Details of the Drug Combination

General Information of Drug Combination (ID: DC75W85)

• Drug Combination Name: Vancomycin + Amikacin
• Indication: Nosocomial Neonatal Sepsis; Status: Phase 3 [1]
• Component Drugs:
  Vancomycin (DM3JFIH): N.A.
  Amikacin (DM5PDRB): 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 Amikacin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[5]
Bacterial infection	1A00-1C4Z	Approved	[6]
Cholangitis	N.A.	Approved	[5]
Cystic fibrosis	CA25	Approved	[5]
Escherichia coli meningitis	N.A.	Approved	[5]
Neonatal sepsis	N.A.	Approved	[5]
Osteomyelitis	N.A.	Approved	[5]
Pneumonia caused by gram negative bacteria	N.A.	Approved	[5]
Pseudomonas aeruginosa infectious disease	N.A.	Approved	[5]
Staphylococcal pneumonia	N.A.	Approved	[5]
Tuberculosis	1B10-1B1Z	Investigative	[4]

Amikacin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Staphylococcus 30S ribosomal subunit (Stap-coc pbp2)	TTQ8KVI	F4NA87_STAAU	Binder	[17]

Amikacin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Aminoglycoside O-phosphotransferase (aphA6)	DEWPAJD	KKA6_ACIBA	Metabolism	[18]
Endoglucanase A (EGA)	DE1C8Q4	A0A660DUI5_9LACO	Metabolism	[19]
Endoglucanase Y (EGY)	DE2AZTG	A0A256VAC0_LACRE	Metabolism	[19]

Amikacin Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Activity	[16]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[20]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[20]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[20]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[20]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[20]
Extracellular calcium-sensing receptor (CASR)	OT2PEJDO	CASR_HUMAN	Increases Activity	[21]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[20]
Survival motor neuron protein (SMN2)	OT54RLO1	SMN_HUMAN	Increases Expression	[22]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[20]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[20]
Phospholipase A2 (PLA2G1B)	OT1GG9FK	PA21B_HUMAN	Increases ADR	[23]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)	OT9HYT7A	PLCB1_HUMAN	Increases ADR	[23]

References

• [1] ClinicalTrials.gov (NCT01867138) Neonatal Suspected Sepsis Treated With Cefazolin or Vancomycin
• [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] Amikacin FDA Label
• [6] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [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] Modulation of melanogenesis and antioxidant defense system in melanocytes by amikacin. Toxicol In Vitro. 2013 Apr;27(3):1102-8.
• [17] Bacterial resistance to aminoglycosides and beta-lactams: the Tn1331 transposon paradigm. Front Biosci. 2000 Jan 1;5:D20-9.
• [18] Relationship between antimicrobial resistance and aminoglycoside-modifying enzyme gene expressions in Acinetobacter baumannii. Chin Med J (Engl). 2005 Jan 20;118(2):141-5.
• [19] Expression of Clostridium thermocellum endoglucanase gene in Lactobacillus gasseri and Lactobacillus johnsonii and characterization of the genetically modified probiotic lactobacilli. Curr Microbiol. 2000 Apr;40(4):257-63.
• [20] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [21] Amikacin-induced type 5 Bartter-like syndrome with severe hypocalcemia. J Postgrad Med. 2009 Jul-Sep;55(3):208-10. doi: 10.4103/0022-3859.57407.
• [22] Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. Hum Mol Genet. 2009 Apr 1;18(7):1310-22. doi: 10.1093/hmg/ddp030. Epub 2009 Jan 15.
• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.