By Dean L. Winslow, MD, FACP, FIDSA, FPIDS

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: Cefazolin (CZ) and ertapenem combination therapy was successfully used to salvage 11 cases of persistent methicillin-susceptible Staphylococcus aureus bacteremia. Modest in vitro synergy between CZ and ertapenem was demonstrated on testing of six clinical isolates, but in vivo activity appeared more potent in an animal model than as predicted by in vitro activity.

SOURCE: Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infec Dis 2019 Nov. 27. doi: 10.1093/cid//ciz995. [Epub ahead of print].

Researchers retrospectively studied 11 patients with persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia (range: four to nine days of persistent bacteremia in the presence of appropriate antistaphylococcal antibiotic therapy before being treated with cefazolin [CZ] plus ertapenem). Endocarditis was documented in six patients. Among the nine patients who had blood cultures drawn daily, bacteremia cleared within 24 hours of initiation of combination CZ and ertapenem in eight patients. In two cases, blood cultures were not obtained until day 3 of salvage therapy, so the duration of bacteremia after salvage therapy initiation could not be determined.

Three of six isolates demonstrated inoculum effect with CZ with minimum inhibitory concentrations (MICs) performed at 107 CFU/mL (rather than at 105 CFU/mL) ranged from 8 to 32 mcg/mL. Inoculum effect in these isolates was not present with nafcillin or ertapenem. Checkerboard synergy testing generally revealed additivity rather than synergy between ertapenem plus CZ or ertapenem plus nafcillin. Using media supplemented with bicarbonate showed significantly elevated MICs to ertapenem vs. values obtained with unsupplemented Mueller-Hinton broth (MHB). Variable effects of bicarbonate supplementation were seen with nafcillin and CZ tested at both low and high inocula.

In time-kill curves conducted at high inoculum size (107 CFU/mL), the combination of CZ plus ertapenem showed variable effects, with some strains showing synergy at 24 hours and others showing additivity. In a rat aortic valve endocarditis model, the combination of CZ 50 mg/kg q8hours plus ertapenem 30 mg/kg q8hours dosed for three days resulted in sterilization of vegetations in five of six rats. Monotherapy with either CZ or ertapenem did not sterilize vegetations in any of the animals.

COMMENTARY

This is an interesting report of 11 patients with prolonged MSSA bacteremia who were treated successfully with the combination of CZ plus ertapenem. The initial rationale for choosing this combination is that CZ binds preferentially to PBP2 and ertapenem binds to PBP1, resulting in complementary effects on different targets, analogous to the effects of ampicillin combined with ceftriaxone that commonly is used successfully in the treatment of Enterococcal endocarditis.1 While the combination of CZ plus ertapenem was generally only additive in vitro, the potent in vivo effects of the combination seen in the rat model of endocarditis and the rapid clearance of bacteremia in the patients suggest that other effects may be occurring. The reduced activity of CZ in the presence of high inocula of bacteria may be related, in part, to the reduced expression of PBP2 in the presence of neutrophils, and the preferential binding of ertapenem to PBP1 may overcome this.2 Lastly, the presence of both antibiotics in sub-MIC concentrations may sensitize MSSA to the antimicrobial effects of the innate immune system that is superior to the effect observed with either antibiotic alone.3

In any case, this paper provides a rationale to look at both CZ plus ertapenem and other combinations of anti-staphylococcal beta-lactam antibiotics with carbapenems to treat refractory MSSA bacteremia, preferably in the setting of a prospective, randomized, controlled trial.

REFERENCES

  1. Pericas JM, Cervera C, del Rio A, et al; Hospital Clinic Endocarditis Study Group. Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: From ampicillin plus gentamicin to ampicillin plus ceftriaxone. Clin Microbiol Infect 2014;20:1075-1083.
  2. Bamberger DM, Herndon BL, Fitch J, et al. Effects of neutrophils on cefazolin activity and penicillin-binding proteins in Staphylococcus aureus abscesses. Antimicrob Agents Chemother 2002;46:2878-2884.
  3. Sakoulas G, Olson J, Yim J, et al. Cefazolin and ertapenem, a synergistic combination used to clear persistent Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2016;60:6609-6618.