Clinical Experience with Off-Label Intrathecal Administration of Selected Antibiotics in Adults: An Overview with Pharmacometric Considerations

Abstract

Drain-associated intracerebral infections are life-threatening emergencies. Their treatment is challenging due to the limited penetration of antibiotics to the site of infection, resulting in potentially inadequate exposure. The emergence of multidrug-resistant pathogens might force the use of off-label intrathecal (IT) doses of antibiotics. We reviewed the literature on general aspects determining intrathecal dosing regimen, using pharmacometric knowledge. We summarised clinical experience with IT doses of antibiotics that are usually not used intrathecally, as well as the outcome of the cases and concentrations reached in the cerebrospinal fluid (CSF). Factors determining the IT regimen are the size of the ventricle system and the CSF drainage volume. With regard to pharmacometrics, pharmacokinetic/pharmacodynamic indices are likely similar to those in non-cerebral infections. The following number (N) of cases were described: benzylpenicillin (>50), ampicillin (1), ceftazidime (2), cephaloridine (56), ceftriaxone (1), cefotiam (1), meropenem (57), linezolid (1), tigecycline (15), rifampicin (3), levofloxacin (2), chloramphenicol (3) and daptomycin (8). Many side effects were reported for benzylpenicillin in the 1940-50s, but for the other antibiotics, when administered correctly, all side effects were minor and reversible. These data might help when choosing an IT dosing regimen in case there is no alternative option due to antimicrobial resistance.

Keywords: antimicrobial; intracerebral infection; intrathecal administration.

Figure 1

Factors involved in the pharmacokinetics of antibiotics in the CSF compartment. BBB: blood–brain barrier; BCSFB: blood–cerebrospinal fluid barrier; AB: antibiotic.

Figure 2

Multicompartment system with different locations of administration. Vp: peripheral volume of distribution; Vc: central volume of distribution; V_CSF: volume of distribution of the CSF compartment; Q: intercompartmental clearance; CL: clearance; IV: intravenous; Q_CSF: intercompartmental clearance between Vc and V_CSF; CL_CSF: clearance from the CSF compartment.