The Use and Misuse of Antibiotics in Neurosurgery

The Blood-Brain and Blood–Cerebrospinal Fluid Barriers

The BBB is formed by the endothelial cells of the cerebral vasculature, supported by astroglia and pericytes, with tight junctions between the endothelial cells and minimal fenestrations or bulk transport across the cells. The BCSFB is formed by the epithelial layer of the choroid plexus, not at the endothelium, but is similar in character with tight junctions between the epithelial cells. For both of the barriers, active influx and efflux transporters located on the endothelial or epithelial cell surface may drastically alter the distribution of an antibiotic into the desired compartment. ^,

Factors such as increasing molecular weight, ionization, plasma protein binding, metabolism at the barrier, and presence of efflux transporters will decrease the permeability of substances across the brain barriers. ^, Other factors such as increased lipophilicity, influx transporters, and inflammation can increase the permeability of the barriers to antibiotics. Antibiotics may cross into the cerebrospinal fluid (CSF) or brain parenchyma more readily at the initiation of treatment, but as the inflammatory response to the infection abates, either from the antibiotic treatment or from administration of other medications such as dexamethasone, the ability of an antibiotic to cross the brain barriers will diminish. ^, However, this effect may not alter outcome.

The overall goal of antibiotic treatment is to deliver an adequate concentration of the drug to the proper compartment. This may be accomplished in several ways. First, the dose of the drug may be increased. This method is helpful in drugs with low systemic toxicities and relatively low permeability across the brain barriers, such as β-lactam antibiotics. Second, the choice of antibiotics may be altered to a drug that has greater penetration into the CNS, such as chloramphenicol or the fluoroquinolones. Third, antibiotics may be delivered directly across the brain barriers, usually by indwelling ventricular or lumbar intrathecal catheters. This method is especially helpful when using antibiotics such as vancomycin or the aminoglycosides, which have higher systemic toxicities and poor permeability across the brain barriers that limit the systemic dose that may be administered.

An excellent review of the BCSFB and BBB has been published by Nau and colleagues.

Pharmacokinetics of Antibiotic Delivery

Effective antibiotic dosing is achieved by understanding the pharmacokinetics of antibiotics, which depends on the systemic pharmacokinetics as well as on the behavior of the antibiotic in its access to and elimination from the CNS. It is important to bear in mind that most data relating to antibiotic pharmacokinetics in the CNS come from studies on CSF samples and patients with meningitis, with far fewer data for cranial intraparenchymal abscesses. ^, A few studies have used microdialysis assays to measure brain interstitial concentrations of antibiotics themselves, but these studies had small numbers of patients, were conducted in patients with other underlying brain injuries, and had limitations in methods.

In determining the proportion of antibiotic reaching the CNS, careful interpretation of experimental data is required. Many studies looking at this proportion used simple plasma-CSF ratios at a single time point. These ratios can vary widely during a dosing cycle and can be quite misleading. ^, The most useful data come from using plasma-CSF AUC ratios. The AUC is the area under the drug concentration–time curve. Plasma-CSF AUC ratios are useful in intermittent dosing, or steady-state concentrations during continuous infusion. For β-lactam antibiotics, the AUC ratio generally ranges from 0.01 to 0.1. Less hydrophilic antibiotics, such as rifampicin, trimethoprim-sulfamethoxazole, and the fluoroquinolones, have ratios that range from 0.1 to 0.9. Vancomycin and the aminoglycosides also have low penetration into the CSF, with ratios less than 0.1. ^, However, data suggest that these ratios may be different in treatment of infections of the brain parenchyma or abscess. One study showed equivalent levels of the antibiotic in the abscess fluid and the plasma 6 hours after administration; however, these are also time point ratios, not AUC ratios.

Concentrations of antibiotics throughout the CSF are not constant. Ventricular CSF will have a lower concentration of protein and antibiotic than lumbar CSF because the CSF produced in the ventricles has not yet mixed with exuded extracellular fluid from the brain parenchyma. Therefore CSF concentrations of antibiotics rely on the permeability of both the BBB and the BCSFB. Penetration of antibiotics through the blood-lesion barrier (specifically the blood-abscess barrier) will vary with the stage of formation of the abscess, the relative vascularity of the lesion, and even the etiology of the lesion. However, it is impossible to differentiate the individual contributions of the blood-lesion barrier and the surrounding BBB to antibiotic concentrations by using measurement of antibiotic levels within abscesses. ^, The half-life of the antibiotic in the CSF is also an important consideration. Most antibiotics are not metabolized in the CSF. Elimination comes either through diffusion back through the BBB and BCSFB, or from turnover of the CSF. In general, the CSF half-life of antibiotics is significantly longer than the plasma half-life. The CSF half-life of antibiotics may also be increased in CNS infections because of decreased turnover of CSF. Conversely, in patients with CSF shunts or external CSF drains, the CSF half-life may be quite variable because the circulation of CSF is altered. ^,

Central Nervous System Toxicity of Antibiotic Therapy

Antibiotics may be toxic to the CNS when administered systemically, or when administered directly to the CNS via an intrathecal route or through antibiotic irrigation. Systemic administration of almost any class of antibiotic may cause CNS toxicity, including encephalopathy, seizures, psychiatric symptoms, cranial nerve injury, and ataxia. ^, Table 55.1 lists selected CNS toxicities of commonly used antibiotics.

Intrathecal antibiotics may also have significant neurological toxicities, although the most commonly used intrathecal antibiotics, vancomycin and gentamicin, appear to have relatively low toxicity when administered intrathecally. In addition, discerning these effects may be difficult in the face of a coexisting serious CNS infection. Intraventricular vancomycin appears to be relatively free of toxicity, even at high CSF levels. Intraventricular gentamicin may have CNS toxicity, causing ototoxicity or epilepsy; however, these effects are not clearly related to CSF levels of gentamicin. ^, Intraventricular administration of β-lactam antibiotics may cause effects similar to those occurring when they are administered systemically, especially seizures, so administration by this route is not recommended.

Surgical Site Infection Risk Reduction

The 2017 Centers for Disease Control and Prevention (CDC) Guideline for the Prevention of Surgical Site Infection does not include any direct evidence from the study of neurosurgical procedures but builds on prior general surgical infection data. ^, General recommendations for infection risk reduction are as follows: Patients should bathe with nonspecific soap on the night prior to surgery, skin preparation in the operating room should include an alcohol-based agent unless contraindicated, glycemic control should be maintained for glucose levels less than 200 mg/dL, normothermia should be maintained, increased fraction of inspired oxygen should be given during surgery and immediately following extubation, and blood transfusion should not be withheld as an infection-prevention strategy. Relevant to neurosurgical procedures, the guidelines also state that topical antimicrobial agents should not be applied to the incision, although one must interpret this cautiously because several recent studies indicating potential benefit in the setting of implants were not considered. For clean and clean-contaminated procedures, the guidelines state that additional prophylactic postoperative antimicrobial agents should not be administered after closure of the incision even if a surgical drain is used. Again, the applicability of this approach to procedures with neurosurgical implants is unknown.

Clean and Clean-Contaminated Neurosurgical Procedures

The value of systemic antibiotic prophylaxis in clean neurosurgical operations is supported by level I evidence from multiple randomized clinical trials and a high-quality meta-analysis. The same is true of systemic antibiotic prophylaxis for shunt operations. ^, Additional meta-analyses have supported its value in preventing meningitis after craniotomy and in spine neurosurgery.

The value of systemic antibiotic prophylaxis in clean-contaminated operations has not been adequately studied to allow a confident conclusion to be reached. In this regard, the current accepted practice in transnasal surgery varies from limited perioperative use to use as if the procedure were contaminated (i.e., therapeutic doses for a therapeutic duration).

It is not feasible to study the differential effectiveness of various antibiotics. If one antibiotic reduces the expected infection rate to 1% and another is twice as good (infection rate of 0.5%), a study of over 5000 patients would be required to have a reasonable chance (power of 0.8) of finding that result to be statistically significant ( P ≤ .05). Although the duration of prophylactic antibiotic administration in neurosurgery has not been specifically studied in a randomized trial, the general principles of systemic prophylactic antibiotic administration are well established in many disciplines. ^, These principles are as follows:

• Use an antibiotic directed at the most common organisms implicated in postoperative infection for the specific operation in the institution in which the operation takes place. The hospital antibiogram is a valuable and necessary reference tool in selecting the most appropriate antibiotic.

• Administer the antibiotic intravenously, timed so that a bactericidal level is obtained at the time of incision.

• Repeat the antibiotic dose at intervals so that bactericidal serum levels are maintained during the operation.

• Do not continue the antibiotic after the end of the operation.

• Avoid vancomycin unless no other antibiotic meets the aforementioned criteria.