Imipenem, doxycycline and amikacin in monotherapy and in combination in Acinetobacter baumannii experimental pneumonia

Rodríguez-Hernández, María Jesús; Pachón, Jerónimo; Pichardo, C.; Cuberos, L.; Ibáñez-Martínez, José; García-Curiel, A.; Caballero, Francisco J.; Moreno, Isidro; Me, Jiménez-Mejías

doi:10.1093/jac/45.4.493

Cited by 101 publications

(83 citation statements)

References 21 publications

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“…A mouse sepsis model was used in order to characterize the efficacy of the OMC vaccine and of antibody treatment. In this model, mice are infected via intraperitoneal injection of a bacterial suspension containing 5% porcine mucin, which has previously been shown to increase the infectivity of A. baumannii and other bacteria in different experimental models (2,28). A. baumannii strains were grown for 18 h at 37°C in Mueller-Hinton broth and then adjusted to the appropriate concentration in physiologic saline.…”

Section: Lc-ms/msmentioning

confidence: 99%

Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-Resistant Acinetobacter baumannii

et al. 2011

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Acinetobacter baumannii causes pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused by A. baumannii has increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention of A. baumannii infection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane of A. baumannii was developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates of A. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.

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Section: Lc-ms/msmentioning

confidence: 99%

Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-Resistant Acinetobacter baumannii

et al. 2011

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“…However, antibiograms performed on these strains showed a rough correlation between virulence and degree of antibiotic resistance, a relationship that has not previously been investigated. The tendency for A. baumannii strains to exhibit a high level of antibiotic resistance is well established in the literature (1,2,6,7,18,20,22,27,28,33,39,49,59). Resistance is due both to chromosomally encoded resistance genes and to ones found on plasmids and transposons (12).…”

Section: Characterization Of Systemic a Baumannii Infection Five CLmentioning

confidence: 99%

“…These include pneumonia models using intranasal or intratracheal routes of infection (16, 18, 19, 36-38, 42, 43, 54), a rat soft tissue model (25,34,41), and a rabbit endocarditis model (39). Studies of systemic infection with A. baumannii have been hampered by the low virulence of bacterial strains in rodent models, leading some investigators to use a variety of techniques to sensitize animals to these organisms.…”

mentioning

confidence: 99%

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

et al. 2011

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Acinetobacter baumannii is a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection. A nearly 1,000-fold difference in virulence was found between bacterial strains, but no significant differences between sexes or mouse strains were observed. It was found that microbes disseminated rapidly from the peritoneal cavity to the lung and spleen, where they replicated. A persistent septic state was observed. The infection progressed rapidly, with mortality between 36 and 48 h. Depletion of neutrophils with antibody to Ly-6G decreased mean time to death and increased mortality. Interleukin-17 (IL-17) promotes the response of neutrophils by inducing production of the chemokine keratinocyte-derived chemoattractant (KC/CXCL1), the mouse homolog of human IL-8. Acinetobacter infection resulted in biphasic increases in both IL-17 and KC/CXCL1. Depletion of neither IL-17 nor KC/CXCL1, using specific antibodies, resulted in a difference in bacterial burdens in organs of infected mice at 10 h postinfection. Comparison of bacterial burdens between IL-17a؊/؊ and wild-type mice confirmed that the absence of this cytokine did not sensitize mice to Acinetobacter infection. These studies definitely demonstrate the importance of neutrophils in resistance to systemic Acinetobacter infection. However, neither IL-17 nor KC/CXCL1 alone is required for effective host defense to systemic infection with this organism.

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“…In order to accomplish these goals it is critical to identify/develop relevant animal models of infection. To date, Acinetobacter has been used in a variety of animal models, including murine (21,22,25,26,31,36) and guinea pig (4) pneumonia models, a rat thigh infection model (27), and a rabbit endocarditis model (35). However, the clinical relevance and suitability of these models vary depending on the hypothesis being tested.…”

mentioning

confidence: 99%

Rat Pneumonia and Soft-Tissue Infection Models for the Study of Acinetobacter baumannii Biology

Russo

Beanan²,

Olson³

et al. 2008

Infect Immun

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Acinetobacter baumannii is a bacterial pathogen of increasing medical importance. Little is known about its mechanisms of pathogenesis, and safe reliable agents with predictable activity against A. baumannii are presently nonexistent. The availability of relevant animal infection models will facilitate the study of Acinetobacter biology. In this report we tested the hypothesis that the rat pneumonia and soft-tissue infection models that our laboratory had previously used for studies of extraintestinal pathogenic Escherichia coli were clinically relevant for A. baumannii. Advantages of these models over previously described models were that the animals were not rendered neutropenic and they did not receive porcine mucin with bacterial challenge. Using the A. baumannii model pathogen 307-0294 as the challenge pathogen, the pneumonia model demonstrated all of the features of infection that are critical for a clinically relevant model: namely, bacterial growth/clearance, an ensuing host inflammatory response, acute lung injury, and, following progressive bacterial proliferation, death due to respiratory failure. We were also able to demonstrate growth of 307-0294 in the soft-tissue infection model. Next we tested the hypothesis that the soft-tissue infection model could be used to discriminate between the inherent differences in virulence of various A. baumannii clinical isolates. The ability of A. baumannii to grow and/or be cleared in this model was dependent on the challenge strain. We also hypothesized that complement is an important host factor in protecting against A. baumannii infection in vivo. In support of this hypothesis was the observation that the serum sensitivity of various A. baumannii clinical isolates in vitro roughly paralleled their growth/clearance in the soft-tissue infection model in vivo. Lastly we hypothesized that the soft-tissue infection model would serve as an efficient screening mechanism for identifying gene essentiality for drug discovery. Random mutants of 307-0294 were initially screened for lack of growth in human ascites in vitro. Selected mutants were subsequently used for challenge in the soft-tissue infection model to determine if the disrupted gene was essential for growth in vivo. Using this approach, we have been able to successfully identify a number of genes essential for the growth of 307-0294 in vivo. In summary, these models are clinically relevant and can be used to study the innate virulence of various Acinetobacter clinical isolates and to assess potential virulence factors, vaccine candidates, and drug targets in vivo and can be used for pharmacokinetic and chemotherapeutic investigations.

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Imipenem, doxycycline and amikacin in monotherapy and in combination in Acinetobacter baumannii experimental pneumonia

Cited by 101 publications

References 21 publications

Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-Resistant Acinetobacter baumannii

Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-Resistant Acinetobacter baumannii

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

Rat Pneumonia and Soft-Tissue Infection Models for the Study of Acinetobacter baumannii Biology

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