Penicillin

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Penicillin core structure
Penicillin core structure

Penicillin (abbreviated PCN) is a group of β-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.

Contents

[edit] Discovery and History

The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928 and the development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey.

However, several others had earlier noted the bacteriostatic effects of Penicillium: The first published reference appears to have been in 1875, when it was reported to the Royal Society in London by John Tyndall[1]. Ernest Duchesne documented it in his 1897 paper; however it was not accepted by the Institut Pasteur because of his young age. In March 2000, doctors at 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. Clorito Picado had reported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigation had started years before Fleming's.

Fleming recounted later that the date of his breakthrough was on the morning of Tuesday, September 28, 1928[2]. At his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), Fleming noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold Staphylococcus plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mold and discovered that it was a Penicillium mold, 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 mold. 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, in particular, noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae)[3]. 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[4].

In 1930 Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to treat sycosis - eruptions in beard follicles - but was unsuccessful, probably because the drug did not get deep enough. Moving onto opthalmia neonatorum - a gonococcal infection in babies - he achieved the first cure on 25 November 1930. He cured four patients (one adult, three babies) of eye infections, although a fifth patient was not so lucky[5].

In 1939, Australian scientist Howard Florey (later 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 it harmless and effective on mice[6].

Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On March 14, 1942, John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin[7][8].

The challenge of mass-producing the drug had been daunting. On March 14, 1942 the first patient was successfully treated for streptococcal septicemia with U.S.-made penicillin. Half of the total supply produced at the time was used on that one patient. By June 1942 there was just enough U.S. penicillin available to treat ten patients[9]. A moldy cantaloupe in a Peoria, Illinois market in 1943 was found to contain the best and highest-quality penicillin after a world-wide search[10]. The discovery of the cantaloupe, and the results of fermentation research on corn-steep liquid at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the USA to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944.

Penicillin was being mass-produced in 1944
Penicillin was being mass-produced in 1944

During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%-15% of lives.[citation needed] 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[11].

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 penicillin's concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[11] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins[12].

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.

[edit] Developments from Penicillin

The narrow range of treatable diseases or spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin that 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 was 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 important, the cephalosporins, have this at the center of their structures. Ondred Abumbumer also made further discoveries towards penicillin [13]

[edit] Mechanism of Action

Main article: beta-lactam antibiotic

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, which 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 autolysins, 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.

[edit] Variants in Clinical Use

The term “penicillin” is often used in the generic sense to refer to one of the narrow-spectrum penicillins, in particular, benzylpenicillin.

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:[12]

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

Specific indications for phenoxymethylpenicillin include:[12]

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

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:[12]

  • 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.[14] 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.[15]
  • 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.

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:[12]

[edit] 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 were developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin.

Narrow spectrum β-lactamase-resistant penicillins has a spectrum directed toward Gram-negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase.

'Moderate spectrum penicillins weredeveloped 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 were 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 increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not, in general, in itself, increase the spectrum of the partner penicillin.


[edit] Adverse Effects

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.[12]

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

Although penicillin is still the most commonly-reported allergy, less than 20% of all patients that believe that they have a penicillin allergy are truly allergic to penicillin;[16] 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.[17] Anaphylaxis will occur in approximately 0.01% of patients.[12] 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.[18][19] However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins.[20][21] 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.[22]

[edit] 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.

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 that the by-product L-Lysine will inhibit the production of homocitrate, so the presence of exogenous lysine should 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. The carbon sources that are available are also important: Glucose will inhibit penicillin, whereas 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.

[edit] See also

[edit] References

  1. ^ Phil. Trans., 1876, 166, pp27-74. Referred to at: Discoveries_of_anti-bacterial_effects_of_penicillium_moulds_before_Fleming
  2. ^ Kendall F. Haven, Marvels of Science (Libraries Unlimited, 1994) p182
  3. ^ 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. 
  4. ^ Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3. 
  5. ^ Wainwright, M & Swan, HT (1986) C.G. Paine And The Earliest Surviving Clinical Records Of Penicillin Therapy Medical History, 30: 42-56 [1]
  6. ^ Drews, Jürgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 1960 - 1964. Retrieved on [[November 17, 2007]]. 
  7. ^ Saxon, W.. "Anne Miller, 90, first patient who was saved by penicillin", The New York Times, June 9, 1999. 
  8. ^ Krauss K, editor (1999). Yale-New Haven Hospital Annual Report (PDF). Yale-New Haven Hospital.
  9. ^ John S. Mailer, Jr., and Barbara Mason. Penicillin : Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois. lib.niu.edu. Retrieved on [[February 11, 2008]].
  10. ^ Mary Bellis. The History of Penicillin. Inventors. About.com. Retrieved on 2007-10-30.
  11. ^ a b Silverthorn, DU. (2004). Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN 0-8053-5957-5. 
  12. ^ a b c d e f g (2006) in Rossi S, editor: Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3. 
  13. ^ 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 [[November 17, 2007]]. 
  14. ^ "Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004" (2005). MMWR Morb. Mortal. Wkly. Rep. 54 (9): 217-9. PMID 15758893. 
  15. ^ 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.
  16. ^ 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. 
  17. ^ Solensky R (2003). "Hypersensitivity reactions to beta-lactam antibiotics". Clinical reviews in allergy & immunology 24 (3): 201–20. PMID 12721392. 
  18. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975. 
  19. ^ Gruchalla RS, Pirmohamed M (2006). "Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601-9. doi:10.1056/NEJMcp043986. PMID 16467547. 
  20. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776. 
  21. ^ 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. 
  22. ^ 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. 
v • d • e
Antibacterials for systemic use: beta-lactam antibiotics - penicillins (J01C)
Antibiotics Amoxicillin • Ampicillin • Azlocillin • Carbenicillin • Cloxacillin • Dicloxacillin • Flucloxacillin • Mezlocillin • Nafcillin • Piperacillin • Pivampicillin • Ticarcillin
Beta-lactamase inhibitors Sulbactam • Tazobactam • Clavulanic acid
Combinations Ampicillin/sulbactam (Sultamicillin) • Co-amoxiclav
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