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Antimicrobial Agents and Chemotherapy, January 2004, p. 93-99, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.93-99.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant Pseudomonas aeruginosa

Evangelos J. Giamarellos-Bourboulis,1* Theodoros Adamis,2 George Laoutaris,1 Lambros Sabracos,2 Vassilios Koussoulas,1 Maria Mouktaroudi,1 Despina Perrea,2 Panayotis E. Karayannacos,3 and Helen Giamarellou1

4th Department of Internal Medicine,1 Laboratory of Experimental Surgery and Surgical Research, University of Athens Medical School,2 Center of Experimental Surgery, Foundation of Biomedical Research, Academy of Athens, Athens, Greece3

Received 2 June 2003/ Returned for modification 7 July 2003/ Accepted 8 October 2003

Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa. Acute pyelonephritis was induced after ligation of the right ureter and injection of 108 CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000 Limulus amoebocyte lysate assay, tumor necrosis factor alpha (TNF-{alpha}) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (P = 0.033 for group D versus group F, P = 0.006 for group D versus group E, P = not significant for group B versus group E, P = 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-{alpha} and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant P. aeruginosa was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.

* Corresponding author. Mailing address: 4th Department of Internal Medicine, "Attikon" University General Hospital, Athens 124 64, Greece. Phone: (30210) 58 31 000. Fax: (30210) 53 26 426. E-mail: giamarel{at}internet.gr.

Antimicrobial Agents and Chemotherapy, January 2004, p. 93-99, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.93-99.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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