Skip to main content Skip to main navigation menu Skip to site footer

Norepinephrine modified the interaction between Escherichia coli and levofloxacin, potentially affecting clinical outcomes and increasing the risk of bacterial colonization

  • Amina Thayyiba ,
  • Eddy Bagus Wasito ,
  • Lindawati Alimsardjono ,


Background: Norepinephrine is the most used vasopressor in intensive care units. It can modulate gene expressions and metabolism pathways in Escherichia coli. As fluoroquinolone’s bactericidal activity is affected by bacterial metabolism and growth rate, simultaneous exposure to these medications might alter the interaction between E. coli and levofloxacin. This study aims to investigate the effect of norepinephrine and levofloxacin given simultaneously on the in vitro growth of E. coli.

Methods: Ten clinical isolates of E. coli were grown in minimal nutrition media with and without norepinephrine, levofloxacin, or both. Bacterial growth was observed for 20 h, and viable cell count was done every 2 h. Growth curves and generation times for each study group were calculated. Statistical analysis compared the viable cell counts on the 4, 14, and 20 h observation time points and the generation times.

Results: Temporary inhibition of E. coli growth was observed until 4h of incubation when therapeutic concentrations of norepinephrine and levofloxacin were given simultaneously, followed by regrowth. The viable cell count of the norepinephrine–levofloxacin group was significantly lower than the control group by the 14 h and 20 h time points. Interestingly, the study group's average generation time of regrowth was 19.3 min, which was significantly faster than the control group (p < 0.05).

Conclusion: Norepinephrine caused alterations in the interaction between E. coli and levofloxacin, which may affect clinical outcomes and increase the risk of bacterial colonization in patients receiving simultaneous norepinephrine and levofloxacin therapy.


  1. Bylund DB, Bylund KC. Norepinephrine. In: Aminoff MJ, Daroff RB. Encyclopedia of the neurological sciences, second edition: Elsevier. 2014:614-616.
  2. Hall ME, Hall JE. Guyton and Hall textbook of medical physiology, fourteenth edition: Elsevier. 2021.
  3. Esler MU, Jennings GA, Korner PA, Blombery PE, Sacharias NI, Leonard PA. Measurement of total and organ specific norepinephrine kinetics in humans. American Journal of Physiology-Endocrinology and Metabolism. 1984;247(1):E21-E28.
  4. Dodt C, Breckling U, Derad I, Fehm HL, Born J. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension. 1997;30(1):71-76.
  5. Robertson DA, Johnson GA, Robertson RM, Nies AS, Shand DG, Oates JA. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation. 1979;59(4):637-643.
  6. Fawzy A, Evans SR, Walkey AJ. Practice patterns and outcomes associated with choice of initial vasopressor therapy for septic shock. Critical Care Medicine. 2015;13(10):2141.
  7. Vail EA, Gershengorn HB, Hua M, Walkey AJ, Wunsch H. Epidemiology of vasopressin use for adults with septic shock. Annals of the American Thoracic Society. 2016;13(10):1760-1767.
  8. Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortlaity among patients with septic shock. JAMA. 2017;317(14):1433-1442.
  9. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine. 2021;47(11):1181-1247.
  10. Neal CP, Freestone PP, Maggs AF, Haigh RD, Williams PH, Lyte M. Catecholamine inotropes as growth factors for Staphylococcus epidermidis and other coagulase-negative staphylococci. FEMS. 2001;194(2):163-169.
  11. Lyte M, Arulanandam B, Nguyen K, Frank C, Erickson A, Francis D. Norepinephrine induced growth and expression of virulence associated factors in enterotoxigenic and enterohemorrhagic strains of Escherichia coli. In: Paul PS, Francis DH, editors. Mechanisms in the Pathogenesis of Enteric Diseases. Boston: Springer. 1997:331-339.
  12. Freestone PP, Williams PH, Haigh RD, Maggs AF, Neal CP, Lyte M. Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a possible contributory factor in trauma-induced sepsis. Shock. 2002;18(5):465-470.
  13. Cogan TA, Thomas AO, Rees LE, Taylor AH, Jepson MA, Williams PH, et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut. 2007; 56(8):1060-1065.
  14. Trucollo B, Whyte P, Bolton DJ. An investigation of the effect of catecholamines and glucocorticoids on the growth and pathogenicity of Campylobacter jejuni. Pathogens. 2020;9(7):555.
  15. Dowd SE. Escherichia coli O157: H7 gene expression in the presence of catecholamine norepinephrine. FEMS Microbiology Letters. 2007;273(2):214-223.
  16. Sharma VK, Akavaram S, Bayles DO. Genomwide transcriptional response of Escherichia coli O157:H7 to norepinephrine. BMC Genomics. 2022;23(1):1-20.
  17. SAIDC Research Network. Causes and outcomes of sepsis in Southeast Asia: a multinational multicentre cross-sectional study. Lancet Global Health. 2017;5(2):e157-e167.
  18. Sakr Y, Jaschinski U, Wittebole X, Szakmany T, Lipman J, Namendys-Silva SA, et al. Sepsis in intensive care unit patients: worldwide data from the intensive care over nations audit. Open Forum Infectious Diseases. 2018;5(12):p.ofy313.
  19. Diekema DJ, Hsueh PR, Mendes RE, Pfaller MA, Rolston KV, Sader HS, et al. The microbiology of bloodstream infection: 20-year trends from the SENTRY antimicrobial surveillance program. Antimicrobial Agents and Chemotherapy. 2019;63(7):e00355-19.
  20. Wozniak TM, Barnsbee L, Lee XJ, Pacella RE. Using the best available data to estimate the cost of antimicrobial resistance: a systematic review. Antimicrobial Resistance and Infection Control. 2019:8(26):1-12.
  21. Su LH, Chen IL, Tang YF, Lee JS, Liu JW. Increased financial burdens and lengths of stay in patients with healthcare-accociated infections due to multidrug-resistant bacteria in intensive care units: a prospensity-matched case-control study. PLoS One. 2020;15(5):e0233265.
  22. World Health Organization. World publishes list of bacteria for which new antibiotics are urgently needed. 2017. [Cited: August 20th 2022]. [Available from:].
  23. Versporten A, Zarb P, Caniaux I, Gros MF, Drapier N, Miller M, et al. Antimicrobial consumption and resistance in adult hospital inpatients in 53 countries: results of an internet-based global point prevalence survey. The Lancet Global Health. 2018;6(6):e619-29.
  24. Erdem H, Hargreaves S, Ankarali H, Caskurlu H, Ceviker SA, Bahar-Kacmaz A, et al. Managing adult patients with infectious diseases in emergency departments: international ID-IRI study. Journal of Chemotherapy. 2021;33(5):302-318.
  25. Sugino A, Peebles CL, Kreuzer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proceedings of the National Academy of Sciences. 1977;74(11):4767-4771.
  26. Shen LL, Kohlbrenner WE, Weigl D, Baranowski J. Mechanism of quinolone inhibition of DNA gyrase: appearance of unique norfloxacin binding sites in enzyme-DNA complexes. Journal of Biological Chemistry. 1989;264(5):2973-2978.
  27. Howard BM, Pinney RJ, Smith JT. Function of the SOS process in repair of DNA damage induced by modern 4-quinolones. Journal of Pharmacy and Pharmacology. 1993;45(7):658-662.
  28. Dörr T, Lewis K, Vulic M. SOS response induces persistence to fluoroquiolones in Escherichia coli. PLOS Genetics. 2009;5(12):e1000760.
  29. Theodore A, Lewis K, Vulic M. Tolerance of Escherichia coli to fluoroquinolones antibiotics depends on specific components of the SOS response pathway. Genetics. 2013; 195(4):1265-1276.
  30. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007;130(5):797-810.
  31. Kim YA, Park YS, Youk T, Lee H, Lee K. Trends in South Korean antimicrobial use and association with changes in Escherichia coli resistance rates: 12-year ecological study using a nationwide surveillance and antimicrobial perscription database. PLoS One. 2018;13(12):e0209580.
  32. Yang P, Chen Y, Jiang S, Shen P, Lu X, Xiao Y. Association between the rate of fluoroquinolones-resistant Gram-negative bacteria and antibiotic consumption from China based on 145 tertiary hospitals data in 2014. BMC Infectious Diseases. 2020;20(1):1-0.
  33. Lyte M, Ernst S. Catecholamine induced growth of Gram negative bacteria. Life Sciences. 1992;50(3): p.203-212.
  34. Freestone PP, Walton NJ, Haigh RD, Lyte M. Influence of dietary catechols on the growth of enteropathogenic bacteria. International Journal of Food Microbiology. 2007;119(3):159-169.
  35. Hollenberg SM. Vasoactive drugs in circulatory shock. American Journal of Respiratory and Critical Care Medicine. 2011;183(7):847-855.
  36. Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. Journal of Cardiovascular Pharmacology and Therapeutics. 2015;20(3):249-260.
  37. Hamzaoui O, Scheeren TW, Teboul JL. Norepinephrine in septick shock: when and how much? Current Opinion in Critical Care. 2017;23(4):342-347.
  38. Inaba M, Matsuda N, Banno H, Jin W, Wachino JI, Yamada K, et al. In vitro reduction of antibacterial activity of tigecycline against multidrug-resistant Acinetobacter baumannii with host stress hormone norepinephrine. International Journal of Antimicrobial Agents. 2016;48(6):680-689.
  39. Ambrose PG, VanScoy BD, Adams J, Fikes S, Bader JC, Bhavnani SM, et al. Norepinephrine in combination with antibiotic therapy increases both the bacterial replication rate and bactericidal activity. Antimicrobial Agents and Chemotherapy. 2018; 62(4):e02257-17.
  40. Hansen GT, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric Gram-negative urinary tract infection pathogens. Journal of Chemotherapy. 2005;17(5):484-492.
  41. Li Y, Zheng B, Xue F, Zhu SN, Lyu Y. Changes in minimum inhibitory concentration of levofloxacin for Escherichia coli strains isolated from urine samples in mainland China, 2004 to 2014. Journal of Microbiology, Immunology and Infection. 2017;50(3):390-392.
  42. Hooper DC, Cosgrove SE, Crowe SM, Hope W, McCarthy JS, Mills J, et al. Kucer's the use of antibiotics. Boca Raton: CRC Press. 2017;2055-2084.
  43. Chien SC, Rogge MC, Gisclon LG, Curtin C, Wong F, Natarajan J, et al. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrobial Agents and Chemotherapy. 1997;41(10):2256-2260.
  44. Stolk RF, van der Pasch E, Naumann F, Schouwstra J, Bressers S, van Herwaarden AE, et al. Norepinephrine dysregulates the immune response and compromises host defense during sepsis. American Journal of Respiratory and Critical Care Medicine. 2020;202(6):830-842.
  45. Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M. Potentially inadvert immunomodulation: norepinephrine use in sepsis. American Journal of Respiratory and Critical Care Medicine. 2016;194(5):550-558.
  46. Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagi U, et al. Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience. 2009;158(3):1184-1193.
  47. Aldriwesh M, Al-Dayan N, Barratt J, Freestone P. The iron biology status of peritoneal dialysis patients may be a risk factor for the development of infectious peritonitis. Peritoneal Dialysis International. 2019;39(4):362-374.
  48. Liu X, Ye H, Zheng X, Zheng Z, Chen W, Yu X. Increased risk of catheter-related infection in critically ill patients given catecholamine inotropes during continuous renal replacement therapy. Hemodialysis International. 2022;26(1):13-22.
  49. Freestone PP, Hirst RA, Sandrini SM, Sharaff F, Fry H, Hyman S, et al. Pseudomonas aeruginosa-catecholamine inotrope interactions: a contributory factor in the development of ventilator-associated pneumonia? Chest. 2012;142(5):1200-1210.
  50. Sudrajad H, Mudigdo A, Purwanto B, Setiamika M. Ethanol extract of propolis decreases the Interleukin-8 (IL-8) expression and blood Malondialdehyde (MDA) level in otitis media rat model induced by Pseudomonas aeruginosa. Bali Medical Journal. 2020;9(2):504–510.
  51. Dharma BDA, Mulyantari NK, Prabawa IPY. Analisis korelasi kadar serum prokalsitonin dengan jumlah leukosit pada penderita dengan kecurigaan sepsis di RSUP Sanglah, Bali, Indonesia. Intisari Sains Medis. 2020;11(1):179–182.
  52. Lobritz MA, Belenky P, Porter CB, Gutierrez A, Yang JH, Schwarz EG, et al. Antibiotic efficacy is linked to bacterial cellular respiration. Proceedings of the National Academy of Sciences. 2015;112(27):8173-8180.

How to Cite

Thayyiba, A., Wasito, E. B., & Alimsardjono, L. (2023). Norepinephrine modified the interaction between Escherichia coli and levofloxacin, potentially affecting clinical outcomes and increasing the risk of bacterial colonization. Bali Medical Journal, 12(1), 1075–1080.




Search Panel

Amina Thayyiba
Google Scholar
BMJ Journal

Eddy Bagus Wasito
Google Scholar
BMJ Journal

Lindawati Alimsardjono
Google Scholar
BMJ Journal