Richard Strauss

Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

BACKGROUND & AIMSnIn the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome.nnnMETHODSnPatients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild).nnnRESULTSnInfliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission.nnnCONCLUSIONSnThe degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

A Randomized, Double-Blind Trial Comparing Ceftobiprole Medocaril with Vancomycin plus Ceftazidime for the Treatment of Patients with Complicated Skin and Skin-Structure Infections

BACKGROUNDnA randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime.nnnMETHODSnPatients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7-14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease.nnnRESULTSnAmong the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar.nnnCONCLUSIONSnCeftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

ABSTRACT Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, −4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, −8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287].

Prediction of in-hospital death from community-acquired pneumonia by varying CRB-age groups

C(U)RB-65 (confusion, (urea >7 mol·L−1,) respiratory frequency ≥30 breaths·min−1, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg and age ≥65 years) is now the generally accepted severity score for patients with community-acquired pneumonia (CAP) in Europe. In an observational study based on the large database from the German nationwide performance measurement programme in healthcare quality, including data from all hospitalised patients with CAP during 2008–2010, different CRB-age groups (≥50 and ≥60 years) across the total CAP population and three entities of CAP (younger population aged <65 years, patients aged ≥65 years not residing in nursing homes and those with nursing home-acquired pneumonia (NHAP)) were validated for their potential to predict in-hospital death. 660 594 patients were investigated. Mortality was n=93 958 (14.0%). In the total population, CRB-80 had the optimal area under the curve (0.690, 95% CI 0.688–0.691). However, in the younger cohort, CRB-50 performed best (0.730, 95% CI 0.724–0.736), with good identification of low-risk patients (CRB-50 risk class 1: 1.28% deaths, negative predictive value 98.7%). In the elderly, CRB-80 as the optimal age group performed worse (0.663, 95% CI 0.660–0.655 in patients not residing in nursing homes; 0.608, 95% CI 0.605–0.611 in those with NHAP). In the latter group, all CRB-age groups failed to identify low-risk patients (CRB-80 risk class 1: 22.75% deaths, negative predictive value 81.8%). Patients with hospitalised CAP aged <65 years may be assessed by the CRB-50 score. In those aged ≥65 years (not NHAP) assessed by the CRB-65 score, low-risk patients are already are at an increased risk of death. In NHAP patients, even the use of CRB-80 does not identify low-risk patients and should be accompanied by the evaluation of functional status and comorbidity.

Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

ABSTRACT Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for ≥30 and ≥50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a ≥30 or ≥50% T>MIC and a clinical cure (P = 0.003 and P = 0.007, respectively; Pearsons χ2 test). The fractional TAR was greater than 90% at a MIC of ≤4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of ≥30 or ≥50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

Population Pharmacokinetic Analysis of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

ABSTRACT Population pharmacokinetic analysis demonstrated that renal function, as assessed by creatinine clearance (CLCR), was the patient characteristic that had a clinically relevant impact on ceftobiprole pharmacodynamics. Dosing adjustments based on CLCR for subjects with renal impairment should provide ceftobiprole exposure similar to that in patients with normal renal function.

Why Do Nonsurvivors from Community-Acquired Pneumonia Not Receive Ventilatory Support?

ObjectiveWe investigated rates and predictors of ventilatory support during hospitalization in seemingly not severely compromised nonsurvivors of community-acquired pneumonia (CAP).MethodsWe used the database from the German nationwide mandatory quality assurance program including all hospitalized patients with CAP from 2007 to 2011. We selected a population not residing in nursing homes, not bedridden, and not referred from another hospital. Predictors of ventilatory support were identified using a multivariate analysis.ResultsOverall, 563,901 patients (62.3xa0% of the whole population) were included. Mean age was 69.4xa0±xa016.6xa0years; 329,107 (58.4xa0%) were male. Mortality was 39,895 (7.1xa0%). A total of 28,410 (5.0xa0%) received ventilatory support during the hospital course, and 76.3xa0% of nonsurvivors did not receive ventilatory support (62.6xa0% of those aged <65xa0years and 78xa0% of those aged ≥65xa0years). Higher age (relative risk (RR) 0.48, 95xa0% confidence interval (CI) 0.44–0.51), failure to assess gas exchange (RR 0.18, 95xa0% CI 0.14–0.25) and to administer antibiotics within 8xa0h of hospitalization (RR 0.48, 95xa0% CI 0.39–0.59) were predictors of not receiving ventilatory support during hospitalization. Death from CAP occurred significantly earlier in the nonventilated group (8.2xa0±xa08.9 vs. 13.1xa0±xa014.1xa0days; pxa0<xa00.0001).ConclusionsThe number of nonsurvivors without obvious reasons for withholding ventilatory support is disturbingly high, particularly in younger patients. Both performance predictors for not being ventilated remain ambiguous, because they may reflect either treatment restrictions or deficient clinical performance. Elucidating this ambiguity will be part of the forthcoming update of the quality assurance program.

Clinical Response Is a Meaningful Endpoint in Ulcerative Colitis Clinical Studies: P-30

BACKGROUND: Vedolizumab (VDZ) has demonstrated efficacy in the treatment of moderately to severely active ulcerative colitis in patients in whom conventional treatment has failed (NCT00783718). In this prespecified exploratory analysis, efficacy was assessed in subgroups based on prior failure of specific classes of agents. METHODS: Eligible adult patients had a Mayo score 6 and endoscopic subscore 2 despite corticosteroids (CSs), purine antimetabolites, and/or TNFa antagonists. After 2 induction doses of VDZ (wk 0, wk 2), patients with clinical response (reduction in Mayo score of 3 points and 30% from baseline, plus decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore 1 point) at wk 6 were randomized 1:1:1 to VDZ 300 mg IV q4wks, VDZ 300 mg IV q8wks, or placebo (PBO) for 46 wks. The primary outcome of the induction phase was clinical response (reduction in complete Mayo score of 3 points and 30% from baseline and a decrease in rectal bleeding subscore of 1 point or an absolute rectal bleeding subscore of 1 point) at 6 weeks. Secondary outcomes were clinical remission (complete Mayo score of 2 points and no individual subscore >1 point) and mucosal healing (Mayo endoscopic subscore of 1 point) at 6 weeks. The primary outcome in maintenance was remission at wk 52. Secondary outcomes were durability of clinical response and remission (endpoint met at both wks 6 and 52), mucosal healing (Mayo endoscopic subscore 1), and CSfree remission at 52 wks. Patients were categorized based on failure of prior treatment with one or more TNFa antagonists, an immunomodulator but not a TNFa antagonist, or corticosteroids only. RESULTS: Overall, patients receiving VDZ had improved clinical response and remission, mucosal healing, durable clinical response and remission, and CS-free remission, compared with placebo recipients (Tables 1 and 2 and data not shown). VDZ efficacy was similar across prior treatment failure subgroups and consistent with the overall study results in the induction (Table 1) and maintenance (Table 2) phases. In the maintenance phase, there was a greater incidence of AEs in patients with prior anti-TNFa failure vs other pooled subgroups for all treatment groups (VDZ q8, 98% vs 73%; VDZ q4, 85% vs 79%; PBO, 89% vs 82%). Overall TNF failure pts had higher rates of AEs than TNF naı̈ve. CONCLUSION(S): VDZ was numerically superior to PBO in inducing clinical response, clinical remission, and mucosal healing by wk 6 in all prior treatment failure categories. In patients with a clinical response at week 6, VDZ was superior to PBO in maintaining clinical response, clinical remission, and mucosal healing at wk 52, regardless of the type of prior treatment failure.