Antimicrobial agents: An introduction, classification, mechanism, with its adverse effects.

Anti-microbial agent

Antimicrobial is an agent that kills or stop the growth of microorganism.

Anti-Microbial-agent
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The antimicrobial agents are interfering with the growth of microbes within a host. Antimicrobial agents or drugs are having the greatest contribution in the 20th century to therapeutics. The arrival of antimicrobial agents changed the viewpoint of the physicians that the power drugs can use for diseases.

They are one of the few curative drugs. Their importance is magnified in the developing countries, where infective diseases predominate.  As a class, they are one of the most frequently used as well as misused drugs.

Chemotherapy- The process for the treatment of diseases caused by bacteria, other microorganisms, parasites, & tumor cells by using drugs.

Antibiotics- Antibiotics is a substance produced by the various species of microorganisms like bacteria, fungi, actinomycetes, to inhibit the growth of other microorganisms and to kill them. When we are using antibiotics as therapeutically, they act as anti-microbial drugs. These are maybe natural and synthetic in their form.

A certain type of antibiotics is found from the organism living in the soil that includes bacterial species like- streptomyces and bacillus, as well as fungi Penicillium, etc.

To commercially produce antibiotics are-

The strain is grown until the maximum antibiotic concentration is reached

Drug is extracted from broth medium

Extensively purified

Maybe chemically altered

Termed semi-synthetic

Bacteriostatic are those on how to inhibit cell growth and cell division. Bactericidal are those how Kill bacteria. Bacteria have their own enzymes for the Cell wall formation, protein synthesis, DNA replication, RNA synthesis, Synthesis of essential metabolites.

  1. Viruses use host enzymes inside host cells.
  2. Fungi and protozoa have their own eukaryotic enzymes.
  3. The more similar the pathogen and host enzymes there will be more side effects of the antimicrobials.

Spectrum activity of antimicrobial agents-

The range of pathogen targeted by a specific antibiotic is referred to as its spectrum, which can be broad or narrow spectrum –

Board spectrum antibiotics-

These are referred to as the drugs that are effective against more than one category of pathogens.

Example- Gram-positive and gram-negative bacteria

Narrow spectrum antibiotics

These are referred to as the drugs that are effective against only one category of pathogens.

Example- Gram-positive and mycobacteria.

Classification of anti-microbial drugs-

On the bases of spectrum Activity Classification-

Narrow spectrum-

-Penicillin G, Streptomycin, Erythromycin

Intermediate spectrum-

-Aminopenicillin, Cephalosporins (2nd and 3rd Generation), Fluoroquinolones, Newer Macrolides

Board Spectrum-

-Tetracycline, Chloramphenicol

On the bases of action classification-

Primarily bacteriostatic-                    

-Sulfonamides, Tetracycline, Chloramphenicol, Erythromycin, Clindamycin, Linezolid, Ethambutol

Primarily bactericidal-

-Penicillin, Cephalosporin, Aminoglycosides, Vancomycin, Polypeptides, Ciprofloxacin, Rifampin, Metronidazole, Isoniazid, Cotrimoxazole, Pyrazinamide

On the bases of chemical classification-

-Sulfonamides and related drugs– Sulfadiazine and others, Sulfones-Dapsone (DDS), Para aminosalicylic acid (PAS).

-Diaminopyrimidine- Trimethoprim, Pyrimethamine.

-Quinolones- Nalidixic acid, Norfloxacin, Ciprofloxacin, Prulifloxacin, etc.

-Β-Lactam antibiotics- Penicillin, Cephalosporins, Monobactam, Carbapenems.

-Tetracycline- Oxytetracycline, Doxycycline, etc.

-Nitrobenzene Derivatives- Chloramphenicol.

-Aminoglycosides- Streptomycin, Gentamicin, Amikacin, Neomycin.

-Macrolide antibiotics- Erythromycin, Roxithromycin, Clarithromycin, Azithromycin.

-Lincosamide antibiotics- Lincomycin, Clindamycin.

-Glycopeptide antibiotics- Vancomycin, Teicoplanin.

-Oxazolidinone- Linezolid.

-Polypeptide antibiotics- Polymyxin-B, Colistin, Tyrothricin.

-Nitrofuran derivatives- Nitrofurantoin, Furazolidone.

-Nitroimidazole- Metronidazole, Tinidazole, etc.

-Nicotinic acid derivatives- Isoniazid, Pyrazinamide, ethionamide.

-Polyene antibiotics- Nystatin, Amphotericin-B, Hamycin.

-Azole derivatives- Miconazole, Clotrimazole, Ketoconazole, Fluconazole.

-Others- Rifampin, Spectinomycin, Cyclomerize, Viomycin, Ethambutol, Thioacetazone, Clofazimine.

Mechanism of action of antimicrobial agents-

Mechanism-of-Anti-Microbial-Drugs
Source-internet

-Inhibit cell wall synthesis-

Penicillin, Cephalosporins, Cycloserine, Vancomycin, Bacitracin.

-Cause leakage from cell membrane-

Polypeptides-Polymyxins, Colistin, Bacitracin and Polyenes- Amphotericin B, Nystatin, Hamycin.

-Inhibit protein synthesis-

Tetracycline, chloramphenicol, Erythromycin, Clindamycin, linezolid.

-Cause misreading of mRNA code and affect permeability-

Aminoglycosides– Streptomycin, Gentamicin, etc.

-Inhibit DNA gyrase-

Fluoroquinolones –Ciprofloxacin and others.

-Interfere with DNA function

Rifampin.

-Interfere with DNA synthesis

Acyclovir, Zidovudine.

-Interfere with intermediary metabolism

Sulfonamides, Pyrimethamine, Metronidazole.

You may read-sulfonamides.

Types of organism against antimicrobial primarily active-

Anti-bacterial– Penicillin, Aminoglycosides, Erythromycin, Fluoroquinolones, etc.

Antifungal– Griseofulvin, Amphotericin B, Ketoconazole, etc.

Antiviral- Acyclovir, Amantadine, zidovudine, etc.

Antiprotozoal- Chloroquine, Pyrimethamine, Metronidazole, Diloxanide, etc.

Antibiotics are obtained from-

Fungi- Penicillin, Griseofulvin, Cephalosporin.

Bacteria- Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin.

Actinomycetes- Aminoglycosides, Macrolides, Tetracycline, Polyenes, Chloramphenicol.

Complications that arise with the use of antimicrobial agents-

  • Toxicity

Local irritancy- This is exerted at the site of administration. Gastric irritation, pain, boil formation at the site of intramuscular injection and thrombophlebitis of the injected vein are the complications that are in irritancy. Practically all anti-microbial agents are especially erythromycin, tetracyclines, certain cephalosporins, and chloramphenicol are irritants.

Systemic toxicity-

Almost all anti-microbial agents are produced dose-related and predictable body toxicities. Characteristic toxicities are exhibited by different anti-microbial agents. Some have a therapeutic index – does up to 100-fold range may be given without apparent damage to host cells. These include penicillin’s, some cephalosporins and erythromycin.

  • Hypersensitivity-

Practically all anti-microbial agents are capable of causing hypersensitivity reactions. These are unpredictable and unrelated to dose. The whole range of reactions from rashes to anaphylactic shock can be produced. The most commonly involved anti-microbial agents are penicillin’s, cephalosporins, sulfonamides, fluoroquinolones.

  • Drug resistance-
Drug-Resistance
Source-internet

It refers to the unresponsiveness of microorganisms or anti-microbial agents and is akin to the phenomenon, tolerance seen in nomenon higher organisms, microbes have always been resistant to certain anti-microbial agents.

Natural resistance-

They lack the metabolic process or the target affected by the particular drug.

This is a group or species characteristic, e.g. gram-negative bacilli are normally unaffected by penicillin G, or M. tuberculosis is insensitive to tetracyclines and these resistance does not pose a significant clinical problem.

Acquired resistance-

It is the development resistance by an organism (which is sensitive earlier) the use of an anti-microbial agent over a period of time.

This may happen with any microbe and it is a major clinical problem.

It may be developed due to single-step mutation (as seen with streptomycin and rifampicin) or multi-step mutation (erythromycin, tetracycline, and chloramphenicol) drug resistance can be transferred from gene transfer (also called infectious resistance) via conjugation, transduction or transformation.

Conjugation– It is due to the physical contact between bacteria and is responsible for multidrug resistance.

This is a very important mechanism for the development of resistance against chloramphenicol and streptomycin and microorganism.

Transduction– It is the transfer of the resistance gene through bacteriophage e.g. penicillin, erythromycin, and chloramphenicol.

Transformation– It is the transfer of resistance through the environment and is not clinically significant e.g. penicillin G.

Resistance once acquired becomes prevalent due to the selection of a widely used antimicrobial agent i.e. antimicrobials allow resistant organisms to grow preferential.

  • Super-infection-

It refers to the appearance of a new infection as a result of antimicrobial therapy.

Superinfection, intestine, respiratory and genitourinary tracts are common sites for the development of new infection.

The organisms frequently involved are Candida albicans, Clostridium difficile, Staphylococci, Proteus and Pseudomonas.

Clostridium difficile superinfection may result in pseudomembranous colitis (recently, monoclonal antibody cephalosporins) for against C. difficile toxin B (Bezlotoxumab) has been approved to reduce the recurrence of C. difficile infection.

Further, due to the loss of commensal flora, there may be decreased formation K leading to enhanced anticoagulant effects of warfarin.

  • Nutritional deficiencies-

Some of the B complex group of vitamins and vitamin K synthesized by the intestinal flora is utilized by man.

Prolonged use of antimicrobials that alter this flora may result in vitamin deficiencies.

Neomycin causes morphological abnormalities in the intestinal mucosa then steatorrhoea and malabsorption syndrome can occur.

  • Masking of an infection-

A short course of an antimicrobial agent may be sufficient to treat one infection but only briefly suppress another one contacted concurrently.

The other infection will be masked preliminary and only to manifest later in a severe form.

The examples are-

-Syphilis masked by the use of a single dose of penicillin which is enough for the treatment of gonorrhea.

-Tuberculosis masked by a short course of streptomycin given for trivial respiratory infection.

Choice of antimicrobial agents-

•        Patient factor

Age-

Chloramphenicol in newborn babies may cause grey baby syndrome and sulfonamides may cause kernicterus.

The half-life of aminoglycosides is prolonged in the elderly.

Tetracyclines are contraindicated in children below 6 years as it accumulates in developing bone and teeth.

Renal and hepatic function-

Drugs that are secreted in bile need not require dose adjustment as they can be excreted in faces. They include penicillin, rifampicin, lincosamides, doxycycline, erythromycin, ceftriaxone, and cefoperazone.

Drug allergy-

History of previous exposure to an antimicrobial agent should be obtained.

If an antimicrobial agent has caused an allergic reaction—it has to be avoided in that patient, e.g. drug of choice for syphilis in a patient allergic to penicillin is tetracycline.

β-lactams, sulfonamides, fluoroquinolones, and nitrofurantoin frequently cause allergy.

Pregnancy-

All antibiotics pose risk to the fetus in pregnancy.

Penicillin’s, most cephalosporins and macrolides appear safe.

Genetic factor-

Antimicrobials producing hemolysis in G-6PD deficient patients are primaquine, chloroquine, chloramphenicol, nitrofurantoin, fluoroquinolones, dapsone, and sulfonamides.

•        Organism related considerations-

-Clinical diagnosis itself direct choice of the anti-microbial agents.

 -A good guess can be made.

-Choice to be based on bacteriological.

•        Drug factor

-Spectrum of activity

-Types of activity

-Sensitivity of the organism

-Relative toxicity

-Pharmacokinetic profile

-Route of administration

-Evidence of clinical efficacy

Combined use of antimicrobial agents-

•        To achieve synergism

•        To reduce severity or incidence of adverse effects

•        To prevent emergence of resistance

•        To broaden the spectrum of anti-microbial action

-Treatment of mixed infection.

-Initial treatment of severe infection

-Topically

Disadvantages of antimicrobial combinations-

  • They foster a casual rather than rational outlook in the diagnosis of infections and the choice of antimicrobial agents.
  • Increased incidence and a variety of adverse effects.
  • The toxicity of one agent may be enhanced by another. E.g vancomycin + tobramycin and gentamicin +cephalothin produce exaggerated kidney failure.
  • Increased chances of superinfections.
  • If inadequate does of non synergistic drugs are used the emergence of resistance may be promoted.
  • The higher cost of therapy.


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