Antibiotic Resistance and MRSA
MRSA stands for methicillin-resistant Staphylococcus aureus. S. aureus is a small sphere shaped bacterium that causes skin boils, life-threatening pneumonia, and almost untreatable bone infections. It often spreads by skin-to skin contact, shared personal items, and shared surfaces, such as locker room benches. When the microbe finds a break in the skin, it grows and releases toxins. Some sixty years ago, S. aureus was susceptible to many antibiotics, including penicillin. However, the microbe developed resistance to penicillin and the pharmaceutical industry produced increasingly potent antibiotics. These included methicillin, which overcame resistance to penicillin. But in 1960, one year after the introduction of methicillin, MRSA was found again in the United States. The resistant bacterium spread through hospitals, so that surgical procedures became more dangerous. MRSA also caused pneumonia, commonly following influenza.
Community-based MRSA (CA-MRSA)
Community associated MRSA, or CA-MRSA, is different from hospital-associated MRSA (HA-MRSA). Many community-associated S. aureus strains are members of a group called USA300, which accounts for half of the CA-MRSA infections. The strain causes flesh-eating skin infection, pneumonia, and muscle infection. In 2005, MRSA accounted for more than 7 million cases of skin and soft tissue infection in outpatient departments in U.S. hospitals. (1)
As expected, CA-MRSA strains are moving into hospitals. In a survey of US hospitals taken from 1999 to 2006, the fraction of S. aureus that was resistant to methicillin increased 90%, almost entirely due to CA-MRSA. (2)
Many infections tend to occur in persons having weakened immune systems, but MRSA can infect anyone. For example, healthy young adults tend to be susceptible to a lethal combination of influenza and MRSA pneumonia.
HA-MRSA has been a problem in hospitals for years and in many countries it is getting worse. In the United States, MRSA rose from 22% of the S. aureus infections in 1995 to 63% in 2007. From 2000-2005, MRSA helped double the number of antibiotic-resistant infections in U.S. hospitals, which reached almost a million per year. In the United States, more people now die each year from MRSA than from AIDS.
Antimicrobial Efficacy of Silver and Antibiotic Resistance
Silver has acquired a worldwide acceptance as a broad spectrum antibiotic. Laboratory and clinical studies have shown it to be safe in long-term use and effective in controlling most pathogenic bacteria, fungi, and parasitic infections including the methicillin-resistant strains ofS. aureus (MRSA). (4)
The Rise and Fall of Antibiotics
Over the past 90 years, antibacterial discovery has gone from boom to bust. For about 30 years in the middle of the 20th century, pharmaceutical companies regularly churned out new classes of the drugs, many of which doctors still use today, such as penicillin and the tetracyclines. However, by the 1980′s, discovery slowed and companies started leaving the field, drawn by the rise of profitable drugs in other therapeutic areas. As a result, only one successful new class of antibacterial drugs has been discovered since the late 1980′s (bedaquiline). This is the story of the Rise and Fall of Antibiotics.
With growing numbers of bacterial strains resistant to existing drugs, pharmaceutical experts have been at a loss to know what to do.
The success of early antibiotics saved many lives. It was reported in 1951 for example, thanks to drug treatment, the pneumonia mortality rate dropped by 50% in the previous decade.
The antibacterial development boom started after the discovery in 1943 of streptomycin, the first antibiotic to treat tuberculosis. Albert Schatz and his supervisor Selman A. Waksman, found the compound in Streptomyces bacteria. Streptomyces lives in soil, and soon pharmaceutical companies in the U.S., Europe and Japan started screening soil microbes.
These companies were tapping into a microbial war that had been going on for many centuries in the soil.
In a typical screening program, company microbiologists would obtain soil samples from across the globe. When soil samples came in, the microbiologists would first isolate the many different microbes present and then grow them separately in liquid cultures. The resulting broths were tested to see whether they could stop the growth of a particular pathogen, such as Staphylococcus aureus or Escherichia coli. If they did, then the real work began of isolating the active molecule.
From the 1940′s to the 1960′s, companies improved this method and discovered about 20 major antibacterial classes, including the tetracyclines, the macrolides and the glycopeptide vancomycin.
As scientists studied the major classes, they found how the antibacterials worked. The beta-lactams, such as penicillin and cephalosporin, inhibited cell wall synthesis. Tetracyclines, macrolides, and aminoglycosides affect protein synthesis. and the quinolones disrupted DNA replication.
Medicinal chemists played a significant role in the boom by developing antibiotics with improved properties. Beecham Research Laboratories, an English Company that became part of GSK, produced several important derivatives of penicillin. An example was methicillin, developed in 1959, had a 2,6-dimethoxyphenyl side chain which shielded the compound from some beta-lactamases, the enzymes that enable bacteria to resist penicillin.
Discoveries of new classes started to taper off during the 1970′s. Companies started to see diminishing returns from their screening programmes. In the 1950′s, companies had to screen through around 1000 bacterial cultures to find a compound no one had seen before. To find Daptomycin, which was discovered in 1987, and is one of the last new classes to reach the market, scientists had to pick through about 10 million cultures. The rise and fall of antibiotics was upon us.
In the late 1990′s, the industry tried to improve antibacterial discovery by turning to genomics. When the genome of Haemophilus influenzae was publicized in 1995, companies such as GSPK thought they could find new drugs by searching for genes essential for bacterial survival in multiple species. Then by using in vitro assays, they screened for compounds that inhibit the activity of associated proteins.
The strategy failed for multiple reasons.
Reasons for Failure of the Genomic approach
First, it focused too much on single targets. Most successful antibacterial drugs targeted more than one bacteria. For example, beta-Lactams hit multiple proteins involved in cell wall synthesis. If a compound shuts down just one target, bacteria can easily mutate that gene and gain resistance to the drug.
The second problem was that chemists synthesized drugs on the basis of hitting targets inside and outside human cells. These rules were not helpful in targeting actual bacteria. Unlike human cells, gram-negative microbes have dual-membrane barriers and protein complexes that actively remove unwanted chemicals. Scientists currently do not understand what allows compounds to slip though these barriers.
With the failure of high volume screening, many companies shifted their emphasis to more lucrative therapeutic areas such as chronic diseases. Also worrying, was that many still effective drugs had lost patent protection, filling the market with cheap alternatives.
At the start of the 1980′s, more than 35 major US and European companies were working on antibacterial drugs. Now there are fewer than 10.
According to the Infectious Diseases Society of America (IDSA), 16 new antibacterial drugs were approved in the US between 1983 and 1987. In the past five years, only two have been approved.
While the supply of new drugs has been drying up, pathogens have been developing resistance to existing drugs. In 2013, the Centers for Disease Control & Prevention issued a warning about gram-negative pathogens called carbapenum-resistant Enterobacteriaceae (CRE). Carbapenums are drugs often used as a last resort in serious infections. One of every two patients with CRE in the bloodstream dies.
Experts think that the future of antibacterial treatments will depend on developing new strategies, and on luring pharmaceutical and biotech companies into the field .
Antibiotic Resistance is Widespread
For some pathogens, such as MRSA and Acinetobacter, physicians have turned to antibiotics abandoned decades ago because of toxic side effects. Several pathogens are close to becoming difficult to treat in some regions. Examples of pathogens that have become extensively resistant are:
Acinetobacter baumanii (Pneumonia and wound infections) resistant to all common drugs available.
Klebsiella pneumoniae (Pneumonia) resistant to carbapenen, fluoroquinolones, amino glycosides and cephalosporins in hospitals in many countries.
Mycobacterium tuberculosis (Tuberculosis) resistant to rifampicin, isoniazid, fluoroquinolone, kanamycin, amikacin, capreomycin on a wordwide scale, particularly Eastern Europe and South Africa.
Neisseria gonorrhoeae (Gonorrhea) resistant to penicillins, tetracyclines, fluoroquinolones, macrolides and cephalosporins in the Western Pacific and Japan.
Salmonella enterica (Food-borne bacteremia) resistant to Ampicillin, chloramphenicol, tertacycline, sulfamethoxazole, trimethoprim and fluoroquinolones on a wordwide scale.
Staphylococcus aureus (many types of infection) resistant to beta-lactams, fluoroquinolones and gentamycin on a worldwide scale.
Resistance Problems – a Perspective
Throughout history pathogens have attacked humans, and before the middle of the twentieth century we relied on our immune systems to survive these attacks. Many people died, but though improvements in diet, sanitation and water purification, our immune systems were strengthened. For other pathogens vaccines were developed, and insecticides used to control mosquitoes. However, our fear of pathogens was eliminated only by antibiotics. By taking pills for a few days, we could quickly recover fro most bacterial diseases.
Nowadays our resistance problems derive from the cumulative effect of several complex factors. One has been our cavalier attitude. For example, in 2009 an American supermarket chain began to advertise free antibiotics to attract customers. Whilst hospitals are beginning to oversee their own use of antibiotics, the agricultural community is largely uncontrolled after drugs are approved by government agencies. Outside of hospitals however, individual patients continue to insist on antibacterial treatments for viral infections which stimulates the emergence of resistant bacteria. It is clear that the educational effort needs to be intensified. Another factor is dosage – doses are kept low enough to cause few side effects, but high enough to kill susceptible cells. Conditions that control the growth of susceptible cells, but not that of mutants, are precisely the cause that leads to enrich mutants. In other words, conventional dosing strategies lead directly to the emergence of resistance .
Silver as an Antibiotic
Silver has been known for its ability to purify drinking water for at least 2000 years, but silver as an antibiotic has become evident in the past 100 years or so following discoveries in microbiology when Loius Pasteur and Robert Koch conducted fundamental research on the concepts of infection and transmission of disease.
Robert Koch established his principles of disease when he first diagnosed anthrax as a fatal infection in human patients and proved that it as caused by an ‘organic’ pathogen. Subsequent research by Pasteur and Koch in 1876-1877 on anthrax, and transfer of Bacillus anthrasis can be regarded as the starting point of modern pathogenic bacteriology.
It is not clear when the antibiotic properties of metallic silver were first recognized, but reviews of silver in healthcare commonly refer to silver vessels being used to transport drinking water for the monarchs of ancient Babylon, Rome and the Persian Empires. Records from the 14th century suggest that the value of silver in surgery as a means of alleviating disease was appreciated (7)
Ambrose Paré (1510-1590) was a perdiatric surgeon who attended the gunshot wounds of Henry II of France, and who pioneered silver clips and instruments in surgery and for life threatening conditions. Later surgeons such as John Woodall (1617) , surgeon general of the East India Company, also claimed that silver clips, silver instruments, silver nitrate and silver foil reduced the incidence of infections (8).
At the turn of the 20th century, metal salts including copper, lead, arsenic, bismuth, antimony, mercury and silver were commonly used to control bacterial and fungal infections (9). Mercury and Silver ions were most effective and provided greatest antibacterial action at a concentration of one part per million (ppm) (10). The term ‘oligodynamic’ coined by the German botanist Karl von Nägeli to describe the ability of micro-organisms to selectively absorb metal ions from dilute solutions (11) was used by pharmacologists at the time to denote high antibiotic efficacy of low concentrations of these metal ions. He was first to recognize that the bactericidal concentrations of silver solutions were related to the amount of free Ag+ within a system (12). Silver proteins of varying strengths were developed ni the early 20th century as an alternative to silver nitrate, although the colloidal form of metallic silver was thought by Dr. Henry Crookes to have profound germicidal action:
“certain metals in a colloidal state exhibit profound germicidal action, but are quite harmless to human beings. There is no microbe known that is not killed by colloidal silver in laboratory tests within six minutes”. (13)
Henry Crookes produced silver colloids which were patented before the outbreak of WW1, and his company Crookes Laboratories eventually became Crookes Healthcare in the 1960′s. In 1971 the successful pharmaceutical business was bought by Boots, which used ‘Crookes’ as a label for marketing brand names such as Nurofen, Strepsils and Optrex. (14)
1. Hersh, A., Chambers, H., Maselli, J., Gonzales, R. “National Trends in Ambulatory Visits and Antibiotic Prescribing for Skin and Soft-Tissue Infections” Archives of Internal Medicine 2008; 168:1585-1591
2. Klein, E., Smith, D., Laxminarayan, R. “Community-Associated Methicillin-Resistant Staphylococcus aureus in Outpatients, United States, 1999-2006.” Emerging Infectious Diseases 2009; 15(12): 1925-1930
3. Klein, E., Smith, D., Laxminarayan, R. “Hospitalizations and Deaths Caused by Methicillin-Resistant Staphylococcus aureus, United States, 1999-2005.” Emerging Infectious Diseases2007; 13(12): 1840-1846
4. Lansdown, Alan, B., G,. “Silver in Medical Devices” Silver in Healthcare, Its Antimicrobial Efficacy and Safety in Use, Royal Society of Chemistry Publishing, 2010
5. Torrice, M. Antibacterial Boom and Bust, Chemical and Engineering News, September 2013, The American Chemical Society.
6. Drlica, K, and Perlin, D.S. Antibiotic Resistance, Understanding and Responding to an Emerging Crisis, Pearson Education, 2011.
7. D. G. Brater and W. J. Daly, Clinical Pharmacology in the Middle Ages: principles that presage the 21st century, Clinical Pharmacology and Therapeutics., 2000, 67, 447.
8. A. B. G. Lansdown, Pin and needle tract infections: the prophylactic role of silver, Wounds UK, 2006, 2, 4, 51
9. T. Solleman, Silver, in A Manual of Pharmacology and its Applications to Therapeutics and Toxicology, Saunders, Philadelphia, 1942, pp. 1102-1109
10. B. D. Davis, Principles of sterilization, in Bacterial and Mycotic Infections of Man, ed. R. J. Dubois, Lippincott, Philadelphia, 1952, pp. 707-725.
11. K. W. von Nägeli, Leben die oligodynamischen Erscheinungen an lebenden Zellen,Denkschr. Schweiz. Naturforsch. Ges. 1893, 33, 174
12. R. E. Burrell, A scientific perspective on the use of topical silver preparations, Ostomy Wound Management, 2003, 49 (Suppl.), 19
13. H. Crookes, Use of Colloidal Silver, London, 1910
14. W. H. Brock, Case of the Poisonous Socks, RSC Publishing, 2011