Share This Article:

Synergistic Combination of Carbapenems and Colistin against P. aeruginosa and A. baumannii

Abstract Full-Text HTML Download Download as PDF (Size:148KB) PP. 253-258
DOI: 10.4236/ojmm.2013.34038    5,245 Downloads   10,024 Views   Citations


Background: Intubated patients are particularly at risk of developing infections caused by these pathogens, specifically, P. aeruginosa and A. baumannii. In the past fifteen years, Carbapenems were known to be the drugs of choice for these bacteria. With the increase in the use and misuse of antibiotics, these bacteria became highly resistant, and almost all available antibiotics, including Carbapenems, became inefficient. Synergistic combination therapy may be a useful strategy in slowing as well as overcoming the emergence of resistance. The aim of this study was to evaluate the anti-bacterial activity on P. aeruginosa and A. baumannii of the combination of two antibiotics: Colistin and a Carbapenem (Meropenem or Imipenem). Methods: The antibacterial activity was assessed by determining the MIC. Then, the effect of combining the antibiotics was studied using the Checkerboard Technique described by White et al., 1996. The Fractional Inhibitory Concentration (FIC) for each strain was then calculated and classified as synergy, additive, indifference or antagonism. 11 strains of A. baumannii and 11 strains of P. aeruginosa were tested in the presence of Meropenem combined with Colistin or Imipenem combined with Colistin. Results: For the combination of Meropenem and Colistin, 6 strains of A. baumannii and 3 strains of P. aeruginosa showed synergy while 5 strains of A. baumannii and 7 strains of P. aeruginosa showed additive effect, only 1 strain of P. aeruginosa showed antagonism. For Imipenem and Colistin, only 1 strain of A. baumannii and 3 strains of Pseudomonas showed synergy while 8 strains of Acinetobacter and 8 strains of Pseudomonas showed additive effect. Conclusion: The “in vitro” combination Colistin-Carbapenem is associated with an improvement in MIC. In the majority of the cases, this improvement suggests a synergistic combination or an additive effect.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Z. Daoud, N. Mansour and K. Masri, "Synergistic Combination of Carbapenems and Colistin against P. aeruginosa and A. baumannii," Open Journal of Medical Microbiology, Vol. 3 No. 4, 2013, pp. 253-258. doi: 10.4236/ojmm.2013.34038.


[1] C. R. Kiffer and A. C. Pignatari, “Pharmacodynamic Evaluation of Commonly Prescribed Oral Antibiotics against Respiratory Bacterial Pathogens,” BMC Infectious Diseases, Vol. 11, 2011, p. 286.
[2] G. Capellier, H. Mockly, C.Charpentier, D. Annane, G. Blasco, T. Desmettre and L. Papazian, “Early-Onset Ventilator-Associated Pneumonia in Adults Randomized Clinical Trial: Comparison of 8 versus 15 Days of Antibiotic Treatment,” PloS One, Vol. 7, No. 8, 2012, Article ID: e41290.
[3] A. C. Breier, C. Brandt, D. Sohr, C. Geffers and P. Gastmeier, “Laminar Airflow Ceiling Size: No Impact on Infection Rates Following Hip and Knee Prosthesis,” Infection Control and Hospital Epidemiology: The Official Journal of the Society of Hospital Epidemiologists of America, Vol. 32, No. 11, 2011, pp. 1097-1102.
[4] S. Micek, M. T. Johnson, R. Reichley and M. H. Kollef, “An Institutional Perspective on the Impact of Recent Antibiotic Exposure on Length of Stay and Hospital Costs for Patients with Gram-Negative Sepsis,” BMC Infectious Diseases, Vol. 12, 2012, p. 56.
[5] M. H. Kollef, G. Sherman, S. Ward and V. J. Fraser, “Inadequate Antimicrobial Treatment of Infections: A Risk Factor for Hospital Mortality among Critically Ill Patients,” Chest, Vol. 115, No. 2, 1999, pp. 462-474.
[6] M. E. Falagas and D. E. Karageorgopoulos, “Pandrug Resistance (PDR), Extensive Drug Resistance (XDR), and Multidrug Resistance (MDR) among Gram-Negative Bacilli: Need for International Harmonization in Terminology,” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, Vol. 46, No. 7, 2008, pp. 1121-1122.
[7] B. L. Angus, A. M. Carey, D. A. Caron, A. M. Kropinski and R. E. Hancock, “Outer Membrane Permeability in Pseudomonas aeruginosa: Comparison of a Wild-Type with an Antibiotic-Supersusceptible Mutant,” Antimicrobial Agents and Chemotherapy, Vol. 21, No. 2, 1982, pp. 299-309.
[8] W. Hengzhuang, H. Wu, O. Ciofu, Z. Song and N. Hoiby, “Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem on Mucoid and Nonmucoid Pseudomonas aeruginosa Biofilms,” Antimicrobial Agents and Chemotherapy, Vol. 55, No. 9, 2011, pp. 4469-4474.
[9] I. Ziha-Zarifi, C. Llanes, T. Kohler, J. C. Pechere and P. Plesiat, “In Vivo Emergence of Multidrug-Resistant Mutants of Pseudomonas aeruginosa Overexpressing the Active Efflux System MexA-MexB-OprM,” Antimicrobial Agents and Chemotherapy, Vol. 43, No. 2, 1999, pp. 287-291.
[10] E. Yoshihara and T. Nakae, “Separation of Gate-and Channel-Forming Domains in the Pore-Forming Protein of the Outer Membrane of Pseudomonas aeruginosa,” FEBS Letters, Vol. 306, No. 1, 1992, pp. 5-8.
[11] K. H. Buscher, W. Cullmann, W. Dick and W. Opferkuch, “Imipenem Resistance in Pseudomonas aeruginosa Resulting from Diminished Expression of an Outer Membrane Protein,” Antimicrobial Agents and Chemotherapy, Vol. 31, No. 5, 1987, pp. 703-708.
[12] D. V. Ivanov and A. M. Egorov, “Spreading and Mechanisms of Antimicrobial Resistance of Microorganisms, Producing Beta-Lactamases. Phenotypical Screening for MBL Producers (carbapenemases B1) among strains of Pseudomonas genus, Isolated in Cases of Nosocomial Infections,” Biomeditsinskaia Khimiia, Vol. 53, No. 6, 2007, pp. 653-661.
[13] L. L. Correa, L. A. Botelho, L. C. Barbosa, C. S. Mattos, J. M. Carballido, C. L. de Castro, C. R. de Mendonca-Souza, “Detection of bla(OXA-23) in Acinetobacter spp. Isolated from Patients of a university Hospital,” The Brazilian Journal of Infectious Diseases: An Official Publication of the Brazilian Society of Infectious Diseases, Vol. 16, No. 6, 2012, pp. 521-526.
[14] R. Zarrilli, D. Vitale, A. Di Popolo, M. Bagattini, Z. Daoud, A. U. Khan, C. Afif and M. Triassi, “A Plasmid-Borne blaOXA-58 Gene Confers Imipenem Resistance to Acinetobacter baumannii Isolates from a Lebanese Hospital,” Antimicrobial Agents and Chemotherapy, Vol. 52, No. 11, 2008, pp. 4115-4120.
[15] M. Giannouli, F. Tomasone, A. Agodi, H. Vahaboglu, Z. Daoud, M. Triassi, A. Tsakris and R. Zarrilli, “Molecular Epidemiology of Carbapenem-Resistant Acinetobacter baumannii Strains in Intensive Care Units of Multiple Mediterranean Hospitals,” Journal of Antimicrobial Chemotherapy, Vol. 63, No. 4, 2009, pp. 828-830.
[16] A. Di Popolo, M. Giannouli, M. Triassi, S. Brisse and R. Zarrilli, “Molecular Epidemiological Investigation of Multidrug-Resistant Acinetobacter baumannii Strains in Four Mediterranean Countries with a Multilocus Sequence Typing Scheme,” Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, Vol. 17, No. 2, 2011, pp. 197-201.
[17] G. F. Araj, A. Z. Avedissian, N. S. Ayyash, H. A. Bey, R. G. El Asmar, R. Z. Hammoud and S. A. Sabai, “A Reflection on Bacterial Resistance to Antimicrobial Agents at a Major Tertiary Care Center in Lebanon over a Decade,” The Lebanese Medical Journal, Vol. 60, No. 3, 2012, pp. 125-135.
[18] G. M. Rossolini and E. Mantengoli, “Treatment and Control of Severe Infections Caused by Multiresistant Pseudomonas aeruginosa,” Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, Vol. 11, Suppl. 4, 2005, pp. 17-32.
[19] W. S. Choi, S. H. Kim, E. G. Jeon, M. H. Son, Y. K. Yoon, J. Y. Kim and D. W. Park, “Nosocomial Outbreak of Carbapenem-Resistant Acinetobacter baumannii in Intensive Care Units and Successful Outbreak Control Program,” Journal of Korean Medical Science, Vol. 25, No. 7, 2010, pp. 999-1004.
[20] J. Li, R. L. Nation, R. W. Milne, J. D. Turnidge and K. Coulthard, “Evaluation of Colistin as an Agent against Multi-Resistant Gram-Negative Bacteria,” International Journal of Antimicrobial Agents, Vol. 25, No. 1, 2005, pp. 11-25.
[21] K. Lee, D. Yong, S. H. Jeong and Y. Chong, “Multidrug-Resistant Acinetobacter spp.: Increasingly Problematic Nosocomial Pathogens,” Yonsei Medical Journal, Vol. 52, No. 6, 2011, pp. 879-891.
[22] G. M. Eliopoulos and R. C. Moellering Jr., “Antibiotic Synergism and Antimicrobial Combinations in Clinical Infections,” Reviews of Infectious Diseases, Vol. 4, No. 2, 1982, pp. 282-293.
[23] Clinical and Laboratory Standards Institute, “Performance Standards for Antimicrobial Susceptibility Testing; Twenty-First Informational Supplement,” Clinical and Laboratory Standards Institute, 2011.
[24] D. K. Joung, H. Joung, D. W. Yang, D. Y. Kwon, J. G. Choi, S. Woo and D. W. Shin, “Synergistic Effect of Rhein in Combination with Ampicillin or Oxacillin against Methicillin-Resistant staphylococcus aureus,” Experimental and Therapeutic Medicine, Vol. 3, No. 4, 2012, pp. 608- 612.
[25] R. L. White, D. S. Burgess, M. Manduru and J. A. Bosso, “Comparison of Three Different in Vitro Methods of Detecting Synergy: Time-kill, Checkerboard, and E Test,” Antimicrobial Agents and Chemotherapy, Vol. 40, No. 8, 1996, pp. 1914-1918.
[26] A. B. Teixeira, A. F. Martins, J. Barin, D. M. Hermes, C. Pormann, A. L. Barth, “First Report of Carbapenem-Resistant Acinetobacter nosocomialis Isolates Harboring ISAba1-blaOXA-23 Genes in Latin America,” Journal of Clinical Microbiology, Vol. 51, No. 8, 2013, pp. 2739- 3741.
[27] N. Masuda, E. Sakagawa, S. Ohya, N. Gotoh, H. Tsujimoto and T. Nishino, “Substrate Specificities of MexAB- OprM, MexCD-OprJ, and MexXY-oprM Efflux pupms in Pseudomonas aeruginosa,” Antimicrobial Agents and Chemotherapy, Vol. 44, No. 12, 2000, pp. 3322-3327.
[28] G. Santella, S. Pollini, J. D. Docquier, M. Almuzara, G. Gutkind, G. M. Rossolini and M. Radice, “Carbapenem Resistance in Pseudomonas aeruginosa Isolates: An Example of Interaction between Different Mechanisms,”
[29] A. Oliver, B. R. Levin, C. Juan, F. Baquero and J. Blazquez, “Hypermutation and the Preexistence of Antibiotic-Resistant Pseudomonas aeruginosa Mutants: Implications for Susceptibility Testing and Treatment of Chronic Infections,” Antimicrobial Agents and Chemotherapy, Vol. 48, No. 11, 2004, pp. 4226-4233.
[30] T. R. Walsh, M. A. Toleman, L. Poirel and P. Nordmann, “Metallo Beta-Lactamses: The Clam before the storm?” Clinical Microbiology Reviews, Vol. 18, No. 2, 2005, pp. 306-325.
[31] A. Y. Peleg, H. Seifert and D. L. Paterson, “Acinetobacter baumannii: Emergence of a Successful Pathogen,” Clinical Microbiology Reviews, Vol. 21, No. 3, 2008, pp. 538- 582.
[32] J. P. Zhang, W. Zhu, S. F. Tian, Y. Z. Chu and B. Y. Chen, “Molecular Characteristics and Resistant Mechanisms of Imipenem-Resistant Acinetobacter baumannii Isolates in Shenyang, China,” Journal of Microbiology, Vol. 48, No. 5, 2010, pp. 689-694.

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.