EFFECTS OF TIGECYCLINE AND DOXYCYCLINE ON INFLAMMATION AND HEMODYNAMICS IN PORCINE ENDOTOXEMIA: A PROSPECTIVE, RANDOMIZED, AND PLACEBO-CONTROLLED TRIAL

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 2g 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-alpha 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-alpha levels. Tigecycline did not affect cytokine levels but counteracted hypotension and hypoperfusion.