Pharm 100 - Lesson D.1
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Paul Ehrlich, who was born in Germany in 1854, introduced the concept of chemotherapy. He designed organoarsenical drugs on rational grounds and thus provided a cure for syphilis in the early years of the twentieth century
Gerhard Domagk introduced the sulfonamide group of drugs in the 1930’s in Germany. These synthetic drugs constituted a major advance since they were efficacious against a variety of bacterial diseases which had previously been associated with severe illness and death
- Alexander Fleming, in 1929, working at St. Mary’s Hospital, London, England, found that avirulent bacterium, Staphylococcus aureus, was not growing on a culture dish when in proximity to a contaminating penicillium mold. He deduced correctly that the penicillin mold was producing and excreting an antibacterial substance, later termed penicillin, that was inhibiting growth of Staphylococcus aureus.
- One of Fleming’s memorable quotations was: “It is not the marble halls which make for intellectual grandeur – it is the spirit and brain of the worker.”
Florey and Chain
Florey and Chain, at Oxford University, were able during the second worldwar to isolate penicillin in sufficient quantity to administer it with great success to patients with a variety of infections due to gram-positive bacteria
In 1943, working at Rutgers University in the United States, Selman Waksman introduced streptomycin, which was efficacious in the treatment of tuberculosis and a variety of infections caused by gram-negative microorganisms.
Antibiotic – Definition
An antibiotic is a chemical substance produced by microorganisms that suppress the growth of other microorganisms and may eventually destroy them. Thus, strictly speaking, synthetic chemicals such as sulfonamides are not antibiotics, but are antimicrobial compounds.
Gram-Positive and Gram-Negative Bacteria
Bacteria are classified by their colour after treatment by a technique known as Gram’s stain and observation under a microscope. Those bacteria, which have taken up the colour, are classified as gram-positive. Those bacteria that are decolourised are classified as gram-negative.
Current Issues in antibiotic Use
Emergence of resistant strains: This is a long standing problem as micro-organisms mutate to have different properties and become resistant to antibiotics. In some countries (not Canada) over the counter use has lead to inappropriate use. The other issue that must be considered that antibiotics take advantage of differences between bacterial and human cells (selective toxicity), and we have exploited the obvious differences and are now seeking new differences where the selective toxicity may be less than desired, hence more toxicity.
Classification of Antibiotics
- (a) Narrow spectrum: e.g. penicillin G (isolated from the penicillium mold) which acts primarilyon gram-positive bacteria.
- Broad spectrum: e.g. tetracyclines and chloramphenicol which act on both gram-positive andgram-negative bacteria.
- (b) Bactericidal: Antibiotics that destroy microorganisms, e.g. penicillin G.
- Bacteriostatic: Antibiotics that prevent multiplication of microorganisms, thus facilitating the ability of the natural defence system of the body (the immune system) to destroy the bacteria, e.g.tetracycline.
Penicillin – Mechanism of Action
The interior of a bacterium is under high internal pressure. Bacteria have rigid cell walls which protect the bacterium from its high internal pressure. Penicillin is closely related to a chemical component, D-alanyl-D-alanine, necessary for the formation of new bacterial cell walls. As a result, it prevents new bacterial cell wall formation and the resulting cells are formed without cell walls. These cells are known as protoplasts and are fragile and can readily burst. Human cells do not have cellwalls and are therefore unaffected by penicillin. Thus, penicillin is selectively toxic to bacteria.
Penicillin – Mechanism of Action photo
- Extracted and purified from Penicillium mold. Narrow spectrum – destroys mainlygram-positive bacteria such as Pneumococcus and Streptococcus. Useful in infections caused by such bacteria, e.g. pneumoniae, middle ear infection, skin infection, and meningitis (inflammation of the meninges, the covering of the brain and spinal cord). It is also very useful in the treatment of syphilis.
- Why do we need other penicillins if penicillin G is such a remarkably effective antibiotic, andhow do we obtain antibiotics related to penicillin G? To obtain antibiotics related to penicillin G, we allow the Penicillium mold to make a portion of the penicillin molecule which is difficult to synthesize in the laboratory. This portion of the penicillin molecule is then modified in many ways in the laboratory to give the semisynthetic group of penicillins.
- It is more acid stable than penicillin G and therefore less is destroyed by stomach acid when it is taken orally. Higher blood levels are achieved with penicillin V than with penicillin G. Thus, when apenicillin is required for oral administration in some infections, penicillin V will be prescribed rather than penicillin G.
- semi synthetic
- One of the ways bacteria become resistant to penicillin G and some other penicillins is by producing an enzyme called penicillinase which breaks down the penicillin molecule and inactivates it. Cloxacillin is resistant to attack by penicillinase and is used particularly against penicillinase producing Staphylococcus aureus.
- semi synthetic
Ampicillin and Amoxacillin
These semisynthetic penicillins have a broader spectrum of antibacterial activity than penicillin G, and are active against several gram-negative bacteria such as Escherichia coli (E. Coli). They aretherefore useful against a range of infections caused by gram-negative bacteria, e.g. urinary tract infection due to E. Coli.
This semisynthetic penicillin has an even broader spectrum of activity than ampicillin and amoxacillin and is effective in severe infections caused by the gram-negative bacterium, Pseudomonasaeruginosa
In recent years, combinations of semisynthetic penicillins plus an inhibitor of penicillinase (e.g.clavulinic acid) have been introduced into therapy. The inhibitor of penicillinase does not have antibacterial activity of its own. However, when combined with amoxacillin, which is susceptible toinactivation by penicillinase, the combination of amoxacillin plus clavulinic acid, named augmentin,is effective against penicillinase-producing strains of bacteria such as Staphylococcus aureus and Haemophilus influenzae.
Adverse Effects of Penicillins
The most common adverse reaction to penicillin is an allergic reaction. If an individual is allergic to a penicillin preparation, they will be allergic to all penicillin preparations. A variety ofstudies suggest that one to ten percent of the population is allergic to penicillin. The most common manifestations of penicillin allergy are rash, diarrhea, face and tongue swelling, and an eruption of itching wheels (urticaria). In rare cases, individuals may experience severe difficulty in breathing and a marked fall in blood pressure. Deaths do occur in some of these rare cases and individuals arerecommended to wear a Medic Alert tag if allergic to penicillin.
These antibiotics are chemically similar to penicillins, but in general are more resistant to penicillinase than is the penicillin group. Cephalosporins are also selective inhibitors of bacterial cell wall synthesis. A range of members of the cephalosporin group have been introduced into therapy over the last three decades. The group is divided into four generations, depending mainly on theirspectrum of antimicrobial activity
- First generation: Cephalothin is a representative of this generation. It has good activity againstgram-positive microorganisms and moderate activity again gram-negative microorganisms.
- Second generation: Cefamandole is a representative of the second generation and it has increased activity against gram-negative microorganisms.
- Third generation: These cephalosporins are less active than the first generation against gram positive microorganisms, but are more active against gram-negative microorganisms. It is ofconsiderable importance that they are active against Pseudomonas aeruginosa. Ceftriaxone is the drug of choice for treatment of gonorrhea. Some third-generation cephalosporins are useful fortherapy of meningitis and drugs of choice for this purpose are ceftriaxone and cefotaxime.
- Fourth generation: An example is cefepine. It has increased stability to penicillinase and a broader spectrum of activity than the third generation.
An example of this class of synthetic antimicrobial agents is ciprofloxacin. It can be used for oral or intravenous therapy of infections caused by a wide variety of gram-positive and gram-negative microorganisms. Its efficacy by the oral route is a particularly useful attribute since it avoids the expense and inconvenience of giving a drug by injection. These agents are a chemically distinct class of antimicrobials and inhibit bacterial DNA synthesis.
This antibiotic is active against several bacterial infections caused by gram-positivemicroorganisms. When an individual is allergic to penicillin, erythromycin is an effective alternative in treating streptococcal and staphylococcal infections. Erythromycin is also effective in treating infections caused by some gram-negative bacteria, e.g. gonococci, Legionnaire’s bacillus and mycoplasma. Erythromycin selectively inhibits bacterial protein synthesis.
Azithromycin and Clarithromycin
These are relatively new antibiotics. They are chemically modified forms of erythromycin. They require less frequent oral administration, produce less frequent gastrointestinal problems, and penetrate into tissues very well. A disadvantage is that they are much more expensive than erythromycin.
This group of antibiotics has broad spectrum activity, exerts bacteriostatic effects by selectively inhibiting bacterial protein synthesis, and is effective when taken orally. Because of widespread usefor many years, often for inappropriate reasons, many bacteria which were formerly susceptible totheir action have become resistant. For this reason, tetracyclines, although useful, are considerably less useful than when first introduced. The tetracyclines have a strong avidity for calcium and cause discolouration of teeth and diminish bone growth. They are therefore not used in pregnancy and inchildren under 12 years of age. When tetracyclines are kept for long periods of time before use, they deteriorate into toxic degradation products. It is therefore important to discard outdated supplies.
This is a broad spectrum, bacteriostatic antibiotic which was very popular in the 1950’s until itwas shown that it caused fatal bone marrow failure in approximately one per 30,000 individuals receiving the drug. For this reason, it is recommended for use only in serious infections caused by bacteria, susceptible to its action, and which cannot be treated with less dangerous antibiotics
- Gentamicin: This antibiotic is widely used for treatment of severe infections caused by gram negative bacteria such as Pseudomonas aeruginosa. However, great care is required to try to minimize toxic reactions which include kidney damage, deafness, loss of balance and vertigo(dizziness and giddiness).
- Streptomycin: This aminoglycoside antibiotic is effective against gram-negative bacteria and was the first effective drug available to combat tuberculosis. Because it shares the toxic effects listedabove for gentamicin, it is now a second-line drug for treatment of cases of tuberculosis where resistance to first-line, safer drugs has occurred.
Treatment of Tuberculosis
Initial isolates of the microorganism, Mycobacterium tuberculosis, require to be tested for susceptibility to the first-line antitubercular drugs. If susceptible, the individual will receive isoniazid plus rifampin daily for six months and pyrazinamide is added daily for the first two months. It is imperative that an individual comply with therapy because of the possibility of emergence of resistant microorganisms which will be very difficult to treat. Tuberculosis has re-emerged as an important problem in recent years in patients infected with HIV. This is due to the fact that the immune systemdeteriorates in HIV-infected individuals. There are a number of second-line drugs available for treating individuals infected with microorganisms resistant to the first-line drugs.
- This agent consists of two components, namely sulfamethoxazole (t½, 10 hours) andtrimethoprim (t½, 11 hours). One of the reasons that sulfamethoxazole was chosen from the manysulfonamide drugs is that it has a similar t½ (elimination half-life) as trimethoprim. Having twocompounds with a similar elimination half-life provides a relative constancy of the blood concentrations of the two agents which is necessary to produce a constant synergistic antibacterial effect
- Co-trimoxazole is useful in the treatment of recurrent bacterial infection of the urinary tract and in the treatment of infections of the respiratory and gastrointestinal tract. It is an important antimicrobial agent used in the treatment of Pneumocystis carinii infection in HIV-positive individuals.
Co-trimoxazole Mechanism of action
Tetrahydrofolic acid is essential for the bacteria to produce one-carbon units which are required for DNA and protein synthesis. If tetrahydrofolic is not formed, growth will slow. Sulfamethoxazole,a member of the sulfonamide group, competitively inhibits para-aminobenzoic incorporation intodihydrofolic acid (Step 1, and see earlier lecture for details and for explanation of selective toxicity). Trimethoprim inhibits dihydrofolic acid reductase (Step 2), thus inhibiting tetrahydrofolic acid formation. The reason for the selective toxicity of trimethoprim is that it is much more inhibitory tothe bacterial than to the human enzyme. Thus, by inhibiting sequential steps in the metabolicpathway, a synergistic antibacterial effect is produced.
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