Antibiotic resistance and the rise of superbugs

Antibiotics have been crucial in the fight against infectious diseases, specifically those caused by bacteria, over the last century. The first antibiotic, penicillin was discovered in 1929, and protected against staphylococcal and streptococcal infections. These are the bacteria which cause diseases such as septicaemia, abscesses and impetigo (Staphylococcus) or scarlet fever and tonsilitis (Streptococcus). However, since the 1940s, cases of resistance to these drugs have begun to appear in pathogens (disease causing microorganisms), leading to complications in treatment of the diseases that they cause, and  around 25,000 deaths a year in the EU.

Antibiotics usually work by inhibiting enzyme action in the bacterium pathogen, which means that the bacteria cannot survive or reproduce. The penicillin family and cephalosporin antibiotics inhibit the enzyme for the production of peptidoglycan, which is used to make bacterial cell walls, without which, the bacteria would burst. The antibiotics aminoglycoside, tetracycline and erythromycin (a penicillin substitute which can treat Legionnaires’ disease) inhibit protein synthesis, preventing the bacteria from making any more enzymes and growing. Some others like sulfamethoxazole work by inhibiting enzymes responsible for metabolic reactions. Because of the way in which antibiotics work (by preventing the formation different aspects of bacterial structure), they cannot treat viral infections, as bacteria are cellular organisms and viruses are not.

  

If one bacterium has an inherent antibiotic resistance or develops a resistance to antibiotics due to a genetic mutation or change in environment, it is then able to pass on its resistance in several ways, creating colonies of resistant bacteria. An example of resistance is the gene for the production of the enzyme penicillinase, which turns penicillin into penicilloic acid, preventing the action of penicillin.

Vertical gene transfer: If a course of antibiotics is prescribed, all non-resistant bacteria will be killed, but the resistant bacteria will thrive. The antibiotics act as a selective pressure, as only the resistant bacteria will reproduce, so the resistance will be passed on to all its offspring.  Because bacterial cells can, in optimum conditions, divide every 20 minutes, in less than 7 hours hours you would have a colony of 1 million bacteria all with antibiotic resistance.

Horizontal gene transfer: Plasmids are rings of DNA present in bacteria. Segments of these plasmids can be exchanged between different species of bacteria, for example Staphylococcus bacteria can share genetic information with Bacillus, Streptococcus and Enterococcus bacteria. This means that bacteria with antibiotic resistance which do not cause disease could pass on their resistance to pathogens. Genes can also be accumulated from dead bacteria in the environment being broken down, and their genetic information taken up by others or by viruses transferring genetic information between cells.

Recent studies have shown that bacteria under stress (in this case growth at high temperatures) can spontaneously develop resistance to unseen antibiotics (in this case the E. coli bacteria developed resistance to rifampicin). Rifampicin is an antibiotic used in the treatment of TB, leprosy and meningococcal meningitis.

 

The overuse or unnecessary use of antibiotics has played the most significant role in allowing resistant strains of bacteria to reproduce and spread. Also by not finishing a course of antibiotics or having too mild a dose, could lead the bacteria to develop a resistance. We would assume, therefore, that when reintroduced with other bacteria, without antibiotic presence, the resistant strain may die out, because it no longer has an advantage over other strains. Unfortunately the same studies as mentioned previously have shown that this is not always the case rifampicin resistant E. coli reproduced at a 20% faster rate, the first time this has ever been seen in resistant bacteria.

Staphylococcus aureus is a bacterium which is carried on the skin, and in the nostrils and throat. The bacteria is mostly harmless but can cause boils (pus filled lumps) or impetigo (fluid-filled blisters or sores that leave a yellow-brown crust) if it gets inside hair follicles. Staphylococcus aureus could enter the bloodstream through a break in the skin such as a wound, burn, due to the insertion of an IV (intravenous) drip or catheter, or due to invasive surgery. Inside the body it could lead to blood poisoning/sepsis (overreaction of the immune system leading to high temperature, dizziness, nausea, inflammation and blood clots), urinary tract infection or endocarditis (infection of the lining of the heart which could damage the heart valves and lead to heart failure).

MRSA is methicillin-resistant staphylococcus aureus, a strain of the bacteria resistant to many classes of antibiotics (including penicillin and cephalosporin families). The first case in the UK was in1961, two years after the introduction of the antibiotic methicillin, but over the past decade MRSA has been a severe problem. Within hospitals and nursing homes, it is known as Hospital-Associated or HA-MRSA, the main route of transmission being the presence of the bacteria on the skin of patients and healthcare workers. Deaths due to MRSA rose to a peak in 2007 and in the USA deaths due to MRSA overtook those due to AIDS, but in 2011 were reduced to only 364 deaths in England and Wales where MRSA was cited as the direct cause. This was due to the isolation of infected patients, the introduction of more rigorous hygiene enforcement for staff and visitors and a swab test and antibacterial wash for patients undergoing surgical procedures. MRSA also spread in homeless shelters and army camps due to close contact and poor hygiene, known as Community-Associated or CA-MRSA. The more serious infections due to Staphylococcus aureus are usually treated with antibiotics, though this would be dependent on the strain of the bacteria, and combination treatments may be necessary.

Clostridium difficile is a bacterium that is present in the human bowel (because it prefers the anaerobic conditions) and does not normally pose any threat. However, after antibiotic treatment, the other bacteria present in the bowel are killed, creating an imbalance leading to the multiplication of the bacteria and the production of harmful toxins. The disease can also be spread as C. difficile spores are present in faeces and can remain on surfaces for months.  C. difficile infections can cause diarrhoea, dehydration, nausea, fevers and abdominal cramps. Occasionally infections can lead to kidney failure due to dehydration, the swelling of the bowel or perforated colon, which can be treated by a colectomy. Similarly, Escherichia coli which naturally occur in the gut of all humans, but can cause urinary tract infections which cause pain when urinating but could also lead to kidney failure or blood poisoning. UTIs are usually treatable by a course of antibiotics, but resistant strains are becoming a big problem, and are thought to be due to the antibiotic resistant strains of the bacteria due to the overuse of antibiotics to prevent disease in agriculture, which accounts for 60% of antibiotic use.

Due to the development of resistant strains of C. difficile, it is important not to continue with an antibiotic treatment which is not working, so as not to put excessive selective pressure on the bacteria. The antibiotics currently used are metronidazole and vancomycin. We can prevent C. difficile by hand washing (though not alcohol hand rubs), disinfection of surfaces around the patient and in hospitals, staff are encouraged to wear gloves when treating patients with the infection In 2011 there were 2,053 deaths due to C. difficile infection, though like MRSA due to the improvement of hygiene, these rates are falling. Unfortunately deaths due to E.coli are rising.

Mycobacterium tuberculosis is the bacterium which causes tuberculosis (TB), one of the oldest infectious diseases which has been in human populations for 40,000 years, a slowly developing condition spread by droplets through the air (i.e. sneezing). Often infections occur in the lungs, known as pulmonary TB, which causes breathlessness, coughing up blood, high temperature, fatigue, severe weight loss. TB can also affect the digestive, lymphatic (glands), skeletal and nervous system as well as the bladder, with various symptoms such as pain, swelling or bleeding of the infected area. TB is not very contagious compared with colds or flu, but in conditions of poverty such as overcrowded housing and poor diet, it can spread quickly with one infected person infecting 15 others each year. Until 2005, all children in the UK were given the BCG vaccine which protects against TB, especially TB meningitis which is common in children, though it does not provide absolute protection against TB in adults. Currently several antibiotics and anti-TB drugs are available to effectively treat tuberculosis, rifampin and isoniazid (the first line treatment) and streptomycins, para-aminosalicylic acid and ethambutol. However, these second line drugs are very expensive can have side effects such as depression, hepatitis and hallucinations.

Since 1990 global cases of TB have decreased by 41%, but misuse of antibiotics has created strains which are resistant and once again TB is on the rise in the UK with 8,963 cases, and is a huge problem in the developing world in countries such as India. It is also thought that over 30% of the World’s population is infected with latent TB, which will only develop once the immune system is weakened. It is becoming even harder to treat. This is because of the development of MDR (multi drug resistant) strains of the virus, which is resistant to first line treatment which is treated in poverty stricken countries by different drug combinations in an attempt to find one that will work, potentially driving further resistance. It is thought that the first case of TDR (totally drug resistant) TB was recorded in India in 2011 (although we cannot be 100% certain that it would have been resistant to all the antibiotics available to us at the moment, though the case was certainly extensively drug resistant). Unfortunately, though trials for new vaccines and drugs are being developed it is likely that we will only extend the antibiotic fuelling bacterial resistance cycle, creating as much harm as good, creating the incurable diseases of future.

http://www.dh.gov.uk/health/tag/antibiotic-resistance/
http://www.nhs.uk/Conditions/MRSA/Pages/Introduction.aspx

http://www.nhs.uk/Conditions/Clostridium-difficile/Pages/Introduction.aspx
http://www.cdc.gov/HAI/organisms/cdiff/Cdiff-current-strain.html

TIME magazine March 4th 2013

New Scientist March 2nd 2013