Firstline - Clinical Decisions

Reasoning

Two antimicrobials with overlapping coverage for gram-negative organisms are typically used for the following reasons:

Use of Two Antimicrobials to Expand the Spectrum of Activity

Is this rationale supported: Yes
The benefit of using two antimicrobials to “double-cover” resistant gram-negative organisms (ie, Pseudomonas) empirically is so if one happens to be resistant hopefully the other will be sensitive
At AHT, empiric double-coverage for Pseudomonas is most rational if a beta-lactam + aminoglycoside is used (see Pseudomonas aeruginosa isolates below)

Mortality Benefit

Is this rationale supported: No
There is no proven benefit of definitive combination therapy versus monotherapy
Combination therapy is associated with increased average drug reactions, super-infections, and cost
A recent HCAP study revealed increased mortality when empiric combination therapy was continued vs. monotherapy

Prevention of Resistance

Is this rationale supported: No
Prevention of the emergence of resistance during therapy is an often cited reason for continuing dual gram-negative coverage, however studies in humans have repeatedly shown that this practice does not offer any benefit or prevent the emergence of resistance

Synergistic Response

Is this rationale supported: Maybe
Synergy has been demonstrated in vitro for beta-lactams added to either aminoglycosides or fluoroquinolones
The clinical relevance of this effect is unknown as studies have shown no benefit with regards to mortality or resistance prevention
Synergistic activity is likely of most benefit in patients with proven intermediate-resistant organisms

Below beta-lactam is resistant:

Cefepime

Pip/Tazo

Meropenem