As Antibiotic Resistance Grows, Investigators Work to Understand Its Role in Pneumonia

Investigators identified 2 strategies to mitigate the risk of antimicrobial resistance (AMR) to meropenem when treating hospital-acquired pneumonia (HAP), according to results of an animal model study published in mBio.^1,2 In the model, investigators from the University of Liverpool tested the effect of meropenem, commonly used for HAP, and determined how resistance to the drug emerges, according to a press release.¹

“Through this work we have highlighted the problem of resistance development in HAP when treated by meropenem and demonstrated potential strategies to prevent this, i.e. increasing the meropenem or using a second antibiotic in combination,” Christopher Darlow, PhD, from the Antimicrobial Pharmacology & Therapeutics group at the University of Liverpool, said in the press release. “Beyond the implications for HAP, this is also a new experimental platform to allow antibiotics–both new and old–to be assessed for their ability to cause development of resistance and identify strategies to mitigate against this.”¹

In the study, the authors noted that AMR is growing in global importance. Additionally, they said that the high bacterial densities can result in the emergence of resistance, which can be normal for HAP. Meropenem demonstrates efficacy against pneumonia and is considered the standard-of-care for HAP, according to the study authors.²

Investigators used novel rabbit infection models of HAP to assess resistance emergence and efficacy on the bacteria, according to the study authors.² This new model allowed the investigators to detect the number of bacteria in the lungs and the amount of antibiotic that is working to treat the infection. According to the study authors, the rabbit model allows for pharmacokinetic sampling and has a high inocula tolerance.² Further, they used it to detect the resistance by measuring the mutations in the genes of the bacteria, Pseudomonas aeruginosa.¹

The models received the vehicle control of meropenem 5 mg/kg subcutaneously every 8 hours or meropenem 30 mg/kg subcutaneously every 8 hours starting 24 hours following inoculation, according to the study authors. The emergence of meropenem-resistant bacteria increased in the group that received 5 mg/kg compared to the models with no treatment. In the increased dosage group, the emergence was suppressed, according to the results of the study.²

In the combination group of 3.33 mg/kg or 5 mg/kg of amikacin intravenously every 8 hours with 5 mg/kg of meropenem subcutaneously every 8 hours, there was minimal effect on the total number of bacteria. However, investigators reported that the resistance population was suppressed when compared to the monotherapy.²

The investigators concluded that doses that were too low did treat HAP but posed a greater risk of resistance. Resistance was reduced by an increased dose of meropenem or by giving amikacin as a dual therapy.¹ They also said there was a phenotypic inverted U relationship between the monotherapy dose and the emergence of resistance.² Furthermore, the investigators detected how the bacteria mutates and how it adapts to develop resistance, shedding light on the underlying mechanisms, according to the press release.¹

The study authors noted that the main limitations of using this model included the infrastructure and skill base to safely and effectively conducted these experiments.²

References

1. Tackling antibiotic resistance when treating pneumonia. News release. EurekAlert. January 18, 2024. Accessed January 26, 2024. https://www.eurekalert.org/news-releases/1031523
2. Farrington N, Dubey V, Johnson A, et al. Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa. mBio. Published online January 18, 2024. doi:10.1128/mbio.03165-23