Methicillin-Susceptible Staphylococcus Aureus Bacteremia: Cefazolin in Prime But Nafcillin Not Ready for an Exit

The antistaphylococcal penicillins (ASPs), such as nafcillin or oxacillin, have long been regarded as first-line treatments for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. These agents are effective but do not have favorable pharmacologic and toxicity profiles. Cefazoline, on the other hand, is better tolerated and easier to use but has been relegated, at least until recently, as an alternative due to concern about clinical failures linked to the cefazolin inoculum effect (CIE). The CIE is an in vitro phenomenon in which isolates are susceptible at standard inocula (10⁵ CFU/mL) but become less susceptible (≥4-fold increase in MIC) or resistant (MIC ≥16 μg/mL) at high inocula (10⁷ CFU/mL). This phenomenon is usually mediated by a type A beta lactamase that hydrolyses cefazolin but not the ASPs. Despite being described in experimental animal models and case reports of treatment failures since the 1970s, the clinical relevance of the CIE has been a matter of contention. Recently, however, the potential in vivo consequence of the CIE has been suggested more strongly. A prospective cohort study from Argentina (where ASPs are not available) that evaluated 77 patients with MSSA bacteremia treated with cefazolin or cephalotin showed a high prevalence of the CIE (54%). This effect was associated with an increase in 30-day mortality (relative risk [RR] 2.65, P = 0.03) in patients with CIE-positive MSSA as compared to patients with CIE-negative MSSA. In another prospective cohort study from South Korea, 22% of MSSA isolates (24/110) exhibited the CIE. Among patients who received cefazolin, treatment failure (61% vs. 29%, P = 0.049) and 1-month mortality (15% vs. 0%, P = 0.047) were significantly higher in the CIE-positive than in the CIE-negative group. No difference in either outcome was noted with the nafcillin treatment group, regardless of the presence of the inoculum effect. These findings suggest that the CIE is clinically relevant and not just an in vitro or remote phenomenon. It is also prevalent among clinical isolates.