Penicillin core structure
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.
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.
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 (now one of Imperial
College's teaching hospitals) in London, 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. 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 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 Walter
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.[citation needed]
A mouldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest quality penicillin after a world-wide
search.[3]
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.[4][5]
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 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.[6]
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.[6]Probenecid is still clinically useful, however, for certain infections requiring
particularly high concentrations of penicillins.[7]
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 Walter 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. 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.[citation needed]
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 (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:[7]
Benzylpenicillin (penicillin G)
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:[7]
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:[7]
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:[7]
- 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.[8] 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.[9]
- 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.[7]
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;[10]
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. Anaphylaxis will occur in approximately 0.01% of patients.[7] There is about a 5% cross-sensitivity between
penicillin-derivatives, cephalosporins and carbapenems.[11]
This risk warrants extreme caution with all β-lactam antibiotics in patients with a history of severe allergic reactions
(urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.
See also
References
- ^ Flemming 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.
- ^ Brown,
Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN
0-7509-3152-3.
- ^ [1]
- ^ Saxon, W.. "Anne Miller, 90,
first patient who was saved by penicillin", The New York Times, 1999-06-09.
- ^ Krauss K, editor (1999). Yale-New Haven Hospital Annual
Report (PDF). Yale-New Haven Hospital.
- ^ a b Silverthorn, DU. (2004).
Human physiology: an integrated approach.. Upper Saddle River (NJ): Pearson Education. ISBN
0-8053-5957-5.
- ^ a b c d e f g (2006) in Rossi S, editor: Australian
Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.
- ^ (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.
- ^ 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.
- ^ 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.
- ^ Gruchalla RS, Pirmohamed M (2006).
"Clinical practice. Antibiotic allergy". N. Engl. J. Med. 354 (6): 601-9. DOI:10.1056/NEJMcp043986. PMID 16467547.
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