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Vaccination
Vaccination is the administration of antigenic material (a vaccine) to stimulate an individual's immune system to develop adaptive immunity to a pathogen. Vaccines can prevent or ameliorate morbidity from infection. The effectiveness of vaccination has been widely studied and verified; for example, the influenza vaccine, the HPV vaccine, and the chicken pox vaccine. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports licensed vaccines are currently available to prevent, or contribute to the prevention and control of, 25 vaccine-preventable infections.
The active agent of a vaccine may be intact but inactivated (non-infective) or attenuated (with reduced infectivity) forms of the causative pathogens, or purified components of the pathogen that have been found to be highly immunogenic (e.g., outer coat proteins of a virus). Toxoids are produced for immunization against toxin-based diseases, such as the modification of tetanospasmin toxin of tetanus to remove its toxic effect but retain its immunogenic effect.
Smallpox was most likely the first disease people tried to prevent by inoculating themselves and was the first disease for which a vaccine was produced. The smallpox vaccine was designed in 1796 by the British physician Edward Jenner, although at least six people had used the same principles years earlier.[9] Louis Pasteur furthered the concept through his work in microbiology. The immunization was called vaccination because it was derived from a virus affecting cows (Latin: vacca—cow). Smallpox was a contagious and deadly disease, causing the deaths of 20–60% of infected adults and over 80% of infected children. When smallpox was finally eradicated in 1979, it had already killed an estimated 300–500 million people in the 20th century.
In common speech, 'vaccination' and 'immunization' have a similar meaning. This distinguishes it from inoculation, which uses unweakened live pathogens, although in common usage either can refer to an immunization. Vaccination efforts have been met with some controversy on scientific, ethical, political, medical safety, and religious grounds. In rare cases, vaccinations can injure people and, in the United States, they may receive compensation for those injuries under the National Vaccine Injury Compensation Program. Early success and compulsion brought widespread acceptance, and mass vaccination campaigns have greatly reduced the incidence of many diseases in numerous geographic regions.
Bacterial Resistance to Antibiotics
Bacterial Resistance to Antibiotics (page 1)
(This chapter has 4 pages)
Introduction
In the past 60 years, antibiotics have been critical in the fight against infectious disease caused by bacteria and other microbes. Antimicrobial chemotherapy has been a leading cause for the dramatic rise of average life expectancy in the Twentieth Century. However, disease-causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. Wound infections, gonorrhea, tuberculosis, pneumonia, septicemia and childhood ear infections are just a few of the diseases that have become hard to treat with antibiotics. One part of the problem is that bacteria and other microbes that cause infections are remarkably resilient and have developed several ways to resist antibiotics and other antimicrobial drugs. Another part of the problem is due to increasing use, and misuse, of existing antibiotics in human and veterinary medicine and in agriculture.
In 1998, in the United States, 80 million prescriptions of antibiotics for human use were filled. This equals 12,500 tons in one year. Animal and agricultural uses of antibiotics are added to human use. Agricultural practices account for over 60% of antibiotic usage in the U.S., so this adds an additional 18,000 tons per year to the antibiotic burden in the environment.
Nowadays, about 70 percent of the bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used for treatment. Some organisms are resistant to all approved antibiotics and can only be treated with experimental and potentially toxic drugs. An alarming increase in resistance of bacteria that cause community acquired infections has also been documented, especially in the staphylococci and pneumococci (Streptococcus pneumoniae), which are prevalent causes of disease and mortality. In a recent study, 25% of bacterial pneumonia cases were shown to be resistant to penicillin, and an additional 25% of cases were resistant to more than one antibiotic.
Microbial development of resistance, as well as economic incentives, has resulted in research and development in the search for new antibiotics in order to maintain a pool of effective drugs at all times. While the development of resistant strains is inevitable, the slack ways that we administer and use antibiotics has greatly exacerbated the process.
Unless antibiotic resistance problems are detected as they emerge, and actions are taken immediately to contain them, society could be faced with previously treatable diseases that have become again untreatable, as in the days before antibiotics were developed.
History of antibiotics and emergence of antibiotic resistance
The first antibiotic, penicillin, was discovered in 1929 by Sir Alexander Fleming, who observed inhibition of staphylococci on an agar plate contaminated by aPenicillium mold. Fleming was searching for potential antibacterial compounds. He noticed that a patch of the mold Penicillium notatum had grown on a plate containing the bacterium Staphylococcus and that around the mold there was a zone where no Staphylococcus could grow. After more research, he was able to show that culture broth of the mold prevented growth of the Staphylococcuseven when diluted up to 800 times. He named the active substance penicillin but was unable to isolate it.
In the center of the plate is a colony of Penicillium notatum, a mold that produces penicillin. After appearance of the mold colony, the plate was overlaid with a bacterial culture of Micrococcus luteus which forms a yellow "lawn" of growth. A zone of inhibition of bacterial growth surrounds the fungal colony where penicillin has diffused into the medium. http://helios.bto.ed.ac.uk/bto/microbes/penicill.htm#Top
While Fleming was working on penicillin, Gerhard Domagk, a German doctor, announced the discovery of a synthetic molecule with antibacterial properties. He named the compound Prontosil, and it became the first of a long series of synthetic antibiotics called sulfonamides or sulfa drugs. Prontosil was introduced to clinical use in the 1930s and was used to combat urinary tract infections, pneumonia and other conditions. While sulfa drugs in many cases are not as effective as natural antibiotics, they are now in widespread use for the treatment of many conditions. Gerhard Domagk was awarded the Nobel prize in 1939 for his discovery of Prontosil.In 1946, penicillin became generally available for treatment of bacterial infections, especially those caused by staphylococci and streptococci. Initially, the antibiotic was effective against all sorts of infections caused by these two Gram-positive bacteria. Penicillin had unbelievable ability to kill these bacterial pathogens without harming the host that harbored them. It is important to note that a significant fraction of all human infections are caused by these two bacteria (i.e., strep throat, pneumonia, scarlet fever, septicemia, skin infections, wound infections, etc.).
In the late 1940s and early 1950s, new antibiotics were introduced, including streptomycin, chloramphenicol and tetracycline, and the age of antibiotic chemotherapy came into full being. These antibiotics were effective against the full array of bacterial pathogens including Gram-positive and Gram-negative bacteria, intracellular parasites, and the tuberculosis bacillus. Synthetic antimicrobial agents such as the "sulfa drugs" (sulfonamides) and anti-tuberculosis drugs, such as para aminosalicylic acid (PAS) and isoniazid (INH), were also brought into wider usage.
The first signs of antibiotic resistance
There has probably been a gene pool in nature for resistance to antibiotic as long as there has been for antibiotic production, for most microbes that are antibiotic producers are resistant to their own antibiotic. In retrospect, it is not surprising that resistance to penicillin in some strains of staphylococci was recognized almost immediately after introduction of the drug in 1946. Likewise, very soon after their introduction in the late 1940s, resistance to streptomycin, chloramphenicol and tetracycline was noted. By 1953, during a Shigella outbreak in Japan, a strain of the dysentery bacillus (Shigella dysenteriae) was isolated which was multiple drug resistant, exhibiting resistance to chloramphenicol, tetracycline, streptomycin and the sulfonamides. Over the years, and continuing into the present almost every known bacterial pathogen has developed resistance to one or more antibiotics in clinical use.
Evidence also began to accumulate that bacteria could pass genes for drug resistance between strains and even between species. For example, antibiotic-resistance genes of staphylococci are carried on plasmids that can be exchanged with Bacillus, Streptococcus and Enterococcus providing the means for acquiring additional genes and gene combinations. Some are carried on transposons, segments of DNA that can exist either in the chromosome or in plasmids. In any case, it is clear that genes for antibiotic resistance can be exchanged between strains and species of bacteria by means of the processes of horizontal gene transmission (HGT).
Multiple drug resistant organisms
Multiple drug resistant organisms are resistant to treatment with several, often unrelated, antimicrobial agents as described above in Shigella. Some of the most important types of multiple drug resistant organisms that have been encountered include:
MRSA - methicillin/oxacillin-resistant Staphylococcus aureus
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases (which are resistant to cephalosporins and monobactams)
PRSP - penicillin-resistant Streptococcus pneumoniae
MRSA and VRE are the most commonly encountered multiple drug resistant organisms in patients residing in non-hospital healthcare facilities, such as nursing homes and other long-term care facilities. PRSP are more common in patients seeking care in outpatient settings such as physicians' offices and clinics, especially in pediatric settings. ESBLs are most often encountered in the hospital (intensive care) setting, but MRSA and VRE also have a significant nosocomial ecology.
Methicillin-Resistant Staph Aureus. MRSA refers to "methicillin-resistantStaphylococcus aureus", which are strains of the bacterium that are resistant to the action of methicillin, and related beta-lactam antibiotics (e.g. penicillin and cephalosporin). MRSA have evolved resistance not only to beta-lactam antibiotics, but to several classes of antibiotics. Some MRSA are resistant to all but one or two antibiotics, notably vancomycin-resistant. But there have been several reports of VRSA (Vancomycin-Resistant Staph Aureus) that are troublesome in the ongoing battle against staph infections.
MRSA are often sub-categorized as Hospital-Associated MRSA (HA-MRSA) or Community-Associated MRSA (CA-MRSA), depending upon the circumstances of acquiring disease. Based on current data, these are distinct strains of the bacterial species.
HA-MRSA occurs most frequently among patients who undergo invasive medical procedures or who have weakened immune systems and are being treated in hospitals and healthcare facilities such as nursing homes and dialysis centers. MRSA in healthcare settings commonly causes serious and potentially life threatening infections, such as bloodstream infections, surgical site infections or pneumonia.
In the case of HA- MRSA, patients who already have an MRSA infection or who carry the bacteria on their bodies but do not have symptoms (colonized) are the most common sources of transmission. The main mode of transmission to other patients is through human hands, especially healthcare workers' hands. Hands may become contaminated with MRSA bacteria by contact with infected or colonized patients. If appropriate hand hygiene such as washing with soap and water or using an alcohol-based hand sanitizer is not performed, the bacteria can be spread when the healthcare worker touches other patients.
MRSA infections that occur in otherwise healthy people who have not been recently (within the past year) hospitalized or had a medical procedure (such as dialysis, surgery, catheters) are categorized as community-associated (CA-MRSA) infections. These infections are usually skin infections, such as abscesses, boils, and other pus-filled lesions.
About 75 percent of CA-MRSA infections are localized to skin and soft tissue and usually can be treated effectively. However, CA-MRSA strains display enhanced virulence, spread more rapidly and cause more severe illness than traditional HA-MRSA infections, and can affect vital organs leading to widespread infection (sepsis), toxic shock syndrome and pneumonia. It is not known why some healthy people develop CA-MRSA skin infections that are treatable whereas others infected with the same strain develop severe, fatal infections.
Studies have shown that rates of CA-MRSA infection are growing fast. One study of children in south Texas found that cases of CA-MRSA had a 14-fold increase between 1999 and 2001.
CA-MRSA skin infections have been identified among certain populations that share close quarters or experience more skin-to-skin contact. Examples are team athletes, military recruits, and prisoners. However, more and more CA-MRSA infections are being seen in the general community as well, especially in certain geographic regions.
Also, CA-MRSA are infecting much younger people. In a study of Minnesotans published in The Journal of the American Medical Association, the average age of people with MRSA in a hospital or healthcare facility was 68. But the average age of a person with CA-MRSA was only 23.
More people in the U.S. now die from MRSA infection than from AIDS. Methicillin-resistant Staphylococcus aureus was responsible for an estimated 94,000 life-threatening infections and 18,650 deaths in 2005, as reported by CDC in the Oct. 17, 2007 issue of The Journal of the American Medical Association. The national estimate is more than double the invasive MRSA prevalence reported five years earlier. That same year, roughly 16,000 people in the U.S. died from AIDS, according to CDC. While most invasive MRSA infections could be traced to a hospital stay or some other health care exposure, about 15% of invasive infections occurred in people with no known health care risk. Two-thirds of the 85% of MRSA infections that could be traced to hospital stays or other health care exposures occurred among people who were no longer hospitalized. People over age 65 were four times more likely than the general population to get an MRSA infection. Incidence rates among blacks were twice that of the general population, and rates were lowest among children over the age of 4 and teens.
ESBL producing strains have been isolated from abscesses, blood, catheter tips, lung, peritoneal fluid, sputum, and throat cultures. They apparently have a world-wide distribution. Rates of isolation vary greatly worldwide and within geographic areas and are rapidly changing over time. In the United States, between 1990 to 1993, a survey of the intensive care units of 400 hospitals recorded an increase from 3.6% to 14.4% in ESBL producing strains ofKlebsiella. In 1994, the CDC reported that 8% of Klebsiella spp from a few large centers produced ESBLs. In Europe, as of 1995, ESBLs occurred in 20%-25% ofKlebsiella ssp from patients in ICUs, although they were found in patients up to 30%-40% frequency in France.
Known risk factors for colonization and/or infection with organisms harboring ESBLs include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially to extended-spectrum beta-lactam antibiotics. Use of extended-spectrum antibiotics exerts a selective pressure for emergence of ESBL producing strains. The resistance plasmids can then be transferred to other bacteria, not necessarily of the same species, conferring resistance to them.
The lower GI tract of colonized patients is the main reservoir of these organisms. Gastrointestinal carriage can persist for months. In some cities in the United States, nursing homes may be an important reservoir of ESBL producing strains. Nursing home patients are more likely to be treated empirically with antibiotics, and thus on admission to a hospital to be more likely to possess an ESBL producing strain. Patient to patient transmission of ESBL producing organisms occurs via the hands of hospital staff. It is known that ESBL producing strains can survive in the hospital environment.
Nosocomial infections in patients occur through the administration of extended spectrum beta-lactam antibiotics or via transmission from other patients via health care workers, who become colonized with resistant strains via exposure to patients or other health care workers. Spread of ESBL producing strains can be minimized by good infection control practices, especially by good hand washing technique.
Bacterial mechanisms of antibiotic resistance
Several mechanisms have evolved in bacteria which confer them with antibiotic resistance. These mechanisms can either chemically modify the antibiotic, render it inactive through physical removal from the cell, or modify target site so that it is not recognized by the antibiotic.
The most common mode is enzymatic inactivation of the antibiotic. An existing cellular enzyme is modified to react with the antibiotic in such a way that it no longer affects the microorganism. An alternative strategy utilized by many bacteria is the alteration of the antibiotic target site. These and other mechanisms are shown in the the figure and accompanying table below.
Three mechanisms of antibiotic resistance in bacteria. Most, but not all, resistance mechanisms are encoded by plasmids, which are potentially transmissible to other bacteria. Clockwise. 12 o'clock: Efflux pumps are high-affinity reverse transport systems located in the membrane that transport the antibiotic out of the cell. This is the mechanism of resistance to tetracycline. 4 o'clock: A specific enzyme modifies the antibiotic in a way that it loses its activity. In the case of streptomycin, the antibiotic is chemically modified so that it will no longer bind to the ribosome to block protein synthesis. 9 o'clock: An enzyme is produced that degrades the antibiotic, thereby inactivating it. For example, the penicillinases are a group of beta-lactamase enzymes that cleave the beta lactam ring of the penicillin molecule.
The acquisition and spread of antibiotic resistance in bacteria
The development of resistance is inevitable following the introduction of a new antibiotic. Initial rates of resistance to new drugs are normally on the order of 1%. However, modern uses of antibiotics have caused a huge increase in the number of resistant bacteria. In fact, within 8-12 years after wide-spread use, strains resistant to multiple drugs become widespread. Multiple drug resistant strains of some bacteria have reached the proportion that virtually no antibiotics are available for treatment.
Antibiotic resistance in bacteria may be an inherent trait of the organism (e.g. a particular type of cell wall structure) that renders it naturally resistant, or it may be acquired by means of mutation in its own DNA or acquisition of resistance-conferring DNA from another source.
Inherent (natural) resistance. Bacteria may be inherently resistant to an antibiotic. For example, an organism lacks a transport system for an antibiotic; or an organism lacks the target of the antibiotic molecule; or, as in the case of Gram-negative bacteria, the cell wall is covered with an outer membrane that establishes a permeability barrier against the antibiotic.
Acquired resistance. Several mechanisms are developed by bacteria in order to acquire resistance to antibiotics. All require either the modification of existing genetic material or the acquisition of new genetic material from another source.
Vertical gene transfer
The spontaneous mutation frequency for antibiotic resistance is on the order of about of about 10-8- 10-9. This means that one in every every 108- 109 bacteria in an infection will develop resistance through the process of mutation. In E. coli, it has been estimated that streptomycin resistance is acquired at a rate of approximately 10-9 when exposed to high concentrations of streptomycin. Although mutation is a very rare event, the very fast growth rate of bacteria and the absolute number of cells attained means that it doesn't take long before resistance is developed in a population.
Once the resistance genes have developed, they are transferred directly to all the bacteria's progeny during DNA replication. This is known as vertical gene transfer or vertical evolution. The process is strictly a matter of Darwinian evolution driven by principles of natural selection: a spontaneous mutation in the bacterial chromosome imparts resistance to a member of the bacterial population. In the selective environment of the antibiotic, the wild type (non mutants) are killed and the resistant mutant is allowed to grow and flourish
Horizontal gene transfer
Another mechanism beyond spontaneous mutation is responsible for the acquisition of antibiotic resistance. Lateral or horizontal gene transfer (HGT) is a process whereby genetic material contained in small packets of DNA can be transferred between individual bacteria of the same species or even between different species.
Mechanisms of horizontal gene transfer (HGT) in bacteria
The combined effects of fast growth rates to large densities of cells, genetic processes of mutation and selection, and the ability to exchange genes, account for the extraordinary rates of adaptation and evolution that can be observed in the bacteria. For these reasons bacterial adaptation (resistance) to the antibiotic environment seems to take place very rapidly in evolutionary time. Bacteria evolve fast!
Tests for sensitivity and resistance to antibiotics. (Left) The size of the zones of inhibition of microbial growth surrounding the antibiotic disks on the plate are an indication of microbial susceptibility to the antibiotic. (Right) By the use of these disks it is also possible to detect the occurrence of individual mutants within the culture that have developed antibiotic resistance. This image shows a close-up of the novobiocin disk (marked by an arrow on the whole plate) near which individual mutant cells in the bacterial population that were resistant to the antibiotic and have given rise to small colonies within the zone of inhibition.
Societal, medical and agricultural practices that lead to antibiotic resistance
In the face of a microbe's inherent ability to develop antibiotic resistance, many societal. medical and agricultural practices contribute to this process, foremost of which are discussed below.
Antibiotics in food and water
Prescription drugs are not the only source of antibiotics in the environment. In the United States, antibiotics can be found in beef cattle, pigs and poultry. The same antibiotics then find their way into municipal water systems when the runoff from housing facilities and feedlots contaminates streams and groundwater. So it's a double hit: we get antibiotics in our food and drinking water, and we meanwhile promote bacterial resistance. Routine feeding of antibiotics to animals is banned in the European Union and many other industrialized countries. Maybe they know something we don't.
Indiscriminate use of antibiotics in agriculture and veterinary practice
The non-therapeutic use of antibiotics in livestock production makes up at least 60 percent of the total antimicrobial production in the United States. Irresponsible use of antibiotics in farm animals can lead to the development of resistance in bacteria associated with the animal or with people who eat the animal. Such resistance can then be passed on to human pathogens by mechanisms of HGT.
Of major concern is the use of antibiotics as feed additives given to farm animals to promote animal growth and to prevent infections (rather than cure infections). The use of an antibiotic in this way contributes to the emergence of antibiotic-resistant pathogens and reduces the effectiveness of the antibiotic to combat human infections.
Antibiotic resistance in genetically modified crops
Antibiotic-resistance genes are used as "markers" in genetically modified crops. The genes are inserted into the plant in early stages of development to in order to detect specific genes of interest . e.g. herbicide-resistant genes or insecticidal toxin genes. The antibiotic-resistance genes have no further role to play, but they are not removed from the final product. This practice has met with criticism because of the potential that the antibiotic-resistance genes could be acquired by microbes in the environment. In some cases these marker genes confer resistance to front-line antibiotics such as the beta-lactams and aminoglycosides.
Inappropriate use of antibiotics in the medical environment
One problem is the casual use of antibiotics in medical situations where they are of no value. This is the fault of both health care workers and patients. Prescribers sometimes thoughtlessly prescribe 'informed' demanding patients with antibiotics. This leads to use of antibiotics in circumstances where they are of not needed, e.g. viral upper respiratory infections such as cold and flu, except when there is serious threat of secondary bacterial infection. Another problem is patient failure to adhere to regimens for prescribed antibiotics.
Patients and doctors need to realize their responsibility when they begin an antibiotic regimen to combat an infectious disease. There are several measures that should be considered.
� Patients should not take antibiotics for which there is no medical value (corollary: doctors should not prescribe antibiotics for which there is no medical value).
� Patients should adhere to appropriate prescribing guidelines and take antibiotics until they have finished.
� Patients should be give combinations of antibiotics, when necessary, to minimize the development of resistance to a single antibiotic (as in the case of TB).
� Patients need to be given another antibiotic or combination of antibiotics if the first is not working.
Combating antibiotic resistance
The following are recommendations to combat the development of antibiotic resistance in bacteria and other microorganisms.
Search for new antibiotics. To combat the occurrence of resistant bacteria, biotechnology and pharmaceutical companies must constantly research, develop and test new antimicrobials in order to maintain a pool of effective drugs on the market.
Stop the use of antibiotics as growth-promoting substances in farm animals. Of major concern is the use of antibiotics as feed additives given to farm animals to promote animal growth and to prevent infections rather than cure infections. The use of such antibiotics contributes to the emergence of antibiotic-resistant bacteria that threaten human health and decreases the effectiveness of the same antibiotics used to combat human infections.
Use the right antibiotic in an infectious situation as determined by antibiotic sensitivity testing, when possible.
Large scale public health education efforts are underway to stress the importance of finishing prescriptions. Indeed, in many places, failure to finish tuberculosis prescriptions can result in jail time.
Summary
The discovery of antibiotics was a leap in modern medicine. They have been able to stop the growth or kill many different kinds of microorganisms. However, bacteria have proven to be much more innovative and adaptive than we imagined and have developed resistance to antibiotics at an ever increasing pace. Bad practices and mismanagement have only exacerbated the situation. We could soon return to a state of medical health that was as dire as that which occurred prior to antibiotic use. However, with more research, education of the public, and well thought out regulations, the problems
can be solved. Several strategies are currently used to find new antibacterial compounds and new strategies are in development and trial.
Not only is there a problem in finding new antibiotics to fight old diseases (because resistant strains of bacteria have emerged), there is a parallel problem to find new antibiotics to fight new diseases. In the past three decades, many "new" bacterial diseases have been discovered (E. coli O157:H7 gastric ulcers, Lyme disease, toxic shock syndrome, "skin-eating" streptococci). Already broad patterns of resistance exist in these pathogens, and it seems likely that we will soon need new antibiotics to replace the handful that are effective now against these bacteria, especially as resistance begins to emerge among them in the selective environment antibiotic chemotherapy.
It is said that the discovery and use of antibiotics and immunization procedures against infectious disease are two developments in the field of microbiology that have contributed about twenty years to the average life span of humans in developed countries where these practices are employed. While the greater part of this span in time is probably due to vaccination, most of us are either still alive or have family members or friends who are still alive because an antibiotic conquered an infection that otherwise would have killed them. If we want to retain this medical luxury in our society we must be vigilant and proactive We must fully understand how and why antimicrobial agents work, and why they don't work, and realize that we must maintain a stride ahead of microbial pathogens that can only be contained by antibiotic chemotherapy.
END OF CHAPTER
(This chapter has 4 pages)
Introduction
In the past 60 years, antibiotics have been critical in the fight against infectious disease caused by bacteria and other microbes. Antimicrobial chemotherapy has been a leading cause for the dramatic rise of average life expectancy in the Twentieth Century. However, disease-causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. Wound infections, gonorrhea, tuberculosis, pneumonia, septicemia and childhood ear infections are just a few of the diseases that have become hard to treat with antibiotics. One part of the problem is that bacteria and other microbes that cause infections are remarkably resilient and have developed several ways to resist antibiotics and other antimicrobial drugs. Another part of the problem is due to increasing use, and misuse, of existing antibiotics in human and veterinary medicine and in agriculture.
In 1998, in the United States, 80 million prescriptions of antibiotics for human use were filled. This equals 12,500 tons in one year. Animal and agricultural uses of antibiotics are added to human use. Agricultural practices account for over 60% of antibiotic usage in the U.S., so this adds an additional 18,000 tons per year to the antibiotic burden in the environment.
Nowadays, about 70 percent of the bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used for treatment. Some organisms are resistant to all approved antibiotics and can only be treated with experimental and potentially toxic drugs. An alarming increase in resistance of bacteria that cause community acquired infections has also been documented, especially in the staphylococci and pneumococci (Streptococcus pneumoniae), which are prevalent causes of disease and mortality. In a recent study, 25% of bacterial pneumonia cases were shown to be resistant to penicillin, and an additional 25% of cases were resistant to more than one antibiotic.
Microbial development of resistance, as well as economic incentives, has resulted in research and development in the search for new antibiotics in order to maintain a pool of effective drugs at all times. While the development of resistant strains is inevitable, the slack ways that we administer and use antibiotics has greatly exacerbated the process.
Unless antibiotic resistance problems are detected as they emerge, and actions are taken immediately to contain them, society could be faced with previously treatable diseases that have become again untreatable, as in the days before antibiotics were developed.
History of antibiotics and emergence of antibiotic resistance
The first antibiotic, penicillin, was discovered in 1929 by Sir Alexander Fleming, who observed inhibition of staphylococci on an agar plate contaminated by aPenicillium mold. Fleming was searching for potential antibacterial compounds. He noticed that a patch of the mold Penicillium notatum had grown on a plate containing the bacterium Staphylococcus and that around the mold there was a zone where no Staphylococcus could grow. After more research, he was able to show that culture broth of the mold prevented growth of the Staphylococcuseven when diluted up to 800 times. He named the active substance penicillin but was unable to isolate it.
In the center of the plate is a colony of Penicillium notatum, a mold that produces penicillin. After appearance of the mold colony, the plate was overlaid with a bacterial culture of Micrococcus luteus which forms a yellow "lawn" of growth. A zone of inhibition of bacterial growth surrounds the fungal colony where penicillin has diffused into the medium. http://helios.bto.ed.ac.uk/bto/microbes/penicill.htm#Top
Several years later, in 1939, Ernst Chain and Howard Florey developed a way to isolate penicillin and used it to treat bacterial infections during the Second World War. The new drug came into clinical usage in 1946 and made a huge impact on public health. For these discoveries Fleming, Chain and Florey were awarded the Nobel prize in 1945. Their discovery and development revolutionized modern medicine and paved the way for the development of many more natural antibiotics.
While Fleming was working on penicillin, Gerhard Domagk, a German doctor, announced the discovery of a synthetic molecule with antibacterial properties. He named the compound Prontosil, and it became the first of a long series of synthetic antibiotics called sulfonamides or sulfa drugs. Prontosil was introduced to clinical use in the 1930s and was used to combat urinary tract infections, pneumonia and other conditions. While sulfa drugs in many cases are not as effective as natural antibiotics, they are now in widespread use for the treatment of many conditions. Gerhard Domagk was awarded the Nobel prize in 1939 for his discovery of Prontosil.
In the late 1940s and early 1950s, new antibiotics were introduced, including streptomycin, chloramphenicol and tetracycline, and the age of antibiotic chemotherapy came into full being. These antibiotics were effective against the full array of bacterial pathogens including Gram-positive and Gram-negative bacteria, intracellular parasites, and the tuberculosis bacillus. Synthetic antimicrobial agents such as the "sulfa drugs" (sulfonamides) and anti-tuberculosis drugs, such as para aminosalicylic acid (PAS) and isoniazid (INH), were also brought into wider usage.
The first signs of antibiotic resistance
There has probably been a gene pool in nature for resistance to antibiotic as long as there has been for antibiotic production, for most microbes that are antibiotic producers are resistant to their own antibiotic. In retrospect, it is not surprising that resistance to penicillin in some strains of staphylococci was recognized almost immediately after introduction of the drug in 1946. Likewise, very soon after their introduction in the late 1940s, resistance to streptomycin, chloramphenicol and tetracycline was noted. By 1953, during a Shigella outbreak in Japan, a strain of the dysentery bacillus (Shigella dysenteriae) was isolated which was multiple drug resistant, exhibiting resistance to chloramphenicol, tetracycline, streptomycin and the sulfonamides. Over the years, and continuing into the present almost every known bacterial pathogen has developed resistance to one or more antibiotics in clinical use.
Evidence also began to accumulate that bacteria could pass genes for drug resistance between strains and even between species. For example, antibiotic-resistance genes of staphylococci are carried on plasmids that can be exchanged with Bacillus, Streptococcus and Enterococcus providing the means for acquiring additional genes and gene combinations. Some are carried on transposons, segments of DNA that can exist either in the chromosome or in plasmids. In any case, it is clear that genes for antibiotic resistance can be exchanged between strains and species of bacteria by means of the processes of horizontal gene transmission (HGT).
Multiple drug resistant organisms
Multiple drug resistant organisms are resistant to treatment with several, often unrelated, antimicrobial agents as described above in Shigella. Some of the most important types of multiple drug resistant organisms that have been encountered include:
MRSA - methicillin/oxacillin-resistant Staphylococcus aureus
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases (which are resistant to cephalosporins and monobactams)
PRSP - penicillin-resistant Streptococcus pneumoniae
MRSA and VRE are the most commonly encountered multiple drug resistant organisms in patients residing in non-hospital healthcare facilities, such as nursing homes and other long-term care facilities. PRSP are more common in patients seeking care in outpatient settings such as physicians' offices and clinics, especially in pediatric settings. ESBLs are most often encountered in the hospital (intensive care) setting, but MRSA and VRE also have a significant nosocomial ecology.
Methicillin-Resistant Staph Aureus. MRSA refers to "methicillin-resistantStaphylococcus aureus", which are strains of the bacterium that are resistant to the action of methicillin, and related beta-lactam antibiotics (e.g. penicillin and cephalosporin). MRSA have evolved resistance not only to beta-lactam antibiotics, but to several classes of antibiotics. Some MRSA are resistant to all but one or two antibiotics, notably vancomycin-resistant. But there have been several reports of VRSA (Vancomycin-Resistant Staph Aureus) that are troublesome in the ongoing battle against staph infections.
MRSA are often sub-categorized as Hospital-Associated MRSA (HA-MRSA) or Community-Associated MRSA (CA-MRSA), depending upon the circumstances of acquiring disease. Based on current data, these are distinct strains of the bacterial species.
HA-MRSA occurs most frequently among patients who undergo invasive medical procedures or who have weakened immune systems and are being treated in hospitals and healthcare facilities such as nursing homes and dialysis centers. MRSA in healthcare settings commonly causes serious and potentially life threatening infections, such as bloodstream infections, surgical site infections or pneumonia.
In the case of HA- MRSA, patients who already have an MRSA infection or who carry the bacteria on their bodies but do not have symptoms (colonized) are the most common sources of transmission. The main mode of transmission to other patients is through human hands, especially healthcare workers' hands. Hands may become contaminated with MRSA bacteria by contact with infected or colonized patients. If appropriate hand hygiene such as washing with soap and water or using an alcohol-based hand sanitizer is not performed, the bacteria can be spread when the healthcare worker touches other patients.
MRSA infections that occur in otherwise healthy people who have not been recently (within the past year) hospitalized or had a medical procedure (such as dialysis, surgery, catheters) are categorized as community-associated (CA-MRSA) infections. These infections are usually skin infections, such as abscesses, boils, and other pus-filled lesions.
About 75 percent of CA-MRSA infections are localized to skin and soft tissue and usually can be treated effectively. However, CA-MRSA strains display enhanced virulence, spread more rapidly and cause more severe illness than traditional HA-MRSA infections, and can affect vital organs leading to widespread infection (sepsis), toxic shock syndrome and pneumonia. It is not known why some healthy people develop CA-MRSA skin infections that are treatable whereas others infected with the same strain develop severe, fatal infections.
Studies have shown that rates of CA-MRSA infection are growing fast. One study of children in south Texas found that cases of CA-MRSA had a 14-fold increase between 1999 and 2001.
CA-MRSA skin infections have been identified among certain populations that share close quarters or experience more skin-to-skin contact. Examples are team athletes, military recruits, and prisoners. However, more and more CA-MRSA infections are being seen in the general community as well, especially in certain geographic regions.
Also, CA-MRSA are infecting much younger people. In a study of Minnesotans published in The Journal of the American Medical Association, the average age of people with MRSA in a hospital or healthcare facility was 68. But the average age of a person with CA-MRSA was only 23.
More people in the U.S. now die from MRSA infection than from AIDS. Methicillin-resistant Staphylococcus aureus was responsible for an estimated 94,000 life-threatening infections and 18,650 deaths in 2005, as reported by CDC in the Oct. 17, 2007 issue of The Journal of the American Medical Association. The national estimate is more than double the invasive MRSA prevalence reported five years earlier. That same year, roughly 16,000 people in the U.S. died from AIDS, according to CDC. While most invasive MRSA infections could be traced to a hospital stay or some other health care exposure, about 15% of invasive infections occurred in people with no known health care risk. Two-thirds of the 85% of MRSA infections that could be traced to hospital stays or other health care exposures occurred among people who were no longer hospitalized. People over age 65 were four times more likely than the general population to get an MRSA infection. Incidence rates among blacks were twice that of the general population, and rates were lowest among children over the age of 4 and teens.
Extended-Spectrum beta-lactamase (ESBL) - producing Gram-negative bacteria Extended-spectrum beta-lactamases (ESBLs) are plasmid-associated beta lactamases that have recently been found in the Enterobacteriaceae. ESBLs are capable of hydrolyzing penicillins, many narrow spectrum cephalosporins, many extended-spectrum cephalosporins, oxyimino-cephalosporins (cefotaxime, ceftazidime), and monobactams (aztreonam). Beta-lactamase inhibitors (e.g. clavulanic acid) generally inhibit ESBL producing strains. ESBL producing isolates are most commonly Klebsiella ssp, predominantly Klebsiella pneumoniae, and E. coli, but they have been found throughout the Enterobacteriaeae.
Because ESBL enzymes are plasmid mediated, the genes encoding these enzymes are easily transferable among different bacteria. Most of these plasmids not only contain DNA encoding ESBL enzymes but also carry genes conferring resistance to several non-ß-Lactam antibiotics. Consequently, most ESBL isolates are resistant to many classes of antibiotics. The most frequent coresistances found in ESBL-producing organisms are aminoglycosides, fluoroquinolones, tetracyclines, chloramphenicol, and sulfamethoxazole-trimethoprim. Treatment of these multiple drug-resistant organisms is a therapeutic challenge.ESBL producing strains have been isolated from abscesses, blood, catheter tips, lung, peritoneal fluid, sputum, and throat cultures. They apparently have a world-wide distribution. Rates of isolation vary greatly worldwide and within geographic areas and are rapidly changing over time. In the United States, between 1990 to 1993, a survey of the intensive care units of 400 hospitals recorded an increase from 3.6% to 14.4% in ESBL producing strains ofKlebsiella. In 1994, the CDC reported that 8% of Klebsiella spp from a few large centers produced ESBLs. In Europe, as of 1995, ESBLs occurred in 20%-25% ofKlebsiella ssp from patients in ICUs, although they were found in patients up to 30%-40% frequency in France.
Known risk factors for colonization and/or infection with organisms harboring ESBLs include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially to extended-spectrum beta-lactam antibiotics. Use of extended-spectrum antibiotics exerts a selective pressure for emergence of ESBL producing strains. The resistance plasmids can then be transferred to other bacteria, not necessarily of the same species, conferring resistance to them.
The lower GI tract of colonized patients is the main reservoir of these organisms. Gastrointestinal carriage can persist for months. In some cities in the United States, nursing homes may be an important reservoir of ESBL producing strains. Nursing home patients are more likely to be treated empirically with antibiotics, and thus on admission to a hospital to be more likely to possess an ESBL producing strain. Patient to patient transmission of ESBL producing organisms occurs via the hands of hospital staff. It is known that ESBL producing strains can survive in the hospital environment.
Nosocomial infections in patients occur through the administration of extended spectrum beta-lactam antibiotics or via transmission from other patients via health care workers, who become colonized with resistant strains via exposure to patients or other health care workers. Spread of ESBL producing strains can be minimized by good infection control practices, especially by good hand washing technique.
Bacterial mechanisms of antibiotic resistance
Several mechanisms have evolved in bacteria which confer them with antibiotic resistance. These mechanisms can either chemically modify the antibiotic, render it inactive through physical removal from the cell, or modify target site so that it is not recognized by the antibiotic.
The most common mode is enzymatic inactivation of the antibiotic. An existing cellular enzyme is modified to react with the antibiotic in such a way that it no longer affects the microorganism. An alternative strategy utilized by many bacteria is the alteration of the antibiotic target site. These and other mechanisms are shown in the the figure and accompanying table below.
Three mechanisms of antibiotic resistance in bacteria. Most, but not all, resistance mechanisms are encoded by plasmids, which are potentially transmissible to other bacteria. Clockwise. 12 o'clock: Efflux pumps are high-affinity reverse transport systems located in the membrane that transport the antibiotic out of the cell. This is the mechanism of resistance to tetracycline. 4 o'clock: A specific enzyme modifies the antibiotic in a way that it loses its activity. In the case of streptomycin, the antibiotic is chemically modified so that it will no longer bind to the ribosome to block protein synthesis. 9 o'clock: An enzyme is produced that degrades the antibiotic, thereby inactivating it. For example, the penicillinases are a group of beta-lactamase enzymes that cleave the beta lactam ring of the penicillin molecule.
| Antibiotic | Method of resistance | ||
| Chloramphenicol | reduced uptake into cell | ||
| Tetracycline | active efflux from the cell | ||
| β-lactams, Erythromycin, Lincomycin | eliminates or reduces binding of antibiotic to cell target | ||
| β-lactams, Aminoglycosides, Chloramphenicol | enzymatic cleavage or modification to inactivate antibiotic molecule | ||
| Sulfonamides, Trimethoprim | metabolic bypass of inhibited reaction | ||
| Sulfonamides, Trimethoprim | overproduction of antibiotic target (titration) | ||
The acquisition and spread of antibiotic resistance in bacteria
The development of resistance is inevitable following the introduction of a new antibiotic. Initial rates of resistance to new drugs are normally on the order of 1%. However, modern uses of antibiotics have caused a huge increase in the number of resistant bacteria. In fact, within 8-12 years after wide-spread use, strains resistant to multiple drugs become widespread. Multiple drug resistant strains of some bacteria have reached the proportion that virtually no antibiotics are available for treatment.
Antibiotic resistance in bacteria may be an inherent trait of the organism (e.g. a particular type of cell wall structure) that renders it naturally resistant, or it may be acquired by means of mutation in its own DNA or acquisition of resistance-conferring DNA from another source.
Inherent (natural) resistance. Bacteria may be inherently resistant to an antibiotic. For example, an organism lacks a transport system for an antibiotic; or an organism lacks the target of the antibiotic molecule; or, as in the case of Gram-negative bacteria, the cell wall is covered with an outer membrane that establishes a permeability barrier against the antibiotic.
Acquired resistance. Several mechanisms are developed by bacteria in order to acquire resistance to antibiotics. All require either the modification of existing genetic material or the acquisition of new genetic material from another source.
Vertical gene transfer
The spontaneous mutation frequency for antibiotic resistance is on the order of about of about 10-8- 10-9. This means that one in every every 108- 109 bacteria in an infection will develop resistance through the process of mutation. In E. coli, it has been estimated that streptomycin resistance is acquired at a rate of approximately 10-9 when exposed to high concentrations of streptomycin. Although mutation is a very rare event, the very fast growth rate of bacteria and the absolute number of cells attained means that it doesn't take long before resistance is developed in a population.
Once the resistance genes have developed, they are transferred directly to all the bacteria's progeny during DNA replication. This is known as vertical gene transfer or vertical evolution. The process is strictly a matter of Darwinian evolution driven by principles of natural selection: a spontaneous mutation in the bacterial chromosome imparts resistance to a member of the bacterial population. In the selective environment of the antibiotic, the wild type (non mutants) are killed and the resistant mutant is allowed to grow and flourish
Horizontal gene transfer
Another mechanism beyond spontaneous mutation is responsible for the acquisition of antibiotic resistance. Lateral or horizontal gene transfer (HGT) is a process whereby genetic material contained in small packets of DNA can be transferred between individual bacteria of the same species or even between different species.
There are at least three possible mechanisms of HGT, equivalent to the three processes of genetic exchange in bacteria. These are transduction, transformation or conjugation.
Conjugation occurs when there is direct cell-cell contact between two bacteria (which need not be closely related) and transfer of small pieces of DNA called plasmids takes place. This is thought to be the main mechanism of HGT.Transformation is a process where parts of DNA are taken up by the bacteria from the external environment. This DNA is normally present in the external environment due to the death and lysis of another bacterium.
Transduction occurs when bacteria-specific viruses (bacteriophages) transfer DNA between two closely related bacteria.
Mechanisms of horizontal gene transfer (HGT) in bacteria
The combined effects of fast growth rates to large densities of cells, genetic processes of mutation and selection, and the ability to exchange genes, account for the extraordinary rates of adaptation and evolution that can be observed in the bacteria. For these reasons bacterial adaptation (resistance) to the antibiotic environment seems to take place very rapidly in evolutionary time. Bacteria evolve fast!
Tests for sensitivity and resistance to antibiotics. (Left) The size of the zones of inhibition of microbial growth surrounding the antibiotic disks on the plate are an indication of microbial susceptibility to the antibiotic. (Right) By the use of these disks it is also possible to detect the occurrence of individual mutants within the culture that have developed antibiotic resistance. This image shows a close-up of the novobiocin disk (marked by an arrow on the whole plate) near which individual mutant cells in the bacterial population that were resistant to the antibiotic and have given rise to small colonies within the zone of inhibition.
Societal, medical and agricultural practices that lead to antibiotic resistance
In the face of a microbe's inherent ability to develop antibiotic resistance, many societal. medical and agricultural practices contribute to this process, foremost of which are discussed below.
Antibiotics in food and water
Prescription drugs are not the only source of antibiotics in the environment. In the United States, antibiotics can be found in beef cattle, pigs and poultry. The same antibiotics then find their way into municipal water systems when the runoff from housing facilities and feedlots contaminates streams and groundwater. So it's a double hit: we get antibiotics in our food and drinking water, and we meanwhile promote bacterial resistance. Routine feeding of antibiotics to animals is banned in the European Union and many other industrialized countries. Maybe they know something we don't.
Indiscriminate use of antibiotics in agriculture and veterinary practice
The non-therapeutic use of antibiotics in livestock production makes up at least 60 percent of the total antimicrobial production in the United States. Irresponsible use of antibiotics in farm animals can lead to the development of resistance in bacteria associated with the animal or with people who eat the animal. Such resistance can then be passed on to human pathogens by mechanisms of HGT.
Of major concern is the use of antibiotics as feed additives given to farm animals to promote animal growth and to prevent infections (rather than cure infections). The use of an antibiotic in this way contributes to the emergence of antibiotic-resistant pathogens and reduces the effectiveness of the antibiotic to combat human infections.
Antibiotic resistance in genetically modified crops
Antibiotic-resistance genes are used as "markers" in genetically modified crops. The genes are inserted into the plant in early stages of development to in order to detect specific genes of interest . e.g. herbicide-resistant genes or insecticidal toxin genes. The antibiotic-resistance genes have no further role to play, but they are not removed from the final product. This practice has met with criticism because of the potential that the antibiotic-resistance genes could be acquired by microbes in the environment. In some cases these marker genes confer resistance to front-line antibiotics such as the beta-lactams and aminoglycosides.
Inappropriate use of antibiotics in the medical environment
One problem is the casual use of antibiotics in medical situations where they are of no value. This is the fault of both health care workers and patients. Prescribers sometimes thoughtlessly prescribe 'informed' demanding patients with antibiotics. This leads to use of antibiotics in circumstances where they are of not needed, e.g. viral upper respiratory infections such as cold and flu, except when there is serious threat of secondary bacterial infection. Another problem is patient failure to adhere to regimens for prescribed antibiotics.
Patients and doctors need to realize their responsibility when they begin an antibiotic regimen to combat an infectious disease. There are several measures that should be considered.
� Patients should not take antibiotics for which there is no medical value (corollary: doctors should not prescribe antibiotics for which there is no medical value).
� Patients should adhere to appropriate prescribing guidelines and take antibiotics until they have finished.
� Patients should be give combinations of antibiotics, when necessary, to minimize the development of resistance to a single antibiotic (as in the case of TB).
� Patients need to be given another antibiotic or combination of antibiotics if the first is not working.
Combating antibiotic resistance
The following are recommendations to combat the development of antibiotic resistance in bacteria and other microorganisms.
Search for new antibiotics. To combat the occurrence of resistant bacteria, biotechnology and pharmaceutical companies must constantly research, develop and test new antimicrobials in order to maintain a pool of effective drugs on the market.
Stop the use of antibiotics as growth-promoting substances in farm animals. Of major concern is the use of antibiotics as feed additives given to farm animals to promote animal growth and to prevent infections rather than cure infections. The use of such antibiotics contributes to the emergence of antibiotic-resistant bacteria that threaten human health and decreases the effectiveness of the same antibiotics used to combat human infections.
Use the right antibiotic in an infectious situation as determined by antibiotic sensitivity testing, when possible.
Stop unnecessary antibiotic prescriptions. Unnecessary antibiotic prescriptions have been identified as causes for an enhanced rate of resistance development. Unnecessary prescriptions of antibiotics are made when antibiotics are prescribed for viral infections (antibiotics have no effect on viruses). This gives the opportunity for indigenous bacteria (normal flora) to acquire resistance that can be passed on to pathogens.
Finish antibiotic prescriptions. Unfinished antibiotic prescriptions may leave some bacteria alive or may expose them to sub-inhibitory concentrations of antibiotics for a prolonged period of time. Mycobacterium tuberculosis is a slow growing bacteria which infects the lung and causes tuberculosis. This disease kills more adults than any other infectious disease. Due to the slow growing nature of the infection, treatment programs last for months or even years. This has led to many cases on unfinished prescriptions and 5% of strains now observed are completely resistant to all known treatments and hence incurable.
Several other possible solutions have been proposed or implemented to combat antibiotic resistance.
In the pharmaceutical industry, past and current strategies to combat resistance have not been effective. Pharmaceutical companies are seeking new, less costly strategies to develop antibiotics.
A decrease in the number of prescriptions for antibiotics, especially in small children, is occurring.
Several countries such as the UK have regulations concerning the use of antibiotics in animal feed.Several other possible solutions have been proposed or implemented to combat antibiotic resistance.
In the pharmaceutical industry, past and current strategies to combat resistance have not been effective. Pharmaceutical companies are seeking new, less costly strategies to develop antibiotics.
A decrease in the number of prescriptions for antibiotics, especially in small children, is occurring.
Large scale public health education efforts are underway to stress the importance of finishing prescriptions. Indeed, in many places, failure to finish tuberculosis prescriptions can result in jail time.
Summary
The discovery of antibiotics was a leap in modern medicine. They have been able to stop the growth or kill many different kinds of microorganisms. However, bacteria have proven to be much more innovative and adaptive than we imagined and have developed resistance to antibiotics at an ever increasing pace. Bad practices and mismanagement have only exacerbated the situation. We could soon return to a state of medical health that was as dire as that which occurred prior to antibiotic use. However, with more research, education of the public, and well thought out regulations, the problems
can be solved. Several strategies are currently used to find new antibacterial compounds and new strategies are in development and trial.
Not only is there a problem in finding new antibiotics to fight old diseases (because resistant strains of bacteria have emerged), there is a parallel problem to find new antibiotics to fight new diseases. In the past three decades, many "new" bacterial diseases have been discovered (E. coli O157:H7 gastric ulcers, Lyme disease, toxic shock syndrome, "skin-eating" streptococci). Already broad patterns of resistance exist in these pathogens, and it seems likely that we will soon need new antibiotics to replace the handful that are effective now against these bacteria, especially as resistance begins to emerge among them in the selective environment antibiotic chemotherapy.
It is said that the discovery and use of antibiotics and immunization procedures against infectious disease are two developments in the field of microbiology that have contributed about twenty years to the average life span of humans in developed countries where these practices are employed. While the greater part of this span in time is probably due to vaccination, most of us are either still alive or have family members or friends who are still alive because an antibiotic conquered an infection that otherwise would have killed them. If we want to retain this medical luxury in our society we must be vigilant and proactive We must fully understand how and why antimicrobial agents work, and why they don't work, and realize that we must maintain a stride ahead of microbial pathogens that can only be contained by antibiotic chemotherapy.
END OF CHAPTER
Tag :
ANTIBIOTICS & MECHANISM,
INSTANT NOTES,
Antimicrobial Agents in the Treatment of Infectious Disease
Antimicrobial Agents in the Treatment of Infectious Disease
(page 1)
Introduction
Most microbiologists distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. A hybrid substance is a semisynthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. Furthermore, some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means. In the medical and parmaceutical worlds, all these antimicrobial agents used in the treatment of disease are referred to as antibiotics, interpreting the word literally.
The modern era of antimicrobial chemotherapy began in 1929, with Fleming's discovery of the powerful bactericidal substance, penicillin, and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity.
In the early 1940's, spurred partially by the need for antibacterial agents in WW II, penicillin was isolated and purified and injected into experimental animals, where it was found not only to cure infections but also to possess incredibly low toxicity for the animals. This fact ushered into being the age of antibiotic chemotherapy, and an intense search for similar antimicrobial agents of low toxicity to animals that might prove useful in the treatment of infectious disease. The rapid isolation of streptomycin, chloramphenicol and tetracycline soon followed, and by the 1950's, these and several other antibiotics were in clinical usage.
Microorganisms that Produce Antibiotics
The bacterial colonies at 10 o'clock, 2 o'clock and 8 o'clock on this agar plate are producing antibiotics that inhibit encroachment by the mold which is growing out from the center.
Most of the natural antibiotics that are being used in agriculture and medicine are produced by three unrelated groups of microbes, including eucaryotic molds and two types of spore-forming bacteria. However, many culturable, and some non culturable microbes, have been shown to produce various substances that inhibit other organisms that grow in their space. If we consider antibiotics as secondary metabolites of microbes, it narrows the field to the handful of microbes discussed below.
1. Penicillium and Cephalosporium molds produce beta-lactam antibiotics such as penicillin and cephalosporin and their relatives. They also produce the base molecule for development of semisynthetic beta-lactam antibiotics, such as amoxacillin and ampicillin. Beta-lactams are used to treat about one-third of outpatients with bacterial infections.
The natural habitat of molds is soil. And although sex is sometimes involved, they reproduce by spore formation. They are foremost in their abilities to degrade organic matter, and they play their most important role in natures in biodegradation and the carbon cycle. Most of us know that molds will grow on nearly anything that is organic and moist, so they are also responsible for a lot food spoilage as well as decomposition of our structural materials and textiles. "Nothing is forever", with molds around.
Three colonies of a Penicillium mold growing on an agar medium. The green fuzzy appearance is the asexual spores of the fungus.
2. Actinomycetes, mainly Streptomyces species, produce tetracyclines, aminoglycosides (streptomycin and its relatives), macrolides (erythromycin and its relatives), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Actinomycetes are the mainstay of the antibiotics industry.
Actinomycetes are a group of branched bacteria that reproduce by spore formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed in Order Actinomycetales. Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia, Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are inhabitants of the soil. The characteristic odor of damp soil is due to the production of substances, called geosmins, by these bacteria
Two different actinomycetes were spotted in the center of the agar plate about two centimeters apart. This peculiar pattern of growth was observed after a 10-day incubation period. What could be going on? Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the prepared mind."
3. Bacillus species, such as B. polymyxa and B. subtilis, produce polypeptide antibiotics (e.g. polymyxin and bacitracin), and B. cereus produces zwittermicin. Bacillus species have the relatively rare ability to form a type of resting cell called an endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that live in the soil. They play an important ecological role in aerobic decomposition, biodegradation and mineral recycling.
A swirl of Bacillus mycoides colonies growth amidst other bacteria and molds from the soil. The swirls are always counterclockwise, at least in the Northern Hemisphere where I have seen it.
These organisms all have in common that they live in soil and they form some sort of a spore or resting structure. It is not known why these microorganisms produce antibiotics, but the answer may be in the obvious - it affords them some nutritional or spatial advantage in their habitat by antagonizing the competition; or it may be in the subtle - it acts as some sort of hormone or signal molecule associated with sporulation or dormancy or germination. Antibiotics are secondary metabolites and they are produced at the same time that the cells begin their sporulation processes.
Antibiotics tend to be rather large, complicated organic molecules and may require as many as 30 separate enzymatic steps to synthesize. The maintenance of a substantial component of the bacterial genome devoted solely to the synthesis of an antibiotic leads one to conclude that the antibiotic is important, if not essential, to the survival of these organisms in their natural habitat.
Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains. In most cases, how or why bacteria are resistant to their own antibiotics is also unknown, but it may be worth pondering or studying if we are to understand the cellular and molecular basis of drug resistance in pathogens.
Antibiotics must have Selective Toxicity for the Microbe
Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically-useful. The reason for this is that only compounds with selective toxicity can be used clinically.
The selective toxicity of antibiotics means that they must be highly effective against the microbe but have minimal or no toxicity to humans. In practice, this is expressed by a drug's therapeutic index (TI) - the ratio of the toxic dose (to the patient) to the therapeutic dose (to eliminate the infection). The larger the index, the safer is the drug (antibiotic) for human use.
The selective toxicity of antibiotics is brought about by finding vulnerable targets for the drug in the microbe that do not exist in the animal (eucaryote) that is given the drug. Most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial protein synthesis, or bacterial nucleic acid synthesis, which are unique in some ways to bacteria. For example, the beta lactam antibiotics (penicillin and its relatives) inhibit peptidoglycan synthesis in the cell wall. Humans have neither a cell wall nor peptidoglycan and so are unaffected by the action of the drug. Other antibiotics, including streptomycin and the tetracyclines, target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eucaryotic organisms. Antibiotics such as the flouroqinolones (e.g. ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA replication, and rifamycins inhibit bacterial (not eucaryotic) DNA transcription.
Kinds of Antimicrobial Agents and their Primary Modes of Action
Protein synthesis inhibitors
The tetracycline core structure. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s. Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antibiotics. It is a classic "broad-spectrum antibiotic" used to treat infections caused by Gram-positive and Gram-negative bacteria and some protozoa.
Doxycycline is a semisynthetic tetracycline developed in the 1960s. It is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness.
Chemical structure of chloramphenicol
Chemical structure of a macrolide antibiotic, erythromycin.
Azithromycin, shown above, is a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is s derived from erythromycin, but it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis.
Clindamycin is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use.
END OF CHAPTER
(page 1)
Introduction
Most microbiologists distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. A hybrid substance is a semisynthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. Furthermore, some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means. In the medical and parmaceutical worlds, all these antimicrobial agents used in the treatment of disease are referred to as antibiotics, interpreting the word literally.
The modern era of antimicrobial chemotherapy began in 1929, with Fleming's discovery of the powerful bactericidal substance, penicillin, and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity.
In the early 1940's, spurred partially by the need for antibacterial agents in WW II, penicillin was isolated and purified and injected into experimental animals, where it was found not only to cure infections but also to possess incredibly low toxicity for the animals. This fact ushered into being the age of antibiotic chemotherapy, and an intense search for similar antimicrobial agents of low toxicity to animals that might prove useful in the treatment of infectious disease. The rapid isolation of streptomycin, chloramphenicol and tetracycline soon followed, and by the 1950's, these and several other antibiotics were in clinical usage.
Microorganisms that Produce Antibiotics
The bacterial colonies at 10 o'clock, 2 o'clock and 8 o'clock on this agar plate are producing antibiotics that inhibit encroachment by the mold which is growing out from the center.
Most of the natural antibiotics that are being used in agriculture and medicine are produced by three unrelated groups of microbes, including eucaryotic molds and two types of spore-forming bacteria. However, many culturable, and some non culturable microbes, have been shown to produce various substances that inhibit other organisms that grow in their space. If we consider antibiotics as secondary metabolites of microbes, it narrows the field to the handful of microbes discussed below.
1. Penicillium and Cephalosporium molds produce beta-lactam antibiotics such as penicillin and cephalosporin and their relatives. They also produce the base molecule for development of semisynthetic beta-lactam antibiotics, such as amoxacillin and ampicillin. Beta-lactams are used to treat about one-third of outpatients with bacterial infections.
The natural habitat of molds is soil. And although sex is sometimes involved, they reproduce by spore formation. They are foremost in their abilities to degrade organic matter, and they play their most important role in natures in biodegradation and the carbon cycle. Most of us know that molds will grow on nearly anything that is organic and moist, so they are also responsible for a lot food spoilage as well as decomposition of our structural materials and textiles. "Nothing is forever", with molds around.
Three colonies of a Penicillium mold growing on an agar medium. The green fuzzy appearance is the asexual spores of the fungus.
2. Actinomycetes, mainly Streptomyces species, produce tetracyclines, aminoglycosides (streptomycin and its relatives), macrolides (erythromycin and its relatives), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Actinomycetes are the mainstay of the antibiotics industry.
Actinomycetes are a group of branched bacteria that reproduce by spore formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed in Order Actinomycetales. Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia, Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are inhabitants of the soil. The characteristic odor of damp soil is due to the production of substances, called geosmins, by these bacteria
Two different actinomycetes were spotted in the center of the agar plate about two centimeters apart. This peculiar pattern of growth was observed after a 10-day incubation period. What could be going on? Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the prepared mind."
3. Bacillus species, such as B. polymyxa and B. subtilis, produce polypeptide antibiotics (e.g. polymyxin and bacitracin), and B. cereus produces zwittermicin. Bacillus species have the relatively rare ability to form a type of resting cell called an endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that live in the soil. They play an important ecological role in aerobic decomposition, biodegradation and mineral recycling.
A swirl of Bacillus mycoides colonies growth amidst other bacteria and molds from the soil. The swirls are always counterclockwise, at least in the Northern Hemisphere where I have seen it.
These organisms all have in common that they live in soil and they form some sort of a spore or resting structure. It is not known why these microorganisms produce antibiotics, but the answer may be in the obvious - it affords them some nutritional or spatial advantage in their habitat by antagonizing the competition; or it may be in the subtle - it acts as some sort of hormone or signal molecule associated with sporulation or dormancy or germination. Antibiotics are secondary metabolites and they are produced at the same time that the cells begin their sporulation processes.
Antibiotics tend to be rather large, complicated organic molecules and may require as many as 30 separate enzymatic steps to synthesize. The maintenance of a substantial component of the bacterial genome devoted solely to the synthesis of an antibiotic leads one to conclude that the antibiotic is important, if not essential, to the survival of these organisms in their natural habitat.
Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains. In most cases, how or why bacteria are resistant to their own antibiotics is also unknown, but it may be worth pondering or studying if we are to understand the cellular and molecular basis of drug resistance in pathogens.
Antibiotics must have Selective Toxicity for the Microbe
Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically-useful. The reason for this is that only compounds with selective toxicity can be used clinically.
The selective toxicity of antibiotics means that they must be highly effective against the microbe but have minimal or no toxicity to humans. In practice, this is expressed by a drug's therapeutic index (TI) - the ratio of the toxic dose (to the patient) to the therapeutic dose (to eliminate the infection). The larger the index, the safer is the drug (antibiotic) for human use.
The selective toxicity of antibiotics is brought about by finding vulnerable targets for the drug in the microbe that do not exist in the animal (eucaryote) that is given the drug. Most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial protein synthesis, or bacterial nucleic acid synthesis, which are unique in some ways to bacteria. For example, the beta lactam antibiotics (penicillin and its relatives) inhibit peptidoglycan synthesis in the cell wall. Humans have neither a cell wall nor peptidoglycan and so are unaffected by the action of the drug. Other antibiotics, including streptomycin and the tetracyclines, target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eucaryotic organisms. Antibiotics such as the flouroqinolones (e.g. ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA replication, and rifamycins inhibit bacterial (not eucaryotic) DNA transcription.
From a patient point of view, the most important property of an antimicrobial agent is its selective toxicity, i.e., that the agent acts in some way that inhibits or kills bacterial pathogens but has little or no toxic effect on the patient.
Characteristics of Antibiotics
Antibiotics may have a cidal (killing) effect or a static (inhibitory) effect on a range of microbes. The range of bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its spectrum of action. Antibiotics effective against procaryotes that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum. If effective mainly against Gram-positive or Gram-negative bacteria, they are narrow spectrum. If effective against a single organism or disease, they are referred to as limited spectrum.
A clinically-useful antibiotic should have as many of these characteristics as possible.
-It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.
-It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.
-It should be nontoxic to the host and without undesirable side effects.
-It should be nonallergenic to the host.
-It should not eliminate the normal flora of the host.
-It should be able to reach the part of the human body where the infection is occurring.
-It should be inexpensive and easy to produce.
-It should be chemically-stable (have a long shelf-life).
-Microbial resistance is uncommon and unlikely to develop.
Kinds of Antimicrobial Agents and their Primary Modes of Action
The table below is a summary of thetypes or classes of antibiotics and their properties including their biological source, spectrum and mode of action.
Classes of Antibiotics and their Properties| Chemical class | Examples | Biological source | Spectrum (effective against) | Mode of action | |
| Beta-lactams (penicillins and cephalosporins) | Penicillin G, Cephalothin | Penicillium notatum andCephalosporiumspecies | Gram-positive bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Semisynthetic beta-lactams | Ampicillin, Amoxicillin | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | ||
| Clavulanic Acid | Augmentin is clavulanic acid plus Amoxicillin | Streptomyces clavuligerus | Gram-positive and Gram-negative bacteria | Inhibitor of bacterial beta-lactamases | |
| Monobactams | Aztreonam | Chromobacterium violaceum | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Carboxypenems | Imipenem | Streptomyces cattleya | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Aminoglycosides | Streptomycin | Streptomyces griseus | Gram-positive and Gram-negative bacteria | Inhibits translation (protein synthesis) | |
| Gentamicin | Micromonosporaspecies | Gram-positive and Gram-negative bacteria esp.Pseudomonas | Inhibits translation (protein synthesis) | ||
| Glycopeptides | Vancomycin | Amycolatopsis orientalisNocardia orientalis(formerly designated) | Gram-positive bacteria, esp.Staphylococcus aureus | Inhibits steps in murein (peptidoglycan) biosynthesis and assembly | |
| Lincomycins | Clindamycin | Streptomyces lincolnensis | Gram-positive and Gram-negative bacteria esp. anaerobicBacteroides | Inhibits translation (protein synthesis) | |
| Macrolides | Erythromycin, Azithromycin | Streptomyces erythreus | Gram-positive bacteria, Gram-negative bacteria not enterics,Neisseria, Legionella, Mycoplasma | Inhibit translation (protein synthesis) | |
| Polypeptides | Polymyxin | Bacillus polymyxa | Gram-negative bacteria | Damages cytoplasmic membranes | |
| Bacitracin | Bacillus subtilis | Gram-positive bacteria | Inhibits steps in murein (peptidoglycan) biosynthesis and assembly | ||
| Polyenes | Amphotericin | Streptomyces nodosus | Fungi (Histoplasma) | Inactivate membranes containing sterols | |
| Nystatin | Streptomyces noursei | Fungi (Candida) | Inactivate membranes containing sterols | ||
| Rifamycins | Rifampicin | Streptomyces mediterranei | Gram-positive and Gram-negative bacteria,Mycobacterium tuberculosis | Inhibits transcription (bacterial RNA polymerase) | |
| Tetracyclines | Tetracycline | Streptomycesspecies | Gram-positive and Gram-negative bacteria, Rickettsias | Inhibit translation (protein synthesis) | |
| Semisynthetic tetracycline | Doxycycline | Gram-positive and Gram-negative bacteria, RickettsiasEhrlichia,Borrelia | Inhibit translation (protein synthesis) | ||
| Chloramphenicol | Chloramphenicol | Streptomyces venezuelae | Gram-positive and Gram-negative bacteria | Inhibits translation (protein synthesis) | |
| Quinolones | Nalidixic acid | synthetic | Mainly Gram-negative bacteria | Inhibits DNA replication | |
| Fluoroquinolones | Ciprofloxacin | synthetic | Gram-negative and some Gram-positive bacteria (Bacillus anthracis) | Inhibits DNA replication | |
| Growth factor analogs | Sulfanilamide, Gantrisin, Trimethoprim | synthetic | Gram-positive and Gram-negative bacteria | Inhibits folic acid metabolism (anti-folate) | |
| Isoniazid (INH) | synthetic | Mycobacterium tuberculosis | Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6) | ||
| para-aminosalicylic acid (PAS) | synthetic | Mycobacterium tuberculosis | Anti-folate |
Antimicrobial Agents Used in the Treatment of Infectious DiseaseExamination of the foregoing table reveals that there are a handful of fundamental ways that antibacterial antibiotics work as therapeutic agents. Recall that the target of an antibiotic should be unique to the bacterium and not found, or not accessible to the antibiotic, in the patient. These are the most important targets in bacteria that have been exploited so far.
1. Attack bacterial cell wall synthesis. Bacteria have murein in their cell walls, not found in the host, and murein (peptidoglycan) is essential to the viability of the bacterium.
2. Interfere with protein synthesis. Attack is almost always ate the level of translation using 70S ribosomes in the translation machinery. 70S cytoplasmic ribosomes are absent in eucaryotes.
3. Interference with nucleic acid synthesis (RNA and DNA), which exploits differences between RNA polymerases and DNA replication strategies in bacteria and eucaryotes.
4. Inhibition of an essential metabolic pathway that exists in the bacterium but does not exist in the host. This is usually brought about through the use of competitive chemical analogs for bacterial enzymatic reactions.
5. Membrane inhibition or disruption doesn't work too well because of the similarities between eucaryotic and bacterial membranes. However, the outer membrane of Gram-negative bacteria is a reasonable point of attack and some membrane inhibitors are included in the discussion below.
Cell wall synthesis inhibitors
Chemical structures of some beta-lactam antibiotics. Clockwise: penicillin, cephalosporin, monobactam, carbapenem. Note the characteristic structure of the beta lactam ring.
The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the drug of choice within the class because it is better absorbed following oral administration than other beta-lactam antibiotics. It is susceptible to degradation by bacterial beta-lactamase enzymes so it may be given with calvulanic acid (below) to decrease its susceptibility. It is used against a wide range of Gram-positive bacteria, including Streptococcus pyogenes, penicillin-sensitive Streptococcus pneumoniae, non beta-lactamase producing strains of Staphylococcus aureus andEnterococcus faecalis. Susceptible Gram-negative organisms include non beta-lactamase producing strains of Haemophilus influenzae, Neisseria gonorrhoeaeand N. meningitidis.
Clavulanic acid is a chemical sometimes added to a semisynthetic penicillin preparation. Thus, amoxicillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams.
The structure of calvulanic acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic. Most commonly it is combined with amoxicillin (above) as Augmentin (trade name) or the veterinary preparation, clavamox.
The core structure of cephalosporin. Substituent groups added at position X on the six-membered ring generates variants of the antibiotic.
Two other classes of beta lactams are the carbapenems and monobactams. The latter are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and the carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy.
Aztreonam is a synthetic monocyclic beta lactam antibiotic (a monobactam) originally isolated from the bacterium Chromobacterium violaceum. It is not useful against Gram-positive bacteria but it has strong activity against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, Haemophilus and Klebsiella.
Bacitracin is a polypeptide antibiotic produced by Bacillus species. It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Teichoic acid synthesis, which requires the same carrier, is also inhibited. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
Bacitracin is a polypeptide antibiotic produced by the licheniformis group ofBacillus subtilis var. Tracy. It is effective used topically, primarily against Gram-positive bacteria. It is used in ointment or cream form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A popular brand name Neosporin, contains bacitracin, neomycin and polymyxin B.
Cell membrane inhibitors
Polymyxin B. Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract. Polymyxins also have antifungal activity.
1. Attack bacterial cell wall synthesis. Bacteria have murein in their cell walls, not found in the host, and murein (peptidoglycan) is essential to the viability of the bacterium.
2. Interfere with protein synthesis. Attack is almost always ate the level of translation using 70S ribosomes in the translation machinery. 70S cytoplasmic ribosomes are absent in eucaryotes.
3. Interference with nucleic acid synthesis (RNA and DNA), which exploits differences between RNA polymerases and DNA replication strategies in bacteria and eucaryotes.
4. Inhibition of an essential metabolic pathway that exists in the bacterium but does not exist in the host. This is usually brought about through the use of competitive chemical analogs for bacterial enzymatic reactions.
5. Membrane inhibition or disruption doesn't work too well because of the similarities between eucaryotic and bacterial membranes. However, the outer membrane of Gram-negative bacteria is a reasonable point of attack and some membrane inhibitors are included in the discussion below.
Cell wall synthesis inhibitors
Cell wall synthesis inhibitors generally inhibit some step in the synthesis of bacterial peptidoglycan. They exert their selective toxicity against bacteria because humans cells lack cell walls.
Beta lactam antibiotics. Chemically, these antibiotics contain a 4-membered beta lactam ring. They are the products of two genera of fungi, Penicillium andCephalosporium, and are correspondingly represented by the penicillins andcephalosporins.
Chemical structures of some beta-lactam antibiotics. Clockwise: penicillin, cephalosporin, monobactam, carbapenem. Note the characteristic structure of the beta lactam ring.
The beta lactam antibiotics are stereochemically related to D-alanyl-D-alanine, which is a substrate for the last step in peptidoglycan synthesis, the final cross-linking between between peptide side chains. Penicillins bind to and inhibit the carboxypeptidase and transpeptidase enzymes that are required for this step in peptidoglycan biosynthesis. Beta lactam antibiotics are bactericidal and require that cells be actively growing in order to exert their toxicity.
Different beta lactams differ in their spectrum of activity and their effect on Gram-negative rods, as well as their toxicity, stability in the human body, rate of clearance from blood, whether they can be taken orally, ability to cross the blood-brain barrier, and susceptibility to bacterial beta-lactamases.
Natural penicillins, such as penicillin G or penicillin V (benzyl penicillin), are produced by fermentation of Penicillium chrysogenum. They are effective against streptococci, gonococci and staphylococci, except where resistance has developed. They are considered narrow spectrum since they are not effective against Gram-negative rods.
Penicillin G (Benzylpenicillin) is typically given by parenteral administration because it is unstable in the acid of the stomach. However, this achieves higher tissue concentrations than orally-administered penicillins and this increases its antibacterial potential. "PenG" may be used in treatment of bacterial endocarditis, gonorrhea, syphilis, meningitis, and pneumonia.
Semisynthetic penicillins first appeared in 1959. A mold produces the main part of the molecule (6-aminopenicillanic acid), which can be modified chemically by the addition of side chains. Many of these compounds have been developed to have distinct benefits or advantages over penicillin G, such as increased spectrum of activity (effectiveness against Gram-negative rods), resistance to penicillinase, effectiveness when administered orally, etc.; amoxicillin andampicillin have broadened spectra against Gram-negative bacteria and are effective orally; methicillin is penicillinase-resistant.
The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the drug of choice within the class because it is better absorbed following oral administration than other beta-lactam antibiotics. It is susceptible to degradation by bacterial beta-lactamase enzymes so it may be given with calvulanic acid (below) to decrease its susceptibility. It is used against a wide range of Gram-positive bacteria, including Streptococcus pyogenes, penicillin-sensitive Streptococcus pneumoniae, non beta-lactamase producing strains of Staphylococcus aureus andEnterococcus faecalis. Susceptible Gram-negative organisms include non beta-lactamase producing strains of Haemophilus influenzae, Neisseria gonorrhoeaeand N. meningitidis.
Clavulanic acid is a chemical sometimes added to a semisynthetic penicillin preparation. Thus, amoxicillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams.
The structure of calvulanic acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic. Most commonly it is combined with amoxicillin (above) as Augmentin (trade name) or the veterinary preparation, clavamox.
Although nontoxic, penicillins occasionally cause death when administered to persons who are allergic to them. In the U.S. there are 300 - 500 deaths annually due to penicillin allergy. In allergic individuals the beta lactam molecule attaches to a serum protein and initiates an IgE-mediated inflammatory response.
Cephalosporins are beta lactam antibiotics with a similar mode of action to penicillins. They are produced by species of Cephalosporium molds. The have a low toxicity and a somewhat broader spectrum than natural penicillins. They are often used as penicillin substitutes against Gram-negative bacteria and in surgical prophylaxis. They are subject to degradation by some bacterial beta-lactamases, but they tend to be resistant to beta-lactamases from S. aureus.
The core structure of cephalosporin. Substituent groups added at position X on the six-membered ring generates variants of the antibiotic.
Two other classes of beta lactams are the carbapenems and monobactams. The latter are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and the carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy.
Aztreonam is a synthetic monocyclic beta lactam antibiotic (a monobactam) originally isolated from the bacterium Chromobacterium violaceum. It is not useful against Gram-positive bacteria but it has strong activity against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, Haemophilus and Klebsiella.
Bacitracin is a polypeptide antibiotic produced by Bacillus species. It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Teichoic acid synthesis, which requires the same carrier, is also inhibited. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
Bacitracin is a polypeptide antibiotic produced by the licheniformis group ofBacillus subtilis var. Tracy. It is effective used topically, primarily against Gram-positive bacteria. It is used in ointment or cream form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A popular brand name Neosporin, contains bacitracin, neomycin and polymyxin B.
Cycloserine inhibits the early stages of murein synthesis where D-alanyl-D-alanine is added to the growing peptide side chain. The antibiotic resembles D-alanine in spatial structure, and it competitively inhibits the racemase reaction that converts L-alanine to D-alanine and the synthetase reaction that joins two D-alanine molecules. The affinity of cycloserine for these enzymes is about a hundred times greater than that of D-alanine. Cycloserine enters bacterial cells by means of an active transport system for glycine and can reach a relatively high intracellular concentration. This concentrating effect, along with its high affinity for susceptible enzymes, enables cycloserine to function as a very effective antimicrobial agent. However, it is fairly toxic and has limited use as a secondary drug for tuberculosis.
Cycloserine is an oral broad spectrum antibiotic effective against tuberculosis, by inhibiting cell wall synthesis of TB bacilli at the early stages of peptidoglycan synthesis. For the treatment against tuberculosis, it is classified as a second line drug.
Cycloserine is an oral broad spectrum antibiotic effective against tuberculosis, by inhibiting cell wall synthesis of TB bacilli at the early stages of peptidoglycan synthesis. For the treatment against tuberculosis, it is classified as a second line drug.
Glycopeptides, such as the antibiotic vancomycin, inhibit both transglycosylation and transpeptidation reactions during peptidoglycan assembly. They bind to the muropeptide subunit as it is transferred out of the cell cytoplasm and inhibit subsequent polymerization reactions. Vancomycin is not effective against Gram-negative bacteria because it cannot penetrate their outer membrane. However, it has become important in clinical usage for treatment of infections by strains of Staphylococcus aureus that are resistant to virtually all other antibiotics (MRSA).
Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant organisms means that it is increasingly being displaced from this role by linezolid and the carbapenems.
Cell membrane inhibitors
These antibiotics disorganize the structure or inhibit the function of bacterial membranes. The integrity of the cytoplasmic and outer membranes is vital to bacteria, and compounds that disorganize the membranes rapidly kill the cells. However, due to the similarities in phospholipids in eubacterial and eucaryotic membranes, this action is rarely specific enough to permit these compounds to be used systemically. The only antibacterial antibiotics of clinical importance that act by this mechanism are the polymyxins, produced by Bacillus polymyxa. Polymyxin is effective mainly against Gram-negative bacteria and is usually limited to topical usage. Polymyxins bind to membrane phospholipids and thereby interfere with membrane function. Polymyxin is occasionally given for urinary tract infections caused by Pseudomonas strains that are gentamicin, carbenicillin and tobramycin resistant. The balance between effectiveness and damage to the kidney and other organs is dangerously close, and the drug should only be given under close supervision in the hospital.
Polymyxin B. Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract. Polymyxins also have antifungal activity.
Protein synthesis inhibitors
Many therapeutically useful antibiotics owe their action to inhibition of some step in the complex process of protein synthesis. Their attack is always at one of the events occurring on the ribosome and never at the stage of amino acid activation or attachment to a particular tRNA. Most have an affinity or specificity for 70S (as opposed to 80S) ribosomes, and they achieve their selective toxicity in this manner. The most important antibiotics with this mode of action are thetetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and theaminoglycosides (e.g. streptomycin).
The aminoglycosides are products of Streptomyces species and are represented by streptomycin, kanamycin, tobramycin and gentamicin. These antibiotics exert their activity by binding to bacterial ribosomes and preventing the initiation of protein synthesis.
Streptomycin binds to 30S subunit of the bacterial ribosome, specifically to the S12 protein which is involved in the initiation of protein synthesis. Experimentally, streptomycin has been shown to prevent the initiation of protein synthesis by blocking the binding of initiator N-formylmethionine tRNA to the ribosome. It also prevents the normal dissociation of ribosomes into their subunits, leaving them mainly in their 70S form and preventing the formation of polysomes. The overall effect of streptomycin seems to be one of distorting the ribosome so that it no longer can carry out its normal functions. This evidently accounts for its antibacterial activity but does not explain its bactericidal effects, which distinguishes streptomycin and other aminoglycosides from most other protein synthesis inhibitors.
Streptomycin is the first aminoglycoside antibiotic to be discovered, and was the first antibiotic to be used in treatment of tuberculosis. It was discovered in 1943, in the laboratory of Selman Waksman at Rutgers University. Waksman and his laboratory discovered several antibiotics, including actinomycin, streptomycin, and neomycin. Streptomycin is derived from the bacterium, Streptomyces griseus. Streptomycin stops bacterial growth by inhibiting protein synthesis. Specifically, it binds to the 16S rRNA of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis.
Streptomycin is the first aminoglycoside antibiotic to be discovered, and was the first antibiotic to be used in treatment of tuberculosis. It was discovered in 1943, in the laboratory of Selman Waksman at Rutgers University. Waksman and his laboratory discovered several antibiotics, including actinomycin, streptomycin, and neomycin. Streptomycin is derived from the bacterium, Streptomyces griseus. Streptomycin stops bacterial growth by inhibiting protein synthesis. Specifically, it binds to the 16S rRNA of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis.
Kanamycin and tobramycin have been reported to bind to the ribosomal 30S subunit and to prevent it from joining to the 50S subunit during protein synthesis. They may have a bactericidal effect because this leads to cytoplasmic accumulation of dissociated 30S subunits, which is apparently lethal to the cells.
Aminoglycosides have been used against a wide variety of bacterial infections caused by Gram-positive and Gram-negative bacteria. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis. Gentamicinis active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. Kanamycin is active at low concentrations against many Gram-positive bacteria, including penicillin-resistant staphylococci. Gentamicin and Tobramycin are mainstays for treatment ofPseudomonas infections. An unfortunate side effect of aminoglycosides has tended to restrict their usage: prolonged use is known to impair kidney function and cause damage to the auditory nerves leading to deafness.
Gentamicin is an aminoglycoside antibiotic, used mostly to treat Gram-negative infections. However, it is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila infections. It is synthesized byMicromonospora, a genus of Gram-positive bacteria widely distributed in water and soil. Like all aminoglycosides, when gentamicin is given orally, it is not systemically active because it is not absorbed to any appreciable extent from the small intestine. It is useful in treatment of infections caused by Pseudomonas aeruginosa.The tetracyclines consist of eight related antibiotics which are all natural products of Streptomyces, although some can now be produced semisynthetically or synthetically. Tetracycline, chlortetracycline anddoxycycline are the best known. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa is less sensitive but is generally susceptible to tetracycline concentrations that are obtainable in the bladder. The tetracyclines act by blocking the binding of aminoacyl tRNA to the A site on the ribosome. Tetracyclines inhibit protein synthesis on isolated 70S or 80S (eucaryotic) ribosomes, and in both cases, their effect is on the small ribosomal subunit. However, most bacteria possess an active transport system for tetracycline that will allow intracellular accumulation of the antibiotic at concentrations 50 times as great as that in the medium. This greatly enhances its antibacterial effectiveness and accounts for its specificity of action, since an effective concentration cannot be accumulated in animal cells. Thus a blood level of tetracycline which is harmless to animal tissues can halt protein synthesis in invading bacteria.
The tetracyclines have a remarkably low toxicity and minimal side effects when taken by animals. The combination of their broad spectrum and low toxicity has led to their overuse and misuse by the medical community and the wide-spread development of resistance has reduced their effectiveness. Nonetheless, tetracyclines still have some important uses, such as the use of doxycycline in the treatment of Lyme disease.
Some newly discovered members of the tetracycline family (e.g. chelocardin) have been shown to act by inserting into the bacterial membrane, not by inhibiting protein synthesis.
The tetracycline core structure. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s. Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antibiotics. It is a classic "broad-spectrum antibiotic" used to treat infections caused by Gram-positive and Gram-negative bacteria and some protozoa.
Doxycycline is a semisynthetic tetracycline developed in the 1960s. It is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness.
Chloramphenicol is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. Unfortunately, aplastic anemia develops in a small proportion (1/50,000) of patients. Chloramphenicol was originally discovered and purified from the fermentation of a Streptomyces species, but currently it is produced entirely by chemical synthesis. Chloramphenicol inhibits the bacterial enzyme peptidyl transferase, thereby preventing the growth of the polypeptide chain during protein synthesis.
Chemical structure of chloramphenicol
Chloramphenicol is entirely selective for 70S ribosomes and does not affect 80S ribosomes. Its unfortunate toxicity towards the small proportion of patients who receive it is in no way related to its effect on bacterial protein synthesis. However, since mitochondria originated from procaryotic cells and have 70S ribosomes, they are subject to inhibition by some of the protein synthesis inhibitors including chloramphenicol. This likely explains the toxicity of chloramphenicol. The eucaryotic cells most likely to be inhibited by chloramphenicol are those undergoing rapid multiplication, thereby rapidly synthesizing mitochondria. Such cells include the blood forming cells of the bone marrow, the inhibition of which could present as aplastic anemia. Chloramphenicol was once a highly prescribed antibiotic and a number of deaths from anemia occurred before its use was curtailed. Now it is seldom used in human medicine except in life-threatening situations (e.g. typhoid fever).
The macrolide family of antibiotics is characterized by structures that contain large lactone rings linked through glycoside bonds with amino sugars. The most important members of the group are erythromycin and oleandomycin.Erythromycin is active against most Gram-positive bacteria, Neisseria,Legionella and Haemophilus, but not against the Enterobacteriaceae. Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. Binding inhibits elongation of the protein by peptidyl transferase or prevents translocation of the ribosome or both. Macrolides are bacteriostatic for most bacteria but are cidal for a few Gram-positive bacteria.
Chemical structure of a macrolide antibiotic, erythromycin.
Azithromycin, shown above, is a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is s derived from erythromycin, but it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis.
Lincomycin and clindamycin are a miscellaneous group of protein synthesis inhibitors with activity similar to the macrolides. Lincomycin has activity against Gram-positive bacteria and some Gram-negative bacteria (Neisseria, H. influenzae). Clindamycin is a derivative of lincomycin with the same range of antimicrobial activity, but it is considered more effective. It is frequently used as a penicillin substitute and is effective against Gram-negative anaerobes (e.g.Bacteroides).
Clindamycin is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use.
Effects on Nucleic Acids
Some antibiotics and chemotherapeutic agents affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. Either case, of course, can block the growth of cells. The majority of these drugs are unselective, however, and affect animal cells and bacterial cells alike and therefore have no therapeutic application. Two nucleic acid synthesis inhibitors which have selective activity against procaryotes and some medical utility are the quinolones and rifamycins.
Nalidixic acid is a synthetic chemotherapeutic agent that has activity mainly against Gram-negative bacteria. Nalidixic acid belongs to a group of compounds called quinolones. Nalidixic acid is a bactericidal agent that binds to the DNA gyrase enzyme (topoisomerase) which is essential for DNA replication and allows supercoils to be relaxed and reformed. Binding of the drug inhibits DNA gyrase activity.
Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. However, the main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. Some quinolones have a broadened spectrum against Gram-positive bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis.
Ciprofloxacin (cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division.
The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces species. Rifampicin is a semisynthetic derivative of rifamycinthat is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells. The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis.
Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.
Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. However, the main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. Some quinolones have a broadened spectrum against Gram-positive bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis.
Ciprofloxacin (cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division.
The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces species. Rifampicin is a semisynthetic derivative of rifamycinthat is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells. The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis.
Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.
Competitive Inhibitors
Many of the synthetic chemotherapeutic agents (synthetic antibiotics) arecompetitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism. Hence, these types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs, since they are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite, but they do not fulfill their metabolic function in the cell. Some are bacteriostatic and some are bactericidal. Their selective toxicity is based on the premise that the bacterial pathway does not occur in the host.
Sulfonamides were introduced as chemotherapeutic agents by Domagk in 1935, who showed that one of these compounds (prontosil) had the effect of curing mice with infections caused by beta-hemolytic streptococci. Chemical modifications of the compound sulfanilamide gave rise to compounds with even higher and broader antibacterial activity. The resulting sulfonamides have broadly similar antibacterial activity, but differ widely in their pharmacological actions. Bacteria which are almost always sensitive to the sulfonamides includeStreptococcus pneumoniae, beta-hemolytic streptococci and E. coli. The sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis (because they cross the blood-brain barrier).
The sulfonamides (e.g. Gantrisin and Trimethoprim) are inhibitors of the bacterial enzymes required for the synthesis of tetrahydofolic acid (THF), the vitamin form of folic acid essential for 1-carbon transfer reactions. Sulfonamides are structurally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathway, and they competitively inhibit that step. Trimethoprim is structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase. Animal cells do not synthesize their own folic acid but obtain it in a preformed fashion as a vitamin. Since animals do not make folic acid, they are not affected by these drugs, which achieve their selective toxicity for bacteria on this basis.
The chemical structures of sulfanilamide and para-aminobenzoic acid (PABA). In bacteria, sulfanilamide acts as a competitive inhibitor of the enzyme dihydropteroate synthetase, DHPS, which catalyses the conversion of PABA to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (DNA and RNA), and in its absence, cells will be unable to divide. Hence, sulfanilamide and other sulfonamides exhibit a bacteriostatic rather than bactericidal effect.
Three additional synthetic chemotherapeutic agents have been used in the treatment of tuberculosis: isoniazid (INH), para-aminosalicylic acid (PAS), and ethambutol. The usual strategy in the treatment of tuberculosis has been to administer a single antibiotic (historically streptomycin, but now, most commonly, rifampicin is given) in conjunction with INH and ethambutol. Since the tubercle bacillus rapidly develops resistance to the antibiotic, ethambutol and INH are given to prevent outgrowth of a resistant strain. It must also be pointed out that the tubercle bacillus rapidly develops resistance to ethambutol and INH if either drug is used alone. Ethambutol inhibits incorporation of mycolic acids into the mycobacterial cell wall. Isoniazid has been reported to inhibit mycolic acid synthesis in mycobacteria and since it is an analog of pyridoxine (Vitamin B6) it may inhibit pyridoxine-catalyzed reactions as well. Isoniazid is activated by a mycobacterial peroxidase enzyme and destroys several targets in the cell. PAS is an anti-folate, similar in activity to the sulfonamides. PAS was once a primary anti-tuberculosis drug, but now it is a secondary agent, having been largely replaced by ethambutol.
Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line anti-tuberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line anti-tuberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
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ANTIBIOTICS & MECHANISM,
INSTANT NOTES,
