Abstract
The emergence of multi-drug-resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded β-lactam antibiotics (ampicillin, carbenicillin, cephalothin and oxacillin) and a well-known antiseptic (chlorhexidine di-acetate) were fashioned into a group of uniform materials based on organic salts (GUMBOS) as an alternative to conventional combination drug dosing strategies. The antibacterial activity of precursor ions (e.g., chlorhexidine diacetate and β-lactam antibiotics), GUMBOS and their unreacted mixtures were studied with 25 clinical isolates with varying antibiotic resistance using a micro-broth dilution method. Acute cytotoxicity and therapeutic indices were determined using fibroblasts, endothelial and cervical cell lines. Intestinal permeability was predicted using a parallel artificial membrane permeability assay. GUMBOS formed from ineffective β-lactam antibiotics and cytotoxic chlorhexidine diacetate exhibited unique pharmacological properties and profound antibacterial activity at lower concentrations than the unreacted mixture of precursor ions at equivalent stoichiometry. Reduced cytotoxicity to invasive cell types commonly found in superficial and chronic wounds was also observed using GUMBOS. GUMBOS show promise as an alternative combination drug strategy for treating wound infections caused by drug-resistant bacteria.
Highlights
Ineffective antibiotics are a pervasive reality that has contributed to higher incidences of infectious diseases caused by multi-drug-resistant bacteria, namely “ESKAPE” pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) [1]
Dissolution rates among the chlorhexidine-based GUMBOS decreased in this order: oxacillin ≥ ampicillin > cephalothin > carbenicillin; which was found to parallel the order of aqueous solubility of GUMBOS
Initial antibacterial studies with β-lactam antibiotics and chlorhexidine diacetate were found most effective against drug-susceptible bacteria, in which the β-lactam antibiotics were preferential toward Gram-positive bacteria (Gram-positive bacteria) and within acceptable minimum inhibitory concentrations (MICs) ranges and chlorhexidine diacetate against
Summary
Ineffective antibiotics are a pervasive reality that has contributed to higher incidences of infectious diseases caused by multi-drug-resistant bacteria, namely “ESKAPE” pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) [1]. Research interest in antibiotic combinations has grown from the conventional use of two antibiotics to substituting one antibiotic with an unconventional over-the-counter consumer drug or prescription-only non-antibiotic drug Examples of these efforts have expanded to include barbiturates, antipsychotics, antivirals and analgesics to improve the efficacy of antibiotic treatment [7,8,9,10,11,12,13]. Conventional antibiotic combinations have not completely addressed the challenge of treating infections caused by multi-drug-resistant bacteria, especially when incremental and ineffective antibiotic dosing strategies are employed that do not overcome individual mechanisms of resistance [19] From these studies, it has become apparent that effective therapy lies in the judicious choice of agent, and in the ability to control the delivery and concentration of drugs used in combination [20].
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