In a recent study published in the American Society for Microbiology, researchers developed a novel rabbit infection model to investigate meropenem's resistance development potential and antibacterial efficacy.
Study: Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa. Image Credit:Sam Rana/Shutterstock.com
Background
Meropenem is an antibacterial drug representing the current gold standard in hospital-acquired pneumonia (HAP) care.
Study findings revealed that meropenem depicts an inverted U-shaped relationship with emergent drug resistance and a dose-response association with bacterial kill.
This study helps identify two main mitigation methods against the emergence of multiple antimicrobial resistance (AMR) bacterial strains – 1. Regimen intensification, and 2. Combination therapy.
Furthermore, the rabbit model developed herein overcomes the limitations of previous murine (mouse) models and can be used to investigate these relationships across drugs and bacterial species in the future.
What is HAP, and why should we care?
Since the discovery of penicillin in 1928, antibiotics have made significant leaps in combatting transmittable diseases and extending human life, arguably representing the most substantial medical leap in centuries.
Unfortunately, as with the overuse of all things good, dependence on antibiotics in tandem with the high mutation potential of most pathogens has resulted in the emergence of novel pathogen strains with resistance against multiple antibiotic regimes (MDR – multiple drug-resistant).
The foremost example of this phenomenon is the bacterial development of antimicrobial resistance (AMR) during hospital-acquired pneumonia (HAP) treatment.
Also called 'nosocomial' pneumonia, HAP is one of the leading global causes of hospital-associated morbidity and mortality. Bacterial pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales usually cause it.
Despite decades of research aimed at combatting these strains and preventing the escalating arms race between pathogens and antibiotics, the molecular pharmacodynamics of the emergence of resistance remains poorly understood.
A notable reason for this discrepancy is that conventional murine (mice) model systems used in these studies weigh too little to survive inoculation hospital-representative bacterial populations.
Nonetheless, drugs have been developed to combat HAP, the most widely used of which is meropenem.
Meropenem is a broad-spectrum carbapenem antibiotic that exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, causing cell death.
It has proven effective against MDRs, including P. aeruginosa, and is backed by extensive safety research, making it the gold standard in treating P. aeruginosa-associated HAP.
Recent research, however, has identified that P. aeruginosa can develop resistance against even meropenem via porin modifications, ß-lactamase-related hydrolysis, and drug efflux.
Together, these factors necessitate the development of novel methodologies to investigate the molecular pharmacodynamics of MDR and discover mitigation strategies against this escalating global concern.
About the study
In the present study, researchers developed a novel rabbit-based animal infection model to evaluate the molecular pharmacodynamics of P. aeruginosa when treated with meropenem.
The neutropenic rabbit model of HAP comprised Male New Zealand White (NZW) rabbits separated into three cohorts – control (n = 14), meropenem monotherapy (n = 24), amikacin monotherapy (n = 6), and meropenem-amikacin combination therapy (n = 6).
"Unlike the murine model, the rabbit model allows serial pharmacokinetic sampling and can tolerate higher inocula for longer, potentially allowing observation of the emergence of resistance. Meropenem was studied given the primacy of this agent for HAP—it serves as a benchmark for the assessment of novel antimicrobial agents that are being considered for development as agents for HAP."
The challenge strain across tests was the Pseudomonas aeruginosa ATCC 27853. Experimentation included preliminary testing to establish baseline reproducible readouts for factors including experiment duration, immunosuppression regimen, endobronchial inoculum, and period of antimicrobial initiation.
Drug pharmacodynamics were investigated by characterizing lungs excised from controls (n = 14), meropenem 5 mg/kg (n = 14), meropenem 30 mg/kg (n = 10), amikacin 3.33 mg/kg (n = 6), or meropenem-amikacin 5-5 mg/kg combinations (n = 6).
A PK-PD mathematical model was developed for all meropenem monotherapy data to evaluate the translation of pharmacodynamics into pharmacokinetic results.
A Monte Carlo simulation was used to estimate the human outcomes of these animal model tests, with adjustments included to account for differences in meropenem protein binding in humans and rabbits. Excised lung histopathology was used to infer the pathogen-induced respiratory system damage.
Finally, to identify P. aeruginosa mutant strains that favor meropenem drug resistance and the mutations that confer resistance to them, next-generation whole-genome sequencing (WGS) and quantitative real-time PCR (qPCR) strategies were employed.
Study findings
Pharmacodynamics results revealed a phenotypic inverted U-shaped relationship between administered drug dosages and resistance emergence.
While 30 mg/kg of meropenem was observed to induce MDR in P. aeruginosa, these results were statistically insignificant. In contrast, 5 mg/kg of meropenem resulted in the emergence of high-fitness resistance phenotypes with multiple genotypic mutations favoring MDR.
"The emergence of resistant mutants, in general, was reduced in frequency during treatment with meropenem 5 mg/kg meropenem with amikacin 3.33 mg/kg amikacin in combination and 30 mg/kg meropenem monotherapy. However, where they emerged, they were mainly facilitated by selection of low-fitness oprD mutants."
Combination therapies involving both meropenem and amikacin were significantly better at preventing emergent resistance, potentially through these drugs' different mechanisms of action.
Simulations of human responses to these drug therapies were shown to be promising, with the caveat that the distribution of meropenem is assumed to be equivalent in humans and rabbits.
Conclusions
The present study used a combination of a novel rabbit infection in vivo model, PK-PD simulations, and next-generation sequencing to elucidate the pharmacodynamics of HAP-associated AMR.
Their findings reveal two primary mitigation measures against bacterial resistance emergence – 1. Increased drug (meropenem) dosages, or 2.
Combination therapies utilizing multiple drugs with different modes of action. This study further presents the novel rabbit animal model as a robust tool for future research aimed at testing MDR.
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