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Published on: January 2, 2014
PBP-3 directed therapy in VIM-producing Pseudomonas aeruginosa creates bacterial transformers, persisters in disguise
Nicholas M Smith1, Katie Rose Boissonneault1, Patricia N Holden1
1Division of Clinical and Translational Therapeutics, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
Objectives:
The proliferation of metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa represents a significant public health threat. P. aeruginosa undergoes significant phenotypic changes that drastically impair antibiotic efficacy. The objectives of this study were (1) to quantify the time-course of killing of VIM-2-producing P. aeruginosa in response to aztreonam-based therapies (including avibactam for coverage of AmpC), and (2) to document the capacity of P. aeruginosa to undergo morphological transformations that facilitate persistence.
Methods:
A well-characterised, clinical VIM-2-producing P. aeruginosa was studied in the hollow fibre infection model (HFIM) over 9 days (7 days of active antibiotic therapy, 2 days of treatment withdrawal) at a 107.5 CFU/mL starting inoculum. HFIM treatment arms included: growth control, aztreonam, ceftazidime/avibactam, aztreonam/ceftazidime/avibactam, polymyxin B, and aztreonam/ceftazidime/avibactam/polymyxin B. In addition, real-time imaging studies were conducted under static conditions to determine the time course of the reversion of persister cells.
Results:
There was a pronounced discrepancy between OD620 and bacterial counts obtained from plating methods (hereafter referred to as 'OD-count discrepancy'). For aztreonam monotherapy, observed counts were 0 CFU/mL by 120 h. Despite this, there was a significant OD-count discrepancy compared with the pre-treatment 0 h. Between therapy withdrawal at 168 h and 216 h, all arms with suppressed counts had regrown to the system-carrying capacity. Real-time imaging of the P. aeruginosa filaments after drug removal showed rapid reversion from a long, filamentous phenotype to many individual rods within 2 h.
Conclusion:
Managing MBL-producing P. aeruginosa requires a multifaceted approach, focused on maximising killing and minimising proliferation of resistant and persistent subpopulations, which will involve eliminating drug-induced phenotypic transformers.
Insights
Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa, a public health threat, can transform into persistent forms. Aztreonam-based therapies reduced bacterial counts, but P. aeruginosa rapidly reverted to rod shapes after treatment withdrawal.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa poses a significant public health risk.
- This pathogen exhibits phenotypic plasticity, leading to reduced antibiotic effectiveness.
Purpose of the Study:
- To quantify the killing efficacy of aztreonam-based therapies against VIM-2-producing P. aeruginosa.
- To document P. aeruginosa's morphological transformations that promote persistence.
Main Methods:
- Utilized the hollow fibre infection model (HFIM) with VIM-2-producing P. aeruginosa over 9 days.
- Tested various treatment arms including aztreonam, ceftazidime/avibactam, polymyxin B, and combinations.
- Employed real-time imaging to observe persister cell reversion.
Main Results:
- Observed a discrepancy between optical density and bacterial counts, indicating phenotypic changes.
- Aztreonam monotherapy resulted in 0 CFU/mL by 120h, yet significant OD-count discrepancy persisted.
- Following treatment withdrawal, P. aeruginosa rapidly reverted from filamentous to rod forms within 2 hours.
Conclusions:
- Effective management of MBL-producing P. aeruginosa necessitates a comprehensive strategy.
- This strategy must prioritize maximizing bacterial killing and minimizing resistant, persistent subpopulations.
- Eliminating drug-induced phenotypic transformers is crucial for successful treatment.
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