tacrolimus and Bacteremia

Kupffer cells (KCs) are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/nuclear factor of activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. Although their effect on lymphocytes has been studied extensively, there are limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs.. Here, we investigated the impact of tacrolimus treatment on innate immunity and, more specifically, on the capability of Kupffer cells (KCs) to fight infections. Retrospective analysis of data of >2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin-resistant S. aureus (MRSA) bacteremia, most bacteria were sequestered in the liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus-treated mice. Using imaging, we unveiled the mechanism underlying this observation: the reduced capability of KCs to capture, phagocytose, and destroy bacteria in tacrolimus-treated animals. Furthermore, in a gene expression analysis of infected KCs, the triggering receptor expressed on myeloid cells 1 (TREM1) pathway was the one with the most significant down-regulation after tacrolimus treatment. TREM1 inhibition likewise inhibited KC bacteria capture. TREM1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment.. Our results indicate that tacrolimus treatment has a significant impact directly on KCs and on TREM1, thereby compromising their capacity to fend off infections.

Topics: Animals; Bacteremia; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Kupffer Cells; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Middle Aged; Organ Transplantation; Phagocytosis; Reactive Oxygen Species; Retrospective Studies; Staphylococcal Infections; Tacrolimus

Bloodstream infection (BSI) is a common complication after living-donor liver transplantation (LDLT). Some patients develop recurrent BSIs. We evaluated the impacts of early recurrent BSIs (ER-BSIs) on outcomes in LDLT recipients. LDLT cases between 2008 and 2016 were included. Early BSI (E-BSI) was defined as a BSI event that occurred within 2 months after LDLT. ER-BSIs were defined as new-onset BSIs within 2 months due to another pathogen at a ≥ 48-h interval or a relapse of BSIs by the same pathogen at a ≥ 1-week interval, with negative cultures in between. The primary objective was evaluating the all-cause mortality of each group of LDLT recipients (90 days and 1 year). The secondary objectives were analyzing associated factors of each all-cause mortality and risk factors for early single BSI and ER-BSI. Among 727 LDLT recipients, 108 patients experienced 149 events of E-BSI with 170 isolated pathogens. Twenty-eight patients (25.9%, 28/108) experienced ER-BSI. The 1-year survival rates of patients without BSI, with early single BSI event, and with ER-BSIs were 92.4%, 81.3%, and 28.6%, respectively. ER-BSI was the most significant risk factor for 1-year mortality (adjusted HR = 5.31; 95% CI = 2.27-12.40). Intra-abdominal and/or biliary complications and early allograft dysfunction were risk factors for both early single BSI and ER-BSI. Interestingly, longer cold ischemic time and recipient operative time were associated with ER-BSI. LDLT recipients with ER-BSI showed very low survival rates accompanied by intra-abdominal complications. Clinicians should prevent BSI recurrence by being aware of intra-abdominal complications.

Topics: Anti-Bacterial Agents; Bacteremia; Bacteria; Bacterial Infections; Drug Resistance, Multiple, Bacterial; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Recurrence; Tacrolimus; Treatment Outcome

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Topics: Antibiotics, Antineoplastic; Bacteremia; BK Virus; Cardiomyopathy, Dilated; Cardiotoxicity; COVID-19; COVID-19 Nucleic Acid Testing; Doxorubicin; Graft Rejection; Gram-Positive Bacterial Infections; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Male; Malnutrition; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Postoperative Complications; Prednisone; Renal Dialysis; SARS-CoV-2; Staphylococcal Infections; Surgical Wound Infection; Tacrolimus; Tracheostomy; Tumor Virus Infections; Vancomycin-Resistant Enterococci; Viremia; Water-Electrolyte Imbalance

Here we present a case report of a 41-year-old woman suffering from high fever and bacteremia due to Helicobacter canis, 11 months after kidney transplantation. Identification of H. canis was achieved by 16s rDNA sequence analysis of a positive blood culture. The patient was restored fully to health after antibiotics therapy (cefuroxime and ciprofloxacin). Until now, only 4 human clinical cases have been described with H. canis bacteremia. This study describes for the first time, to our knowledge, an infection with H. canis in a kidney transplant patient.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Cefuroxime; Ciprofloxacin; DNA, Bacterial; DNA, Ribosomal; Female; Graft Rejection; Helicobacter; Helicobacter Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prednisolone; Sequence Analysis, DNA; Tacrolimus

The microbial origin, timing, risk factors, and outcome of bloodstream infections (bacteremia and fungemia) were prospectively analyzed in 130 consecutive liver transplant recipients receiving tacrolimus-based immunosuppression; median followup was 3 yr. 22% (29/130) of the patients developed 36 episodes of bloodstream infections (0.28 episodes/patient). Bloodstream infections accounted for 36% (36/100) of all major infections. 81% (29/36) of bloodstream infections were due to bacteremia and 19% (7/36) due to fungemia (candidemia 14% and cryptococcemia 5%). Intravascular catheters were the most frequent source and methicillin-resistant Staphylococcus aureus was the most frequent pathogen causing bloodstream infections. 70% of the catheter related and all bacteremias due to intra-abdominal infections occurred < or = 90 d, whereas 75% of the bacteremias due to biliary source occurred > 90 d after transplantation. Length of initial post-transplant intensive care unit stay (p = 0.014) and readmission to the intensive care unit (p = 0.003) were independently significant predictors of bloodstream infections. 40% of the candidemias occurred within 30 d of transplantation and were of unknown portal, whereas the portal in all candidemias occurring > 30 d post-transplant was known (catheter, hepatic abscess, urinary tract). Mortality in patients with bloodstream infections was 52% (15/29) vs. 9% (9/101) in patients without bloodstream infections (p = 0.0001). In conclusion, intravascular catheters (and not intra-abdominal infections) have emerged as the most common source of bloodstream infections, and gram-positive cocci (S. aureus) as the predominant pathogens in bloodstream infections after liver transplantation.

Topics: Abdomen; Adult; Aged; Bacteremia; Biliary Tract; Candidiasis; Catheterization, Peripheral; Critical Care; Cryptococcosis; Equipment Contamination; Female; Follow-Up Studies; Forecasting; Fungemia; Humans; Immunosuppressive Agents; Length of Stay; Liver Abscess; Liver Transplantation; Male; Methicillin Resistance; Middle Aged; Patient Readmission; Prospective Studies; Risk Factors; Staphylococcal Infections; Staphylococcus aureus; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; Urinary Tract Infections

The influence of six immunosuppressive agents on the occurrence of endogenous bacteraemia in mice was evaluated. The mortality rates in conventional ddY mice given cyclophosphamide (CY), fluorouracil (5-FU), methotrexate (MTX), cisplatin (CDDP) or FK-506 intraperitoneally, or dexamethasone (DXM) subcutaneously were 70, 100, 100, 100, 0 and 0%, respectively. Pseudomonas aeruginosa was isolated from 70% of mice treated with CY but from only 10% of mice treated with 5-FU and 30% treated with MTX. Enterobacteria were isolated from 90% of mice treated with 5-FU. Specific-pathogen-free (SPF) mice fed P. aeruginosa were also treated with these agents. All mice in the CY, 5-FU, MTX and CDDP groups died whereas mice treated with DXM and FK-506 showed 20% and 0% mortality, respectively. Pure cultures of P. aeruginosa were obtained from all of the mice treated with CY. Polymicrobial bacteraemia with P. aeruginosa and enterobacteria occurred in 5, 25, 5 and 5% of mice treated with 5-FU, MTX, CDDP and DXM, respectively. Enterobacterial bacteraemia was observed in 70% of mice treated with CDDP and in 5% of the DXM group. Different types of bacteraemia were induced by different immunosuppressive agents. The mechanism of immunosuppression may affect the frequency of bacteraemia and the causative organism.

Topics: Animals; Bacteremia; Cisplatin; Cyclophosphamide; Enterobacteriaceae Infections; Fluorouracil; Immunosuppressive Agents; Male; Methotrexate; Mice; Pseudomonas Infections; Specific Pathogen-Free Organisms; Tacrolimus