Details of the Drug Combination

General Information of Drug Combination (ID: DCKTUWU)

• Drug Combination Name: Vancomycin + Imipenem
• Indication: Cirrhosis; Status: Phase 4 [1]
• Component Drugs:
  Vancomycin (DM3JFIH): N.A.
  Imipenem (DMI9FBP): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vancomycin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial endocarditis	N.A.	Approved	[2]
Clostridioides difficile infection	1A04	Approved	[2]
Methicillin-resistant staphylococci infection	1A00-1A09	Approved	[3]
Neonatal sepsis	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
MRSA infection	1D01.0Y	Investigative	[4]
Skin infection	1F28-1G0Z	Investigative	[2]

Vancomycin Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
VanA ligase (vanA)	DEOFMQ7	Q0WYK7_ENTFL	Metabolism	[7]
VanA ligase (vanA)	DEO97D6	VANA_ENTFC	Metabolism	[7]
VanB ligase (vanB)	DE27YVU	Q58F99_ENTFC	Metabolism	[7]
VanC2 ligase (vanC)	DEIF4P9	VANC_ENTGA	Metabolism	[8]
VanG ligase (vanG)	DEPH3S7	A0A076ZC24_STRAP	Metabolism	[9]
VanA ligase (vanA)	DEO8E75	A0A437UFE2_ENTAV	Metabolism	[7]
VanB ligase (vanB)	DER7KFQ	VANB_ENTFA	Metabolism	[7]
VanC2 ligase (vanC)	DEH73ZC	Q47720_ENTCA	Metabolism	[10]
D-alanylalanine synthetase (ddl)	DE035GU	A0A1Q6S944_9FIRM	Metabolism	[9]
VanG ligase (vanG)	DEPN8F9	A0A076YRI6_STRAG	Metabolism	[9]
VanB ligase (vanB)	DEMDEJ8	Q58F99_ENTFC	Metabolism	[11]
VanB ligase (vanB)	DE2GMEK	Q58F99_ENTFC	Metabolism	[11]
VanA ligase (vanA)	DEN6VO0	A0A376GZ73_ENTGA	Metabolism	[12]
VanA ligase (vanA)	DESOXHP	A0A4U9YK96_ENTCA	Metabolism	[13], [12]

Vancomycin Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[14]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[15]
HLA class II histocompatibility antigen, DM beta chain (HLA-DMB)	OT17HGXJ	DMB_HUMAN	Affects Expression	[14]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[14]

Indication(s) of Imipenem

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[5]
Bacterial infection	1A00-1C4Z	Approved	[6]
Endometritis	N.A.	Approved	[5]
Peritonitis	N.A.	Approved	[5]
Pelvic inflammatory disease	GA05	Investigative	[5]

Imipenem Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Penicillin binding protein 2 (Bact mrdA)	TTHWB7G	MRDA_ECOLI	Binder	[16]

Imipenem Interacts with 17 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Beta-lactamase (blaB)	DEC3G7M	A0A1S7IV31_ENTAS	Metabolism	[17]
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Metabolism	[18]
AmpC beta-lactamase (ampC)	DERI7LO	A0A0H3KQ39_BURM1	Metabolism	[19]
Beta-lactamase (blaB)	DEYIEO5	AMPC_SERMA	Metabolism	[18]
Beta-lactamase (blaB)	DEBKS91	A0A1B1FBM9_ACIBA	Metabolism	[20]
Beta-lactamase (blaB)	DEUHIQS	A0A1S7IV31_ENTAS	Metabolism	[21]
Beta-lactamase (blaB)	DECWSA9	AMPC_MORMO	Metabolism	[22]
Carbapenemase (cphA)	DEB90AL	BLAB_AERHY	Metabolism	[23]
Carbapenemase (cphA)	DETRKSD	A0A3G1JAD7_ALCXX	Metabolism	[24]
Beta-lactamase (blaB)	DECB2MX	A0A1M5PLB6_9FLAO	Metabolism	[25]
Beta-lactamase (blaB)	DEEQ3RW	K0GG60_CITBR	Metabolism	[26]
Carbapenemase (cphA)	DEQ4LIN	Q8L1M8_9ENTR	Metabolism	[27]
Beta-lactamase (blaB)	DEQ0K5J	A0A223JZR3_9ENTR	Metabolism	[26]
Beta-lactamase (blaB)	DE7MYGB	A0A291NY45_PROSP	Metabolism	[18]
Carbapenemase (cphA)	DE9QNXV	A0A366EJX1_9ENTR	Metabolism	[28]
Beta-lactamase (blaB)	DEL6894	A0A2S8DM15_SHIBO	Metabolism	[26]
Beta-lactamase (blaB)	DE8KH4C	A0A3B7D7C4_9VIBR	Metabolism	[29]

Imipenem Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[30]

References

• [1] ClinicalTrials.gov (NCT01820026) Empirical vs 2nd Line Antibiotic Therapy in Health-care Associated Infections in Cirrhosis
• [2] Vancomycin FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] Cilastatin FDA Label
• [6] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [7] Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother. 1993 Aug;37(8):1563-71.
• [8] Sequence of the vanC gene of Enterococcus gallinarum BM4174 encoding a D-alanine:D-alanine ligase-related protein necessary for vancomycin resistance. Gene. 1992 Mar 1;112(1):53-8.
• [9] vanG element insertions within a conserved chromosomal site conferring vancomycin resistance to Streptococcus agalactiae and Streptococcus anginosus. mBio. 2014 Jul 22;5(4):e01386-14.
• [10] Bacterial resistance to vancomycin: overproduction, purification, and characterization of VanC2 from Enterococcus casseliflavus as a D-Ala-D-Ser ligase. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10040-4.
• [11] vanI: a novel D-Ala-D-Lac vancomycin resistance gene cluster found in Desulfitobacterium hafniense. Microb Biotechnol. 2014 Sep;7(5):456-66.
• [12] Emergence of high-level resistance to glycopeptides in Enterococcus gallinarum and Enterococcus casseliflavus. Antimicrob Agents Chemother. 1994 Jul;38(7):1675-7.
• [13] vanA in Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus detected in French cattle. Foodborne Pathog Dis. 2009 Nov;6(9):1107-11.
• [14] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [15] [Successful treatment of MRSA-associated glomerulonephritis with antibiotic therapy]. Nihon Jinzo Gakkai Shi. 2003;45(1):37-41.
• [16] 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.
• [17] FRI-4 carbapenemase-producing Enterobacter cloacae complex isolated in Tokyo, Japan. J Antimicrob Chemother. 2018 Nov 1;73(11):2969-2972.
• [18] 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.
• [19] Characterization of the AmpC beta-Lactamase from Burkholderia multivorans. Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01140-18.
• [20] 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.
• [21] AmpC beta-lactamase-producing Enterobacterales: what a clinician should know. Infection. 2019 Jun;47(3):363-375.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Carbapenemase VCC-1-producing Vibrio cholerae in coastal waters of Germany. Emerg Infect Dis. 2017 Oct;23(10):1735-1737.
• [30] 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.