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Penicillin



  Penicillin (sometimes abbreviated PCN) is a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. “Penicillin” is also the informal name of a specific member of the penicillin group Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain.

Additional recommended knowledge

Contents

History

The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928, though others had earlier noted the antibacterial effects of Penicillium such as Ernest Duchesne who documented it in his 1897 paper however it was not accepted by the Institut Pasteur because of his young age.

The development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey. In March 2000, doctors of the San Juan de Dios Hospital in San Jose (Costa Rica) published manuscripts belonging to the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887-1944). The manuscripts explained Picado's experiences between 1915 and 1927 about the inhibitory actions of the fungi of genera Penic. Apparently Clorito Picado had reported his discovery to the Paris Academy of Sciences in Paris, yet did not patent it, even though his investigation had started years before Fleming's.

Fleming, at his laboratory in St. Mary's Hospital (Imperial College) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould Staphylococcus plate culture. Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mould and discovered that it was a Penicillium mould, now known to be Penicillium notatum. Charles Thom, an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mould. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae).[1] After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940. .[2]

In 1939, Australian scientist Howard Florey, Baron Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved its harmlessness and effect on mice.[3]

A moldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest quality penicillin after a world-wide search.[4]

Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On 1942-03-14 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.[5][6]

 

During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces; saving an estimated 12-15% of lives. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug necessitating frequent dosing. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.[7]

This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[7]Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins.[8]

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Florey, Baron Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Chemist John Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work, and after WWII, Australia was the first country to make the drug available for civilian use. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections.

Developments from penicillin

The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.

The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were significant for their activity against beta-lactamase-producing bacteria species, but are ineffective against the methicillin-resistant Staphylococcus aureus strains that subsequently emerged.

The line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have this at the centre of their structures.[9]

Mechanism of action

β-lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and auto lysins which further digest the bacteria's existing peptidoglycan.

Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not lose their cell wall completely and are called spheroplasts after treatment with penicillin.

Penicillin shows a synergistic effect with aminoglycosides since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.

Variants in clinical use

The term “penicillin” is often used generically to refer to one of the narrow-spectrum penicillins, particularly benzylpenicillin.

Benzathine benzylpenicillin

Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin L-A.

Specific indications for benzathine pencillin include:[8]

  • Prophylaxis of rheumatic fever
  • Early or latent syphilis

Benzylpenicillin (penicillin G)

Penicillin G
Systematic (IUPAC) name
4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-((phenylacetyl)amino)- (2S-(2α,5α,6β))-
Identifiers
CAS number 61-33-6
ATC code  ?
PubChem  ?
Chemical data
Formula C16H18N2O4S 
Mol. mass 334.4 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes parenteral

Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.

Specific indications for benzylpenicillin include:[8]

  • Cellulitis
  • Bacterial endocarditis
  • Gonorrhea
  • Meningitis
  • aspiration pneumonia, lung abscess
  • Community-acquired pneumonia
  • Syphilis
  • Septicaemia in children

Phenoxymethylpenicillin (penicillin V)

Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required.

Specific indications for phenoxymethylpenicillin include:[8]

  • Infections caused by Streptococcus pyogenes
    • Tonsillitis
    • Pharyngitis
    • Skin infections
  • Prophylaxis of rheumatic fever
  • Moderate-to-severe gingivitis (with metronidazole)

Penicillin V is the first choice in the treatment of odontogenic infections.

Procaine benzylpenicillin

Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required.

This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings.

Specific indications for procaine penicillin include:[8]

  • Syphilis
    • It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R.[10] As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels.[11]
  • Respiratory tract infections where compliance with oral treatment is unlikely
  • Cellulitis, erysipelas

Procaine penicillin is also used as an adjunct in the treatment of anthrax.

Semi-synthetic penicillins

Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action.

Narrow spectrum penicillinase-resistant penicillins

This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin. Penicillin is rampantly used for curing infections and to prevent growth of harmful mold.

Narrow spectrum β-lactamase-resistant penicillins

This molecule has a spectrum directed towards Gram negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase.

Moderate spectrum penicillins

This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability.

And the prodrugs of ampicillin that are converted in the body to ampicillin:

Extended Spectrum Penicillins

This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa. These are divided into carboxypencillins and ureidopenicillins.

Carboxypencillins

Ureidopenicillins

Penicillins with beta-lactamase inhibitors

Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not generally, in itself, increase the spectrum of the partner penicillin.

Other Penicillins

  • Metampicillin
  • Broadcillin
  • Epicillin
  • Ampicillin benzathine
  • Talampicillin
  • Combipenix
  • Ampicillinoic acid
  • N-(N'-Methylasparaginyl)amoxicillin
  • Aspoxicillin
  • N-Propionylampicillin
  • Lenampicillin
  • Sulacillin

Adverse effects

Adverse drug reactions

Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include: diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics) and/or pseudomembranous colitis.[8]

Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin.

Allergy/hypersensitivity

Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin;[12] nevertheless, penicillin is still the most common cause of severe allergic drug reactions.

Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent.[13] Anaphylaxis will occur in approximately 0.01% of patients.[8] It has previously been accepted that there was up to a 10% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems, due to the sharing of the β-lactam ring.[14][15] However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins.[16][17] Recent papers have shown that major feature in determining immunological reactions is the similarity of the side chain of first generation cephalosporins to penicillins, rather than the β-lactam structure that they share.[18]

Penicillin Production

The production of penicillin is an area that requires scientists and engineers to work together to achieve the most efficient way of producing large amounts of penicillin.

It must be understood that penicillin is a secondary metabolite of fungus Penicillium, which means the fungus will not produce the antibiotics while it is growing, but will produce penicillin when it feels threatened. There are also other factors that inhibit penicillin production. One of these factors is the synthesis pathway of penicillin:

α-ketoglutarate + AcCoA -> homocitrate -> L-α-aminoadipic acid -> L-Lysine + β-lactam

It turns out the by-product L-Lysine will inhibit the production of homocitrate, so the presence of exogenous lysine by be avoided in the penicillin production.

The penicillium cells are grown using a technique called fed-batch culture, this way the cells are constantly subject to stress and will produce plenty of penicillin. It turns out the carbon sources that are available is also important, glucose will inhibit penicillin while lactose does not. The pH level, nitrogen level, Lysine level, Phosphate level and oxygen availability of the batches must be controlled automatically.

Other area of biotechnology such as directed evolution can also be applied to mutate the strains into producing a much larger number of penicillin. These directed evolution techniques include error-prone PCR, DNA shuffling, ITCHY and strand over-lap PCR.

See also

  • AGG01
  • β-Lactam antibiotic
  • History of Development of Penicillin Article
  • Model of Structure of Penicillin, by Dorothy Hodgkin et al., Museum of the History of Science, Oxford

References

  1. ^ Fleming A. (1929). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzæ.". Br J Exp Pathol 10 (31): 226–36.
  2. ^ Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3. 
  3. ^ Drews, Jürgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 1960 - 1964. Retrieved on 2007-11-17.
  4. ^ Mary Bellis. The History of Penicillin. Inventors. About.com. Retrieved on 2007-10-30.
  5. ^ Saxon, W.. "Anne Miller, 90, first patient who was saved by penicillin", The New York Times, 1999-06-09. 
  6. ^ Krauss K, editor (1999). Yale-New Haven Hospital Annual Report (PDF). Yale-New Haven Hospital.
  7. ^ a b Silverthorn, DU. (2004). Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5. 
  8. ^ a b c d e f g (2006) in Rossi S, editor: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 
  9. ^ James, PharmD, Christopher W.; Cheryle Gurk-Turner, RPh (January 2001). "Cross-reactivity of beta-lactam antibiotics". Baylor University Medical Center Proceedings 14 (1): 106-107. Dallas, Texas: Baylor University Medical Center. Retrieved on 2007-11-17.
  10. ^ (2005) "Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004". MMWR Morb. Mortal. Wkly. Rep. 54 (9): 217-9. PMID 15758893.
  11. ^ United States Food & Drug Administration. "FDA Strengthens Labels of Two Specific Types of Antibiotics to Ensure Proper Use." Published December 1, 2004. Last accessed June 18, 2007.
  12. ^ Salkind AR, Cuddy PG, Foxworth JW (2001). "Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy". JAMA 285 (19): 2498–2505.
  13. ^ Solensky R (2003). "Hypersensitivity reactions to beta-lactam antibiotics". Clinical reviews in allergy & immunology 24 (3): 201–20. PMID 12721392.
  14. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975.
  15. ^ Gruchalla RS, Pirmohamed M (2006). "Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601-9. doi:10.1056/NEJMcp043986. PMID 16467547.
  16. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776.
  17. ^ Pichichero ME (2007). "Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift". Diagn. Microbiol. Infect. Dis. 57 (3 Suppl): 13S–18S. doi:10.1016/j.diagmicrobio.2006.12.004. PMID 17349459.
  18. ^ Antunez C, Blanca-Lopez N, Torres MJ, et al (2006). "Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins". J. Allergy Clin. Immunol. 117 (2): 404–10. doi:10.1016/j.jaci.2005.10.032. PMID 16461141.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Penicillin". A list of authors is available in Wikipedia.
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