The world is facing an ongoing crisis and the implications of an era of antibiotic/antimicrobial resistance (AMR) are not fully understood by the majority of the public at large. Although this phenomenon has been well documented in the circles of science and medicine for the last several decades, and governmental agencies are taking some steps to combat antibiotic resistance, society in general does not yet fully grasp the grave problem at hand and the consequences we will face if viable solutions are not developed. Estimates from the US Centers for Disease Control and Prevention (CDC) United States indicate that about 23,000 people die every year from antibiotic-resistant infections (Biba, 2017). “The Review on Antimicrobial Resistance (AMR) determined that, left unchecked, in the next 35 years antimicrobial resistance could kill 300,000,000 people worldwide and stunt global economic output by $100 trillion” (Aminov, 2017). Antibiotic resistance and the presence of super-bugs are increasing and their harmful effects will be felt all over the world with tragic results. We must clearly understand how antibiotic resistance develops, what steps can be done to slow it down, and what alternative strategies are being developed to combat resistance and infection.
The introduction of antibiotics is still a recent phenomenon. “The origin story of antibiotics is well known, almost mythic, and antibiotics, along with the other basic public health measures, have had a dramatic impact on the quality and longevity of our modern life” (Osterholm, 2017). The highest rate of decline in infectious disease mortality in the United States was between 1938 and 1952, contributed to in part by a decline in deaths related to pneumonia, influenza, and tuberculosis (Armstrong, 1999). These declines corresponded to the introduction of sulphonamides in 1935, penicillin in 1941, and streptomycin in 1943 (Armstrong, 1999). Alexander Fleming, who discovered penicillin in 1928, was among the first who cautioned about the potential resistance to penicillin if used in too little doses or for too short a period of time during treatment (Aminov, 2010). Antimicrobial resistance occurs naturally over time, usually through genetic changes, but resistance is rapidly increasing due to humans using antibiotics without restraint. One example is Methicillin-resistant S. aureus (MRSA) “which led to other multiantibiotic-resistant variants, (the acronym now denotes multidrug-resistant S. aureus) [;it] has now moved outside the hospital and become a major community-acquired pathogen, with enhanced virulence and transmission characteristics.” (Davies et al., 2010) In many foreign countries, antibiotic sales are inadequately regulated, are sold over the counter, self-prescribed, used for too short a time period or used erroneously to combat viral infections. The more different antibiotics we use, the more opportunities bacteria have to develop new genes to resist antibiotics (Biba, 2017). This is especially true in agriculture worldwide where we have fed huge amounts of antibiotics to livestock not only to reduce infection, but also as a method to increase growth and thus, food production (Biba, 2017). The other major factor in the growth of antibiotic resistance is spread of the resistant strains of bacteria from person to person, or from the non-human sources in the environment. (2017, November 29) Retrieved from https://www.cdc.gov/drugresistance/about.html
Some of the simplest methods used to counter antibiotic resistance in a clinical setting are: 1) Preventing infections from developing and in turn reducing the amount of antibiotics used. Preventing infections also prevents the spread of resistant bacteria. 2) Doctors and other health professionals around the world are increasingly adopting the principles of responsible antibiotic use, using antibiotics only when necessary to treat and/or prevent disease; selecting the proper antibiotics, and to administer them for the proper duration. (2017, November 29) Retrieved from https://www.cdc.gov/drugresistance/about.html
However, more must be done, and other strategies must be considered if we are to succeed in combating the accelerating trend of antibiotic resistance. Resistance cannot be halted using infection prevention or altering antibiotic use alone. For example, resistance in Klebsiella pneumoniae to a last resort carbapenem treatment has spread to all regions of the world, as has resistance to Colistin, the last resort treatment for life-threatening infections caused by Enterobacteriaceae, rendering some infections untreatable. (2017, November 29) Retrieved from http://www.who.int/mediacentre/factsheets/fs194/en/ Meanwhile, the World Health Organization states that “Gram-negative bacteria are considered the most critical priority in the list of the 12 families of bacteria that pose the greatest threat to human health” (“Science Daily,” 2017). The approach to combating the crisis must be all encompassing and no stone must be left unturned.
Resistance at a biochemical level can come about due to numerous factors. For example: (1) mutations, a major contributor to the evolution of drug resistance, making the bacterium insensitive to antibiotic action such as mutations in RNA polymerase mediating resistance to rifampin; (2) enzyme modification such as methylation of an adenine residue in 23S rRNA making it insensitive to macrolides that inhibit bacterial translation; (3) or inactivation as in the β-lactam antibiotics by the action of plasmid-encoded β-lactamases; (Aminov, 2010) (4) “Others alter cellular metabolic or structural products, as in the case with vancomycin-resistant enterococci, where a cassette of genes mediates changes to a peptidoglycan motif that dramatically weakens vancomycin binding” (Culyba et al., 2015).
One approach to the resistance problem is to compound drugs for more efficiency or repurpose already discovered drugs. As mentioned previously, Gram-negative Enterobacteriaceae with resistance to carbapenem, carbapenemases, (beta-lactamases with versatile hydrolytic capacities that have ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems) conferred by New Delhi metallo-β-lactamase 1 (NDM-1) is resistant to many antibiotic classes and potentially signals the end of treatment with β-lactams, fluoroquinolones, and aminoglycosides—the main antibiotic classes for the treatment of Gram-negative infections (Kumarasamy et al., 2010). However, compounds can be designed to attack the resistance mechanism itself. Against β-lactam resistant Klebsiella, Proteus and E. coli, neither clavulanate nor ampicillin alone was very effective, but compounding them substantially reduced the amount of ampicillin required to inhibit growth (Levy 2000). “This is an excellent example of how one can take a resistance trait, develop a method to reverse the resistance mechanism and so restore the action of the antibiotic” (Levy 2000). The urgency behind developing new therapies has also generated repurposing screens in which previously studied drugs and other compounds are tested for potential antimicrobial uses. According to J. A. Andersson, there is “further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multi-drug resistant pathogens (Andersson et al., 2017).
Another approach is to combat multi-drug resistant pathogens with host-directed therapies or to combine antibiotics with non-antibiotic therapeutics. The idea of attacking host targets is not novel, but it is garnering more attention as of late. There are studies developing therapies that either moderate the inflammatory response to infection or that limit microbial growth by blocking access to host resources without attempting to kill microbes (Spellberg et al., 2013). The sequestration of host nutrients to create a resource-limited environment in which microbes cannot reproduce is a highly specific strategy (Spellberg et al., 2013). Meanwhile, “an innovative strategy that is gaining momentum is the synergistic use of antibiotics with FDA-approved non-antibiotics,” that enables it to breach the outer membrane barrier of bacteria and so restore the activity of an antibiotic (“Science Daily,” 2017). Combining antibiotics such as the broad-spectrum tetracycline with various FDA-approved non-antibiotic drugs have emerged as a novel combination strategy against otherwise untreatable extensively drug-resistant pathogens (Schneider et al., 2017).
The battle against antibiotic resistance must be continuous and multifaceted. According to Dr. Stuart B Levy, “bacteria will always be victorious—they are more numerous and genetically more flexible” (Levy, 2000). Dr. Brad Spellberg reminds us that “antibiotic resistance already exists, widely disseminated in nature, to drugs we have not yet invented and ultimately… we will run out of targets, and resistance mechanisms will become so prevalent as to preclude effective clinical deployment of antibiotics” (Spellberg et al., 2013) Thus, there is an urgency in our attempt to mitigate resistance and we must investigate all alternatives. Among other approaches are antibiotics targeting the ribosome and protein synthesis, many of which “are in development or in different phases of clinical trials” (Khan et al., 2016). Other studies advocate revisiting the expansion and use of vaccines. There is no single target solution to antimicrobial resistance. Antibiotics are a precious resource and we have previously identified some of the reasons resistance is developing so rapidly. The Director-General of the World Health Organization, Dr. Margaret Chan warned the United Nations, “the world is heading towards a post-antibiotic era in which common infections will once again kill and sophisticated interventions, like organ transplantation, joint replacements, cancer chemotherapy, and care of pre-term infants, will become more difficult or even too dangerous to undertake (Biba, 2017). The world must take a more aggressive approach to this problem, and only working together through sharing research will viable solutions be obtained or otherwise it will be too late.