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{| border="1" cellpadding="3" cellspacing="0" width="250px" align="right" style="border-collapse: collapse; margin: 0 0 0 0.5em"
{{drugbox
|-
| Verifiedfields = changed
| bgcolor="#ffffff" align="center" colspan="2" |
| Watchedfields = changed
[[Image:Methicillin.png|250px|Molecular structure of methicillin]]<br />
| verifiedrevid = 404016571
''Methicillin''
| IUPAC_name = (2''S'',5''R'',6''R'')-6-(2,6-dimethoxybenzamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
|-
| image =Methicillin.png
| align="center" colspan="2" | ''6-(2,6-dimethoxybenzamido)-3,3-dimethyl-<br />7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-<br />2-carboxylic acid''
 
|- align="center" style="border-bottom: 3px solid gray"
<!--Clinical data-->
| '''[[CAS number]]''' <br/> [http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?term=61-32-5&rn=1 61-32-5]
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| '''[[ATC code]]'''  <br /> [http://www.whocc.no/atcddd/indexdatabase/index.php?query=J01CF03 J01CF03] 
| pregnancy_US = <!-- A / B / C / D / X -->
|- align="center" style="border-bottom: 3px solid gray"
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| '''[[PubChem]]''' <br /> [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6087 CID 6087]
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| '''[[DrugBank]]'''  <br /> n/a
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
|-
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| bgcolor="#eeeeee" | [[Chemical formula]]
| routes_of_administration = [[Intravenous|IV]]
| bgcolor="#ddeeff" | C<sub>17</sub>H<sub>20</sub>N<sub>2</sub>O<sub>6</sub>S
 
|-
<!--Pharmacokinetic data-->
| bgcolor="#eeeeee" | [[Molecular weight]]
| bioavailability = Not orally absorbed
| bgcolor="#ddeeff" | 380.42
| metabolism = hepatic, 20–40%
|-
| elimination_half-life = 25–60 minutes
| bgcolor="#eeeeee" | [[Bioavailability]]
| excretion = renal
| bgcolor="#ddeeff" | ? (not orally-absorbed)
 
|-
<!--Identifiers-->
| bgcolor="#eeeeee" | Metabolism
| CASNo_Ref = {{cascite|correct|CAS}}
| bgcolor="#ddeeff" | hepatic, 20–40%
| CAS_number_Ref = {{cascite|correct|??}}
|-
| CAS_number = 61-32-5
| bgcolor="#eeeeee" | [[Elimination half-life]]
| ATC_prefix = J01
| bgcolor="#ddeeff" | 25–60 minutes
| ATC_suffix = CF03
|-
| ATC_supplemental = {{ATCvet|J51|CF03}}
| bgcolor="#eeeeee" | [[Excretion]]
| PubChem = 6087
| bgcolor="#ddeeff" | renal
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
|-
| DrugBank = DB01603
| bgcolor="#eeeeee" | [[Pregnancy category (pharmaceutical)|Pregnancy category]]
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| bgcolor="#ddeeff" | ?
| ChemSpiderID = 5862
|-
| UNII_Ref = {{fdacite|changed|FDA}}
| bgcolor="#eeeeee" | [[Regulation of therapeutic goods|Legal status]]
| UNII = Q91FH1328A
| bgcolor="#ddeeff" | ?
| ChEMBL_Ref = {{ebicite|changed|EBI}}
|-
| ChEMBL = 575
| bgcolor="#eeeeee" | Routes of administration
 
| bgcolor="#ddeeff" | [[Intravenous|IV]]
<!--Chemical data-->
|-
| C=17 | H=20 | N=2 | O=6 | S=1
|}
| molecular_weight = 380.42 g/mol
| smiles = OC(=O)[C@@H]2N3C(=O)[C@@H](NC(=O)c1c(OC)cccc1OC)[C@H]3SC2(C)C
}}
__Notoc__
{{SI}}
{{SI}}
{{EH}}
{{CMG}}
==Overview==
'''Meticillin''' ([[International Nonproprietary Name|INN]], [[British Approved Name|BAN]]) or '''methicillin''' ([[United States Adopted Name|USAN]]) is a [[narrow-spectrum antibiotic|narrow-spectrum]] [[β-lactam antibiotic]] of the [[penicillin]] class. It should not be confused with the antibiotic [[metacycline]]. In 2005, the name of the drug was changed from methicillin to meticillin in accordance with the International Pharmacopoeia guidelines.<ref> UK parliament [http://www.publications.parliament.uk/pa/cm200405/cmhansrd/vo050405/text/50405w39.htm MRSA]</ref>
 
==History==
Meticillin was developed by [[Beecham (pharmaceutical company)|Beecham]] in 1959.<ref name="Dutfield2009">{{cite book|author=Graham Dutfield|title=Intellectual property rights and the life science industries: past, present and future|url=http://books.google.com/books?id=hnleY38aUxYC&pg=PA140|accessdate=18 November 2010|date=30 July 2009|publisher=World Scientific|isbn=978-981-283-227-6|pages=140–}}</ref> It was previously used to treat [[infection]]s caused by susceptible [[Gram-positive]] [[bacteria]], in particular, [[penicillinase]]-producing organisms such as ''[[Staphylococcus aureus]]'' that would otherwise be resistant to most penicillins.
 
Its role in therapy has been largely replaced by [[flucloxacillin]] and [[dicloxacillin]], but the term [[methicillin-resistant Staphylococcus aureus|meticillin-resistant ''Staphylococcus aureus'']] (MRSA) continues to be used to describe ''S. aureus'' strains resistant to all penicillins.<ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1079642/ MRSA—past, present, future]</ref>
 
Meticillin is no longer manufactured because the more stable and similar penicillins such as [[oxacillin]] (used for clinical antimicrobial susceptibility testing), flucloxacillin, and dicloxacillin are used medically.
 
== Mode of action ==
Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial [[cell wall]]s. It inhibits cross-linkage between the linear [[peptidoglycan]] polymer chains that make up a major component of the cell wall of Gram-positive bacteria. It does this by binding to and competitively inhibiting the [[DD-transpeptidase|transpeptidase]] enzyme (also known as [[penicillin-binding proteins]] (PBPs)). These PBPs crosslink glycopeptides (''<small>D</small>-alanyl-alanine''), forming the peptidoglycan cell wall. Meticillin and other β-lactam antibiotics are structural analogs of <small>D</small>-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called [[penicillin-binding proteins]] (PBPs).<ref>Gladwin M., Trattler B. Clinical Microbiology made ridiculously simple. 3rd edition. Miami: MedMaster, Inc.; 2004.</ref>
 
Meticillin is actually a [[penicillinase]]-resistant B-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other B-lactam antibiotics which hydrolyses the antibiotic, rendering it nonfunctional. Meticillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present.
 
== Spectrum of bacterial resistance and susceptibility ==
At one time, meticillin was used to treat infections caused by certain Gram-positive bacteria including ''Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes'', and ''Streptococcus pneumoniae''. Today, meticillin is not as effective against these organisms due to resistance.


'''Methicillin''' ([[United States Approved Name|USAN]]) or '''meticillin''' ([[International Nonproprietary Name|INN]], [[British Approved Name|BAN]]) is a [[narrow-spectrum antibiotic|narrow spectrum]] [[beta-lactam antibiotic]] of the [[penicillin]] class. It was developed by [[Beecham (pharmaceutical company)|Beecham]] in 1959. It was previously used to treat [[infection]]s caused by susceptible [[Gram-positive]] [[bacteria]], particularly  [[beta-lactamase]]-producing organisms such as ''[[Staphylococcus aureus]]'' that would otherwise be resistant to most [[penicillin]]s, but is no longer clinically used. Its role in therapy has been largely replaced by [[flucloxacillin]] and [[dicloxacillin]], however the term [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA) continues to be used to describe ''[[Staphylococcus aureus]]'' strains resistant to all [[penicillin]]s.
Resistance to meticillin is conferred by activation of a new bacterial PBP gene (''[[mec2]]''). This encodes for the [[PBP2a]]. PBP2a works in a similar manner to other PBPs, but it is bound by β-lactams with very low affinity, meaning they cannot hydrolyse it and kill the bacteria. Expression of ''PBPA2'' confers resistance to all β-lactams.  


==Mode of action==
These susceptibility data are given on a few medically significant bacteria:
''Main article: [[Beta-lactam antibiotic]]''
* ''Staphylococcus aureus'' - 0.125 - >100 μg/ml
* Meticillin resistant ''Staphylococcus aureus'' ([[MRSA]]) - 15.6 - >1000 μg/ml
* ''Streptococcus pneumoniae'' 0.39 μg/ml


Like other beta-lactam antibiotics, methicillin acts by inhibiting the synthesis of bacterial [[cell wall]]s. It inhibits cross-linkage between the linear [[peptidoglycan]] polymer chains that make up a major component of the cell wall of [[Gram-positive]] bacteria. It does this by binding to and competitively inhibiting the [[transpeptidase]] enzyme used by bacteria to cross-link the peptide (''D-alanyl-alanine'') used in peptidogylcan synthesis. Methicillin and other [[beta-lactam antibiotics]] are structural analogs of ''D-alanyl-alanine'', and the transpeptidase enzymes that bind to them are sometimes called [[penicillin binding proteins]] (PBPs). (Gladwin and Trattler, 2004)
== Medicinal chemistry ==


==Medicinal chemistry==
Meticillin is insensitive to [[beta-lactamase]] (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ''ortho''-dimethoxyphenyl group directly attached to the [[Side chain|side-chain]] carbonyl group of the penicillin nucleus facilitates the β-lactamase  resistance, since those enzymes are relatively intolerant of side-chain [[steric hindrance]]. Thus, it is able to bind to PBPs and inhibit [[peptidoglycan]] crosslinking, but it is not bound by or inactivated by β-lactamases.
Methicillin is insensitive to [[beta-lactamase]] (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ''ortho''-dimethoxyphenyl group directly attached to the [[side chain]] carbonyl group of the penicillin nucleus facilitates the &beta;-lactamase  resistance, since those enzymes are relatively intolerant of side-chain [[steric hindrance]]. Thus it is able to bind to [[penicillin binding protein]]s (PBPs) and inhibit [[peptidoglycan]] crosslinking, but is not bound by or inactivated by &beta;-lactamases.


==Clinical use==
== Clinical use ==
Methicillin is not commonly used in clinical practice, but serves a purpose in the [[laboratory]] to determine antibiotic sensitivity in [[microbiological culture]]. Methicillin was previously used to treat infections caused by susceptible [[Gram-positive]] bacteria. It is unstable in the presence of [[gastric acid]], with a degradation half-life of 5 minutes at pH 2, so it must be administered by [[Injection (medicine)|injection]]. (Mitscher, 2002)


==See also==
Meticillin is no longer used to treat patients. Compared to other β-lactamase-resistant penicillins, it is less active, can be administered only [[Route of administration#Parenteral|parenterally]], and has a higher frequency of [[interstitial nephritis]], an otherwise-rare side effect of penicillins. However, selection of Meticillin depended on the outcome of susceptibility test of the microorganism, since it is no longer produced, it is also not routinely tested any more. It also served a purpose in the [[laboratory]] to determine the antibiotic sensitivity of ''Staphylococcus aureus'' to other β-lactamase-resistant penicillins; this role has now been passed on to other penicillines, namely ''[[Cloxacillin]]'' as well as genetic testing for the presence of ''[[mecA]]'' gene by ''[[PCR]]''.
*[[Beta-lactam antibiotic]]
*[[Flucloxacillin]]
*[[Methicillin-resistant Staphylococcus aureus|Methicillin-resistant ''Staphylococcus aureus'']]


==References==
== References ==
*Mitscher LA. Antibiotics and antimicrobial agents. In: Williams DA, Lemke TL, editors. Foye's Principles of medicinal chemistry, 5th edition. Philadelphia: Lippincott Williams & Wilkins; 2002.
{{wikinews|Supergerm deaths soar, surpass AIDS in the United States}}
*Gladwin M., Trattler B. Clinical Microbiology made ridiculously simple. 3rd edition. Miami: MedMaster, Inc.; 2004.
{{reflist|2}}


[[Category:Drug]]
[[Category:Beta-lactam antibiotics]]
[[Category:Beta-lactam antibiotics]]
{{SIB}}
[[Category:Phenol ethers]]
[[de:Methicillin]]
[[nl:Meticilline]]
[[sr:Метицилин]]
[[th:เมทิซิลลิน]]
{{WH}}
{{WikiDoc Sources}}

Latest revision as of 13:56, 10 April 2015

Methicillin
Clinical data
Routes of
administration		IV
ATC code
Pharmacokinetic data
BioavailabilityNot orally absorbed
Metabolismhepatic, 20–40%
Elimination half-life25–60 minutes
Excretionrenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC17H20N2O6S
Molar mass380.42 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Meticillin (INN, BAN) or methicillin (USAN) is a narrow-spectrum β-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline. In 2005, the name of the drug was changed from methicillin to meticillin in accordance with the International Pharmacopoeia guidelines.[1]

History

Meticillin was developed by Beecham in 1959.[2] It was previously used to treat infections caused by susceptible Gram-positive bacteria, in particular, penicillinase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins.

Its role in therapy has been largely replaced by flucloxacillin and dicloxacillin, but the term meticillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe S. aureus strains resistant to all penicillins.[3]

Meticillin is no longer manufactured because the more stable and similar penicillins such as oxacillin (used for clinical antimicrobial susceptibility testing), flucloxacillin, and dicloxacillin are used medically.

Mode of action

Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. It does this by binding to and competitively inhibiting the transpeptidase enzyme (also known as penicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Meticillin and other β-lactam antibiotics are structural analogs of D-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called penicillin-binding proteins (PBPs).[4]

Meticillin is actually a penicillinase-resistant B-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other B-lactam antibiotics which hydrolyses the antibiotic, rendering it nonfunctional. Meticillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present.

Spectrum of bacterial resistance and susceptibility

At one time, meticillin was used to treat infections caused by certain Gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, meticillin is not as effective against these organisms due to resistance.

Resistance to meticillin is conferred by activation of a new bacterial PBP gene (mec2). This encodes for the PBP2a. PBP2a works in a similar manner to other PBPs, but it is bound by β-lactams with very low affinity, meaning they cannot hydrolyse it and kill the bacteria. Expression of PBPA2 confers resistance to all β-lactams.

These susceptibility data are given on a few medically significant bacteria:

  • Staphylococcus aureus - 0.125 - >100 μg/ml
  • Meticillin resistant Staphylococcus aureus (MRSA) - 15.6 - >1000 μg/ml
  • Streptococcus pneumoniae 0.39 μg/ml

Medicinal chemistry

Meticillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ortho-dimethoxyphenyl group directly attached to the side-chain carbonyl group of the penicillin nucleus facilitates the β-lactamase resistance, since those enzymes are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to PBPs and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by β-lactamases.

Clinical use

Meticillin is no longer used to treat patients. Compared to other β-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare side effect of penicillins. However, selection of Meticillin depended on the outcome of susceptibility test of the microorganism, since it is no longer produced, it is also not routinely tested any more. It also served a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other β-lactamase-resistant penicillins; this role has now been passed on to other penicillines, namely Cloxacillin as well as genetic testing for the presence of mecA gene by PCR.

References

  1. ↑ UK parliament MRSA
  2. ↑ Graham Dutfield (30 July 2009). Intellectual property rights and the life science industries: past, present and future. World Scientific. pp. 140–. ISBN 978-981-283-227-6. Retrieved 18 November 2010.
  3. ↑ MRSA—past, present, future
  4. ↑ Gladwin M., Trattler B. Clinical Microbiology made ridiculously simple. 3rd edition. Miami: MedMaster, Inc.; 2004.
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