Efficacy of Lysophosphatidylcholine as Direct Treatment in Combination with Colistin against Acinetobacter baumannii in Murine Severe Infections Models
by
and
Andrea Miró-Canturri
1,2,†, 
Rafael Ayerbe-Algaba
1,2,†,
Manuel Enrique Jiménez-Mejías
1,2,*,
Jerónimo Pachón
2,3 and
Younes Smani
1,2,* 1
Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, 41013 Seville, Spain
2
Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, CSIC, University of Seville, 41013 Seville, Spain
3
Department of Medicine, University of Seville, 41009 Seville, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Antibiotics 2021, 10(2), 194; https://doi.org/10.3390/antibiotics10020194
Submission received: 18 January 2021
/
Revised: 10 February 2021
/
Accepted: 13 February 2021
/
Published: 17 February 2021
(This article belongs to the Special Issue Non-antimicrobial Agents as Adjuvants against Bacterial Infections)
Abstract
:The stimulation of the immune response to prevent the progression of an infection may be an adjuvant to antimicrobial treatment. Here, we aimed to evaluate the efficacy of lysophosphatidylcholine (LPC) treatment in combination with colistin in murine experimental models of severe infections by Acinetobacter baumannii. We used the A. baumannii Ab9 strain, susceptible to colistin and most of the antibiotics used in clinical settings, and the A. baumannii Ab186 strain, susceptible to colistin but presenting a multidrug-resistant (MDR) pattern. The therapeutic efficacies of one and two LPC doses (25 mg/kg/d) and colistin (20 mg/kg/8 h), alone or in combination, were assessed against Ab9 and Ab186 in murine peritoneal sepsis and pneumonia models. One and two LPC doses combined with colistin and colistin monotherapy enhanced Ab9 and Ab186 clearance from spleen, lungs and blood and reduced mice mortality compared with those of the non-treated mice group in both experimental models. Moreover, one and two LPC doses reduced the bacterial concentration in tissues and blood in both models and increased mice survival in the peritoneal sepsis model for both strains compared with those of the colistin monotherapy group. LPC used as an adjuvant of colistin treatment may be helpful to reduce the severity and the resolution of the MDR A. baumannii infection.
1. Introduction
Acinetobacter baumannii is a Gram-negative bacterium with high clinical relevance owing to the increase in the number of nosocomial infections caused by this pathogen, as well as its ability to develop resistance to most antimicrobial agents used by physicians [1]. Treatment of A. baumannii infections, especially those caused by multidrug-resistant (MDR) strains, is a major concern. In many areas of the world that have a high prevalence of MDR A. baumannii, few options of treatment are present, and last resort treatments such as colistin are no longer effective in an increasing number of cases, leading to a 28-day mortality of 43% in hospitalized patients with bacteremia, ventilator-associated or hospital acquired pneumonia, or urosepsis [2]. The number of antibiotics approved by the Food and Drug Administration (FDA) cannot keep pace with the resistance mechanisms acquired by A. baumannii. Therefore, the development of new strategic antimicrobial therapeutic approaches, like the use of non-antibiotics in combination with one of the scarce but clinically relevant antibiotics, has become an urgent need.
A therapeutic alternative for the treatment of infections by MDR A. baumannii is immune system modulation to improve the infection clearance. We previously demonstrated the efficacy of lysophosphatidylcholine (LPC), a phospholipid involved in the recruitment and stimulation of immune cells [3,4,5,6], as a preemptive treatment in murine peritoneal sepsis and pneumonia experimental models by susceptible and MDR A. baumannii strains [7]. Of note, LPC preemptive treatment in combination with colistin, tigecycline or imipenem has improved the in vivo antibacterial activity of these antimicrobials in murine experimental peritoneal sepsis and pneumonia by drug-susceptible and MDR A. baumannii [8]. In the same line, preemptive LPC treatment in combination with ceftazidime has potentiated the in vivo antibacterial activity of ceftazidime in these severe infection models by MDR Pseudomonas aeruginosa [9]. Recently, Yadav et al. reported that LPC in vitro potentiated the effect of a nonbactericidal concentration of polymexin B against the growth of Pseudomonas aeruginosa and Klebsiella pneumoniae [10]. They found that a combination of LPC with polymexin B made pores in the bacterial membrane and caused the degradation of DnaK, the regulator of protein folding [10].
Currently, there are no data regarding the efficacy of the direct treatment with LPC in combination with colistin after infection by MDR A. baumannii, and whether this combined treatment can equalize or improve the preemptive LPC treatment in combination with colistin against MDR A. baumannii. Therefore, the aim of this study was to evaluate the efficacy of the direct treatment with LPC in combination with colistin in murine experimental models of peritoneal sepsis and pneumonia by drug-susceptible and MDR clinical isolates of A. baumannii.
2. Materials and Methods
2.1. Bacterial Strains
Drug-susceptible A. baumannii (Ab9) and MDR A. baumannii (Ab186) (resistant to imipenem, tigecycline, ciprofloxacin and ceftazidime) clinical strains were used in this study [8]. Both strains were susceptible to colistin with an MIC of 0.5 mg/L. The MIC of LPC against both strains was >8.000 mg/L [8]. Ab9 was recovered from surgical wound exudates, and Ab186 was recovered from blood cultures; the strains belong to ST297 and ST2 (international clone II), respectively [8,11].
2.2. Antimicrobial Agents and Reagents
A clinical formulation of colistin methanesulfonate (Promixin®, Bresso, Italia) was used. The anesthetic was 2:1 Ketamine hydrochloride® (Pfizer, Madrid, Spain):Diazepam ® (Roche, Madrid, Spain).
2.3. Animals
One hundred and seventy-five immunocompetent C57BL7/6 female mice weighing 18–20 g (Production and Experimentation Animal Center, University of Seville, Seville, Spain) were used. Animals were housed in regulation boxes and given free access to food and water. This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals [12]. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University Hospital of Virgen del Rocío of Seville, Spain (approval 1556-N-16).
2.4. Experimental Murine Model of Peritoneal Sepsis
A previously characterized murine model of peritoneal sepsis caused by A. baumannii was used [8]. Briefly, animals were inoculated intraperitoneally (i.p.) with 0.5 mL of the 100% minimal lethal dose (MLD100) of Ab9 (5.9 log10 CFU/mL) or Ab186 (5 log10 CFU/mL), mixed 1:1 with 10% porcine mucin (Sigma, Madrid, Spain). LPC (Sigma, Madrid, Spain) and colistin treatments were administered 4 h after bacterial inoculation. Groups of mice were randomly ascribed to the following groups: (i) control (without treatment), (ii) LPC administered once i.p. at 25 mg/kg 4 h [7] after bacterial inoculation, (iii) colistin administered i.p. at 20 mg/kg/8 h for 72 h [8], (iv) the combination of colistin at 20 mg/kg/8 h with one dose of LPC at 25 mg/kg/d and (v) the combination of colistin at 20 mg/kg/8 h with two doses of LPC at 25 mg/kg/d (first and second at 4 and 28 h, respectively, after bacterial infection).
Mortality was recorded over 72 h. After the death or the euthanization of the mice by sodium thiopental (Zambon S.p.A., Vicenza, Italy) at the end of the experimental period, aseptic thoracotomies were performed, and blood samples were obtained by cardiac puncture. Spleens and lungs were aseptically removed and homogenized (Stomacher 80®; Tekman Co., London, UK) in 2 mL of sterile 0.9% NaCl solution. Tenfold dilution of the homogenized spleen and lungs and blood obtained by cardiac puncture were plated onto sheep agar for the quantitative cultures (to determine the log10 CFU/g of spleen and lungs and log10 CFU/mL of blood).
2.5. Experimental Murine Model of Pneumonia
A previously described experimental murine pneumonia model was used to evaluate the efficacy of LPC as monotherapy and in combination with colistin against Ab9 and Ab186 strains [8]. Briefly, the mice were anesthetized by 2:1 Ketamine hydrochloride:Diazepam, suspended vertically, and the trachea of each was then cannulated with a blunt-tipped metal needle. The feel of the needle tip against the tracheal cartilage confirmed the intratracheal location. A microliter syringe (Hamilton Co., Reno, NV, USA) was used for the inoculation of 50 µL of bacterial suspension (10 and 9 log10 CFU/mL for Ab9 and Ab186 strains, respectively), which had been grown for 24 h in LB broth at 37 °C and mixed at a 1:1 ratio with 0.9% NaCl solution containing 10% (wt/vol) porcine mucin. The mice remained in a vertical position for 3 min and then in a 30° position until they awakened. Treatment groups were similar to those used for the experimental model of peritoneal sepsis. After death or sacrifice of the mice at the end of the experimental period, aseptic thoracotomies were performed, blood was obtained by cardiac puncture and lungs were aseptically removed and homogenized. Quantitative data were obtained as described above to determine the log10 CFU/g of lungs and log10 CFU/mL of blood, and mice mortality was recorded over 72 h.
2.6. Statistical Analysis
Group data are presented as means ± standard errors of the means (SEM). Differences in the bacterial spleen, lung and blood concentrations (mean ± SEM log CFU per gram of tissue or per mL of blood) were assessed by analysis of variance (ANOVA) and the post hoc Dunnett test. Differences in mortality (%) and blood sterility (%) between groups were compared by the χ2 test. p values of <0.05 were considered significant. The SPSS (version 23.0; SPSS Inc., Armonk, NY, USA) statistical package was used.
3. Results
3.1. Efficacy of LPC in Combination with Colistin in a Murine Experimental Model of Peritoneal Sepsis
The efficacies of colistin and LPC in monotherapies and in combination against Ab9 and Ab186, expressed as survival and bacterial concentrations in spleen, lungs and blood, are shown in Table 1 and Table 2.
(i) Survival. Table 1 and Table 2 show that colistin alone and in combination with one and two doses of LPC increased mice survival compared with that of the control group for Ab9 and Ab186 (p < 0.05). In contrast, LPC in monotherapy did not reduce mice mortality.
(ii) Bacterial clearance from spleen, lungs and blood. Table 1 and Table 2 show that monotherapy with colistin cleared Ab9 and Ab186 from the spleen, lungs and blood by 5.07 and 5.68 log10 CFU/g and 5.33 log10 CFU/mL (p < 0.05; Ab9), respectively, and 6.93 and 6.73 CFU/g and 6.7 log10 CFU/mL (p < 0.05; Ab186), respectively, compared with the levels of the control group. One dose of LPC in combination with colistin decreased spleen, lung and blood concentrations of Ab9 and Ab186 by 5.57 and 6.02 log10 CFU/g and 5.67 log10 CFU/mL (p < 0.05; Ab9), respectively, and 8.21 and 8.2 log10 CFU/g and 8.67 log10 CFU/mL (p < 0.05; Ab186), respectively, compared with the levels for the control group. In addition, the increase of the dose of LPC slightly increased the bacterial clearance. Two doses of LPC in combination with colistin reduced the bacterial burden in the spleen, lungs and blood by 6.13 and 6.72 log10 CFU/g and 6.74 log10 CFU/mL (p < 0.05; Ab9), respectively, and 9.57 and 8.88 log10 CFU/g and 8.81 CFU/mL (p < 0.05; Ab186), respectively, compared with the levels for the control group. Of note, one dose of LPC in combination with colistin decreased spleen, lung and blood concentrations of Ab9 and Ab186 by 5.84 and 5.86 log10 CFU/g and 6.28 log10 CFU/mL, respectively (p < 0.05; Ab9), and 8.9 and 8.6 log10 CFU/g and 9.07 log10 CFU/mL (p < 0.05; Ab186), respectively, compared with the levels for the LPC monotherapy group. Finally, two doses of LPC in combination with colistin decreased spleen, lung and blood concentrations for Ab9 and Ab186 by 6.4 and 6.56 log10 CFU/g and 6.74 log10 CFU/mL (p < 0.05; Ab9), respectively, and 10.26 and 9.28 log10 CFU/mL and 9.21 log10 CFU/mL (p < 0.05; Ab186), respectively, when compared with the levels for the LPC monotherapy.
3.2. The Efficacy of LPC in Combination with Colistin in a Murine Experimental Model of Pneumonia
The efficacies of colistin and LPC in monotherapies and in combination against Ab9 and Ab186, expressed as survival and bacterial concentrations in spleen, lungs and blood, are shown in Table 3 and Table 4.
(i) Survival. Table 3 and Table 4 show that colistin alone and in combination with one and two doses of LPC increased mice survival compared with that of the control group for Ab9 and Ab186 (p < 0.05). In contrast, LPC in monotherapy did not reduce mice mortality.
(ii) Bacterial clearance of lungs and blood. Table 3 and Table 4 show that monotherapy with colistin cleared Ab9 and Ab186 from the lungs and blood by 6.53 and 5.81 log10 CFU/g and mL (p < 0.05; Ab9), respectively, and 7.75 and 6.79 log10 CFU/g and mL (p < 0.05; Ab186), respectively, compared with the levels of the control group. One dose of LPC in combination with colistin decreased lung and blood concentrations of Ab9 and Ab186 by 6.76 and 6.08 log10 CFU/g and mL (p < 0.05; Ab9) respectively, and 8.1 and 7.17 log10 CFU/g and mL (p < 0.05; Ab186), respectively, compared with the levels for the control group. In addition, the increase of the dose of LPC slightly increased the bacterial clearance. Two doses of LPC in combination with colistin reduced the bacterial burden in lungs and blood by 7.74 and 6.64 log10 CFU/g and mL (p < 0.05; Ab9), respectively, and 8.56 and 7.33 CFU/g and mL (p < 0.05; Ab186), respectively, compared with the levels for the control group.
Finally, one and two doses of LPC in combination with colistin decreased the lung concentrations of Ab9 by 6.25 and 7.25 log10 CFU/g (p < 0.05) and Ab186 by 7.9 and 8.36 log10 CFU/g (p < 0.05), compared with the levels for the LPC monotherapy. Similar results were observed in blood, with a reduction of 5.4 and 5.95 log10 CFU/mL (p < 0.05; Ab9) and 6.74 and 6.9 log10 CFU/mL (p < 0.05; Ab186) compared with the levels for the LPC monotherapy.
4. Discussion
Previous studies from our group demonstrated that preemptive LPC monotherapy and LPC in combination with antibiotics such as colistin reduced bacterial tissue loads and bacteremia and increased mice survival in murine experimental models of severe infections by A. baumannii [7,8]. Even though LPC as preemptive monotherapy and in combination with colistin presented remarkable results, we hypothesized that it may be given as direct treatment in combination with colistin.
Currently, colistin is among the last treatments available worldwide, being a last resort against MDR A. baumannii strains. Nevertheless, its therapeutic efficacy using optimal doses is limited, being effective just in 60% of patients infected with an MDR strain susceptible to colistin [13,14]. For that reason, two different clinical isolates were chosen, one drug-susceptible and one MDR, both susceptible to colistin. In the present study, monotherapy with colistin against drug-susceptible and MDR A. baumannnii strains significantly reduced bacterial concentrations in the spleen, lungs and blood and increased mice survival compared with the control group. However, it is important to highlight that colistin monotherapy presented a mortality rate of 75% in the case of the MDR strain in the peritoneal sepsis model. This result revealed a failure in the treatment with colistin, and the mice survival values are similar to and even higher than the rates obtained in a clinical practice when dealing with a colistin-susceptible strain with a highly resistant pattern. In accordance with our hypothesis, treatment with one or two doses of LPC in combination with colistin in a peritoneal sepsis model increased (without statistical difference) mice survival and reduced bacterial loads in tissues and blood, compared with colistin monotherapy. No differences were found between a single dose and multiple doses of LPC. It is noteworthy to mention that higher efficacy of the combination of LPC plus colistin was observed against the MDR strain Ab186, where survival rates were markedly increased. In the case of the pneumonia model, no differences were found in survival rates compared with colistin monotherapy, but decreases in lung and blood bacterial concentrations were observed.
Differences in bacterial concentrations were not due to different pharmacokinetic parameters between strains, since the MIC value of colistin for both strains is 0.5 mg/L. Different responses to the colistin treatment may be explained by immune responses caused by both strains. Indeed, Ab9 induced more TNF-alpha release than that of Ab186 [8]. Other studies reported by our group showed that a drug-susceptible A. baumannii strain induced more TNF-α and interleukin 6 releases than MDR and pan-drug-resistant A. baumannii clinical isolates [15,16]. In line with this hypothesis, increased lethality and severity of the infection by A. baumannii was observed when neutrophils were depleted, together with a delayed production of cytokines involved in neutrophil function, such as TNF-α, interleukin 1, keratinocyte chemoattractant protein (KC/CXCL1) and macrophage inflammatory protein (MIP-1) [17]. Neutrophils are essential players during A. baumannii infection and present an important role against sepsis and pneumonia infection [18,19]. It was reported that LPC blocks neutrophil deactivation during a murine cecal ligation and puncture model and increased the bactericidal activity of these immune cells [20]. Thus, the additive action of LPC to the antibiotic treatment may be due to the enhanced activity of neutrophils.
It is also believed that other mechanisms of action of LPC, independent of immune system regulation, are present, which might facilitate the action of antimicrobial agents. It was reported that LPC made pores in the membrane of P. aeruginosa and K. pneumoniae and degrades DnaK, the regulator of protein folding, which might potentiate the nonbactericidal effect of polymexin B [10]. In the same line, LPC interacts with the cytoplasmic membrane, induces the membrane depolarization and permeability of methicillin-resistant Staphylococcus aureus and potentiates the activity of ceftazidime [21]. Further investigations are needed to decipher the mechanism of action of LPC in combination with colistin against A. baumannii.
Interestingly, direct treatment with LPC in combination with colistin presents similar efficacy to preemptive treatment with LPC in combination with colistin against the MDR Ab186 strain. A reduction of the bacterial burden in spleen and lungs of around 2 log10 CFU/g in a murine model of peritoneal sepsis and pneumonia models compared with LPC in combination with colistin preemptive treatment was observed [8]. This comparison increases the interest towards LPC as a future adjuvant therapy with colistin, which may reduce the phenomenon of resistance to antibiotics [22].
5. Conclusions
The present study suggests that treatment with LPC in combination with colistin after bacterial infection improves the in vivo antibacterial activity in murine experimental models of peritoneal sepsis and pneumonia by MDR A. baumannii by further reducing bacterial loads in tissues and blood and increasing mice survival.
Author Contributions
M.E.J.-M. and Y.S. conceptualized the study and designed the experiments, analyzed the results and wrote the manuscript. A.M.-C. and R.A.-A. performed the experiments and analyzed the results. J.P. reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This work was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain (PI16/01306 and PI19/01453), and by the Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain, Spanish Network for Research in Infectious Diseases (RD16/0016/0009), co-financed by the European Development Regional Fund “A Way to Achieve Europe”, Operative Program Intelligent Growth 2014–2020. Y.S. is supported by the Subprograma Miguel Servet Tipo I, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain [CP15/00132].
Institutional Review Board Statement
This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals [12]. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University Hospital of Virgen del Rocío of Seville, Spain (approval 1556-N-16, 23 February 2017).
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Sazlly Lim, S.M.; Sime, F.B.; Roberts, J.A. Multidrug-resistant Acinetobacter baumannii infections: Current evidence on treatment options and the role of pharmacokinetics/pharmacodynamics in dose optimisation. Int. J. Antimicrob. Agents 2019, 53, 726–745. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paul, M.; Daikos, G.L.; Durante-Mangoni, E.; Yahav, D.; Carmeli, Y.; Benattar, Y.D.; Skiada, A.; Andini, R.; Eliakim-Raz, N.; Nutman, A.; et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: An open-label, randomised controlled trial. Lancet Infect. Dis. 2018, 18, 391–400. [Google Scholar] [CrossRef]
- Mesquita, R.D.; Carneiro, A.B.; Bafica, A.; Gazos-Lopes, F.; Takiya, C.M.; Souto-Padron, T.; Vieira, D.P.; Ferreira-Pereira, A.; Almeida, I.C.; Figueiredo, R.T.; et al. Trypanosoma cruzi infection is enhanced by vector saliva through immunosuppressant mechanisms mediated by lysophosphatidylcholine. Infect. Immun. 2008, 76, 5543–5552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Quinn, M.T.; Parthasarathy, S.; Steinberg, D. Lysophosphatidylcholine: A chemotactic factor for human monocytes and its potential role in atherogenesis. Proc. Natl. Acad. Sci. USA 1998, 85, 2805–2809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sakai, M.; Miyazaki, A.; Hakamata, H.; Kodama, T.; Suzuki, H.; Kobori, S.; Shichiri, M.; Horiuchi, S. The scavenger receptor serves as a route for internalization of lysophosphatidylcholine in oxidized low density lipoprotein-induced macrophage proliferation. J. Biol. Chem. 1996, 271, 27346–27352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lauber, K.; Bohn, E.; Kröber, S.M.; Xiao, Y.J.; Blumenthal, S.G.; Lindemann, R.K.; Marini, P.; Wiedig, C.; Zobywalski, A.; Baksh, S.; et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 2003, 113, 717–730. [Google Scholar] [CrossRef] [Green Version]
- Smani, Y.; Domínguez-Herrera, J.; Ibáñez-Martínez, J.; Pachón, J. Therapeutic efficacy of lysophosphatidylcholine in severe infections caused by Acinetobacter baumannii. Antimicrob. Agents Chemother. 2015, 59, 3920–3924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Parra Millán, R.; Jiménez Mejías, M.E.; Sánchez Encinales, V.; Ayerbe Algaba, R.; Gutiérrez Valencia, A.; Pachón Ibáñez, M.E.; Díaz, C.; Pérez del Palacio, J.; López Cortés, L.F.; Pachón, J.; et al. Efficacy of lysophosphatidylcholine in combination with antimicrobial agents against Acinetobacter baumannii in experimental murine peritoneal sepsis and pneumonia models. Antimicrob. Agents Chemother. 2016, 60, 4464–4470. [Google Scholar] [CrossRef] [Green Version]
- Parra-Millán, R.; Jiménez-Mejías, M.E.; Ayerbe-Algaba, R.; Domínguez-Herrera, J.; Díaz, C.; Pérez Del Palacio, J.; Pachón, J.; Smani, Y. Impact of the immune response modification by lysophosphatidylcholine in the efficacy of antibiotic therapy of experimental models of peritoneal sepsis and pneumonia by Pseudomonas aeruginosa: LPC therapeutic effect in combined therapy. Enferm. Infecc. Microbiol. Clin. 2020, in press. [Google Scholar] [CrossRef]
- Yadav, J.; Ismaeel, S.; Qadri, A. Lysophosphatidylcholine potentiates antibacterial activity of polymexin B. Antimicrob. Agents Chemother. 2020, 64, e01337-20. [Google Scholar] [CrossRef]
- Fernández-Cuenca, F.; Tomás-Carmona, M.; Caballero-Moyano, F.; Bou, G.; Martínez-Martínez, L.; Vila, J.; Pachón, J.; Miguel Cisneros, J.; Rodríguez-Baño, J.; Pascual, A. In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp.: Multicenter national study GEIH-REIPI-Ab 2010. Enferm. Infecc. Microbiol. Clin. 2013, 31, 4–9. [Google Scholar] [CrossRef]
- National Research Council. Guide for the Care and Use of Laboratory Animals, 8th ed.; National Academies Press: Washington, DC, USA, 2011.
- Garnacho-Montero, J.; Ortiz-Leyba, C.; Jiménez-Jiménez, F.J.; Barrero-Almodóvar, A.E.; García-Garmendia, J.L.; Bernabeu-Wittell, M.; Gallego-Lara, S.L.; Madrazo-Osuna, J. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: A comparison with imipenem-susceptible VAP. Clin. Infect. Dis. 2003, 36, 1111–1118. [Google Scholar] [CrossRef] [Green Version]
- Markou, N.; Markantonis, S.L.; Dimitrakis, E.; Panidis, D.; Boutzouka, E.; Karatzas, S.; Rafailidis, P.; Apostolakos, H.; Baltopoulos, G. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, Gram negative bacilli infections: A prospective, open-label, uncontrolled study. Clin. Ther. 2008, 30, 143–151. [Google Scholar] [CrossRef]
- Smani, Y.; Domínguez-Herrera, J.; Pachón, J. Rifampin protects human lung epithelial cells against cytotoxicity induced by clinical multi and pandrug-resistant Acinetobacter baumannii. J. Infect. Dis. 2011, 203, 1110–1119. [Google Scholar] [CrossRef]
- Smani, Y.; Docobo-Pérez, F.; McConnell, M.J.; Pachón, J. Acinetobacter baumannii-induced lung cell death: Role of inflammation, oxidative stress and cytosolic calcium. Microb. Pathog. 2011, 50, 224–232. [Google Scholar] [CrossRef]
- García-Patiño, M.G.; García-Contreras, R.; Licona-Limón, P. The immune response against Acinetobacter baumannii, an emerging pathogen in nosocomial infections. Front. Immunol. 2017, 8, 441. [Google Scholar] [CrossRef] [PubMed]
- van Faassen, H.; KuoLee, R.; Harris, G.; Zhao, X.; Conlan, J.W.; Chen, W. Neutrophils play an important role in host resistance to respiratory infection with Acinetobacter baumannii in mice. Infect. Immun. 2007, 75, 5597–5608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Breslow, J.M.; Meissler, J.J., Jr.; Hartzell, R.R.; Spence, P.B.; Truant, A.; Gaughan, J.; Eisenstein, T.K. Innate immune responses to systemic Acinetobacter baumannii infection in mice: Neutrophils, but not interleukin-17, mediate host resistance. Infect. Immun. 2011, 79, 3317–3327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, J.J.; Jung, J.S.; Lee, J.E.; Lee, J.; Huh, S.O.; Kim, H.S.; Jung, K.C.; Cho, J.Y.; Nam, J.S.; Suh, H.W.; et al. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat. Med. 2004, 10, 161–167. [Google Scholar] [CrossRef] [PubMed]
- Miyazaki, H.; Midorikawa, N.; Fujimoto, S.; Miyoshi, N.; Yoshida, H.; Matsumoto, T. Antimicrobial effects of lysophophatidylcholine on methicillin-resistant Staphylococcus aureus. Ther. Adv. Infect. Dis. 2017, 4, 89–94. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davies, J.; Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417–433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Table 1.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of peritoneal sepsis with A. baumannii Ab9.
Table 1.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of peritoneal sepsis with A. baumannii Ab9.
| Treatment | n | Spleen (log10 CFU/g) | Lung (log10 CFU/g) | Blood (log10 CFU/mL) | Mortality (%) |
|---|---|---|---|---|---|
| CTL | 10 | 9.55 ± 0.99 | 9.85 ± 0.72 | 8.59 ± 0.04 | 100 |
| LPC | 8 | 9.82 ± 0.08 | 9.69 ± 0.91 | 9.20 ± 0.04 a | 100 |
| CST | 8 | 4.48 ± 0.30 a,b | 4.17 ± 0.29 a | 3.26 ± 0.40 a,b | 25 a |
| LPC1 + CST | 8 | 3.98 ± 0.66 a,b | 3.83 ± 0.65 a | 2.92 ± 0.58 a,b | 0 a |
| LPC2 + CST | 8 | 3.42 ± 0.50 a,b | 3.13 ± 0.46 a | 1.85 ± 0.38 a,b | 0 a |
CTL, control (no treatment); LPC, lysophosphatidylcholine; CST, colistin; LPC1, one dose of lysophosphatidylcholine; LPC2 two doses of lysophosphatidylcholine; n = number of mice. a p < 0.05 compared to the controls. b p < 0.05 compared to the LPC group.
Table 2.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of peritoneal sepsis with A. baumannii Ab186.
Table 2.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of peritoneal sepsis with A. baumannii Ab186.
| Treatment | n | Spleen (log10 CFU/g) | Lung (log10 CFU/g) | Blood (log10 CFU/mL) | Mortality (%) |
|---|---|---|---|---|---|
| CTL | 13 | 9.79 ± 0.06 | 9.63 ± 0.13 | 8.89 ± 0.03 | 100 |
| LPC | 8 | 10.48 ± 0.03 | 10.03 ± 0.03 | 9.29 ± 0.03 | 100 |
| CST | 8 | 2.86 ± 1.54 a,b | 2.90 ± 1.57 a,b | 2.19 ± 1.63 a,b | 75 |
| LPC1 + CST | 12 | 1.58 ± 0.48 a,b | 1.43 ± 0.54 a | 0.22 ± 0.21 a,b | 0 a,b |
| LPC2 + CST | 12 | 0.22 ± 0.29 a,b | 0.75 ± 0.32 a | 0.08 ± 0.12 a,b | 0 a,b |
CTL, control (no treatment); LPC, lysophosphatidylcholine; CST, colistin; LPC1, one dose of lysophosphatidylcholine; LPC2 two doses of lysophosphatidylcholine; n = number of mice. a p < 0.05 compared to the controls. b p < 0.05 compared to the LPC group.
Table 3.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of pneumonia with A. baumannii Ab9.
Table 3.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of pneumonia with A. baumannii Ab9.
| Treatment | n | Lung (log10 CFU/g) | Blood (log10 CFU/mL) | Mortality (%) |
|---|---|---|---|---|
| CTL | 8 | 9.64 ± 0.55 | 7.95 ± 0.83 | 87.5 |
| LPC | 8 | 9.13 ± 0.28 | 7.27 ± 0.04 a | 100 |
| CST | 8 | 3.11 ± 1.18 a,b | 2.14 ± 0.57 a,b | 12.5 a,b |
| LPC1 + CST | 8 | 2.88 ± 1.12 a,b | 1.87 ± 0.6 a,b | 12.5 a,b |
| LPC2 + CST | 8 | 1.90 ± 1.13 a,b | 1.31 ± 0.80 a,b | 12.5 a,b |
CTL, control (no treatment); LPC, lysophosphatidylcholine; CST, colistin; LPC1, one dose of lysophosphatidylcholine; LPC2 two doses of lysophosphatidylcholine; n = number of mice. a p < 0.05 compared to the controls. b p < 0.05 compared to the LPC group.
Table 4.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of pneumonia with A. baumannii Ab186.
Table 4.
The therapeutic effect of one or two doses of LPC in combination with colistin in a murine model of pneumonia with A. baumannii Ab186.
| Treatment | n | Lung (log10 CFU/g) | Blood (log10 CFU/mL) | Mortality (%) |
|---|---|---|---|---|
| CTL | 8 | 9.21 ± 0.45 | 7.76 ± 0.39 | 100 |
| LPC | 8 | 9.01 ± 0.07 | 7.33 ± 0.03 | 100 |
| CST | 8 | 1.66 ± 0.49 a,b | 0.97 ± 0.30 a,b | 0 a,b |
| LPC1 + CST | 8 | 1.11 ± 0.54 a,b | 0.59 ± 0.29 a,b | 0 a,b |
| LPC2 + CST | 8 | 0.65 ± 0.43 a,b | 0.43 ± 0.28 a,b | 0 a,b |
CTL, control (no treatment); LPC, lysophosphatidylcholine; CST, colistin; LPC1, one dose of lysophosphatidylcholine; LPC2 two doses of lysophosphatidylcholine; n = number of mice. a p < 0.05 compared to the controls. b p < 0.05 compared to the LPC group.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Miró-Canturri, A.; Ayerbe-Algaba, R.; Jiménez-Mejías, M.E.; Pachón, J.; Smani, Y. Efficacy of Lysophosphatidylcholine as Direct Treatment in Combination with Colistin against Acinetobacter baumannii in Murine Severe Infections Models. Antibiotics 2021, 10, 194. https://doi.org/10.3390/antibiotics10020194
AMA Style
Miró-Canturri A, Ayerbe-Algaba R, Jiménez-Mejías ME, Pachón J, Smani Y. Efficacy of Lysophosphatidylcholine as Direct Treatment in Combination with Colistin against Acinetobacter baumannii in Murine Severe Infections Models. Antibiotics. 2021; 10(2):194. https://doi.org/10.3390/antibiotics10020194
Chicago/Turabian StyleMiró-Canturri, Andrea, Rafael Ayerbe-Algaba, Manuel Enrique Jiménez-Mejías, Jerónimo Pachón, and Younes Smani. 2021. "Efficacy of Lysophosphatidylcholine as Direct Treatment in Combination with Colistin against Acinetobacter baumannii in Murine Severe Infections Models" Antibiotics 10, no. 2: 194. https://doi.org/10.3390/antibiotics10020194
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
