Details of the Drug Combination

General Information of Drug Combination (ID: DCCXROK)

• Drug Combination Name: Cefotaxime + Metronidazole
• Indication: Appendicitis; Status: Phase 1 [1]
• Component Drugs:
  Cefotaxime (DMEB837): N.A.
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cefotaxime

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial arthritis	N.A.	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Escherichia coli meningitis	N.A.	Approved	[2]
Meningococcal meningitis	N.A.	Approved	[2]
Neonatal sepsis	N.A.	Approved	[2]
Peritonitis	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]

Cefotaxime Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial DD-carboxypeptidase (Bact vanYB)	TTLP6GN	VANY_ENTFA	Inhibitor	[8]

Cefotaxime Interacts with 19 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Beta-lactamase (blaB)	DEAYSTX	C0W968_9FIRM	Metabolism	[9]
Beta-lactamase (blaB)	DEITMS0	Q9XBM2_ACIFE	Metabolism	[10]
Beta-lactamase (blaB)	DEP0IWS	A0A378EHS6_KLEPR	Metabolism	[11]
Beta-lactamase (blaB)	DEEAL81	BLA2_KLEPO	Metabolism	[12], [13]
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Metabolism	[14], [15]
Ampc beta-lactamase (ampC)	DE0TCN3	B4EPS2_BURCJ	Metabolism	[16]
Beta-lactamase (blaB)	DE5HV8P	A0A4Q5I6I2_9BACE	Metabolism	[17]
Beta-lactamase (blaB)	DE47ARF	B5WXV2_9BACT	Metabolism	[17]
Beta-lactamase (blaB)	DEHJVX4	A0A414C8Y0_9BACT	Metabolism	[17]
Beta-lactamase (blaB)	DEG2PK9	B5WXV3_BACOV	Metabolism	[17]
Beta-lactamase (blaB)	DEWHJ7A	B5WXV7_BACT4	Metabolism	[17], [18]
Beta-lactamase (blaB)	DEU1RXB	BLAC_BACVU	Metabolism	[17]
Beta-lactamase (blaB)	DEMIUB2	BLAT_ECOLX	Metabolism	[13]
Beta-lactamase (blaB)	DEYIEO5	AMPC_SERMA	Metabolism	[19]
Beta-lactamase (blaB)	DEVHXAU	BLC2_SALTM	Metabolism	[18]
Beta-lactamase (blaB)	DEZLFV5	B8R6A5_9BURK	Metabolism	[16]
PenA beta-lactamase (penA1)	DE2ARDZ	O08350_BURCE	Metabolism	[20]
Beta-lactamase (blaB)	DE5AHG6	BLAC_CITKO	Metabolism	[21]
Beta-lactamase (blaB)	DEKGVS4	PENA_BURM1	Metabolism	[22]

Indication(s) of Metronidazole

Disease Entry	ICD 11	Status	REF
Abscess	N.A.	Approved	[4]
Amoebiasis	1A36	Approved	[5]
Anaerobic bacteria infectious disease	N.A.	Approved	[4]
Bacteremia	1A73	Approved	[4]
Bacterial vaginosis	MF3A	Approved	[4]
Bladder squamous cell carcinoma	N.A.	Approved	[4]
Endometritis	N.A.	Approved	[4]
Liver abscess (disease)	N.A.	Approved	[4]
Peritonitis	N.A.	Approved	[4]
Trichomoniasis	N.A.	Approved	[4]
Crohn disease	DD70	Phase 3	[6]
Perianal crohn disease	DD70.4	Phase 3	[7]
Giardiasis	N.A.	Investigative	[4]

Metronidazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Modulator	[23]

Metronidazole Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[25]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[26]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[28]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[28]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[28]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[29]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[30]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[31]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[31]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[32]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[33]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[34]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[34]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[33]

References

• [1] ClinicalTrials.gov (NCT02404064) Laparoscopic Appendectomy for Uncomplicated Appendicitis: Does Antimicrobial Prophylaxis Really Matter?
• [2] Cefotaxime FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 064200.
• [4] Metronidazole FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [6] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Extended-spectrum cephalosporinases: structure, detection and epidemiology. Future Microbiol. 2007 Jun;2:297-307.
• [9] ACI-1 beta-lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages. Environ Microbiol. 2018 Jun;20(6):2288-2300.
• [10] ACI-1 from Acidaminococcus fermentans: characterization of the first beta-lactamase in Anaerobic cocci. Antimicrob Agents Chemother. 2000 Nov;44(11):3144-9.
• [11] 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.
• [12] Antibiotic resistance and production of extended-spectrum beta-lactamases amongst Klebsiella spp. from intensive care units in Europe. J Antimicrob Chemother. 1996 Sep;38(3):409-24.
• [13] Oral streptococcal strains isolated from odontogenic infections and their susceptibility to antibiotics. Rev Med Chir Soc Med Nat Iasi. 2006 Oct-Dec;110(4):1012-5.
• [14] Citrobacter freundii bacteremia: Risk factors of mortality and prevalence of resistance genes. J Microbiol Immunol Infect. 2018 Aug;51(4):565-572.
• [15] Analyses of a ceftazidime-avibactam-resistant Citrobacter freundii isolate carrying blaKPC-2 reveals a heterogenous population and reversible genotype. mSphere. 2018 Sep 26;3(5). pii: e00408-18.
• [16] Cell wall recycling-linked coregulation of AmpC and PenB beta-lactamases through ampD mutations in Burkholderia cenocepacia. Antimicrob Agents Chemother. 2015 Dec;59(12):7602-10.
• [17] Presence of the cfxA gene in Bacteroides distasonis. Res Microbiol. 2003 Jun;154(5):369-74.
• [18] Cephalosporinases associated with outer membrane vesicles released by Bacteroides spp. protect gut pathogens and commensals against beta-lactam antibiotics. J Antimicrob Chemother. 2015 Mar;70(3):701-9.
• [19] Determination of the antibiotic resistance rates of Serratia marcescens isolates obtained from various clinical specimens. Niger J Clin Pract. 2019 Jan;22(1):125-130.
• [20] Characterization of the penA and penR genes of Burkholderia cepacia 249 which encode the chromosomal class A penicillinase and its LysR-type transcriptional regulator. Antimicrob Agents Chemother. 1997 Nov;41(11):2399-405.
• [21] Novel TEM-type extended-spectrum beta-lactamase, TEM-134, in a Citrobacter koseri clinical isolate. Antimicrob Agents Chemother. 2005 Apr;49(4):1564-6.
• [22] Overcoming an extremely drug resistant (XDR) pathogen: avibactam restores susceptibility to ceftazidime for Burkholderia cepacia complex isolates from cystic fibrosis patients. ACS Infect Dis. 2017 Jul 14;3(7):502-511.
• [23] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [24] Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother. 2007 Apr;41(4):653-8.
• [25] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [26] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [27] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [28] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [29] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [30] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [31] Mechanism of metronidazole-resistance by isolates of nitroreductase-producing Enterococcus gallinarum and Enterococcus casseliflavus from the human intestinal tract. FEMS Microbiol Lett. 2003 Aug 29;225(2):195-200.
• [32] Isolation of metronidazole-resistant Bacteroides fragilis carrying the nimA nitroreductase gene from a patient in Washington State. J Clin Microbiol. 2004 Sep;42(9):4127-9. Case Reports
• [33] 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.
• [34] 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.