Spectrum of Activity of Chemotherapeutic Agents

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Chapter: Medicinal Chemistry : History and Development of Chemotherapy

The ability of drug with all ranges (gram positive and gram negative) of antibiotic action, chloramphenicol, and tetracycline, to antagonize numerous pathogens have resulted mention as broad-spectrum antibiotics.


The ability of drug with all ranges (gram positive and gram negative) of antibiotic action, chloramphenicol, and tetracycline, to antagonize numerous pathogens have resulted mention as broad-spectrum antibiotics. Many of the broad-spectrum antibiotics are active only at high concentration. Some drugs are primarily static and they may exert cidal action at high concentration (e.g. sulphonamides, erythromycin, nitrofurantoin, etc). The bacteriostatic agents are those that interfere with the growth or replication of microorganisms, but does not kill it. The bactericidal drugs are those that kills the microorganisms. Concentration of drugs at the site of infection is an important factor for the therapeutic effect in case of antimicrobials. The classes of antibiotics and their spectrum of activity is detailed in Table 1.1.

Table 1.1 Classes of antibiotics and their spectrum of activity.


Bacterial Resistance to Antimicrobial Agents

The bacterial resistance development depends on three factors. They are as follows:

·The necessary dose or concentration not reached to target.

·The chemotherapeutic agent is not active.

·The target is altered.

The outer membrane of the gram-negative bacteria is a permeability barrier that excludes large polar molecules, including antibiotic, through a protein called porins. Loss of porin channel may prevent the entry of antibiotics and reduces the concentration in target site. If there is an active transport mechanism for the entry of drug into the cell, mutational changes will occur in the transport to produce resistant. For example, passage of gentamycin across the microbial cell membrane by concentration gradient by involving the respiratory electron transport and oxidative phosphorylation. Mutation in this enzyme pathway decreases the concentration to the target.

Inactivation of drugs are seen in case of aminoglycoside and β-lactums. In aminoglycosides, the acquisition of cell membrane bound inactivating enzymes which phosphorylates/adenylates or acetylates the drug molecule and produces conjugated aminoglycosides. These conjugated amino glycosides do not bind to target ribosome and so are incapable of enhancing active transport. Nosocomial microbes have rich plasmids producing multidrug resistance and cross resistance.

In fluroquinolone, the resistance is occurred by alteration of target. The resistance is noted due to chromosomal mutations producing a DNA gyrase or topoisomerase IV with reduced affinity to the fluroquinolone or due to reduced permeability of the drug.


Selection of Antimicrobial Agents

The selection is based on thorough knowledge of pharmacological and microbiological factors. Antibiotics are used in three general ways such as empirical therapy, definitive therapy, and prophylactic therapy. When used in empirical, the drug intended should cover all the microorganisms, if the pathogen is exactly not known. In the combination therapy, treatment with a broad spectrum antibiotic is necessary. After the identification of infecting microorganism, selective drug can be used.



It is the combined use of drugs intended to achieve better action; in chemotherapy it is used for the synergistic action (e.g. a sulphonamide used with trimethoprim to produce additive action). Other examples are in the combination of β-lactamase inhibition by clavulanic acid or sulbactum with amoxycillin or ampicillin for β-lacamase producing H. influenza, Neisseria gonorrhoeae, and other organisms.. Combination of bactericidal with a bacteriostatic drug produces synergistic action. The combination therapy of antimicrobials are also used in the treatment of mixed infection and initial treatment of severe infections.

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