Overall, 802 patients were enrolled between May 2012 and June 2014, and 761 were randomized to receive ceftaroline fosamil (n = 506) or vancomycin plus aztreonam (n = 255) . Of the 761 randomized patients, 42 were admitted to the ICU prior to, or at the start of, study drug administration (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10); reasons for all ICU admissions were related to the disease under study. Baseline and disease characteristics for ICU and non-ICU patients, including primary cSSTI diagnosis and comorbidities, are summarized in Table 1.
The mean (SD) ages of patients in the ICU and non-ICU subsets (MITT population) were 57 (16.6) and 53 (16.4) years, respectively. The majority of patients in both groups were < 65 years of age [64.3% (27/42) and 75.5% (543/719), respectively] and male [57.1% (24/42) and 60.4% (434/719), respectively]. Among the 42 patients admitted to the ICU, the primary cSSTI diagnosis was burn infection in 66.7% (28/42) and cellulitis in 23.8% (10/42). In contrast, the most common primary cSSTI diagnoses in the non-ICU subset were cellulitis [59.2% (426/719)] and major cutaneous abscess [22.5% (162/719)]. Median baseline lesion size was 899 cm2 for the ICU subset and 376 cm2 for the non-ICU subset. Bacteremia was present in 14.3% (6/42) of patients in the ICU subset and 3.9% (28/719) of patients in the non-ICU subset, and SIRS was present in 26.2% (11/42) and 40.8% (293/719) of patients, respectively. Systemic antibiotics within the 4 weeks before starting the study were received by 35.7% (15/42) and 47.4% (341/719) of patients in the ICU and non-ICU subsets, respectively.
Within the ICU subset, there were notable imbalances between the ceftaroline fosamil and vancomycin plus aztreonam treatment groups in some baseline and disease characteristics (Table 1). For example, burn infection was the predominant primary cSSTI diagnosis in both groups, but was more frequent in the vancomycin plus aztreonam group; bacteremia was also documented more frequently in the vancomycin plus aztreonam ICU group. In contrast, more than twice the proportion of patients in the ceftaroline fosamil ICU group (41%) had received prior antibiotics compared with those in the vancomycin plus aztreonam ICU group (20%).
Pathogens isolated at baseline from ICU and non-ICU patients are shown in Table S5. Pathogens most frequently isolated in ICU patients (MITT population) included S. aureus (25 patients [59.5%], including 4 with methicillin-susceptible S. aureus and 21 with MRSA), streptococci [5 patients (11.9%)], and Gram-negative Enterobacteriaceae [7 patients (16.7%)]. No ESBL-positive organisms were identified in ICU patients. A similar baseline pathogen profile was observed in non-ICU patients, with S. aureus being the most commonly isolated (see Table S5); however, as would be expected for this much larger group, there was a wider and more diverse collection of pathogens in non-ICU patients, including some ESBL-positive Enterobacteriaceae isolates. Minimum inhibitory concentration (MIC) distributions for ceftaroline and vancomycin against MSSA and MRSA isolates from ICU and non-ICU patients available for susceptibility testing (see Figure S6) showed that all isolates were within current respective European Committee on Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute MIC susceptibility breakpoints [16, 17].
In the ICU subset, the median (range) durations of exposure to ceftaroline fosamil and vancomycin plus aztreonam were 7 (3–14) and 10 (5–14) days, respectively, in the MITT population, and 8 (3–14) and 10 (5–14) days, respectively, in the CE population. Corresponding values for the non-ICU subset were 8 (0–14) and 8 (0–14) days (MITT population), and 8 (2–14) and 8 (0–14) days (CE population). Clinical responses at the TOC visit (Table 2) were comparable between treatment groups in non-ICU patients (both 79%). In the ceftaroline fosamil group, the clinical cure rate in the ICU subset (69%) was lower than for non-ICU patients. In contrast, for vancomycin plus aztreonam the clinical cure rate was higher in the ICU subset (90%) relative to non-ICU patients. Compared with non-ICU patients, the substantially wider 95% confidence intervals for the estimates of differences in clinical cure rate between treatment groups in the ICU subset in both the MITT and CE populations (Table 2), reflect the much smaller sample size of the ICU subset.
An overview of AEs and serious AEs (SAEs) in ICU and non-ICU patients up to the LFU visit is shown in Table 3. In the ICU subset, there were six SAEs in six patients (18.3%) in the ceftaroline fosamil group (one case each of myocardial infarction, pneumonia, abdominal infection, toxic epidermal necrolysis, peripheral arterial occlusive disease, and venous thrombosis), and one SAE in one patient (10.0%) in the vancomycin plus aztreonam group (one case of pulmonary embolism). Three of the SAEs in the ceftaroline fosamil ICU subset (myocardial infarction, pneumonia and abdominal infection) were reported to be of severe intensity. None of the reported SAEs in either treatment group in the ICU subset were considered by the investigator to be related to study treatment.
Exploratory Healthcare Resource Use Analyses
In the overall COVERS study population, median (range) hospital LOS for both treatment groups in the MITT and CE populations was 11 days (MITT population: ceftaroline fosamil, 2–55 days; vancomycin plus aztreonam, 1–45 days; CE population: ceftaroline fosamil, 4–55 days; vancomycin plus aztreonam, 4–45 days) and there was no significant difference (P = 0.802 and P = 0.858, respectively) between treatment groups (Fig. 1a). The relationships between exploratory variables and hospital LOS (assessed by Cox proportional hazards model) are summarized in Table 4. Of note, ICU admission (P < 0.001) was a risk factor predicting increased hospital LOS in both the MITT and CE populations, as was the presence of comorbidities (P < 0.001 and P = 0.003, respectively).
Within the ICU subset, median hospital and ICU LOS were shorter for ceftaroline fosamil (8 days) compared with vancomycin plus aztreonam (13 days) overall, and median ICU LOS was shorter for ceftaroline fosamil across all primary cSSTI diagnoses (see Fig. 1b, Table S7).