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Comparative Investigation into the Roles of Imipenem:Cyclodextrin Complexation and Antibiotic Combination in
Sara Mahmoud Farhan1, Rehab Mahmoud Abd El-Baky1,2, Hala Rady Ahmed2
1Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia 11566, Egypt.
Abstract:
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.
Insights
Drug-resistant Gram-negative bacteria pose a global threat. Imipenem-cyclodextrin complexes significantly reduced bacterial counts more effectively than antibiotic combinations, highlighting cyclodextrins
Area of Science:
- Microbiology
- Pharmaceutical Sciences
- Drug Delivery
Background:
- Extensively drug-resistant (XDR), multidrug-resistant (MDR), and pandrug-resistant (PDR) Gram-negative microorganisms (GNBs) represent a critical global health challenge.
- Traditional antibiotic combinations face limitations in combating these resistant pathogens.
- Cyclodextrins (CDs) offer potential as novel excipients for enhancing antimicrobial efficacy.
Purpose of the Study:
- To evaluate the efficacy of imipenem-cyclodextrin inclusion complexes against lethal GNBs, specifically *Klebsiella* spp. and *Acinetobacter baumannii*.
- To compare the antimicrobial activity of imipenem:CD complexes with conventional amikacin and imipenem antibiotic combinations.
- To investigate the role of CDs as biofunctional excipients in overcoming bacterial resistance.
Main Methods:
- Formation of imipenem inclusion complexes with β- and hydroxypropyl-β-cyclodextrins using physical and kneading methods.
- In silico analysis (molecular docking, FTIR) to confirm complex formation and binding.
- In vitro antimicrobial susceptibility testing, checkerboard assays, time-killing assays, and PCR for resistance gene identification (blaIMP, aac(6')-Ib).
Main Results:
- Piperacillin/tazobactam and gentamicin showed the lowest resistance rates (33.3% and 34%).
- The combination of amikacin and imipenem demonstrated synergistic effects (FICI ≤ 0.5) with a significant bacterial count reduction (p < 0.05).
- Imipenem:CD inclusion complexes exhibited superior bacterial count reduction compared to the imipenem and amikacin combination.
Conclusions:
- Imipenem:CD inclusion complexes show significant potential in combating drug-resistant Gram-negative bacteria.
- Cyclodextrins can serve as effective biofunctional excipients to enhance the therapeutic efficacy of antibiotics.
- This approach offers a promising strategy to address the growing threat of superbug resistance.
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