tacrolimus and Shock--Septic

Salmonellosis caused by Salmonella enteritidis is an acute and in most cases zoonotic disease, but chronic human carriers are also known. Mostly, affected persons recover without treatment, but severe complications occur occasionally. For the first time we report a case of probably food-borne invasive Salmonella enteritidis infection with septic shock in a patient with Tacrolimus treatment, 13 years after renal transplantation, probably acquired by uncooked ground pork meat.

Topics: Aged; Animals; Colitis; Cooking; Food Microbiology; Foodborne Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Meat; Opportunistic Infections; Salmonella enteritidis; Salmonella Infections; Shock, Septic; Swine; Tacrolimus; Tomography, X-Ray Computed

Microbial components such as lipopolysaccharide (LPS) bind to Toll-like receptors (TLRs) and activate innate and inflammatory responses. Responses to LPS and other microbial components are limited by the activation of negative feedback mechanisms that reduce responsiveness to subsequent LPS exposure, often termed LPS tolerance. Our laboratory has previously shown that calcineurin, a phosphatase known for its activation of T cells via NFAT, negatively regulates the TLR pathway in macrophages; consequently, calcineurin inhibitors (FK506 and cyclosporin A) mimic TLR ligands in activating the TLR pathway, NF-KB, and associated innate and inflammatory responses. This study investigated the physiological consequences of calcineurin inactivation for LPS-induced inflammatory responses in vitro and in vivo using two models: calcineurin inhibition by FK506 (tacrolimus) and myeloid cell-specific calcineurin deletion. Activation of dendritic cells and macrophages with FK506 in vitro was shown to induce a state of reduced responsiveness to LPS (i.e. a form of LPS tolerance). Similarly, macrophages from FK506-treated mice or from mice in which the calcineurin B1 (CnB1) subunit was conditionally knocked out in myeloid cells were found to have diminished LPS-induced inflammatory responses. In addition, mice with CnB1-deficient myeloid cells and mice undergoing FK506 treatment showed improved survival and recovery when challenged with high doses of systemic LPS compared to controls. These results demonstrate that inactivation of calcineurin in macrophages and other myeloid cells by inhibition or deletion can induce a form of LPS tolerance and protect the host from LPS toxicity in vivo.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cell Survival; Cells, Cultured; Dendritic Cells; Feedback, Physiological; Female; Immune Tolerance; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Shock, Septic; Signal Transduction; Tacrolimus

Tacrolimus is a potent immunosuppressive agent widely used in renal and liver transplantations. Its potential side effects due to overdosing are variable. Most commonly toxic tacrolimus blood levels affect the central and peripheral nervous systems. Once absorbed, tacrolimus binds to plasma proteins and accumulates within erythrocytes. Current treatment strategies to overcome acute intoxications focus on the induction of hepatic cytochrome P450 enzymes to accelerate tacrolimus degradation. We report the case of a 69-year-old renal transplant recipient presenting with acute liver failure, septic shock, and tacrolimus intoxication. The intoxication was resolved by massive gastrointestinal bleeding and subsequent transfusion of packed erythrocytes. We concluded that exchange blood transfusions offer an alternative therapeutic approach for patients with severe liver function impairment and tacrolimus intoxication.

Topics: Aged; Diabetes Mellitus; Female; Gastrointestinal Hemorrhage; Hemofiltration; Hemoglobins; Hemorrhoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Renal Dialysis; Shock, Septic; Tacrolimus

The novel effects of FK506 on shock induced by lipopolysaccharide and phorbol myristate acetate (LPS/PMA) were studied using beagles. Five groups were studied: endotoxin shock control group (both 0.5 mg/kg of LPS and 30 microg/kg of PMA, n = 6); methylprednisolone-treated endotoxin shock group (n = 5); FK506-treated endotoxin shock groups in which intravenous infusions of FK506 at 2.5 microg/kg/h (low dose, n = 5), 8 microg/kg/h (medium dose, n = 5), and 25 microg/kg/h (high dose, n = 5) were administered. In the control group, the survival rate was 33%. Also, arterial hypoxemia, systemic hypotension, and marked increases in pulmonary vascular resistance (PVR) and wet-to-dry weight ratio (W/D) were observed. FK506 treatment at both medium and high doses significantly attenuated these LPS/PMA-induced physiological changes, and the survival rates were 80 and 100%, respectively. On the other hand, in the methylprednisolone group, no obvious effects were observed. The present study suggests that FK506 could have prophylactic potential against acute lung injury in endotoxin shock.

Topics: Animals; Dogs; Hemodynamics; Immunosuppressive Agents; Organ Size; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; Survival Rate; Tacrolimus

Necrotizing fasciitis is a rare but devastating condition usually caused by group A streptococci. A renal transplant recipient with necrotizing fasciitis complicated by the streptococcal toxic shock syndrome is presented. The importance of prompt diagnosis, antimicrobial treatment and early surgical intervention in achieving a successful outcome is discussed.

Topics: Debridement; Diagnosis, Differential; Fasciitis, Necrotizing; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Shock, Septic; Tacrolimus