Drug Information

Drug (ID: DG00233) and It's Reported Resistant Information

• Name: Co-trimoxazole
• Indication:
  In total 1 Indication(s)
  Bowel habit change [ICD-11: ME05]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  HIV associated with tuberculosis [ICD-11: 1C60]; [3]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [4]
  Pneumonia [ICD-11: CA40]; [5]
  Sepsis with septic shock [ICD-11: 1G41]; [6]
  Urinary tract infection [ICD-11: GC08]; [1]
• Formula: C24H29N7O6S
• IsoSMILES: CC1=CC(=NO1)NS(=O)(=O)C2=CC=C(C=C2)N.COC1=CC(=CC(=C1OC)OC)CC2=CN=C(N=C2N)N
• InChI: 1S/C14H18N4O3.C10H11N3O3S/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15;1-7-6-10(12-16-7)13-17(14,15)9-4-2-8(11)3-5-9/h5-7H,4H2,1-3H3,(H4,15,16,17,18);2-6H,11H2,1H3,(H,12,13)
• InChIKey: WZRJTRPJURQBRM-UHFFFAOYSA-N
• PubChem CID: 358641
• ChEBI ID: CHEBI:3770
• TTD Drug ID: D0P0VD

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [2]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: OXA-23 carbapenemase (BLA OXA-23) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cutaneous bacterial infection [ICD-11: 1B21.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii isolates; 470
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay; Agar dilution method assay
• Mechanism Description: The isolate was resistant to antibiotics other than ampicillin-sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23.carbapenem resistance in the isolated carbapenem-resistant A. baumannii strain was at least partially conferred by bla OXA-23-like carbapenemase.

HIV associated with tuberculosis [ICD-11: 1C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Missense mutation; p.V96I
• Resistant Disease: HIV-infected Pneumocystis pneumonia [ICD-11: 1C60.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii isolates; 42068
• Experiment for Molecule Alteration: nested PCR
• Mechanism Description: Among the 76 enrolled HIV-positive patients, only 17 (22.4%) were positive for P. jirovecii. DHPS gene sequencing showed a novel nucleotide substitution at position 288 (Val96Ile) in three patients (3/12; 25.0%). Patients infected with the mutant P. jirovecii genotype had severe episodes of PCP, did not respond to SXT and had a fatal outcome.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [5]

• Molecule Alteration: Missense mutation; p.S37T
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [8]

• Molecule Alteration: Missense mutation; p.T55A
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

Key Molecule: Dihydrofolate reductase (DHFR) [8]

• Molecule Alteration: Missense mutation; p.P57S
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

Key Molecule: Dihydrofolate reductase (DHFR) [8]

• Molecule Alteration: Missense mutation; p.T55A+p.P57S
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocytis jirovecii strain; 42068
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: In these 5 resistance-fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation.

ICD-16: Genitourinary system diseases

Urinary tract infection [ICD-11: GC08]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

References

• Ref 1: Global spread of mobile antimicrobial drug resistance determinants in human and animal Escherichia coli and Salmonella strains causing community-acquired infections. Clin Infect Dis. 2009 Aug 1;49(3):365-71. doi: 10.1086/600301.
• Ref 2: New aminoglycoside acetyltransferase gene, aac(3)-Id, in a class 1 integron from a multiresistant strain of Vibrio fluvialis isolated from an infant aged 6 months. J Antimicrob Chemother. 2004 Jun;53(6):947-51. doi: 10.1093/jac/dkh221. Epub 2004 Apr 29.
• Ref 3: Novel dihydropteroate synthase gene mutation in Pneumocystis jirovecii among HIV-infected patients in India: Putative association with drug resistance and mortality .J Glob Antimicrob Resist. 2019 Jun;17:236-239. doi: 10.1016/j.jgar.2019.01.007. Epub 2019 Jan 15. 10.1016/j.jgar.2019.01.007
• Ref 4: Investigation and analysis of the characteristics and drug sensitivity of bacteria in skin ulcer infections .Chin J Traumatol. 2017 Aug;20(4):194-197. doi: 10.1016/j.cjtee.2016.09.005. Epub 2017 May 24. 10.1016/j.cjtee.2016.09.005
• Ref 5: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. doi: 10.1128/AAC.48.11.4301-4305.2004.
• Ref 6: Antimicrobial resistance patterns, clinical features, and risk factors for septic shock and death of nosocomial E coli bacteremia in adult patients with hematological disease: A monocenter retrospective study in China .Medicine (Baltimore). 2017 May;96(21):e6959. doi: 10.1097/MD.0000000000006959. 10.1097/MD.0000000000006959
• Ref 7: Daptomycin .J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. 10.1093/jac/dkx349
• Ref 8: Low prevalence of Pneumocystis pneumonia (PCP) but high prevalence of pneumocystis dihydropteroate synthase (dhps) gene mutations in HIV-infected persons in Uganda. PLoS One. 2012;7(11):e49991. doi: 10.1371/journal.pone.0049991. Epub 2012 Nov 16.