Imipenem

Imipenem
Clinical data
Trade names	Primaxin
AHFS/Drugs.com	International Drug Names
MedlinePlus	a686013
Pregnancy; category	AU: B3 ; US: C (Risk not ruled out) ;
Routes of; administration	IM, IV
ATC code	J01DH51 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only) ; CA: ℞-only ; UK: POM (Prescription only) ; US: ℞-only ;
Pharmacokinetic data
Protein binding	20%
Metabolism	Renal
Elimination half-life	38 minutes (children), 60 minutes (adults)
Excretion	Urine (70%)
Identifiers
	IUPAC name (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
CAS Number	64221-86-9 ;
PubChem CID	5282372;
DrugBank	DB01598 ;
ChemSpider	4445535 ;
UNII	Q20IM7HE75;
KEGG	D00206 ;
ChEBI	CHEBI:51799 ;
ChEMBL	ChEMBL43708 ;
CompTox Dashboard (EPA)	DTXSID2023143 ;
ECHA InfoCard	100.058.831
Chemical and physical data
Formula	C12H17N3O4S
Molar mass	299.347 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(O)/C1=C(\SCC/N=C/N)C[C@H]2N1C(=O)[C@@H]2[C@H](O)C.O;
	InChI InChI=1S/C12H17N3O4S.H2O/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17;/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19);1H2/t6-,7-,9-;/m1./s1 ; Key:GSOSVVULSKVSLQ-JJVRHELESA-N ;
(verify)

Imipenem (Primaxin among others) is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s.[1] Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria,[2] thus play a key role in the treatment of infections not readily treated with other antibiotics.[3]

Imipenem was patented in 1975 and approved for medical use in 1985.[4] It was discovered via a lengthy trial-and-error search for a more stable version of the natural product thienamycin, which is produced by the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but is unstable in aqueous solution, so impractical to administer to patients.[5] Imipenem has a broad spectrum of activity against aerobic and anaerobic, Gram-positive and Gram-negative bacteria.[6] It is particularly important for its activity against Pseudomonas aeruginosa and the Enterococcus species. It is not active against MRSA, however.

Medical uses

Spectrum of bacterial susceptibility and resistance

Acinetobacter anitratus, Acinetobacter calcoaceticus, Actinomyces odontolyticus, Aeromonas hydrophila, Bacteroides distasonis, Bacteroides uniformis, and Clostridium perfringens are generally susceptible to imipenem, while Acinetobacter baumannii, some Acinetobacter spp., Bacteroides fragilis, and Enterococcus faecalis have developed resistance to imipenem to varying degrees. Not many species are resistant to imipenem except Pseudomonas aeruginosa (Oman) and Stenotrophomonas maltophilia.[7]

Coadministration with cilastatin

Imipenem is rapidly degraded by the renal enzyme dehydropeptidase 1 when administered alone, and is almost always coadministered with cilastatin to prevent this inactivation[8]

Adverse effects

Common adverse drug reactions are nausea and vomiting. People who are allergic to penicillin and other β-lactam antibiotics should take caution if taking imipenem, as cross-reactivity rates are high. At high doses, imipenem is seizurogenic.[9]

Mechanism of action

Imipenem acts as an antimicrobial through inhibiting cell wall synthesis of various Gram-positive and Gram-negative bacteria. It remains very stable in the presence of β-lactamase (both penicillinase and cephalosporinase) produced by some bacteria, and is a strong inhibitor of β-lactamases from some Gram-negative bacteria that are resistant to most β-lactam antibiotics.

References

U.S. Patent 4,194,047
Clissold, SP; Todd, PA; Campoli-Richards, DM (Mar 1987). "Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy". Drugs. 33 (3): 183–241. doi:10.2165/00003495-198733030-00001. PMID 3552595.
Vardakas, KZ; Tansarli, GS; Rafailidis, PI; Falagas, ME (Dec 2012). "Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis". The Journal of Antimicrobial Chemotherapy. 67 (12): 2793–803. doi:10.1093/jac/dks301. PMID 22915465.
Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 497. ISBN 9783527607495.
Kahan, FM; Kropp, H; Sundelof, JG; Birnbaum, J (Dec 1983). "Thienamycin: development of imipenen-cilastatin". The Journal of Antimicrobial Chemotherapy. 12 Suppl D: 1–35. doi:10.1093/jac/12.suppl_d.1. PMID 6365872.
Kesado, Tadataka; Hashizume, Terutaka; Asahi, Yoshinari (1980). "Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics". Antimicrobial Agents and Chemotherapy. 17 (6): 912–7. doi:10.1128/aac.17.6.912. PMC 283902. PMID 6931548.
"Imipenem spectrum of bacterial susceptibility and Resistance" (PDF). Retrieved 4 May 2012.
"IMIPENEM/CILASTATIN". livertox.nih.gov. Retrieved 2019-03-08.
Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A. (2014-08-01). "The risk of seizures among the carbapenems: a meta-analysis". Journal of Antimicrobial Chemotherapy. 69 (8): 2043–2055. doi:10.1093/jac/dku111. ISSN 0305-7453.

External links

Imipenem bound to proteins in the PDB

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[1] U.S. Patent 4,194,047

[2] Clissold, SP; Todd, PA; Campoli-Richards, DM (Mar 1987). "Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy". Drugs. 33 (3): 183–241. doi:10.2165/00003495-198733030-00001. PMID 3552595.

[3] Vardakas, KZ; Tansarli, GS; Rafailidis, PI; Falagas, ME (Dec 2012). "Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis". The Journal of Antimicrobial Chemotherapy. 67 (12): 2793–803. doi:10.1093/jac/dks301. PMID 22915465.

[4] Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 497. ISBN 9783527607495.

[5] Kahan, FM; Kropp, H; Sundelof, JG; Birnbaum, J (Dec 1983). "Thienamycin: development of imipenen-cilastatin". The Journal of Antimicrobial Chemotherapy. 12 Suppl D: 1–35. doi:10.1093/jac/12.suppl_d.1. PMID 6365872.

[6] Kesado, Tadataka; Hashizume, Terutaka; Asahi, Yoshinari (1980). "Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics". Antimicrobial Agents and Chemotherapy. 17 (6): 912–7. doi:10.1128/aac.17.6.912. PMC 283902. PMID 6931548.

[7] "Imipenem spectrum of bacterial susceptibility and Resistance" (PDF). Retrieved 4 May 2012.

[8] "IMIPENEM/CILASTATIN". livertox.nih.gov. Retrieved 2019-03-08.

[9] Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A. (2014-08-01). "The risk of seizures among the carbapenems: a meta-analysis". Journal of Antimicrobial Chemotherapy. 69 (8): 2043–2055. doi:10.1093/jac/dku111. ISSN 0305-7453.