Antimicrobial Agents

Anti-Microbial Agents—these are the substances, either natural or synthetic, which can kill or inhibit the growth of the microorganism.

Antibiotics—it is a natural chemical substance produced by the living microorganism either to kill or inhibit the growth of the susceptible microorganism. (Penicillin)

Chemotherapeutic Agents—it is a substance which is obtained from synthetic or non-living source either to kill or inhibit the growth of the susceptible micro-organism.

Anti-microbial agents are of 2 types—

1.   Bactericidal

2.   Bacteriostatic

Bactericidal—these are the substances that can kill the susceptible microorganism.

Ex—	β-Lactums—Penicillin (cannot kill enterococcal bacteria)
	Aminoglycosides—Gentamicin, Streptomycin
	Quinolones (action is very quick)

Bacteriostatic—these are the substances that can inhibit the growth of the susceptible microorganism.

Ex—	Chloramphenicol (used in typhoid) Tetracycline Erythromycin Sulfonamide

*** the drug potency depends upon the defense mechanism of the host.

*** defense mechanism can be suppressed by neutropenia, AIDS etc.

MIC (minimum inhibitory concentration)

It is the minimum concentration of drug which can inhibit the growth of the microorganism.

MBC (minimum bactericidal concentration)

It is the minimum concentration of drug which can kill the microorganism.

Chemotherapeutic Spectrum / Antimicrobial Spectrum—

It is divided into—Narrow Spectrum & Broad Spectrum.

Narrow spectrum—antibiotics which act against a limited group usually either gm +ve or gm –ve.

Ex—	Isoniazide (INH) acts against TB Antistaphylococcal Penicillin acts only against staphylococcus only

Broad spectrum—antibiotics which act against both gm +ve and gm –ve and other microorganisms.

Ex—	Amoxicillin Quinolones Emipenems Penicillin Tazobactum

Mechanism of Action of Antimicrobial Agents—

1.   Inhibition of the cell wall synthesis (Penicillin, Cephalosporin, Vancomycin, Bacitracin, Carbapenem, Monobactum)

2.   Interference of the cell membrane function (Amphotericin-B, Polymixin, Isoniazide, Azoles)

3.   Inhibition of the protein synthesis (Tetracycline, Chloramphenicol, Aminoglycosides, Macrolides)

4.   Inhibition of the nucleic acid synthesis (Rifampicin, Sulphonamide, Trimethoprim, Quinolones)

Classification of the Antimicrobial Agents—

Broad classification—	Bactericidal Bacteriostatic
According to the spectrum—	Narrow Broad
According to the species—	Antiviral Antibacterial Antifungal Antiprotozoal Antihelminthic

Drug Combination—

simultaneous use of two or more drugs separately or combination of drugs in a single pharmaceutical formulation is called drug combination.

Effects of Combination Therapy—

A. Additive effect—additive effect occurs if two drugs with the same effect, when given together, produce an effect that is equal in magnitude to the sum of the effects when the drugs are given individually. Example—

Ephedrine + Aminophylline in bronchial asthma.

B. Synergism (chemotherapeutic potential)—it occurs when a chemotherapeutic agent potentates the action of other chemotherapeutic agent. Example—

i. Co-trimoxazole—it includes Trimethoprim and Sulfamethoxazole. It inhibits the successive steps of metabolic pathway in folic acid synthesis of bacteria. Folic acid synthesis—

ii. Amoxicillin + Clavulanic acid. Here Clavulanic acid inhibits the β-lactamase enzyme which destroys amoxicillin.

iii. Penicillin + Aminoglycosides. One drug facilitates the penetration of other drug through cell wall. Here penicillin penetrates the cell wall andAminoglycosides enter the cell. In case of enterococcal endocarditis this drug is given.

C. Antagonism—bacteriostatic and bactericidal cannot be given together. Penicillin + Tetracycline cannot be given together. Bactericidal drugs act on the rapidly proliferating bacteria. Bacteriostatic stops this rapid proliferation and thus bactericidals cannot act.

Advantages of combination therapy—

a.  To avoid the development of resistance.

b.  To avoid the toxicity of individual drug.

c.  To provide broad coverage in poly-microbial infection (intra-abdominal, hepatic, cerebral, genitourinary). Acts on the gm +ve, gm –ve and anaerobic bacteria.

d.  Sever infections where the cause is unknown. It is called Initial Blind / Umbrella / Empirical therapy.

e.  Enhancement of the anti-microbial activity in specific infection (Potentiation). In enterococcal endocarditis Penicillin and Aminoglycosides are given together.

f.   When the pathogen cannot be easily killed and prevention of emergence of resistance. (Tuberculosis, Leprosy)

Disadvantage of Combination Therapy—

a.  Increases toxicity

b. Antagonism

c.  Increases cost

Hazards of Antimicrobial Agents—

a.  Development of bacterial resistance (drug resistance)

b.  Cross resistance

c.  Toxicity

d.  Chronicity

e.  Relapse

f.   Allergy and Hypersensitivity reaction

g.  Superinfection

Rational Use of Drug / Principle of Antimicrobial Therapy—

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

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.

Causative organism of Superinfection—

1.  Candida or fungal infection commonly.

2.  Enterobacteriaceae (Shigella, Salmonella, Escherichia, Klebsiella)

3.  Pseudomonas

4.  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—

§  Exogenous Organism

§  Endogenous Proliferation

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.

Incidence of Superinfection—

a.  Lowest with narrow spectrum (Penicillin-G)

b.  Higher with extended spectrum (Chloramphenicol, Tetracycline)

c.  Highest with broad spectrum (3^rd generation Cephalosporin)

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 andMetronidazole.

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

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

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 acetyltransferase)

·    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.

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o     Very severe type of reaction but incidence is very rare (0.05%)

Mechanism of Action—

When Penicillin enters the body, the body produce IgE mediated antibody and attaches it on the cell membrane of the mast cell. During 2^nd exposure the antigen comes to the mast cell and antigen antibody reaction takes place and there is degranulation of the mast cell. Large amount of histamine is released along with heparin and other chemical mediators. Due to more histamine—

§  Vasodilatation occurs and the patient develops shock.

§  Severe asthma develops due to bronchoconstriction.

Clinical features—

1.   Onset is most dramatic

2.   Very severe hypotension

3.   Shock

4.   Severe bronchoconstriction and asthma

5.   Abdominal pain

6.   Purpuric skin lesion

7.   Nausea

8.   Vomiting

9.   Extreme weakness

Drug of choice—

1.   Adrenalin

2.   Corticosteroid

3.   Anti-histamine

4.   Maintenance of the fluid and electrolyte balance

Differences between Amoxicillin and Ampicillin—

Traits	Amoxicillin	Ampicillin
Lipid solubility	More	Less
Absorption in GIT	More	Less
Bioavailability	Higher	Lower
Half life	8 hours	6 hours
Duration of action	More	Less
Effect of food on absorption	Food effects absorption	Not so
Route	Mainly oral	Oral and parenteral
Adverse effects	Less	More

Drugs with their routes of administration—

Drug	Routes of Administration
Benzyl Penicillin	IV, IM (very painful as IM)
Ampicillin	Oral, Parenteral
Amoxicillin	Oral
Penicillin-V	Oral
Procaine Penicillin Benzathene Penicillin	Oral (always)