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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice

Author(s): Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa , Somashekharayya Hiremath, Avinash Pawar, Mahesh Nanjundappa and Ramesh Jayaraman *

Volume 21, Issue 2, 2020

Page: [132 - 139] Pages: 8

DOI: 10.2174/1389200221666200310105227

Price: $65

Abstract

Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI).

Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients.

Methods: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment.

Results: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68).

Conclusion: Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.

Keywords: Pharmacokinetics, pharmacodynamics, bacterial burden, ciprofloxacin, cUTI, mouse, diabetes.

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[1]
Craig, W.A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis., 1998, 26(1), 1-10.
[http://dx.doi.org/10.1086/516284] [PMID: 9455502]
[2]
Preston, S.L.; Drusano, G.L.; Berman, A.L.; Fowler, C.L.; Chow, A.T.; Dornseif, B.; Reichl, V.; Natarajan, J.; Corrado, M. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA, 1998, 279(2), 125-129.
[http://dx.doi.org/10.1001/jama.279.2.125] [PMID: 9440662]
[3]
Ambrose, P.G.; Bhavnani, S.M.; Rubino, C.M.; Louie, A.; Gumbo, T.; Forrest, A.; Drusano, G.L. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin. Infect. Dis., 2007, 44(1), 79-86.
[http://dx.doi.org/10.1086/510079] [PMID: 17143821]
[4]
Andes, D.; Craig, W.A. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int. J. Antimicrob. Agents, 2002, 19(4), 261-268.
[http://dx.doi.org/10.1016/S0924-8579(02)00022-5] [PMID: 11978497]
[5]
Zhao, M.; Lepak, A.J.; Andes, D.R. Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Bioorg. Med. Chem., 2016, 24(24), 6390-6400.
[http://dx.doi.org/10.1016/j.bmc.2016.11.008] [PMID: 27887963]
[6]
Drusano, G.L. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat. Rev. Microbiol., 2004, 2(4), 289-300.
[http://dx.doi.org/10.1038/nrmicro862] [PMID: 15031728]
[7]
Forrest, A.; Nix, D.E.; Ballow, C.H.; Goss, T.F.; Birmingham, M.C.; Schentag, J.J. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob. Agents Chemother., 1993, 37(5), 1073-1081.
[http://dx.doi.org/10.1128/AAC.37.5.1073] [PMID: 8517694]
[8]
Zykov, I.N.; Samuelsen, Ø.; Jakobsen, L.; Småbrekke, L.; Andersson, D.I.; Sundsfjord, A.; Frimodt-Møller, N. Pharmacokinetics and pharmacodynamics of fosfomycin and its activity against extended-spectrum-β-lactamase-, plasmid-mediated AmpC-, and carbapenemase-producing Escherichia coli in a murine urinary tract infection model. Antimicrob. Agents Chemother., 2018, 62(6), 25.
[PMID: 29581117]
[9]
Frimodt-Møller, N. Correlation between pharmacokinetic/pharmacodynamic parameters and efficacy for antibiotics in the treatment of urinary tract infection. Int. J. Antimicrob. Agents, 2002, 19(6), 546-553.
[http://dx.doi.org/10.1016/S0924-8579(02)00105-X] [PMID: 12135846]
[10]
Monogue, M.L.; Nicolau, D.P. Translational efficacy of humanized exposures of cefepime, ertapenem, and levofloxacin against extended-spectrum-β-lactamase-producing Escherichia coli in a murine model of complicated urinary tract infection. Antimicrob. Agents Chemother., 2017, 61(11), e01329-e17.
[http://dx.doi.org/10.1128/AAC.01329-17] [PMID: 28848015]
[11]
Peterson, J.; Kaul, S.; Khashab, M.; Fisher, A.C.; Kahn, J.B. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology, 2008, 71(1), 17-22.
[http://dx.doi.org/10.1016/j.urology.2007.09.002] [PMID: 18242357]
[12]
Golan, Y. Empiric therapy for hospital-acquired, Gram-negative complicated intra-abdominal infection and complicated urinary tract infections: a systematic literature review of current and emerging treatment options. BMC Infect. Dis., 2015, 15, 313.
[http://dx.doi.org/10.1186/s12879-015-1054-1] [PMID: 26243291]
[13]
Theuretzbacher, U. Global antimicrobial resistance in Gram-negative pathogens and clinical need. Curr. Opin. Microbiol., 2017, 39, 106-112.
[http://dx.doi.org/10.1016/j.mib.2017.10.028] [PMID: 29154024]
[14]
Boucher, H.W.; Ambrose, P.G.; Chambers, H.F.; Ebright, R.H.; Jezek, A.; Murray, B.E.; Newland, J.G.; Ostrowsky, B.; Rex, J.H. Infectious Diseases Society of America. White Paper: Developing antimicrobial drugs for resistant pathogens, narrow-spectrum indications, and unmet needs. J. Infect. Dis., 2017, 216(2), 228-236.
[http://dx.doi.org/10.1093/infdis/jix211] [PMID: 28475768]
[15]
Andes, D.R.; Lepak, A.J. In vivo infection models in the pre-clinical pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Curr. Opin. Pharmacol., 2017, 36, 94-99.
[http://dx.doi.org/10.1016/j.coph.2017.09.004] [PMID: 28964956]
[16]
Rosen, D.A.; Hung, C.; Kline, K.A.; Hultgren, S.J. Streptozotocininduced diabetic mouse model of urinary tract infection. Infect. Immun., 2008, 76(9), 4290-4298.
[http://dx.doi.org/10.1128/IAI.00255-08] [PMID: 18644886]
[17]
Turnidge, J. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Drugs, 1999, 58(2)(Suppl. 2), 29-36.
[http://dx.doi.org/10.2165/00003495-199958002-00006] [PMID: 10553702]
[18]
Jayaraman, R.; Reniguntla, M.K.; Yedle, R.; Puttaswamy, R.; Puttarangappa, P.; Pawar, A.; Hiremath, S.; Nanjundappa, M. Pharmacokinetics/pharmacodynamics (PK/PD) of ciprofloxacin in the complicated urinary tract infection (cUTI) model in diabetic mice. American Society of Microbiology Microbe, 2019. Abstr AAR-776
[19]
Jayaraman, R. Pharmacokinetics/pharmacodynamics (PK/PD) of ciprofloxacin in the complicated urinary tract infection (cUTI) model in diabetic mice. Oral Abstract Presentation, Symposium: PK/PD for My FDA Package? What Do I Need? American Society of Microbiology Microbe, San Francisco. 2019.
[20]
Weinstein, M.P. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 9th Edition; CLSI: USA, 2012.
[21]
Langford, D.J.; Bailey, A.L.; Chanda, M.L.; Clarke, S.E.; Drummond, T.E.; Echols, S.; Glick, S.; Ingrao, J.; Klassen-Ross, T.; Lacroix-Fralish, M.L.; Matsumiya, L.; Sorge, R.E.; Sotocinal, S.G.; Tabaka, J.M.; Wong, D.; van den Maagdenberg, A.M.; Ferrari, M.D.; Craig, K.D.; Mogil, J.S. Coding of facial expressions of pain in the laboratory mouse. Nat. Methods, 2010, 7(6), 447-449.
[http://dx.doi.org/10.1038/nmeth.1455] [PMID: 20453868]
[22]
Jayaram, R.; Gaonkar, S.; Kaur, P.; Suresh, B.L.; Mahesh, B.N.; Jayashree, R.; Nandi, V.; Bharat, S.; Shandil, R.K.; Kantharaj, E.; Balasubramanian, V. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob. Agents Chemother., 2003, 47(7), 2118-2124.
[http://dx.doi.org/10.1128/AAC.47.7.2118-2124.2003] [PMID: 12821456]
[23]
Gabrielsson, J.; Green, A.R. Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J. Pharmacol. Exp. Ther., 2009, 331(3), 767-774.
[http://dx.doi.org/10.1124/jpet.109.157172] [PMID: 19779129]
[24]
Hvidberg, H.; Struve, C.; Krogfelt, K.A.; Christensen, N.; Rasmussen, S.N.; Frimodt-Møller, N. Development of a long-term ascending urinary tract infection mouse model for antibiotic treatment studies. Antimicrob. Agents Chemother., 2000, 44(1), 156-163.
[http://dx.doi.org/10.1128/AAC.44.1.156-163.2000] [PMID: 10602738]
[25]
Shandil, R.K.; Jayaram, R.; Kaur, P.; Gaonkar, S.; Suresh, B.L.; Mahesh, B.N.; Jayashree, R.; Nandi, V.; Bharath, S.; Balasubramanian, V. Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy. Antimicrob. Agents Chemother., 2007, 51(2), 576-582.
[http://dx.doi.org/10.1128/AAC.00414-06] [PMID: 17145798]
[26]
Vanwert, A.L.; Srimaroeng, C.; Sweet, D.H. Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol. Pharmacol., 2008, 74(1), 122-131.
[http://dx.doi.org/10.1124/mol.107.042853] [PMID: 18381565]
[27]
Schentag, J.J.; Meagher, A.K.; Forrest, A. Fluoroquinolone AUIC break points and the link to bacterial killing rates. Part 1: In vitro and animal models. Ann. Pharmacother., 2003, 37(9), 1287-1298.
[http://dx.doi.org/10.1345/aph.1C199] [PMID: 12921513]

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