MICROBIAL BIOTECHNOLOGY - ANTIBIOTICS

DEFINITION:
In common usage, an antibiotic (from the Ancient Greek: – anti, "against", and – bios, "life") is a substance or compound that kills or inhibits the growth of bacteria.
The term "antibiotic" was coined by Selman Waksman in 1942 to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution.

A drug used to treat infections caused by bacteria and other microorganisms. Originally, an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another.


ANTIBIOTIC CLASS:
Antibiotics are one class of "antimicrobials", a larger group which also includes anti-viral, anti-fungal, and anti-parasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infection. The term originally described only those formulations derived from living organisms, but is now applied also to synthetic antimicrobials, such as the sulfonamides.

HISTORY OF ANTIBIOTICS:
Late 1800s
The search for antibiotics began in the late 1800s, with the growing acceptance of the germ theory of disease, a theory which linked bacteria and other microbes to the causation of a variety of ailments. As a result, scientists began to devote time to searching for drugs that would kill these disease-causing bacteria.

1871



The surgeon Joseph Lister began researching the phenomenon that urine contaminated with mold would not allow the successful growth of bacteria.

1890s
German doctors, Rudolf Emmerich and Oscar Low were the first to make an effective medication that they called pyocyanase from microbes. It was the first antibiotic to be used in hospitals. However, the drug often did not work.

1928
Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be destroyed by the mold Penicillium notatum, demonstrating antibacterial properties.


1935
Prontosil, the first sulfa drug, was discovered in 1935 by German chemist Gerhard Domagk (1895–1964).

1942
The manufacturing process for Penicillin G Procaine was invented by Howard Florey (1898–1968) and Ernst Chain (1906–1979). Penicillin could now be sold as a drug. Fleming, Florey, and Chain shared the 1945 Nobel Prize for medicine for their work on penicillin.


1943
In 1943, American microbiologist Selman Waksman (1888–1973) made the drug streptomycin from soil bacteria, the first of a new class of drugs called aminoglycosides. Streptomycin could treat diseases like tuberculosis; however, the side effects were often too severe.


1955
Tetracycline was patented by Lloyd Conover, which became the most prescribed broad spectrum antibiotic in the United States.

1957
Nystatin was patented and used to cure many disfiguring and disabling fungal infections.

1981
SmithKline Beecham patented Amoxicillin or amoxicillin/clavulanate potassium tablets, and first sold the antibiotic in 1998 under the tradenames of Amoxicillin, Amoxil, and Trimox. Amoxicillin is a semi synthetic antibiotic.

DISCOVERY OF PENICILLIN:
The first effective antibiotic discovered was penicillin. French physician Ernest Duchesne noted in his 1896 thesis that certain Penicillium molds killed bacteria. Duchesne died within a few years, and his research was forgotten for a generation, until an accident intervened.

Alexander Fleming had been culturing bacteria on agar plates, one of which was ruined by an accidental fungal contamination. Rather than discarding the contaminated plate, Fleming noticed a clear zone surrounding the colony of mold.

Having previously studied the ability of the enzyme lysozyme to kill bacteria, Fleming realized that the mold was secreting something that stopped bacterial growth. He knew that this substance might have enormous utility to medicine. Although he was unable to purify the compound (the beta-lactam ring in the penicillin molecule was not stable under the purification methods he tried), he reported it in the scientific literature. Since the mold was of the genus Penicillium, he named this compound penicillin.

DISCOVERY OF SULFANILIMIDE AND TYROTHRICIN:
In the 1930s German scientists investigated the antibacterial properties of certain dyes. One of these was a sulfonamide, prontosil, which was used to treat infections in humans, where its effect was found to be due to its conversion in the host to the active form, sulfanilimide. By today's more broad definition, this would likely qualify as the first successful use of an oral antibiotic. During the same era, Rene Dubos isolated tyrothricin, an antibiotic used topically for skin infections, from soil bacteria.

With the increased need for treating wound infections in World War II, resources were poured into investigating and purifying penicillin, and a team led by Howard Walter Florey succeeded in producing usable quantities of the purified active ingredient which were quickly tested on clinical cases.

WINNERS OF NOBEL PRIZE:
In 1928, Alexander Fleming discovered penicillin, a substance produced by fungi that appeared able to inhibit bacterial growth. In 1939, Edward Chain and Howard Florey further studied penicillin and later carried out trials of penicillin on humans (with what were deemed fatal bacterial infections). Fleming, Florey and Chain shared the Nobel Prize in 1945 for their work which ushered in the era of antibiotics.

SOURCES OF ANTIBIOTICS:
BACTERIA:

• Bacillus brevis
• B. polymyxa
• B. subtilis

• streptococcus cremoris

ACTINOMYCETES:

• Micromonospora purpurea
• Nocardia mediterranei
• Streptomyces griseus
• S. aureofaciens
• S. erythreus

• S. noursei

FUNGI:

• Cephalosporium acremonium
• Penicillium chrysogenum
• P. griseofulvum
• P. notatum

REQUIREMENTS OF ANTIBIOTIC:

• Should not be toxic
• Should not precipitate serum proteins
• Should not cause haemolysis
• Should not cause histamine like responses
• Should preferably, be soluble in water
• Should not be pyrogenic
• Reasonably stable
• Should be effective against pathogens
• Well tolerated in the doses required.
• Should have a few undesirable side effects

ADSORPTION OF ANTIBIOTICS:
Adsorption of antibiotics depends on the route of administration and the diffusion capacity of the drug from the site. Drugs administered parentally are more quickly adsorbed than orally or locally routed. The onset of drug action depends upon the route of administration and its adsorption. Delay in administration and its adsorption depends on the fact that the drug must be converted to an active compound or to the products, which are secondly responsible for the action.

METABOLISM AND EXCRETION OF ANTIBIOTICS:
The drug is metabolized by any one of the following ways:

• Kidneys are the most important channels for the elimination of drugs.
• They are also excreted through faeces, sweat, and through the respiration, especially the volatile drugs

ROUTE OF ADMINISTRATION OF ANTIBIOTICS:
LOCAL APPLICATION:
They are applied mainly to skin, mucous membranes of alimentary canal, respiratory, genitourinary tract and to the cornea. Even the tissue and organs sealed deeply can also be treated with the local injection to antibiotics.

ORAL:
They can be taken orally.

PARENTRAL:
Antibiotics are injected intra-muscularly, intravenously, intrathecally (in spinal cord) and in the bone marrow etc. this route of administration is referred to as parentral. Intravenously route is less painful, less irritant and fast results; larger quantities of drugs can be given (bolus dose) while intra-muscularly routed is cheaper and less complicated.

INHALATION:
Antibiotics are also used in the form of aerosol that is they are dispersed in to the small molecules and are sprayed in respiratory passages.

SPECTRUM OF ANTIBIOTICS:
BROAD SPECTRUM ANTIBIOTICS:
The term broad-spectrum antibiotic refers to an antibiotic with activity against a wide range of disease-causing bacteria. It is also means that it acts against both Gram-positive and Gram-negative bacteria.

EXAMPLES OF BROAD SPECTRUM ANTIBIOTICS:
A good example of a commonly used broad-spectrum antibiotic is levofloxacin.
Clavamox for cats is used for urinary tract infection. It is a broad spectrum antibiotic which combines Amoxicillin and clavulanic acid for infections caused by bacteria. Usually the dose of Clavamox cats is 6.25mg per pound given every 12 hours.

Munumbicins, wide-spectrum antibiotics produced by Streptomyces NRRL 30562, endophytic on Kennedia nigriscansa. Munumbicins A, B, C and D are newly described antibiotics with a wide spectrum of activity against many human as well as plant pathogenic fungi and bacteria, and a Plasmodium sp.

Another antibiotic, for example, is tetracycline (brand names: Achromycin and Sumycin), a broad-spectrum agent effective against a wide variety of bacteria including Hemophilus influenzae, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Neisseria gonorrhoea, and many others.

Broad-spectrum antibiotics are properly used in the following medical situations:

• Empirically prior to identifying the causative bacteria when there is a wide differential and potentially serious illness would result in delay of treatment. This occurs, for example, in meningitis, where the patient can become so ill that he/she could die within hours if broad-spectrum antibiotics are not initiated.
• For drug resistant bacteria that do not respond to other, more narrow-spectrum antibiotics.
• In super-infections where there are multiple types of bacteria causing illness, thus warranting either a broad-spectrum antibiotic or combination antibiotic therapy.

NARROW SPECTRUM ANTIBIOTICS:
This is in contrast to a narrow-spectrum antibiotic which is effective against only specific families of bacteria.

MODE OF ACTION OF ANTIBIOTICS:
All the antibiotics have different mode of action by which they act as therapeutic agents. Some of the modes of action by different antibiotics are mentioned below:

CELL WALL SYNTHESIS INHIBITORS:
Bacteria contain murein or peptidoglycan that is highly essential in maintaining the cell wall structure. Cell wall synthesis inhibitors such as beta-lactams, cephalosporins and glycopeptides block the ability of microorganisms to synthesize their cell wall by inhibiting the synthesis of peptidoglycan.



INTERFERING WITH PROTEIN SYNTHESIS:
These classes of antibiotics inhibit the protein synthesis machinery in the cell. Some examples include tetracyclines, chloramphenicol, aminoglycosides and macrolides.

CELL MEMBRANE INHIBITORS:
Antibiotics such as polymyxins disrupt the integrity and structure of cell membranes, thereby killing them. These set of antibiotics are mostly effective on gram negative bacteria because these are the bacteria that contain a definite cell membrane.

EFFECT ON NUCLEIC ACIDS:
DNA and RNA are extremely essential nucleic acids present in every living cell. Antibiotics such as quinolones and rifamycins bind to the proteins that are required for the processing of DNA and RNA, thus blocking their synthesis and thereby affecting the growth of the cells.

COMPETITIVE INHIBITORS:
Also referred to as anti-metabolites or growth factor analogs, these are antibiotics that competitively inhibit the important metabolic pathways occurring inside the bacterial cell. Important ones in this class are sulfonamides such as Gantrisin and Trimethoprim.
Differences in mode of action of (ß-lactam antibiotics influence morphology, LPS release and in vivo antibiotic efficacy.

SOMETHING ABOUT PENICILLIN:

• Alexander Fleming discovered penicillin.
• Clutter buck et al., (1932) studied the chemical nature.
• Studies on P. notatum confirmed that it produce 2 ppm active substance.
• Biological activity was studied by chain et al.
• During world war II-importance realized, as penicillin had been used to treat many wounded soldiers.

INDUSTRIAL PRODUCTION OF ANTIBIOTIC- PENICILLIN:
The industrial production of penicillin was broadly classified in to two processes namely,

• Upstream processing
• Downstream processing

UPSTREAM PROCESSING:
Upstream processing encompasses any technology that leads to the synthesis of a product. Upstream includes the exploration, development and production.

SELECTION & IMPROVEMENT OF STRAIN:
It is highly desirable to choose a high yielding strain which could be obtained by sequential genetic selection. In other words, such a strain can be obtained by step-wise development with the help of a series of mutagenic treatments, each followed by the selection of mutants. Mutations in Penicillium chrysogenum are induced by UV. Mutant possesses a far greater capacity for antibiotic production rather than the wild strain.

STORAGE OF STRAINS:
Production strains are stored in a dormant form by any one of the following standard culture preservation techniques;

• A spore suspension may be mixed with a sterile, finely divided inert Support and desiccated.
• Spore suspension can be lyophilized in appropriate media.
• Spore suspension can be stored under liquid nitrogen, i.e. in a frozen state.

INOCULUM PREPARATION:
The aim is to develop pure inoculums in sufficient volume and in the fast growing phase for the production stage fermenter. The time taken for each stage is measured in days, and it decreases as the sequence progresses.

The medium is designed to provide the organism with all the nutrients that it requires. For example, Mayer and Coghill suggested the following sporulation medium;

The flask containing the Seeded medium is incubated on a rotary shaker to effect aeration and agitation. Adequate oxygen is supplied in the form of sterile air. In addition, the temperature 24 degree Celsius is controlled.

INOCULATION METHODS:
Any one of the following methods may be used to inoculate the fermentation medium in the submerged culture production of penicillin.

• Dry spores may be used to seed the fermentation medium.
• The fermentation medium may be seeded by pellet inocula obtained by the germination of spores, with the formation of mycelia growth, under submerged conditions. It is a common practice to seed the fermentation medium with pellets two or three days after the medium has been seeded with pairs.

RAW MATERIALS:

CARBON SOURCES:
Lactose acts as a very satisfactory carbon compound, provided that is used in a concentration of 6%. Others such as glucose & sucrose may be used.

NITROGEN SOURCES:
Ammonium sulphate and ammonium acetate can be used as nitrogenous sources.

MINERAL SOURCES:
Elements namely potassium, phosphorus, magnesium, sulphur, zinc and copper are essential for penicillin production. Some of these are applied by corn steep liquor.

FERMENTATION PROCESS:
The fermentation process is usually carried out in a large fermenter. The fermentation medium is formulated and fed in to the fermenter. The inoculum is also maintained properly.

Then a small amount of inoculum is seeded in to the fermenter. The fermentation conditions such as temperature, PH, mineral contents should also be maintained. The process starts immediately after the addition of the inoculum strain. After the required amount of time, the required antibiotic is produced in the fermenter.



DOWNSTREAM PROCESSING:
The extraction and purification of a biotechnological product from fermentation is referred to as downstream processing.

STAGES IN DOWNSTREAM PROCESSING:

SOLID – LIQUID SEPARATION:
The first step in product recovery is the separation of whole cells and other insoluble ingredients from the culture broth. Several methods such as floatation, flocculation etc, are used to serve this purpose.

CONCENTRATION:
This is a step followed to concentrate the desired product. The methods used to concentrate includes adsorption, precipitation etc.

PURIFICATION:
Chromatographic techniques are generally used to purify the product. As concerned with the production of antibiotics ion exchange chromatography seems to be the better option.

EXTRACTION AND PURIFICATION OF PENICILLIN:
There are some special techniques used for the extraction of penicillin from the fermentation medium. They are as follow

REMOVAL OF MYCELIUM:
At harvest, the penicillin is in solution exocellularly, together with a range of other metabolites and medium components. First remove the mycelium by filtration. A rotary vacuum filter is employed for the filtration of fermented production medium. This stage is carried to avoid contamination of the filtrate with Penicillinase producing micro organisms which may cause serious or total loss of an antibiotic.

COUNTERCURRENT SOLVENT EXTRACTION OF PENICILLIN:
The next stage is to extract the penicillin. The PH is adjusted to 2-2.5 with the help of phosphoric or sulphuric acids. In aqueous solution at low PH values there is a partition coefficient in favour of certain organic solvents. This step has to be carried out quickly for penicillin is very unstable at low PH values. Podbielniak countercurrent solvent extractor is used for this purpose. Antibiotic is then extracted back into an aqueous buffer at a PH of 7-7.5, the partition coefficient now being strongly in favour of the aqueous phase. The resulting aqueous solution is again acidified & re-extracted with an organic solvent. These shifts between the water and solvent help in the purification of penicillin. The Spent solvent is rediscovered by distillation for reuse

TREATMENT OF CRUDE EXTRACT:
The treatment of the crude penicillin extract varies according to the


objective, but involves the formation of an appropriate penicillin salt. The solvent extract recovered in the previous stage is carefully extracted back with aqueous sodium hydroxide. This is followed by charcoal treatment to eliminate pyrogens and by sterilization. Pure metal salts of penicillin can be safely sterilized by dry heat, if desired. Thereafter, the aqueous solution of penicillin is subjected to crystallization.

For parental use, the antibiotic is packed in sterile vials as a powder or suspension. For oral use, it is tabletted usually now with a film coating. Searching tests (ex: for purity, potency) are performed on the appreciable number of random samples of the finished product. It must satisfy fully all the strict government standards before being marketed.



APPLICATIONS OF ANTIBIOTICS:
Unlike previous treatments for infections, which included poisons such as strychnine, antibiotics were labeled "magic bullets": drugs which targeted disease without harming the host. The effectiveness of individual antibiotics varies with the location of the infection and the ability of the antibiotic to reach this site. Oral antibiotics are the simplest approach when effective, with intravenous antibiotics reserved for more serious cases. Antibiotics may sometimes be administered topically, as with eye drops or ointments.

• An American, Dr. Selman Waksman, discovered streptomycin which proved to be effective against diseases that penicillin could not cure, such as the bubonic plague.
• Sulfa drug was a chemical that had been found in a substance used to make dyes. These were powerful weapons against disease but had serious drawbacks. It was then found that sulfa drugs did not kill germs but rather weakened germs, which gave the body a chance to defend itself.
• One laboratory discovered Aureomycin and that does the work of both penicillin and streptomycin.
• In 1949, an Indiana laboratory discovered Terramycin, now considered to be one of the most effective antibiotics ever found because of its wide effect on so many bacterial diseases.
• Another laboratory discovered Chloromycetin, which was proven effective against typhus, whooping cough and typhoid.
• Poultry growers use fluoroquinolone drugs to keep chickens and turkeys from dying from E. coli infection, a disease that they could pick up from their own droppings.
• They are used in the preparation of media.
• They are also used as markers. (Antibiotic resistant gene) Ex. Ampicillin
• Clinical Applications of Antibiotics and Anti-Inflammatory Drugs in Ophthalmology:
• Clinical Applications of Antibiotics and Anti-Inflammatory Drugs in Ophthalmology is a complete, current guide to antibiotic and anti-inflammatory pharmacotherapy in ophthalmology and ocular surgery.

Clinical Applications of Antibiotics and Anti-Inflammatory Drugs in Ophthalmology include up-to-date information on:

• New generation fluoroquinolones
• New uses of tetracyclines
• New anti-inflammatory drugs
• Endophthalmitis prophylaxis and management

And treatment of:

• Corneal ulcers
• Uveitis
• Cystoids macular edema
• Post-refractive keratitis

Close attention is given to pre- operative and post- operative antibiotic prophylaxis and no steroidal anti-inflammatory therapy to optimize outcomes in cataract and refractive surgeries.

OTHER CLINICAL APPLICATIONS OF ANTIBIOTICS:

• Tyrothricin used to treat throat and mouth infection

• Bacitracin used to treat dermatitis, superficial pyogenic infection, dysentery.

• Rifamycin used to treat meningitis.
• Nisin is used in cheese industry for food preservation (non medical use).

• Cephalosporin used to treat urinary tract infections & meningitis.
• Gentamycin and novobiocin are used to treat abscess.

• The oral options to treat acne include tetracycline or erythromycin.
• Streptomycin is used to treat tuberculosis.

• Nystatin and Griseofulvin used to treat skin and hair lesions.

• Tetracyclines and Erythyromycin are used to treat cholera, tetanus and arthritis.

• Penicillin used to cure pneumonia, pharyngitis, fever and genital infections.

• Polymyxin is used to treat urinary tract infection.

TREATING ACNE WITH ANTIBIOTICS:
Acne is caused at least in part from bacteria; it is very helpful to many to actually use antibiotics to help treat the condition. It is necessary for you to seek out a doctor to help in the purchase of prescription antibiotics, but many are given by family doctors for patients that are in need an oral antibiotic!. Oral antibiotics can be beneficial as well as topical products. If you have a large area that is in need of treatment, these can be quite difficult to treat with topical ointments. It can be easier then to just take the medication orally. The oral options to treat acne include tetracycline or erythromycin. These are the most common options for oral antibiotics for acne treatment!. These medications can help you to stop the bacteria that is irritating your skin and therefore causing it to be irritated, but this does not, by itself, improve the acne that you have. As soon as the bacterium gets to the pores, again, you still have a problem.

Topical products can actually be better for some individuals because they do not cause any real side effects that ingesting can cause such as stomach problems and drug interactions with other medications that you are taking. The most common types of antibiotics for topical treatments of acne include clindamycin, erythromycin and in some cases tetracycline.

DEMERITS OF ANTIBIOTIC THERAPY:

• Antibiotics develop drug-resistant strain in body.
• Antibiotics develop narrow spectrum property of antibacterial activity in body.
• Body failure to respond in certain infection caused by gram negative bacilli and other microorganisms.
• They develop nutritional deficiency in the body.

SIDE EFFECTS OF ANTIBIOTICS:
It is well known that large doses of penicillin and streptomycin have a neurotoxic effect. Tetracyclines affect the liver, chloromycetin has a toxic effect on the haemotopoietic organs, and chlortetracycline and tetracycline upon intravenous injection may lead to collapse with a lethal outcome. After injection of penicillin and streptomycin a rash, contact dermatitis, angioneurotic odema, anaphylactic reactions or allergic asthma may occur. On local application of antibiotics, allergic reaction may arise. Staphylococcal colitis proceeds very severally, and is characterized by profuse diarrhea, dehydration of the body, toxic phenomena, shock and collapse. Penicillin treatment may cause a rapid drop in blood pressure, cyanosis, superficial breathing, loss of consciousness, and convulsions are observed, and in some cases death may occur.

Sometimes antibiotics may cause skin allergy reaction. This is caused by action of streptomycin. Quite often allergic manifestations are observed in the mucous membranes such as hyperaemia and oedema of the pharynx and tongue.

Antibacterial agents may induce genetic disorder in micro organism’s cells and cause chromosomal aberration; some of them possess a teratogenic effect leading to the development of foetal monstrosities if they are taken in the first days of pregnancy.

ANTIBIOTIC RESISITANCE:
The emergence of antibiotic resistance is an evolutionary process that is based on selection for organisms that have enhanced ability to survive doses of antibiotics that would have previously been lethal. Antibiotics like Penicillin and Erythromycin which used to be one-time miracle cures are now less effective because bacteria have become more resistant. Antibiotics themselves act as a selective pressure which allows the growth of resistant bacteria within a population and inhibits susceptible bacteria. Additional mutations, however, may compensate for this fitness cost and aids the survival of these bacteria.

The underlying molecular mechanisms leading to antibiotic resistance can vary. Intrinsic resistance may naturally occur as a result of the bacteria's genetic makeup. The bacterial chromosome may fail to encode a protein which the antibiotic targets. Acquired resistance results from a mutation in the bacterial chromosome or the acquisition of extra-chromosomal DNA. The spread of antibiotic resistance mechanisms occurs through vertical transmission of inherited mutations from previous generations and genetic recombination of DNA by horizontal genetic exchange.


Antibiotic resistance exchanged between different bacteria by plasmids that carry genes which encode antibiotic resistance which may result in co-resistance to multiple antibiotics. These plasmids can carry different genes with diverse resistance mechanisms to unrelated antibiotics but because they are located on the same plasmid multiple antibiotic resistances to more than one antibiotic is transferred. Alternatively, cross-resistance to other antibiotics within the bacteria results when the same resistance mechanism is responsible for resistance to more than one antibiotic is selected for.

ANTIBIOTIC MISUSE:
Several organizations concerned with antimicrobial resistance are lobbying to improve the regulatory climate. Approaches to tackling the issues of misuse and overuse of antibiotics by the establishment of the U.S. Interagency Task Force on Antimicrobial Resistance which aims actively address the problem antimicrobial resistance are being organised and coordinated by the US Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) and also includes several other federal agencies. An NGO campaign group is Keep Antibiotics Working. In France, an "Antibiotics are not automatic" government campaign starting in 2002 led to a marked reduction of unnecessary antibiotic prescriptions, especially in children.

The overuse of antibiotics like penicillin and erythromycin which used to be one-time miracle cures was associated with emerging resistance since the 1950s. Therapeutic usage of antibiotics in hospitals has been seen to be associated with increases in multi-antibiotic resistant bacteria.
Common forms of antibiotic misuse include failure to take into account the patient's weight and history of prior antibiotic use when prescribing, since both can strongly affect the efficacy of an antibiotic prescription, failure to take the entire prescribed course of the antibiotic, failure to prescribe or take the course of treatment at fairly precise correct daily intervals (e.g. "every 8 hours" rather than merely "3x per day"), or failure to rest for sufficient recovery to allow clearance of the infecting organism. These practices may facilitate the development of bacterial populations with antibiotic resistance. Inappropriate antibiotic treatment is another common form of antibiotic misuse. A common example is the prescription and use of antibiotics to treat viral infections such as the common cold that have no effect.

Antibiotic use in food animal production has been associated with the emergence of antibiotic-resistant strains of bacteria including Salmonella spp., Campylobacter spp., Escherichia coli, and Enterococcus spp.

Excessive use of prophylactic antibiotics in travelers may also be classified as misuse.
In the United Kingdom, there are NHS posters in many doctors surgeries indicating that 'unfortunately, no amount of antibiotics will get rid of your cold', following on from many patients specifically requesting antibiotics from their doctor inappropriately, believing they will help treat viral infections.

Drug companies continue to seek new antibiotics in nature and their chemists are now making synthetic antibiotics. Since it is very difficult for a chemist to imitate the work done by microbes, most antibiotics nowadays are semi-synthetic. Chloromycetin, cycloserine and a synthetic tetracycline were the first few antibiotics that have been produced entirely by man.

RESISTANCE MODIFYING AGENTS:
One solution to combat resistance currently being researched is the development of pharmaceutical compounds that would revert multiple antibiotic resistances. These so called resistance modifying agents may target and inhibit MDR mechanisms, rendering the bacteria susceptible to antibiotics to which they were previously resistant. These compounds targets include among others.

SOME OF THE ANTIBIOTIC PRODUCING COMPANIES:

INDIAN COMPANIES:

• Biochem pahamaceutical – Bombay.
• Glaxo india Ltd – Bombay.
• Hindustan antibiotic Ltd – Pimpri, Pune.
• Indian drugs & pharmaceuticals- Rishikesh.
• Sarabai chemicals – vadodara
• Pfizer Ltd, bombay

FOREIGN COMPANIES:

• American Cynamid - USA
• Glaxo laboratories Ltd – England.
• Hoechst AG, W. Germany.
• Pfizer, - USA.
• Wyeth laboratories – USA
• Imperial chemical industry Ltd – England.

CONCLUSION:
Almost everyone has used an antibiotic like penicillin or Terramycin at one time or another. You may have tried using an antibiotic ointment for bad cuts or scrapes, or your doctor may have prescribed antibiotics to help you get over fever, boils, pneumonia and other infections. Antibiotics work very well against so many infections that they are often called "miracle drugs". But the more accurate name for them would be "microbe drugs" for that is what antibiotics really are.

RULE OF ANTIBIOTICS:
The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them.
—Paul L. Marino, The ICU Book