Tetracyclines in traumatic brain injury and sepsis: same, same, but different!*.

www.ccmjournal. org 1965 In this issue of Critical Care Medicine, Adembri et al (1) report on their prospective, experimental animal study in which they have compared the potential therapeutic efficacy of two tetracyclines, minocycline and the newer generation tigecycline, on functional neurobehavioral impairment and regional histopathological damage in a standardized in vivo model of combined traumatic brain injury (TBI), inflicted via controlled cortical impact, and superimposed sepsis, inflicted via polymicrobial cecal ligation and puncture. The authors are credited for their ongoing efforts to further explore their previously well characterized and clinically relevant model now in more detail in the context of pharmacological manipulation (2). Infections occur commonly among patients after TBI and have been associated with increased lengths of stays in ICUs and in hospital, an elevated risk of poor neurological outcome and mortality, and substantially increased healthcare costs (3). Nosocomial infections affect approximately 2 million patients in the United States each year, increasing overall patient care costs by an estimated $4.5 to $5.7 billion (4). It is estimated that approximately 50% of patients with severe TBI develop at least one infectious complication during hospitalization with pneumonia representing the most frequent manifestation and reported prevalences ranging between 41% and 74% (5). Furthermore, sepsis has been found to affect between 10% and 41% of patients with severe TBI during hospitalization (6). The development of pneumonia among TBI patients may be explained, in part, by aspiration due to a decreased level of consciousness, prolonged ventilator times causing ventilatorassociated pulmonary complications, and the presence of indwelling invasive devices, but emerging evidence also suggests endogenous catecholamines released via TBI-triggered sympathetic activation to modulate cells of the immune system, thus inducing systemic immunosuppression (7, 8). This immunosuppression may, on one hand, protect the brain from further inflammatory damage; on the other hand, it may also increase the susceptibility to further infections. The treatment with both antibiotics reduced microorganism growth and body weight and increased the mortality caused by superimposed sepsis, but it had no effect on vestibulomotor and cognitive function. Minocycline alone, in contrast to tigecyline, attenuated postlesional cortical lesion volume, hippocampal CA3 neuronal loss, tumor necrosis factor-α expression in the pericontusional cortex, the extent of microglial activation and infiltration in the perilesional and pericoroidal plexus zone, and overall cerebral inflammation. These results correspond to previous studies in which minocycline was neuroprotective in various models of acute and chronic cerebral damage including models of isolated TBI associated with enhanced inflammatory and immune responses (9–11). However, minocyline may also exert neuroprotective effects independent of its anti-inflammatory properties (12). The novelty here is the unique “two-hit” experimental condition by coupling two validated and clinically relevant models into one robust experimental scenario of a frequent clinical complication. To date, only very little is known about minocycline regarding its ability to reduce the exacerbation of the regional, posttraumatic cascades induced by superimposed or combined insults such as sepsis and TBI. The present study provides first insights into this highly complex field of growing clinical interest. Tigecycline is the prototype of the recently introduced and IV administered glycylcycline class of antibiotics, which was developed in response to the increasing problem of antibiotic resistance. Although tigecycline is structurally related to minocycline, alterations in the molecule resulted in its expanded spectrum of activity and decreased susceptibility to resistance when compared with other tetracyclines. In contrast to minocycline, there are no data yet available about the neuroprotective and immunomodulatory potential of tigecycline in post-TBI infections. Recently, Cockeran et al (13) have even suggested that tigecycline, independent of antimicrobial activity, may potentiate the proinflammatory functions of human neutrophils by functioning as a Ca-ionophore. Further, there are no data available regarding the possible neuroprotective dose of tigecycline. In the present study, the authors have used tigecycline doses that have been shown to be effective in treating severe sepsis in rats, such as bacterial endocarditis (tigecycline 7.5 mg/kg ip). Tigecycline may have failed to reduce cell loss in the cortex or hippocampus due to its limited cerebral penetration as reflected by lower concentrations in cerebral tissue homogenates. Minocycline, however, was administered a priori in dosages that have previously been shown to be neuroprotective in experimental models in rodents (minocycline 45 mg/kg ip). Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000445 Marc Maegele, MD Department of Orthopedics, Trauma and Sports Medicine Cologne-Merheim Medical Center (CMMC) Private University of Witten-Herdecke Cologne, Germany Tetracyclines in Traumatic Brain Injury and Sepsis: Same, Same, But Different! *