- Email: [email protected]
The anti-inflammatory activity of telithromycin in a mouse model of septic shock
364
Letters to the Editor / International Journal of Antimicrobial Agents 29 (2007) 356–365
CTX-M-12 was first detected from K. pneumoniae isolates from an outbreak among six newborn babies in Kenya in 2001 [5]. Then, the ESBL was also detected from a clinical isolate of K. pneumoniae from Colombia [6]. Recently, we have described three clinical isolates of E. coli from Korea that produce CTX-M-12 [7]. It is interesting that CTX-M12 has emerged in Korea, which is geographically distanced from Africa and South America. Insofar as there are limited data on the plasmid context of blaCTX-M-12 , it is equally probable that it has evolved independently (by new gene escape or mutation of other blaCTX-M genes) in Kenya, Colombia and Korea.
Acknowledgments This work was supported by a research grant from the Korea Food and Drug Administration. We thank E.-C. Kim (Seoul National University), Y.J. Park (The Catholic University of Korea), J.O. Kang (Hanyang University), S.G. Hong (Pochon CHA University), W.G. Lee (Ajou University), Y. Uh (Yonsei University). J. Lee (Konyang University), J.Y. Ahn (Soonchunhyang University), J.H. Shin (Chonnam University) and S.-H. Lee (Hanmaeum General Hospital) for providing the clinical isolates of K. pneumoniae. References [1] Ryoo NH, Kim E-C, Hong SG, et al. Dissemination of SHV-12 and CTX-M-type extended-spectrum -lactamases among clinical isolates of Escherichia coli and Klebsiella pneumoniae and emergence of GES-3 in Korea. J Antimicrob Chemother 2005;56:698–702. [2] Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 7th edn. Approved standard M7-A7. Wayne, PA: CLSI; 2006. [3] Bae IK, Lee BH, Hwang HY, et al. A novel ceftazidime-hydrolysing extended-spectrum -lactamase CTX-M-54 with a single amino acid substitution at position 167 in the omega loop. J Antimicrob Chemother 2006;58:315–9. [4] Poirel L, Lartique MF, Decousser JW, Nordmann P. ISEcp1B-mediated transposition of blaCTX-M in Escherichia coli. Antimicrob Agents Chemother 2005;49:447–50. [5] Kariuki S, Corkill JE, Revathi G, Musoke R, Hart CA. Molecular characterization of a novel plasmid-encoded cefotaximase (CTX-M-12) found in clinical Klebsiella pneumoniae isolates from Kenya. Antimicrob Agents Chemother 2001;45:2141–3. [6] Villegas MV, Correa A, Perez F, et al. CTX-M-12 -lactamase in a Klebsiella pneumoniae clinical isolate in Colombia. Antimicrob Agents Chemother 2004;48:629–31. [7] Bae IK, Lee Y-N, Hwang HY, et al. Emergence of CTX-M-12 extended-spectrum -lactamase-producing Escherichia coli in Korea. J Antimicrob Chemother 2006;58:1257–9.
Il Kwon Bae You-Nae Lee Seok Hoon Jeong ∗ Department of Laboratory Medicine, Kosin University College of Medicine, 602-030, 34 Amnam-Dong, Suh-Gu, Busan, South Korea
Kyungwon Lee Department of Laboratory Medicine, Yonsei University College of Medicine, 120-752, 134 Sin Chon-Dong Seodaemun-Gu, Seoul, South Korea Hyukmin Lee Department of Laboratory Medicine, Kwandong University College of Medicine, 412-270, 697-24 Hwajeong-Dong Deogyang-Gu, Goyang, Gyeonggi-Do, South Korea Hyo-Sun Kwak Gun-Jo Woo Center for Food Safety Evaluation, Korea Food and Drug Administration, 122-704, 231 Jinheung-Ro, Eunpyung-Gu, Seoul, South Korea ∗ Corresponding
author. Tel.: +82 51 990 6373; fax: +82 51 990 3034. E-mail address: [email protected] (S.H. Jeong) 25 September 2006
doi: 10.1016/j.ijantimicag.2006.10.009
The anti-inflammatory activity of telithromycin in a mouse model of septic shock Sir, The injection of mice with a lethal dose of lipopolysaccharide (LPS) provides an experimental model of septic shock [1] that has been used to assess the anti-inflammatory properties of a number of antimicrobial agents, such as tetracyclines [2], clindamycin [3], and fluoroquinolones [4]. Ketolides are a new group of macrolide-like antibiotics that accumulate within mammalian cells [5]. Telithromycin, a ketolide antibiotic, is able to inhibit in vitro secretion of inflammatory cytokines by LPS- or Shiga toxin-stimulated human monocytes [6,7]. We have tested the ability of telithromycin to reduce mortality and to modulate cytokine and nitric oxide production in a murine model of LPS-induced shock. Female BALB/c mice were injected intraperitoneally with a single dose of 25 mg or 50 mg of LPS from Escherichia coli O26:B6 (Sigma Chemical Co., St. Louis, MO) per kg of body weight. To investigate the efectiveness of telithromycin (a gift from Aventis Pharma, Neuville-sur-Saonc, France), mice received a single dose of 20 mg of antibiotic per kg of body weight by intraperitoneal injection, 1 h prior to the injection of LPS. Control mice received LPS alone or telithromycin alone. Doses of 50 mg/kg always resulted in 100% mortality, but telithromycin protected 50% of animals. When mice were challenged with the low dose of LPS, 37.5% of mice survived but telithromycin increased the survival rate to 87.5% (P < 0.05 for each comparison by the Kaplan-Meier rank test). In separate experiments, tumor necrosis factor alpha (TNF-␣), interleukin-1 beta (IL-1) and IL-10 plasma levels were measured with commercial enzyme immunoassay kits
Letters to the Editor / International Journal of Antimicrobial Agents 29 (2007) 356–365
365
pathologic mechanisms of septic shock, we measured the plasma levels of nitrite, a stable metabolite of nitric oxide. Both LPS doses induced nitrite levels that were greater than seven-fold the basal concentrations, but pretreatment with telithromycin significantly inhibited this LPS effect (P < 0.01 for measures at 8 h after 25 mg/kg of LPS, and <0.05 for the rest of determinations). Our data show that telithromycin is able to prevent LPSinduced lethality in mice through downregulation of IL-1 and TNF-␣, as it has been suggested in the case of other immunomodulatory antimicrobial agents [3,4]. Also, the inhibition of proinflammatory cytokines by telithromycin correlated with significant decreases in nitric oxide production. A similar finding has been observed in LPS-treated mice after treatment with tetracyclines [2]. In conclusion, the antibacterial activity of telithromycin is associated with interesting anti-inflammatory effects.
References
Fig. 1. Effects of telithromycin and LPS on plasma levels of IL-1 (A), TNF␣ (B) and IL-10 (C). Mice were treated by i.p. route with saline (), 20 mg of telithromycin per kg (), 25 mg of LPS per kg ( ), telithromycin 1 h before 25 mg of LPS per kg ( ), 50 mg of LPS per kg ( ) and telithromycin 1 h before 50 mg of LPS per kg ( ). Results are mean ± standard deviation of three mice. * P < 0.05 vs. LPS alone (Student’s t test).
(Pierce Endogen, Rockford, IL), and differences were analyzed by using Student’s t test. A P value of less than 0.05 was considered significant. Mice pretreated with telithromycin had significantly lower levels of IL-1 and TNF-␣ than nonpretreated mice at 8 h and 2 h after the administration of 50 mg of LPS/kg, respectively (Fig. 1A and B), but pretreatment with telithromycin resulted in significant increases in the levels of IL-10 at both 2 h and 8 h after LPS injection (50 mg/kg) (Fig. 1C). Since the increased expression of the inducible nitric oxide synthase (iNOS) isoform is associated with the
[1] Stenger S, Modlin R. Pathology and pathogenesis of bacterial infections. In: Kaufmann SHE, Sher A, Ahmed R, editors. Immunology of infectious diseases. Washington: ASM Press; 2002. [2] Milano S, Arcoleo F, D’Agostino P, et al. Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood. Antimicrob Agents Chemother 1997;41:117– 21. [3] Hirata N, Hiramatsu K, Kishi K, et al. Pretreatment of mice with clindamycin improves survival of endotoxic shock by modulating the release of inflammatory cytokines. Antimicrob Agents Chemother 2001;45:2638–42. [4] Khan AA, Slifer TR, Araujo FG, et al. Protection against lipopolysaccharide-induced death by fluoroquinolones. Antimicrob Agents Chemother 2000;44:3169–73. [5] Zhanel GG, Walters M, Noreddin A, et al. The ketolides: a critical review. Drug 2002;62:1771–804. [6] Araujo FG, Slifer TL, Remington J. Inhibition of secretion of interleukin-1␣ and tumor necrosis factor alpha by the ketolide antibiotic telithromycin. Antimicrob Agents Chemother 2002;46:3327–30. [7] Nakagawa S, Kojio S, Taneike I, et al. Inhibitory action of telithromycin against Shiga toxin and endotoxin. Biochem Biophys Res Commun 2003;310:1194–9.
Magdalena Leiva Alfonso Ruiz-Bravo ∗ Encarnaci´on Moreno Maria Jimenez-Valera Department of Microbiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain ∗ Corresponding
author. Tel.: +34 958 243872; fax: +34 958 246235. E-mail addresses: [email protected] (A. Ruiz-Bravo), [email protected] (M. Jimenez-Valera) 14 July 2006 doi: 10.1016/j.ijantimicag.2006.10.010
Letters to the Editor / International Journal of Antimicrobial Agents 29 (2007) 356–365
CTX-M-12 was first detected from K. pneumoniae isolates from an outbreak among six newborn babies in Kenya in 2001 [5]. Then, the ESBL was also detected from a clinical isolate of K. pneumoniae from Colombia [6]. Recently, we have described three clinical isolates of E. coli from Korea that produce CTX-M-12 [7]. It is interesting that CTX-M12 has emerged in Korea, which is geographically distanced from Africa and South America. Insofar as there are limited data on the plasmid context of blaCTX-M-12 , it is equally probable that it has evolved independently (by new gene escape or mutation of other blaCTX-M genes) in Kenya, Colombia and Korea.
Acknowledgments This work was supported by a research grant from the Korea Food and Drug Administration. We thank E.-C. Kim (Seoul National University), Y.J. Park (The Catholic University of Korea), J.O. Kang (Hanyang University), S.G. Hong (Pochon CHA University), W.G. Lee (Ajou University), Y. Uh (Yonsei University). J. Lee (Konyang University), J.Y. Ahn (Soonchunhyang University), J.H. Shin (Chonnam University) and S.-H. Lee (Hanmaeum General Hospital) for providing the clinical isolates of K. pneumoniae. References [1] Ryoo NH, Kim E-C, Hong SG, et al. Dissemination of SHV-12 and CTX-M-type extended-spectrum -lactamases among clinical isolates of Escherichia coli and Klebsiella pneumoniae and emergence of GES-3 in Korea. J Antimicrob Chemother 2005;56:698–702. [2] Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 7th edn. Approved standard M7-A7. Wayne, PA: CLSI; 2006. [3] Bae IK, Lee BH, Hwang HY, et al. A novel ceftazidime-hydrolysing extended-spectrum -lactamase CTX-M-54 with a single amino acid substitution at position 167 in the omega loop. J Antimicrob Chemother 2006;58:315–9. [4] Poirel L, Lartique MF, Decousser JW, Nordmann P. ISEcp1B-mediated transposition of blaCTX-M in Escherichia coli. Antimicrob Agents Chemother 2005;49:447–50. [5] Kariuki S, Corkill JE, Revathi G, Musoke R, Hart CA. Molecular characterization of a novel plasmid-encoded cefotaximase (CTX-M-12) found in clinical Klebsiella pneumoniae isolates from Kenya. Antimicrob Agents Chemother 2001;45:2141–3. [6] Villegas MV, Correa A, Perez F, et al. CTX-M-12 -lactamase in a Klebsiella pneumoniae clinical isolate in Colombia. Antimicrob Agents Chemother 2004;48:629–31. [7] Bae IK, Lee Y-N, Hwang HY, et al. Emergence of CTX-M-12 extended-spectrum -lactamase-producing Escherichia coli in Korea. J Antimicrob Chemother 2006;58:1257–9.
Il Kwon Bae You-Nae Lee Seok Hoon Jeong ∗ Department of Laboratory Medicine, Kosin University College of Medicine, 602-030, 34 Amnam-Dong, Suh-Gu, Busan, South Korea
Kyungwon Lee Department of Laboratory Medicine, Yonsei University College of Medicine, 120-752, 134 Sin Chon-Dong Seodaemun-Gu, Seoul, South Korea Hyukmin Lee Department of Laboratory Medicine, Kwandong University College of Medicine, 412-270, 697-24 Hwajeong-Dong Deogyang-Gu, Goyang, Gyeonggi-Do, South Korea Hyo-Sun Kwak Gun-Jo Woo Center for Food Safety Evaluation, Korea Food and Drug Administration, 122-704, 231 Jinheung-Ro, Eunpyung-Gu, Seoul, South Korea ∗ Corresponding
author. Tel.: +82 51 990 6373; fax: +82 51 990 3034. E-mail address: [email protected] (S.H. Jeong) 25 September 2006
doi: 10.1016/j.ijantimicag.2006.10.009
The anti-inflammatory activity of telithromycin in a mouse model of septic shock Sir, The injection of mice with a lethal dose of lipopolysaccharide (LPS) provides an experimental model of septic shock [1] that has been used to assess the anti-inflammatory properties of a number of antimicrobial agents, such as tetracyclines [2], clindamycin [3], and fluoroquinolones [4]. Ketolides are a new group of macrolide-like antibiotics that accumulate within mammalian cells [5]. Telithromycin, a ketolide antibiotic, is able to inhibit in vitro secretion of inflammatory cytokines by LPS- or Shiga toxin-stimulated human monocytes [6,7]. We have tested the ability of telithromycin to reduce mortality and to modulate cytokine and nitric oxide production in a murine model of LPS-induced shock. Female BALB/c mice were injected intraperitoneally with a single dose of 25 mg or 50 mg of LPS from Escherichia coli O26:B6 (Sigma Chemical Co., St. Louis, MO) per kg of body weight. To investigate the efectiveness of telithromycin (a gift from Aventis Pharma, Neuville-sur-Saonc, France), mice received a single dose of 20 mg of antibiotic per kg of body weight by intraperitoneal injection, 1 h prior to the injection of LPS. Control mice received LPS alone or telithromycin alone. Doses of 50 mg/kg always resulted in 100% mortality, but telithromycin protected 50% of animals. When mice were challenged with the low dose of LPS, 37.5% of mice survived but telithromycin increased the survival rate to 87.5% (P < 0.05 for each comparison by the Kaplan-Meier rank test). In separate experiments, tumor necrosis factor alpha (TNF-␣), interleukin-1 beta (IL-1) and IL-10 plasma levels were measured with commercial enzyme immunoassay kits
Letters to the Editor / International Journal of Antimicrobial Agents 29 (2007) 356–365
365
pathologic mechanisms of septic shock, we measured the plasma levels of nitrite, a stable metabolite of nitric oxide. Both LPS doses induced nitrite levels that were greater than seven-fold the basal concentrations, but pretreatment with telithromycin significantly inhibited this LPS effect (P < 0.01 for measures at 8 h after 25 mg/kg of LPS, and <0.05 for the rest of determinations). Our data show that telithromycin is able to prevent LPSinduced lethality in mice through downregulation of IL-1 and TNF-␣, as it has been suggested in the case of other immunomodulatory antimicrobial agents [3,4]. Also, the inhibition of proinflammatory cytokines by telithromycin correlated with significant decreases in nitric oxide production. A similar finding has been observed in LPS-treated mice after treatment with tetracyclines [2]. In conclusion, the antibacterial activity of telithromycin is associated with interesting anti-inflammatory effects.
References
Fig. 1. Effects of telithromycin and LPS on plasma levels of IL-1 (A), TNF␣ (B) and IL-10 (C). Mice were treated by i.p. route with saline (), 20 mg of telithromycin per kg (), 25 mg of LPS per kg ( ), telithromycin 1 h before 25 mg of LPS per kg ( ), 50 mg of LPS per kg ( ) and telithromycin 1 h before 50 mg of LPS per kg ( ). Results are mean ± standard deviation of three mice. * P < 0.05 vs. LPS alone (Student’s t test).
(Pierce Endogen, Rockford, IL), and differences were analyzed by using Student’s t test. A P value of less than 0.05 was considered significant. Mice pretreated with telithromycin had significantly lower levels of IL-1 and TNF-␣ than nonpretreated mice at 8 h and 2 h after the administration of 50 mg of LPS/kg, respectively (Fig. 1A and B), but pretreatment with telithromycin resulted in significant increases in the levels of IL-10 at both 2 h and 8 h after LPS injection (50 mg/kg) (Fig. 1C). Since the increased expression of the inducible nitric oxide synthase (iNOS) isoform is associated with the
[1] Stenger S, Modlin R. Pathology and pathogenesis of bacterial infections. In: Kaufmann SHE, Sher A, Ahmed R, editors. Immunology of infectious diseases. Washington: ASM Press; 2002. [2] Milano S, Arcoleo F, D’Agostino P, et al. Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood. Antimicrob Agents Chemother 1997;41:117– 21. [3] Hirata N, Hiramatsu K, Kishi K, et al. Pretreatment of mice with clindamycin improves survival of endotoxic shock by modulating the release of inflammatory cytokines. Antimicrob Agents Chemother 2001;45:2638–42. [4] Khan AA, Slifer TR, Araujo FG, et al. Protection against lipopolysaccharide-induced death by fluoroquinolones. Antimicrob Agents Chemother 2000;44:3169–73. [5] Zhanel GG, Walters M, Noreddin A, et al. The ketolides: a critical review. Drug 2002;62:1771–804. [6] Araujo FG, Slifer TL, Remington J. Inhibition of secretion of interleukin-1␣ and tumor necrosis factor alpha by the ketolide antibiotic telithromycin. Antimicrob Agents Chemother 2002;46:3327–30. [7] Nakagawa S, Kojio S, Taneike I, et al. Inhibitory action of telithromycin against Shiga toxin and endotoxin. Biochem Biophys Res Commun 2003;310:1194–9.
Magdalena Leiva Alfonso Ruiz-Bravo ∗ Encarnaci´on Moreno Maria Jimenez-Valera Department of Microbiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain ∗ Corresponding
author. Tel.: +34 958 243872; fax: +34 958 246235. E-mail addresses: [email protected] (A. Ruiz-Bravo), [email protected] (M. Jimenez-Valera) 14 July 2006 doi: 10.1016/j.ijantimicag.2006.10.010