Pivmecillinam: Difference between revisions

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{{drugbox |
{{drugbox
| IUPAC_name = <!--Mecillinam: (2''S'',5''R'',6''R'')-6-[(azepan-1-ylmethylene)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid-->
| IUPAC_name = 2,2-dimethylpropanoyloxymethyl (2''S'',5''R'',6''R'')-6-[(azepan-1-ylmethylene)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
| image = Pivmecillinam.svg
| image = Pivmecillinam.svg
| CAS_number = 32886-97-8
| CAS_number = 32886-97-8
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| ATC_suffix = CA08
| ATC_suffix = CA08
| ATC_supplemental =
| ATC_supplemental =
| PubChem =
| PubChem = 36272
| DrugBank =
| DrugBank =
| smiles = CC1(C(N2C(S1)C(C2=O)N=CN3CCCCCC3)C(=O)OCOC(=O)C(C)(C)C)C
| smiles =
| C=21|H=33|N=3|O=5|S=1
| C=21|H=33|N=3|O=5|S=1
| molecular_weight = 439.569 g/mol
| molecular_weight = 439.569 g/mol
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}}
}}


'''Pivmecillinam''' or '''amdinocillin pivoxil''' (trade names '''Selexid''', '''Penomax''' and '''Coactabs''') is an orally-active [[prodrug]] of [[mecillinam]], an extended-spectrum [[penicillin]] [[antibiotic]]. Pivmecillinam is the [[pivalic acid|pivaloyloxymethyl]] [[carboxylate ester|ester]] of mecillinam. Neither drug is available in the United States.<ref name=POC-IT>{{cite web |url=http://prod.hopkins-abxguide.org/antibiotics/antibacterial/pcn_others/amdinocillin__mecillinam_.html |title=Amdinocillin (Mecillinam) |author=Pham P, Bartlett JG |date=August 28, 2008 |work=Point-of-Care Information Technology ABX Guide |publisher=[[Johns Hopkins University]]}} Retrieved on August 31, 2008. Freely available with registration.</ref>
'''Pivmecillinam''' ([[International Nonproprietary Name|INN]]) or '''amdinocillin pivoxil''' ([[United States Approved Name|USAN]], trade names '''Selexid''', '''Penomax''' and '''Coactabs''') is an orally-active [[prodrug]] of [[mecillinam]], an extended-spectrum [[penicillin]] [[antibiotic]]. Pivmecillinam is the [[pivalic acid|pivaloyloxymethyl]] [[carboxylate ester|ester]] of mecillinam. Neither drug is available in the United States.<ref name=POC-IT>{{cite web |url=http://prod.hopkins-abxguide.org/antibiotics/antibacterial/pcn_others/amdinocillin__mecillinam_.html |title=Amdinocillin (Mecillinam) |author=Pham P, Bartlett JG |date=August 28, 2008 |work=Point-of-Care Information Technology ABX Guide |publisher=[[Johns Hopkins University]]}} Retrieved on August 31, 2008. Freely available with registration.</ref>


In the [[Nordic countries]], pivmecillinam has been widely used to treat lower urinary tract infections since the 1970s. It has been proposed as the [[first-line treatment|first-line drug]] of choice for [[empirical treatment]] of acute [[cystitis]].<ref name=Nicolle>{{cite journal |author=Nicolle LE |title=Pivmecillinam in the treatment of urinary tract infections |journal=J Antimicrob Chemother |volume=46 Suppl A |issue= |pages=35–39 |year=2000 |month=August |pmid=10969050 |doi= 10.1093/jac/46.suppl_1.35|url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10969050}}</ref><ref>{{cite journal |author=Graninger W |title=Pivmecillinam—therapy of choice for lower urinary tract infection |journal=Int J Antimicrob Agents |volume=22 Suppl 2 |issue= |pages=73–8 |year=2003 |month=October |pmid=14527775 |doi= 10.1016/S0924-8579(03)00235-8|url=http://linkinghub.elsevier.com/retrieve/pii/S0924857903002358}}</ref>
Pivmecillinam is only considered to be active against [[Gram-negative bacteria]], and is used primarily in the treatment of lower [[urinary tract infection]]s. In the [[Nordic countries]], pivmecillinam has been widely used in that indication since the 1970s. It has been proposed as the [[first-line treatment|first-line drug]] of choice for [[empirical treatment]] of acute [[cystitis]].<ref name=Nicolle>{{cite journal |author=Nicolle LE |title=Pivmecillinam in the treatment of urinary tract infections |journal=J Antimicrob Chemother |volume=46 Suppl A |issue= |pages=35–39 |year=2000 |month=August |pmid=10969050 |doi= 10.1093/jac/46.suppl_1.35|url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10969050}}</ref><ref>{{cite journal |author=Graninger W |title=Pivmecillinam—therapy of choice for urinary tract infection |journal=Int J Antimicrob Agents |volume=22 Suppl 2 |issue= |pages=73–8 |year=2003 |month=October |pmid=14527775 |doi= 10.1016/S0924-8579(03)00235-8|url=http://linkinghub.elsevier.com/retrieve/pii/S0924857903002358}}</ref> It has also been used to treat [[paratyphoid fever]].<ref>{{cite journal |author=Tanphaichitra D, Srimuang S, Chiaprasittigul P, Menday P, Christensen OE |title=The combination of pivmecillinam and pivampicillin in the treatment of enteric fever |journal=Infection |volume=12 |issue=6 |pages=381–3 |year=1984 |pmid=6569851 |doi= 10.1007/BF01645219|url=}}</ref>


==Activity==
==Activity==
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==Adverse effects==
==Adverse effects==
{{see also|Beta-lactam antibiotic#Adverse effects|l1=Beta-lactam antibiotic: Adverse effects}}
{{see also|Beta-lactam antibiotic#Adverse effects|l1=Beta-lactam antibiotic: Adverse effects}}
The [[adverse drug reaction|adverse effect]] profile of mecillinam is similar to that of other penicillins.<ref name=Neu>{{cite journal |author=Neu HC |title=Amdinocillin: a novel penicillin. Antibacterial activity, pharmacology and clinical use |journal=Pharmacotherapy |volume=5 |issue=1 |pages=1–10 |year=1985 |pmid=3885172 |doi= |url=}}</ref> The most common side effects of mecillinam use are [[rash]] and gastrointestinal upset, including [[nausea]] and [[vomiting]].<ref name=Nicolle/><ref name=eMC>{{cite web |url=http://emc.medicines.org.uk/emc/assets/c/html/DisplayDoc.asp?DocumentID=2566 |title=Selexid Tablets |date=June 5, 2008 |publisher=electronic Medicines Compendium}} Retrieved on August 31, 2008.</ref>
The [[adverse drug reaction|adverse effect]] profile of pivmecillinam is similar to that of other penicillins. The most common side effects of mecillinam use are [[rash]] and gastrointestinal upset, including [[nausea]] and [[vomiting]].<ref name=Nicolle/><ref name=eMC>{{cite web |url=http://emc.medicines.org.uk/emc/assets/c/html/DisplayDoc.asp?DocumentID=2566 |title=Selexid Tablets |date=June 5, 2008 |publisher=electronic Medicines Compendium}} Retrieved on August 31, 2008.</ref>


Prodrugs that release [[pivalic acid]] when broken down by the body — such as pivmecillinam, [[pivampicillin]] and [[cefditoren pivoxil]] — have long been known to deplete levels of [[carnitine]].<ref>{{cite journal |author=Holme E, Greter J, Jacobson CE, ''et al.'' |title=Carnitine deficiency induced by pivampicillin and pivmecillinam therapy |journal=Lancet |volume=2 |issue=8661 |pages=469–73 |year=1989 |month=August |pmid=2570185 |doi= 10.1016/S0140-6736(89)92086-2|url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(89)92086-2}}</ref><ref name=Brass>{{cite journal |author=Brass EP |title=Pivalate-generating prodrugs and carnitine homeostasis in man |journal=Pharmacol Rev |volume=54 |issue=4 |pages=589–98 |year=2002 |month=December |pmid=12429869 |doi= 10.1124/pr.54.4.589|url=http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12429869}}</ref> This is not due to the drug itself, but to pivalate, which is mostly removed from the body by forming a conjugate with carnitine. Although short-term use of these drugs can cause a marked decrease in blood levels of carnitine,<ref>{{cite journal |author=Abrahamsson K, Holme E, Jodal U, Lindstedt S, Nordin I |title=Effect of short-term treatment with pivalic acid containing antibiotics on serum carnitine concentration—a risk irrespective of age |journal=Biochem. Mol. Med. |volume=55 |issue=1 |pages=77–9 |year=1995 |month=June |pmid=7551831 |doi= 10.1006/bmme.1995.1036|url=http://linkinghub.elsevier.com/retrieve/pii/S1077315085710368}}</ref> it is unlikely to be of clinical significance;<ref name=Brass/> long-term use, however, appears problematic and is not recommended.<ref name=Brass/><ref>{{cite journal |author=Holme E, Jodal U, Linstedt S, Nordin I |title=Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children |journal=Scand J Clin Lab Invest |volume=52 |issue=5 |pages=361–72 |year=1992 |month=September |pmid=1514015 |doi= 10.3109/00365519209088371|url=}}</ref><ref>{{cite journal |author=Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N |title=Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid |journal=Pediatrics |volume=120 |issue=3 |pages=e739–41 |year=2007 |month=September |pmid=17724113 |doi=10.1542/peds.2007-0339}}</ref>
Prodrugs that release [[pivalic acid]] when broken down by the body — such as pivmecillinam, [[pivampicillin]] and [[cefditoren pivoxil]] — have long been known to deplete levels of [[carnitine]].<ref>{{cite journal |author=Holme E, Greter J, Jacobson CE, ''et al.'' |title=Carnitine deficiency induced by pivampicillin and pivmecillinam therapy |journal=Lancet |volume=2 |issue=8661 |pages=469–73 |year=1989 |month=August |pmid=2570185 |doi= 10.1016/S0140-6736(89)92086-2|url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(89)92086-2}}</ref><ref name=Brass>{{cite journal |author=Brass EP |title=Pivalate-generating prodrugs and carnitine homeostasis in man |journal=Pharmacol Rev |volume=54 |issue=4 |pages=589–98 |year=2002 |month=December |pmid=12429869 |doi= 10.1124/pr.54.4.589|url=http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12429869}}</ref> This is not due to the drug itself, but to pivalate, which is mostly removed from the body by forming a conjugate with carnitine. Although short-term use of these drugs can cause a marked decrease in blood levels of carnitine,<ref>{{cite journal |author=Abrahamsson K, Holme E, Jodal U, Lindstedt S, Nordin I |title=Effect of short-term treatment with pivalic acid containing antibiotics on serum carnitine concentration—a risk irrespective of age |journal=Biochem. Mol. Med. |volume=55 |issue=1 |pages=77–9 |year=1995 |month=June |pmid=7551831 |doi= 10.1006/bmme.1995.1036|url=http://linkinghub.elsevier.com/retrieve/pii/S1077315085710368}}</ref> it is unlikely to be of clinical significance;<ref name=Brass/> long-term use, however, appears problematic and is not recommended.<ref name=Brass/><ref>{{cite journal |author=Holme E, Jodal U, Linstedt S, Nordin I |title=Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children |journal=Scand J Clin Lab Invest |volume=52 |issue=5 |pages=361–72 |year=1992 |month=September |pmid=1514015 |doi= 10.3109/00365519209088371|url=}}</ref><ref>{{cite journal |author=Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N |title=Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid |journal=Pediatrics |volume=120 |issue=3 |pages=e739–41 |year=2007 |month=September |pmid=17724113 |doi=10.1542/peds.2007-0339}}</ref>


==References==
==References==
⚫
[[Image:Mecillinam.svg|thumb|270px|[[Skeletal formula]] of mecillinam, the active moiety of pivmecillinam]]<!--width parameter used so image will align with Drugbox-->
{{Reflist}}
{{Reflist}}

⚫
[[Image:Mecillinam.svg|thumb|270px|[[Skeletal formula]] of mecillinam, the active moiety of pivmecillinam]]<!--width parameter used so image will align with Drugbox-->


{{Beta-lactam antibiotics}}
{{Beta-lactam antibiotics}}

Revision as of 11:21, 29 June 2009

Pivmecillinam
Clinical data
Pregnancy
category

  • Appears safe in pregnancy[1]
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityLow
Protein binding5 to 10% (as mecillinam)
MetabolismPivmecillinam is hydrolyzed to mecillinam
Elimination half-life1 to 3 hours
ExcretionRenal and biliary, mostly as mecillinam
Identifiers
  • 2,2-dimethylpropanoyloxymethyl (2S,5R,6R)-6-[(azepan-1-ylmethylene)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.046.600 Edit this at Wikidata
Chemical and physical data
FormulaC21H33N3O5S
Molar mass439.569 g/mol g·mol−1
3D model (JSmol)
  • CC1(C(N2C(S1)C(C2=O)N=CN3CCCCCC3)C(=O)OCOC(=O)C(C)(C)C)C

Pivmecillinam (INN) or amdinocillin pivoxil (USAN, trade names Selexid, Penomax and Coactabs) is an orally-active prodrug of mecillinam, an extended-spectrum penicillin antibiotic. Pivmecillinam is the pivaloyloxymethyl ester of mecillinam. Neither drug is available in the United States.[2]

Pivmecillinam is only considered to be active against Gram-negative bacteria, and is used primarily in the treatment of lower urinary tract infections. In the Nordic countries, pivmecillinam has been widely used in that indication since the 1970s. It has been proposed as the first-line drug of choice for empirical treatment of acute cystitis.[1][3] It has also been used to treat paratyphoid fever.[4]

Activity

See also: Mecillinam

Adverse effects

See also: Beta-lactam antibiotic: Adverse effects

The adverse effect profile of pivmecillinam is similar to that of other penicillins. The most common side effects of mecillinam use are rash and gastrointestinal upset, including nausea and vomiting.[1][5]

Prodrugs that release pivalic acid when broken down by the body — such as pivmecillinam, pivampicillin and cefditoren pivoxil — have long been known to deplete levels of carnitine.[6][7] This is not due to the drug itself, but to pivalate, which is mostly removed from the body by forming a conjugate with carnitine. Although short-term use of these drugs can cause a marked decrease in blood levels of carnitine,[8] it is unlikely to be of clinical significance;[7] long-term use, however, appears problematic and is not recommended.[7][9][10]

References

  1. ^ a b c Nicolle LE (2000). "Pivmecillinam in the treatment of urinary tract infections". J Antimicrob Chemother. 46 Suppl A: 35–39. doi:10.1093/jac/46.suppl_1.35. PMID 10969050. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Pham P, Bartlett JG (August 28, 2008). "Amdinocillin (Mecillinam)". Point-of-Care Information Technology ABX Guide. Johns Hopkins University. Retrieved on August 31, 2008. Freely available with registration.
  3. ^ Graninger W (2003). "Pivmecillinam—therapy of choice for urinary tract infection". Int J Antimicrob Agents. 22 Suppl 2: 73–8. doi:10.1016/S0924-8579(03)00235-8. PMID 14527775. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ Tanphaichitra D, Srimuang S, Chiaprasittigul P, Menday P, Christensen OE (1984). "The combination of pivmecillinam and pivampicillin in the treatment of enteric fever". Infection. 12 (6): 381–3. doi:10.1007/BF01645219. PMID 6569851.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ "Selexid Tablets". electronic Medicines Compendium. June 5, 2008. Retrieved on August 31, 2008.
  6. ^ Holme E, Greter J, Jacobson CE; et al. (1989). "Carnitine deficiency induced by pivampicillin and pivmecillinam therapy". Lancet. 2 (8661): 469–73. doi:10.1016/S0140-6736(89)92086-2. PMID 2570185. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b c Brass EP (2002). "Pivalate-generating prodrugs and carnitine homeostasis in man". Pharmacol Rev. 54 (4): 589–98. doi:10.1124/pr.54.4.589. PMID 12429869. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Abrahamsson K, Holme E, Jodal U, Lindstedt S, Nordin I (1995). "Effect of short-term treatment with pivalic acid containing antibiotics on serum carnitine concentration—a risk irrespective of age". Biochem. Mol. Med. 55 (1): 77–9. doi:10.1006/bmme.1995.1036. PMID 7551831. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Holme E, Jodal U, Linstedt S, Nordin I (1992). "Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children". Scand J Clin Lab Invest. 52 (5): 361–72. doi:10.3109/00365519209088371. PMID 1514015. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N (2007). "Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid". Pediatrics. 120 (3): e739–41. doi:10.1542/peds.2007-0339. PMID 17724113. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Skeletal formula of mecillinam, the active moiety of pivmecillinam
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