Commercial Production of Antibiotics The micro-organism should grow well in submerged culture medium (liquid medium) in a special apparatus called fermentor The antibiotic produced should be released in the liquid medium used. To increased the production of antibiotic: Development of a high production micro-organism strain through mutation (either by chemical or UV.means) and selection. Optimization of fermentation process through: Medium composition (carbon and nitrogen sours, C/N ratio, vitamins, growth hormones and any additive). Optimum condition of fermentation (temp., PH, aeration, stirring, volume and inoculums size).

Commercial Production of Antibiotics Uses of beneficial additives to the medium: Methionine is added to Cephalsporium spp. To increases the production of cephalosporines. Phenylacetamide to Penicillum spp. For a high production of penicillin G. In case of production of tetracycline using Sterpt. aureofaciens, addition of mercaptothiazole (inhibits chlorination of tetracycline) to avoid production of chlortetracycline (highly irritant and very difficult to separated from tetracycline) and increase tetracycline production.

Commercial Production of Antibiotics Isolation and purification of antibiotics: Most of antibiotics are released into the culture medium except nystatin, amphotericin B and griseofulvin remain inside the microorganism cells they isolated by extraction of micro-organism cells. Most of antibiotics are obtained from growth medium by the following Selective adsorption e.g. charcoal in case of amino glycosides antibiotics. Selective precipitation e.g. methyl orange in case of polymyxin production. Selective solvent - solvent extraction.

Clinically Important Bacteria Aerobic, Gram-positive cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus agalactiae Streptococcus pyogenes Anaerobic, Gram-positive rods Actinomyces sp. Clostridium botulinum Clostridium difficile Clostridium perfringens Clostridium tetani

Bacterial Classification Aerobic, Gram-positive rods Bacillus anthracis Bacillus cereus Bifidobacterium bifidum Lactobacillus sp. Listeria monocytogenes Nocardia sp. Rhodococcus equi Erysipelothrix rhusiopathiae Corynebacterium diptheriae Propionibacterium acnes Anaerobic, Gram-positive cocci Peptostreptococcus Aerobic, Gram-negative cocci Neisseria gonorrhoeae Neisseria meningitidis Moraxella catarrhalis

Bacterial Classification Vibrio vulnificus Acinetobacter sp. Flavobacterium sp. Pseudomonas aeruginosa Burkholderia cepacia Burkholderia pseudomallei Xanthomonas maltophilia

Bacterial Classification Aerobic, Gram-negative rods Actinobacillus sp. Acinetobacter baumannii Bordetella pertussis Brucella sp. Campylobacter sp. Capnocytophaga sp. Cardiobacterium hominis Eikenella corrodens Francisella tularensis Haemophilus ducreyi

Bacterial Classification Haemophilus influenzae Helicobacter pylori Kingella kingae Legionella pneumophila Pasteurella multocida Klebsiella granulomatis Citrobacter sp. Enterobacter sp. Escherichia coli Klebsiella pneumoniae Proteus sp.

Bacterial Classification Salmonella enteriditis Salmonella typhi Shigella sp. Serratia marcescens Yersinia enterocolitica Yersinia pestis Aeromonas sp. Plesiomonas shigelloides Vibrio cholerae Vibrio parahaemolyticus

Bacterial Classification Vibrio vulnificus Acinetobacter sp. Flavobacterium sp. Pseudomonas aeruginosa Burkholderia cepacia Burkholderia pseudomallei Xanthomonas maltophilia

Bacterial Classification Gram-negative spiral Spirillum minus Anaerobic, Gram-negative cocci Veillonella sp. Anaerobic, Gram-negative rods Bacteroides fragilis Bacteroides sp. Prevotella sp. Fusobacterium sp.

Bacterial Classification Atypical Borrelia burgdorferi Borrelia recurrentis Bartonella henselae Chlamydia trachomatis Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetii Ehrlichia chaffeensis Anaplasma phagocytophilum Legionella sp. Leptospira sp.

Bacterial Classification Mycobacterium bovis Mycobacterium tuberculosis Mycobacterium avium, Mycobacterium intracellulare Mycobacterium kansasii Mycobacterium leprae Mycobacterium marinum Rickettsia rickettsii Orientia tsutsugamushi Treponema pallidum

Combination Therapy In most cases, infection caused by a single defined organism is best treated with a single antibiotic. When organism is exposed to two antibiotics to which it is sensitive, the response to the combination will be: Additive Antagonism Synergism

Combination Therapy Additive in which the antibiotics combination is more effective than either antibiotic alone or the response represents a summation of two drugs. Antagonism, the combination of two antibiotics may produce less response than one of the drugs alone. Synergism, a combination of two antibiotics may have a greater effect than the sum of two individual drug effect, it is usually defined as a four-fold or greater decrease in MIC of the individual antibiotic.

Mechanisms of Synergy The effect of one drug permits increased entry of the second drug to its site of action inside the cell, e.g. Penicillin and amino glycosides, in which penicillin acts as inhibitor of cell wall synthesis leading to increase the entering of the amino glycoside into the bacterial cell One of the drug inhibits the inactivation of the other drug, e.g. clavulanic acid (β-lactamase inhibitor) and penicillins.

Mechanisms of Synergy The two drugs inhibit the different steps in the critical metabolic pathway of organism e.g. sulfonamides ( inhibit folic acid synthesis ) and trimethoprim ( inhibits the reduction of folic acid to THFA). Two drugs interact with different viable enzyme systems inside the bacterial cell.

Advantages Synergetic effect. Prevention of resistance. Very useful in mixed infection. Disadvantages It exposes the patient to an increased risk of drug toxicity. It increases the therapy cost. It sometimes be less effective than therapy with a single antibiotic.