Oral meropenem for superbugs: challenges and opportunities

Raza, Aun; Ngieng, Shih Chen; Sime, Fekade Bruck; Cabot, Peter J.; Roberts, Jason A.; Popat, Amirali; Kumeria, Tushar; Falconer, James R.

doi:10.1016/j.drudis.2020.11.004

Cited by 29 publications

(31 citation statements)

References 77 publications

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“…Also, many studies have shown that the energy-dependent endocytosis of MSNs could inhibit or downregulate the P-gp efflux pump, resulting in a bypass from efflux. − Furthermore, it is well reported that polymethacrylate polymers (Eudragit S100, RS100, L50-100, etc.) have the ability to downregulate the P-gp efflux pump ,− or could help the drug to escape from P-gp because the pump does not recognize drug due to polymer coating. , Therefore, the improvement in permeation and decrease in secretory transport of MER across the Caco-2 monolayer could be attributed to the following reasons: (1) The efficient cellular uptake of Eudragit coated particles which is evident from confocal microscopy, flow cytometry, and STEM-EDXS demonstrated that MER could be efficiently delivered into Caco-2 cells and may help in transcellular drug transport. (2) The pH-responsive release of MER could reduce the drug degradation outside the cells and increase the intracellular drug concentration.…”

Section: Resultsmentioning

confidence: 99%

Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Raza

Sime

Cabot

et al. 2021

ACS Biomater. Sci. Eng.

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Meropenem (MER) is an effective broad-spectrum antibiotic currently only available in the parenteral form requiring frequent drug preparation and administration due to its extremely poor stability. The unavailability of oral Meropenem is primarily due to its ultrapoor handling and processing stability, hydrophilic nature that inhibits the passive diffusion across the gastrointestinal (GI) epithelium, degradation in the harsh gastric environment, and GI expulsion through enterocyte efflux glycoproteins. In this regard, we have developed an oral drug delivery system that confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41 ∼141 nm) using a novel liquid carbon dioxide (CO2) method. MER was efficiently encapsulated within pristine, phosphonate (negatively charged MSN), and amine (positively charged MSN) modified MSNs with loading capacity ranging between 25 wt % and 31 wt %. Next, the MER-MCM-NH2 particles were electrostatically coated with Eudragit S100 enteric polymer that protected MER against gastric pH (pH 1.9) and enabled site-specific delivery in the small intestine (pH 6.8). Cellular uptake results in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient cellular uptake of nanoparticles in all three cell lines. More importantly, the bidirectional transport (absorptive and secretory) of MER across Caco-2 monolayer was significantly improved for both MSN-based formulations, particularly MSNs coated with a polymer (Eud-MER-MCM-NH2) where permeability was significantly enhanced (∼2.4-fold) for absorptive transport and significantly reduced (∼1.8-fold) for secretory transport. Finally, in vitro antibacterial activity [minimum inhibitory concentration (MIC)] and time-kill assay against S. aureus and P. aeruginosa showed that drug-loaded nanoparticles were able to retain antibacterial activity comparable to that of free MER in a solution at equivalent dose. Thus, Eudragit-coated silica nanoparticles could offer a promising and novel solution for oral delivery of Meropenem and other such drugs.

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Section: Resultsmentioning

confidence: 99%

Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Raza

Sime

Cabot

et al. 2021

ACS Biomater. Sci. Eng.

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“…In contrast, the highest levels of resistance were detected for meropenem (55.0%), especially for E. coli (59.0% of isolates resistant to meropenem) and C. youngae (88.9% of isolates resistant or intermediately resistant to meropenem). This finding raises concern due to the categorization of carbapenems as antimicrobials of ‘last resort’ for the treatment of severe infections ( Raza et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial resistance and virulence profiles of Enterobacterales isolated from two-finger and three-finger sloths (Choloepus hoffmanni and Bradypus variegatus) of Costa Rica

Fernandes

Carneiro

Rosales

et al. 2022

PeerJ

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Background Wildlife has been recently recognized as an environmental reservoir for antimicrobial resistance (AMR). However, less information on this topic is available in animals released back into the wild after rehabilitation in wildlife facilities, compared with studies performed exclusively in captive or free-ranging wildlife. This study aimed to evaluate the potential influence of captivity and/or treatment while in captivity of wild sloths on the AMR and virulence profiles of sloths’ Enterobacterales. Methods Oral and rectal swab samples were collected from 39 two-finger (Choloepus hoffmanni) and three-finger sloths (Bradypus variegatus) of Costa Rica (n = 78) and analyzed using conventional bacteriological techniques. A generalized linear mixed model was applied to estimate the isolates’ multiple antimicrobial resistance and virulence indices as a function of animal status. Results A considerable level of resistance was detected, especially for Citrobacter youngae and Escherichia coli, with 17.5% of isolates classified as multidrug-resistant. Virulence indices of isolates from rehabilitated sloths were significantly higher than the ones from sloths being hand-reared for shorter periods. Conclusions To our knowledge, this is the first description of sloths’ antimicrobial resistant Enterobacterales, suggesting that sloths’ rehabilitation and consequent exposure to humans, may promote the selection of bacteria with higher virulence. Ultimately, these bacteria may represent a threat to human and animal health due to their zoonotic potential and AMR and virulence profiles.

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“…Here, A. hydrophila/caviae, B. vesicularis, S. putrefaciens, and M. morganii presented intermediate resistance to imipenem, with M. morganii also showing intermediate resistance to meropenem. Regardless of the low incidence of resistance to carbapenems, this finding should be further assessed due to the categorisation of these antimicrobial compounds as last resort options for the treatment of serious Gram-negative infections, being of major importance for human medicine [25].…”

Section: Discussionmentioning

confidence: 99%

Antibiotic Resistance and Virulence Profiles of Gram-Negative Bacteria Isolated from Loggerhead Sea Turtles (Caretta caretta) of the Island of Maio, Cape Verde

et al. 2021

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Previous studies revealed high levels of antimicrobial resistance (AMR) in loggerhead sea turtles (Caretta caretta), describing this species as prime reservoir of antimicrobial-resistant bacteria. This study aimed to characterise, for the first time, the AMR and virulence profiles of Gram-negative bacteria isolated from 33 nesting loggerhead turtles of the island of Maio, Cape Verde. Cloacal, oral, and egg content swab samples (n = 99) were collected and analysed using conventional bacteriological techniques. Shewanella putrefaciens, Morganella morganii, and Vibrio alginolyticus were isolated from the samples under study. The isolates obtained from this loggerhead subpopulation (North-East Atlantic) revealed lower levels of AMR, compared with the results of studies performed in other subpopulations (e.g., Mediterranean). However, the detection of resistance to carbapenems and multiple antimicrobial resistance indices higher than 0.20, raises concern about the potential association of these animals to points of high antimicrobial exposure. Furthermore, virulence phenotypic characterisation revealed that the isolates presented complex virulence profiles, including the ability to produce biofilms. Finally, due to their pathogenic potential, and considering the evidence of illegal consumption of turtle-related products on the island of Maio, the identified bacteria may represent a significant threat to public health.

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Oral meropenem for superbugs: challenges and opportunities

Cited by 29 publications

References 77 publications

Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Antimicrobial resistance and virulence profiles of Enterobacterales isolated from two-finger and three-finger sloths (Choloepus hoffmanni and Bradypus variegatus) of Costa Rica

Antibiotic Resistance and Virulence Profiles of Gram-Negative Bacteria Isolated from Loggerhead Sea Turtles (Caretta caretta) of the Island of Maio, Cape Verde

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Oral meropenem for superbugs: challenges and opportunities

Cited by 29 publications

References 77 publications

Liquid CO2 Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Liquid CO2 Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Antimicrobial resistance and virulence profiles of Enterobacterales isolated from two-finger and three-finger sloths (Choloepus hoffmanni and Bradypus variegatus) of Costa Rica

Antibiotic Resistance and Virulence Profiles of Gram-Negative Bacteria Isolated from Loggerhead Sea Turtles (Caretta caretta) of the Island of Maio, Cape Verde

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Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem

Liquid CO₂ Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem