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| [[Image:Penicillin-core.png|thumb|right|150px|Penicillin nucleus]] | | #REDIRECT [[Penicillin]] |
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| {{SI}}
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| {{CMG}}
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| ==Overview==
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| '''Penicillin''' (sometimes abbreviated '''PCN''') refers to a group of [[beta-lactam antibiotic]]s used in the treatment of [[bacteria]]l infections caused by susceptible, usually [[Gram-positive]], organisms. The name “penicillin” can also be used in reference to a specific member of the penicillin group [[Penam]] Skeleton, which has the molecular formula R-C<sub>9</sub>H<sub>11</sub>N<sub>2</sub>O<sub>4</sub>S, where R is a variable [[side chain]].
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| ==History==
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| 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 Picado Twight|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.
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| 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 [[microbiological culture|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]]'').<ref name="Flemming1929">{{cite journal | author=Flemming A. | title=On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of ''B. influenzæ''. | journal=Br J Exp Pathol | year=1929 | volume=10 | issue=31 | pages=226–36}}</ref>
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| 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. .<ref name="Brown2004">{{cite book | author= Brown, Kevin. | title=Penicillin Man: Alexander Fleming and the Antibiotic Revolution. | location=Stroud | publisher=Sutton | year=2004 | isbn = 0-7509-3152-3}}</ref>
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| 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 [[Albert Alexander|Reserve Constable Albert Alexander]]), but they proved its harmlessness and effect on mice.
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| A mouldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest quality penicillin after a world-wide search.<ref>[http://inventors.about.com/od/pstartinventions/a/Penicillin.htm]</ref>
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| Some of the pioneering trials of penicillin took place at the [[Radcliffe Infirmary]] in Oxford. On March 3, 1942 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.<ref>{{cite news | author=Saxon, W. | url=http://www.wellesley.edu/Chemistry/Chem101/antibiotics/obit-a-miller.html | title=Anne Miller, 90, first patient who was saved by penicillin | publisher=The New York Times | date=[[1999-06-09]]}}</ref><ref>{{cite web | author=Krauss K, editor | title=Yale-New Haven Hospital Annual Report | url=http://www.ynhh.org/general/annreport/ynhh99ar.pdf | format=PDF | year=1999 | publisher=Yale-New Haven Hospital | location=New Haven}}</ref>
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| [[Image:PenicillinPSAedit.jpg|thumb|right|300px|Penicillin was being mass-produced in 1944]]
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| 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.<ref name="Silverthorn2004">{{cite book | author=Silverthorn, DU. | title=Human physiology: an integrated approach. | edithion=3rd ed. | location=Upper Saddle River (NJ) | publisher=Pearson Education | year=2004 | id=ISBN 0-8053-5957-5}}</ref>
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| 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.<ref name="Silverthorn2004" />Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins.<ref name="AMH2006">{{cite book | editor=Rossi S, editor | title=[[Australian Medicines Handbook]] | year=2006 | location=Adelaide | publisher=Australian Medicines Handbook | id=ISBN 0-9757919-2-3}}</ref>
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| 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 Physiology or Medicine|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.
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| ==Developments from penicillin==
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| 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.
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| 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|methicillin-resistant ''Staphylococcus aureus'']] strains that subsequently emerged.
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| 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 [[carbapenem]]s and, most importantly, the [[cephalosporin]]s, have this at the centre of their structures.
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| ==Mechanism of action==
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| {{main|beta-lactam antibiotic}}
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| β-lactam antibiotics work by inhibiting the formation of [[peptidoglycan]] [[cross-link]]s in the bacterial [[cell wall]]. The [[beta-lactam|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]]). 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.
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| When the bacteria lose their cell walls they are then called [[spheroplast]]s.
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| 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 [[Minimum Bactericidal Concentration|MBC]] for susceptible organisms.
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| ==Variants in clinical use==
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| The term “penicillin” is often used generically to refer to one of the narrow-spectrum penicillins, particularly benzylpenicillin.
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| ===Benzathine benzylpenicillin===
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| '''Benzathine benzylpenicillin''' ([[International Nonproprietary Name|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'''.
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| Specific indications for benzathine pencillin include:<ref name="AMH2006"/>
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| *Prophylaxis of [[rheumatic fever]]
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| *Early or latent [[syphilis]]
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| ===Benzylpenicillin (penicillin G)===
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| {{drugbox |
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| | IUPAC_name = 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-((phenylacetyl)amino)- (2S-(2alpha,5alpha,6beta))-
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| | image = Penicillin-G.png
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| | image2 = Penicillin_3D_Model.png
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| | imagename = Penicillin G
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| | width = 180px
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| | CAS_number = 61-33-6
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| | chemical_formula =
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| | molecular_weight = 334.4 [[gram|g]]/[[mole (unit)|mol]]
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| | C=16 | H=18 | N=2 | Co= | I= | Br= | Cl= | F= | O=4 | P= | S=1 | Se= | Na= | charge=
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| | routes_of_administration = [[parenteral]]
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| }}
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| '''Benzylpenicillin''', commonly known as '''penicillin G''', is the [[Gold standard (test)|gold standard]] penicillin. Penicillin G is typically given by a [[route of administration|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.
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| Specific indications for benzylpenicillin include:<ref name="AMH2006"/>
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| *[[Cellulitis]]
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| * Bacterial [[endocarditis]]
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| *[[Gonorrhea]]
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| *[[Meningitis]]
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| *[[Aspiration pneumonia]], lung [[abscess]]
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| *Community-acquired [[pneumonia]]
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| *[[Syphilis]]
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| *[[Septicaemia]] in children
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| ===Phenoxymethylpenicillin (penicillin V)===
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| '''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.
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| Specific indications for phenoxymethylpenicillin include:<ref name="AMH2006"/>
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| *Infections caused by ''[[Streptococcus pyogenes]]''
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| **[[Tonsillitis]]
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| **[[Pharyngitis]]
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| **[[Skin]] infections
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| *Prophylaxis of [[rheumatic fever]]
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| *Moderate-to-severe gingivitis (with [[metronidazole]])
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| Penicillin V is the first choice in the treatment of [[Wiktionary:odontogenic|odontogenic]] infections.
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| ===Procaine benzylpenicillin===
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| '''Procaine benzylpenicillin''' ([[International Nonproprietary Name|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 [[hydrolysis|hydrolysed]] to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required.
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| 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.
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| Specific indications for procaine penicillin include:<ref name="AMH2006"/>
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| *[[Syphilis]]
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| **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'''.<ref>{{cite journal |author= |title=Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004 |journal=MMWR Morb. Mortal. Wkly. Rep. |volume=54 |issue=9 |pages=217-9 |year=2005 |pmid=15758893 |doi=}}</ref> 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.<ref>United States Food & Drug Administration. [http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01329.html "FDA Strengthens Labels of Two Specific Types of Antibiotics to Ensure Proper Use."] Published December 1, 2004. Last accessed June 18, 2007.</ref>
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| *[[Respiratory tract]] infections where compliance with oral treatment is unlikely
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| *[[Cellulitis]], [[erysipelas]]
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| Procaine penicillin is also used as an adjunct in the treatment of [[anthrax]].
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| ==Semi-synthetic penicillins==
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| 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.
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| ===Narrow spectrum penicillinase-resistant penicillins===
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| 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.
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| *[[Methicillin]] discontinued (not used clinically)
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| *[[Dicloxacillin]]
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| *[[Flucloxacillin]]
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| *[[Oxacillin]]
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| *[[Nafcillin]]
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| *[[Cloxacillin]]
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| ===Narrow spectrum β-lactamase-resistant penicillins===
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| 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.
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| *[[Temocillin]]
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| ===Moderate spectrum penicillins===
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| This group was developed to increase the spectrum of action and, in the case of [[amoxicillin]], improve oral bioavailability.
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| *[[Amoxicillin]]
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| *[[Ampicillin]]
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| And the [[prodrugs]] of [[ampicillin]] that are converted in the body to [[ampicillin]]:
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| *[[Hetacillin]], not used now.
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| *Bacampicillin
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| *[[Pivampicillin]]
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| ===Extended Spectrum Penicillins===
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| This group was developed to increase efficacy against [[Gram-negative]] organisms. Some members of this group also display activity against ''[[Pseudomonas aeruginosa]]''.
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| *[[Piperacillin]]
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| *[[Ticarcillin]]
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| *[[Azlocillin]]
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| *[[Carbenicillin]]
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| *[[Mezlocillin]]
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| ===Penicillins with beta-lactamase inhibitors===
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| Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against [[beta-lactamase|β-lactamase]]-producing organisms. The addition of the beta-lactamase inhibitor does not generally, in itself, increase the spectrum of the partner penicillin.
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| * [[Co-amoxiclav|Amoxicillin/clavulanic acid]]
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| * [[Ampicillin/sulbactam]]
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| * [[Ticarcillin|Ticarcillin/clavulanic acid]]
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| * [[Piperacillin/tazobactam]]
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| ===Other Penicillins===
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| <!--These penicillins may be classified or may be under studying.
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| They need more information.-->
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| * Metampicillin
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| * Broadcillin
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| * Epicillin
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| * Ampicillin benzathine
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| * Talampicillin
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| * Combipenix
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| * Ampicillinoic acid
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| * N-(N'-Methylasparaginyl)amoxicillin
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| * Aspoxicillin
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| * N-Propionylampicillin
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| * Lenampicillin
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| * Sulacillin
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| ==Adverse effects==
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| ===Adverse drug reactions===
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| Common [[adverse drug reaction]]s (≥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.<ref name="AMH2006" />
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| Pain and inflammation at the injection site is also common for [[parenteral]]ly-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin.
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| ===Allergy/hypersensitivity===
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| 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;<ref>{{cite journal|author=Salkind AR, Cuddy PG, Foxworth JW|title=Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy|journal=JAMA|year=2001|volume=285|issue=19|pages=2498–2505|url=http://jama.ama-assn.org/cgi/content/abstract/285/19/2498}}</ref> nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
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| [[Allergy|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.<ref name="AMH2006" /> There is about a 5% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems.<ref>{{cite journal |author=Gruchalla RS, Pirmohamed M |title=Clinical practice. Antibiotic allergy |journal=N. Engl. J. Med. |volume=354 |issue=6 |pages=601-9 |year=2006 |pmid=16467547 |doi=10.1056/NEJMcp043986}}</ref> 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.
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| ==See also==
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| *[[AGG01]]
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| *[[Beta-lactam antibiotic|β-Lactam antibiotic]]
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| *[http://www.articlexplosion.com/articledetail.php?artid=19798&catid=83&title=The+History+And+Development+Of+Penicillin History of Development of Penicillin Article]
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| ==References==
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| {{reflist|2}}
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| {{PenicillinAntiBiotics}}
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| [[Category:Drugs]]
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| [[Category:Beta-lactam antibiotics]]
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| [[ar:بنسلين]]
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| [[bg:Пеницилин]]
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| [[ca:Penicil·lina]]
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| [[fr:Pénicilline]]
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| [[id:Penisilin]]
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| [[no:Penicillin]]
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| [[pl:Penicyliny]]
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| [[sr:Пеницилин]]
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| [[th:ฟีนอกซิลเมตทิลเพนิซิลลิน]]
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| [[tr:Penisilin]]
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| [[zh:青霉素]]
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