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This is all about the Penicillin , which includes its mode of action, manufacturing process, product recovery etc.

This is all about the Penicillin , which includes its mode of action, manufacturing process, product recovery etc.



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Penicillin Penicillin Presentation Transcript

  • PENICILLIN PRAKSH DHAKAL Public Health Microbiology Tribhuvan University
  • INTRODUCTION :  First described by Fleming in 1929.  Isolated by Florey and Chain in 1940 from Penicillium notatum.  The first clinical application of penicillin was in 1941.  Penicillins are produced by Penicillium and Aspergillus species.  Penicillins belongs to the group of antibiotics called β-lactams which also include cephalosporin,carbapenems,monbactams.  They are labile in acid and may be inactivated by splitting the β-lactam ring with β-lactamases.
  •  Currently the group of penicllins includes more than 20 antibiotics which are divided into several categories. 1. Natural Penicillins : ( Penicllin G, Procaine, Penicillin G, Penicillin V, Benzathine) The natural penicillins were the first antibiotics introduced in clinical practice. Natural antibiotics are active against gram-positive bacteria such as Streptococcus spp, Staphylococcus spp., Bacillus spp., in less degree against Enterococcus spp. L.monocytogenes, E.rhusiopathiae and corynebacteria (including C.diphtheriae), the most of anaerobic bacteria (Peptostreptococcus spp., Clostridium spp.) are highly sensitive to natural penicillins. Natural penicillins are highly effective against spirochetes (Treponema, Borrelia, Leptospira). View slide
  •  2 . Penicillinase-Resistant Penicillins : (Cloxacillin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin). Methicillin was the first member of this group, followed by oxacillin, nafcillin, cloxacillin and dicloxacillin. Currently Oxacillin is the most widespread among penicillinase-resistant penicillins and is actively used for the treatment of infections caused by staphylococci including PRSA. View slide
  •  3.Aminopenicillins (Ampicillin, Amoxicillin, Bacampicillin). Aminopenicillins were the first penicillins discovered to be active against gram- negative bacteria (such as E. coli and H. influenzae). Aminopenicillins are acid-resistant and that is why are administered orally. Aminopenicillins possess a broader spectrum of antibacterial activity against some strains such as E.coli, Shigella spp., Salmonella spp. and P.mirabilis, which are characterized by low levels of production of chromosomal β-lactamase. Aminopenicillins are susceptible to hydrolysis by β -lactamses and that is why are usually come in combination with β - lactamse inhibitors.
  •  4.Extended Spectrum Penicillins (sometimes called anti-pseudomonal penicillins). Extended spectrum penicillins include both alpha- carboxypenicillins (carbenicillin and ticarcillin) and acylaminopenicillins (piperacillin, azlocillin, and mezlocillin). These antibiotics possess similar spectrum of antibacterial activity as aminopenicillins but with additional bactericidal activity against the majority of gram negative microorganisms such as Pseudomonas aeruginosa. Along with aminopenicillins, extended spectrum penicillins are inactivated by beta-lactamase. These drugs can be used in monotherapy of infectious diseases or in combination with aminoglycosides.
  •  Penicillins indication The indications for penicillins vary depending on penicillins group. Natural penicillins are used in:  Infections caused by S.pyogenes, and their consequences:  tonsilopharyngitis  scarlet fever  erysipelas  year-round rheumatism prevention.  Infections caused by S.pneumoniae:  community-acquired pneumonia  meningitis  sepsis  Infections caused by other streptococci:  Infective endocarditis (in combination with gentamicin or streptomycin);  Meningococcal infections (meningitis)  Syphilis  Leptospirosis  Tick-borne borreliosis (Lyme disease)  Gangrenous emphysema  Actinomycosis
  •  Penicillinase-Resistant Penicillins and namely oxacillin is used in: Staphylococcal infections of different localizations and susceptible to oxacillin Infections of skin, soft tissue, bone and joints Pneumonia Infectious endocarditis Meningitis Sepsis
  •  Aminopenicillins are indicated for the treatment of: Infections of upper and lower respiratory system including sinusitis, aggravation of chronic bronchitis, pneumonia Urinary tract infections: cystitis, pyelonephritis Meningitis caused by H.influenzae and L.monocytogenes Endocarditis Intestinal infections caused by Shigella and Salmonella (ampicillin) Eradication of H.pylori in patients with stomach and duodenal ulcers Prophylaxisof endocarditis Intraabdominal infections Skin and soft tissue infections
  •  Carboxypenicillins are usually indicated for the treatment of: Nosocomial infections caused by sensitive strains P.aeruginosa. Carboxypenicillins must be used only in combination with other antibacterial preparations (aminoglycosides, fluorquinolones). Ticarcillin in combination with clavulonate is indicated in: Lower respiratory tract infections Urinary tract infections Intraabdominal infections Sepsis Infections of skin, soft tissue, bones and joints
  • ACTION MECHANISM :  All β -lactam antibiotics exert bactericidal action which is associated with inhibition of bacterial cell wall production. Their target is penicillin-depending bacterial proteins which fulfill a function of enzymes on the final stage of peptidoglycan synthesis- biopolymer and the main component of bacterial cell wall. Suppressing of peptidoglycan synthesis leads to consecutive bacterial lysis. Some of penicillin antibiotic exert bacteriostatic effect in low doses which may or may not control the infection
  • CHEMICAL STRUCTURE :  The basic structure of penicillin is 6- aminopenicillanic acid(6-APA), consisting of a thiazolidine ring with a condensed B-lactam ring.
  • BIOSYNTHESIS AND REGULATION :  B-lactam –thiazolidine ring of penicillin is constructed from L-cysteine and L-valine.  Biosynethesis occurs in a non ribosomal process by means of a dipeptide composed of L-alpha- aminoadipic acid ( L-alpha –AAA) and L-cysteine or a breakdown product of cystathionine.  Then subsequently , L valine is connected via an epimerization reaction resulting in the formation of the tripeptide delta –(L –alpha-aminoadipyl)- cysteniyl –D-valine.
  •  The first product of the cyclization of the tripeptide which can be isolated is isopenicillin N, but the biochemical reactions leading to this intermediate are not understood.  Benzylpenicillin is produced in the exchange of L- alpha-AAA with activated phenylacetic acid.  Penicllin biosynthesis is affected by phosphate concentration and also shows a distinct catabolite repression by glucose, in addition to regulation by concentration of ammonium ion, the latter by an unexpalined mechanism.
  • STRAIN DEVELOPMENT :  The pencillin production of Fleming’s isolate was about 2 international units/ml ; today’s process yield a penicillin titer of about 85,000 units/ml .  This is an increase from 0.0012 g/l to about 50 g/l .
  • PRODUCTION METHOD :  Penicllin G and V are produced using submerged process in 40,000 to 200,000 liter fermenters  Due to difficulties with O2 supply ,larger tanks cannot be employed.  It is a aerobic process with a volumetric oxygen absorption rate of 0.4-0.5 mM/l-min.  The inoculum is started using lyophilized spores.  Spore concentration ( optimal 5x103/ml ) and pellet formation are crucial for the subsqent yield.  For optimal penicillin formation ,pellets must be grow not as compact balls , but in loose form.
  •  The growth phase is of 40 hrs duration cwith a doubling time of 6 hrs, during which time the greatest part of the cell mass is formed.  Oxygen supply should be maintained.  After growth phase penicillin production phase occurs. In this phase growth is sharply reduced,  By feeding with various culture medium components , the production phase can be extended to 120-180 hrs.  The medium varies according to strain used and usually consists of corn steep liquor ( 4-5 % by dry wt) which may be replaced by other nitrogen sources, in addition soy meal, yeast extract or whey; a carbon source and buffers.
  •  PH is kept constant at 6.5.  Phenyl acetic acid or pehnoxyacetic acid is fed continuously as precursor.  About 65 % of the metabolized carbon source is used for maintenance energy, 25% for growth and only 10 % for penicillin production.  Yield increase of 25 % is reported by adding glucose and acetic acid.  Pencillin is excreted into the medium and less than 1% remains mycelium bound.
  •  After separation of mycelium, product recovery is accomplished by means of a two stage continuous countercurrent extraction of the fermenter broth with amyl or butyl acetate at 0-3Oc and PH 2.3-3.0 . The yield is around 90 %.