Infections of the CNS, which include meningitis, encephalitis, ventriculitis, and brain abscesses, are difficult to treat. Success of anti-infective therapy is dependent on a drug’s physiochemical penetrative properties (i.e., cerebrospinal [CSF] or parenchymal concentrations relative to plasma concentrations) and on drug concentrations achievable in the CNS.

Typically, antistaphylococcal penicillin has been the drug of choice for serious methicillin-susceptible Staphylococcus aureus (MSSA) infections. Despite their widespread use, antistaphylococcal penicillins are associated with fluid retention, elevated liver enzymes, and interstitial nephritis with prolonged use. Studies are also lacking comparisons with other classes of antibiotics. There is growing evidence that the first-generation cephalosporin, cefazolin, may be a suitable alternative due to its superior tolerability, less frequent dosing, and clinical outcomes.

The purpose of this narrative review was to summarize the available data and to provide recommendations for the use of cefazolin for CNS infections.

The authors reviewed the drug and patient characteristics that affect CNS penetration of beta-lactams as well as the pharmacokinetic properties of the antistaphylococcal penicillins and cefazolin. With regards to the pharmacokinetic properties of anti-infectives that contribute to beta-lactam effectiveness, the primary determinant is the unbound (free) drug concentration in a 24-hour period that remains above the minimum inhibitory concentration (MIC), which is expressed as fT > MIC.

Extended and continuous infusions of beta-lactams can maximize the fT > MIC. For cephalosporins, the fT > MIC needed for efficacy is 50% to 70%. The breakpoint for cefazolin (as a surrogate for antistaphylococcal penicillins) against MSSA is <2 mcg/mL and is <0.12 mcg/mL for Streptococcus spp. Although there is a paucity of information, limited data indicated that extended infusions of cefazolin are associated with improved outcomes, such as higher tissue concentrations, reduced infection rates, and decreased patient outpatient burden.

In the absence of meningeal inflammation, nafcillin, oxacillin, and cefazolin all have limited CSF penetration. Even though cefazolin may have lower proportional blood-to-CSF penetration (i.e., “percent penetration”), it achieves therapeutic concentrations within the CSF, with case reports indicating that 100% fT > MIC can be achieved. Patients undergoing craniotomy achieve higher CSF concentrations of cefazolin than do patients receiving similar doses of nafcillin or methicillin.

Promising clinical data are emerging on the use of cefazolin in CNS infections. A review of nine cases in which cefazolin was utilized for 2 to 6 weeks for spinal epidural abscesses (including seven cases of MSSA) found that eight of the nine patients had improvement in neurologic function and/or imaging findings; no information was provided on outcomes for one patient.

One limitation associated with the use of cefazolin for MSSA CNS infections is the cefazolin inoculum effect (CIE), an in vitro phenomenon in which the bacterial inoculum size increases from 105 to 107 colony-forming units (CFU)/mL. The inoculum effect is thought to be secondary to the blaZ gene, which is associated with the production of staphylococcal beta-lactamases. The MIC90 has been reported to be >16 mcg/mL when the MSSA inoculum was 107 CFU/mL.

Resistance to clindamycin and erythromycin predicts the presence of CIE. Based in part on the successful use of cefazolin in endocarditis, it is felt that CIE is more of a theoretical concern. A low prevalence of CIE has also been seen in blood stream infections (BSIs), with cefazolin considered a drug of choice for MSSA BSIs. This is important in light of the nafcillin shortage. Further, the American Heart Association has recommended cefazolin as a first-line alternative to nafcillin or oxacillin in patients with MSSA.

There is a paucity of literature examining the use of cefazolin in CNS infections. A direct comparison of 79 adult patients with MSSA spinal epidural abscesses treated for 8 weeks found that there was no difference in failure rate at 12 weeks or in epidural abscess–related death, mortality, or 90-day recurrence rates between cefazolin and antistaphylococcal penicillins. When cefazolin was compared with cloxacillin in 98 patients with MSSA spinal epidural abscesses, there was no significant difference in the antibiotic failure rate, recurrence rate, or adverse events rate between the groups, although all of the adverse outcomes were more common in the cloxacillin cohort. When cefazolin was compared with cloxacillin for documented acute bacterial meningitis, median CSF concentrations were 2.8 mg/dL, with full recovery in the cefazolin group with daily doses ranging from 6 g to 12 g. Two patients in the cloxacillin group had persistent CSF cultures and required a change in therapy. Among both groups, 70% had received combination therapy.

Maximum doses of up to 12 g per day of cefazolin have been used for serious infections, although FDA labeling cites 6 g/24 hours as the highest recommended dosage. Dosages of >6 g/day may be recommended in obese patients as these dosages have been associated with lower rates of treatment failure. There are few studies on extended dosing of cefazolin in the treatment of bone and joint infections demonstrating high overall cure rates, with few (2/88 patients) incidences of moderate-grade adverse events that required dosage adjustments.

While adverse events are infrequent in patients with normal renal function, encephalopathy, seizures, and coma have been reported in renal impairment in patients for whom the drug was not renally adjusted. Encephalopathy, which is reversible, occurs within 1 to 10 days of initiation of therapy.

The authors concluded that cefazolin may be preferred over antistaphylococcal penicillins in patients who develop intolerable side effects on nafcillin and who require less frequent dosing. Cefazolin may be dosed 2 g IV every 8 hours or as a continuous infusion of 8 g to 10 g daily to optimize time above the MIC. If available, therapeutic drug monitoring may be beneficial in obese patients or in those with renal impairment to assure a balance between effectiveness (>2 mcg/mL) and avoiding neurotoxicity, which occurs with serum concentrations of >300 mcg/mL serum or CSF concentrations of >30-34 mcg/mL.

Despite the retrospective, observational nature of the limited clinical trials involving cefazolin for CNS infections, this narrative review provides pharmacists with supportive information on the potential use of the cephalosporin as a therapeutic modality, although more research is needed.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

« Click here to return to Infusion Pharmacy Update.