Details of the Drug Combination

General Information of Drug Combination (ID: DCNU2DA)

• Drug Combination Name: Amikacin + Cefazolin
• Indication: Nosocomial Neonatal Sepsis; Status: Phase 3 [1]
• Component Drugs:
  Amikacin (DM5PDRB): Small molecular drug
  Cefazolin (DMPDYFR): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amikacin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Cholangitis	N.A.	Approved	[2]
Cystic fibrosis	CA25	Approved	[2]
Escherichia coli meningitis	N.A.	Approved	[2]
Neonatal sepsis	N.A.	Approved	[2]
Osteomyelitis	N.A.	Approved	[2]
Pneumonia caused by gram negative bacteria	N.A.	Approved	[2]
Pseudomonas aeruginosa infectious disease	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]
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	[8]

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	[9]
Endoglucanase A (EGA)	DE1C8Q4	A0A660DUI5_9LACO	Metabolism	[10]
Endoglucanase Y (EGY)	DE2AZTG	A0A256VAC0_LACRE	Metabolism	[10]

Amikacin Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Activity	[7]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[11]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[11]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[11]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[11]
Extracellular calcium-sensing receptor (CASR)	OT2PEJDO	CASR_HUMAN	Increases Activity	[12]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[11]
Survival motor neuron protein (SMN2)	OT54RLO1	SMN_HUMAN	Increases Expression	[13]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[11]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[11]
Phospholipase A2 (PLA2G1B)	OT1GG9FK	PA21B_HUMAN	Increases ADR	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)	OT9HYT7A	PLCB1_HUMAN	Increases ADR	[14]

Indication(s) of Cefazolin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[5]
Bacterial infection	1A00-1C4Z	Approved	[6]
Cholangitis	N.A.	Approved	[5]
Staphylococcal pneumonia	N.A.	Approved	[5]

Cefazolin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Penicillin binding protein (Bact PBP)	TTJP4SM	NOUNIPROTAC	Binder	[15]

Cefazolin Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[16]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[17]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[18]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[19]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[19]

Cefazolin Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[20]
Beta-lactamase (blaB)	DEP0IWS	A0A378EHS6_KLEPR	Metabolism	[21]
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Metabolism	[22]
Beta-lactamase (blaB)	DENJ2SQ	BLAB_BACFG	Metabolism	[23]

References

• [1] ClinicalTrials.gov (NCT01867138) Neonatal Suspected Sepsis Treated With Cefazolin or Vancomycin
• [2] Amikacin FDA Label
• [3] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] Cefazolin FDA Label
• [6] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 065244.
• [7] Modulation of melanogenesis and antioxidant defense system in melanocytes by amikacin. Toxicol In Vitro. 2013 Apr;27(3):1102-8.
• [8] Bacterial resistance to aminoglycosides and beta-lactams: the Tn1331 transposon paradigm. Front Biosci. 2000 Jan 1;5:D20-9.
• [9] Relationship between antimicrobial resistance and aminoglycoside-modifying enzyme gene expressions in Acinetobacter baumannii. Chin Med J (Engl). 2005 Jan 20;118(2):141-5.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Bacteriological characteristics of Staphylococcus aureus isolates from humans and bulk milk. J Dairy Sci. 2008 Feb;91(2):564-9.
• [16] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [17] Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
• [18] Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem. 2005 Jun 30;48(13):4410-9.
• [19] Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm Res. 2004 Jan;21(1):61-7.
• [20] Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue: possible relationship to hypoprothrombinemia. Drug Metab Dispos. 2002 Oct;30(10):1123-8.
• [21] Analysis of the drug-resistant characteristics of Klebsiella pneumoniae isolated from the respiratory tract and CTX-M ESBL genes. Genet Mol Res. 2015 Oct 5;14(4):12043-8.
• [22] Citrobacter freundii bacteremia: Risk factors of mortality and prevalence of resistance genes. J Microbiol Immunol Infect. 2018 Aug;51(4):565-572.
• [23] Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates. Clin Microbiol Infect. 2019 Sep;25(9):1156.e9-1156.e13.