Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

Abstract

bImmune 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 (MLD 100 ) 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 MLD 100 in murine peritoneal sepsis and pneumonia models. The levels of pro-and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-␣) 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-␣ and lower IL-10 levels than those with Ab186 (4 g/ml versus 3 g/ml [P < 0.05] and 2 g/ml versus 3.4 g/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.A cinetobacter baumannii is a Gram-negative coccobacillus with high clinical relevance due to the different severe nosocomial infections that it causes, mainly in intensive care units, and its capacity to develop resistance to most of the antimicrobial agents used in clinical practice (1).A multidrug resistance pattern is commonly observed for A. baumannii isolates, raising the threat of impossible-to-treat infections (2). These multidrug-resistant (MDR) isolates are generally susceptible to polymyxins (colistin and polymyxin B) and resistant to imipenem and tigecycline (3, 4). The limited antimicrobial alternatives for the treatment of severe infections by MDR A. baumannii make the search for other therapeutic options urgent. Polymyxins have been used as a last resort to treat infections by MDR A. baumannii. In humans, suboptimal and optimal doses of colistin to treat ventilator-associated pneumonia due to MDR A. baumannii prevent mortality in only 38.1% and 62.5% of cases, respectively (5, 6). Recently, in a clinical trial at our hospital, treatm...

Immune Response Resetting in Ongoing Sepsis

“…These findings are reminiscent of data reported by others on surviving sepsis patients treated with antimicrobial drugs (89)(90)(91). Also, there is some experimental evidence elsewhere that LPC has immune modulatory and host protection properties that have been tested therapeutically in preclinical models with modest results (123)(124)(125). The latter references support the interpretation that the plasma LPC upregulation that we have observed in surviving mice may have had an active mechanistic role in rescuing animals from sepsis, but this assumption remains to be tested in future studies.…”

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

“…Reference A. baumannii ATCC 17978 (45), P. aeruginosa PAO1 (46) and E. coli ATCC 25922 (47) strains were used. We also used 2 clinical susceptible (Ab9) and multidrug-resistant (MDR) (Ab186) A. baumannii from REIPI-GEIH 2010 collection (5), 2 clinical susceptible (Pa39) and MDR (Pa238) P. aeruginosa from REIPI-GEIH 2008 collection (48), and 2 clinical susceptible (C1-7-LE) and MDR (EcMCR + , carrying mcr-1 gene) E. coli (49, 50). We also used a collection of A. baumannii and E. coli clinical strains from REIPI-GEIH 2010 collection and Bact-OmpA collection (51, 52).…”

“…Two key approaches can help alleviate the problem of antibiotic resistance, firstly targeting of bacterial virulence factors without inhibiting bacterial growth, which can slow the development of drug resistance by reducing the selective pressure on the bacteria (1, 2) and, secondly, by the modulation/regulation of the immune system response to improve the infection development (3, 4). In this way, some studies were focused on the stimulation of the immune system to treat bacterial infections using molecules, including lysophosphatidylcoline as monotherapy and as adjuvant for the antimicrobial treatment (3, 5, 6) or 3’-5’-cyclic diguanylic acid (c-di-GMP) which increase neutrophils protecting against A. baumannii infection (7).…”

Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

“…The screening of the best LN-1-255 dosage was performed using reduced (n ϭ 4 to 6) groups of mice in assays by duplicate. The optimum imipenem dose was 30 mg/kg, intramuscularly, a dosage previously described as effective against A. baumannii in experimental pneumonia models (20,21,37).…”