Effects of Tigecycline and Doxycycline on Inflammation and Hemodynamics in Porcine Endotoxemia

Abstract

Antibiotics might, apart from an antimicrobial effect, also exert anti-inflammatory effects. The novel antibiotic tigecycline, potentially useful in septic shock from gram-negative multiresistant bacteria, is structurally related to antibiotics with known anti-inflammatory properties. However, its anti-inflammatory effects have not been previously explored in vivo. Using a sterile integrative porcine sepsis model, we investigated the anti-inflammatory and circulatory effects of tigecycline in comparison with doxycycline and placebo. Eighteen pigs were randomized to receive tigecycline 100 mg, doxycycline 200 mg, or placebo and subjected to 6-h endotoxin infusion at 0.5 μg kg(-1) h(-1). Markers of inflammation, nitric oxide production, vascular permeability, hemodynamics, organ dysfunction, tissue metabolism, and acid-base parameters were monitored. Peak plasma tumor necrosis factor-α was lower in the doxycycline group (P = 0.031) but not in the tigecycline group (P = 0.86) compared with placebo, with geometric mean plasma concentrations of 16, 79, and 63 ng mL(-1), respectively. Mean arterial pressure was higher 4 to 6 h in the tigecycline group, with values at 6 h of 107 ± 9 mmHg compared with the placebo and doxycycline groups (85 ± 27 mmHg and 90 ± 32 mmHg, respectively; P = 0.025). The white blood cell and the neutrophil granulocyte counts were less reduced in the doxycycline group but not in the tigecycline group at 4 to 6 h (P = 0.009 and P = 0.019, respectively). Other markers of inflammation, organ dysfunction, tissue metabolism, and acid-base parameters were unaffected by tigecycline. Consistent with known anti-inflammatory properties, doxycycline yielded decreased tumor necrosis factor-α levels. Tigecycline did not affect cytokine levels but counteracted hypotension and hypoperfusion.

A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6

“…In the held-out data (study G in Table 1 ) both cytokines were assayed using DuoSet [24], though all IL-6 baseline values were set to 200 ng/L (employed limit of quantification (LOQ) in for this data). Because of the varying TNF-α baselines between studies using the DuoSet assay, and because all baseline measurements of IL-6 were below the LOQ, the median of the individual EBEs were used as the typical values when simulating from the final model (205 and 49.3 ng/L for TNF-α and IL-6, respectively).…”

“…Data from a study that was not used in the model building process [24] was available to evaluate the final models’ ability to predict the observed TNF-α and IL-6 time-courses. The external evaluation was performed by comparing the median of the observations from this separate study, to simulations from the final model using the design of the external study.…”

Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future

“…In contrast to proinflammatory effects of certain antibiotics that lyse bacteria, several protein synthesis inhibiting antibiotics exhibit anti-inflammatory activities. Macrolides, rifampicin, and tetracycline demonstrate anti-inflammatory and immunomodulatory properties with a potential application in systemic inflammation ( 228 – 231 ). Rifampicin and tetracycline are contraindicated in the neonatal period; the use of macrolides for other indications, namely, Ureaplasma spp .…”

Non Antimicrobial Effects of Antibacterial Agents

“…Glisilsiklin bir antimikrobiyal olan tigesiklin ile yapılan antienflamatuvar etkiyi göstermeye yönelik bir çalışmada domuz sepsis modelinde TNF-alfa seviyesini plaseboya göre anlamlı azaltmadığı ve anti-enflamatuvar etkisinin belirgin olmadığı gösterilmiştir [36] .…”