their disposition toward the cerebrospinal fluid (CSF), which is influenced by the physicochemical characteristics of antibacterials. A reduced distribution into CSF has been documented for beta-lactams, especially cephalosporins and carbapenems, on the basis of their hydrophilic nature. However, they represent a cornerstone of the majority of combined therapeutic schemes for their ability to achieve bactericidal concentrations, especially in the presence of inflamed meninges. The good tolerability of beta-lactams makes possible high daily dose intensities, which may be associated with increased probability of cure. Furthermore, the adoption of continuous infusion seems to be a fruitful option. Fluoroquinolones, namely moxifloxacin, and antituberculosis drugs, together with the agents such as linezolid, reach the highest CSF/plasma concentration ratio, which is greater than 0.8, and for most of these drugs it is near 1. For all drugs that are currently used for the treatment of CNS infections, the evaluation of pharmacokinetic/pharmacodynamic parameters, on the basis of dosing regimens and their time-dependent or concentration-dependent pattern of bacterial killing, remains an important aspect of clinical investigation and medical practice.

Septic cavernous sinus thrombosis caused by tuberculosis infection

“…The abnormal manifestations on CT had been considered as small septic pulmonary emboli. His fever, neurological symptoms and the abnormal findings on CT resolved with an antibiotic regimen containing moxifloxacin, which has been proved to have good CSF penetration and is recommended in the treatment of TB meningitis 6 7. Although the empiric antibiotic treatment in Honolulu also included ceftriaxone and meropenem, moxifloxacin was the last prescribed before the relief of symptoms.…”

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

“…Also of critical impact is the presence of inflammation within the meninges, as this significantly alters the permeability of the BBB, profoundly increasing CSF exposures for the majority of antibiotics. 107,108,110 …”

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study

“…Meropenem plus vancomycin is a frequently used antimicrobial combination for management of IVC-related infections because of its broad spectrum of antimicrobial activity [2, 4]. Nevertheless, relatively little is known about the pharmacokinetics (PK) of meropenem in the cerebrospinal fluid (CSF) of patients with ventriculitis [5, 6]. …”

“…In randomised clinical trials, meropenem was as effective as cefotaxime and ceftriaxone for treating community-acquired bacterial meningitis in children and adults [10, 11]. The penetration of antibiotics into the CNS is dependent on several factors, such as the presence of meningeal inflammation [5, 6]. The meninges in ventriculitis are typically normal or only minimally inflamed [5, 6].…”

“…The penetration of antibiotics into the CNS is dependent on several factors, such as the presence of meningeal inflammation [5, 6]. The meninges in ventriculitis are typically normal or only minimally inflamed [5, 6]. Thus, penetration into the CNS in patients with ventriculitis should not be extrapolated from other patient populations.…”