The continued growth of multidrug resistant organisms, particularly carbapenem resistant Gram negative rods, places a heavy burden on the healthcare system globally
Effective treatment regimens remain a challenge. Although combination therapy is typically used, robust evidence to support this strategy is lacking.
There are specific combinations which appear to have a greater effective synergistic activity than others and are highlighted below.
Certain combinations appear to lack synergistic activity.
Widespread antibiotic use results in rapid emergence of multi drug resistant Gram negative bacilli (GNB) and poses a major public health concern, specifically carbapenem resistant GNB (CR-GNB).
The World Health Organization has given high priority to CR-GNB, specifically Acinetobacter baumannii, Enterobacteraceae (specifically Klebsiella pneumonia) and Pseudomonas aureginosa.
CR-GNB is a large threat due to:a. Increased incidence of these resistant pathogens has caused a global epidemic
b. Lack of safe and effective treatment options
c. High mortality rates associated with CR-GNB (up to 44%)
Although treatment recommendations can be found for CR-GNB, there is a lack of evidence on the effectiveness of these combinations in well controlled trials.
Most in vitro evaluations are limited to a single micro-organism and include only a small number of specific combinations.
The COHERENCE Project is aimed to analyze data in sepsis patients on antibiotic combinations for treating CR-GNB
A recent systematic and meta-analysis review by Scudeller et al (International J of Antimicrob Agents doi.org/10.1016/j.ijantimicag.2021.106344) reviewed 136 studies of CR-GNB to summarize synergy and antagonism of 182 antibiotic combinations.
Results from in vitro data can help identify the potential use of antibiotic combinations in the face of the lack of verification by well conducted clinical trials.
Each antibiotic combination was given an effect size based on pharmacokinetic/pharmacodynamics data or time-kill studies.
Colistin and carbapenem based combinations were the most commonly assessed regimens.
The table highlights the antibiotic combination with the highest synergistic effect size per organism as well as those combinations with no synergistic effect.
Antibiotic Synergistic Effect By CR-GNB Organism
Compared to monotherapy, combinations increased bacteriocidal activity with lower re-growth rates.
These combinations often include “old” antibiotics coupled with “new” antibiotics.
There remains uncertainty if these combinations will improve clinical outcomes.
Colistin/Rifampicin combinations appear to have high in vitro synergistic activity for A. baumannii and K pneumonia. Whereas, Imipenem/tobramycin provide the highest synergy for P. aeruginosa.
Antibiotic stewards need clear direction on how to optimize the old and new antibiotic options in CR-GNB.