Details of the Drug

General Information of Drug (ID: DMI9FBP)

• Drug Name: Imipenem
• Synonyms: Imipemide; Tienamycin; Imipenem anhydrous; Imipenem (INN); N-Formimidoylthienamycin; Primaxin (TN); Imipenem, N-Formimidoyl thienamycin; [5R-[5.alpha.,6.alpha.(R*)]]-6-(1-Hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate; (5R,6S)-3-(2-Formimidoylamino-ethylsulfanyl)-6-((R)-1-hydroxy-ethyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5R,6S)-6-((R)-1-Hydroxyethyl)-3-(2-(iminomethylamino)ethylthio)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carbonsaeure; (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

Indication

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[1]
Bacterial infection	1A00-1C4Z	Approved	[2]
Endometritis	N.A.	Approved	[1]
Peritonitis	N.A.	Approved	[1]
Pelvic inflammatory disease	GA05	Investigative	[1]

• Therapeutic Class: Antibiotics
• Affected Organisms: Staphylococcus aureusEscherichia coliEnterococcus faecalisHaemophilus influenzaeHaemophilus parainfluenzaeSerratia marcescensMorganella morganiiProteus vulgarisProvidencia rettgeriPseudomonas aeruginosaStaphylococcus epidermidisStreptococcus agalactiaeEnterobacter cloacaeKlebsiella pneumoniaeKlebsiella aerogenesCitrobacter freundiiBacteroides caccaeBacteroides ovatusBacteroides thetaiotaomicronBacteroides stercorisBacteroides uniformisBacteroides vulgatusFusobacterium nucleatumParabacteroides distasonisAcinetobacter spp.Enterobacter spp.Klebsiella spp.Citrobacter spp.Proteus spp.Bifidobacterium spp.Clostridium spp.Eubacterium spp.Peptococcus spp.Peptostreptococcus spp.Propionibacterium spp.Bacteroides spp.Fusobacterium spp.Serratia spp.Gardnerella vaginalis
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 299.35
  Logarithm of the Partition Coefficient (xlogp); -0.7
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 6
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
  Clearance: The renal clearance of drug is 0.05 L/h/kg [4]
  Elimination: 69% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 1 hour [5]
  Metabolism: The drug is metabolized via renal dehydropeptidase []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 222.819 micromolar/kg/day [6]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.86% [5]
  Vd: The volume of distribution (Vd) of drug is 0.23-0.31 L/kg [7]
  Water Solubility: The ability of drug to dissolve in water is measured as 10 mg/mL [3]
• Chemical Identifiers:
  Formula: C12H17N3O4S
  IUPAC Name: (5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  Canonical SMILES: C[C@H]([C@@H]1[C@H]2CC(=C(N2C1=O)C(=O)O)SCCN=CN)O
  InChI: InChI=1S/C12H17N3O4S/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)/t6-,7-,9-/m1/s1
  InChIKey: ZSKVGTPCRGIANV-ZXFLCMHBSA-N
• Cross-matching ID:
  PubChem CID: 104838
  ChEBI ID: CHEBI:471744
  CAS Number: 64221-86-9
  UNII: Q20IM7HE75
  DrugBank ID: DB01598
  TTD ID: D0H3TD
  INTEDE ID: DR2447
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial Penicillin binding protein 2 (Bact mrdA)	TTHWB7G	MRDA_ECOLI	Binder	[8]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Substrate	[9]
Beta-lactamase (blaB)	DEC3G7M	A0A1S7IV31_ENTAS	Substrate	[10], [11]
Beta-lactamase (blaB)	DEYIEO5	AMPC_SERMA	Substrate	[9], [12]
Carbapenemase (cphA)	DEB90AL	BLAB_AERHY	Substrate	[13], [14]
Beta-lactamase (blaB)	DEBKS91	A0A1B1FBM9_ACIBA	Substrate	[15]
AmpC beta-lactamase (ampC)	DERI7LO	A0A0H3KQ39_BURM1	Substrate	[16]
Carbapenemase (cphA)	DETRKSD	A0A3G1JAD7_ALCXX	Substrate	[17]
Beta-lactamase (blaB)	DECWSA9	AMPC_MORMO	Substrate	[18]
Beta-lactamase (blaB)	DEUHIQS	A0A1S7IV31_ENTAS	Substrate	[19], [20]
Beta-lactamase (blaB)	DECB2MX	A0A1M5PLB6_9FLAO	Substrate	[21]
Beta-lactamase (blaB)	DEEQ3RW	K0GG60_CITBR	Substrate	[22]
Beta-lactamase (blaB)	DEQ0K5J	A0A223JZR3_9ENTR	Substrate	[22]
Beta-lactamase (blaB)	DE7MYGB	A0A291NY45_PROSP	Substrate	[9]
Beta-lactamase (blaB)	DEL6894	A0A2S8DM15_SHIBO	Substrate	[22]
Beta-lactamase (blaB)	DE8KH4C	A0A3B7D7C4_9VIBR	Substrate	[23]
Carbapenemase (cphA)	DEQ4LIN	Q8L1M8_9ENTR	Substrate	[24]
Carbapenemase (cphA)	DE9QNXV	A0A366EJX1_9ENTR	Substrate	[25]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Gene/Protein Processing	[26]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Imipenem (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Polyethylene glycol	DM4I1JP	Moderate	Increased risk of lowers seizure threshold by the combination of Imipenem and Polyethylene glycol.	Irritable bowel syndrome [DD91]	[27]
Valganciclovir	DMS2IUH	Moderate	Increased risk of lowers seizure threshold by the combination of Imipenem and Valganciclovir.	Virus infection [1A24-1D9Z]	[28]

References

• [1] Cilastatin FDA Label
• [2] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [3] BDDCS applied to over 900 drugs
• [4] Balfour JA, Bryson HM, Brogden RN: Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs. 1996 Jan;51(1):99-136. doi: 10.2165/00003495-199651010-00008.
• [5] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [6] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [7] Buckley MM, Brogden RN, Barradell LB, Goa KL: Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1992 Sep;44(3):408-44.
• [8] A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with gram-negative urosepsis. Urosepsis Study Group. J Endotoxin Res. 2000;6(1):25-31.
• [9] Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents. 2012 Oct;40(4):297-305.
• [10] FRI-4 carbapenemase-producing Enterobacter cloacae complex isolated in Tokyo, Japan. J Antimicrob Chemother. 2018 Nov 1;73(11):2969-2972.
• [11] Survey of clinical extended-spectrum beta-lactamase-producing Enterobacter cloacae isolates in a Chinese Tertiary Hospital, 2012-2014. Microb Drug Resist. 2017 Jan;23(1):83-89.
• [12] Serratia marcescens producing SME carbapenemases: an emerging resistance problem in the UK? J Antimicrob Chemother. 2017 May 1;72(5):1535-1537.
• [13] A carbapenem-resistant clinical isolate of Aeromonas hydrophila in Japan harbouring an acquired gene encoding GES-24 beta-lactamase. J Med Microbiol. 2018 Nov;67(11):1535-1537.
• [14] Chronic colitis after Aeromonas infection. Gut. 1989 May;30(5):686-90. Case Reports
• [15] A high mortality rate associated with multidrug-resistant Acinetobacter baumannii ST79 and ST25 carrying OXA-23 in a Brazilian intensive care unit. PLoS One. 2018 Dec 28;13(12):e0209367.
• [16] Characterization of the AmpC beta-Lactamase from Burkholderia multivorans. Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01140-18.
• [17] Proteomic identification of Axc, a novel beta-lactamase with carbapenemase activity in a meropenem-resistant clinical isolate of Achromobacter xylosoxidans. Sci Rep. 2018 May 25;8(1):8181.
• [18] Molecular investigation of extended-spectrum beta-lactamase genes and potential drug resistance in clinical isolates of Morganella morganii. Ann Saudi Med. 2016 May-Jun;36(3):223-8.
• [19] AmpC beta-lactamase-producing Enterobacterales: what a clinician should know. Infection. 2019 Jun;47(3):363-375.
• [20] Molecular analysis of colonized bacteria in a human newborn infant gut. J Microbiol. 2005 Aug;43(4):345-53.
• [21] Whole-genome sequence of Chryseobacterium oranimense, a colistin-resistant bacterium isolated from a cystic fibrosis patient in France. Antimicrob Agents Chemother. 2015 Mar;59(3):1696-706.
• [22] Hospital sewage water: a reservoir for variants of New Delhi metallo-beta-lactamase (NDM)- and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Int J Antimicrob Agents. 2018 Jan;51(1):82-88.
• [23] Carbapenemase VCC-1-producing Vibrio cholerae in coastal waters of Germany. Emerg Infect Dis. 2017 Oct;23(10):1735-1737.
• [24] Occurrence of a new metallo-beta-lactamase IMP-4 carried on a conjugative plasmid in Citrobacter youngae from the People's Republic of China. FEMS Microbiol Lett. 2001 Jan 1;194(1):53-7.
• [25] Pseudocitrobacter gen. nov., a novel genus of the Enterobacteriaceae with two new species Pseudocitrobacter faecalis sp. nov., and Pseudocitrobacter anthropi sp. nov, isolated from fecal samples from hospitalized patients in Pakistan. Syst Appl Microbiol. 2014 Feb;37(1):17-22.
• [26] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [27] Product Information. Suprep Bowel Prep Kit (magnesium/potassium/sodium sulfates). Braintree Laboratories, Braintree, MA.
• [28] Product Information. Cytovene (ganciclovir). Genentech, South San Francisco, CA.