tacrolimus and Staphylococcal-Infections

Delayed fracture healing caused by soft tissue loss can be resolved by the administration of a Th1 immunosuppressant, such as FK506. Additionally, open fractures are at high risk for infection. We hypothesized that the inclusion of an immunosuppressant to a subject at risk for a musculoskeletal infection will increase the likelihood of infection.. A rat model of musculoskeletal infection was used. Sprague Dawley rats received a stabilized femur defect and were inoculated with 10. The dosing regimen of FK506 that restored bone healing increased the bioburden in the bone and on the fixation implant compared to the carrier control animals. As expected, the administration of FK506 decreased circulating white blood cells, lymphocytes, neutrophils, and monocytes. Additionally, the red blood cell count, hematocrit, and body weight were lower in those animals that received FK506 compared to carrier control.. FK506 administration decreased the systemic immune cell counts and increased the bacterial bioburden within a model of musculoskeletal infection. Collectively, these outcomes could be attributed to the overall T cell suppression by FK506 and the altered antimicrobial activity of innate cells, thereby allowing S. aureus to thrive and subsequently leading to infection of severe, musculoskeletal injuries. These observations reveal the crucial continued investigation for the clinical use of FK506, and other immunosuppressant compounds, in trauma patients who are at increased risk of developing infections.

Topics: Animals; Disease Models, Animal; Femur; Immunosuppressive Agents; Rats; Rats, Sprague-Dawley; Rodentia; Staphylococcal Infections; Staphylococcus aureus; Tacrolimus

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

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

Topics: Adolescent; Amputation, Surgical; Colitis, Ulcerative; Diagnosis, Differential; Fingers; Humans; Immunosuppressive Agents; Male; Pyoderma Gangrenosum; Staphylococcal Infections; Staphylococcus aureus; Tacrolimus

Bacterial parotitis is a common childhood disease with a favorable outcome. Staphylococcus aureus is the most frequently involved pathogen. Clinical presentation in adult patients can be misleading, Onset occurs in patients with multiple comorbidities, making diagnosis difficult--particularly in ICU. Different pathogens are found in adults with worse outcomes observed. We report here the case of a critically ill patient and discuss diagnosis and management of bacterial parotitis.

Topics: Aged; Anti-Bacterial Agents; Critical Care; Electroencephalography; Humans; Immunocompromised Host; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Microbial Sensitivity Tests; Parotid Gland; Parotitis; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Tacrolimus

Enterotoxin-producing Staphylococcus aureus may cause severe inflammatory intestinal disease, particularly in infants or immunodeficient or elderly patients. They are also recognized to be associated with sudden infant death syndrome. Little is known, however, about mucosal responses to staphylococci.. The mucosal lesion in three infants with staphylococcal enterocolitis was assessed by immunohistochemistry and electron microscopy. The organisms underwent extensive molecular analysis. Their toxins were assessed for capacity to induce T-cell activation and host mucosal responses examined by in vitro organ culture. Epithelial responses were studied by coculture with HEp-2 and Caco-2 cells.. Intestinal biopsies from the patients showed marked epithelial damage with mucosal inflammation. The three staphylococci, representing two distinct clones, were methicillin-sensitive, producing SEG/I enterotoxins and Rho-inactivating EDIN toxins. Their enterotoxins potently activated T cells, but only whole organisms could induce in vitro enteropathy, characterized by remarkable epithelial desquamation uninhibited by tacrolimus. EDIN-producing staphylococci, but not their supernatants, induced striking cytopathy in HEp-2 epithelial cells but not in Caco-2 cells. Although HEp-2 and Caco-2 cells produced similar IL-8, CCL20, and cathelicidin LL37 responses upon bacterial exposure, only Caco-2 cells expressed mRNA for the β-defensins HBD2 and HBD3, while HEp-2 cells were unable to do so.. Staphylococci induce enterocolitis by a combination of direct enterocyte cytopathy mediated by EDIN toxins, disrupting the epithelial barrier, and enterotoxin superantigen-induced mucosal T-cell activation. Gut epithelial production of β-defensins may contribute to host defense against invasive staphylococcal disease.

Topics: beta-Defensins; Biopsy; Cell Line; Coculture Techniques; Enterocolitis; Enterotoxins; Female; Humans; Infant; Intestinal Mucosa; Lymphocyte Activation; Male; Staphylococcal Infections; Staphylococcus aureus; Superantigens; T-Lymphocytes; Tacrolimus

Many cases of patients with chronic renal failure (CRF) on hemodialysis are known to be infected with Staphylococcus aureus (S. aureus) from the sites of blood vessel puncture for hemodialysis and the custody of the vascular access catheter. S. aureus produces superantigens, such as toxic shock syndrome toxin-1 (TSST-1), which may influence the sensitivity of peripheral-blood mononuclear cells (PBMCs) to immunosuppressive drugs after they are received postrenal transplantation.. We examined the drug-sensitivities of PBMCs stimulated with TSST-1 in 18 CRF patients on hemodialysis. PBMCs were isolated from venous blood before hemodialysis, and were cultured in the presence of concanavalin A (ConA) or TSST-1 and serial concentrations of the drugs. In vitro drug concentrations giving 50% inhibition (IC(50)) of PBMC blastogenesis were calculated. INF-gamma and IL-4 in supernatants of cultured PBMCs were measured with ELISA.. The median (range) IC(50) values (ng/ml) for four drugs; tacrolimus, cyclosporine, methylprednisolone, and prednisolone, evaluated in ConA-stimulated PBMCs of CRF patients were 0.04 ng/ml (0.03-0.21), 3.0 (0.1-15.1), 3.0 (1-104), and 16.2 (5.9-35.4), respectively. The values for the four drugs evaluated in TSST-1-stimulated PBMCs were 0.22 (0.08-0.36), 18.9 (5.1-38.2), 328.3 (1.9-1000), and 150.9 (94.7-880), respectively, which were significantly higher than those evaluated in the ConA-stimulated PBMCs (p=0.003-0.023). Amounts of INF-gamma and IL-4 produced from cells were not significantly different between the ConA-or TSST-1-stimulated PBMCs in the presence or absence of immunosuppressive drugs.. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in CRF patients after renal transplantation. Furthermore, INF-gamma and IL-4 related pathways appear not to play major roles in the TSST-1-induced attenuation of the drug sensitivities.

Topics: Aged; Bacterial Toxins; Calcineurin; Cells, Cultured; Cyclosporine; Dose-Response Relationship, Drug; Enterotoxins; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inhibitory Concentration 50; Interferon-gamma; Interleukin-4; Kidney Failure, Chronic; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Methylprednisolone; Microbial Sensitivity Tests; Prednisolone; Renal Dialysis; Staphylococcal Infections; Superantigens; Tacrolimus

We report a case of staphylococcal impetigo in a girl treated with tacrolimus ointment (Protopic) for atopic dermatitis.. A 15 year-old girl was receiving treatment with tacrolimus 0.03% (Protopic) for an episode of atopic dermatitis. On reduction of applications of tacrolimus, a vesicular-pustular rash appeared and was treated with pristinamycin and valaciclovir. At the end of antibiotic and antiviral therapy, the vesicular-pustular rash recurred while the goal was receiving treatment once more with tacrolimus ointment 0.1%. The bacteriological and virological skin samples revealed B-haemolytic streptococcus group A. The negative results for cutaneous virological samples ruled out Kaposi-Juliusberg syndrome and a diagnosis of staphylococcal impetigo was made. The intrinsic imputability of tacrolimus was I3 (C3 S2).. The most obvious specific feature of this impetigo was its limitation to areas of eczema treated by application of tacrolimus. In prospective studies in large patient cohorts, tacrolimus ointment has been associated with two types of adverse effect: local irritations and skin infections chiefly caused by Staphylococcus aureus. To date, there have been no reports in the literature of impetigo due to haemolytic B streptococcus following application of tacrolimus. Because of its immunodepressant effect, tacrolimus ointment may result in increased incidence of skin infections even though a number of studies have shown a reduction in such infections.

Topics: Administration, Oral; Adolescent; Eczema; Female; Humans; Immunosuppressive Agents; Impetigo; Staphylococcal Infections; Tacrolimus; Treatment Outcome

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

Topics: Administration, Topical; Adult; Colony Count, Microbial; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus; 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