Current concepts in combination antibiotic therapy for critically ill patients

Widespread emergence of multidrug resistant (MDR) bacterial pathogens is a problem of global dimension. MDR infections are difficult to treat and frequently associated with high mortality. More than one antibiotic is commonly used to treat such infections, but scientific evidence does not favor use of combination therapy in most cases. However, there are certain subgroups where combination therapy may be beneficial, e.g. sepsis due to carbapenem-resistant Enterobacteriaceae (CRE), bacteremic pneumococcal pneumonia, and patients with multiple organ failure. Well-designed prospective studies are needed to clearly define the role of combination therapy in these subgroups.     

Intensive insulin therapy in the critically ill patients.

BACKGROUND: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. METHODS: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). RESULTS: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. CONCLUSIONS: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.     

Effects of early changes in organ dysfunctions on the outcomes of critically ill patients in need of renal replacement therapy

INTRODUCTION: Acute kidney injury usually develops in critically ill patients in the context of multiple organ dysfunctions. OBJECTIVE: To evaluate the effect of changes in associated organ dysfunctions over the first three days of renal replacement therapy on the outcomes of patients with acute kidney injury. METHODS: Over a 19-month period, we evaluated 260 patients admitted to the intensive care units of three tertiary-care hospitals who required renal replacement therapy for > 48 h. Organ dysfunctions were evaluated by SOFA score (excluding renal points) on the first (D1) and third (D3) days of renal replacement therapy. Absolute (A-SOFA) and relative (Delta-SOFA) changes in SOFA scores were also calculated. RESULTS: Hospital mortality rate was 75%. Organ dysfunctions worsened (A-SOFA>0) in 53%, remained unchanged (A-SOFA=0) in 17% and improved (A-SOFA<0) in 30% of patients; and mortality was lower in the last group (80% vs. 84% vs. 61%, p=0.003). SOFA on D1 (p<0.001), SOFA on D3 (p<0.001), A-SOFA (p=0.019) and Delta-SOFA (p=0.016) were higher in non-survivors. However, neither A-SOFA nor Delta-SOFA discriminated survivors from non-survivors on an individual basis. Adjusting for other covariates (including SOFA on D1), A-SOFA and Delta-SOFA were associated with increased mortality, and patients in whom SOFA scores worsened or remained unchanged had poorer outcomes. CONCLUSIONS: In addition to baseline values, early changes in SOFA score after the start of renal replacement therapy were associated with hospital mortality. However, no prognostic score should be used as the only parameter to predict individual outcomes.     

Granulocyte colony-stimulating factor therapy and systemic inflammation in critically ill patients

Objective and design: The effect of the granulocyte colony-stimulating factor filgrastim on systemic inflammation was investigated in a prospective, randomized, placebo- controlled, double-blind study in critically ill patients.Subjects: 59 Critically ill patients were recruited within 48 h of intubation due to ventilatory insufficiency.Treatment: Subcutaneous dosage of placebo or 300 g filgrastim once daily.Methods: Serum samples were collected at study entry, and 1 and 3 days after the start (Day1 and Day3, respectively). Levels of soluble E-selectin (sE-selectin) and interleukin(IL)-10 were determined by ELISA, and those of IL-6, and soluble IL-2 receptor (sIL-2R) by Immulite^® chemiluminescence immunoassay.Results: The median sE-selectin level decreased by day 3 significantly in the control group but not in the filgrastim group. The difference in the change between the study groups was significant (p = 0.049). IL-10 levels decreased significantly in the filgrastim group, tended to decrease in controls (p = 0.052), and the difference in the change tended to be significant (p = 0.058). IL-6 levels decreased in both groups comparably. sIL-2R levels were elevated and stable.Conclusions: Filgrastim prolongs endothelial activation and possibly inhibits development of immune suppression mediated by IL-10.Received 25 May 2004; returned for revision 30 June 2004; accepted by M. J. Parnham 3 January 2005     

Current chemotherapeutic regimens for brain metastases treatment

Brain metastasis is a common complication in advanced systemic cancer, with an increasing incidence. The diagnosis of brain metastasis historically portended a dismal prognosis. The successful development of effective treatments for patients with brain metastasis is complicated by the differences among cancer subtypes, the limited understanding of the underlying pathophysiology of BM, the impact of the blood-brain barrier, and other factors. There is now renewed interest in treating this often devastating complication of cancer, and in understanding the underlying mechanisms of disease in this “sanctuary” site. Promising treatment strategies include brain-penetrant targeted therapies and immunotherapy, and strategies for enhanced delivery of therapy. This review highlights a selection of these approaches.     

Candidemia in critically ill patient: An analysis of daily antifungal therapy related costs

Data on the cost of antifungal therapy in critically ill patients with candidemia are lacking. Therefore, a historical observational cohort study was conducted to evaluate the daily cost of antifungal treatment in the critically ill with a microbiologically documented nosocomial candidemia. Over a four-year period (2003–2006), costs were calculated according to the causative pathogen, the source of infection and survivors versus non-survivors, respectively. Candidemia in critically ill patients represents a significant economic burden in terms of daily antimicrobial costs.     

Strategy for the treatment of fungal infections in critically ill surgical patients]

To improve the outcome of invasive Candida infections, earlier empirical therapy before the establishment of the definitive diagnosis is considered to be necessary. However, appropriate use of empirical therapy for suspected candidiasis in febrile non-neutropenic surgical patients has not been defined. According to the guidelines from the Infectious Diseases Society of America, empirical therapy of suspected candidiasis in this setting should be limited to patients with Candida colonization of multiple sites, multiple other risk factors, and absence of any other causes of fever. A corrected colonization index which takes into account both the density and the degree of colonization of Candida spp. was shown to be the independent factors that predict subsequent candidal infection. It may also be appropriate to commence empirical therapy on the basis of a positive serodiagnostic test. Beta-D glucan is a cell-wall constituent of fungi, which is assumed to be a marker of fungal sepsis. However, it has been shown that beta-D-glucan can also be detected in patients without fungal infections, such as those on haemodialysis, and its positive predictive value is relatively low. The mono-utilization of beta-D-glucan for the assessment of fungal infection should therefore be avoided. The combined assessment of beta-D-glucan and extent of colonization with Candida spp. is believed to have the advantage of lessening the likelihood of a false positive reaction of beta-D-glucan.