Revisiting an ‘old’ antibiotic class polymyxins by drug combination therapy targeting Gram-negative superbugs: Toyyiban perspective
The Islamic concept of halalan-toyyiban encompasses medicines and pharmaceuticals. Halal pharmaceuticals mean the products are free from any unlawful (haram) constituents while in another aspect, toyyib pharmaceuticals particularly concern on the products’ wholesomeness, quality and safety. Polymyxins, an ‘old’ class antibiotic have been employed as the last-line defence for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. Nevertheless, the exceptional clinical applications of polymyxins are restrained due to their dose-limiting nephrotoxicity and neurotoxicity. In addition, pharmacokinetic/pharmacodynamic (PK/PD) studies indicate that polymyxin monotherapy often fails to achieve an effective in vivo plasma exposure concentration, potentially lead to the emergence of bacterial heteroresistance. To optimise the significant potential of polymyxins, therefore, polymyxin combination therapy has been recommended. The strategy provides some advantages as it significantly confers safer clinical dosage of polymyxins administration thus likely to reduce its toxicity effects. Looking from the toyyiban perspective, this review discusses on the synergistic killing of polymyxin combination for the treatment of MDR Gram-negative infection to reduce its potential toxicity and emergence of resistance.
Abdelraouf, K., Braggs, K. H., Yin, T., et al. (2012). Characterization of polymyxin B-induced nephrotoxicity: implications for dosing regimen design. Antimicrobial Agents and Chemotherapy, 56(9): 4625–4629.
Abdul Rahim, N., Cheah, S.E., Johnson, M.D., et al. (2015). Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two 'old' antibiotics-polymyxin B and chloramphenicol. Journal of Antimicrobial and Chemotherapy, 70(9): 2589–2597.
Al-Qaradawi, Y. (2000). The Islamic principles petaining to the lawful and the prohibited. The lawful and prohibited in Islam. Dar Al Taqwa.
Arnold, T. M., Forrest, G. N., & Messmer, K. J. (2007). Polymyxin antibiotics for Gram-negative infections. American Journal of Health-System Pharmacy, 64(8): 819–826.
Belenky, P., Ye, J. D., Porter, C. B. M., et al. (2015). Bactericidal antibiotics induce toxic metabolic perturbations that lead to cellular damage. Cell Reports, 13(5): 968–980.
Berg, J. R., Spilker, C. M., & Lewis, S. A. (1996). Effects of polymyxin B on mammalian urinary bladder. Journal of Membrane Biology, 154(2): 119–130.
Berg, J. R., Spilker, C. M., & Lewis, S. A. (1998). Modulation of polymyxin B effects on mammalian urinary bladder. American Journal of Physiology. 275(2 Pt 2), F204-215.
Bergen, P. J., Bulitta, J. B., Forrest, A., et al. (2010). Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrobial Agents and Chemotherapy, 54(9): 3783–3789.
Bergen, P. J., Bulman, Z. P., Landersdorfer, C. B., et al. (2015). Optimizing polymyxin combinations against resistant Gram-negative bacteria. Infectious Diseases and Therapy, 4(4): 391–415.
Bergen, P. J., Landersdorfer, C. B., Zhang, J., et al. (2012). Pharmacokinetics and pharmacodynamics of 'old' polymyxins: What is new? Diagnostic Microbiology and Infectious Diseases, 74(3): 213–223.
Bergen, P. J., Li, J., Rayner, C. R., et al. (2006). Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 50(6): 1953–1958.
Cabiscol, E., Tamarit, J., & Ros, J. 2000. Oxidative stress in bacteria and protein damage by reactive oxygen species. International Microbiology, 3(1): 3–8.
Cheah, S. E., Wang, J., Nguyen, V. T., et al. (2015). New pharmacokinetic / pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: Smaller response in lung infection. Journal of Antimicrobial and Chemotherapy, 70(12): 3291–3297.
Deris, Z. Z., Akter, J., Sivanesan, S., et al. (2014). A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity. Journal of Antibiotics (Tokyo), 67(2): 147–151.
Deris, Z. Z., Yu, H.H., Davis, K., et al. (2012). The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrobial Agents and Chemotherapy, 56(10): 5103–5112.
Dong, T.G., Dong, S., Catalano, C., et al. (2015). Generation of reactive oxygen species by lethal attacks from competing microbes. Proceeding of National Academy of Sciences of the USA. 112(7): 2181–2186.
Dwyer, D. J., Kohanski, M. A., & Collins, J. J. (2009). Role of reactive oxygen species in antibiotic action and resistance. Current Opinion in Microbiology, 12(5): 482–489.
Dwyer, D. J., Kohanski, M. A., Hayete, B., et al. (2007). Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Molecular System Biology, 3: 91.
Elias, L. S., Konzen, D., Krebs, J. M., et al. (2010). The impact of polymyxin B dosage on in-hospital mortality of patients treated with this antibiotic. Journal of Antimicrobial and Chemotherapy, 65(10): 2231–2237.
Falagas, M. E., & Kasiakou, S. K. (2006). Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Critical Care, 10(1): R27.
Garnacho-Montero, J., Ortiz-Leyba, C., Jimenez-Jimenez, F.J., et al. (2003). Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: A comparison with imipenem-susceptible VAP. Clinical Infectious Diseases, 36(9): 1111–1118.
Garonzik, S.M., Li, J., Thamlikitkul, V., Paterson, D.L., Shoham, S., Jacob, J., Silveira F.P., Forrest A, Nation, R.L. 2011. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother, 55(7), 3284-3294.
Hartzell, J. D., Neff, R., Ake, J., et al. (2009). Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clinical Infectious Diseases, 48(12), 1724–1728.
Halim, M. A., Salleh, M. M. M., Kashim, M. I. A. M., et al. (2014). Halal pharmaceutical: Legal, shariah issues and fatwa of drug, gelatine and alcohol. International Journal of Asian Social Science, 4(12): 1176–1190.
Iris Keren, Y. W., Inocencia, J., Lawrence R. et al. (2013). Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science, 339: 1213–1216.
Jones, K. E., Patel, N. G., Levy, M. A., et al. (2008). Global trends in emerging infectious diseases. Nature, 451(7181): 990–993.
Karvanen, M., Plachouras, D., Friberg, L.E., et al. 2013. Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration. Antimicrobial Agents and Chemotherapy, 57(1): 668–671.
Kindrachuk, K. N., Fernandez, L., Bains, M., et al. (2011). Involvement of an ATP-dependent protease, PA0779/AsrA, in inducing heat shock in response to tobramycin in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 55(5): 1874–1882.
Kvitko, C. H., Rigatto, M. H., Moro, A. L., et al. (2011). Polymyxin B versus other antimicrobials for the treatment of pseudomonas aeruginosa bacteraemia. Journal of Antimicrobial and Chemotherapy, 66(1): 175–179.
Lee, H. J., Bergen, P. J., Bulitta, J. B., et al. (2013). Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrobial Agents and Chemotherapy, 57(8): 3738–3745.
Lehar, J., Krueger, A. S., Avery, W., et al. (2009). Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nature Biotechnology, 27(7): 659–666.
Li, J., Milne, R. W., Nation, R. L., et al. (2003). Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrobial Agents and Chemotherapy, 47(5): 1766–1770.
Li, J., Nation, R. L., Turnidge, J. D., et al. 2006. Colistin: The re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet of Infectious Diseases, 6(9): 589–601.
Malaysian Standard. (2012). Halal pharmaceuticals — general guidelines MS 2424:2012.
Markou, N., Fousteri, M., Markantonis, S. L., et al. 2012. Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study. Journal of Antimicrobial and Chemotherapy, 67(10): 2459–2462.
Mogi, T., Murase, Y., Mori, M., et al. 2009. Polymyxin B identified as an inhibitor of alternative NADH dehydrogenase and malate: Quinone oxidoreductase from the Gram-positive Bacterium Mycobacterium smegmatis. Journal of Biochemistry, 146(4): 491–499.
Nation, R. L., Li, J., Cars, O., et al. (2015). Framework for optimisation of the clinical use of colistin and polymyxin B: The Prato polymyxin consensus. The Lancet Infectious Diseases, 15(2): 225–234.
Norazmi, M. N. & Lim, L. S. 2015. Halal pharmaceutical indusry: Opportunities and challenges. Trends in Pharmacological Sciences, 36(8): 496–497.
Oleksiuk, L. M., Nguyen, M. H., Press, E. G., et al. 2014. In vitro responses of Acinetobacter baumannii to two- and three-drug combinations following exposure to colistin and doripenem. Antimicrobial Agents and Chemotherapy, 58(2): 1195–1199.
Parchem, N. L., Bauer, K. A., Cook, C. H., et al. (2016). Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant Gram-negative pneumonia. European Journal of Clinical Microbiology & Infectious Diseases, 35(9): 1433–1439.
Peng, K., & Abdul Karim R. H. (2013). Good Manufacturing practices for halal pharmaceuticals. Phamaceutical engineering, 33(4): 493–501.
Plachouras, D., Karvanen, M., Friberg, L. E., et al. (2009). Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrobial Agents and Chemotherapy, 53(8): 3430–3436.
Poirel, L., Jayol, A., & Nordmann, P. (2017). Polymyxins: Antibacterial activity, suscceptibility testing, and resistance mechanisms encoded by plamids or chromosomes. Clinical Microbiology Reviews, 30(2): 557–596.
Poudyal, A., Howden, B. P., Bell, J. M., et al. 2008. In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae. Journal of Antimicrobial and Chemotherapy, 62(6): 1311–1318.
Principe, L., Capone, A., Mazzarelli, A., et al. (2013). In Vitro activity of doripenem in combination with various antimicrobials against multidrug-resistant Acinetobacter baumannii: Possible options for the treatment of complicated infection. Microbial Drug Resistance, 19(5): 407–414.
Qureshi, Z. A., Paterson, D. L., Peleg, A. Y., et al. 2012. Clinical characteristics of bacteraemia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type beta-lactamases. Clinical Microbiology and Infection, 18(9): 887–893.
Rigatto, M. H., & Falci., D. R. (2016). Polymyxins combined with other antibiotics for the treatment of multi-resistant Gram negative bacteria: Review of the literature. Principle and Practice in Clinical Research, 1(4): 91–96.
Rigatto, M. H., Vieira, F. J., Antochevis, L. C., et al. (2015). Polymyxin B in combination with antimicrobials lacking in vitro activity versus polymyxin B in monotherapy in critically ill patients with Acinetobacter baumannii or Pseudomonas aeruginosa infections. Antimicrobial Agents and Chemotherapy, 59(10): 6575–6580.
Rybak, M. J., & McGrath, B. J. (1996). Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician. Drugs, 52(3): 390–405.
Sadeeqa, S., Sarriff, A., Masood, I., et al. (2015). Kap among doctors working in hospitals, regarding halal pharmaceuticals; a cross sectional assessment. Acta Poloniae Pharmaceutica, 72(3): 615–624.
Sampson, T. R., Liu, X., Schroeder, M. R., et al. (2012). Rapid killing of Acinetobacter baumannii by polymyxins is mediated by a hydroxyl radical death pathway. Antimicrobial Agents Chemother, 56(11): 5642–5649.
Sandri, A. M., Landersdorfer, C. B., Jacob, J., et al. (2013). Population pharmacokinetics of intravenous polymyxin B in critically ill patients: Implications for selection of dosage regimens. Clinical Infectious Diseases, 57(4): 524–531.
Sarriff, A., & Abdul Razzaq, H. A. (2013). Exploring the halal status of cardiovascular, endocrine, and respiratory group of medications. Malaysians Journal of Medical Sciences, 20(1): 69–75.
Shields, R. K., Clancy, C. J., Gillis, L. M., et al. (2012). Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One, 7(12).
Tamma, P. D., Cosgrove, S. E., & Maragakis, L. L. (2012). Combination therapy for treatment of infections with Gram-negative bacteria. Clinical Microbiology Review, 25(3): 450–470.
Tascini, C., Tagliaferri, E., Giani, T., et al. (2013). Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy, 57(8): 3990–3993.
Trimble, M. J., Mlynarcik, P., Kolar, M., et al. (2016). Polymyxin: Alternative mechanisms of action and resistance. Cold Spring Harbor Perspectives in Medicine, 6(10).
Tumbarello, M., Viale, P., Viscoli, C., et al. (2012). Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: Importance of combination therapy. Clinical Infectious Diseases, 55(7): 943–950.
Tuon, F. F., Rigatto, M. H., Lopes, C. K., et al. (2014). Risk factors for acute kidney injury in patients treated with polymyxin B or colistin methanesulfonate sodium. International Journal of Antimicrobial Agents, 43(4): 349–352.
Tzouvelekis, L. S., Markogiannakis, A., Piperaki, E., et al. (2014). Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clinical Microbiology and Infection, 20(9): 862–872.
Velkov, T., Roberts, K. D., Nation, R. L., et al. (2013). Pharmacology of polymyxins: New insights into an 'old' class of antibiotics. Future Microbiology, 8(6): 711–724.
Yahav, D., Farbman, L., Leibovici, L., et al. Colistin: New lessons on an old antibiotic. Clinical Microbiology and Infection, 18(1): 18–29.
Yu, Z., Qin, W., Lin, J., et al. (2015). Antibacterial mechanisms of polymyxin and bacterial resistance. BioMed Research International, 2015, 679109.
Zarif, M. M. M., Murad, A. H. A., & Yusof, A. F. M. (2013). The use of forbidden materials in medicinal products: An Islamic perspective. Middle-East Journal of Scientific Research, 30(12): 5–10.
Zavascki, A. P., Goldani, L. Z., Li, J., et al. (2007). Polymyxin B for the treatment of multidrug-resistant pathogens: A critical review. Journal of Antimicrobial and Chemotherapy, 60(6): 1206–1215.
Zusman, O., Avni, T., Leibovici, L., et al. (2013). Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems. Antimicrobial Agents and Chemotherapy, 57(10): 5104–5111.
Author(s) shall retain the copyright of their work and grant the Journal/Publisher right for the first publication with the work simultaneously licensed under:
Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). This license allows for the copying, distribution and transmission of the work, provided the correct attribution of the original creator is stated. Adaptation and remixing are also permitted.
This broad license intends to facilitate free access to, as well as the unrestricted reuse of, original works of all types for non-commercial purposes.
The author(s) permits HH Publisher to publish this article that has not been submitted elsewhere.