title: Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis--A randomised placebo-controlled pilot trial.
abstract: An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72 h and from baseline to 120 h. Data from 23 patients were analysed. At 72 h all patients in group 1 showed doxycycline concentrations >1 mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120 h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities.
authors.affiliation: Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland. Electronic address: eija.nukarinen@hus.fi.
authors.forename: Eija
authors.initials: E
authors.lastname: Nukarinen
authors.affiliation: Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, PB 263, 00029 HUS, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Tervahartiala
authors.affiliation: Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland.
authors.forename: Miia
authors.initials: M
authors.lastname: Valkonen
authors.affiliation: Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Hynninen
authors.affiliation: Department of Infectious Diseases, University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Kolho
authors.affiliation: Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, PB 263, 00029 HUS, Finland; Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, PB 4046, 141 04 Huddinge, Sweden.
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, PB 705, 00029 HUS, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Backman
authors.affiliation: Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital, PB 340, 00029 HUS, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hästbacka
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004318:Doxycycline / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage*; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline
keywords: Doxycycline; Doxycycline hyclate (PubChem CID: 5473805); Matrix metalloproteinase; Severe sepsis