Drug Information

Drug (ID: DG00043) and It's Reported Resistant Information

• Name: Zithromax
• Synonyms: Azithromycin; Zithromax; 83905-01-5; Azithromycinum; Azithromycine; Sumamed; Zitromax; Zmax; Hemomycin; Azitrocin; Azasite; Azenil; Aritromicina; Zitrotek; Zithrax; Mixoterin; Setron; Aziwok; Zitrim; Aztrin; Zifin; Tobil; Zmas; Zeto; Azithromycinum [Latin]; Azithromycine [French]; Zithromax IV; AZITHROMYCIN DIHYDRATE; Misultina; Azitromax; Z-Pak; Tromix; Aritromicina [Spanish]; Azitromicina; CP-62993; UNII-J2KLZ20U1M; DRG-0104; CCRIS 1961; HSDB 7205; Azithromycin (anhydrous); C38H72N2O12; BRN 5387583; J2KLZ20U1M; Azythromycin; CHEBI:2955
• Indication:
  In total 1 Indication(s)
  Syphilis [ICD-11: 1A61-1A6Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (9 diseases)
  Bacillus infection [ICD-11: 1C4Y]; [2]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Bacterial meningitis [ICD-11: 1D02]; [4]
  Diarrhea [ICD-11: DA90]; [5]
  Gonococcal infection [ICD-11: 1A72]; [6]
  Gonorrhea [ICD-11: 1A70]; [7]
  Mycoplasma genitalium infection [ICD-11: GA05]; [8]
  Periodontal disease [ICD-11: DA0C]; [9]
  Streptococcal pharyngitis [ICD-11: 1B51]; [1]
• Target: Bacterial 50S ribosomal RNA (Bact 50S rRNA); NOUNIPROTAC; [1]
• Formula: C38H72N2O12
• IsoSMILES: CC[C@@H]1[C@@]([C@@H]([C@H](N(C[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O
• InChI: 1S/C38H72N2O12/c1-15-27-38(10,46)31(42)24(6)40(13)19-20(2)17-36(8,45)33(52-35-29(41)26(39(11)12)16-21(3)48-35)22(4)30(23(5)34(44)50-27)51-28-18-37(9,47-14)32(43)25(7)49-28/h20-33,35,41-43,45-46H,15-19H2,1-14H3/t20-,21-,22+,23-,24-,25+,26+,27-,28+,29-,30+,31-,32+,33-,35+,36-,37-,38-/m1/s1
• InChIKey: MQTOSJVFKKJCRP-BICOPXKESA-N
• PubChem CID: 447043
• ChEBI ID: CHEBI:2955
• TTD Drug ID: D03HJK
• VARIDT ID: DR00367
• INTEDE ID: DR0168
• DrugBank ID: DB00207

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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: erm(X)cj (Unclear) [3]

• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Streptococcal pharyngitis [ICD-11: 1B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMA) [1]

• Molecule Alteration: Missense mutation; Macrolide-binding site on the ribosome
• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: E. coli transformed with mutant erm(A) harbouring G98A, A137C or C140T mutations (phenotypes 1 and 2) did not express high-level azithromycin or clindamycin resistance.

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMA) [1]

• Molecule Alteration: Missense mutation; p.G98A
• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: E. coli transformed with mutant erm(A) harbouring G98A, A137C or C140T mutations (phenotypes 1 and 2) did not express high-level azithromycin or clindamycin resistance.

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMA) [1]

• Molecule Alteration: Missense mutation; p.A137C
• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: E. coli transformed with mutant erm(A) harbouring G98A, A137C or C140T mutations (phenotypes 1 and 2) did not express high-level azithromycin or clindamycin resistance.

Bacillus infection [ICD-11: 1C4Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm34 (ERM34) [2]

• Molecule Alteration: Methylation; Ribosomal methylation
• Resistant Disease: Bacillus clausii infection [ICD-11: 1C4Y.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus clausii ATCC 21536; 79880
• Experiment for Molecule Alteration: Cloning experiments and gene seqencing assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: This pattern of resistance generally due to the presence of an erm gene encoding a ribosomal methylase.

Bacterial meningitis [ICD-11: 1D02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [4]

• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

ICD-13: Digestive system diseases

Diarrhea [ICD-11: DA90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (cytidine-2'-O)-methyltransferase TlyA (TLYA) [5]

• Molecule Alteration: Missense mutation; p.A2075G
• Resistant Disease: Traveler's diarrhea [ICD-11: DA90.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Campylobacter jejuni isolates; 197
• In Vitro Model: Campylobacter jejuni ATCC 33560; 197
• Experiment for Molecule Alteration: Gene sequencing assay
• Experiment for Drug Resistance: E-test assay
• Mechanism Description: Point mutation occurred on the 23S rRNA gene at the A2075G transitions, and the number of mutated gene copies was proportional to azithromycin resistance.

References

• Ref 1: Unusual resistance patterns in macrolide-resistant Streptococcus pyogenes harbouring erm(A). J Antimicrob Chemother. 2009 Jan;63(1):42-6. doi: 10.1093/jac/dkn432. Epub 2008 Oct 24.
• Ref 2: Characterization of a new erm-related macrolide resistance gene present in probiotic strains of Bacillus clausii. Appl Environ Microbiol. 2004 Jan;70(1):280-4. doi: 10.1128/AEM.70.1.280-284.2004.
• Ref 3: Inducible macrolide resistance in Corynebacterium jeikeium. Antimicrob Agents Chemother. 2001 Jul;45(7):1982-9. doi: 10.1128/AAC.45.7.1982-1989.2001.
• Ref 4: Disruption of an Enterococcus faecium species-specific gene, a homologue of acquired macrolide resistance genes of staphylococci, is associated with an increase in macrolide susceptibility. Antimicrob Agents Chemother. 2001 Jan;45(1):263-6. doi: 10.1128/AAC.45.1.263-266.2001.
• Ref 5: Determination of azithromycin heteroresistant Campylobacter jejuni in traveler's diarrhea .Gut Pathog. 2019 May 6;11:19. doi: 10.1186/s13099-019-0301-1. eCollection 2019. 10.1186/s13099-019-0301-1
• Ref 6: WHO global antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017-18: a retrospective observational study .Lancet Microbe. 2021 Nov;2(11):e627-e636. doi: 10.1016/S2666-5247(21)00171-3. Epub 2021 Sep 2. 10.1016/S2666-5247(21)00171-3
• Ref 7: Multiresistant Neisseria gonorrhoeae: a new threat in second decade of the XXI centuryMed Microbiol Immunol. 2020 Apr;209(2):95-108. doi: 10.1007/s00430-019-00651-4. Epub 2019 Dec 4.
• Ref 8: Impact of mass drug administration of azithromycin for trachoma elimination on prevalence and azithromycin resistance of genital Mycoplasma genitalium infectionSex Transm Infect. 2019 Nov;95(7):522-528. doi: 10.1136/sextrans-2018-053938. Epub 2019 Apr 13.
• Ref 9: Antimicrobial resistance of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythia in periodontitis patientsJ Glob Antimicrob Resist. 2020 Sep;22:215-218. doi: 10.1016/j.jgar.2020.02.024. Epub 2020 Mar 10.