BOLD Practice: Gram Negative Combination Antibiotic Therapy

When is it appropriate to give combination therapy for gram negatives i.e. Pseudomonas in sepsis/pneumonia?


I wanted to raise the topic of combination antibiotic therapy (double coverage) as it recently came up on shift and thought it would be a good topic to discuss in an open forum. Specifically I wanted to address when is it appropriate to give combination therapy for gram negatives i.e. Pseudomonas in sepsis/pneumonia. The quality of evidence for this issue seems to be pretty poor. There were 2 guideline updates in 2016 that address this issue. The Surviving Sepsis Campaign addressed it with the following recommendations:

“6. We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence).
7. We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence).
8. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence).”
This suggests to me that combination therapy would only be considered in cases of septic shock and even then it is a weak recommendation.

The ATS/IDSA guidelines for HAP/VAP were also updated in 2016. These are the guidelines that infamously removed HCAP as a separate entity so we are left with only recommendations for HAP and VAP which are diagnosed after 48hrs (hopefully our patients are going upstairs before that!). Even for HAP, the use of combination therapy seems to be limited.


The following recommendations were made regarding Pseudomonas coverage for HAP:


“2. For patients with HAP who are being treated empirically, we recommend prescribing antibiotics with activity against P. aeruginosa and other gram-negative bacilli (strong recommendation, very low-quality evidence).

i. For patients with HAP who are being treated empirically and have factors increasing the likelihood for Pseudomonas or other gram-negative infection (ie, prior intravenous antibiotic use within 90 days, structural lung disease increasing the risk of gram-negative infection (ie, bronchiectasis or cystic fibrosis) or a high risk for mortality), we suggest prescribing antibiotics from 2 different classes with activity against P. aeruginosa (weak recommendation, very low-quality evidence). (Risk factors for mortality include need for ventilatory support due to HAP and septic shock). All other patients with HAP who are being treated empirically may be prescribed a single antibiotic with activity against P. aeruginosa.”

Again, combination therapy would be considered in only our most sick patients i.e. on mechanical ventilation, shock, or IV abx use within 90days. These recommendations are also based on very low quality evidence.

It’s hard to make a strong argument either way when the evidence is mostly low quality but I think it would be reasonable to utilize monotherapy for gram negative coverage in most cases of sepsis and PNA given the potential for harm: adverse events, resistance, cost; and only consider its use in cases of septic shock, mechanical ventilation, or recent IV abx use. I also came across this interesting blog post from Josh Farkas (an ICU doc who runs the PulmCrit blog) about the lack of evidence for double coverage for VAP which doesn’t exactly address my issue but I think there is a lot of overlap in the principles discussed: Would love to hear your thoughts on the issue!

The views expressed on this blog are the author's own and do not reflect the views of their employer. Please read our full disclaimer here. Any references to clinical cases refer to patients treated at a virtual hospital, Janus General Hospital.

Jay Khadpe MD

Associate Professor of Emergency Medicine
Associate Residency Director
University of Florida College of Medicine – Jacksonville

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