Synergistic Antibacterial Effects of Meropenem in Combination with Aminoglycosides against Carbapenem-Resistant Escherichia coli Harboring blaNDM-1 and blaNDM-5

Terbtothakun, Pawarisa; Nwabor, Ozioma Forstinus; Siriyong, Thanyaluck; Voravuthikunchai, Supayang Piyawan; Chusri, Sarunyou

doi:10.3390/antibiotics10081023

Cited by 14 publications

(8 citation statements)

References 68 publications

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“…Therefore, it can facilitate the permeability of other antibiotics such as carbapenems when used in combination. Depending on the previous findings, antibiotic combination therapy can decrease the chance of developing resistance upon using them as monotherapies [46][47][48]. The in vitro activity of amikacin and imipenem each alone and in combination against selected bla IMP and aac(6 )-Ib producing GNBs was evaluated in the present study.…”

Section: Discussionmentioning

confidence: 99%

Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in Combatting Antimicrobial Resistance in Gram-Negative Bacteria

Farhan,

El-Baky,

Ahmed

et al. 2023

Pharmaceuticals

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Extensively drug-resistant (XDR), multidrug-resistant (MDR) and pandrug-resistant (PDR) Gram-negative microorganisms (GNBs) are considered a significant global threat. β-lactam and aminoglycoside combinations and imipenem:cyclodextrin inclusion complexes were studied for the treatment of lethal GNBs. This is because of the broad empiric coverage of the two drugs and their possession of different spectra of activity. Two cyclodextrins (β- and hydroxy propyl β-cyclodextrins) were utilized for inclusion complex formation with imipenem using the physical and kneading methods. In silico investigation using the molecular docking and Fourier-infrared spectroscopy (FTIR) were employed to estimate binding constant and confirm complex formation, respectively. The in vitro effects of amikacin and imipenem combination in comparison to the effect of imipenem-β- and hydroxy propyl β-cyclodextrin (CD) complexes against Klebsiella spp. and Acinetobacter baumannii were studied. The isolated microorganisms’ antimicrobial responsiveness to various antibiotics (19 antibiotics) was evaluated. It was found that piperacillin/tazobactam and gentamycin (resistance rates were 33.3% and 34%, respectively) were the most effective antimicrobials. The in vitro studies have been performed by the checkerboard technique and time-killing assay. The studied combination of amikacin and imipenem showed a substantial drop in bacterial count (p < 0.05). The in vitro studies demonstrated a synergism for the investigated combination. Conventional PCR was used in molecular studies to identify the resistance genes bla IMP and aac (6′)-Ib. The blaIMP and aac (6′)-Ib were recorded in 38.2% and 3.6% of the studied isolates, respectively. The in vitro studies showed synergistic effects among the tested antibiotics with FICIs of ≤0.5. Finally, the study compared the reduction in bacterial count between the tested antibiotic combinations and imipenem:CD physical and kneaded mixtures. Imipenem:CD inclusion complexes demonstrated a significant bacterial count reduction over the antibiotic combination. These results highlight the emerging role of CDs as safe biofunctional excipients in the combat against superbug bacterial resistance.

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Section: Discussionmentioning

confidence: 99%

Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in Combatting Antimicrobial Resistance in Gram-Negative Bacteria

Farhan,

El-Baky,

Ahmed

et al. 2023

Pharmaceuticals

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“…Aminoglycoside antibiotics including amikacin, gentamicin, kanamycin, streptomycin, and tobramycin alongside carbapenems such as meropenem/imipenem represent valid combination treatment therapies yielding synergistic effects for infections caused by carbapenem resistant Enterobacteriaceae (CRE) (Hajjej et al ., 2016; Terbtothakun et al ., 2021). The presence of multiple aminoglycoside genes encoding aminoglycoside-modifying enzymes (AMEs) among all three pOXA-48 AMR variants may prevent synergistic therapies involving both carbapenems and aminoglycosides.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analyses of plasmid resistome changes in pOXA-48

Fordham

Mantzouratou

Sheridan

2022

Preprint

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Infections caused by carbapenem resistant Enterobacteriales (CPE) represent a significant threat in clinical settings. blaOXA-48 is one of the most frequent carbapenemase genes among Enterobacteriales. The blaOXA-48 is typically encoded on the prototypical IncL conjugative pOXA-48 plasmid. The pOXA-48 plasmid encodes only the blaOXA-48 resistance gene. However, aminoglycoside and extended spectrum β-lactamase (ESBL) resistance genes have also been detected on the same pOXA-48 plasmid backbone. These pOXA-48 plasmids encoding additional antimicrobial resistance (AMR) genes have been associated with both poor patient outcome and increased minimal inhibitory concentrations (MICs) to antibiotics including broad-spectrum cephalosporins. The blaOXA-48 gene was sourced from the pOXA-48 reference plasmid and set as a query using the BLASTn tool. Non-duplicate blaOXA-48 containing plasmids were downloaded, incompatibility typed and annotated for resistance genes using ResFinder 4.0. Bioinformatic analyses identified three distinct variants of the pOXA-48 plasmid encoding 4, 5, and 6 antimicrobial resistance genes. All plasmids encoded the ESBL blaCTX-M-14b, blaOXA-48 and either 2, 3 or 4 aminoglycoside resistance genes, in addition to conjugative transfer machinery. Plasmid variants 1 and 3 encoded aminoglycoside genes bracketed between IS26 and ISEc63 insertion elements, forming a potential transposon. The potential transposon structure had resemblance to the Tn5393 transposon (accession: M96392), including both aph(3'')-Ib, aph(6)-Id genes, and a Tn3 resolvase. The IS element ISEcp1 lies upstream of blaCTX-M-14b. All three plasmid variants appear related. Notably, all pOXA-48 plasmid variants were identified in multiple countries. In particular, variant 1 including 6 AMR genes was detected in 7 unique countries. Plasmids encoding additional AMR genes were associated with clinical/surveillance samples suggesting antibiotic pressure in clinical settings may promote changes in the resistome of pOXA-48. Acquisition of pOXA-48 resistant plasmids carrying additional AMR genes beyond blaOXA-48 can change the resistome of susceptible isolates in a single-step, rendering previously susceptible strains refractory to almost all available treatment options.

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“…This study underscores the potential for double resistance under specific conditions influenced by intrinsic and extrinsic factors of the host organism, pathogen, and antibiotics [ 38 ]. The pursuit of synergistic effects between antibiotics and their enhanced activity in clinically relevant microorganisms has prompted investigations into combination therapy characteristics [ 1 , 84 , 85 ].…”

Section: Resistance In Combination Therapies: Reality or Myth?mentioning

confidence: 99%

Unraveling resistance mechanisms in combination therapy: A comprehensive review of recent advances and future directions

Morales-Durán,

León-Buitimea,

Morones-Ramírez

2024

Heliyon

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Synergistic Antibacterial Effects of Meropenem in Combination with Aminoglycosides against Carbapenem-Resistant Escherichia coli Harboring blaNDM-1 and blaNDM-5

Cited by 14 publications

References 68 publications

Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in Combatting Antimicrobial Resistance in Gram-Negative Bacteria

Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in Combatting Antimicrobial Resistance in Gram-Negative Bacteria

Bioinformatic analyses of plasmid resistome changes in pOXA-48

Unraveling resistance mechanisms in combination therapy: A comprehensive review of recent advances and future directions

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