Mecillinam
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Mecillinam
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| Systematic (IUPAC) name | |
| (2S,5R,6R)-6-(azepan-1-ylmethylideneamino)-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | |
| Identifiers | |
| CAS number | 32886-97-8 (pivmecillinam) |
| ATC code | J01 J01 (pivmecillinam) |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C15H23N3O3S |
| Mol. mass | 325.426 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | Negligible (mecillinam) Low (pivmecillinam) |
| Protein binding | 5 to 10% |
| Metabolism | Some hepatic metabolism. Pivmecillinam is hydrolyzed to mecillinam |
| Half life | 1 to 3 hours |
| Excretion | Renal and biliary, mostly unchanged |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
â„ž Prescription only |
| Routes | Intravenous, intramuscular Pivmecillinam is given orally |
Mecillinam (INN) or amdinocillin (USAN), trade name Coactin, is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 (PBP2),[2] and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever.[3][4][5] Because mecillinam has very low oral bioavailability, an orally-active prodrug was developed: pivmecillinam or amdinocillin pivoxil (trade names Selexid and Coactabs), the pivaloyloxymethyl ester of mecillinam. Neither drug is available in the United States.[6]
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 drug of choice for empirical treatment of acute cystitis.[7][1]
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With the codename FL 1060, mecillinam was developed by the Danish pharmaceutical company Leo Pharmaceutical Products (now LEO Pharma). It was first described in the scientific literature in a 1972 paper.[8][9]
Mecillinam is active against most pathogenic Gram-negative bacteria, except Pseudomonas aeruginosa and some species of Proteus.[6] Several studies have also found it to be as effective as other antibiotics for treating Staphylococcus saprophyticus infection, even though it is Gram-positive, possibly because mecillinam reaches very high concentrations in urine.[1]
Worldwide resistance to mecillinam in bacteria causing urinary tract infection has remained very low since its introduction; a 2003 study conducted in 16 European countries and Canada found resistance to range between 1.2% (Escherichia coli) to 5.2% (Proteus mirabilis).[10] Another large study conducted in Europe and Brazil obtained similar results—95.9% of E. coli strains, for instance, were sensitive to mecillinam.[11]
- See also: Beta-lactam antibiotic: Adverse effects
The adverse effect profile of mecillinam is similar to that of other penicillins.[2] The most common side effects of mecillinam use are rash and gastrointestinal upset, including nausea and vomiting.[1][12]
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.[13][14] 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,[15] it is unlikely to be of clinical significance;[14] long-term use, however, appears problematic and is not recommended.[16][14][17]
- ^ a b c d Nicolle LE (August 2000). "Pivmecillinam in the treatment of urinary tract infections". J Antimicrob Chemother 46 Suppl A: 35–39. PMID 10969050. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10969050.
- ^ a b Neu HC (1985). "Amdinocillin: a novel penicillin. Antibacterial activity, pharmacology and clinical use". Pharmacotherapy 5 (1): 1–10. PMID 3885172.
- ^ Clarke PD, Geddes AM, McGhie D, Wall JC (July 1976). "Mecillinam: a new antibiotic for enteric fever". Br Med J 2 (6026): 14–5. PMID 820402.
- ^ Geddes AM, Clarke PD (July 1977). "The treatment of enteric fever with mecillinam". J Antimicrob Chemother 3 Suppl B: 101–2. PMID 408321.
- ^ 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. PMID 6569851.
- ^ a b 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.
- ^ Graninger W (October 2003). "Pivmecillinam—therapy of choice for lower urinary tract infection". Int J Antimicrob Agents 22 Suppl 2: 73–8. PMID 14527775. http://linkinghub.elsevier.com/retrieve/pii/S0924857903002358.
- ^ Lund F, Tybring L (April 1972). "6β-amidinopenicillanic acids—a new group of antibiotics". Nature New Biol 236 (66): 135–7. PMID 4402006.
- ^ Tybring L, Melchior NH (September 1975). "Mecillinam (FL 1060), a 6β-amidinopenicillanic acid derivative: bactericidal action and synergy in vitro". Antimicrob Agents Chemother 8 (3): 271–6. PMID 170856. PMC: 429305. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=170856.
- ^ Kahlmeter G (January 2003). "An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO·SENS Project". J Antimicrob Chemother 51 (1): 69–76. PMID 12493789. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12493789.
- ^ Naber KG, Schito G, Botto H, Palou J, Mazzei T (May 2008). "Surveillance Study in Europe and Brazil on Clinical Aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): Implications for Empiric Therapy". Eur Urol. doi:. PMID 18511178.
- ^ "Selexid Tablets". electronic Medicines Compendium (June 5, 2008). Retrieved on August 31, 2008.
- ^ Holme E, Greter J, Jacobson CE, et al (August 1989). "Carnitine deficiency induced by pivampicillin and pivmecillinam therapy". Lancet 2 (8661): 469–73. PMID 2570185. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(89)92086-2.
- ^ a b c Brass EP (December 2002). "Pivalate-generating prodrugs and carnitine homeostasis in man". Pharmacol Rev 54 (4): 589–98. PMID 12429869. http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12429869.
- ^ Abrahamsson K, Holme E, Jodal U, Lindstedt S, Nordin I (June 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. PMID 7551831. http://linkinghub.elsevier.com/retrieve/pii/S1077315085710368.
- ^ Holme E, Jodal U, Linstedt S, Nordin I (September 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. PMID 1514015.
- ^ Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N (September 2007). "Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid". Pediatrics 120 (3): e739–41. doi:. PMID 17724113.
