# Pharmacology/Antibiotics

Antibiotics are drugs that are used in the treatment or prevention of bacterial infections. Strictly speaking, antibiotics are natural substances produced by micro-organisms as opposed to semi-synthetic or synthetic antibiotics, which are either natural substances artificially modified or totally human created respectively. In common parlance and clinical practice this distinction is not used currently.
Antibiotics form part of a wider range of antimicrobial agents, a group which also includes antifungals, antivirals, antiprotozoals and disinfectants. This group is also known as chemotherapeutic agents.

## Concepts in antibiotic pharmacology
### Blind therapy

Initial or Blind or Umbrella or Empirical therapy refers to the treatment of an infection without knowing the causative pathogen. This will refer to the first presentation of an infected patient, where the clinician must decide which antibiotics to use prior to laboratory confirmation.

### Bacteriostatic

A drug that inhibits growth or development of a bacterium, rather than directly killing it.
Bacteriostatic drugs depend upon the immune system of the patient for activity, and so make for a poor choice where the immune system is compromised, for example patients with AIDS. A drug that is bactericidal for one strain of bacteria may only inhibit the growth of another strain. Although it might seem logical that bactericidal drugs would be preferable to bacteriostatic drugs, the type of infection is important in determining which kind of drug to use. Endocarditis seems to be best treated by bactericidal drugs. Meningitis is another candidate for bactericidal drugs. Strikingly, a bacteriostatic drug can antagonize the action of a bactericidal one in the treatment of meningitis. In treating urinary tract infections and preventing staphylococcal wound infections, studies have shown that bacteriostatic drugs work as well as bactericidal drugs.
In central nervous system infections, a rapidly bactericidal drug can release bacterial products that stimulate inflammation. For this reason, it is recommended that corticosteroids be given at the same time as a bactericidal antibiotic for bacterial meningitis. Certain bacteriostatic drugs may be preferable in cases of streptococcal and clostridial gangrene, because they inhibit the production of the toxins that cause much of the morbidity.
Some infectious disease physicians wrongly believe that bacteria-killing drugs are automatically preferable to those that inhibit bacterial growth.
The MIC (minimum inhibitory concentration) is the minimum concentration of drug which can inhibit the growth of the microorganism.

### Bacteriocidal

A drug that directly kills a bacterium. The MBC (minimum bactericidal concentration) is the minimum concentration of drug which can kill the microorganism.

### Chemotherapeutic Spectrum / Antimicrobial Spectrum

The range of bacteria that an antibiotic affects, divided into Narrow Spectrum and Broad Spectrum.
* Narrow spectrum antibiotics act against a limited group of bacteria, for example sodium fusidate only acts against staphylococcal bacteria.
* Broad spectrum—antibiotics act against a larger group of bacteria, for example amoxicillin.

### Combination therapy

The use of two or more agents simultaneously. This combination can produce:
* An additive effect
* Synergistic effect, where the effect of using both agents together is greater than the sum of the effects of the drugs. This can be seen in
** Co-trimoxazole
** Co-amoxiclav
** Penicillin with an Aminoglycoside for endocarditis
** Quinupristin with dalfopristin
* Antagonism, where the combination reduces the activity of each antibiotic. This is seen where a bacteriostatic and a bactericidal drug are used in combination.
Reasons why this may be preferred include:
* To avoid the development of resistance, particularly in bacteria
* To provide broad coverage in polymicrobial infection
* Severe infections where the cause is unknown, or in empirical therapy.
* Synergy in specific infections
* Where the pathogen cannot be easily killed and prevention of emergence of resistance. (Tuberculosis, Leprosy)
Reasons why combination therapy might not be preferred include:
* Increased toxicity
* Antagonism - the two agents interact resulting in reduced antibiotic effect
* Increased cost
Some agents are available in combination within a single pharmaceutical preparation, for example co-amoxiclav contains both the active agent "amoxicillin" and the enzyme inhibitor "clavulanic acid", which extends the spectrum of amoxicillin.

## Superinfection

It is a phenomenon may be defined as appearance of bacteriological and clinical evidence of new infection during the chemotherapy of a primary one.
Some causative organism of Superinfection
* Candida or fungal infection commonly
* Enterobacteriaceae (Shigella, Salmonella, Escherichia, Klebsiella)
* Pseudomonas
* Staphylococcus
Mechanism of Action—
Normal bacterial flora like E. coli produces vit-K. But antibiotics can destroy the flora, those who are sensitive to that antibiotic and there is imbalance of the flora. Then there is development of endogenous bacteria and overgrowth of micro-organism. So, there is another infection called Superinfection. Superinfection may occur in two ways—
Superinfections mostly occur in broad spectrums. Due to antimicrobial therapy there is removal of the inhibitory influence of the drug sensitive flora that is normally inhibited in the nasopharynx and other body orifices. Many of these floras produce antibacterial substance called Bacteriosin. As a result of alteration of normal microbial flora of the host, there is establishment of growth of exogenous microorganism and endogenous proliferation of microorganism which are relatively not sensitive to that particular antibiotic. So, secondary infection is superimposed on the original infection. Usually they are Candida. The Superinfection is common and usually dangerous.
The incidence of superinfection can be reduced by using a narrow spectrum, such as benzylpenicillin, in preference to a broad spectrum antibiotic, such as cefotaxime.

## Mechanism of Action

Variation in site of action can indicate why certain antibiotics operate against certain bacteria, but not others.
The principle sites of action are:
* Cell wall synthesis : Beta-lactam (Penicillin, Cephalosporin, Carbapenem and Monobactam), Fosfomycin, Glycopeptide
* Cell membrane function : Polymixine
* Protein synthesis : Macrolide, Tetracyclin, Lincosamide
* Nucleic acid synthesis : Fluoroquinolone, Nitroimidazole, Nitrofurantoin, Folic Acid Antagonist, Aminoglycoside

## Complications of antimicrobial therapy

* Development of bacterial resistance (drug resistance) including cross resistance.
* Toxicity
* Chronicity
* Relapse
* Allergy and Hypersensitivity reaction
* Superinfection
Causes of anti-microbial failure—
1. Development of drug resistance
2. Improper diagnosis
3. Improper selection of antimicrobials
4. Improper dose and dosing schedule
5. If the combination therapy is not used where necessary

## Rational use of antibiotics

The main basis is “SANE”
S → Specificity
A → Availability
N → Need to the community
E → Efficacy
1. Right diagnosis should be made either clinically or by laboratory.
2. Right decision should be made whether the chemotherapy is needed or not.
3. Proper selection of drug—
* Specificity
* Routes of administration
* Cost effectiveness
* Safe drug
* Proper combination
* Easy availability
* Essential drug (drugs needed for the vast majority of the population—ORS, Paracetamol)
4. Right dose—usually we give initially loaded dose followed by maintenance dose.
5. Right duration—at least 3-5 days antibiotic should be continued.
6. Right time schedule—to maintain MIC and MBC.
7. Status of the patient—
* Age of the patient
* Hepatic and renal function
* Pregnancy
* Lactating mother
* Immune system of the patient
* Site of infection
Chemoprophylaxis—
It is the use of drug to prevent infection by one organism virtually uniform susceptibility.
Categories—
A. True prevention—protection from invasion of microorganism, to which they are exposed.
* a. Penicillin prevent group-A β-hemolytic streptococci. The illness is mainly Rheumatic fever, Acute-Glomerulonephritis etc.
* b. Co-trimoxazole to prevent recurrent UTI caused by E. coli.
* c. Rifampicin and Minocycline to prevent meningococcal infection.
B. Secondary infection is prevented in patients ill with other diseases.
* a. Quinolones are used to prevent septicemia in immune compromised patients such as AIDS, Leucopenia etc.
C. Suppression of existing infection before it causes over disease.
* a. PPD (purified protein derivatives) test positive, Isoniazide is given against Tuberculosis.
* b. Chloroquine and Mefloquine are given to prevent malaria.
* c. Anti tetanus vaccine is given in trauma
D. Surgical chemoprophylaxis—it is the use of anti-microbials on a prophylactic basis in case of a surgery. It may be used for various surgical conditions. It is justified as follows—
* a. In operations where large number of bacteria are present in the target tissue.
* b. Where the infection risk is low but the consequence may be fatal (prosthatic valve).
* c. In susceptible patients (neutropenic patients)
* d. Based on the knowledge of the probable organism
Example—
1. In colorectal surgery there is high risk of infection with bacteroids, E. coli, Clostridia. So chemoprophylaxis may be achieved with Cephalosporin and Metronidazole.
2. In gastric conditions where acid secretion is low, infection risk is high. Such as prophylaxis of Cephalosporin may be given.
3. In gynaecological infection chemoprophylaxis is indicated prior to hysterectomy or perineal floor repair operation with Cephalosporins, Metronidazole. The lower genital tract contains bacteroids, coliform and anaerobes.
4. In valvular disease Penicillin is given.
5. In leg amputation Penicillin and Metronidazole is given to prevent gas gangrene

## Antimicrobial resistance

Bacteria are said to be resistant if their growth is not halted by the maximal level of an antibiotic that is tolerated by the host.
Development of antimicrobial resistance is one of the important causes of failure of anti-microbial therapy. Resistance develops as a result of the followings—
Natural resistant strains—during treatment some bacteria are naturally eliminated and those which are not will then proliferate.
Spontaneous mutation—it permits selective multiplication of resistant strains.
Transmission of genes from other bacteria—such transmission may be plasmid mediated or the resistance may occur by chromosomal or extra-chromosomal mechanisms.
The resistance is mediated via—
1. Production of enzyme that can modify the drug or inactivate the drug
2. ↓ the passage of anti-microbials into the cells
3. ↑ the influx of anti-microbial into the cell
4. Modification of the target site of the drug
Development of Bacterial Resistance—
Genetic—may be of 2 types—
1. Chromosomal—
This develops due to spontaneous mutation of DNA. Due to spontaneous mutation of DNA—
· Alteration of PBP (Penicillin binding protein) capacity
· Alteration of PBP
· Alteration of amino acids in ribosomes
· Alteration of DNA gyrase (it is inhibited by Quinolones)
· Alteration of protein of ribosomes
· Alteration of pathway of synthesis of folate
2. Extrachromosomal / Plasmid mediated—
Plasmid—plasmids are extra-chromosomal DNA molecule which may exist free in the bacterial cytoplasm. As they are extra-chromosomal the genetic information is readily transformed among the bacteria of same species and sometimes among the bacteria of other species. This transfer is encoded in the R-factor.
· Production of enzymes that destroy the active drugs. (β-lactamase, acetylating, adenylating, phosphorylating enzymes, chloramphenicol acetyl transferase)
· Reduced efficacy of drug for target.
· Production of new synthetic pathway to bypass the metabolic block. (Sulfonamide)
· Reduced uptake of drug. (Penicillin—altered porin channel in gm –ve, Aminoglycosides—no entry in gm +ve)
· Enhanced influx of drug from bacteria. (Tetracycline)
Non-genetic—
1. Some organisms may inherently resistant to an antibiotic. (Vancomycin—gm -ve)
2. Microorganisms those are metabolically inactive. (Mycobacterium—non multiplying)
3. Microorganisms may loss their specific target structure for a drug of several generations.
(Mycoplasma, Chlamydia, Rickettsia all of these are devoid of cell wall, Tetracycline is given in these cases)
Limitation of Resistance—
a. To give rational dose of drug, avoidance of discriminate.
b. Use of antimicrobial combination in appropriate circumstances.
c. Constant monitoring of resistance pattern in hospital or community acquired.
Cross Resistance—means when one group of microorganisms is resistant then at the same time another group of microorganism can be resistant when they share the same chemical structure of mechanism of action.
Ex—if Polymixin is resistant then Colistin is also resistant, if Neomycin is resistant then Kanamycin is also resistant.

## Health Hazard

Today’s society has access to more antibiotics than ever before, and tomorrow’s society will have even more access than today’s. Antibiotic cures for different ailments are used frequently by the human population. This seemingly benign, even beneficial, proliferation of antibiotic use has some dangerous repercussions.
Bacteria become drug resistant by exposure to a drug over a period of time long enough for it to build a resistant gene. This new resistant gene may be passed on to other bacteria through conjugation (transfer directly between cells) or transformation (picking up bits of DNA released by other bacteria). Some antibiotics such as tetracycline can actually catalyze the exchange of resistant genes between bacteria.
Disease in humans can be caused by either bacteria or viruses. A bacteria is a living, single-celled organism, while a virus is only living in conjunction with a host and is completely unresponsive to antibiotics. So, it is the reaction of bacteria, not viruses, to antibiotics that poses a hazard to human beings. This does bring to light the frequent inappropriate use of antibiotics in “treating” the common cold which is caused by a virus. Using antibiotics to battle the cold is done in vain, the only thing to be done in this case would be to let it run its course. By using antibiotics at this inappropriate time, the only effect on the body is the increased destruction of beneficial bacteria.
There are over 100 trillion bacteria in the human body, but most are innocuous, and can even be beneficial in warding off diseases. Many physicians still think of antibiotics as benign, but research has proved that they can actually change the microbial ecology of the body and facilitate the spread of drug-resistant genes to the public. Antibiotics kill off harmless bacteria that actually create competition for drug-resistant microbes. An example of the hazards of this can be seen in “Hospital-acquired infections”, where patients are often treated with multiple, powerful antibiotics which leaves them with minimal beneficial bacteria to ward off the many drug-resistant pathogens to which they are exposed.
Antibiotics are also erroneously used by farmers in the food of their livestock. These antibiotics are simply used to promote quick growth, and have massive repercussions on the human population consuming this livestock. Humans ingest the animals, who have been routinely exposed to antibiotics and have thus built up drug resistant bacterial genes, and introduce microbes into their bacteria infested GI tracts, thereby encouraging these resistant genes to spread from the infected livestocks' bacteria to their own bacteria.
Attempts to correct, or even to simply slow down, this eruption of hazardous effects of antibiotic use have been targeted towards the FDA and Department of Agriculture to reduce the use of antibiotics in livestock food, and towards physicians to utilize antibiotics more prudently. Yet, with little success in these endeavors thus far, and the increased discovery of additional antibiotics, some for lasting conditions such as heart disease, which would require the use of antibiotics over the span of one’s entire lifetime, the repercussions of society’s inappropriate and overuse of antibiotics is culminating into a dangerous epidemic.--Miacris 08:26, 20 November 2005 (UTC)