What is the evidence with using ertapenem monotherapy to treat methicillin-susceptible staphylococcus aureus infections?

Comment by InpharmD Researcher

There is a limited amount of evidence supporting ertapenem monotherapy to treat methicillin-susceptible Staphylococcus aureus (MSSA) infections. One post-hoc analysis in MSSA complicated skin and skin structure infections demonstrated that ertapenem achieved similar clinical cure and bacterial eradication rates to piperacillin-tazobactam, though MSSA-specific outcomes were not prespecified. Additional in-vitro evidence indicates that ertapenem has low minimum inhibitory concentrations (MICs) against MSSA (MIC90 ~0.25 to ≤1 µg/mL), with all isolates categorized as susceptible and MICs below total plasma concentrations achieved with 1 g intravenous (IV) dosing. However, in high-inoculum and biofilm models, ertapenem monotherapy was bactericidal, but did not fully eradicate biofilms, whereas combination regimens showed greater activity. Overall, data are insufficient to support the routine use of ertapenem monotherapy for MSSA infections.

Background

Several in vitro susceptibility and pharmacodynamic studies evaluated ertapenem activity against methicillin-susceptible Staphylococcus aureus (MSSA) isolates from respiratory, intra-abdominal, skin/soft tissues, urinary, and bloodstream sources. Across studies, ertapenem demonstrated low minimum inhibitory concentrations (MICs) against MSSA, with MIC90 values generally 0.25 to ≤1 µg/mL, and all MSSA isolates tested were categorized as susceptible; MICs were below total plasma concentrations achieved with standard 1 g intravenous (IV) dosing. In high-inoculum and biofilm models, ertapenem monotherapy showed bactericidal activity against MSSA and greater activity than nafcillin in biofilms, though eradication was incomplete, and combination regimens showed greater effects. Notably, these findings can not directly establish clinical efficacy of ertapenem monotherapy for MSSA infections. [1], [2], [3]

References: [1] Hicks PS, Pelak B, Woods GL, Bartizal KF, Motyl M. Comparative in vitro activity of ertapenem against bacterial pathogens isolated from patients with lower respiratory tract infections. Clin Microbiol Infect. 2002;8(11):753-757. doi:10.1046/j.1469-0691.2002.00461.x
[2] Friedland I, Mixson LA, Majumdar A, Motyl M, Woods GL. In vitro activity of ertapenem against common clinical isolates in relation to human pharmacokinetics. J Chemother. 2002;14(5):483-491. doi:10.1179/joc.2002.14.5.483
[3] Gilbertie J, Ulloa ER, Daiker JC, et al. Potent Activity of Ertapenem Plus Cefazolin Within Staphylococcal Biofilms: A Contributing Factor in the Treatment of Methicillin-Susceptible Staphylococcus aureus Endocarditis. Open Forum Infect Dis. 2022;9(5):ofac159. Published 2022 Mar 23. doi:10.1093/ofid/ofac159
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the evidence with using ertapenem monotherapy to treat methicillin-susceptible staphylococcus aureus infections?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Efficacy of ertapenem against methicillin-susceptible Staphylococcus aureus in complicated skin/skin structure infections: results of a double-blind clinical trial versus piperacillin-tazobactam
Design

Post-hoc subgroup analysis of a double-blind multicentre non-inferiority trial

N= 185
Objective

To compare the efficacy of ertapenem with piperacillin-tazobactam in the treatment of serious staphylococcal infections and to examine the demographic and disease characteristics of patients with methicillin-susceptible S. aureus (MSSA) infection
Study Groups

Ertapenem group (n= 67)

Piperacillin-tazobactam group (n= 68)
Inclusion Criteria

Men and women ≥18 years of age with complicated skin/skin structure infection requiring parenteral antimicrobial therapy
Exclusion Criteria

Rapidly progressive or terminal illness, immunosuppressive illness or therapy, a pathogen resistant to either study drug, >24 h of systemic antimicrobial therapy effective against presumed or documented pathogens
Methods

Patients were randomly assigned 1:1 to treatment with either ertapenem 1 g intravenous (IV) once a day or piperacillin-tazobactam 3.375 g IV every 6 h. Patients in the ertapenem group also received subsequent placebo infusions of normal saline every 6 h. Follow-up oral antimicrobial therapy was not permitted.
Duration

April 1998 through November 1999
Outcome Measures

Primary: Proportion of clinically evaluable patients with an investigator assessment of cure at test of cure (TOC)

Other: Bacterial eradication rates at TOC
Baseline Characteristics   Monomicrobial (n= 129)

Polymicrobial (n= 56)
Female 36 (28%)

8 (14%)
Age, years 42 (18–93)

48 (18–89)

Stratum

I (complicating underlying condition)

Diabetic lower extremity infection

Other

 

23 (18%)

22 (17%)

1 (1%)

 

22 (39%)

18 (32%)

4 (7%)

Stratum

II (all other infections)

Cutaneous/deep abscess

Posttraumatic/surgical site infection

Cellulitis

Perineal cellulitis/abscess

Other

 

106 (82%)

55 (43%)

32 (25%)

14 (11%)

2 (2%)

3 (2%)

 

34 (61%)

14 (25%)

10 (18%)

8 (14%)

0 (0%)

2 (4%)
Severe infection 18 (14%)

7 (12%)
Bacteremic at baseline 13 (10%)

3 (5%)

Table represents the baseline demographic and disease characteristics of treated patients with MSSA monomicrobial and polymicrobial complicated skin/skin structure infections.
Results   Ertapenem (n= 67)

Piperacillin-tazobactam (n= 68)

 OR (95% CI), p-value*

Therapy completion

Overall

Monomicrobial

Polymicrobial

 

58/67 (86.6%)

42/48 (87.5%)

16/19 (84.2%)

 

57/68 (83.8%)

43/50 (86.0%)

14/18 (77.8%)

 

1.3 (0.5–3.3), p= 0.64

 

 

Test of cure (TOC)

Overall

Monomicrobial

Polymicrobial

 

54/67 (80.6%)

40/48 (83.3%)

14/19 (73.7%)

 

55/68 (80.9%)

42/50 (84.0%)

13/18 (72.2%)

1.0 (0.4–2.4), p= 0.99

 

Abbreviations: CI, confidence interval; OR, odds ratio

*OR compares cure rates overall at the completion of therapy in patients in the ertapenem group to rates in patients in the piperacillin-tazobactam
Adverse Events

Not specified
Study Author Conclusions

Ertapenem 1 g daily is an effective alternative to piperacillin-tazobactam 13.5 g administered in four equally divided daily doses for treatment of MSSA complicated skin/skin structure infections. If culture results show a monomicrobial MSSA (or other pathogen) infection, changing the antimicrobial regimen to an effective, more narrow-spectrum agent should be considered.
Critique

The study was a post-hoc subgroup analysis of a randomized trial and was limited to patients with complicated skin and skin structure infections in whom MSSA was isolated; MSSA-specific outcomes were not a prespecified primary endpoint of the original study.

 

References:
[1] Gesser RM, McCarroll KA, Woods GL. Efficacy of ertapenem against methicillin-susceptible Staphylococcus aureus in complicated skin/skin structure infections: results of a double-blind clinical trial versus piperacillin-tazobactam. Int J Antimicrob Agents. 2004;23(3):235-239. doi:10.1016/j.ijantimicag.2003.07.013