Skip to main content

Advertisement

SpringerLink
Log in

Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections

  • Original Article
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) presents a significant clinical concern, prompting the WHO to prioritize CRE as a top priority pathogen in their 2017 global antibiotic-resistant bacteria priority list. Due to the fast-depleting antibiotic arsenal, clinicians are now resorting to using once-abandoned, highly toxic antibiotics such as the polymyxins and aminoglycosides, creating an urgent need for new antibiotics. Drug repurposing, the application of an approved drug for a new therapeutic indication, is deemed a plausible solution to this problem. A total of 1,163 FDA-approved drugs were screened for activity against a clinical carbapenem- and multidrug-resistant E. coli isolate using a single-point 10 μM assay. Hit compounds were then assessed for their suitability for repurposing. The lead candidate was then tested against a panel of clinical CREs, a bactericidal/static determination assay, a time-kill assay and a checkerboard assay to evaluate its suitability for use in combination with Tigecycline against CRE infections. Three drugs were identified. The lead candidate was determined to be Zidovudine (azidothymidine/AZT), an oral anti-viral drug used for HIV treatment. Zidovudine was shown to be the most promising candidate for use in combination with Tigecycline to treat systemic CRE infections. Further experiments should involve the use of animal infection models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gupta N, Limbago BM, Patel JB, Kallen AJ (2011) Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis 53:60–67

    Article  PubMed  Google Scholar 

  2. Satlin MJ, Chen L, Patel G, Gomez-Simmonds A, Weston G et al (2017) Multicenter clinical and molecular epidemiological analysis of bacteremia due to carbapenem-resistant Enterobacteriaceae (CRE) in the CRE epicenter of the United States. Antimicrob Agents Chemother 61:e02349–e02316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nordmann P (2014) Carbapenemase-producing Enterobacteriaceae: overview of a major public health challenge. Med Mal Infect 44:51–56

    Article  CAS  PubMed  Google Scholar 

  4. Baldwin CM, Lyseng-Williamson KA, Keam SJ (2008) Meropenem: a review of its use in the treatment of serious bacterial infections. Drugs 68:803–838

    Article  CAS  PubMed  Google Scholar 

  5. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL (2015) Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2:ofv050

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vergidis PI, Falagas ME (2008) New antibiotic agents for bloodstream infections. Int J Antimicrob Agents 32:S60–S65

    Article  CAS  PubMed  Google Scholar 

  7. El-Gamal MI, Brahim I, Hisham N, Aladdin R, Mohammed H et al (2017) Recent updates of carbapenem antibiotics. Eur J Med Chem 131:185–195

    Article  CAS  PubMed  Google Scholar 

  8. Hsu LY, Apisarnthanarak A, Khan E, Suwantarat N, Ghafur A et al (2017) Carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev 30:1–22

    Article  PubMed  Google Scholar 

  9. Jain A, Hopkins KL, Turton J, Doumith M, Hill R et al (2014) NDM carbapenemases in the United Kingdom: an analysis of the first 250 cases. J Antimicrob Chemother 69:1777–1784

    Article  CAS  PubMed  Google Scholar 

  10. Kazmierczak KM, Rabine S, Hackel M, McLaughlin RE, Biedenbach DJ et al (2015) Multiyear, multinational survey of the incidence and global distribution of metallo-β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 60:1067–1078

    Article  PubMed  Google Scholar 

  11. Ling ML, Tee YM, Tan SG, Amin IM, How KB et al (2015) Risk factors for acquisition of carbapenem resistant Enterobacteriaceae in an acute tertiary care hospital in Singapore. Antimicrob Resist Infect Control 4:26

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mataseje LF, Abdesselam K, Vachon J, Mitchel R, Bryce E et al (2010) Results from the Canadian Nosocomial Infection Surveillance Program on carbapenemase-producing Enterobacteriaceae, 2010 to 2014. Antimicrob Agents Chemother 60:6787–6794

    Article  Google Scholar 

  13. Pitout JD, Nordmann P, Poirel L (2015) Carbapenemase-producing Klebsiella pneumoniae, a key pathogen set for global nosocomial dominance. Antimicrob Agents Chemother 59:5873–5884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu Y, Gu B, Huang M, Liu H, Xu T et al (2015) Epidemiology of carbapenem resistant Enterobacteriaceae (CRE) during 2000-2012 in Asia. J Thorac Dis 7:376–385

    PubMed  PubMed Central  Google Scholar 

  15. Xu A, Zheng B, Xu YC, Huang ZG, Zhong NS et al (2016) National epidemiology of carbapenem-resistant and extensively drug-resistant Gram-negative bacteria isolated from blood samples in China in 2013. Clin Microbiol Infect 22:S1–S8

    Article  PubMed  Google Scholar 

  16. Nordmann P, Naas T, Poirel L (2011) Global Spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 17:1791–1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Logan LK, Weinstein RA (2017) The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis 15:S28–S36

    Article  Google Scholar 

  18. Temkin E, Adler A, Lerner A, Carmeli Y (2014) Carbapenem-resistant Enterobacteriaceae: biology, epidemiology, and management. Ann NY Acad Sci 1323:22–42

    Article  CAS  PubMed  Google Scholar 

  19. Frieden T (2013) Antibiotic Resistance Threats in the United States, 2013. Executive Summary. Centers for Disease Control and Prevention, Atlanta, GA, USA. Available online: http://www.cdc.gov/drugresistance/threat-report-2013/ . Accessed 1 July 2017

  20. WHO (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ . Accessed 1 July 2017

  21. Falagas ME, Kasiakou SK (2005) Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 40:1333–1341

    Article  CAS  PubMed  Google Scholar 

  22. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS (2014) Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother 58:654–663

    Article  PubMed  PubMed Central  Google Scholar 

  23. Karaiskos I, Giamarellou H (2014) Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother 15:1351–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zayyad H, Eliakim-Raz N, Leibovici L, Paul M (2017) Revival of old antibiotics: needs, the state of evidence and expectations. Int J Antimicrob Agents 49:536–541

    Article  CAS  PubMed  Google Scholar 

  25. Brust K, Evans A, Plemmons R (2014) Tigecycline in treatment of multidrug-resistant Gram-negative bacillus urinary tract infections: a systematic review. J Antimicrob Chemother 69:2606–1260

    Article  CAS  PubMed  Google Scholar 

  26. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL (2015) Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2:1–15

    Google Scholar 

  27. Noskin GA (2005) Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis 41:S303–S314

    Article  CAS  PubMed  Google Scholar 

  28. Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ et al (2015) Tigecycline activity tested against carbapenem-resistant Enterobacteriaceae from 18 European nations: results from the SENTRY surveillance program (2010-2013). Diagn Microbiol Infect Dis 83:183–186

    Article  CAS  PubMed  Google Scholar 

  29. Chiu SK, Chan MC, Huang LY, Lin YT, Lin JC et al (2017) Tigecycline resistance among carbapenem-resistant Klebsiella pneumoniae: clinical characteristics and expression levels of efflux pump genes. PLoS One 12:e0175140

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rodríguez-Avial C, Rodríguez-Avial I, Merino P, Picazo JJ (2012) Klebsiella pneumoniae: development of a mixed population of carbapenem and tigecycline resistance during antimicrobial therapy in a kidney transplant patient. Clin Microbiol Infect 18:61–66

    Article  PubMed  Google Scholar 

  31. FDA (2013) FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new boxed warning. FDA, Rockville, MD. https://www.fda.gov/drugs/drugsafety/ucm369580.htm. Accessed 1 July 2017

  32. Dixit D, Madduri RP, Sharma R (2014) The role of tigecycline in the treatment of infections in light of the new black box warning. Expert Rev Anti-Infect Ther 12:397–400

    Article  CAS  PubMed  Google Scholar 

  33. Prasad P, Sun J, Danner RL, Natanson C (2012) Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 54:1699–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Falagas ME, Grammatikos AP, Michalopoulos A (2008) Potential of old-generation antibiotics to address current need for new antibiotics. Expert Rev Anti-Infect Ther 6:593–600

    Article  PubMed  Google Scholar 

  35. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K (2005) Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 25:11–25

    Article  PubMed  Google Scholar 

  36. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K et al (2006) Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 6:589–601

    Article  CAS  PubMed  Google Scholar 

  37. Kaye KS, Gales AC, Dubourg G (2017) Old antibiotics for multidrug-resistant pathogens: from in vitro activity to clinical outcomes. Int J Antimicrob Agents 49:542–548

    Article  CAS  PubMed  Google Scholar 

  38. Pogue JM, Ortwine JK, Kaye KS (2016) Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins? Int J Antimicrob Agents 48:622–626

    Article  CAS  PubMed  Google Scholar 

  39. Tran TB, Velkov T, Nation RL, Forrest A, Tsuji BT et al (2016) Pharmacokinetics/ pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents 48:592–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yun B, Azad MA, Wang J, Nation RL, Thompson PE et al (2015) Imaging the distribution of polymyxins in the kidney. J Antimicrob Chemother 70:827–829

    Article  CAS  PubMed  Google Scholar 

  41. Aran JM, Erre JP, Lima da Costa D, Debbarh I et al (1999) Acute and chronic effects of aminoglycosides on cochlear hair cells. Ann NY Acad Sci 884:60–68

    Article  CAS  PubMed  Google Scholar 

  42. Huth ME, Ricci AJ, Cheg AG (2011) Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolarynol 2011:937861

    CAS  Google Scholar 

  43. Cosgrove SE, Vigliani GA, Fowler VG Jr, Abrutyn E, Corey GR et al (2009) Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 48:713–721

    Article  PubMed  Google Scholar 

  44. Selimoglu E (2007) Aminoglycoside-induced ototoxicity. Curr Pharm Des 13:119–126

    Article  CAS  PubMed  Google Scholar 

  45. Kaye KS, Pogue JM, Tran TB, Nation RL, Li J (2016) Agents of last resort: polymyxin resistance. Infect Dis Clin N Am 30:391–414

    Article  Google Scholar 

  46. Hu Y, Liu F, Lin IY, Gao GF, Zhu B (2016) Dissemination of the mcr-1 colistin resistance gene. Lancet Infect Dis 16:146–147

    Article  PubMed  Google Scholar 

  47. Olaitan AO, Morand S, Rolain JM (2016) Emergence of colistin-resistant bacteria in humans without colistin usage: a new worry and cause for vigilance. Int J Antimicrob Agents 47:1–3

    Article  CAS  PubMed  Google Scholar 

  48. Olaitan AO (2016) Emergence of polymyxin resistance in Gram-negative bacteria. Int J Antimicrob Agents 48:581–582

    Article  CAS  PubMed  Google Scholar 

  49. Garneau-Tsodikova S, Labby KJ (2016) Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. Med Chem Commun 7:11–27

    Article  CAS  Google Scholar 

  50. Poirel L, Jayol A, Nordmann P (2017) Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 30:557–596

    Article  PubMed  Google Scholar 

  51. Rolain JM, Olaitan AO (2016) Plasmid-mediated colistin resistance: the final blow to colistin? Int J Antimicrob Agents 47:4–5

    Article  CAS  PubMed  Google Scholar 

  52. Jayol A, Poirel L, Dortet L, Nordmann P (2016) National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant OXA-48-producing Klebsiella pneumoniae, France, 2014. Euro Surveill 21

  53. Jeannot K, Bolard A, Plésiat P (2017) Resistance to polymyxins in Gram-negative organisms. Int J Antimicrob Agents 49:526–535

    Article  CAS  PubMed  Google Scholar 

  54. Quan J, Li X, Chen Y, Jiang Y, Zhou Z et al (2017) Prevalence of mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from bloodstream infections in China: a multicentre longitudinal study. Lancet Infect Dis 17:400–410

    Article  CAS  PubMed  Google Scholar 

  55. Wang Y, Tian GB, Zhang R, Shen Y, Tyrrell JM et al (2017) Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study. Lancet Infect Dis 17:390–399

    Article  CAS  PubMed  Google Scholar 

  56. Zowawi HM, Harris PN, Roberts MJ, Tambyah PA, Schembri MA et al (2015) The emerging threat of multidrug-resistant Gram-negative bacteria in urology. Nat Rev Urol 12:570–584

    Article  CAS  PubMed  Google Scholar 

  57. Kinch MS, Patridge E, Plummer M, Hoyer D (2014) An analysis of FDA-approved drugs for infectious disease: Antibacterial agents. Drug Discov Today 19:1283–1287

    Article  CAS  PubMed  Google Scholar 

  58. Brenner R, Ellis-Grosse EJ, Echols R (2006) Moving goalposts - regulatory oversight of antibacterial drugs. Nat Biotechnol 24:1515–1520

    Article  CAS  PubMed  Google Scholar 

  59. Fernandes P (2006) Antibacterial discovery and development - The failure of success? Nat Biotechnol 24:1497–1503

    Article  CAS  PubMed  Google Scholar 

  60. Nambiar S, Laessig K, Toerner J, Farley J, Cox E (2014) Antibacterial drug development: Challenges, recent developments, and future considerations. Clin Pharmacol Ther 96:147–149

    Article  CAS  PubMed  Google Scholar 

  61. Ashburn TT, Thor KB (2004) Drug repositioning: Identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683

    Article  CAS  PubMed  Google Scholar 

  62. Nosengo N (2016) New tricks for old drugs. Nature 534:314–316

    Article  PubMed  Google Scholar 

  63. Oprea TI, Mestres J (2012) Drug repurposing: Far beyond new targets for old drugs. AAPS J 14:759–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Clinical and Laboratory Standards Institute (2012) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, approved standard, 9th ed, vol 32, no. 2. Document M07-A9. CLSI, Wayne, PA, USA

  65. French GL (2006) Bactericidal agents in the treatment of MRSA infections - the potential role of daptomycin. J Antimicrob Chemother 58:1107–1117

    Article  CAS  PubMed  Google Scholar 

  66. Hsieh MH, Yu CM, Yu VL, Chow JW (1993) Synergy assessed by checkerboard. A critical analysis. Diagn Microbiol Infect Dis 16:343–349

    Article  CAS  PubMed  Google Scholar 

  67. Sader HS, Farrell DJ, Flamm RK, Jones RN (2014) Variation in potency and spectrum of tigecycline activity against bacterial strains from U.S. medical centers since its approval for clinical use (2006 to 2012). Antimicrob Agents Chemother 58:2274–2280

    Article  PubMed  PubMed Central  Google Scholar 

  68. Small PM, Chambers HF (1990) Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 34:1227–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R (2005) FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10:176–182

    Article  CAS  PubMed  Google Scholar 

  70. Jones PA, Taylor SM, Wilson VL (1983) Inhibition of DNA methylation by 5-azacytidine. Recent Results Cancer Res 84:202–211

    CAS  PubMed  Google Scholar 

  71. Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H et al (1997) Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403–1409

    CAS  PubMed  Google Scholar 

  72. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50:219–244

    CAS  PubMed  Google Scholar 

  73. Chabner BA, Drake JC, Johns DG (1973) Deamination of 5-azacytidine by a human leukemia cell cytidine deaminase. Biochem Pharmacol 22:2763–2765

    Article  CAS  PubMed  Google Scholar 

  74. Michalopoulos AS, Falagas ME (2011) Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care 1:30–35

    Article  PubMed  PubMed Central  Google Scholar 

  75. Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S (2005) Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 49:220–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. EMA (2017) EMA public assessment report on Vidaza. Document number: Vidaza -EMEA/H/C/000978 -IB/0040. Date: 20/03/2017.www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000978/WC500050239.pdf. Accessed 4 October 2017

  77. Power DG, Kemeny NE (2009) The role of floxuridine in metastatic liver disease. Mol Cancer Ther 8:1015–1025

    Article  CAS  PubMed  Google Scholar 

  78. Wambaugh MA, Shakya VPS, Lewis AJ, Mulvey MA, Brown JCS (2017) High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance. PLoS Biol 15:e2001644

    Article  PubMed  PubMed Central  Google Scholar 

  79. Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M et al (1987) A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206:685–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Leichman CG (1994) Prolonged infusion of fluorinated pyrimidines in gastrointestinal malignancies: a review of recent clinical trials. Cancer Investig 12:166–175

    Article  CAS  Google Scholar 

  81. Mitsuya H, Weinhold K, Furman P, St Clair MH, Lehrman SN et al (1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 82:7096–7100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Furman P, Fyfe J, St Clair MH, Weinhold K, Rideout J et al (1986) Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 83:8333–8337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Doléans-Jordheim A, Bergeron E, Bereyziat F, Ben-Larbi S, Dumitrescu O et al (2011) Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains. Eur J Clin Microbiol Infect Dis 30:1249–1256

    Article  PubMed  Google Scholar 

  84. Beach JW (1998) Chemotherapeutic agents for human immunodeficiency virus infection: mechanism of action, pharmacokinetics, metabolism, and adverse reactions. Clin Ther 20:2–25

    Article  CAS  PubMed  Google Scholar 

  85. Elwell LP, Ferone R, Freeman GA, Fyfe JA, Hill JA et al (1987) Antibacterial activity and mechanism of action of 3′-azido-3′-deoxythymidine (BW A509U). Antimicrob Agents Chemother 31:274–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lewin CS, Amyes SG (1989) Conditions required for the antibacterial activity of zidovudine. Eur J Clin Microbiol Infect Dis 8:737–741

    Article  CAS  PubMed  Google Scholar 

  87. Blum MR, Liao SH, Good SS, de Miranda P (1988) Pharmacokinetics and bioavailability of zidovudine in humans. Am J Med 85:189–194

    Article  CAS  PubMed  Google Scholar 

  88. Klecker RW Jr, Collins JM, Yarchoan R, Thomas R, Jenkins JF et al (1987) Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 41:407–412

    Article  PubMed  Google Scholar 

  89. Ayers KM (1988) Preclinical toxicology of zidovudine. An overview. Am J Med 85(2A):186–188

    CAS  PubMed  Google Scholar 

  90. Hargreaves M, Fuller G, Costello C, Gazzard B (1988) Zidovudine overdose. Lancet 332:509

    Article  Google Scholar 

  91. Pickus OB (1988) Overdose of zidovudine. N Engl J Med 318:1206

    CAS  PubMed  Google Scholar 

  92. Keith BR, White G, Wilson HR (1989) In vivo efficacy of zidovudine (3′-azido-3′-deoxythymidine) in experimental gram-negative-bacterial infections. Antimicrob Agents Chemother 33:479–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Spratt BG (1994) Resistance to antibiotics mediated by target alterations. Science 264:388–393

    Article  CAS  PubMed  Google Scholar 

  94. Lewin CS, Watt B, Paton R, Amyes SGB (1990) Isolation of zidovudine resistant Escherichia coli from AIDS patients. FEMS Microbiol Lett 58:141–143

    CAS  PubMed  Google Scholar 

  95. Lewin CS, Allen R, Amyes SGB (1990) Zidovudine-resistance in Salmonella typhimurium and Escherichia coli. J Antimicrob Chemother 25:706–708

    Article  CAS  PubMed  Google Scholar 

  96. Lewin CS, Allen RA, Amyes SGB (1990) Mechanisms of zidovudine resistance in bacteria. J Med Microbiol 33:235–238

    Article  CAS  PubMed  Google Scholar 

  97. Hu Y, Coates A (2014) Combination comprising zidovudine and polymyxin. WO 2014147405 A1

Download references

Acknowledgements

The authors thank the Agency for Science, Technology and Research (A*STAR) Biomedical Research Council for funding.

Author information

Author notes

  1. S. M. S. Ng, J. S. P. Sioson and J. M. Yap contributed equally to this work.

Authors and Affiliations

  1. Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, Singapore, 138669, Singapore

    S. M. S. Ng, J. S. P. Sioson, J. M. Yap, F. M. Ng, H. S. V. Ching, J. Hill & C. S. B. Chia

  2. Department of Laboratory Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore

    J. W. P. Teo & R. Jureen

Authors
  1. S. M. S. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. S. P. Sioson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. M. Yap
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. M. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. S. V. Ching
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. W. P. Teo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Jureen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. S. B. Chia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. S. B. Chia.

Ethics declarations

Ethical statement

Not required as no humans or animals were involved in this study.

Conflicts of interest

The authors of this paper declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ng, S.M.S., Sioson, J.S.P., Yap, J.M. et al. Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections. Eur J Clin Microbiol Infect Dis 37, 141–148 (2018). https://doi.org/10.1007/s10096-017-3114-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-017-3114-5

Keywords

Search

Navigation