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Azithromycin Exerts Bactericidal Activity and Enhances Innate Immune Mediated Killing of MDR Achromobacter
Erlinda R Ulloa1,2,3, Armin Kousha2,4, Hannah Tsunemoto5
1Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), University of California San Diego, La Jolla, CA 92093, USA.
Abstract:
Azithromycin (AZM), the most commonly prescribed antibiotic in the United States, is thought to have no activity against multidrug-resistant Gram-negative pathogens such as Achromobacter xylosoxidans (AX) per standard minimum inhibitory concentration testing in cation-adjusted Mueller Hinton Broth. Here we provide the first report of AZM bactericidal activity against carbapenem-resistant isolates of AX, with a multifold decrease in minimum inhibitory concentration across 12 clinical isolates when examined under physiologic testing conditions that better recapitulate the in vivo human environment. This pharmaceutical activity, evident in eukaryotic tissue culture media, is associated with enhanced AZM intracellular penetration and synergistic killing with human whole blood, serum, and neutrophils. Additionally, AZM monotherapy inhibited preformed AX biofilm growth in a dose-dependent manner together with a reduction in viable bacteria. In an illustrative case, AZM in combination with piperacillin-tazobactam exerted clear therapeutic effects in a patient with carbapenem-resistant AX mediastinitis, sternal osteomyelitis, and aortic graft infection. Our study reinforces how current antimicrobial testing practices fail to recapitulate the host environment or host-pathogen interactions and may misleadingly declare complete resistance to useful agents, adversely affecting patient outcomes. We conclude that AZM merits further exploration in the treatment of drug-resistant AX infections. Novel approaches to antimicrobial susceptibility testing that better recapitulate the host environment should be considered, especially as infections caused by multidrug-resistant Gram-negative bacterial pathogens are expanding globally with high morbidity and mortality.
Insights
Azithromycin shows bactericidal activity against drug-resistant Achromobacter xylosoxidans under conditions mimicking the human body. Standard tests may underestimate its effectiveness against these challenging Gram-negative infections.
Area of Science:
- Infectious Diseases
- Antimicrobial Resistance
- Microbiology
Background:
- Azithromycin (AZM) is a widely used antibiotic, but standard testing suggests it lacks activity against multidrug-resistant Gram-negative bacteria like Achromobacter xylosoxidans (AX).
- Current antimicrobial susceptibility testing methods may not accurately reflect the in vivo environment, potentially leading to underestimation of antibiotic efficacy.
Purpose of the Study:
- To investigate the bactericidal activity of Azithromycin against carbapenem-resistant Achromobacter xylosoxidans isolates.
- To evaluate Azithromycin's efficacy under physiologic conditions that better simulate the human host environment.
- To explore Azithromycin's potential in treating complex, drug-resistant bacterial infections.
Main Methods:
- Minimum inhibitory concentration (MIC) testing of Azithromycin against 12 clinical isolates of carbapenem-resistant Achromobacter xylosoxidans.
- Testing performed under physiologic conditions, including eukaryotic tissue culture media, and assessment of synergy with human blood components (whole blood, serum, neutrophils).
- Evaluation of Azithromycin's effect on preformed Achromobacter xylosoxidans biofilms and a case study of combination therapy in a patient.
Main Results:
- A multifold decrease in Azithromycin's MIC was observed against carbapenem-resistant Achromobacter xylosoxidans under physiologic testing conditions compared to standard broth microdilution.
- Azithromycin demonstrated enhanced intracellular penetration and synergistic killing with human blood components, and inhibited biofilm formation in a dose-dependent manner.
- Combination therapy with Azithromycin and piperacillin-tazobactam showed therapeutic benefits in a patient with severe carbapenem-resistant Achromobacter xylosoxidans infection.
Conclusions:
- Current standard antimicrobial testing may inaccurately classify Azithromycin as inactive against resistant Gram-negative pathogens like Achromobacter xylosoxidans.
- Azithromycin exhibits significant bactericidal activity and biofilm inhibition against resistant Achromobacter xylosoxidans under host-mimicking conditions.
- Azithromycin warrants further investigation for treating drug-resistant Achromobacter xylosoxidans infections, highlighting the need for advanced susceptibility testing methods.
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