Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction

ABSTRACT

Introduction: Anti-Microbial Resistance (AMR) is a pandemic which threatens modern medicine. There is a lack of effective drug treatment due to the slow pace, high cost and low achievable sales prices of new antibiotic monotherapies. New hope comes in the shape of antibiotic combination therapy, which although used by mother nature, is under-explored and could provide the solution to AMR.

Areas covered: We performed a search of Pubmed and Medline using the keywords ‘combination therapy’, ‘antimicrobial resistance’ for articles between 1930 and 2019, as supplemented with other relevant references to our knowledge. We have reviewed the theoretical considerations for combination development and examine the existing and future clinical indications of combination therapies. We have discussed the potential of antibiotic combinations to provide therapeutic synergy, rejuvenating the effectiveness of old antibiotics to which the bacteria had developed resistance previously. We have examined the current thinking and evidence on resistance reduction using combination therapies, with a review on toxicity and drug-drug antagonism.

Expert opinion: Antibiotic combination therapy, exploiting synergies, old-drug rejuvenation and resistance reduction could provide the solution to AMR. The number of pharmaceutical companies in this area is likely to expand, bringing promising combinations to the bedside, to save millions of lives worldwide.

KEYWORDS:

• Anti-Microbial Resistance
• antibiotic combinations
• synergy
• Superbug

Article highlights

• Antimicrobial resistance (AMR) is a leading cause of mortality worldwide.

• Bacteria mutate faster than we can develop new antibiotics, combining antibiotics in novel regimens holds the key for controlling AMR.

• When certain carefully selected drugs are combined in the correct formulation, the bactericidal effects are synergistic, with potential to kill the highly resistant bacteria.

• Combination therapy is already used clinically for treating infections such as tuberculosis, the human immunodeficiency virus and non-infective diseases such as for cancer chemotherapy.

• Synergistic combination treatments can be developed cheaply, used in patients safely since the constituent drugs are well known, and thus could potentially be widely distributed.

• As new combination antimicrobial regimens emerge from the laboratories, these need urgent funding to be brought to the bedside, potentiating a new golden-age for combination therapy.

Declaration of interest

A Coates is the CSO of Helperby Therapeutics Ltd, and a director and shareholder. Y Hu is the Scientific Director of Helperby Therapeutics Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Helperby Therapeutics Group Ltd, UK. PJY was funded by a KL2 Fellowship (PJY through the N|H/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001BB1).