ANTIMICROBIAL CHEMOTHERAPY

Antibiotics are substances that are derived from various species of microorganisms and are capable of
inhibiting the growth of other microorganisms when administered in small concentrations. Antimicrobial
agents that are produced synthetically but have action similar to that of antibiotics have been defined as
chemotherapeutic agents (sulphonamides, quinolones ).

Bacteriostatic and Bactericidal Agents

Antimicrobial agents that reversibly inhibit growth of bacteria are called bacteriostatic (tetracycline,
chloramphenicol) whereas those with an irreversible lethal action on bacteria are known as bactericidal
(penicillins, isoniazid).

Desirable properties of an antimicrobial agent:

• Selective toxicity: should act on bacteria without damaging the host tissues
• Bactericidal rather than bacteriostatic
• Effective against a broad range of bacteria
• Should not be allergenic
• Should remain active in plasma, body fluids etc.
• Stable and preferably water soluble
• Desired levels should be reached rapidly and maintained for adequate period of time
• Should not give rise to resistance in bacteria
• Long shelf life
• Reasonable cost

Mechanism of Action of Antibiotics

Various antibiotics act on different sites of bacteria and some agents have more than one primary site of
action or mechanism by which bacteria are destroyed.

The Penicillins
Penicillins and cephalosporins act by inhibiting transpeptidases, the enzyme that catalyzes the final cross
linking step in synthesis of peptidoglycan. In non-growing cells, no new cross-linkages are required and
penicillin is inactive. An intact beta-lactam is essential for the antibacterial activity of the penicillin.
Classification of Penicillins
Natural
· Benzylpenicillin (penicillin G)
· Phenoxymethyl penicillin (penicillin V)
Semisynthetic and penicillinase resistant
· Methicillin
· N afcillin
· Cloxacillin
· Oxacillin
· Dicloxacillin
· Floxacillin
Extended spectrum
. Aminopenicillins
- Ampicillin
- Amoxycillin
Carboxypenicillins
- Carbenicillin
- Ticracillin
Ureidopenicillin
- Piperacillin

Resistance to penicillin is mainly due to the modification of the antibiotic by the enzyme beta lactamase or
penicillin amidase, commonly called as penicillinase. The enzyme penicillinase is found both in Gram
positive and Gram negative organisms.
Beta Ladamase Inhibitors: The activity of beta lactamase can be inhibited by clavulinic acid which is a
product of Strept.clavuligerus. This is a semisynthetic sulfone derivative with weak antibacterial activity of
its own. It acts best when administered in combination with ampicillin.
Tazobactam; This is a penicillonic acid sulfone derivative. It gives best results when used in combination
with piperacillin.
Cephalosporins are also beta-Iactam drugs that act in the same manner as penicillins. The structures,
however, are different. Cephalopsorins are the products of molds of genus Cephalosporium, except
cefoxilin which is produced from Streptomyces.

Other Beta Lactam Antibiotics

Carbapenems: These drugs have the widest antibacterial range. Structurally these differ from other beta
lactam antibiotics. Imipenem is the first compound of this group that has been clinically used.
Quinolones: (or 4-quinolones) are the first wholly synthetic antimicrobials. Quinolones act on DNA gyrase
(topoisomerase II) which prevents DNA polymerase from proceeding at replication fork and consequently
stopping DNA synthesis
Aminoglycosides: are a group of antibiotics in which amino sugars are linked by glycoside bonds. Best
known aminoglycoside is streptomycin. Streptomycin, other aminoglycoside and tetracyclines act at the
level of ribosomes not compatible with ribosomal subunit and inhibit initiation phase of protein synthesis.
All the amino glycoside antibiotics (gentamicin, neomycins, paromomycins, tobramycins, kanamycins, and
spectinomycins) have action against a wide spectrum of organisms and are bactericidal with the exception
of spectinomycin.
Tetracyclines: are a group of broad spectrum antibiotics produced by Streptomyces species.
Three of the commonly used tetracyclines are, oxytetracycline, chlortetracycline and tetracycline itself.
Tetracyclines are bacteriostatic and inhibit only rapidly multiplying organisms. Chloramphenicol: is also
a bacteriostatic drug, interferes with the protein synthesis.
Macrolides: are a group of antibiotics named for the presence of a macrocyclic lactone ring. The only one
in clinical use is erythromycin. It acts by inhibiting the protein synthesis. Its spectrum is like penicillin and
quite frequently is used as an alternative to penicillin.

Antibiotics Against Anaerobes

Most of the anaerobes (anaerobic cocci, clostridia and Bacteroides except Bact. fragilis) are susceptible to
benzyl penicillin. Bact. fragilis as well as many other anaerobes are treatable with erythromycin,
lincomycin, tetracyclines and chloramphenicol. Clindamycin is another important antibiotic which is
effective against almost all the strains of Bacteroides.
ANTIVIRAL DRUGS
Several antiviral compounds are now licensed in developed countries for clinical use like Acyclic guanosine
(acyclovir), Azidothymidine (AZT, ziduvudine), Amantadine, Ribavirin etc.

ANTIFUNGAL DRUGS
Polyenes: Two commonly used antifungal drugs that belong to this group are nystatin and amphotericin
B. Both are fungicidal. These drugs combine with the sterols in fungal plasma membranes, making the
membranes excessively permeable and killing the cell.
Imidazole: To this group belong miconazole, clotrimazole and ketaconazole which primarily interfere with
sterol synthesis in fungi.
Griseofulvin: This antifungal agent is produced by Penicillium species. It has the property of binding
selectively to keratin found in the skin, hair follicles and nails. Its mode of action is to interfere with
mitosis and thereby inhibiting fungal reproduction.

DRUG RESISTANCE
Origin of Drug Resistant Strains
The drug resistant strains arise either by mutation and selection or by genetic exchange in which a
sensitive organism receives the genetic material (part of DNA) from the resistant organism and the part of
DNA carries with it the information of mode of inducing resistance against one or multiple antimicrobial
agents. The drug resistance can arise by random mutation and when with it the organism becomes
resistant to a drug, the application of that drug shall select out the resistant organisms and let them
multiply.
Transmissible (Infectious) Drug Resistance
Extrachromosomal material called plasmid (or episome) is also capable of conferring resistance to
antibiotics. There is adequate evidence to suggest that transfer of resistance can occur within the
intestinal tract of human beings as well as the animals.

BIOCHEMICAL MECHANISMS OF DRUG RESISTANCE

The biochemical changes which are seen in bacteria which have become resistant due to mutation are:
· Increased synthesis of drug antagonist
· Decreased permeability to drug
· Increased destruction of inhibitor
· Induction of different relative affinity of substrate and antagonist.

Distinguishing features between mutation and transferable drug resistance

Feature Mutation resistance Transferable

No. of drugs to which resistant Usually one Usually multiple

Degree of resistance Low High
Can be overcome by increasing Yes No
dose Preventable by combination of Yes No
drugs Infectious No Yes
Metabolically defective Yes Normal
Virulence of bacterium Low Not decreased