Therapeutic evaluation of immunomodulators in reducing surgical wound infection.

Despite many advances in infection control practices, including prophylactic antibiotics, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospitalization, and death worldwide. Our innate immune system possesses a multitude of powerful antimicrobial strategies which make it highly effective in combating bacterial, fungal, and viral infections. However, pathogens use various stealth mechanisms to avoid the innate immune system, which in turn buy them time to colonize wounds and damage tissues at surgical sites. We hypothesized that immunomodulators that can jumpstart and activate innate immune responses at surgical sites, would likely reduce infection at surgical sites. We used three immunomodulators; fMLP (formyl-Methionine-Lysine-Proline), CCL3 (MIP-1α), and LPS (Lipopolysaccharide), based on their documented ability to elicit strong inflammatory responses; in a surgical wound infection model with Pseudomonas aeruginosa to evaluate our hypothesis. Our data indicate that one-time topical treatment with these immunomodulators at low doses significantly increased proinflammatory responses in infected and uninfected surgical wounds and were as effective, (or even better), than a potent prophylactic antibiotic (Tobramycin) in reducing P. aeruginosa infection in wounds. Our data further show that immunomodulators did not have adverse effects on tissue repair and wound healing processes. Rather, they enhanced healing in both infected and uninfected wounds. Collectively, our data demonstrate that harnessing the power of the innate immune system by immunomodulators can significantly boost infection control and potentially stimulate healing. We propose that topical treatment with these immunomodulators at the time of surgery may have therapeutic potential in combating SSI, alone or in combination with prophylactic antibiotics.

Association between perioperative allogeneic red blood cell transfusion and infection after clean-contaminated surgery: a retrospective cohort study.

BACKGROUND: Allogeneic red blood cell (RBC) transfusion can induce immunosuppression, which can then increase the susceptibility to postoperative infection. However, studies in different types of surgery show conflicting results regarding this effect. METHODS: In this retrospective cohort study conducted in a tertiary referral centre, we included adult patients undergoing clean-contaminated surgery from 2014 to 2018. Patients who received allogeneic RBC transfusion from preoperative Day 30 to postoperative Day 30 were included into the transfusion group. The control group was matched for the type of surgery in a 1:1 ratio. The primary outcome was infection within 30 days after surgery, which was defined by healthcare-associated infection, and identified mainly based on antibiotic regimens, microbiology tests, and medical notes. RESULTS: Among the 8098 included patients, 1525 (18.8%) developed 1904 episodes of postoperative infection. Perioperative RBC transfusion was associated with an increased risk of postoperative infection after controlling for 27 confounders by multivariable regression analysis (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.39-1.84; P<0.001) and propensity score weighing (OR: 1.64; 95% CI: 1.45-1.85; P<0.001) and matching (OR: 1.70; 95% CI: 1.43-2.01; P<0.001), and a dose-response relationship was observed. The transfusion group also showed higher risks of surgical site infection, pneumonia, bloodstream infection, multiple infections, intensive care admission, unplanned reoperation, prolonged postoperative length of hospital stay, and all-cause death. CONCLUSIONS: Perioperative allogeneic RBC transfusion is associated with an increased risk of infection after clean-contaminated surgery in a dose-response manner. Close monitoring of infections and enhanced prophylactic strategies should be considered after transfusion.

Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm.

Bacterial infections in the central nervous system (CNS) can be life threatening and often impair neurological function. Biofilm infection is a complication following craniotomy, a neurosurgical procedure that involves the removal and replacement of a skull fragment (bone flap) to access the brain for surgical intervention. The incidence of infection following craniotomy ranges from 1% to 3% with approximately half caused by Staphylococcus aureus (S. aureus). These infections present a significant therapeutic challenge due to the antibiotic tolerance of biofilm and unique immune properties of the CNS. Previous studies have revealed a critical role for innate immune responses during S. aureus craniotomy infection. Experiments using knockout mouse models have highlighted the importance of the pattern recognition receptor Toll-like receptor 2 (TLR2) and its adaptor protein MyD88 for preventing S. aureus outgrowth during craniotomy biofilm infection. However, neither molecule affected bacterial burden in a mouse model of S. aureus brain abscess highlighting the distinctions between immune regulation of biofilm vs. planktonic infection in the CNS. Furthermore, the immune responses elicited during S. aureus craniotomy infection are distinct from biofilm infection in the periphery, emphasizing the critical role for niche-specific factors in dictating S. aureus biofilm-leukocyte crosstalk. In this review, we discuss the current knowledge concerning innate immunity to S. aureus craniotomy biofilm infection, compare this to S. aureus biofilm infection in the periphery, and discuss the importance of anatomical location in dictating how biofilm influences inflammatory responses and its impact on bacterial clearance.

Surgical Site Infections and Perioperative Optimization of Host Immunity by Selection of Anesthetics.

Surgical site infections are significant health care issues, and efforts to mitigate their occurrence have been ongoing worldwide, mainly focusing to reduce the spillage of microbes to the otherwise sterile tissues. Optimization of host immunity has been also recognized including temperature regulation (normothermia), adequate oxygenation, and glucose management. A number of papers have described the role of anesthetics in host immunity. The role of anesthetics in postoperative outcomes including surgical site infections has been also studied. We will review the current literature and propose the importance of anesthetic selection to potentially mitigate surgical site infections.

IsdB antibody-mediated sepsis following S. aureus surgical site infection.

Staphylococcus aureus is prevalent in surgical site infections (SSI) and leads to death in approximately 1% of patients. Phase IIB/III clinical trial results have demonstrated that vaccination against the iron-regulated surface determinant protein B (IsdB) is associated with an increased mortality rate in patients with SSI. Thus, we hypothesized that S. aureus induces nonneutralizing anti-IsdB antibodies, which facilitate bacterial entry into leukocytes to generate "Trojan horse" leukocytes that disseminate the pathogen. Since hemoglobin (Hb) is the primary target of IsdB, and abundant Hb-haptoglobin (Hb-Hp) complexes in bleeding surgical wounds are normally cleared via CD163-mediated endocytosis by macrophages, we investigated this mechanism in vitro and in vivo. Our results demonstrate that active and passive IsdB immunization of mice renders them susceptible to sepsis following SSI. We also found that a multimolecular complex containing S. aureus protein A-anti-IsdB-IsdB-Hb-Hp mediates CD163-dependent bacterial internalization of macrophages in vitro. Moreover, IsdB-immunized CD163-/- mice are resistant to sepsis following S. aureus SSI, as are normal healthy mice given anti-CD163-neutralizing antibodies. These genetic and biologic CD163 deficiencies did not exacerbate local infection. Thus, anti-IsdB antibodies are a risk factor for S. aureus sepsis following SSI, and disruption of the multimolecular complex and/or CD163 blockade may intervene.

Incidental COVID-19 in a heart-kidney transplant recipient with malnutrition and recurrent infections: Implications for the SARS-CoV-2 immune response.

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.

Toll-like receptors: exploring their potential connection with post-operative infectious complications and cancer recurrence.

Cancer is the leading cause of death in North America. Despite modern advances in cancer therapy, many patients will ultimately develop cancer metastasis resulting in mortality. Surgery to resect early stage solid malignancies remains the cornerstone of cancer treatment. However, surgery places patients at risk of developing post-operative infectious complications that are linked to earlier cancer metastatic recurrence and cancer mortality. Toll-like receptors (TLRs) are evolutionarily-conserved sentinel receptors of the innate immune system that are activated by microbial products present during infection, leading to activation of innate immunity. Numerous types of solid cancer cells also express TLRs, with their activation augmenting their ability to metastasize. Similarly, healthy host-tissue TLRs activated during infection induce a prometastatic environment in the host. Cancer cells additionally secrete TLR activating ligands that activate both cancer TLRs and host TLRs to promote metastasis. Consequently, TLRs are an attractive therapeutic candidate to target infection-induced cancer metastasis and progression.

Updates in penile prosthesis infections.

Inflatable penile prostheses are an important tool in the treatment of medically refractory erectile dysfunction. One of the major complications associated with these prostheses is infections, which ultimately require device explanation and placement of a new device. Over the past several decades, significant work has been done to reduce infection rates and optimize treatment strategies to reduce patient morbidity. This article reviews the current state of knowledge surrounding penile prosthesis infections, with attention to the evidence for methods to prevent infection and best practices for device reimplantation.

Surgical Upper Extremity Infections in Immunosuppressed Patients: A Comparative Analysis With Diagnosis and Treatment Recommendations for Hand Surgeons.

Background: Immunosuppression is encountered in patients with oncologic, transplant, and autoimmune disorders. The purpose of this study is to provide guidance for physicians treating surgical hand and upper extremity (UE) infections in immunosuppressed (IS) patients. Methods: We retrospectively reviewed our database of patients presenting with UE infections over 3 years. IS patients were matched randomly to non-IS patients. Patient background, infection presentation, surgical evaluation, and microbiology variables were recorded. Infection variables included mechanism, location, and type. Outcomes included inpatient length of stay (LOS) and need for repeat drainage. Results: We identified 35 IS and 35 non-IS out of 409 UE infection patients. Patients most commonly had a hematologic malignancy (34%) as their IS class, and the most frequent immunosuppressive medication was glucocorticoids (57%). IS patients were more likely to be older and less likely to have a history of drug abuse or hepatitis C virus infections. IS infections were more likely to have idiopathic mechanisms, more likely to involve deeper anatomy such as joints, bone, tendon sheath, or muscle/fascia, and less likely to present with leukocytosis. IS cultures more commonly exhibited atypical Mycoplasma or fungus. There was no difference between IS and non-IS patients regarding LOS or recurrent drainage. Conclusions: Mechanism and white blood cell count are less reliable markers of infection severity in IS patients. Physicians treating infections in IS patients should maintain a higher suspicion for deeper involved anatomy and atypical microbiology. Nonetheless, with careful inpatient management and closer surveillance, outcomes in IS patients can approach that of non-IS patients.

Surgical-site mucormycosis infection in a solid-organ transplant recipient and a concise review of the literature.

Surgical-site mucormycosis infections in solid-organ transplant recipients are rare conditions, with only 15 previously reported cases. We describe a case of a 49-year-old man who received a liver transplant due to alcoholic cirrhosis. On postoperative day 14, necrosis was noticed at the surgical site. After mucormycosis was diagnosed, monotherapy with amphotericin was started along with surgical debridements. Due to continued clinical deterioration, triple antifungal therapy was started with amphotericin, micafungin and posaconazole. Treatment with a granulocyte-macrophage colony-stimulating factor was also started. Despite therapy, the patient expired on postoperative day 31. We review the risk factors for mucormycosis infection in solid-organ transplant recipients as well as evidence for current treatment options. We also review the 15 previously reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients, including time to infection, infecting organisms, mortality and treatments.

Perioperative immune function and pain control may underlie early hospital readmission and 90 day mortality following lung cancer resection: A prospective cohort study of 932 patients.

BACKGROUND: Mortality following lung cancer resection has been shown to double between 30 and 90 days and readmission following surgery is associated with an increased risk of mortality. The aim of this study was to describe the causes of readmission and mortality and enable the identification of potentially modifiable factors associated with these events. METHODS: Prospective cohort study at a United Kingdom tertiary referral centre conducted over 55 months. Binary logistic regression was used to identify factors associated with death within 90 days of surgery. RESULTS: The 30 day and 90 day mortality rates were 1.4% and 3.3% respectively. The most common causes of death were pneumonia, lung cancer and Acute Respiratory Distress Syndrome/Multi Organ Failure. Potentially modifiable risk factors for death identified were: Postoperative pulmonary complications (Odds ratio 6.1), preoperative lymphocyte count (OR 0.25), readmission within 30 days (OR 4.2) and type of postoperative analgesia (OR for intrathecal morphine 4.8). The most common causes of readmission were pneumonia, shortness of breath and pain. CONCLUSIONS: Postoperative mortality is not simply due to fixed factors; the impacts of age, gender and surgical procedure on postoperative survival are reduced when the postoperative course of recovery is examined. Perioperative immune function, as portrayed by the occurrence of infection and lower lymphocyte count in the immediate perioperative period, and pain control method are strongly associated with 90 day mortality; further studies in these fields are indicated as are studies of psychological factors in recovery. CLINICAL REGISTRATION NUMBER: ISRCTN00061628.

Early Postoperative Anti-TNF Therapy Does Not Increase Complications Following Abdominal Surgery in Crohn's Disease.

BACKGROUND: The impact of postoperative anti-TNF therapy on infectious complications following Crohn's disease surgery remains controversial. Use of anti-TNF therapy 2-4 weeks postoperatively appears safe, but safety of use within 2 weeks is unknown. AIMS: We sought to evaluate the effect of anti-TNF therapy initiated within 2 weeks of abdominal surgery in patients with Crohn's disease. METHODS: We conducted a retrospective review of adult Crohn's disease patients undergoing abdominal surgery between 2004 and 2011. Infectious and non-infectious complications were compared between patients exposed to anti-TNF therapy within 2 weeks or between 2 and 4 weeks postoperatively and to those without exposure using chi-squared and regression analysis. RESULTS: Three hundred thirty-one abdominal surgeries were included; 241 were without anti-TNF exposure, 46 received postoperative anti-TNF within 2 weeks of surgery, and 44 received anti-TNF therapy 2-4 weeks after surgery. Patients who received anti-TNF therapy within 2 weeks of surgery, those initiated between 2 and 4 weeks of surgery, and those who did not receive anti-TNF therapy within 4 weeks of surgery had no significant difference in rates of infectious complications (22%, 32%, 33%, p = 0.332). Rates of non-infectious complications (4%, 9%, 14%, p = 0.143), mortality (0%, 0%, 3%, p = 0.105), hospital readmission (17%, 16%, 15%, p = 0.940), and reoperation (11%, 11%, 16%, p = 0.563) were also similar between groups. CONCLUSIONS: Use of early anti-TNF therapy within 2 weeks or between 2 and 4 weeks following abdominal surgery did not increase risk of postoperative surgical infections in Crohn's patients.

Volatile Anesthetic Attenuates Phagocyte Function and Worsens Bacterial Loads in Wounds.

BACKGROUND: Previously we have shown that volatile anesthetic isoflurane attenuated neutrophil recruitment and phagocytosis in mouse sepsis and skin inflammation models. The objectives of this study were to test ex vivo function of neutrophils in patients who underwent cardiac catheterization under volatile anesthesia versus intravenous anesthesia (IA), and also to assess the effect of anesthesia on surgical site infections (SSIs) using mouse model to understand the clinical relevance of anesthesia-induced immunomodulation. METHODS: Whole blood from patients who underwent cardiac catheterization procedures either by volatile anesthesia or IA was collected and subjected to phagocytosis assay and a lipopolysaccharide-induced tumor necrosis factor-α assay. Mouse SSI with Staphylococcus aureus USA300 was created, and the effect of isoflurane and propofol exposure (short or long exposure) on bacterial loads was tested. RESULTS: Neutrophil phagocytosis was significantly attenuated after the induction of volatile anesthesia in patients, but not by IA. Monocyte phagocytosis was not affected by the anesthesia regimen. Bacterial loads following SSIs were significantly higher in mice receiving long, but not short, isoflurane exposure. Propofol exposure did not affect bacterial loads. DISCUSSION: Neutrophil phagocytosis can be affected by the type of anesthesia, and preclinical model of SSIs showed potential clinical relevance. The effects of anesthesia regimen on SSIs in patients needs to be studied extensively in the future.

The perioperative dynamics of IL-7 following robot-assisted and open colorectal surgery.

Interleukin-7 is critical for T-cell development and displays antimicrobial and antitumor properties. It is referred to as a "critical enhancer of protective immunity". However, there is no information on interleukin-7 dynamics following colorectal surgery. Moreover, although robot-assisted surgery is gaining popularity, data on the immune response to it is almost non-existent. In this prospective non-randomized case-control study we found interleukin-7 dynamics to differ following robot-assisted and open approach and to affect postoperative immunity. Linear increases were seen in the robotic group while a cubic pattern with a maximum at 8 h in the open one. Low preoperative interleukin-7 was associated with developing surgical site infection. In turn, higher preoperative interleukin-7 was associated with preserved immune function: less pronounced drop in lymphocyte count and higher Δlymphocyte/Δneutrophil ratio in patients undergoing robotic surgery. The changes in other cytokines, namely, interleukin-12(p70), TNFα, interferon-γ, and interleukin-10 were independently associated with interleukin-7 dynamics. In turn, relative changes in interleukin-7 were independent predictors of changes in interferon-γ, key cytokine of favourable Th1 immune response. Taken together, we demonstrated different perioperative dynamics of interleukin-7, which may contribute to favourable outcomes following robotic colorectal surgery including lower incidence of surgical site infections, milder surgery-induced lymphopenia, and beneficial interferon-γ dynamics.

Deep Sternal Wound Tuberculosis with Hypo-gamma-globulinemia.

A 44-year-old man was referred to our hospital for the treatment of a pulmonary and deep sternal wound tuberculosis infection, which is an extremely rare type of extrapulmonary tuberculosis. Laboratory testing revealed a serum immunoglobulin (Ig) G level of 286 mg/dL, IgA of 22 mg/dL and IgM of 13 mg/dL. We therefore diagnosed him with hypo-gamma-globulinemia. He was treated with anti-tuberculosis medications and intravenous immunoglobulin. At present, the tuberculosis has not relapsed in the past six years. It may be useful to assess the humoral immunity status in tuberculosis patients with a normal T cell function, and immunoglobulin therapy may be beneficial for protecting such patients from reactivation of tuberculosis.

Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists.

Administration of preoperative antimicrobial prophylaxis, often with a cephalosporin, is the mainstay of surgical site infection prevention guidelines. Unfortunately, due to prevalent misconceptions, patients labeled as having a penicillin allergy often receive alternate and less-effective antibiotics, placing them at risk of a variety of adverse effects including increased morbidity and higher risk of surgical site infection. The perioperative physician should ascertain the nature of previous reactions to aid in determining the probability of the prevalence of a true allergy. Penicillin allergy testing may be performed but may not be feasible in the perioperative setting. Current evidence on the structural determinants of penicillin and cephalosporin allergies refutes the misconception of cross-reactivity between penicillins and cefazolin, and there is no clear evidence of an increased risk of anaphylaxis in cefazolin-naive, penicillin-allergic patients. A clinical practice algorithm for the perioperative evaluation and management of patients reporting a history of penicillin allergy is presented, concluding that cephalosporins can be safely administered to a majority of such patients.

Bilateral acute retinal necrosis after bilateral cataract surgery in an immunocompromised patient: a case report.

PURPOSE: To report a case of bilateral varicella zoster virus (VZV)-associated acute retinal necrosis (ARN) occurring after both eyes sequential cataract surgery in an elderly immunocompromised patient. METHODS: Medical records and investigation results of the patient were reviewed. RESULTS: Patient experienced floaters and blurring of vision in both eyes 4 weeks after her second uncomplicated cataract surgery. Clinical signs of granulomatous keratic precipitates, prominent vitritis, retinitis and vascular thrombosis were noted in both eyes. Aqueous samples from both eyes were positive for VZV. Disease was treated with intravitreal foscarnet bilaterally and 10 days of systemic intravenous acyclovir (10 mg/kg) followed by oral valaciclovir 1 g three times daily. Final visual acuity at 4 months after initial presentation was 20/60 in both eyes with no retinal detachment noted. CONCLUSIONS: Cataract surgery may have been the trigger for bilateral VZV-associated ARN. Immunocompromised patients can develop ARN and require close observation after cataract surgery. This is, to our knowledge, the first report of bilateral ARN following routine cataract surgery.

[Clinical experience with various techniques integrated treat the wounded with gunshot fractures of limbs]. / Klinicheskii opyt primeneniya razlichnykh metodik kompleksnogo lecheniya ranenykh s ognestrel'nymi perelomami kostei konechnostei.

AIM: To increase an efficiency of complex treatment of patients with diaphyseal gunshot fractures of long bones by introduction of modern minimally invasive surgical techniques of internal osteosynthesis into clinical practice of civil health care and to improve the outcomes in victims. MATERIAL AND METHODS: Prospective comparative clinical trial included 104 victims from the Republic of Yemen with gunshot wounds of limbs of various severity for the period 2009-2011. There were diaphyseal fractures of long bones of limbs associated with soft tissue injuries. Men were predominant (80.7%). Age ranged from 15 to 80 years (mean 38,5 ± 5,7 years). Various surgical techniques of simultaneous and staged treatment were used for gunshot fractures of long bones of limbs. Additional immune therapy was prescribed to prevent infectious complications in the most severe cases. RESULTS AND DISCUSSION: Victims were comprehensively treated according to different staged treatment: conventional surgical treatment with external fixation devices or early primary minimally invasive functionally stable osteosynthesis with LCP/BIOS plates were applied for low-energy fractures; in case of high-energy fractures the first stage included external fixation devices deployment followed by their subsequent replacement during delayed minimally invasive osteosynthesis. The essence of improvement is pursuit to simultaneous minimally invasive surgery by using of current plates for osteosynthesis and preventive immunotherapy of immune dysfunction to eliminate infectious complications. As a result, we obtained 2-fold decrease of surgical invasiveness (r≤0,01) and hospital-stay (r≤0,01). Repeated osteosynthesis was not made. Also 4-fold and 40-fold reduction of infectious and noninfectious complications was observed. This management was accompanied by reduced rehabilitation tine and significantly improved quality of life. CONCLUSION: Improved technique and algorithm of complex treatment of diaphyseal gunshot fractures of long bones of limbs were described. Early minimally invasive functionally stable osteosynthesis with modern implants and non-specific immune prevention of infectious complications are more effective and economically justified compared with conventional treatment including external fixation devices without immunoactive therapy.

Prograf produces more benefits for CYP3A5 low expression patients in early stage after kidney transplantation.

OBJECTIVE: This study is to analyze concentration changes of the prolonged-release and shorter-acting formulation of tacrolimus in patients with different CYP3A5 genotypes after kidney transplantation. METHODS: A single-factor retrospective analysis was performed in patients underwent allogeneic kidney transplantation with postoperative administration of Advagraf or Prograf in our hospital from May 2013 to June 2014. The CYP3A5 genotypes were determined, and tacrolimus trough concentrations in whole blood were measured within 28days after transplantation. The rates of acute rejection rate, chronic rejection and infection were recorded and compared after one year follow-up after surgery. RESULTS: The study included 106 patients administered Advagraf (45 cases) or Prograf (61 cases). The low expression genotype of CYP3A5 was detected in 40 (37.7%) patients. A higher dose of Advagraf was required to increase the tacrolimus trough concentrations within 21days after transplantation. Moreover, a higher dose for Advagraf than Prograf was required to increase the tacrolimus trough concentrations in low expression patients. In the low expression patients, Prograf more frequently achieved the target tacrolimus trough concentrations within seven days after transplantation (five days: 7.14% vs. 84%, P=0.001; seven days: 33.33% vs. 77.78%, P=0.001). The patient and kidney graft survival rates one year after transplantation both were 100%. The estimated glomerular filtration rate showed no significant difference between different CYP3A5 phenotypes or formulations of tacrolimus (P>0.05). However, the incidence of infections was higher in the Advagraf group in low expression patients (P<0.05). CONCLUSION: Tacrolimus of different formulations had different impact on patients with different CYP3A5 genotypes after kidney transplantation.