Drug Information

Drug (ID: DG00033) and It's Reported Resistant Information

• Name: Levofloxacin
• Synonyms: Aeroquin; Cravit; Elequine; Floxacin; Floxel; Iquix; LFX; LVX; Leroxacin; Lesacin; Levaquin; Levofloxacine; Levofloxacino; Levofloxacinum; Levokacin; Levox; Levoxacin; Mosardal; Nofaxin; Oftaquix; Quixin; Reskuin; Tavanic; Volequin; Cravit Ophthalmic; DR 3354; DR3355; HR 355; Cravit (TN); D-Levofloxacin; DR-3355; HR-355; Iquix (TN); L-Ofloxacin; LEVAQUIN IN DEXTROSE 5% IN PLASTIC CONTAINER; Levaquin (TN); Levofloxacin (INN); Levofloxacin tablet, suspension or intravenous; Levofloxacine [INN-French]; Levofloxacino [INN-Spanish]; Levofloxacinum [INN-Latin]; MP-376; Oftaquix (TN); Quixin (TN); R-Ofloxacin; RWJ 25213-097; RWJ-25213; Tavanic (TN); Levofloxacin [USAN:INN:JAN]; DR-3355: L-isomer of ofloxacin; Ofloxacin S-(-)-form; S-(-)-Ofloxacin; (-)-(S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid; (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyridol[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate; (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7Hpyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate; (3S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid; (R)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid; (R)-isomer; (S)-(-)-Ofloxacin; (S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid; (S)-Ofloxacin
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (11 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [4]
  HIV associated with tuberculosis [ICD-11: 1C60]; [1], [2]
  Leprosy [ICD-11: 1B20]; [5]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [6]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [7]
  Pneumonia [ICD-11: CA40]; [4]
  Prostate cancer [ICD-11: 2C82]; [6]
  Pyelonephritis [ICD-11: GB54]; [8]
  Sepsis with septic shock [ICD-11: 1G41]; [9]
  Tissue pyogenic bacterial infection [ICD-11: 1B7Y]; [10]
• Target: Bacterial DNA gyrase (Bact gyrase); GYRA_STAAU GYRB_STAAU; [1]
• Target: Staphylococcus Topoisomerase IV (Stap-coc parC); PARC_STAAS; [1]
• Formula: C18H20FN3O4
• IsoSMILES: C[C@H]1COC2=C3N1C=C(C(=O)C3=CC(=C2N4CCN(CC4)C)F)C(=O)O
• InChI: 1S/C18H20FN3O4/c1-10-9-26-17-14-11(16(23)12(18(24)25)8-22(10)14)7-13(19)15(17)21-5-3-20(2)4-6-21/h7-8,10H,3-6,9H2,1-2H3,(H,24,25)/t10-/m0/s1
• InChIKey: GSDSWSVVBLHKDQ-JTQLQIEISA-N
• PubChem CID: 149096
• ChEBI ID: CHEBI:63598
• TTD Drug ID: D02RSN
• VARIDT ID: DR00046
• INTEDE ID: DR2456
• DrugBank ID: DB01137

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

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

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [11]

• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [11]

• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Key Molecule: DNA gyrase subunit A (GYRA) [12], [13]

• Molecule Alteration: Missense mutation; p.T83I
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA gyrase subunit A (GYRA) [12], [13]

• Molecule Alteration: Missense mutation; p.D87H
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA gyrase subunit A (GYRA) [12], [13]

• Molecule Alteration: Missense mutation; p.G81D
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Burkholderia cepacia isolates; 292
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.S463A
• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.S464Y
• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [3]

• Molecule Alteration: Missense mutation; p.S80I
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Leprosy [ICD-11: 1B20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.D464N
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.N502D
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.E504V
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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.

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [6]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis genital infection [ICD-11: 1B2Z.7]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [6]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis mycoplasma infection [ICD-11: 1B2Z.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

Tissue pyogenic bacterial infection [ICD-11: 1B7Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [10]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus infection [ICD-11: 1B7Y.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Klebsiella pneumoniae isolates; 573
• In Vitro Model: Acinetobacter isolates; 469
• In Vitro Model: Enterobacter cloacae isolates; 550
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: Up-regulation of P-glycoprotein led to levofloxacin resistance in the staphylococcus infection.

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: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Molecule Alteration: Missense mutation; p.N538D
• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

ICD-02: Benign/in-situ/malignant neoplasm

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [6]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis prostate cancer [ICD-11: 2C82.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

References

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• Ref 2: New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLoS One. 2012;7(6):e39754. doi: 10.1371/journal.pone.0039754. Epub 2012 Jun 28.
• Ref 3: Type II and type IV topoisomerase mutations in clinical isolates of Morganella morganii harbouring the qnrD gene. Ann Clin Microbiol Antimicrob. 2014 Aug 9;13:34. doi: 10.1186/s12941-014-0034-4.
• Ref 4: Hospital-acquired infection in patients with systemic lupus erythematosus: a case-control study in a southern Chinese populationClin Rheumatol. 2018 Mar;37(3):709-717. doi: 10.1007/s10067-017-3919-8. Epub 2017 Nov 27.
• Ref 5: Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. PLoS Negl Trop Dis. 2012;6(10):e1838. doi: 10.1371/journal.pntd.0001838. Epub 2012 Oct 11.
• Ref 6: Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates. Braz J Microbiol. 2014 May 19;45(1):239-42. doi: 10.1590/s1517-83822014000100034. eCollection 2014.
• Ref 7: Daptomycin .J Antimicrob Chemother. 2018 Jan 1;73(1):1-11. doi: 10.1093/jac/dkx349. 10.1093/jac/dkx349
• Ref 8: Study on risk factors, bacterial species, and drug resistance of acute pyelonephritis associated with ureteral stent after percutaneous nephrolithotomyEur J Clin Microbiol Infect Dis. 2021 Apr;40(4):707-713. doi: 10.1007/s10096-020-04050-z. Epub 2020 Oct 9.
• Ref 9: 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 10: Pathogen characteristics reveal novel antibacterial approaches for interstitial lung disease .Pulm Pharmacol Ther. 2014 Dec;29(2):250-4. doi: 10.1016/j.pupt.2014.03.005. Epub 2014 Apr 1. 10.1016/j.pupt.2014.03.005
• Ref 11: [Investigation of fluoroquinolone resistance mechanisms in clinical Acinetobacter baumannii isolates]. Mikrobiyol Bul. 2016 Apr;50(2):278-86. doi: 10.5578/mb.24126.
• Ref 12: The contribution of antibiotic resistance mechanisms in clinical Burkholderia cepacia complex isolates: an emphasis on efflux pump activity. PLoS One. 2014 Aug 25;9(8):e104986. doi: 10.1371/journal.pone.0104986. eCollection 2014.
• Ref 13: Complete genome sequences for 59 burkholderia isolates, both pathogenic and near neighbor. Genome Announc. 2015 Apr 30;3(2):e00159-15. doi: 10.1128/genomeA.00159-15.