Drug Information

Drug (ID: DG00193) and It's Reported Resistant Information

• Name: Imipenem
• Synonyms: Imipemide; Tienamycin; Imipenem anhydrous; Imipenem (INN); N-Formimidoylthienamycin; Primaxin (TN); Imipenem, N-Formimidoyl thienamycin; [5R-[5.alpha.,6.alpha.(R*)]]-6-(1-Hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate; (5R,6S)-3-(2-Formimidoylamino-ethylsulfanyl)-6-((R)-1-hydroxy-ethyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5R,6S)-6-((R)-1-Hydroxyethyl)-3-(2-(iminomethylamino)ethylthio)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carbonsaeure; (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (7 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [2]
  Malaria [ICD-11: 1F45]; [1]
  Melioidosis [ICD-11: 1C42]; [3], [4]
  Pneumonia [ICD-11: CA40]; [5]
  Pseudomonas aeruginosa infection [ICD-11: 1A0Y]; [6]
  Pyothorax [ICD-11: CA44]; [7]
• Target: Bacterial Penicillin binding protein 2 (Bact mrdA); MRDA_ECOLI; [1]
• Formula: C12H17N3O4S
• IsoSMILES: C[C@H]([C@@H]1[C@H]2CC(=C(N2C1=O)C(=O)O)SCCN=CN)O
• InChI: 1S/C12H17N3O4S/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)/t6-,7-,9-/m1/s1
• InChIKey: ZSKVGTPCRGIANV-ZXFLCMHBSA-N
• PubChem CID: 104838
• ChEBI ID: CHEBI:471744
• TTD Drug ID: D0H3TD
• INTEDE ID: DR2447
• DrugBank ID: DB01598

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

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: CATB10-Ib variant (CATB10) [8]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa TS-103; 287
• In Vitro Model: Pseudomonas aeruginosa TS-832035; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: P. aeruginosa TS-832035 produces a carbapenemase, coded by a blaVIM-1 determinant carried by the chromosomal class 1 integron In70.2 (containing also the aacA4, aphA15, and aadA1 genes in its cassette array),which induce the resistance to carbapenems.

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: A. xylosoxydans AX22 exhibited broad-spectrum resistance to Beta-lactams and aminoglycosides. The Beta-lactam resistance pattern (including piperacillin, ceftazidime, and carbapenem resistance) was unusual for this species, and the high-level carbapenem resistance suggested the production of an acquired carbapenemase. In fact, carbapenemase activity was detected in a crude extract of AX22 (specific activity, 184 +/- 12 U/mg of protein), and this activity was reduced (>80%) after incubation of the crude extract with 2 mM EDTA, suggesting the presence of a metallo-Beta-lactamase determinant.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Porin D (OPRD) [9], [10], [11]

• Molecule Alteration: Missense mutation; c.752insAGTC
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: P. aeruginosa OprD is a 443-amino-acid protein that facilitates the uptake of basic amino acids, imipenem, and gluconate across the outer membrane.Nucleotide sequence analysis revealed a 4-bp (AGTC) insertion in the oprD gene, resulting in a frameshift in the cognate open reading frame. These isolates became imipenem susceptible when the chromosomal oprD lesion was complemented, indicating that the 4-bp insertion in the oprD gene resulted in imipenem resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pyruvate decarboxylase 5 (PDC5) [6], [12]

• Molecule Alteration: Missense mutation; p.R79Q+p.T105A
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Key Molecule: Pyruvate decarboxylase 3 (PDC3) [6], [12]

• Molecule Alteration: Missense mutation; p.T97A
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa 12B; 287
• In Vitro Model: Pseudomonas aeruginosa kG2505; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; Etest method assay
• Mechanism Description: Reduced susceptibility to imipenem, ceftazidime, and cefepime was observed only with recombinant P. aeruginosa strains expressing an AmpC Beta-lactamase that had an alanine residue at position 105.Recently, several ESACs have been described from Escherichia coli contributing to reduced susceptibility to imipenem.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Pseudomonas aeruginosa infection [ICD-11: 1A0Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [6]

• Molecule Alteration: Missense mutation; p.T105A
• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• Experiment for Molecule Alteration: PCR amplification and sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Reduced susceptibility to imipenem was related to the T105A substitution.

Melioidosis [ICD-11: 1C42]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Outer membrane porin (OMP38) [3], [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Melioidosis [ICD-11: 1C42.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Burkholderia pseudomallei isolates; 28450
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Bps is highly resistant to many antimicrobial agents and this resistance may result from the low drug permeability of outer membrane proteins, known as porins.An Escherichia coli strain defective in most porins, but expressing BpsOmp38, exhibited considerably lower antimicrobial susceptibility than the control strain. In addition, mutation of Tyr119, the most prominent pore-lining residue in BpsOmp38, markedly altered membrane permeability, substitution with Ala (mutant BpsOmp38Y119A) enhanced uptake of the antimicrobial agents, while substitution with Phe (mutant BpsOmp38Y119F) inhibited uptake.

Malaria [ICD-11: 1F45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CAM-1 carbapenemase (CAM1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pseudomonas infection [ICD-11: 1F45.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Pseudomonas aeruginosa N17-01167; 287
• In Vitro Model: Pseudomonas aeruginosa N17-01173; 287
• In Vitro Model: Pseudomonas aeruginosa N17-02436; 287
• In Vitro Model: Pseudomonas aeruginosa N17-02437; 287
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Vitek 2 assay; Etest assay
• Mechanism Description: A novel class B Beta-lactamase gene, blaCAM-1, exhibited resistance to imipenem, meropenem, doripenem, cefotaxime, ceftazidime, cefoxitin, piperacillin/tazobactam, ceftazidime/avibactam and ceftolozane/tazobactam.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [5]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae 11978; 573
• Experiment for Molecule Alteration: DNA sequencing and protein assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: The Beta-lactamase OXA-48 hydrolyzed imipenem at a high level.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: OmpK37 (OMPK37) [13]

• Molecule Alteration: Expression; Inherence
• Sensitive Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Klebsiella pneumoniae strain CSUB10R; 573
• In Vitro Model: Klebsiella pneumoniae strain CSUB10S; 573
• In Vitro Model: Klebsiella pneumoniae strain LB4; 573
• In Vitro Model: Klebsiella pneumoniae strain LB66; 573
• In Vitro Model: Klebsiella pneumoniae strain SD8; 573
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Due to its porin deficiency, strain CSUB10R is more resistant to Beta-lactams than is parental strain CSUB10S. As expected, for k. pneumoniae CSUB10R expressing Ompk36 or Ompk35, the MICs reverted to values similar to those observed for strain CSUB10S.

References

• Ref 1: Identification of a novel metallo-Beta-lactamase, CAM-1, in clinical Pseudomonas aeruginosa isolates from Canada. J Antimicrob Chemother. 2019 Jun 1;74(6):1563-1567. doi: 10.1093/jac/dkz066.
• Ref 2: In70 of plasmid pAX22, a bla(VIM-1)-containing integron carrying a new aminoglycoside phosphotransferase gene cassette. Antimicrob Agents Chemother. 2001 Apr;45(4):1249-53. doi: 10.1128/AAC.45.4.1249-1253.2001.
• Ref 3: Functional reconstitution, gene isolation and topology modelling of porins from Burkholderia pseudomallei and Burkholderia thailandensis. Biochem J. 2004 Feb 1;377(Pt 3):579-87. doi: 10.1042/BJ20031118.
• Ref 4: Porin involvement in cephalosporin and carbapenem resistance of Burkholderia pseudomallei. PLoS One. 2014 May 1;9(5):e95918. doi: 10.1371/journal.pone.0095918. eCollection 2014.
• Ref 5: Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004 Jan;48(1):15-22. doi: 10.1128/AAC.48.1.15-22.2004.
• Ref 6: Extended-spectrum cephalosporinases in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009 May;53(5):1766-71. doi: 10.1128/AAC.01410-08. Epub 2009 Mar 2.
• Ref 7: Community-acquired Pseudomonas aeruginosa pneumonia manifested by bloody pleural effusion in a previously healthy infant: A case reportJ Clin Lab Anal. 2022 Jun;36(6):e24466. doi: 10.1002/jcla.24466. Epub 2022 May 13.
• Ref 8: Metallo-Beta-lactamase expression confers an advantage to Pseudomonas aeruginosa isolates compared with other Beta-lactam resistance mechanisms, favoring the prevalence of metallo-Beta-lactamase producers in a clinical environment. Microb Drug Resist. 2010 Sep;16(3):223-30. doi: 10.1089/mdr.2010.0016.
• Ref 9: Analysis of the Pseudomonas aeruginosa oprD gene from clinical and environmental isolates. Environ Microbiol. 2002 Dec;4(12):872-82. doi: 10.1046/j.1462-2920.2002.00281.x.
• Ref 10: Genetic markers of widespread extensively drug-resistant Pseudomonas aeruginosa high-risk clones. Antimicrob Agents Chemother. 2012 Dec;56(12):6349-57. doi: 10.1128/AAC.01388-12. Epub 2012 Oct 8.
• Ref 11: A novel Pseudomonas aeruginosa strain with an oprD mutation in relation to a nosocomial respiratory infection outbreak in an intensive care unit. J Clin Microbiol. 2014 Dec;52(12):4388-90. doi: 10.1128/JCM.02782-14. Epub 2014 Oct 8.
• Ref 12: Identifying novel Beta-lactamase substrate activity through in silico prediction of antimicrobial resistance. Microb Genom. 2021 Jan;7(1):mgen000500. doi: 10.1099/mgen.0.000500.
• Ref 13: Identification and characterization of a new porin gene of Klebsiella pneumoniae: its role in beta-lactam antibiotic resistance. J Bacteriol. 1999 May;181(9):2726-32. doi: 10.1128/JB.181.9.2726-2732.1999.