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Purpose of Review: Multidrug-resistant (MDR) bacteria can cause serious infections in solid-organ transplant recipients. This review focuses on the role of MDR bacteria in posttransplant infections., Recent Findings: The incidence of MDR bacterial infections among solid-organ transplant recipients is increasing steadily. There is wide variability in the specific MDR bacteria causing infection based on the organ transplanted, geography, timing with respect to transplantation, and additional risk factors. Rarely these infections can be transmitted via the transplanted organ. Prompt recognition and early appropriate treatment of MDR bacterial infections are especially critical in this immunosuppressed population. In order to promptly initiate appropriate antimicrobial therapy for these organisms, high-risk patients should receive appropriate broad-spectrum antibiotics., Summary: MDR bacterial infections vary widely and require careful antibiotic selection to reduce mortality.

NO has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined the impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. Colon ascendens stent peritonitis markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22 h after CASP. The detrimental effects of NOS3 deficiency on myocardial function after CASP seem to be caused by impaired Ca handling of cardiomyocytes. The impaired Ca handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca cycling capacity of sarcoplasmic reticulum Ca-ATPase. The NOS3 deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice.

Analysis of literature data on drug-induced hepatotoxicity reveals that often upper respiratory febrile illnesses and/or inflammation states precede liver injury/diseases related to administration of drugs or hepatotoxicity associated with administration of therapeutic doses of acetaminophen in some genetically predisposed subjects. The goals of this paper are to review the potential role of alterations in the balance between TH1 cells producing cytokines associated with a cell-mediated response and TH2 cells associated with an antibody response, as well as other endogenous substances, eg, growth factors, leading to a shift in immune response to one that may participate in the liver cells injury during administration of certain drugs, especially in subjects with genetic polymorphisms in drug-metabolizing enzymes. The papers cited in this review were selected to illustrate specific issue related to how profuse and dysregulated production of cytokines, growth factors, and/or other endogenous substances during viral/bacterial infections and inflammation states play a role in the development of drug-induced liver injury. Several cases of liver injury related to administration of drugs appear to be initiated or intensified by upper respiratory febrile illnesses and/or inflammation states, which stimulate sometimes dysregulated production of interferon gamma and/or other proinflammatory cytokines/growth factors. This, in turn, results in down-regulation of various induced and constitutive isoforms of cytochromes P-450, and other enzymes involved in the metabolism of several exogenous (eg, drugs) and endogenous lipophilic (eg, steroids) substances, thus having an important impact on the alterations in bioactivation and detoxication processes in the body and on the balance between production, utilization, and elimination of endogenous bioproducts of these reactions. Activation of systemic host defense mechanisms results in down-regulation of various enzymes involved in drug metabolism and elimination, as well as in production, utilization, and excretion of many endogenous substances that have beneficial effects on vital processes in the body. It seems that treatment of acute and chronic infections and/or inflammations with, for example, antibacterials not metabolized in the liver, and use of medications that decrease proinflammatory cytokine levels (eg, pentoxifylline, a TNF-alpha synthesis inhibitor, directed against TNF-alpha-induced priming of human neutrophils, immunotherapy with IL-4, IL-1 receptor antagonists or factors inducing IL-1ra, dietary supplementation with long-chain n-3 fatty acids, and other antioxidant agents) may perhaps, in some cases, be helpful in the prevention and management of drug-induced hepatotoxicity. Drug-mediated injuries may eventually be prevented by screening methods that can identify genetic polymorphism of drug-metabolizing enzymes and gene polymorphisms or RNA-expression profiles of some proinflammatory cytokines before a patient uses a drug.

Background: Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandin E2 (PGE2) from activated macrophages. PGE2 is increased during trauma and sepsis and has been implicated as a negative immunomodulator. The objective of this study was to determine the therapeutic benefits of a COX-2 inhibitor (NS-398) on survival and leukocyte production in a murine model of burn sepsis., Methods: To determine the in vitro ability of NS-398 to inhibit macrophage production of PGE2, peritoneal elicited macrophages were stimulated for 18 hours with medium alone, endotoxin (ETX) (1 mumol/L), or ETX plus NS-398 (0.3 mumol/L). Macrophage supernatant PGE2 levels were determined by an enzyme immunoassay. To test the in vivo efficacy of NS-398, mice subjected to a 15% dorsal scald burn plus 1,000 colony-forming units of topical Pseudomonas aeruginosa received either 10 mg/kg NS-398 intraperitoneally or placebo 4 to 6 hours after infection and twice daily for 3 days. Survival was measured up to 14 days, and circulating white blood cell (WBC) count and absolute neutrophil count (ANC) were determined 3 days after injury., Results: Macrophage PGE2 production was significantly increased in the ETX-treated group compared with the medium-alone group, and this increase was completely normalized with the addition of NS-398. NS-398 also augmented WBC count (4,288 +/- 649 vs. 7,866 +/- 435 per mm3; p < 0.01) and ANC (1,068 +/- 255 vs. 3,663 +/- 474 per mm3) after burn infection and attenuated macrophage depression of hematopoietic proliferation. Finally, NS-398 treatment significantly improved survival after burn infection, from 0 to 45.5%., Conclusion: Inhibition of the COX-2 isoform of cyclooxygenase with NS-398 inhibited macrophage PGE2 production, restored ANC, and improved survival during burn infection. NS-398, therefore, has potential therapeutic benefits in septic patients who have developed neutropenia.

Objective: The authors examined the prevalence and complications of pancreatitis in severely burned patients. Factors predictive for the development of pancreatitis after burns are considered., Summary Background Data: Pancreatitis has been documented at necropsy after burns; however, it is not clinically recognized as a common complication of burn injury. Recent improvements in survival rates could yield previously unrecognized complications, such as pancreatitis, particularly in those patients who previously would have not survived. The hypothesis is that pancreatitis is a frequent complication after major burn injury and causes significant morbidity for patients with large burns., Methods: This retrospective review of adult patients with large burns examines postburn pancreatitis using stepwise logistic regression analysis., Results: Forty-nine of 121 (40%) patients developed hyperamylasemia or hyperlipasemia well after the admission period (23 +/- 3 days), and all enzyme abnormalities were temporally associated with emerging infections. Most of these patients (40/49, 82%) had symptoms of pancreatitis. Three patients (6%) had pancreatic pseudocysts or abscesses. Inhalation injury (p = 0.0001), associated trauma (p = 0.0311), and escharotomy (p = 0.0415) were risk factors for pancreatitis. Using Fischer's exact test, patients with pancreatitis had increased mortality and length of stay. Patients with high enzyme elevations and > or = 50% body surface area burned were at severe risk of pancreatic pseudocyst or abscess development (43%; 90% confidence interval of 23-77%)., Conclusions: Pancreatitis is a frequent complication after large burn injuries. Patients at high risk for pancreatitis complications should receive surveillance examinations during their acute hospitalization.

Liver function tests were studied in chronically infected surgical patients, patients who recovered from infection, nonseptic malnourished patients and healthy control subjects. Liver function tests were abnormal in the septic patients but returned to normal values upon recovery from infection despite persistent loss of body weight. Malnourished, nonseptic patients similarly had normal liver function tests. These findings suggest that infection rather than accompanying malnutrition is the major cause of the abnormal liver function tests commonly observed in chronically septic surgical patients. Standard liver function tests may be helpful both in the diagnosis of occult intra-abdominal sepsis and also in indicating the efficacy of its treatment.

We previously reported increased lipid peroxide and decreased alpha-tocopherol levels in the blood of critically ill septic patients. To clarify these results, we investigated lipid peroxidation in experimental septic rats and severely traumatized rats. In septic rats, both platelet count and plasma alpha-tocopherol decreased significantly, while lipid peroxide in plasma and major organs significantly increased. Serum transaminases also increased significantly. Traumatized rats had a significant but transient decrease in platelet count and a continuous decrease in plasma alpha-tocopherol; lipid peroxide did not change significantly in the plasma but increased significantly in the lung and kidney. Serum transaminases of traumatized rats showed transient increases. Thus, although traumatic stress caused lipid peroxidation similar to sepsis in the major organs, plasma lipid peroxide did not change.