Details of the Drug Combination

General Information of Drug Combination (ID: DCQGT1X)

• Drug Combination Name: Vancomycin + Cefazolin
• Indication: Surgical Site Infections; Status: Phase 4 [1]
• Component Drugs:
  Vancomycin (DM3JFIH): N.A.
  Cefazolin (DMPDYFR): 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 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	[16]

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	[17]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[18]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[19]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[20]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[20]

Cefazolin Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[21]
Beta-lactamase (blaB)	DEP0IWS	A0A378EHS6_KLEPR	Metabolism	[22]
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Metabolism	[23]
Beta-lactamase (blaB)	DENJ2SQ	BLAB_BACFG	Metabolism	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Thoracic Surgery	DC5Y73O	N. A.	Phase 1	[25]

References

• [1] ClinicalTrials.gov (NCT03402945) Prevention of Infections in Cardiac Surgery (PICS) Prevena Study
• [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] Cefazolin FDA Label
• [6] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 065244.
• [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] Bacteriological characteristics of Staphylococcus aureus isolates from humans and bulk milk. J Dairy Sci. 2008 Feb;91(2):564-9.
• [17] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [18] Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Citrobacter freundii bacteremia: Risk factors of mortality and prevalence of resistance genes. J Microbiol Immunol Infect. 2018 Aug;51(4):565-572.
• [24] 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.
• [25] ClinicalTrials.gov (NCT02285140) Prevention of Infections in Cardiac Surgery