De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study

Background

In severe sepsis, guidelines recommend de-escalating the empirical antimicrobial treatment as soon as the microbiological results are available. We aimed to determine the rate of de-escalation of the empirical antimicrobial treatment in neutropenic patients with severe sepsis. The characteristics of antimicrobial treatment associated with de-escalation and its impact on short- and long-term survival were also determined.

Methods

In the intensive care unit (ICU) of a cancer referral center, we prospectively collected observational data related to the antimicrobial management in neutropenic patients who developed severe sepsis and were admitted to ICU for at least 48 h. De-escalation of antimicrobial therapy consisted either of deleting one of the empirical antibiotics of a combined treatment, or, whenever possible, to use a betalactam antibiotic with a narrower spectrum of activity. Multivariate logistic regression was conducted to determine the factors associated with de-escalation, while a Cox proportional hazards model with a time-dependent covariate was fitted to assess the effect of de-escalation on 30-day survival. Finally 1-year survival after ICU discharge was compared across de-escalation groups.

Results

Cumulative incidence of de-escalation of the empirical antimicrobial treatment among the 101 patients of the cohort was 44 %, [95 % confidence interval (CI) 38–53 %], including 30 (68 %) patients with ongoing neutropenia. A microbiological documentation was available in 63 (63 %) patients. Factors associated with de-escalation were the adequation of the empirical antimicrobial treatment in ICU [OR = 10.8 (95 % CI 1.20–96)] for adequate documented treatment versus appropriate empirical treatment, the compliance with guidelines regarding the empirical choice of the anti-pseudomonal betalactam [OR = 10.8 (95 % CI 1.3–89.5)]. De-escalation did not significantly modify the hazard of death within the first 30 days [HR = 0.51 (95 % CI 0.20–1.33)], nor within 1 year after ICU discharge [HR = 1.06 (95 % CI 0.54–2.08)].

Conclusion

Our data suggest that, in ICU, de-escalation of the empirical antimicrobial treatment is frequently applied in neutropenic cancer patients with severe sepsis. No evidence of any prognostic impact of this de-escalation was found.     

De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock

Purposes

We set out to assess the safety and the impact on in-hospital and 90-day mortality of antibiotic de-escalation in patients admitted to the ICU with severe sepsis or septic shock.

Methods

We carried out a prospective observational study enrolling patients admitted to the ICU with severe sepsis or septic shock. De-escalation was defined as discontinuation of an antimicrobial agent or change of antibiotic to one with a narrower spectrum once culture results were available. To control for confounding variables, we performed a conventional regression analysis and a propensity score (PS) adjusted-multivariable analysis.

Results

A total of 712 patients with severe sepsis or septic shock at ICU admission were treated empirically with broad-spectrum antibiotics. Of these, 628 were evaluated (84 died before cultures were available). De-escalation was applied in 219 patients (34.9 %). By multivariate analysis, factors independently associated with in-hospital mortality were septic shock, SOFA score the day of culture results, and inadequate empirical antimicrobial therapy, whereas de-escalation therapy was a protective factor [Odds-Ratio (OR) 0.58; 95 % confidence interval (CI) 0.36–0.93). Analysis of the 403 patients with adequate empirical therapy revealed that the factor associated with mortality was SOFA score on the day of culture results, whereas de-escalation therapy was a protective factor (OR 0.54; 95 % CI 0.33–0.89). The PS-adjusted logistic regression models confirmed that de-escalation therapy was a protective factor in both analyses. De-escalation therapy was also a protective factor for 90-day mortality.

Conclusions

De-escalation therapy for severe sepsis and septic shock is a safe strategy associated with a lower mortality. Efforts to increase the frequency of this strategy are fully justified.     

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment

Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable. Published online: 5 March 1999     

The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter,single-blind,randomized and controlled trial

Introduction

Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis.

Methods

We performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis.

Results

A total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded.

Conclusions

The use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00711620","term_id":"NCT00711620"}}NCT00711620.     

Topiramate versus amitriptyline in migraine prevention: A 26-week,multicenter, randomized,double-blind,double-dummy,parallel-group noninferiority trial in adult migraineurs

Objective: The primary objective of this study was to compare the efficacy and tolerability of topiramate and amitriptyline in the prophylaxis of episodic migraine headache.Methods: This was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority study. Adults with 3 to 12 migraines per month were randomized in a 1:1 ratio to receive an initial dose of 25 mg/d of either topiramate or amitriptyline, subsequently titrated to a maximum of 100 mg/d (or the maximum tolerated dose). The primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. Secondary efficacy variables included changes from the prospective baseline phase to the end of the double-blind phase in the mean monthly (28-day) rate of days with migraine, mean monthly rate of days with headache (migraine and nonmigraine), mean monthly rate of acute abortive medication use, mean monthly migraine duration, and mean monthly migraine severity. Additional secondary efficacy variables included changes in the mean monthly severity of migraine-associated symptoms (photophobia, phonophobia, and nausea), change in the mean monthly frequency f migraine-associated vomiting, and response rates (based on monthly migraine days and total headache days). The Migraine-Specific Quality of Life Questionnaire (MSQ) and the Weight Satisfaction Scale Questionnaire, which measures subjective satisfaction with current weight, were administered. Treatment-emergent adverse events (TEAEs) were monitored through the end of double-blind treatment.Results: The intent-to-treat population included 331 subjects (172 topiramate, 159 amitriptyline; 84.9% female; 84.6% white; mean [SD] age, 38.8 [11.0] years; mean weight, 77.1 [20.1] kg) who provided at least 1 efficacy assessment. The least squares mean (LSM) change from baseline in the mean monthly number of migraine episodes was not significantly different between the topiramate and amitriptyline groups (-2.6 and -2.7, respectively; 95% CI, -0.6 to 0.7). There were no significant differences between treatment groups in any of the prespecified secondary outcome measures. Subjects receiving topiramate had a significantly greater improvement in mean functional disability scores during migraine attacks compared with amitriptyline (LSM change: -0.33 vs -0.19; 95% CI, -0.3 to 0.0; P = 0.040) and in the role function-restrictive, role function-preventive, and emotional function domains of the MSQ (P = 0.012, P = 0.014, and P = 0.029, respectively). Subjects receiving topiramate had a mean weight loss of 2.4 kg, compared with a mean weight gain of 2.4 kg in subjects receiving amitriptyline. Subjects in the topiramate group reported an overall improvement from baseline in weight satisfaction, whereas the amitriptyline group reported an overall deterioration in weight satisfaction (P < 0.001, topiramate vs amitriptyline). TEAEs of mild or moderate severity were reported in 118 subjects (66.7%) in the topiramate group and 112 subjects (66.3%) in the amitriptyline group. Among the most common TEAEs (reported in ±5% of subjects during the double-blind phase) in the topiramate group were paresthesia (29.9%), fatigue (16.9%), somnolence (11.9%), hypoesthesia (10.7%), and nausea (10.2%). The most commonly reported TEAEs in the amitriptyline group were dry mouth (35.5%), fatigue (24.3%), somnolence (17.8%), weight increase (13.6%), dizziness (10.7%), and sinusitis (10.7%).Conclusions: In this noninferiority study, topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy end points. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction.     

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.     

Cefoxitin versus gentamicin and metronidazole in prevention of post-appendicectomy sepsis: a randomized, prospective trial

Three hundred and seven patients with appendicitis were randomized to receive cefoxitin or gentamicin and metronidazole. For early appendicitis, a single preoperative dose of antibiotics was given. For late cases, the antibiotics were continued postoperatively for seven days. Both cefoxitin and gentamicin-metronidazole were effective in the reduction of post-appendicectomy septic complications in early or late appendicitis and there was no statistically significant difference between them. Mild transient and reversible nephrotoxicity was detected in 1.9% of patients who received gentamicin-metronidazole for seven days. Nephrotoxicity was not detected in any other patients. The cost of cefoxitin is higher, but this has to be balanced against the costs of monitoring serum gentamicin and creatinine levels, and the need to adjust the gentamicin dosage in 19% of patients when gentamicin-metronidazole was used. Both cefoxitin and gentamicin-metronidazole are effective and safe when used carefully. Cefoxitin has a slight advantage in its lack of potential nephrotoxicity and ototoxicity.     

Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial

Objectives:     

Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit

BACKGROUND: Mortality in patients with severe sepsis remains high despite the development of several therapeutic strategies. The aim of this randomized, double-blind, placebo-controlled trial was to evaluate whether homeopathy is able to influence long-term outcome in critically ill patients suffering from severe sepsis. METHODS: Seventy patients with severe sepsis received homeopathic treatment (n = 35) or placebo (n = 35). Five globules in a potency of 200c were given at 12h interval during the stay at the intensive care unit. Survival after a 30 and 180 days was recorded. RESULTS: Three patients (2 homeopathy, 1 placebo) were excluded from the analyses because of incomplete data. All these patients survived. Baseline characteristics including age, sex, BMI, prior conditions, APACHE II score, signs of sepsis, number of organ failures, need for mechanical ventilation, need for vasopressors or veno-venous hemofiltration, and laboratory parameters were not significantly different between groups. On day 30, there was non-statistically significantly trend of survival in favour of homeopathy (verum 81.8%, placebo 67.7%, P= 0.19). On day 180, survival was statistically significantly higher with verum homeopathy (75.8% vs 50.0%, P = 0.043). No adverse effects were observed. CONCLUSIONS: Our data suggest that homeopathic treatment may be a useful additional therapeutic measure with a long-term benefit for severely septic patients admitted to the intensive care unit. A constraint to wider application of this method is the limited number of trained homeopaths.     

Cefepime versus cefotaxime for empirical treatment of bacterial pneumonia in HIV-infected patients: an open, randomized trial

An open, randomized, multicentre clinical trial was conducted to compare the efficacy and safety of cefepime 2 g iv bd (2 g tds daily in cases of Pseudomonas aeruginosa pneumonia) with cefotaxime 2 g iv tds, in the empirical treatment of bacterial pneumonia in HIV-infected patients. The primary end-point was effectiveness after 3-5 days of treatment, taking success to be when the study drug was continued during this period of time. Clinical and bacteriological responses at end of treatment (EOT) were also evaluated. Analyses of the intention-to-treat population (n = 160) and the as-per-protocol groups (n = 150) were carried out. Treatment groups were comparable with regard to sex, age, HIV status and degree of severity of pneumonia. The primary end-point for cefepime was considered successful for the intention-to-treat and as-per-protocol groups in 85.7% and 93.5% of cases, respectively, and for cefotaxime, in 77.6% and 80.8% of cases, respectively (P = 0.22 and P = 0.02). In the as-per-protocol group, cefotaxime treatment was independently related to failure at the primary end-point. A satisfactory clinical response in the intention-to-treat population was observed in 83.3% of cefepime and 82.9% of cefotaxime patients. Bacteriological cure was obtained in 100% of evaluable cefepime and 93.4% of evaluable cefotaxime patients at EOT. Safety of the study drugs was comparable in both treatment groups. Cefepime 2 g iv bd was at least as effective and as well tolerated as cefotaxime 2 g iv tds in the treatment of bacterial pneumonia in HIV-infected patients.     

Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study

Purpose

Ulinastatin, a serine protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. We studied the effect of ulinastatin on 28-day all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals.

Methods

Patients with sepsis were randomized within 48 h of onset of one or more organ failures to receive intravenous administration of ulinastatin (200,000 IU) or placebo 12 hourly for 5 days.

Results

Of 122 randomized subjects, 114 completed the study (55 receiving ulinastatin, 59 receiving placebo). At baseline, the mean APACHE II score was 13.4 (SD = 4.4), 48 (42 %) patients were receiving mechanical ventilation, 58 (51 %) were on vasopressors, and 35 % had multiple organ failure. In the modified intention-to-treat analysis (patients receiving six or more doses of study drugs), 28-day all-cause mortality was 7.3 % with ulinastatin (4 deaths) versus 20.3 % (12 deaths) with placebo (p = 0.045). On multivariate analysis too, treatment with ulinastatin (odds ratio 0.26, 95 % CI 0.07–0.95; p = 0.042) independently decreased 28-day all-cause mortality. However, the mortality difference did not reach statistical significance in the intention-to-treat analysis [10.2 % (6/59 deaths) with ulinastatin versus 20.6 % (13/63 deaths) in the placebo group; p = 0.11]. The ulinastatin group had lower incidence of new-onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean ± SD 19.4 ± 10.6 days vs. 10.2 ± 12.5 days, p = 0.019), and shorter hospital stay (11.8 ± 7.1 days vs. 24.2 ± 7.2 days, p < 0.001).

Conclusions

In this pilot study, intravenous administration of ulinastatin reduced mortality in patients with severe sepsis in the modified intention-to-treat analysis, but not in the intention-to-treat analysis.     

Gastric versus transpyloric feeding in severe traumatic brain injury: a prospective, randomized trial

Purpose  

To evaluate the efficacy of transpyloric feeding (TPF) compared with gastric feeding (GF) with regard to the incidence of ventilator-associated pneumonia in severe traumatic brain injury patients (TBI).     

Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study

A continuous infusion of vancomycin (CIV) may provide an alternative mode of infusion in severe hospital-acquired methicillin-resistant staphylococcal (MRS) infections. A multicenter, prospective, randomized study was designed to compare CIV (targeted plateau drug serum concentrations of 20 to 25 mg/liter) and intermittent infusions of vancomycin (IIV; targeted trough drug serum concentrations of 10 to 15 mg/liter) in 119 critically ill patients with MRS infections (bacteremic infections, 35%; pneumonia, 45%). Microbiological and clinical outcomes, safety, pharmacokinetics, ease of treatment adjustment, and cost were compared. Microbiological and clinical outcomes and safety were similar. CIV patients reached the targeted concentrations faster (36 +/- 31 versus 51 +/- 39 h, P = 0.029) and fewer samples were required for treatment monitoring than with IIV patients (7.7 +/- 2.2 versus 11.8 +/- 3.9 per treatment, P < 0.0001). The variability between patients in both the area under the serum concentration-time curve (AUC(24h)) and the daily dose given over 10 days of treatment was lower with CIV than with IIV (variances, 14,621 versus 53,975 mg(2)/liter(2)/h(2) [P = 0.026] and 414 versus 818 g(2) [P = 0.057], respectively). The 10-day treatment cost per patient was $454 +/- 137 in the IIV group and was 23% lower in the CIV group ($321 +/- 81: P < 0.0001). In summary, for comparable efficacy and tolerance, CIV may be a cost-effective alternative to IIV.     

Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial

Severe pruritus may be an idiopathic phenomenon or associated with advanced systemic disease. It is one of the most distressing and difficult to treat symptoms. Uncontrolled studies have suggested that, in patients experiencing severe pruritus, paroxetine appeared to have a rapid anti-pruritic effect. This study was a prospective double-blind, randomized within patient comparison of paroxetine and placebo. The intensity of pruritus was measured subjectively with a numerical analogue scale. The primary endpoint of the trial was the mean pruritus score, measured for seven days after randomization and after cross-over. The secondary endpoint was individual global response to the treatment. Response was defined as at least 50% reduction of intensity of pruritus in the last three days of the treatment period vs. baseline. Adverse effects and patient satisfaction and preferences were also recorded. Twenty-six patients were included in the study; 17 of them had solid tumors, 4 had hematological malignancies and 5 had various nonmalignant or idiopathic conditions. Eight patients had drug-induced pruritus (none opioid-induced), 7 patients had paraneoplastic pruritus and 3 had cholestatic pruritus. After a run-in period, patients were randomly assigned to treatment with 20 mg paroxetine or placebo. The crossover took place after 7 days. Two patients discontinued treatment because of adverse effects of paroxetine. Twenty-four patients treated with paroxetine had lower pruritus intensity scores over the 7 treatment periods (mean±SE = 5.2 ± 0.32) as compared to placebo (mean±SE = 6.0±0.32). Mean difference between placebo and paroxetine was 0.78 (95% CI = 0.37–1.19). Nine of twenty-four patients (37.5%) fulfilled criteria of response. The onset of anti-pruritic action was observed usually after 2–3 days, irrespective of the order of treatment. The outcome of this study indicates that paroxetine is effective in the treatment of severe pruritus of non-dermatological origin.