Ciu 219
Ciu 219
Ciu 219
Background. Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalospo-
rin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (includ-
ing methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria,
including Enterobacteriaceae and Pseudomonas aeruginosa.
Methods. This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneu-
monia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous ceftobiprole
500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was
clinical cure at the test-of-cure visit.
Results. Overall cure rates for ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT],
95% condence interval [CI] for the difference, 10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI,
10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, 7.3 to 8.8), and
77.8% vs 76.2% (CE, 95% CI, 6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, 26.0
to 1.5) and 37.7% vs 55.9% (CE, 95% CI, 36.4 to 0). Microbiological eradication rates in HAP (excluding VAP)
patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, 16.7 to 7.6), and in VAP
patients 30.4% vs 50.0% (ME, 95% CI, 38.8 to 0.4). Treatment-related adverse events were comparable for cefto-
biprole (24.9%) and ceftazidime/linezolid (25.4%).
Conclusions. Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP
(excluding VAP). Further investigations are needed before recommending the use of ceftobiprole in VAP patients.
Clinical Trials Registration. NCT00210964, NCT00229008.
Keywords. ceftazidime; ceftobiprole; linezolid; hospital-acquired pneumonia; ventilator-associated pneumonia.
Hospital-acquired pneumonia (HAP) is the second and a leading cause of death in hospitalized patients
most frequent hospital-acquired infection in adults, [1, 2]. Common pathogens in HAP are Staphylococcus
aureus (including methicillin-resistant S. aureus
[MRSA]), Pseudomonas aeruginosa, Acinetobacter bau-
Received 3 December 2013; accepted 20 March 2014; electronically published 9
April 2014. mannii, Klebsiella species, Escherichia coli, and Entero-
Correspondence: Marc Engelhardt, MD, Basilea Pharmaceutica International Ltd, bacter species; Streptococcus pneumoniae may also play
Basel Switzerland (marc.engelhardt@basilea.com).
a role in HAP [3].
Clinical Infectious Diseases 2014;59(1):5161
The Author 2014. Published by Oxford University Press on behalf of the Infectious There is a signicant unmet need for new antibiotics
Diseases Society of America. All rights reserved. For Permissions, please e-mail: effective against bacterial pathogens responsible for
journals.permissions@oup.com.
DOI: 10.1093/cid/ciu219
HAP. Treatment guidelines for HAP recommend
Figure 1. Patient disposition. Abbreviations: Ceftaz, ceftazidime; Dx, diagnosis; mITT, microbiological intent-to-treat; NP, nosocomial pneumonia; TOC,
test-of-cure; Tx, treatment.
All Patients, No. (%) HAP (Excluding VAP), No. (%) VAP, No. (%)
Abbreviations: AB, antibiotics; APACHE, Acute Physiology and Chronic Health Evaluation; CrCl, creatinine clearance; CRP, C-reactive protein; HAP, hospital-acquired
pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; SIRS, systemic inflammatory response
syndrome; VAP, ventilator-associated pneumonia.
Three hundred eighty-six patients in each treatment group were in Europe, 12% in the United States, 32% in other regions.
available for safety assessment. 71% vs 62% of the patients in the ceftobiprole and the compar-
Of the 247 patients who discontinued the study, 126 patients ator groups, respectively, were men, and 45% vs 47% were aged
(32%) were from the ceftobiprole group, and 121 (31%) were >65 years. A substantial proportion of the patient population
from the ceftazidime/linezolid group. The most common rea- was severely ill: 41% of the patients in each treatment group
sons for discontinuation were death (77 ceftobiprole [20%] had an APACHE II score 15, and 12% of ceftobiprole patients
and 74 ceftazidime/linezolid [19%]), and AEs (14 ceftobiprole and 13% of ceftazidime/linezolid patients had an APACHE II
[4%], and 6 ceftazidime/linezolid [2%]). score 20. Seventy-two percent and 73% of the patients, respec-
tively, presented with systemic inammatory response syn-
Baseline Data drome, 10% and 12%, respectively, had bacteremia, and 58%
Baseline demographic and clinical characteristics are provided and 62% had received prior antibiotics within 24 hours of en-
in Table 1. The study recruited patients in 32 countries; 56% rollment. A pathogen considered to cause pneumonia was
Ceftobiprole Ceftazidime/Linezolid
Analysis Set Group No. No.a (%) No. No.a (%) Difference (%)b (95% CI)c
Intent-to-treat
All patients 391 195 (49.9) 390 206 (52.8) 2.9 (10.0 to 4.1)
HAP (excluding VAP) 287 171 (59.6) 284 167 (58.8) 0.8 (7.3 to 8.8)
VAP 104 24 (23.1) 106 39 (36.8) 13.7 (26.0 to 1.5)
HAP, mechanically ventilated 69 21 (30.4) 70 19 (27.1) 3.3 (11.8 to 18.3)
Clinically evaluable
All patients 251 174 (69.3) 244 174 (71.3) 2.0 (10.0 to 6.1)
HAP (excluding VAP) 198 154 (77.8) 185 141 (76.2) 1.6 (6.9 to 10.0)
VAP 53 20 (37.7) 59 33 (55.9) 18.2 (36.4 to .0)
HAP (excluding VAP), 38 21 (55.3) 37 15 (40.5) 14.7 (7.6 to 37.1)
mechanically ventilated
Abbreviations: CI, confidence interval; HAP, hospital-acquired pneumonia; VAP, ventilator-associated pneumonia.
a
No. of patients with clinical cure at test of cure.
b
Difference ceftobiprole minus ceftazidime/linezolid.
c
Two-sided 95% CI is based on the normal approximation to the difference of the 2 proportions.
found at baseline in 69% of the patients in the ceftobiprole demonstrated in patients with HAP (excluding VAP) within
group and in 68% of the patients in the ceftazidime/linezolid the predened noninferiority margin of 15%. The cure rates
group. Ten percent and 12% of the patients, respectively, were at TOC for HAP (excluding VAP) patients in the ITT analysis
infected with MRSA. In patients with VAP, 73% in the ceftobi- set were 59.6% for ceftobiprole and 58.8% for ceftazidime/line-
prole and 81% in the ceftazidime/linezolid group had been ven- zolid (difference, 0.8 [95% CI, 7.3 to 8.8]), and 77.8% and
tilated for 5 days prior to enrollment. 76.2%, respectively, in the CE analysis set (difference, 1.6
[95% CI, 6.9 to 10.0]) (Table 2). Results for the primary end-
Outcomes point in HAP (excluding VAP) patients were also comparable
Results for the primary endpoint are provided in Table 2. The for ceftobiprole and ceftazidime/linezolid when analyzed by
study achieved its primary objective demonstrating noninferior- baseline demographic and clinical characteristics. Clinical
ity of ceftobiprole to ceftazidime/linezolid for clinical cure rate cure rates for HAP (excluding VAP) patients were comparable
at the TOC visit within the protocol-dened margin of 15% in in subgroup analyses by sex, geographical region, age, and dis-
the coprimary ITT and CE analysis sets. The cure rates in the ease severity (APACHE II score) (Table 3).
ITT analysis set were 49.9% and 52.8% for ceftobiprole and cef- In the CE analysis set, a higher proportion of HAP (excluding
tazidime/linezolid, respectively (difference, 2.9% [95% CI, VAP) patients in the ceftobiprole group than in the ceftazidime/
10.0 to 4.1]), and 69.3% and 71.3%, respectively (2.0% linezolid group (CE, 86.9% vs 78.4%; difference 8.5 [95% CI, .9
[95% CI, 10.0 to 6.1]), in the CE analysis set. 16.1]) showed early improvement (4 days after onset of therapy)
Consistent with regulatory guidance distinguishing HAP (ex- as assessed by the investigator based on the resolution of clinical
cluding VAP) and VAP [28, 29], further efcacy analyses were signs and symptoms. The largest difference was for patients
conducted of the HAP (excluding VAP) and VAP patient pop- with a baseline culture positive for MRSA, with 94.7% in the
ulations. The results for HAP (excluding VAP) patients and ceftobiprole group having early improvement vs 52.6% in the
VAP patients are therefore discussed separately below. ceftazidime/linezolid group (difference, 42.1 [95% CI, 17.5
66.7]) (Table 4).
Subgroup Analyses of the Primary Endpoint Of the 198 ceftobiprole and 185 ceftazidime/linezolid HAP
In the ITT analysis set, 73% of all patients enrolled were HAP (excluding VAP) patients in the CE analysis set, 38 (19%) and
(excluding VAP) patients (287 in the ceftobiprole group and 284 37 (20%), respectively, required mechanical ventilation during
in the ceftazidime/linezolid group). Baseline characteristics of treatment, or developed pneumonia within 48 hours after the
HAP (excluding VAP) patients were comparable to those of start of ventilation (ie, did not fall within the denition of
the overall study population (Table 1). Noninferiority of cefto- VAP). For these ventilated HAP (excluding VAP) patients, high-
biprole to ceftazidime/linezolid for clinical cure at TOC was er cure rates were observed in the ceftobiprole group than in the
Ceftobiprole Ceftazidime/Linezolid
ceftazidime/linezolid group: 55.3% vs 40.5%, respectively (CE; characterized by a substantial heterogeneity in baseline charac-
difference, 14.7 [95% CI, 7.6 to 37.1]) (Table 2). teristics (Table 1).
Noninferiority was not demonstrated in VAP patients. The
cure rates at TOC for VAP patients in the ITT analysis set Subgroup Analyses of Secondary Endpoints
were 23.1% for ceftobiprole and 36.8% for ceftazidime/linezolid Microbiological Eradication
(difference, 13.7 [95% CI, 26.0 to 1.5]) (Table 2). An For the main secondary endpoint, the microbiological eradica-
MVLRA did not reveal any specic patient factors in VAP pa- tion rates at TOC for HAP (excluding VAP) patients in the
tients that could explain the differential clinical and microbio- microbiologically evaluable analysis set were 62.9% for ceftobi-
logical outcome between the treatment arms in this subgroup. prole and 67.5% for ceftazidime/linezolid (difference, 4.6%
The subgroup of VAP patients was relatively small, and was [95% CI, 16.7 to 7.6]) (Table 5). For patients with VAP, the
Ceftobiprole Ceftazidime/Linezolid
Analysis Set Group No. n (%) No. n (%) Difference (%)a (95% CI)b
ITT
HAP (excluding VAP) 287 221 (77.0) 284 214 (75.4) 1.7 (5.3 to 8.6)
Any valid gram-positive 85 69 (81.2) 102 75 (73.5) 7.6 (4.3 to 19.6)
Any Staphylococcus aureus 55 45 (81.8) 76 55 (72.4) 9.4 (4.9 to 23.8)
Any MRSA 28 22 (78.6) 32 19 (59.4) 19.2 (3.6 to 42.0)
Clinically evaluable
HAP (excluding VAP) 198 172 (86.9) 185 145 (78.4) 8.5 (.916.1)
Any valid gram-positive 61 53 (86.9) 69 51 (73.9) 13.0 (.4 to 26.4)
Any S. aureus 39 36 (92.3) 49 35 (71.4) 20.9 (5.736.0)
Any MRSA 19 18 (94.7) 19 10 (52.6) 42.1 (17.566.7)
Clinical improvement was assessed by the investigator. All categories include monomicrobial and polymicrobial infections.
Abbreviations: CI, confidence interval; HAP, hospital-acquired pneumonia; ITT, intent-to-treat; MRSA, methicillin-resistant Staphylococcus aureus; n, number of
patients with clinical improvement at Day 4; VAP, ventilator-associated pneumonia.
a
Difference for ceftobiprole minus ceftazidime/linezolid.
b
Two-sided 95% CI is based on the normal approximation to the difference of the 2 proportions.
rates were 30.4% for ceftobiprole and 50.0% for ceftazidime/ baseline pathogens, numerically lower clinical cure and micro-
linezolid (difference, 19.6% [95% CI, 38.8 to 0.4]) biological eradication rates were observed in the ceftobiprole
(Table 5). group.
Table 5. Microbiological Eradication at Test of Cure (Microbiological Intent-to-Treat and Microbiologically Evaluable Analysis Sets)
Ceftobiprole Ceftazidime/Linezolid
Analysis Set Group No. n (%) No. n (%) Difference (%)a (95% CI)b
Microbiological ITT
All patients 269 105 (39.0) 267 127 (47.6) 8.5 (16.9 to .2)
HAP (excluding VAP) 179 87 (48.6) 181 97 (53.6) 5.0 (15.3 to 5.3)
VAP 90 18 (20.0) 86 30 (34.9) 14.9 (27.9 to 1.9)
Microbiologically evaluable
All patients 162 87 (53.7) 170 106 (62.4) 8.6 (19.2 to 1.9)
HAP (excluding VAP) 116 73 (62.9) 120 81 (67.5) 4.6 (16.7 to 7.6)
VAP 46 14 (30.4) 50 25 (50.0) 19.6 (38.8 to 0.4)
Abbreviations: CI, confidence interval; HAP, hospital-acquired pneumonia; ITT, intent-to-treat; n, number of patients with microbiological eradication at test of cure;
VAP, ventilator-associated pneumonia.
a
Difference for ceftobiprole minus ceftazidime/linezolid.
b
Two-sided 95% CI is based on the normal approximation to the difference of the 2 proportions.
HAP (excluding VAP), No. (%) VAP, No. (%) All Patients, No. (%)
Numbers in bold refer to the number of patients with a pathogen in the respective group.
Abbreviations: HAP, hospital-acquired pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus;
n, number of patients with an outcome of clinical cure or eradication for the respective pathogen at test of cure; VAP, ventilator-associated pneumonia.
a
Forty-six patients with Enterobacteriaceae isolated at baseline, including E. coli (monomicrobial), n = 11; E. coli plus Klebsiella spp, n = 1; E. coli plus Proteus spp,
n = 1; E. coli plus Providencia spp, n = 1; K. pneumoniae (monomicrobial), n = 9; Klebsiella oxytoca, n = 1; K. pneumoniae plus Proteus spp, n = 1; K. pneumoniae
plus Serratia spp, n = 1; K. pneumoniae plus Enterobacter spp, n = 1; Enterobacter spp, n = 8; Serratia spp, n = 5; Proteus mirabilis, n = 3; Citrobacter spp, n = 2;
Providencia spp, n = 1.
b
Forty-five patients with Enterobacteriaceae isolated at baseline, including E. coli (monomicrobial), n = 8; E. coli plus K. pneumoniae, n = 1; E. coli plus Proteus spp,
n = 1; E. coli plus K. pneumoniae plus Serratia spp, n = 1; K. pneumoniae (monomicrobial), n = 14; Klebsiella oxytoca, n = 1; Klebsiella spp, n = 2; K. pneumoniae plus
Proteus spp, n = 2; K. pneumoniae plus Proteus spp plus Serratia spp, n = 1; Enterobacter spp, n = 7; Serratia spp, n = 2; Proteus mirabilis, n = 3; Citrobacter spp,
n = 1; Hafnia alvei, n = 1.