Assessment of Susceptibility, Pharmacodynamics, and Therapeutic Response for Interpretation of Piperacillin-Tazobactam in Vitro Activity in the Treatment of Pseudomonas aeruginosa Infection


Pseudomonas aeruginosa remains an important pathogen. Our purpose was to determine the minimum inhibitory con-centration (MIC) and pharmacodynamic (PD) parameters predicting a positive response to therapy with piperacil-lin-tazobactam. Medical records were retrospectively reviewed at 3 centers. Data were recorded to assess age, type of disease, renal function, weight (body mass), MIC, antimicrobial treatment, and clinical outcome. Success was response to piperacillin-tazobactam alone, or in combination with another active agent; failure was lack of response. Of 78 eva-luable patients, 63 responded (7 UTI; 56 non-UTI) and 15 did not; 26 responding received combination therapy and 37 monotherapy. Piperacillin-tazobactam treatment was successful in 53 of 63 of non-UTI disease with a MIC of ≤64/4 μg/mL, but in only 3 of 7 with a MIC of >64/4 μg/mL (P = 0.023); overall 9 of 10 infections by strains with MICs = 32 - 64 μg/mL had a successful outcome. Piperacillin estimated time above MIC at 20% separated those responding from those that did not (P = 0.019).

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T. Gonzalzles, M. Suseno, J. Gaydos, P. Schreckenberger, C. Sincak, M. Mehta and L. Peterson, "Assessment of Susceptibility, Pharmacodynamics, and Therapeutic Response for Interpretation of Piperacillin-Tazobactam in Vitro Activity in the Treatment of Pseudomonas aeruginosa Infection," Open Journal of Medical Microbiology, Vol. 2 No. 3, 2012, pp. 101-109. doi: 10.4236/ojmm.2012.23015.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] B. Spellberg, R. Guidos, D. Gilbert, J. Bradley, H. W. Boucher, W. M. Scheld, et al.,”The Epidemic of Antibiotic-Resistant Infections: A Call to Action for the Medical Community from the Infectious Diseases Society of America,” Clinical Infectious Diseases, Vol. 46, No. 2, 2008, pp. 155-164. doi:10.1086/524891
[2] L. C. McDonald, “Trends in Antimicrobial Resistance in Health Care—Associated Pathogens and Effect on Treatment,” Clinical Infectious Diseases, Vol. 42, Suppl. 2, 2006, pp. S65-S71. doi:10.1086/499404
[3] M. W. Douglas, K. Mulholland, V. Denyer and T. Gottlieb,” Multi-Drug Resistant Pseudomonas aeruginosa Outbreak in a Burns Unit—An Infection Control Study,” Burns, Vol. 27, No. 2, 2001, pp. 131-135. doi:10.1016/S0305-4179(00)00084-X
[4] D. L. Paterson, “The Epidemiological Profile of Infections with Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter Species,” Clinical Infectious Diseases, Vol. 43, Suppl. 2, 2006, pp. S43-S48. doi:10.1086/504476
[5] A. M. Ferrara, “Potentially Multidrug-Resistant Non-Fermentative Gram-Negative Pathogens Causing Nosocomial Pneumonia,” International Journal of Antimicrobial Agents, Vol. 27, No. 3, 2006, pp. 183-195. doi:10.1016/j.ijantimicag.2005.11.005
[6] R. N. Jones, and A. L. Barry, “Studies to Optimize the in Vitro Testing of Piperacillin Combined with Tazobactam,” Diagnostic Microbiology and Infectious Diseases, Vol. 12, No. 6, 1989, pp. 495-510. doi:10.1016/0732-8893(89)90084-9
[7] Clinical and Laboratory Standards Institute, “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard M7-A7,” 7th Edition, Clinical and Laboratory Standards Institute, Wayne, 2006.
[8] Clinical and Laboratory Standards Institute, “Performance Standards for Antimicrobial Disk Susceptibility Tests: Approved Standard M2-A9,” 9th Edition, Clinical and Laboratory Standards Institute, Wayne, 2006.
[9] Clinical and Laboratory Standards Institute, “Performance Standards for Antimicrobial Susceptibility Testing: Eighteenth Informational Supplement M100-S18,” Clinical and Laboratory Standards Institute, Wayne, 2008.
[10] W. A. Craig, “Basic Pharmacodynamics of Antibacterials with Clinical Applications to the Use β-Lactams, Glycopeptides, and Linezolid,” Infectious Disease Clinics of North America, Vol. 17, No. 3, 2003, pp. 479-501. doi:10.1016/S0891-5520(03)00065-5
[11] C. A. Johnson, C. E. Halstenson, J. S. Kelloway, B. E. Shapiro, S. W. Zimmerman, A. Tonelli, et al., “Single-Dose Pharmacokinetics of Piperacillin and Tazobactam in Patients with Renal Disease,” Clinical Pharmacology and Therapeutics, Vol. 51, No. 1, 1992, pp. 32-41. doi:10.1038/clpt.1992.5
[12] D. J. Occhipinti, S. L. Pendland, L. L. Schoonover, E. B. Rypins, L. H. Danziger and K. A. Rodvold, “Pharmacokinetics and Pharmacodynamics of Two Multiple-Dose Piperacillin-Tazobactam Regimens,” Antimicrobial Agents and Chemotherapy, Vol. 41, No. 11, 1997, pp. 25112517.
[13] F. S?rgel and M. Kinzig, “The Chemistry, Pharmacokinetics and Tissue Distribution of Piperacillin-Tazobactam,” Journal of Antimicrobial Chemotherapy, Vol. 31, Suppl. A, 1993, pp. 39-60.
[14] J. D. Turnidge, “The Pharmacodynamics of β-Lactams,” Clinical Infectious Diseases, Vol. 27, No. 1, 1998, pp. 10-22. doi:10.1086/514622
[15] G. Manjunath, M. J. Sarnak and A. S. Levey, “Estimating the Glomerular Filtration Rate. Dos and Don’Ts for Assessing Kidney Function,” Postgraduate Medicine, Vol. 110, No. 6, 2001, pp. 55-62.
[16] J. A. Giron, B. R. Meyers, S. Z. Hirschman and E. Srulevitch, “Pharmacokinetics of Piperacillin in Patients with Moderate Renal Failure and in Patients Undergoing Hemodialysis,” Antimicrobial Agents and Chemotherapy, Vol. 19, No. 2, 1981, pp. 279-283. doi:10.1128/AAC.19.2.279
[17] A. A. Vinks, J. G. den Hollander, S. E. Overbeek, R. W. Jelliffe and J. W. Mouton, “Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin during Intermittent or Continuous Infusion in Patients with Cystic Fibrosis,” Antimicrobial Agents and Chemotherapy, Vol. 47, No. 2, 2003, pp. 541-547. doi:10.1128/AAC.47.2.541-547.2003
[18] Y.-K. Kim, H. Pai, H.-J. Lee, S.-E. Park, E.-H. Choi, J. Kim, et al., “Bloodstream Infections by Extended-Spectrum β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in Children: Epidemiology and Clinical Outcome,” Antimicrobial Agents and Chemotherapy, Vol. 46, No. 5, 2002, pp. 1481-1491. doi:10.1128/AAC.46.5.1481-1491.2002
[19] M. S. Bader, J. Hawboldt and A. Brooks, “Management of Complicated Urinary Tract Infections in the Era of Antimicrobial Resistance,” Postgraduate Medicine, Vol. 122, No. 6, 2010, pp. 7-15. doi:10.3810/pgm.2010.11.2217
[20] D. P. Nicolau, “Carbapenems: A Potent Class of Antibiotics,” Expert Opinion in Pharmacotherapy, Vol. 9, No. 1, 2008, pp. 23-37.
[21] G. G. Zhanel, R. Wiebe, L. Dilay, K. Thomson, E. Rubinstein, D. J. Hoban, et al., “Comparative Review of the Carbapenems,” Drugs, Vol. 67, No. 7, 2007, pp. 1027-1052. doi:10.2165/00003495-200767070-00006
[22] Zosyn?, “Piperacillin and Tazobactam for Injection, Prescribing Information,” Last accessed June 27, 2012.
[23] V. H. Tam, E. A. Gamez, J. S. Weston, et al., “Outcomes of Bacteremia Due to Pseudomonas aeruginosa with Reduced Susceptibility to Piperacillin-Tazobactam: Implications on the Appropriateness of the Resistance Breakpoint,” Clinical Infectious Diseases, Vol. 46, No. 6, 2008, pp. 862-867. doi:10.1086/528712
[24] T. P. Lodise Jr., B. Lomaestro, K. A. Rodvold, L. H. Danziger and G. L. Drusano, “Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo simulation,” Antimicrobial Agents and Chemotherapy, Vol. 48, No. 12, 2004, pp. 4718-4724. doi:10.1128/AAC.48.12.4718-4724.2004
[25] C. A. DeRyke, J. L. Kuti and D. P. Nicolau, “Reevaluation of Current Susceptibility Breakpoints for GramNegative Rods Based on Pharmacodynamic Assessment,” Diagnostic Microbiology and Infectious Diseases, Vol. 58, No. 3, 2007, pp. 337-344.
[26] C. R. Frei, N. P. Wiederhold and D. S. Burgess, “Antimicrobial Breakpoints for Gram-Negative Aerobic Bacteria Based on Pharmacokinetic—Pharmacodynamic Models with Monte Carlo simulation,” Journal of Antimicrobial Chemotherapy, Vol. 61, No. 3, 2008, pp. 621-628. doi:10.1093/jac/dkm536
[27] E. L. Fasola, C. E. Fasching and L. R. Peterson, “Molecular Correlation between in Vitro and in Vivo Activity of Beta-Lactam and Beta-Lactamase Inhibitor Combinations against Methicillin-Resistant Staphylococcus aureus,” Journal of Laboratory and Clinical Medicine, Vol. 125, No. 2, 1995, pp. 200-211.
[28] T. Yokota, “Inactivation of Beta-Lactamases by Sulbactam and Enhanced Clinical Activity Due to Target-Site Binding of the Combination of Sulbactam and Ampicillin,” APMIS Supplementum, Vol. 5, 1989, pp. 9-16.
[29] P. J. Gavin, M. T. Suseno, R. B. Thomson Jr., J. M. Gaydos, C. L. Pierson, D. C. Halstead, et al., “Clinical Correlation of the CLSI Susceptibility Breakpoint for Piperacillin-Tazobactam against Extended-Spectrum-β-Lactamase-Producing Escherichia coli and Klebsiella Species,” Antimicrobial Agents and Chemotherapy, Vol. 50, No. 6, 2006, pp. 2244-2247. doi:10.1128/AAC.00381-05
[30] J. Rodríguez-Ba?o, E. Picón, P. Gijón, J. R. Hernández, M. Ruíz, C. Pe?a, et al., “Community-Onset Bacteremia Due to Extended-Spectrum β-Lactamase-Producing Escherichia coli: Risk Factors and Prognosis,” Clinical Infectious Diseases, Vol. 50, No. 1, 2010, pp. 40-48. doi:10.1086/649537
[31] J. Rodríguez-Ba?o, M. D. Navarro, P. Retamar, E. Picón, á. Pascua and The Extended-Spectrum Beta-Lactamases— Red Espa?ola de Investigación en PatologíaInfecciosa/ Grupo de Estudio de Infección Hospitalaria Group, “βlactam/β-lactam Inhibitor Combinations for the Treatment of Bacteremia Due to Extended-Spectrum β-LactamaseProducing Escherichia coli: A Post Hoc Analysis of Prospective Cohorts,” Clinical Infectious Diseases, Vol. 54, No. 2, 2012, pp. 167-174. doi:10.1093/cid/cir790
[32] A. H. Strayer, D. H. Gilbert, P. Pivarnik, A. A. Medeiros, S. H. Zinner and M. N. Dudley, “Pharmacodynamics of Piperacillin Alone and in Combination with Tazobactam against Piperacillin-Resistant and Susceptible Organisms in an in Vitro Model of Infection,” Antimicrobial Agents and Chemotherapy, Vol. 42, No. 10, 1994, pp. 1098-1104.
[33] The Medical Letter on Drugs and Therapeutics, “Piperacillin/Tazobactam,” The Medical Letter, Inc., New Rochelle, 1995.
[34] P. G. Ambrose, S. M. Bhavnani and R. N. Jones, “Pharmacokinetics-Pharmacodynamics of Cefepime and Piperacillin-Tazobactam against Escherichia coli and Klebsiella pneumoniae Strains Producing Extended-Spectrum β-Lactamases: Report from the ARREST Program,” Antimicrobial Agents and Chemotherapy, Vol. 47, No. 5, 2003, pp. 1643-1646. doi:10.1128/AAC.47.5.1643-1646.2003
[35] M. N. Dudley, “Combination β-Lactam and β-LactamaseInhibitor Therapy: Pharmacokinetic and Pharmacodynamic Considerations,” American Journal of HealthSystem Pharmacy, Vol. 52, No. 6, 1995, pp. S23-S28.
[36] F. J. Pérez-Llarena and G. Bou, “Beta-Lactamase Inhibitors: The Story So Far,” Current Medicinal Chemistry, Vol. 16, No. 28, 2009, pp. 3740-3765. doi:10.2174/092986709789104957
[37] K. J. Eagye, D. P. Nicolau, S. R. Lockhart, J. P. Quinn, G. V. Doern, G. Gallagher and M. A. Abramson, “A Pharmacodynamic Analysis of Resistance Trends in Pathogens from Patients with Infection in Intensive Care Units in the United States between 1993 and 2004,” Annals of Clinical Microbiology and Antimicrobials, Vol. 6, 2007, pp. 11-17. doi:10.1186/1476-0711-6-11
[38] L. R. Peterson and D. N. Gerding, “Influence of Protein Binding of Antibiotics on Serum Pharmacokinetics and Extravascular Penetration: Clinically Useful Concepts,” Clinical Infectious Diseases, Vol. 2, No. 3, 1980, pp. 340348. doi:10.1093/clinids/2.3.340

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