Antibiotic Resistance -A Guide
An antibiotic is a substance obtained from isolated cultures of certain microorganisms or is of semi-synthetic origin used to treat or prevent microbial infections either by killing microorganisms or inhibiting the growth of microorganisms in or on the body. They can be administered topically, orally or by injection. Antibiotics don’t affect against virus and thus can’t be used against viral infections.
Sir Alexander Fleming, a Scottish researcher was the first to discover an antibiotic named Penicillin in1928. He was performing experiments with the influenza virus in the Laboratory of the Inoculation Department at St. Mary’s Hospital in London. Often described as a careless lab technician, he went on a two-week vacation. On his return, he found that a mold had started growing accidentally on contaminated Staphylococcus culture plates. Fleming described mold colony as:
“Fluffy white mass which rapidly increases in size and after a few days sporulates and changes color from dark green to black to bright yellow.”
Upon examination of that mold he had found that culture of mold prevented the growth of Staphylococci. He published an article in the British Journal of Experimental Pathology in 1929 reads as;
“The Staphylococcus colonies became transparent and were obviously undergoing lysis … the broth in which the mold had been grown at room temperature for one to two weeks had acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more common pathogenic bacteria.”
Fleming described his discovery of penicillin as; “One sometimes finds what one is not looking for. When I woke up just after dawn on Sept. 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.”
Fleming stopped studying Penicillin in 1931; his work was continued and finished by two Oxford researchers Howard Florey and Edward Chain. They carried out human trials on Penicillin. For their work Fleming, Chain and Florey shared Noble Prize in 1945.
Antibiotic – resistance
Antibiotics are the most common means of treating infection most common bacterial infections. However, massive use and misuse of antibiotics have developed resistance in microbes against that antibiotic. Antibiotics resistance has caused increase risk of occurrence and spread of antibiotic-resistant bacterial infections.
In 1945 Alexander Fleming pointed towards antibiotics resistance in his noble prize acceptance speech, saying:
“Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant.”
The ability of a microbe to withstand the effect of an antibiotic is termed as antibiotics resistance. It is a specific type of drug resistance which can evolve naturally by natural selection after random mutation or it can be made artificially by applying an evolutionary stress on a population. After the evolution of antibiotic resistance, the resistance gene can be transmitted to other bacteria with the help of horizontal gene transfer by plasmid exchange. Bacteria can acquire resistance to a single antibiotic as well as to multiple antibiotics. When certain bacteria become to several antibiotics it is called multidrug-resistant bacteria or superbug.
Pathways to acquire antibiotics resistance
Bacteria acquire antibiotics resistance by two pathways:
- Random mutations in DNA providing resistance by chance to bacteria
- Through horizontal gene transfer in which bacteria receive the antibiotic-resistant gene from other bacteria nearby.
Antibiotic resistance can affect people at any stage of life. It can affect healthcare, agriculture and veterinary industries making it a potential threat and one of the most urgent public health care problem. More than 150 million antibiotics prescriptions per year are written to the patient in the US. Among these patients, 2.8 million people get an infection of antibiotic-resistant microbes with 35000 deaths per year.
Factors contributing to antibiotics resistance
- Environmental pressure is generated by antibiotic action the bacteria will try to survive antibiotic action by undergoing mutation. LexA protein is a bacterial protein which is playing a key role in generating bacterial mutation. Some mutation allows bacteria to survive and they will reproduce and will pass this antibiotic resistance to their offsprings.
- The pattern of antibiotics use is another factor greatly contributing to the number of antibiotic-resistant microbes.
- Incorrect diagnosis, improper usage of antibiotics, unnecessary prescription and use of antibiotics in livestock to promote growth are other major factors contributing to antibiotic resistance.
Staphylococcus aureus a skin and mucus membrane pathogen is the first bacterium who developed penicillin resistance in 1947 just after 4 years of penicillin mass production had been started. Methicillin was used for Staphylococcus aureus but was replaced by oxacillin because of kidney toxicity caused by Methicillin. MRSA (methicillin-resistant staphylococcus aureus) was first been detected in 1961 in Britain. In 1999 37% of fatal blood poisoning was due to MRSA. staphylococcus aureus acquired resistant against penicillin, tetracycline, Methicillin and erythromycin. Vancomycin is the only effective drug against Staph. available at the time. In 2002 the first strain of VRSA (Vancomycin-resistant Staphylococcus aureus) was reported in the United States. In 2003 linezolid-resistance was also reported in Staphylococcus aureus.
Streptococcus pneumoniae cause pneumonia, leading to ear and sinus infections as well as meningitis. Bacteria can also enter into the bloodstream causing bacteraemia. Symptoms include cough, fever, chest pain, shortness of breath, joint and ear pain, sensitivity to light and chills. It can cause brain damage, hearing loss and even death. Bacteria developed antibiotic resistance making its infection tough to treat.
Enterobacteriaceae is a family of enteric pathogens including Salmonella, Shigella and Escherichia coli etc. They can cause gastroenteritis, vomiting and diarrhoea. Sometimes, These organisms can also cause bloodstream, urinary tract and wound infections. Carbapenem is used to treat some antibiotic-resistant bacterial infections caused by Enterobacteriaceae. However, some bacteria are developing resistance against Carbapenems. Infections caused by carbapenem-resistant Enterobacteriaceae are tough to treat.
Another superbug found in hospitals is Enterococcus faecium. In 1983 penicillin-resistant Enterococcus (PRE) was seen. In 1987 Vancomycin-resistant Enterococcus (VRE) and late 1990’s linezolid-resistant Enterococcus (LRE) was reported.
Strains of Streptococcus pyogenes resistant to macrolide have been reported but the microbe is sensitive to penicillin. Streptococcus pneumoniae is developing resistance to penicillin and other beta-lactams.
National Action Plan by the White House
In 2015 a National Action Plan was given by the White House to combat antibiotic resistance. This includes:
- Development of new antibiotics and vaccines as well as diagnostic tests for the detection of antibiotic-resistant microbes.
- Stop usage of antibiotics by the farmer to animals which are being used to treat diseases in humans.
- Monitoring of antibiotic-resistance and tracking its spread by public health officials.
- Stop the use of unnecessary antibiotics by doctors to develop safer practices in clinics and hospitals.
We can also stop antibiotics resistance development and protecting yourself from getting an infection by following ways:
- Stop unnecessary use of antibiotics only use it when you are certain that you need to use it or ask your doctor. Antibiotics don’t work against common viral infections such as common cold, bronchitis and many sinuses and ear infections.
- Finish your treatment even you start feeling better you need to take your entire prescription. Bacteria are most likely to develop antibiotics resistance if you stop using antibiotics before the infection is completely wiped out.
- Vaccinate yourself for the disease whose vaccination is available. Prefer vaccination over antibiotic treatment for diseases whose vaccine is available such as whooping cough and tetanus.
- Keep yourself self by maintaining proper hygiene especially in hospital settings. Make sure that caregivers are washing their hands properly.
Mechanisms for Antibiotic-resistance
Bacteria can resist antibiotics by either changing or destroying the antibiotic or by making changes which not allows antibiotics to work on target sites. Following are the ways through which a bacterium resistant an antibiotic:
- Bacteria can resistant antibiotic by pumping the antibiotic pit of the cell and hence less concentration of antibiotic will be able to reach the target site. Mutations in bacterial DNA allows bacteria to develop some pumps which can pump antibiotics out of the bacterial cell and lowering its concentration inside the cell. These pumps are often activated by a substrate-binding which is associated with an antibiotic. Bacteria had developed fluoroquinolone resistance by following this mechanism.
- Bacteria can also resist antibiotics by destroying antibiotics thorough special enzymes. For example production of lactamase causes the destruction of lactam ring the active component of penicillins. ESBL-producing bacteria (extended-spectrum lactamase) became a major problem in recent years. They can degrade lactam ring of many broad-spectrum antibiotics even sometimes the last available choice is being now not effective against certain pathogens.
- For reaching the target sites certain antibiotics need to pass the bacterial membrane. Bacteria reduces its membrane permeability making it more difficult for an antibiotic to pass the membrane and reach the target site.
- Bacteria sometimes produce certain enzymes which can modify the antibiotic by adding different chemicals to the antibiotics. This modification prohibits binding of antibiotic with its target site.
- Certain mutation in bacterial DNA allows bacteria to develop certain changes in the structure or composition of the antibiotic target. This camouflage of target site prohibits the antibiotic to interact with the target. Bacteria can also add different chemicals groups to the target site of antibiotic protecting bacteria from the antibiotic.
- Bacteria can also develop antibiotics resistance by altering their metabolic pathways. For example, para-aminobenzoic acid (PABA) is an important precursor molecule for the synthesis of folic acid. Sulfonamides action is by stopping the synthesis of para-aminobenzoic acid and thus prohibiting folic acid synthesis. Some bacteria develop Sulfonamides resistance by altering their folic acid synthesis pathway. These resistant bacteria don’t need para-aminobenzoic acid for their folic acid synthesis
- Sometimes bacterial cell starts producing alternative of the proteins that are inhibited by the antibiotics. For example, Staphylococcus aureus can acquire a mecA gene which is a resistance gene allowing bacteria to produce a new penicillin-binding protein. Certain Proteins are needed for bacterial cell wall synthesis whose production is being inhibited by penicillin. The new penicillin-binding protein is resistant to lactam as it has low binding affinity to lactam. This change allows bacteria to survive even in the presence of an antibiotic. Methicilin-resistant Staphylococcus aureus (MRSA) have this mechanism for resistance against methicillin.
- Ribosomal recycling and splitting is another method of antibiotic resistance. Lincomycin and erythromycin perform their action by stalling ribosome. Listeria monocytogenes unstall ribosomes by producing a heat shock protein. Ribosomes are liberated from drug and perform their role of protein synthesis making bacteria resistant to an antibiotic.
- Bacteria can also have intrinsic resistance in which bacteria stop producing the target of antibiotic. For example, antibiotics which target cell wall bacteria can resist to it not having a cell wall. Production of resistance against antibiotic in bacteria who were previously susceptible to the antibiotic is termed as acquired resistance.
Horizontal Gene Transfer:
Antibiotics resistance can be acquired by horizontal gene transfer. Conjugation is the most common mechanism of horizontal gene transfer. In conjunction, the antibiotic-resistant plasmid gene is transferred between the bacteria of same specie with by transferring plasmid containing the antibiotic-resistant gene.
Bacteria can also acquire antibiotic resistance through transformation such as in Streptococcus pneumoniae that acquire antibiotic resistance gene by up taking naked fragments of extracellular DNA. This up taking of extracellular DNA fragments helped Streptococcus pneumoniae to develop streptomycin resistance by an up taking extracellular streptomycin-resistant gene.
Transduction is a method of horizontal gene transfer. Bacteriophages are the virus that can infect bacteria. Bacteriophage can bring along genes that they picked up from other bacteria during infection. Thus bacteriophages can uptake the antibiotic resistance gene and can transfer it to bacteria while injecting their DNA into the bacterial cell. Tetracycline resistance gene is being transferred between Streptococcus pyogenes strains with Bacteriophage-mediated transfer.
Some of the antibiotics, their release year, resistant organisms and year in which organism had developed antibiotic-resistant are given as:
|Approved Antibiotics||Releasing Year||Identified Resistant Germ||Year Identified|
|Penicillin||1941||Penicillin-resistant Staphylococcus aureus||1942|
|Penicillin-resistant Streptococcus pneumoniae||1967|
|Penicillinase-producing Neisseria gonorrhoeae||1976|
|Vancomycin-resistant Staphylococcus aureus||2002|
|Amphotericin B||1959||Amphotericin B-resistant Candida auris||2016|
|Methicillin||1960||Methicillin-resistant Staphylococcus aureus||1960|
|Extended-spectrum beta-lactamase- producing|
|Azithromycin||1980||Azithromycin-resistant Neisseria gonorrhoeae||2011|
|Imipenem||1985||Klebsiella pneumoniae carbapenemase (KPC)-|
producing Klebsiella pneumoniae
|Ciprofloxacin||1987||Ciprofloxacin-resistant Neisseria gonorrhoeae||2007|
|Ceftazidime-avibactam||2015||Ceftazidime-avibactam-resistant KPC-producing Klebsiella pneumoniae||2015|