“The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. Here is a hypothetical illustration. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death?”
Above statement has been borrowed from the Alexander Fleming’s noble lecture delivered on December 11, 1945.[1]Fleming’s serendipitous discovery of penicillin and its therapeutic potential in treating bacterial infection was a boon to mankind. However, shortly thereafter resistance to penicillin as well other discoverd antibiotics was observed. Scientist sought solution to this emerging problem in tempering old antibiotics and discovering new ones. Interest in soil microbiology grew globally. Soil samples from remote areas of world became treasure trove for microbiologist as well as pharmacological industry.[2]Over the next few decades many more antibiotics were discovered from single order of bacteria, actinomycetes. But bacteria walked one step ahead of mankind by acquiring resistance against antibiotics, through genes borrowed from the same environmental colleagues, who supplied antibiotics to humans. Over the years, bacteria have evolved from penicillin sensitive to dreaded pathogens like methicillin resistant staph. aureus (MRSA), vancomycin resistant staph. aureus (VRSA), vancomycin resistant enterococci (VRE), extended spectrum beta lactamase (ESBL) producing Enterobacteriaceae, carbapenem resistant Enterobacteriaceae, multi drug resistant pseudomonas, multidrug resistant Acinetobacter and pan drug resistant m. tuberculosis, pushing us back into pre-antibiotic era.
Antibiotic resistance has become a dangerous threat to individual, society and environment exemplifying ‘tragedy of commons’ described six decades ago by ecologist Garrett Hardin, who explained how humans has reached to numerous environmental catastrophes like population explosion and global warming.[3]In simple statement, tragedy of commons is long term harm to self, others and environment, when unrestrained individual behavior to maximize personal short-term gain, results in depletion or devastation of resources. Tragedy of commons is a problem involved in sustaining a public resource that everyone is free to overuse, resulting in extensive devastation because of limitless exploitation.[4]The common resource of antibiotics is not meant for antibiosis in nature, rather they exert this effect when applied at unnaturally high concentrations and bacteria combat this environmental pollution with expression of resistance. Injudicious use of antibiotics in humans, agriculture and animal husbandry has resulted in selection and spread of resistance in clinical, commensal as well as environmental bacteria.[5]
ANTIBIOTICS AND RESISTANCE ARE ANCIENT
Over last eight decades we have become heavily dependent upon antibiotics derived from environmental bacteria to fight pathogenic bacteria, for health and food production. But we are not the first to exploit and use bacteria, to combat microbial infection. While humans leapt from hunter-gatherer behavior to agrarian life style some 12000 years before, one species of ant has already been growing a unique crop in south American forest for fifty million years. In Amazon basin attini ants cultivate fungus for food and protect its fungal garden from microbial pests with antibiotics produced from bacteria belonging to actinomycetes, a bacterial order which is the source of eighty percent of antibiotics discovered so far.[6]Evidence of tetracycline intake in ancient population has been documented in the skeletal remains of Sudanese Nubia and Egyptian Dakhleh Oasis dating back to third century. Probable source of antibiotic has been suggested as streptomycetes contaminating stored food grains.[7],[8]
Despite utilizing antibiotics over millions of years, antibiotic resistance did not develop in wild environment of attini ants.[9]while humans could not prevent this catastrophe in just 80 years of use.
Soil bacteria possesses the ability to make antibiotics, as well as to live with antibiotics. Bacteria have been exposed to antibiotics produced by other competing microorganisms for millennia. Antibiotic resistance genes have a long evolutionary history predating well before the discovery and exposure of antibiotics in concentration much above that produced in nature and resultant selection pressure.
Genome of shigella flexneri isolated from a soldier died of dysentery in March 1915, fourteen years before Fleming’s serendipity, revealed resistance genes to penicillin and erythromycin.[10]Metagenomic analysis of ancient DNA from 30,000-year-old Beringian permafrost sediments revealed highly diverse collection of genes encoding resistance to beta lactam, tetracycline and glycopeptide antibiotics.[11]Structure-based phylogeny has established that extended spectrum beta lactamases (ESBL) enzymes originated more than two billion years ago.[12],[13]Evolutionary history of b-lactamase genes in Klebsiellaoxytocahas suggested that these genes have beenevolving for over 100 million years in this host, withoutconcomitant evolution of the antimicrobial resistancephenotype.[14]
Thus, antibiotics and resistance are present in microbial world for millennia. We only acknowledged its existence recently. Many biosynthetic gene clusters that make “antibiotics” are also known contain genes that confer “resistance” to those same antibiotics.[15],[16]
WHO WILL WIN THE WAR? OUR WITS VERSUS THEIR GENES
The fight against infection could not be won with antibiotics alone. Exposure to antibiotic is not a prerequisite to develop resistance as evident by the fact that Penicillinase was identified in E. coli in 1940, several years before introduction of penicillin in therapeutics.[17]Selection pressure of antibiotics only encourages sensitive bacteria to acquire resistant already present in nature.
In his visionary article Dr. Joshua Lederberg said that‘future of humanity and microbes likely will unfold as episodes of a suspense thriller that could be titled Our Wits versus Their Genes’.[18]However, as the climax is arriving, it is becoming more evident that our wits of discovering secondary metabolites of bacteria, and tinkering, producing and using it as antibiotic in exuberant amount, cannot not keep pace with bacterial ability to manipulate its genetic pool of resistance.
Contrary to this fact, at the beginning of post antibiotic era, antibiotic resistance was recognized as a problem that can be solved in the hope that new drug would be discovered, and existing ones could be further manipulated. In1962, Nobel laureate Sir Frank MacFarlane Burnet, an eminent virologist and immunologist declared that ‘one can think of the middle of the 20th century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious diseases as a significant factor in social life’.[19]It was presumed initially, that antibiotic resistance would largely be result of target modification through mutation which will remain limited to bacterial clone by vertical inheritance.[20]
But discovery of horizontal transfer (HGT) of resistance genes via plasmid came out to be fundamental challenge to this model. Plasmid carry considerable variety of genes determining resistance to multiple antibiotics as well as genes conferring virulence to bacterium. HGT enables bacteria to share resistant genes between themselves as survival tool.[21]This sharing of genes is so ubiquitous that entire bacterial world can be considered a pan organism containing pangenome.[22]Part of pangenome encoding resistance is termed as resistome, a common pool shared between all bacteria, benign or pathogenic, native to soil, animal or human.[23]This pool of vertically transmitted genes accrued over million years of evolutionary advantage, can be distributed horizontally in a single generation under antibiotic selection pressure, via HGT.
Vancomycin resistance in staph. Aureus (VRSA) is conferred by the vanA operon, originally a part of a vancomycin-resistant enterococci (VRE) plasmid.[24]Acinetobacter baumannii, a benign soil bacterium till 1970, became menacing multidrug resistance by acquiring many resistance and virulence genes from environmental resistome. One clinical strain of A. baumannii harbored 45 resistance genes derived from several other species of bacteria obtained in a single horizontal transfer event.[25]The percentage of recently acquired gene in A. baumannii is currently estimated at 17%, including genes from Legionella pneumophilia.[26]Extended Spectrum Beta Lactamase blaCTX-M and carbapenemase blaNDM which has conferred resistance to Enterobacteriaceae, Acinetobacter and pseudomonas has been identified to originate in environmental bacteria Kluyvera and Erythrobacter litoralis, respectively.[27],[28]
Alternatively, evolutionary history of antibiotic resistance genes can be divided into the macro- and microevolutionary periods, belonging to pre-antibiotic and post antibiotic era. The former is characterized by million years of diversification in natural ecosystems, mostly through duplications and mutations, with a limited contribution of horizontal gene transfer to the process, without phenotypic expression. Micro-evolutionary phase is a relatively brief period of human intervention beginning in 1940 with mass production of antibiotics and consequent selective pressure. Resistant phenotypes were selected and disseminated from environmental resistome to taxonomically divergent commensal and pathogenic bacteria through horizontal gene transfer.[20]
Injudicious use of antibiotics increases selection pressure among pathogenic and commensal bacteria of patient’s microbiota, encouraging exchange of resistant genes. Antibiotics are misused to treat inflammation and non-bacterial infection, or inappropriate antibiotics is used in inappropriate doses, for inappropriate duration, without consideration of tissue penetration and concentration. Resistant bacteria replace the normal skin and gut microbiota of patients. Poor infection control practice leads to dissemination of this resistant bacteria to hospital environment as well as other patients. Once patient is discharged, he spreads the resistant bacteria to community, expanding the pool of bacterial resistome.
Antibiotic prescription review of multiple hospitals in 10 U.S. states expressed need to improve antibiotic prescribing in 37% of cases.[29]Data have revealed that in intensive care units 30% to 60% of prescribed antibiotics have been found to be unnecessary and inappropriate.[30]
Antibiotics use in animal husbandry and agriculture is another very importance source that exerts evolutionary pressure for spread of resistance genes. Statistics of ‘The State of the World’s Antibiotics 2015’ revealed that two- thirds of all antibiotics produced globally each year (65,000 tons of 100,000 tons) are used in animal husbandry.[31]
Misuse of antibiotics in in livestock animals started with an accidental observation at Lederle Laboratory in America, soon after the beginning of antibiotic era. Working on vitamin B12 as animal protein factor to enhance chicken growth, Robert Stokstad and Thomas Jukes supplemented feed with cellular waste of Streptomyces aureofaciens rich in vitamin B12. Chicks that received supplements containing Streptomyces auerofaciens grew 24 percent more than those receiving liver extract, which also contained high levels of B12.[32]Thus, begin the era of antibiotics fortification of animal diets to produce dramatically faster growth, less disease, and earlier marketability in chickens, turkeys, cows and pigs, ‘without detectable loss in meat quality.
Unmetabolized antibiotics excreted from human and animal body, unused animal feeds fortified with antibiotics and waste products from antibiotic producing pharmaceutical industry are spilled over in waste water treatment plant or sewers, where bacterial from different environment interact and transfer genes through HGT.[33]These anthropogenic activity leads to elevated concentration of antibiotics and consequent selection pressure in the environment promoting exchange of resistance genes and expansion of environmental resistome.[34]
In an experimental study 412 bacterial isolates cultured from ten soil samples from agriculture, urban and pristine environments were found be multidrug resistant. Majority of these were resistant to 16-23 antibiotics including penicillin, cephalosporines, ciprofloxacin, vancomycin and colistin.[35]
THE SOLUTION: VICTORY VERSUS TRUCE
We can never win the war against bacterial infection with antibiotics, as both the antibiotics and the resistance are derived from the same source, that is bacteria. Any antibiotic that would be discovered in future, resistance against it would already be existing in microbial world, which will be acquired by the target bacteria sooner or later. Given the necessity of antibiotics in medicine, its impossible to remove selective pressure of antibiotics from the environment, therefore, evolution of resistome cannot be reversed.[36]But evolutionary pressure can be minimized by limiting the use of antibiotics in humans, animals and agriculture which may retard the selection and dissemination of resistance genes and consequent evolution of clinical and environmental resistome. Therefore, solution of the war against infection exists not in striding for victory but making truce.
In clinical setting antibiotic use can be minimized by preventing infection through infection control practices and judicious use of antibiotics through antibiotic stewardship programs. In agriculture and animal husbandry use of antibiotics for infection prevention and growth promotion should be strongly discouraged and vaccination and improved hygiene and welfare practices should be promoted. Antibiotics should be given for treating infection under veterinary supervision. Infection control measure aims at preventing transmission of resistant bacteria between patients through healthcare providers. It comprises of standard precaution and transmission based (standard, droplet and airborne) precaution with hand hygiene, personal protective equipment (PPE), environmental cleaning and cough etiquettes.[37]Infection control practice should be inculcated into the behavior of healthcare providers which should be reflected in clinical examination, nursing care and invasive procedures.
Antimicrobial stewardship is a set of coordinated strategy to use antibiotics responsibly with optimal selection, dosage, and duration that results in the best clinical outcome, with least collateral damage. Joseph and Rodvold described 4 D’s of optimal antimicrobial therapy, right Drug, right Dose, De-escalation, and right Duration of therapy.[38]Appropriate antibiotics according to site of infection and based on pharmacokinetic and dynamic guided by guidelines and hospital antibiogram should be prescribed and modified based on antibiotic sensitivity report. Surgical source control where possible, must not be delayed.
Prophylactic use of antibiotics should be limited to primary prophylaxis of surgical site infection and secondary prophylaxis of recurrent or reactivating infection like rheumatic fever, spontaneous bacterial peritonitis and urinary tract infection in accordance with the local guidelines.[39]Therapeutic prescription of antibiotics should be directed against suspected or proven bacterial infection. Fever and leukocytosis is a manifestation of systemic inflammatory response syndrome (SIRS). Infection is one of the many causes of SIRS, and bacteria is one of the many causes of infection.
Government should formulate strategies for infection control policy and antimicrobial stewardship programs along with restricted drug promotion and advertising, surveillance of antibiotic use and resistance detection in human and animals.[40]
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