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Analysis of amikacin-resistant Pseudomonas aeruginosa developing in patients receiving amikacin
J Maloney1, D Rimland, D S Stephens
1Department of Medicine, Emory University School of Medicine, Atlanta, GA.
Abstract:
During a 36-month period, 28 patients treated for infections due to amikacin-susceptible Pseudomonas aeruginosa subsequently developed infections or colonization with amikacin-resistant P aeruginosa at the same site. Eleven amikacin-susceptible/-resistant pairs of isolates were analyzed for aminoglycoside-inactivating enzymes, plasmid profiles, cellular proteins, outer membrane proteins (OMPs), lipopolysaccharide (LPS) profiles, and amikacin uptake. While clearly distinct from isolates of other patients, sensitive and resistant isolates from the same patients were indistinguishable in plasmid profile, LPS profiles, and OMPs. These results suggest that the resistant P aeruginosa isolates were derived from the sensitive isolates. None of the resistant isolates produced enzymes known to inactivate amikacin. In nine of 11 resistant isolates tested, transport of amikacin into P aeruginosa was reduced. A major mechanism of in vivo development of amikacin resistance in P aeruginosa is alteration in permeability to amikacin, but the aquisition of plasmids or changes in OMPs or LPS profile may not account for this phenomenon.
Insights
Pseudomonas aeruginosa can develop amikacin resistance during treatment. Reduced amikacin uptake due to permeability changes, not enzyme production, appears to be the primary mechanism in this bacterial pathogen.
Area of Science:
- Microbiology
- Infectious Diseases
- Molecular Biology
Background:
- Pseudomonas aeruginosa is an opportunistic pathogen frequently causing difficult-to-treat infections.
- Amikacin is a critical aminoglycoside antibiotic used against P. aeruginosa.
- In vivo development of antibiotic resistance is a significant clinical challenge.
Purpose of the Study:
- To investigate the mechanisms by which amikacin-susceptible P. aeruginosa develops resistance during therapy.
- To compare susceptible and resistant isolates from the same patients to identify resistance determinants.
Main Methods:
- Analysis of 28 patients with P. aeruginosa infections over 36 months who developed amikacin resistance.
- Comparative analysis of 11 susceptible/resistant isolate pairs.
- Characterization included enzyme activity, plasmid profiles, cellular proteins, outer membrane proteins (OMPs), lipopolysaccharide (LPS) profiles, and amikacin uptake assays.
Main Results:
- Resistant P. aeruginosa isolates were derived from pre-existing susceptible strains within the same patients.
- No amikacin-inactivating enzymes were detected in resistant isolates.
- Reduced amikacin transport into the bacterial cell was observed in 9 out of 11 resistant isolates, suggesting altered permeability.
Conclusions:
- The primary mechanism for in vivo amikacin resistance development in P. aeruginosa is a decrease in permeability.
- Acquisition of plasmids or changes in OMPs or LPS profiles do not appear to be the main drivers of this resistance.
- Understanding permeability alterations is crucial for combating amikacin resistance in P. aeruginosa infections.