Stephanie Bass

Comparison of treatment outcomes with vancomycin alone versus combination therapy in severe Clostridium difficile infection

BACKGROUND The recommended treatment for severe Clostridium difficile infection (CDI) is oral vancomycin alone. Combination therapy with metronidazole is only recommended in cases complicated by shock, ileus, or toxic megacolon. However, patients with severe infection are often treated with combination therapy despite a lack of data supporting this practice. AIM To evaluate differences in outcomes for patients with severe CDI treated with oral vancomycin alone versus combination therapy. METHODS Medical records of 78 patients with severe CDI receiving either oral vancomycin alone or combination therapy for ≥ 72h were retrospectively reviewed. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥ 48h without development of a complication. Other endpoints included cure rates, complication rates, and recurrence rates. FINDINGS There was no difference in the incidence of clinical cure between monotherapy and combination therapy (57.1% vs 65.1%, P = 0.49). Median time to clinical cure was 7.0 days for the monotherapy group and 8.0 days for combination therapy (P = 0.19). After adjustment for potential confounders, the hazard ratio of the time to clinical cure for combination therapy compared with monotherapy was 0.58 (P = 0.10). There was no difference in recurrence rate or rates of individual complications between groups; however, there was a significantly higher composite complication rate in the combination therapy group. CONCLUSION These data suggest that there is no difference in treatment outcomes between monotherapy and combination therapy for severe CDI.

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

ABSTRACT The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Impact of Combination Antimicrobial Therapy on Mortality Risk for Critically Ill Patients with Carbapenem-Resistant Bacteremia

ABSTRACT There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P = 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered.

Effect of vancomycin dose on treatment outcomes in severe Clostridium difficile infection

Current guidelines recommend vancomycin 125 mg four times daily for the treatment of severe Clostridium difficile infection (CDI). However, the optimal dose of vancomycin has not been elucidated. This study was conducted to evaluate outcome differences in patients with severe CDI treated with either low-dose (≤500 mg daily) or high-dose (>500 mg daily) oral vancomycin. The medical records of 78 patients with severe CDI were evaluated retrospectively. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥48 h without development of a complication. Other endpoints included cure rates, complication rates and recurrence rates. Overall, 48 patients (61.5%) achieved clinical cure at Day 10 after treatment initiation. The cure rates in the high-dose and low-dose vancomycin groups were 60% and 64%, respectively (P = 0.76). Using a multivariate Cox proportional hazards model adjusting for baseline discrepancies, vancomycin dose was not independently associated with clinical cure. No difference in time to cure, complication rates or mortality was observed between the groups. There was a trend towards lower rates of recurrence associated with higher doses of oral vancomycin (12% vs. 1.9%; P = 0.09). In conclusion, these data suggest that there is no difference in treatment outcomes between high-dose and low-dose vancomycin for the treatment of severe CDI. The potential difference in recurrence rates between the groups warrants further investigation.

Intravenous acetylcysteine for indications other than acetaminophen overdose

PURPOSE The use of intravenous acetylcysteine for off-label indications, specifically non-acetaminophen-induced acute liver failure (NAI-ALF), severe alcoholic hepatitis, and contrast-induced nephropathy (CIN), is reviewed. SUMMARY I.V. acetylcysteine is most often used as an antidote for acetaminophen overdose due to its ability to increase levels of glutathione; however, it is also used to treat NAI-ALF and severe alcoholic hepatitis and to prevent CIN. Although the i.v. and oral formulations of acetylcysteine have been evaluated for these indications, most studies have examined the i.v. form. I.V. acetylcysteine is used in the treatment of NAI-ALF to improve oxygenation to the liver. One large randomized trial of 173 adults with NAI-ALF from any etiology and of any grade encephalopathy demonstrated overall improvement in transplant-free survival, particularly for patients with low-grade encephalopathy, though overall survival was not improved. When used to treat severe alcoholic hepatitis, i.v. acetylcysteine serves as an antioxidant and glutathione source. A trial of 174 patients with severe alcoholic hepatitis revealed that patients had 28-day survival benefit when treated with acetylcysteine; improvement in patients with hepatorenal syndrome was also noted. When used for the prevention of CIN, i.v. acetylcysteine provides antioxidants and vasodilation. The benefit for this indication is limited to surrogate markers such as serum creatinine and in patients with multiple risk factors for the development of CIN. CONCLUSION Data regarding the use of i.v. acetylcysteine for the treatment of NAI-ALF and severe alcoholic hepatitis and in the prevention of CIN are inconclusive, though some evidence supports its use in certain populations.

Noninferiority of Inhaled Epoprostenol to Inhaled Nitric Oxide for the Treatment of ARDS

Background: Inhaled nitric oxide and inhaled epoprostenol have been evaluated for the management of hypoxemia in acute respiratory distress syndrome, with clinical trials demonstrating comparable improvements in oxygenation. However, these trials have several limitations, making it difficult to draw definitive conclusions regarding clinical outcomes. Objective: The aim of this study was to evaluate the noninferiority and safety of inhaled epoprostenol compared with inhaled nitric oxide in mechanically ventilated acute respiratory distress syndrome (ARDS) patients with a primary outcome of ventilator-free days from day 1 to day 28. Methods: This was a retrospective, noninterventional, propensity-matched, noninferiority cohort study. Propensity score for receipt of inhaled nitric oxide was developed and patients were matched accordingly using a prespecified algorithm. Secondary objectives included evaluating day 28 intensive care unit–free days, changes in PaO2/FiO2 ratio after inhalation therapy initiation, and hospital mortality. Safety endpoints assessed included hypotension, methemoglobinemia, renal dysfunction, rebound hypoxemia, significant bleeding, and thrombocytopenia. Results: Ninety-four patients were included, with 47 patients in each group. Patients were well-matched with similar baseline characteristics, except patients in inhaled nitric oxide group had lower PaO2/FiO2 ratio. Management of ARDS was similar between groups. Mean difference in ventilator-free days between inhaled epoprostenol and inhaled nitric oxide was 2.16 days (95% confidence interval = −0.61 to 4.9), with lower limit of 95% confidence interval greater than the prespecified margin, hence satisfying noninferiority. There were no differences in any secondary or safety outcomes. Conclusions: Inhaled epoprostenol was noninferior to inhaled nitric oxide with regard to ventilator-free days from day 1 to day 28 in ARDS patients.

High-dose versus standard dose oseltamivir for treatment of severe influenza in adult intensive care unit patients.

Dear Editor, The Centers for Disease Control and Prevention (CDC) suggest that higher doses (i.e., 300 mg/day) of oseltamivir may be warranted in patients with severe influenza infection [1]. Two prospective, controlled trials have not demonstrated differences in clinical outcomes between patients treated with high-dose versus standard dose oseltamivir; however, only a small number of critically ill adults requiring intensive care unit (ICU) admission were included in these analyses [2, 3]. To provide additional insight into the optimal dosing of oseltamivir in patients with severe influenza, we conducted a retrospective cohort study to evaluate differences in clinical outcomes for 123 critically ill patients with influenza receiving high-dose or standard dose oseltamivir. With Investigational Review Board approval, we collected demographic and treatment-related data on adult patients with laboratory-confirmed influenza who required ICU admission with supplemental oxygen above baseline and who were treated with oseltamivir for at least 24 h. Patients were divided into high-dose ([150 mg/day) or standard dose (B150 mg/day) oseltamivir therapy based on renally adjusted daily dose (Table 2 in Supplementary Material). The primary objective was difference in ICU-free days. Secondary objectives included a comparison of the change in the Sequential Organ Failure Assessment (SOFA) score between 0 and 48 h after oseltamivir initiation (delta SOFA0–48h), ventilator-free days, and 28-day mortality. For a full description of methods, please refer to the Supplementary Material. As anticipated, differences in baseline characteristics were noted (Table 3 in Supplementary Material). Compared with the standard dose group (n = 46), patients in the highdose group (n = 77) were younger (52.7 vs. 60.4 years; p\ 0.01), had a higher median SOFA score on day 1 of therapy (7 vs. 5; p = 0.02), had a higher fraction (%) of inspired oxygen (FiO2) on day 1 of therapy (75 ± 28 vs. 51 ± 24 %; p\ 0.01), and were more commonly infected with influenza A (78 vs. 54 %; p = 0.02) . There were no differences in baseline comorbidities or in the use of vasoactive medications, antibiotics, corticosteroids, and other influenza antivirals between groups (Table 4 in Supplementary Material). Patients in the high-dose group had fewer ICU-free days than the standard dose group, fewer ventilator-free days, and a higher 28-day mortality rate (Table 1). There were no differences in other secondary outcomes, including hospital length of stay and time to return to baseline oxygen requirements. On multivariable analyses, high-dose therapy was not independently associated with time to ICU discharge [hazard ratio 1.35, 95 % confidence interval (CI) 0.81–2.27] or 28-day mortality (odds ratio 2.63, 95 % CI 0.93–7.55).

Comparison of oral vancomycin capsule and solution for treatment of initial episode of severe Clostridium difficile Infection.

Objective: Vancomycin is recommended as a first-line therapy for severe Clostridium difficile infection (CDI). Due to the high cost of commercially available vancomycin capsules, hospitals frequently compound oral solution despite a lack of data comparing outcomes. This study was conducted to determine treatment outcome differences based on oral vancomycin formulation. Methods: Medical charts of 76 patients with an initial episode of severe CDI receiving oral vancomycin as a commercially available capsule or a compounded oral solution for at least 72 hours were retrospectively reviewed. The primary objective was to compare the time to clinical cure of CDI. Results: Baseline characteristics between groups were similar except for the median lactate, which was higher in compounded oral solution group (1.5 vs 0.6 mmol/L, P < .001). There was no difference in clinical cure at day 10 (64% solution vs 59% capsules, P = .664). Median time to clinical cure was 8 days for solution and 7 for capsules (P = .597). After adjustment, the hazard ratio of time to clinical cure for solution compared to capsules was 1.15 (P = .69). No significant differences in mortality, recurrence, or complications were noted. Conclusion: Formulation of oral vancomycin did not impact treatment outcomes in this retrospective study.

Compliance with Procalcitonin Algorithm Antibiotic Recommendations for Patients in Medical Intensive Care Unit.

To describe compliance with antibiotic recommendations based on a previously published procalcitonin (PCT)‐guided algorithm in clinical practice, to compare PCT algorithm compliance rates between PCT assays ordered in the antibiotic initiation setting (PCT concentration measured less than 24 hours after antibiotic initiation or before antibiotic initiation) with those in the antibiotic continuation setting (PCT concentration measured 24 hours or more after antibiotic initiation), and to evaluate patient‐ and PCT‐related factors independently associated with algorithm compliance in patients in the medical intensive care unit (MICU).