DRUG FORECAST

Ceftobiprole, a Broad-Spectrum Cephalosporin

With Activity against Methicillin-Resistant
Staphylococcus aureus (MRSA)
Jamie Kisgen, PharmD, and Dana Whitney, PharmD, BCPS

Key words: Ceftobiprole, BAL 9141, same period (from 127,036 to 278,203).1 ability to overcome bacterial resistance.
BAL 5788, RO 63-9141, pyrrolidinones, In 2005, approximately 94,360 patients Ceftobiprole is a broad-spectrum ceph-
cephalosporin in the U.S. developed a serious MRSA alosporin with additional properties that
infection, with 18,650 deaths (20%) re- circumvent many of the mechanisms of
INTRODUCTION lated to the hospital stay.2 Of these severe resistance to beta-lactams. Ceftobiprole
The introduction of methicillin in 1959 MRSA infections, 85% were associated has been evaluated in phase 3 trials for
was a ground-breaking achievement in with health care exposure and one-third treating complicated skin and soft-tissue
the war against penicillin-resistant Staph- occurred during hospitalization. infections (cSSSIs) caused by gram-
ylococcus aureus. Methicillin was devel- Methicillin resistance is conferred by positive and gram-negative bac teria.
oped to overcome the primary mode of a penicillin-binding protein (PBP) that is Recent studies examining the use of
resistance found with resistant strains of encoded by the mecA gene found in the ceftobiprole for the treatment of commu-
S. aureus, inactivation of penicillin by staphylococcal cassette chromosome nity-associated and hospital-associated
beta-lactamase. In 1961, this monumen- mec (SCCmec).3–5 These mobile genetic pneumonia have also been completed
tal achievement was overshadowed by elements may carry additional genetic but have been published only in abstract
the discovery of several strains of S. au- material that encode resistance to other form.
reus in the United Kingdom, which had classes of antimicrobials. Penicillin re-
developed resistance to methicillin sistance in Streptococcus pneumoniae is PHARMACOLOGY AND
(methicillin-resistant S. aureus [MRSA]). mediated through a similar adaptive MECHANISM OF ACTION
MRSA was subsequently isolated mechanism by the bacteria. Alterations Ceftobiprole medocaril is a water-
throughout the world and, in addition to of PBP 2 to PBP 2x by S. pneumoniae soluble prodrug developed to facilitate
causing hospital-acquired infections, may lead to a decrease in activity of peni- the intravenous (IV) administration of
has now spread to the community. With cillin, necessitating higher doses to the active parent drug, ceftobiprole.5,11
this resistance mechanism, MRSA has achieve adequate activity, or may pre- As a result of its limited oral bioavailabil-
proved to be resistant to all subsequent vent the binding altogether (penicillin- ity, it will likely be available in an IV for-
beta-lactam molecules developed over resistant S. pneumoniae [PRSP]). mulation only. After IV administration,
the past several decades. Ceftobiprole, a Ceftobiprole (BAL 9141) is the first of ceftobiprole medocaril is converted to
new-generation cephalosporin, is the first a new generation of extended-spectrum the active drug, ceftobiprole, by type A
beta-lactam agent to demonstrate potent cephalosporins with activity against clin- plasma esterases. This process is rapid
in vitro and in vivo activity against MRSA. ically important gram-positive bacteria, (less than one minute) and complete,
MRSA is a major cause of hospital and including MRSA, PRSP, and Enterococ- with minimal influence from other med-
community-acquired infections world- cus faecalis.6–10 If approved, ceftobiprole ications or disease states.
wide and a major cause of morbidity and would become the only cephalosporin Ceftobiprole is a beta-lactam anti -
mortality. Klein et al. determined that with established activity against E. fae- microbial agent that shows potent bacte-
from 1999 to 2005, the estimated number calis and MRSA. The drug has shown ricidal activity by binding to PBP, inhibit-
of hospitalizations involving S. aureus in- activity against clinically important gram- ing transpeptidation and formation of the
fections increased by 62% (from 294,570 negative pathogens, including Citrobac- bacterial cell wall, leading to cell lysis and
to 477,927), with MRSA-related infec- ter spp., Escherichia coli, Enterobacter death. The drug can bind to several dif-
tions more than doubling during this spp., Klebsiella spp., Serratia marcescens, ferent PBPs found in both gram-negative
and Pseudomonas aeruginosa. and gram-positive bacteria.12,13 Ceftobi-
Dr. Kisgen is an Infectious Diseases Phar- The limited number of approved drugs prole rapidly binds and forms a stable in-
macy Specialist at Sarasota Memorial Health with activity against multidrug-resistant hibitory acyl-enzyme complex with PBP
Care System in Sarasota, Florida. Dr. Whitney bacteria such as MRSA and P. aeruginosa 2´ (PBP 2a) and PBP 2x, which provide
is an Infectious Diseases Pharmacy Special- has increased the demand for new agents activity against beta-lactam–resistant
ist at Boston Medical Center in Boston, Mas- with a novel mechanism of action or an staphylococci and streptococci, respec-
sachusetts. Drug Forecast is a regular column tively. The stability of the acyl-enzyme
coordinated by Alan Caspi, PhD, PharmD, Disclosure: Dr. Whitney has received an complex, in combination with the long
MBA, President of Caspi & Associates in New honorarium from Ortho-McNeil and has side chain that sits deep in the PBP 2´-
York, New York. been a one-time advisory board consultant binding pocket, enhances the stability of
for ceftobiprole and doripenem. the bond and inhibition of the enzyme.

Vol. 33 No. 11 • November 2008 • P&T® 631

DRUG FORECAST

MICROBIOLOGY sible mechanism of ceftobiprole resist- mL). Breakpoints for susceptibility of

Ceftobiprole has demonstrated activ- ance was associated with multiple mecA ceftobiprole have not been established.
ity against clinically important gram-pos- mutations in several isolates expressing
itive bacteria, including penicillin-resistant the mecA gene and another potential role PHARMACOKINETICS AND
S. pneumoniae (PRSP), methicillin-resist- for chromosomal genes mediating resist- PHARMACODYNAMICS
ant S. aureus (MRSA), and E. faecalis with ance in particular strains lacking mecA. The pharmacokinetic properties of cef-
MIC90 values of 0.25, 2, and 2 mcg/mL, Ceftobiprole is active against clinically tobiprole have been evaluated in healthy
respectively (Table 1).6–10 Ceftobiprole has impor tant gram-negative path ogens, volunteers, in patients with varying de-
also demonstrated potent in vitro activity including Citrobacter spp., Escherichia grees of renal dysfunction, and in patients
against several clinical isolates of com- coli, Enterobacter spp., Klebsiella spp., enrolled in clinical trials for the treatment
munity-associated methicillin-resistant Serratia marcescens, and Pseudomonas of cSSSIs.11,17–20 The volume of distribu-
S. aureus (CA-MRSA), vancomycin-inter- aeruginosa.6–10 Although ceftobiprole has tion at steady state (Vss) is approximately
mediate S. aureus (VISA), and vanco- demonstrated activity against isolates ex- 18 to 20 liters. Like other beta- lactams,
mycin-resistant S. aureus (VRSA), with a pressing AmpC beta-lactamases, it has this drug is comparable to the extracellu-
minimum inhibitory concentration (MIC) not consistently shown activity against lar fluid compartment in adults.
of 2 mcg/mL.14,15 The clinical utility of isolates expressing extended spectrum After a two-hour infusion of 500 mg,
ceftobiprole for infections caused by VISA beta-lactamases (ESBLs). Investigators the peak plasma concentration (Cmax) and
and VRSA, however, has not been deter- have not been able to demonstrate reli- the area-under-the-curve (AUC) concen-
mined. In vitro resistance to ceftobiprole able in vitro activity of this agent against tration in healthy volunteers were 29.2
has been found in specific strains of isolates of Enterococcus faecium, Steno- mcg/mL and 90 mcg • hour/mL, respec-
S. aureus, with high-volume broth cul- trophomonas maltophilia, Burkholderia tively. Accumulation of ceftobiprole was
tures containing subinhibitory concen- cepacia, Acinetobacter spp., or clinically not apparent after five days of administra-
trations of ceftobiprole.16 significant anaerobic bacteria like Bac- tion of 500 mg every eight hours infused
Banerjee et al. determined that one pos- teroides spp. (MIC90 values above 8 mcg/ over two hours, Cmax 33 mcg/mL and an

Table 1 In Vitro Activity of Ceftobiprole against Clinically Significant Pathogens

Bacterial Isolate MIC50 MIC90 Range

Gram-positive pathogens
• Methicillin-susceptible Staphylococcus aureus (MSSA) 0.25 0.5 0.25–2
• Methicillin-resistant S. aureus (MRSA) 1 2 0.12–2
• Methicillin-susceptible coagulase-negative Staphylococcus spp. 0.12 0.25 ≤0.015–1
• Methicillin-resistant coagulase-negative Staphylococcus spp. 1 2 ≤0.015–4
• Penicillin-susceptible Streptococcus pneumoniae (PSSP) ≤0.06 ≤0.06 ≤0.015–0.03
• Penicillin-intermediate S. pneumoniae (PISP) ≤0.06 0.12 ≤0.015–0.5
• Penicillin-resistant S. pneumoniae (PRSP) 0.25 0.25 ≤0.015–1
• Beta-hemolytic Streptococcus spp. ≤0.06 ≤0.06 ≤0.015–0.06
• Enterococcus faecalis 0.5 2 0.12– >8
• Enterococcus faecium >8 >8 0.25– >8
Gram-negative pathogens
• Citrobacter freundii ≤0.06 2 ≤ 0.015– >8
• Enterobacter spp. ≤0.06 >8 ≤0.015– >8
• Enterobacter cloacae ≤0.06 0.12 ≤ 0.03– >8
• Escherichia coli ≤0.06 0.12 ≤ 0.015–2
• Escherichia coli (ESBL-positive) >8 >8 0.03– >8
• Klebsiella pneumoniae ≤0.06 >8 ≤ 0.015– >8
• Klebsiella pneumoniae (ESBL-positive) >8 >8 ≤ 0.015– >8
• Proteus mirabilis ≤0.06 0.12 ≤ 0.015–0.03
• Indole-positive Proteus spp.* ≤0.06 >8 ≤ 0.015– >8
• Serratia marcescens ≤0.06 1 0.03– >8
• Haemophilus influenzae ≤0.06 ≤0.06 0.12–0.25
• Moraxella catarrhalis ≤0.06 0.12 ≤ 0.015–1
• Acinetobacter spp. >8 >8 ≤ 0.015– >8
• Pseudomonas aeruginosa 2 >8 0.12– >8
• Stenotrophomonas maltophilia >8 >8 >8
* Includes Proteus vulgaris, Providencia spp., and Morganella spp.
ESBL = extended-spectrum beta-lactamase; MIC = minimum inhibitory concentration.
Data from Walkty A,6 Jones ME, 7 Fritsche TR,8 Jones RN,9 and Pillar CM.10

632 P&T® • November 2008 • Vol. 33 No. 11

 DRUG FORECAST

AUC of 102 mcg • hour mL. Protein bind- The in vitro and in vivo pharmaco- blind, phase 3 trials (STRAUSS 1 and 2)
ing is limited (16%) and is independent of dynamics of ceftobiprole have been stud- evaluated the clinical efficacy of cefto-
the drug concentration; therefore, alter- ied extensively and are similar to those of biprole for hospitalized patients with
ations in protein binding are unlikely to other beta-lactam antimicrobial drugs.20,22 complicated skin and skin structure
affect its overall activity.11 The pharmacodynamic parameter most infections (cSSSIs).
Ceftobiprole is neither an inhibitor of correlated with clinical efficacy of cefto-
nor a substrate for the cytochrome P450 biprole is the percentage of time in which The STRAUSS 1 Study24
(CYP 450) system.11 Studies with cyclo- the free serum concentration (%fT) is STRAUSS 1 compared ceftobiprole
sporine have also demonstrated that above the MIC. Like other cephalo - with vancomycin for the treatment of
ceftobiprole is neither an inhibitor of nor sporins, the optimal %fT above the MIC cSSSIs caused by documented or sus-
a substrate of the p-glycoprotein (PGP) required for ceftobiprole to achieve a pected gram-positive pathogens. Patients
transporter system. Based on combina- bacteriostatic effect is 30% of the dosing were considered eligible for enrollment
tion studies with probenecid, ceftobip- interval for staphylococci and 40% of the if they were older than 18 years of age
role is eliminated by the kidneys as un- dosing interval for gram-negative bacilli, and had a cSSSI caused by gram-posi-
changed drug via glomerular filtration, respectively. For maximal bactericidal tive pathogens based on predefined cri-
not through active tubular secretion.11 activity, the %fT above the MIC should be teria. Patients were classified according
The half-life of ceftobiprole is approx- at least 50% (staphylococci) and 60% to infection type, and the investigators
imately three hours, with more than 80% (gram-negative bacilli) of the dosing limited the percentage of patients with
of the active drug recovered in the urine interval. cellulitis to less than 20%. Patients with
within 12 hours after the administration. Using pharmacokinetic data from 150 diabetic foot infections, infections from
Although slight variations in the subjects, Lodise et al. performed a Monte animal or human bites, or osteomyelitis
drug’s pharmacokinetic properties are Carlo simulation to determine the prob- were excluded.
apparent based on a patient’s sex, no dos- ability of target attainment (PTA) of cefto- Patients were randomly assigned, in a
ing adjustments are necessary.11,21 Phar- biprole against gram-positive and gram- 1:1 ratio, according to the type of infec-
macokinetic properties, in terms of race negative pathogens.20 Several different tion (abscess, wound infections, or cellu-
and optimal dosing for pediatric patients, dosing strategies, in vitro MIC data, and litis) to receive either IV ceftobiprole
have not been published. the four goals for target attainment, as 500 mg every 12 hours as a 60-minute
The pharmacokinetic parameters of just described, were used. infusion or IV vancomycin 1,000 mg
ceftobiprole in patients with normal renal When the investigators used 500 mg every 12 hours as a 60-minute infusion
function and in those with mild, moder- every 12 hours over one hour, they found for 7 to 14 days.
ate, and severe renal impairment have no significant difference in the PTA for The primary efficacy endpoint of this
been determined.11,19,20 Twenty male sub- gram-positive isolates with MIC values of non-inferiority trial was a clinical cure rate
jects with varying degrees of renal func- 1 mcg/mL or below, using a target for the at the test-of-cure (TOC) visit (7 to 14
tion were studied to determine the opti- PTA of 50% for bactericidal activity. Using days after the end of therapy). This out-
mal dosing schedule for those patients the dosing scheme of 500 mg every eight come was assessed in the clinically evalu-
with renal impairment for use in future hours and three dif ferent lengths of able and intent-to-treat (ITT) populations
clinical trials. Roos et al. determined that infusions (30 minutes, one hour, two (Figures 1 and 2). The ITT population
systemic exposure, as measured by the hours), they determined that the two- included all randomized patients. The
AUC concentration, was elevated in the hour infusion improved the likelihood of clinically evaluable patients had a proto-
patients with renal impairment. target attainment for gram-positive and col-defined cSSSI, completed the TOC
Renal impairment was defined as a cre- gram-negative organisms with an MIC visit (6 to 14 days after therapy), and re-
atinine clearance (CrCl) below 80 mL/ of 2 mcg/mL or greater. ceived 80% or more of the study drug
minute; normal clearance was defined as For isolates with MIC values of 1 mcg/ course. Based on an expected clinical
a CrCl above 80 mL/minute. Compared mL or below, the infusion time had little cure rate of 80%, ceftobiprole was consid-
with subjects with normal renal function, effect on the PTA for a %fT above the ered non-inferior if the lower limit of the
patients with mild renal impairment MIC target of 40%, 50%, or 60%. The inves- 95% confidence interval (CI) for the differ-
(CrCl, 50 to 80 mL/minute) experienced tigators did notice a decreased PTA for ence in clinical cure rate was –10% or
an increase of 29% in the AUC concentra- the two-hour dosing scheme against more.
tion; patients with moderate renal impair- AmpC-producing gram-negative isolates The ITT analysis included a total of 784
ment (CrCl, 30 to 50 mL/minute), an and P. aeruginosa (MIC50 = 4), compared patients, with 42% patients from the U.S.;
AUC increase of 250%; and patients with with isolates that were non–AmpC- 397 patients were randomly assigned to
severe renal impairment (CrCl, below 30 producing gram-negative isolates, PTA receive ceftobiprole, and 387 patients
mL/minute), an AUC increase of 330%. (of 60%fT > MIC) 87.8%, 62%, and 94.1%, received vancomycin. The clinically eval-
The half-life of ceftobiprole increased respectively. uable population consisted of 559 patients
with decreasing renal function. The with a clinical outcome evaluated at the
longest half-life occurred in patients with CLINICAL EFFICACY TOC visit (282 in the ceftobiprole group,
severe renal impairment (11 hours). As Skin and Skin-Structure 277 in the vancomycin group).
a result, dosage adjustment is necessary Infections23–26 In the ITT population, there were no
in patients with renal insufficiency. Two randomized, multicenter, double- significant differences in demographics,

Vol. 33 No. 11 • November 2008 • P&T® 633

DRUG FORECAST

pending the results of culture, at the dis-

Ceftobiprole Comparator cretion of the clinician if suspected or
100 documented anaerobic pathogens were
present.
90 The trial was of a non-inferiority de-
81.9 80.8
77.8 77.5 sign. The primary efficacy endpoint was
80
the clinical cure rate at the TOC visit (7
70 to 14 days after the end of therapy). As
with STRAUSS 1, the primary outcome
Clinical cure (%)

60 was the rate of clinical cure, as measured

50 in both the clinically evaluable and ITT
populations. Based on an expected non-
40 evaluable rate of 30%, 816 patients were
needed to reject the null hypothesis of
30 inferiority for ceftobiprole of 10%, using
20 a power of 80% and a two-sided alpha of
0.05. Ceftobiprole was considered non-
10 inferior to the combination of vanco-
mycin and ceftazidime if the lower limit
0
of the 95% CI for the difference in clinical
STRAUSS 1 STRAUSS 2
cure rate was –10% or above. A second-
Figure 1 Clinical cure rates for the intent-to-treat population.
ar y outcome in the group of micro -
(Data from Noel GJ, Straus RS, Amsler K, et al. Antimicrob Agents Chemother 2008;
biologically evaluable patients was an-
52:37–44;24 and Noel GJ, Bush K, Bagchi P, et al. Clin Infect Dis 2008;46:647–655.26)
alyzed to determine the microbiologic
eradication rate at the TOC visit.
baseline characteristics, type of infection, ceftobiprole 500 mg every eight hours as A total of 828 patients were initially ran-
or duration of treatment between the two a 120-minute infusion and placebo every domized and were included in the ITT
treatment groups. The proportion of men 12 hours as a 60-minute infusion, or van- analysis, with 33% of patients from the
in the clinically evaluable group was sig- comycin 1,000 mg every 12 hours as a U.S.; 547 (66%) received ceftobiprole, and
nificantly lower in the ceftobiprole group 60-minute infusion and ceftazidime 1,000 281 (33%) were assigned to the compara-
(55%) than in the vancomycin group mg every eight hours as a 120-minute tor group. There were no significant
(61%) (P = 0.025). Clinical cure rates in infusion for 7 to 14 days. Metronidazole differences between groups in terms of
the ceftobiprole and vancomycin groups (e.g., Flagyl, Pfizer) could be added em- demographics, baseline characteristics,
were similar in the ITT group (77.8% vs. pirically in either group for 48 hours, type of infection, or duration of treatment.
77.5%; CI, –5.5 to 6.1) and in the clinically
evaluable group (93.3 vs. 93.5%; CI, –4.4
to 3.9). Ceftobiprole Comparator
100
93.3 93.5
The STRAUSS 2 Study26 90.5 90.2
90
In STRAUSS 2, investigators compared
ceftobiprole monotherapy with vanco- 80
mycin and ceftazidime (Fortaz, Glaxo-
SmithKline) in combination for the treat- 70
Clinical cure (%)

ment of cSSSIs. Patients were considered

60
eligible if they were older than 18 years
of age and had a cSSSI, including patients 50
with diabetic foot infections. Patients with
foreign-body infections, critical limb 40
ischemia, septic ar thritis, or osteo - 30
myelitis were excluded. The patients
were stratified by infection type, and the 20
investigators limited the percentage of
patients with cellulitis to less than 20%. 10
Patients were randomly assigned, in a 0
2:1 ratio, to receive ceftobiprole plus pla- STRAUSS 1 STRAUSS 2
cebo or vancomycin plus ceftazidime. Un- Figure 2 Clinical cure rates for the clinically evaluable population.
like STRAUSS 1, in which patients re- (Data from Noel GJ, Straus RS, Amsler K, et al. Antimicrob Agents Chemother 2008;
ceived ceftobiprole 500 mg ever y 12 52:37–44;24 and Noel GJ, Bush K, Bagchi P, et al. Clin Infect Dis 2008;46:647–655.26)
hours, patients in STRAUSS 2 received
continued on page 639

634 P&T® • November 2008 • Vol. 33 No. 11

 DRUG FORECAST
continued from page 634
Infections of the fascial plane or mus- Pneumonia Trials27–30 72%, respectively.
cle (36%) and the number of patients Phase 3 trials demonstrating the clini- In the subgroup of patients with venti-
undergoing surgical debridement (39%) cal efficacy of ceftobiprole for the treat- lator-associated pneumonia (25% of pa-
as part of initial therapy were similar in ment of community-acquired pneumonia tients), non-inferiority could not be estab-
both groups. Ninety-two percent of the (CAP) and hospital-acquired pneumonia lished, because clinical cure rates were
ceftobiprole patients and 90% of the van- (HAP) have been completed. Preliminary lower with ceftobiprole than with the com-
comycin/ceftazidime patients completed data from one randomized, double-blind, parator drug. Details of the study, includ-
the trial. The clinically evaluable popula- multicenter study demonstrated the non- ing inclusion and exclusion criteria, dose,
tion consisted of 729 patients. Clinical inferiority of ceftobiprole when compared duration of therapy, and differences be-
outcomes were evaluated at the TOC visit with ceftriaxone (Rocephin, Roche) with tween the groups, have not been pub-
for 485 (89%) patients receiving ceftobi- or without the addition of linezolid, for lished. A subgroup analysis will probably
prole group and 244 (87%) receiving van- hospitalized patients with CAP.27,28 be performed to determine potential dif-
comycin/ceftazidime. Investigators enrolled 666 patients into ferences in the patients with ventilator-as-
For the primary outcome of clinical the study (328 patients in the ceftobiprole sociated pneumonia that might have led to
cure rates in the ITT and CE populations, arm and 338 patients in the comparator the decreased response.
ceftobiprole was considered non-inferior arm). Patients were stratified before ran-
to vancomycin/ceftazidime at the TOC domization according to Pneumonia Out- ADVERSE DRUG REACTIONS
visit (7 to 14 days after therapy). Clinical comes Research Team (PORT) Severity Ceftobiprole is as tolerable and safe
cure rates in the ceftobiprole and van- Index scores and the need for linezolid in as other agents used for the treatment of
comycin/ceftazidime groups were simi- patients with proven or suspected MRSA cSSSIs, including vancomycin and cef-
lar in the ITT group (81.9% vs. 80.8%; CI, or ceftriaxone-resistant S. pneumoniae. tazidime.24,26 The pooled analysis from
–4.5% to 6.7%) and in the clinically evalu- Non-inferiority was defined in both the STRAUSS 1 and 2 showed similar ad-
able group (90.5% vs. 90.2%; CI –4.2% to clinically evaluable and ITT populations verse events reported for both ceftobi-
4.9%). There were no significant differ- as a difference of 10% in the cure rate be- prole and the comparator. At least one ad-
ences in clinical cure rate or microbio- tween treatment groups. verse event was reported in more than
logic eradication based on the type of The primar y outcome clinical cure 50% of patients in both studies, and most
infection. Diabetic foot infection was the rate at the TOC visit (7 to 14 days after events were considered mild or moder-
most common diagnosis in 31% of therapy) for the clinically evaluable pop- ate in intensity.
patients in the ceftobiprole group and ulation was 86.7% for ceftobiprole and Adverse events leading to discontinu-
in 32% of those receiving vancomycin/ 87.6% for the comparator drug. Clinical ation of the study drugs were similar in
ceftazidime. Response rates were 86.2% cure rates in the ITT population were both trials. The most common adverse
for the ceftobiprole patients and 81.8% 77.4% with ceftobiprole and 80.2% with reactions in clinical trials included gastro-
for the other group (CI, –5.4% to 15.7%). the comparator agent. intestinal effects (nausea, vomiting, diar-
For the secondary outcome, the micro- Microbiologic eradication rates in both rhea), dysgeusia (sense of distor ted
biologically evaluable population con- groups were also similar: 88% with cef- taste), headache, and infusion-site reac-
sisted of 590 patients in the clinically tobiprole and 92% with the comparator tions (Table 2). These events occurred
evaluable group with microbiologic data drug. Patients with S. pneumoniae infec- with similar frequency in both treatment
available—391 patients (71%) received tion had comparable cure rates in each groups.
ceftobiprole, and 199 (71%) received van- arm: 90% with ceftobiprole and 89% with
comycin/ceftazidime. Clinical cure and the comparator drug; however, the au- DRUG INTERACTIONS
microbiological eradication rates at the thors did not report rates of penicillin- The potential for clinically significant
TOC visit were similar in the microbio- resistant S. pneumoniae (PRSP). drug interactions with ceftobiprole is
logically evaluable population for both In patients with baseline PORT scores considered low because of its favorable
gram-positive and gram-negative infec- above 90, clinical cure rates were 90.2% pharmacokinetic profile. To date, no pub-
tions. In most patients (53%), infections for the clinically evaluable ceftobiprole lished studies have indicated a clinically
had been caused by gram-positive patho- patients and 84.5% for the comparator significant drug interaction that would
gens, and more than 64% of pathogens in arm (95% CI, –6.7 to 18.1). Details of the call for dose adjustments or discontinu-
the microbiologically evaluable popula- study, including inclusion and exclusion ation of therapy. Like all antimicrobial
tion were S. aureus. Of those, only 32.8% criteria, dose, length of therapy, and dif- agents, ceftobiprole has the potential to
of the isolates were methicillin-resistant. ferences between the groups, have not decrease the effectiveness of oral con-
Of the 12 patients in the ceftobiprole yet been published. traceptives.
group with P. aeruginosa isolated as the The preliminary results of a phase 3 Coadministration of warfarin (Cou-
only pathogen, three patients (25%) failed trial in patients with hospital-acquired madin, Bristol-Myers Squibb) with cefto-
to respond to therapy; all of the isolates pneumonia showed the non-inferiority of biprole sometimes causes an increased
from these three patients demonstrated ceftobiprole versus ceftazidime/linezolid prothrombin time and an International
an MIC of 8 mcg/mL or more. All nine for the primary outcome;29,30 primary out- Normalized Ratio (INR). Compatibility
vancomycin/ceftazidime patients with come clinical cure rates at the TOC visit data for the coadministration of other
P. aeruginosa infection achieved clinical (7 to 14 days after therapy) for the clini- medications with ceftobiprole, however,
cure at the TOC visit. cally evaluable population were 69% and have not been published.

Vol. 33 No. 11 • November 2008 • P&T® 639

DRUG FORECAST

tion, 5% dextrose in water, and lactated

Table 2 Pooled Incidence of Treatment-Related Adverse Events Ringer’s solution. The researchers then
For Complex Skin and Skin Structure Infections mixed the solutions in equal amounts
with 70 medications using simulated
Ceftobiprole Comparator Y-site administration. Of the 70 drugs
(n = 932) Drug* (n = 661) tested in combination with ceftobiprole,
___________ _____________
Adverse Event No. (%) No. (%) 32 (45.7%) were considered incompatible
for Y-site administration regardless of the
Nausea 113 (12) 49 (7) diluent used or the order of administra-
Vomiting 61 (7) 27 (4) tion. For seven of the medications (10%),
Diarrhea 62 (7) 32 (5) compatibility was dependent on the type
Constipation 33 (4) 25 (4) of solution used to dilute ceftobiprole.
Dysgeusia† 30 (3) 2 (1) Some of the clinically important med-
Headache 68 (7) 39 (6) ications found to be incompatible with
Dizziness† 14 (4) 8 (2) ceftobiprole include aminoglycosides,
Insomnia‡ 26 (5) 13 (5) amiodarone (Cordarone), calcium glu-
Infusion-site reaction† 48 (9) 26 (9) conate, diltiazem (Cardizem), dopamine,
Hypersensitivity§ 49 (5) 62 (9) dobutamine, fluoroquinolones, human
Overall adverse drug events regular insulin, hydromorphone, labet-
• One or more adverse drug events 507 (54) 352 (53) alol (Normodyne, Trandate), magne-
• One or more serious adverse drug events 63 (7) 47 (7) sium sulfate, midazolam (Versed), mor-
• Discontinued therapy because of adverse phine sulfate, and potassium phosphate.
drug events 39 (4) 32 (5) The timing of administration and avail-
* Comparator regimen: vancomycin (STRAUSS 1); vancomycin plus ceftazidime ability of IV lines are expected to be a
(STRAUSS 2). concern for patients receiving ceftobi-
† Data reported for STRAUSS 1 only. prole with incompatible medications.
‡ Data reported for STRAUSS 2 only.
§ Data for STRAUSS 1 is a combination of rash and pruritus. The overall incidence of CONCLUSION
hypersensitivity was not reported in this trial.
Ceftobiprole is an advanced-generation
Data from Noel GJ. Clin Microbiol Infect 2007;13(Suppl 2):25–29;23 Noel GJ, Straus RS,
cephalosporin with a broad spectrum of
Amsler K, et al. Antimicrob Agents Chemother 2008;52:37–44;24 and Noel GJ, Bush K, Bagchi P,
et al. Clin Infect Dis 2008;46:647–655.26 activity against gram-negative pathogens,
including P. aeruginosa and Enterobac-
teriaceae (ESBL-negative) with the added
advantage of enhanced gram-positive
DOSAGE AND ADMINISTRATION ment (CrCl of 30 to 50 mL/minute), the activity against MRSA, PRSP, and ampi-
Based on the pharmacokinetic, phar- predicted dosing of ceftobiprole would cillin-susceptible E. faecalis. Activity
macodynamic, and clinical data pub- probably be 500 mg every 12 hours. against other clinically important path-
lished, ceftobiprole dosing is likely to be In patients with severe impairment ogens (such as ESBL-producing Enter-
based on the indication and the intended (CrCl of below 30 mL/minute), the pre- obacteriaceae, Acinetobacter spp., S. mal-
bacterial coverage. For cSSSIs caused dicted dosing of ceftobiprole would be tophilia, and Bacteroides spp.) remains
by culture-proven or presumed gram- 250 mg every 12 hours. limited; most of the isolates tested have
positive infections, the dose of ceftobi- Of note, patients were excluded from an MIC above 8 mcg/mL.
prole is expected to be 500 mg every 12 STRAUSS 1 and STRAUSS 2 if they had Ceftobiprole’s pharmacokinetic and
hours infused over one hour. 23,24 For severe renal dysfunction or oliguria (a pharmacodynamic profile is similar to
cSSSIs (including diabetic foot infec- urine output below 20 mL/hour that was that of other cephalosporins, including
tions) caused by culture-proven or pre- unresponsive to fluid challenge).24,26 cefepime (Maxipime, Elan) and ceftaz-
sumed gram-negative or mixed infec- Pharmacokinetic data for ceftobiprole idime (Fortaz). Like other beta-lactams,
tions or for patients with CAP or HAP, the in patients receiving hemodialysis, peri- the pharmacodynamic parameter most
predicted dosing for ceftobiprole is ex- toneal dialysis, or continuous renal re- correlated with efficacy is the percentage
pected to be 500 mg every eight hours in- placement therapy have not been pub- of time in which the free serum concen-
fused over two hours.26–30 lished; however, it is unlikely that a tration is above the MIC. The activity of
Ceftobiprole is eliminated primarily via dosage adjustment would be necessary ceftobiprole against clinically important
the kidneys; thus, the dosage would prob- for patients with hepatic dysfunction. gram-negative pathogens is comparable
ably need to be adjusted in patients with The physical compatibility of ceftobi- to that of ceftazidime.
renal insufficiency. Preliminary data sug- prole with commonly administered IV Ceftobiprole has proven efficacy in two
gest that for patients with mild renal im- medications has been reported.31 Chan phase 3 clinical trials for the treatment of
pairment (CrCl of 50 to 80 mL/minute), et al. diluted ceftobiprole to a test con- cSSSIs, including diabetic foot infections,
no dosage adjustment is needed.11,19,20 centration of 2 mg/mL using three sepa- caused by gram-positive or gram-nega-
In patients with moderate renal impair- rate solutions: 0.9% sodium chloride injec- tive bacteria. Additional studies of cefto-

640 P&T® • November 2008 • Vol. 33 No. 11

 DRUG FORECAST

biprole for the treatment of CAP and hos- microbial activity of ceftobiprole, a novel 20. Lodise TP, Pypstra R, Kahn JB, et al. Prob-
pital-acquired pneumonia (HAP) have anti–methicillin-resistant Staphylococcus ability of target attainment for ceftobi-
aureus cephalosporin, tested against con- prole as derived from a population phar-
also been completed but are available only
temporary pathogens: Results from the macokinetic analysis of 150 subjects.
in abstract form. Investigators noted in SENTRY Antimicrobial Surveillance Pro- Antimicrob Agents Chemother 2007;51:
the trial for HAP that non-inferiority could gram (2005–2006). Diagn Microbiol Infect 2378–2387.
not be established in the subgroup of Dis 2008;61(1):86–95. 21. Schmitt-Hoffmann AH. Influence of gen-
patients with ventilator-assisted pneumo- 9. Jones RN, Deshpande LM, Mutnick AH, der on the pharmacokinetics of BAL9141
et al. In vitro evaluation of BAL9141, a after intravenous infusion of Pro-drug
nia (VAP), because clinical cure rates were novel parenteral cephalosporin active BAL5788 (Abstract 902). Presented at
significantly lower in the ceftobiprole against oxacillin-resistant staphylococci. the 14th European Congress of Clinical
group of patients than in the comparator J Antimicrob Chemother 2002;50:915–932. Microbiology and Infectious Diseases,
group. It is not clear why ceftobiprole 10. Pillar CM, Aranza MK, Shah D, et al. Prague, May 1–4, 2004.
In vitro activity profile of ceftobiprole, an 22. Andes DR, Craig WA. In vivo pharmaco-
underperformed in this group of patients;
anti-MRSA cephalosporin, against recent dynamics of RO 63-9141 against multiple
the use of ceftobiprole for the treatment gram-positive and gram-negative isolates bacterial pathogens (Abstract F-1079).
of VAP warrants further research. of European origin. J Antimicrob Chemo- Presented at the 40th Interscience Con-
With antimicrobial resistance on the ther 2008;61(3):595–602. ference on Antimicrobial Agents and
rise and the pipeline of active agents 11. Murthy B, Schmitt-Hoffman A. Pharma- Chemotherapy, Toronto, 2000.
cokinetics and pharmacodynamics of 23. Noel GJ. Clinical profile of ceftobiprole, a
against gram-negative pathogens rela- ceftobiprole, an anti-MRSA cephalosporin novel beta-lactam antibiotic. Clin Micro-
tively nonexistent, hospitals and clini- with broad-spectrum activity. Clin Phar- biol Infect 2007;13(Suppl 2):25−29.
cians are constantly being challenged to macokinet 2008;47:21–33. 24. Noel GJ, Straus RS, Amsler K, et al. Treat-
develop new strategies to treat compli- 12. Hebeisen P, Heinze-Krauss I, Angehrn P, ment of complicated skin and skin struc-
et al. In vitro and in vivo properties of RO ture infections caused by gram-positive
cated infections while preserving anti-
63-9141, a novel broad-spectrum cephalo- bacteria with ceftobiprole: Results of a
microbials for the future. Although cefto- sporin with activity against methicillin- double-blind, randomized trial. Anti -
biprole provides us with another option in resistant staphylococci. Antimicrob microb Agents Chemother 2008;52:37–44.
our antimicrobial armamentarium, fur- Agents Chemother 2001;45:825–836. 25. Stevens DL, Bisno AL, Chambers HF,
ther research of its role in clinical practice 13. Lovering A, Daniel F, Page MG, et al. et al. Practice guidelines for the diagno-
Mechanism of action of ceftobiprole: sis and management of skin and soft-
is still required. The judicious use of this Structural bases for anti-MRSA activity tissue infections. Clin Infect Dis 2005;41:
agent will be imperative, in view of the (poster 1586). Presented at the 16th 1373–1406.
lack of newer antimicrobial agents (with European Congress of Clinical Micro- 26. Noel GJ, Bush K, Bagchi P, et al. A ran-
activity against multidr ug-resistant, biology and Infectious Diseases, Nice, domized, double-blind trial comparing
France, April 1–4, 2006. ceftobiprole medocaril with vancomycin
gram-negative pathogens) that are ex-
14. Bogdanovich T, Ednie LM, Shapiro S, plus ceftazidime for the treatment of
pected to be available in the near future. et al. Antistaphylococcal activity of cefto- patients with complicated skin and skin
biprole, a new broad-spectrum cephalo- structure infections. Clin Infect Dis 2008;
REFERENCES sporin. Antimicrob Agents Chemother 46:647–655.
2005;49:4210–4219. 27. Nicholson SC, Strauss RS, Michiels B,
1. Klein E, Smith DL, Laxminarayan R. Hos- 15. Leonard SN, Cheung CM, Rybak MJ. et al. Efficacy of ceftobiprole for the treat-
pitalizations and deaths caused by methi- Activities of ceftobiprole, linezolid, van- ment of severely ill patients hospitalized
cillin-resistant Staphylococcus aureus, comycin, and daptomycin against com- with community-acquired pneumonia
United States, 1999–2005. Emerg Infect munity-associated and hospital-associ- (poster C-17). Presented at the Ameri-
Dis 2007;13(12):1840–1846. ated methicillin-resistant Staphylococcus can Thoracic Society International Con-
2. Klevens RM, Morrison MA, Nadle J, et al. aureus. Antimicrob Agents Chemother ference, Toronto, May 16–21, 2008.
Invasive methicillin-resistant Staphylo- 2008;52:2974–2976. 28. Basilea announces positive top-line data
coccus aureus infections in the United 16. Banerjee R, Gretes M, Basuino L, et al. from phase III study of ceftobiprole in
States. JAMA 2007;298:1763–1771. In vitro selection and characterization of community-acquired pneumonia requir-
3. Utsui Y, Yokota T. Role of an altered peni- ceftobiprole-resistant methicillin-resist- ing hospitalization. Basel: Basilea Phar-
cillin-binding protein in methicillin- and ant Staphylococcus aureus. Antimicrob maceutica, Ltd.; September 14, 2007.
cephem-resistant Staphylococcus aureus. Agents Chemother 2008;52:2089–2096. Available at: www.basilea.com.
Antimicrob Agents Chemother 1985;3: 17. Schmitt-Hoffmann A, Roos B, Schleimer 29. Nicholson SC, Strauss RS, Michiels B,
397–403. M, et al. Single-dose pharmacokinetics et al. Efficacy of ceftobiprole compared to
4. Livermore DM. Can beta-lactams be re- and safety of a novel broad-spectrum ceftriaxone +/- linezolid for the treatment
engineered to beat MRSA? Clin Micro- cephalosporin (BAL5788) in healthy vol- of subjects hospitalized with community-
biol Infect 2006;12(Suppl 2):11–6. unteers. Antimicrob Agents Chemother acquired pneumonia (poster C-16). Pre-
5. Adis R&D profile. Ceftobiprole medocaril. 2004;48:2570–2575. sented at American Thoracic Society
Drugs RD 2006;7(5):305–311. 18. Schmitt-Hoffmann A, Nyman L, Roos B, Inter national Conference, Toronto, May
6. Walkty A, DeCorby M, Nichol K, et al. et al. Multiple-dose pharmacokinetics 16–21, 2008.
In vitro activity of ceftobiprole against and safety of a novel broad-spectrum 30. Basilea announces positive top-line data
clinical isolates of Pseudomonas aerugi- cephalosporin (BAL5788) in healthy vol- from phase III study of ceftobiprole in
nosa obtained from Canadian intensive unteers. Antimicrob Agents Chemother hospital-acquired pneumonia. Basel:
care unit (ICU) patients as part of the 2004;48:2576–2580. Basilea Pharmaceutica, Ltd.; October 9,
CAN–ICU Study. J Antimicrob Chemother 19. Roos B, Schmidt-Hoffman A, Schleimer 2007. Available at: www.basilea.com.
2008;62(1):206–208. M. Safety and pharmacokinetics of 31. Chan P, Bishop A, Kupiec TC, et al. Com-
7. Jones ME. In vitro profile of a new beta- BAL5788 in healthy subjects with normal patibility of ceftobiprole medocaril with
lactam, ceftobiprole, with activity against or impaired renal function (Abstract selected drugs during simulated Y-site
methicillin-resistant Staphylococcus au- A-23). Presented at the 43rd Annual Inter- administration. Am J Health Syst Pharm
reus. Clin Microbiol Infect 2007;13(Suppl science Conference on Antimicrobial 2008;65(16):1545–1551. I
2):17−24. Agents and Chemotherapy, Chicago, Sep-
8. Fritsche TR, Sader HS, Jones RN. Anti- tember 14–17, 2003.

Vol. 33 No. 11 • November 2008 • P&T® 641