Antimicrobial therapy for bacterial meningitis

Abstract

Bacterial meningitis is an uncommon condition in mature horses (Newton 1988). It is more prevalent in neonates, where it is reported to occur in 8–10% of septicaemic foals (Moore 1995), where reported survival rates are poor (Newton 1988; Santschi and Foreman 1989; Moore 1995). Survival rate for adult horses was reported as 60% in a case series of 5 horses with bacterial meningitis (Mitchell et al. 2006). There are no published comprehensive case series of bacterial meningitis in foals. Early diagnosis is essential to provide accurate prognosis and to institute proper treatment (Santschi and Foreman 1989). The primary goal of treatment is rapid sterilisation of the cerebrospinal fluid (CSF) using appropriate antimicrobial therapy based on bacterial culture and sensitivity testing of the CSF (Moore 1995). However, due to the specialist nature of the central nervous system (CNS) and presence of the blood brain barrier (BBB), CNS concentrations of antimicrobial agents may be substantially below those obtained in serum, and below the minimal inhibitory concentration or minimal bactericidal concentration for the bacterial isolates involved in the disease process. This paper reviews the nature of poor antimicrobial penetration into the CNS and discusses the antimicrobial drugs that may be appropriate to use in treatment of bacterial meningitis in horses. Meningitis is defined as inflammation of the 3 membranes, or meninges, surrounding the brain and spinal cord. These consist of the dura mater, the arachnoid and pia mater (Fig 1). Inflammation of the meninges due to bacterial infection is termed bacterial meningitis. The space between the arachnoid and pia mater is filled with CSF. This protects the brain and spinal cord against impact from the surrounding bony wall, provides nutrition to the brain and spinal cord and permits variations in blood volume within the cranial cavity. The existence of a barrier between the brain or CSF and the peripheral circulation was first recognised by Ehrlich in 1885 (Saunders et al. 1999), and allows the adult brain to function in a well-controlled internal environment that is separate from that of the internal environment of the rest of the body as a whole. The integrity of this barrier is due to the presence of tight junctions between the cerebral endothelial cells forming the BBB and between the blood and choroid plexus epithelial cells (blood-cerebrospinal fluid barrier) (Saunders et al. 1999). The presence of endothelial cell tight junctions and basement membrane also restricts entry of certain therapeutic agents into the CSF and CNS. The presence of the BBB, combined with the lack of a traditional lymphatic system, are important factors in mediating the immune response within the CNS. As such, the CNS is often classified as an ‘immune privileged’ site (Wekerle et al.1986). In health, the key factors that determine penetration of a molecule into the CNS and CSF in adults are lipid solubility and molecular size (Saunders et al. 1999). Highly lipid soluble molecules are considered to dissolve in the lipid structure of cell membranes and can thus transverse cell membranes. For molecules of low lipid solubility there is a clear relationship between molecular size and penetration into the brain and CSF. In healthy human subjects, molecules with size greater than 5000 Daltons are unable to penetrate from blood to CSF (Saunders et al. 1999). In addition, a high degree of plasma protein binding of therapeutic agents limits their permeability to the CNS, since plasma proteins (principally albumin) are too large to cross the BBB. This situation is altered in acute CNS inflammation, where penetration of molecules of larger molecular weight