Efficacy of Lysophosphatidylcholine in Combination With Antimicrobial Agents Against Acinetobacter Baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Antimicrob Agents Chemother. 2016 Jul 22;60(8):4464-70. doi: 10.1128/AAC.02708-15. Print 2016 Aug.

Abstract

Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 μg/ml versus 3 μg/ml [P < 0.05] and 2 μg/ml versus 3.4 μg/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

MeSH terms

  • Acinetobacter baumannii / drug effects*
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use*
  • Colistin / pharmacology
  • Colistin / therapeutic use
  • Enzyme-Linked Immunosorbent Assay
  • Imipenem / pharmacology
  • Imipenem / therapeutic use
  • Interleukin-10 / metabolism
  • Lysophosphatidylcholines / pharmacology*
  • Lysophosphatidylcholines / therapeutic use*
  • Mice
  • Microbial Sensitivity Tests
  • Minocycline / analogs & derivatives
  • Minocycline / pharmacology
  • Minocycline / therapeutic use
  • Pneumonia / drug therapy*
  • Pneumonia / microbiology
  • Sepsis / drug therapy*
  • Sepsis / microbiology
  • Tigecycline
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Bacterial Agents
  • Lysophosphatidylcholines
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Tigecycline
  • Imipenem
  • Minocycline
  • Colistin