Details of the Drug Combination

General Information of Drug Combination (ID: DCKLK02)

• Drug Combination Name: Clindamycin + Flucloxacillin
• Indication: Cellulitis; Status: Phase 4 [1]
• Component Drugs:
  Clindamycin (DM15HL8): Small molecular drug
  Flucloxacillin (DMNUWST): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clindamycin

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Aspiration pneumonia	N.A.	Approved	[3]
Bacteremia	1A73	Approved	[3]
Bacterial vaginosis	MF3A	Approved	[3]
Pleural empyema	N.A.	Approved	[3]
Staphylococcal pneumonia	N.A.	Approved	[3]
Staphylococcus aureus infection	N.A.	Approved	[3]
Streptococcal pneumonia	N.A.	Approved	[3]
Pelvic inflammatory disease	GA05	Investigative	[3]

Clindamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[6]

Clindamycin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Beta-lactamase (blaB)	DEMSNER	A4LA84_EDWTA	Metabolism	[8]

Clindamycin Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[9]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[10]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[10]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[11]

Indication(s) of Flucloxacillin

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[4]
Chronic kidney disease	GB61	Investigative	[5]

Flucloxacillin 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	[14]

Flucloxacillin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[15]

Flucloxacillin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]

Flucloxacillin Interacts with 23 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 Response To Substance	[17]
Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1)	OT7US3NO	SIAT1_HUMAN	Increases ADR	[17]
Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B)	OTAHWAKE	AG10B_HUMAN	Increases ADR	[17]
Multiple C2 and transmembrane domain-containing protein 2 (MCTP2)	OTFMZ8I2	MCTP2_HUMAN	Increases ADR	[17]
Olfactory receptor 5H2 (OR5H2)	OTHX3135	OR5H2_HUMAN	Increases ADR	[17]
HLA class I histocompatibility antigen protein P5 (HCP5)	OTV0YRI8	HCP5_HUMAN	Increases ADR	[17]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[18]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[12]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[12]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Secretion	[12]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[12]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[12]
High mobility group protein B1 (HMGB1)	OT4B7CPF	HMGB1_HUMAN	Increases Secretion	[12]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[12]
All-trans-retinol dehydrogenase ADH1B (ADH1B)	OTV3TB81	ADH1B_HUMAN	Affects Binding	[13]
Glutamate dehydrogenase 1, mitochondrial (GLUD1)	OTXKOCUH	DHE3_HUMAN	Affects Binding	[13]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[13]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Affects Binding	[13]
Carbamoyl-phosphate synthase , mitochondrial (CPS1)	OTXV8NSR	CPSM_HUMAN	Affects Binding	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[19]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Affects Binding	[13]
Hemoglobin subunit alpha (HBA1)	OTW2BQF4	HBA_HUMAN	Affects Binding	[13]
tRNA-splicing endonuclease subunit Sen2 (TSEN2)	OT1UWYRI	SEN2_HUMAN	Affects Binding	[13]

References

• [1] ClinicalTrials.gov (NCT01876628) Adjunctive Clindamycin for Cellulitis: C4C Trial.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Clindamycin FDA Label
• [4] Drug information of Flucloxacillin, 2008. eduDrugs.
• [5] Flucloxacillin and paracetamol induced pyroglutamic acidosis. BMJ Case Rep. 2021 Jan 8;14(1):e237536.
• [6] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [7] In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab Dispos. 2003 Jul;31(7):878-87.
• [8] Comparison of antimicrobial susceptibility, beta-lactamase production, plasmid analysis and serum bactericidal activity in Edwardsiella tarda, E. ictaluri and E. hoshinae. J Med Microbiol. 1993 Oct;39(4):273-81.
• [9] A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008 Aug;36(8):1689-97.
• [10] 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.
• [11] Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 2010 Jul;116(1):140-50. doi: 10.1093/toxsci/kfq085. Epub 2010 Mar 25.
• [12] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [13] Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. Toxicol Sci. 2023 Mar 20;192(1):106-116. doi: 10.1093/toxsci/kfad015.
• [14] Mechanisms of resistance to beta-lactam antibiotics in Staphylococcus aureus. Scand J Infect Dis Suppl. 1984;42:64-71.
• [15] 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.
• [16] Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A-catalysed hydroxylation by sulfaphenazole. Br J Pharmacol. 2019 Feb;176(3):466-477.
• [17] HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009 Jul;41(7):816-9. doi: 10.1038/ng.379. Epub 2009 May 31.
• [18] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [19] Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics. Toxicol In Vitro. 2019 Aug;58:51-59. doi: 10.1016/j.tiv.2019.03.015. Epub 2019 Mar 12.