Re: 'Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteremia' by Weis et al.
Authors: M.S. Gelfand, K.O. Cleveland
Journal: Clinical Microbiology and Infection (2019)

The recent article by Weis et al. [[1]Weis S. Kesselmeier M. Davis J.S. Morris A.M. Scherag A. Hagel S. et al.Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcal aureus bacteraemia.Clin Microbiol Infect. 2019; 25: 818-827Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar] discussing cefazolin versus anti-staphylococcal penicillins for the treatment of patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia was quite helpful and informative for clinicians debating the more appropriate choice. Another consideration in the discussion about therapeutic choice includes treatment of central nervous system (CNS) infections due to MSSA. Cefazolin has historically been a second choice among β-lactam antibiotics (after anti-staphylococcal penicillins) for invasive infections due to methicillin-susceptible Staphylococcal aureus (MSSA). Reasons for this have included concerns about its efficacy in high inoculum infections such as infective endocarditis and its stability in the presence of certain staphylococcal β-lactamases. The paper by Weis et al. and a number of more recent studies, however, have concluded that cefazolin is tolerated better than anti-staphylococcal penicillins and is at least as effective as those agents in the treatment of MSSA bacteraemia [[1]Weis S. Kesselmeier M. Davis J.S. Morris A.M. Scherag A. Hagel S. et al.Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcal aureus bacteraemia.Clin Microbiol Infect. 2019; 25: 818-827Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. As a result of these publications and other factors including favourable pharmacokinetics, convenience of use as an outpatient intravenous agent in haemodialysis and other patients, and lower cost, cefazolin has become a popular choice in the management of MSSA bacteraemia and other invasive MSSA infections. Many patients included in the aforementioned studies had infective endocarditis and were therefore at risk for concomitant staphylococcal cerebritis, brain abscesses and/or meningitis. Standard references recommend against the use of cefazolin for the management of central nervous system (CNS) infections caused by MSSA because of poor CNS penetration [[2]Tunkel A.R. Treatment of bacterial meningitis caused by specific pathogens in adults.in: Sullivan M. UpToDate. 2019https://www.uptodate.com/contents/treatment-of-bacterial-meningitis-caused-by-specific-pathogens-in-adultsDate accessed: May 31, 2019Google Scholar]. The introduction of an earlier first-generation cephalosporin, cephalothin, was followed by a number of reports of breakthrough pneumococcal meningitis [[3]Mangi R.J. Kundargi R.S. Quintiliani R. Andriole V.T. Development of meningitis during cephalothin therapy.Ann Intern Med. 1973; 78: 347-351Crossref PubMed Scopus (73) Google Scholar]. With a very large number of patients receiving cefazolin for treatment of MSSA bacteraemia and infective endocarditis, both in studies and in clinical practice, one would expect reports of breakthrough CNS infections to possibly emerge. The paucity of literature reports of breakthrough CNS infections in patients treated with cefazolin for MSSA bacteraemia leads one to question the rationale for recommendations against the use of cefazolin in MSSA CNS infections and, by implication, in patients at risk for CNS infections due to other MSSA infections such as infective endocarditis. By the time cefazolin was introduced, another first-generation cephalosporin, cephalothin, had gained a reputation as an inferior agent for treatment of meningitis [[3]Mangi R.J. Kundargi R.S. Quintiliani R. Andriole V.T. Development of meningitis during cephalothin therapy.Ann Intern Med. 1973; 78: 347-351Crossref PubMed Scopus (73) Google Scholar]. Poor penetration into the uninflamed cerebrospinal fluid (CSF) and breakthrough pneumococcal meningitis cases in patients receiving cephalothin for bacteraemic pneumococcal pneumonia were reported [[3]Mangi R.J. Kundargi R.S. Quintiliani R. Andriole V.T. Development of meningitis during cephalothin therapy.Ann Intern Med. 1973; 78: 347-351Crossref PubMed Scopus (73) Google Scholar]. Lower antimicrobial activity of desacetylcephalothin, an in vivo metabolite present in the CSF, and rapid elimination of cephalothin from the CSF were proposed as possible explanations in addition to poor CSF penetration. Breakthrough meningitis cases have not been reported with cefazolin in either pneumococcal or staphylococcal infections, but cefazolin, possibly by association with cephalothin, has been designated as an antibiotic to be avoided in CNS infections. Cefazolin does have poor penetration across uninflamed meninges and a substantial serum protein binding of 80%. In a rabbit model of pneumococcal meningitis, cefazolin showed CSF penetration of 3.1%, which is slightly higher than the penicillin G penetration of 2.8%. In this model cefazolin was at least equal to penicillin G in in vivo sterilization of the CSF. Patients receiving multiple doses of cefazolin have shown CSF accumulation of cefazolin at 11.3 ± 2.7% of the serum concentrations. Frame and colleagues reported that cefazolin achieved higher concentrations in human brain tissue than did nafcillin [[4]Frame P.T. Watanakunakorn C. McLaurin R.L. Khodadad G. Penetration of nafcillin, methicillin, and cefazolin into human brain tissue.Neurosurgery. 1983; 12: 142-147Crossref PubMed Scopus (12) Google Scholar]. In a patient with MSSA ventriculitis being treated with continuous intravenous infusions of high-dose cefazolin at 10 g and then 8 g daily, Gregoire et al. [[5]Gregoire M. Gaborit B. Deschanvres C. Lecomte R. Deslandes G. Dailly E. et al.High-dosage cefazolin achieves sufficient cerebrospinal diffusion to treat an external ventricular drainage-related Staphylococcus aureus ventriculitis.Antimicrob Agents Chemother. 2019; 63 (e01844-18)Google Scholar] reported CSF cefazolin concentrations of 11.9 mg/L and 6.1 mg/L respectively. Nafcillin and oxacillin, which are currently recommended for the treatment of MSSA CNS infections, also have poor CSF penetration in the absence of meningeal inflammation. In a rabbit model of MSSA meningitis, oxacillin and nafcillin achieved CSF concentrations of 1–2% of simultaneously measured serum concentrations. Nafcillin has demonstrated adequate CSF concentrations in a limited number of patients with MSSA CNS infections including meningitis. Thus it appears that recommendations against the use of cefazolin in patients with MSSA CNS infections are not based on evidence of clinical failure such as breakthrough CNS infections in patients at increased risk (MSSA infective endocarditis or complicated bloodstream infections). Many patients with MSSA bacteraemia, including patients with infective endocarditis, have been successfully treated with cefazolin with no emerging reports of breakthrough CNS infections. Currently used high-dose regimens of cefazolin (usually 6 g daily) provide a margin of safety in this clinical setting. In the absence of clinical studies comparing cefazolin and anti-staphylococcal penicillins one cannot recommend cefazolin as the first choice in treatment of MSSA CNS infections. However, patients with suspected MSSA cerebritis as a complication of bacteraemia or endocarditis who are progressing well clinically with cefazolin treatment need not have their therapy changed. M. S. G. has received speaker's fees from Allergan, Merck, Melinta, and Tetraphase. K. O. C. has received speaker's fees from Allergan, Merck, Melinta, Theravance, Cumberland, Pfizer, and Paratek. No funding was received for this work.