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Postdoctoral Fellow, Departments of Pharmacy Practice and Family Medicine, University of Florida, Gainesville, FL
Professor of Pharmacy and Medicine; Director of Clinical Research in Family Medicine, Departments of Pharmacy Practice and Family Medicine, University of Florida
Reprints: Dr. Anderson, Family Medicine on 4th Ave., 625 SW 4th Ave., Gainesville, FL 32601, fax 352/392-7766, sda2{at}ufl.edu
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DATA SOURCES: Literature identification was conducted through MEDLINE (1966–February 2008) and International Pharmaceutical Abstracts (1970–February 2008) using the terms ceftobiprole, medocaril, BAL 5788, RO-5788, BAL 9141, RO 63-9141, pyrrolidinone cephalosporin, MRSA, complicated skin and skin-structure infections (cSSSIs), community-acquired pneumonia, and nosocomial pneumonia. Additional publications were identified through a review of articles and abstracts from infectious disease meetings.
STUDY SELECTION AND DATA EXTRACTION: All articles in English were evaluated and all pertinent information was included.
DATA SYNTHESIS: Ceftobiprole medocaril is an extended-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus spp., vancomycin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa. Inactivity includes extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae and Enterococcus faecium. Preliminary data suggest that ceftobiprole may be effective with a 1-hour infusion of 500 mg every 12 hours for gram-positive infections and 500 mg every 8 hours with a 2-hour infusion for polymicrobial infections. Two clinical trials support these dosing regimens for cSSSIs. Ceftobiprole was noninferior to vancomycin in suspected gram-positive cSSSIs, with cure rates of 93.3% and 93.5%, respectively. Furthermore, ceftobiprole was noninferior to vancomycin and ceftazidime in polymicrobial cSSSIs (cure rates 90.5% vs 90.2%, respectively). Although the total number of adverse effects was similar to those of the comparator, more patients in the ceftobiprole group experienced nausea, vomiting, and dysgeusia.
CONCLUSIONS: The activity of ceftobiprole and limited clinical data suggest that it may be useful as empiric monotherapy for cSSSI and in combination with other antimicrobials in lower respiratory tract infections for which Phase 3 clinical trials are currently exploring. Although not shown in vitro, ceftobiprole may induce resistance due to its broad spectrum of activity. Approval is expected for the treatment of cSSSI.
Key Words: ceftobiprole, cephalosporin, community-acquired pneumonia, complicated skin and skin-structure infections, medocaril, methicillin-resistant Staphylococcus aureus, nosocomial pneumonia, pyrrolidinone
Published Online, May 13, 2008. www.theannals.com, DOI 10.1345/aph.1L016
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-08-010-H01-P
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Pharmacology and Mechanism of Action |
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Davies et
al.9
determined the PBP affinity of ceftobiprole in S. aureus, Streptococcus
pneumoniae, Escherichia coli, and Pseudomonas aeruginosa.
Ceftobiprole had good affinity (50% inhibitory concentration
[IC50] 
1 µg/mL) for PBP1, PBP2, PBP3, and PBP4 in a
methicillin-susceptible S. aureus (MSSA) isolate and for PBP2a in an
MRSA isolate. In S. pneumoniae, ceftobiprole had an
IC50 of 0.06 µg/mL or less for PBP1a, PBP2b, and PBP2x in
a penicillin-susceptible isolate and an IC50 of 1 µg/mL
or less for PBP1a and PBP2x in a penicillin-resistant S. pneumoniae
isolate. Ceftobiprole exhibited high affinity for PBP1a, PBP2, PBP3, and PBP4
in E. coli. An IC50 of 0.5 µg/mL or less was
shown for PBP1a, PBP1b, PBP3, and PBP4, and no affinity was observed for
PBP5/6 in P. aeruginosa. Potent inhibition of multiple PBPs,
specifically PBP2a in MRSA, PBP2x in penicillin-resistant S.
pneumoniae, and PBP3 in E. coli and P. aeruginosa,
explains ceftobiprole's broad activity
spectrum.8,10
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Microbiology |
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2 µg/mL) and
streptococci (1
µg/mL).12
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GRAM-POSITIVE ORGANISMS
Ceftobiprole is very active against staphylococci, with the majority of
isolates having a 90% minimum inhibitory concentration
(MIC90) of 4 µg/mL or less, although some
Staphylococcus haemolyticus isolates have an MIC90
of 8
µg/mL.11-16
In addition, activity toward S. aureus remains in MRSA,
community-acquired MRSA, vancomycin-intermediate (VISA) and
vancomycin-resistant (VRSA)
isolates.15,17-20
Activity against S. pneumoniae is very high, even when
penicillin-resistant isolates are
tested.11,12,21,22
Mutations in PBP1a, PBP2x, and PBP2b may increase the MIC, but ceftobiprole
remains active against the majority of penicillin-resistant,
macrolide-resistant, and fluoroquinolone-resistant S.
pneumoniae.21,22
Ceftobiprole is active against ampicillin-susceptible isolates of E.
faecalis and Enterococcus faecium, while only remaining active
against vancomycin-resistant E. faecalis, but not
vancomycin-resistant E. faecium
(VRE).11,12,18,23,24
Ceftobiprole differentiates itself from ampicillin by retaining activity at a
high
inoculum.23
GRAM-NEGATIVE ORGANISMS
Ceftobiprole has activity in gram-negative organisms similar to that of
some existing extended-spectrum cephalosporins, such as ceftriaxone and
ceftazidime. Organisms producing ESBLs and enzymes with carbapenemase activity
(KPC, IMP, VIM) are expected to be resistant to ceftobiprole. Ceftobiprole may
be active against bacteria producing class A (TEM, SHV) and AmpC
β-lactamases.25
In vitro data suggest activity against most Enterobacteriaceae, with reduced
activity to Enterobacter spp., Serratia marcescens,
indole-positive Proteae, and especially ESBL-producing E.
coli and Klebsiella
pneumoniae.11,12,26
Ceftobiprole may have similar activity to cefepime and ceftazidime against
P. aeruginosa and limited activity against Acinetobacter
baumannii, Burkholderia cepacia, and Stenotrophomonas
maltophilia.11,12,27
Ceftobiprole is active against both non– and
β-lactamase–producing Haemophilus influenzae and
Moraxella catarrhalis, and Neisseria
spp.11,12,28
ANAEROBES
Interpreting anaerobic activity of ceftobiprole is difficult due to
reporting of mixed species, and in vitro activity may depend on the isolate
source (intraabdominal vs diabetic
foot).29 In
summary, ceftobiprole is active against mixed anaerobic isolates.
Bacteroides spp., Lactobacillus spp., and
Prevotella spp. are not therapeutic
targets.11,12,27-31
In general, activity includes Propionibacterium acnes,
peptostreptococci, Finegoldia magna, Fusobacterium nucleatum, and
C.
perfringens.12,27-31
Ceftobiprole does not have in vitro activity against Clostridium
difficile; thus, monitoring for C. difficile infection is
necessary.31
BACTERICIDAL ACTIVITY
Bactericidal activity is defined by a 99.9%, or 3-log10
or greater, reduction in colony-forming units from the starting inoculum after
a proper incubation interval. The concentration where bactericidal activity
first occurs is defined as the minimum bactericidal concentration (MBC). The
bactericidal activity of ceftobiprole has been assessed against gram-positive
and gram-negative
isolates.18,20,24,32
Deshpande et al.18,32 tested over 100 staphylococci, streptococci, enterococci, and gram-negative isolates. Ceftobiprole showed bactericidal activity against MSSA, MRSA, coagulase-negative staphylococci, hetero-VISA, penicillin-susceptible S. pneumoniae, penicillin-resistant group B streptococci, ampicillin-susceptible enterococci, H. influenzae, and E. faecalis isolates. Some Staphylococcus isolates displayed a decreasing rate of killing at concentrations above the MBC, or "eagle effect," which may occur with β-lactam antibiotics. Forty-five percent of penicillin-nonsusceptible S. pneumoniae and 3 of 5 isolates of S. marcescens had an MBC:MIC ratio greater than 4, and 1 ampicillin-susceptible E. faecium isolate was bacteriostatic. Other investigators verified bactericidal activity of ceftobiprole at 4 times the MIC for susceptible MRSA, community-acquired MRSA, VISA, and VRSA strains.20 Bactericidal activity against β-lactamase–producing and vancomycin-resistant E. faecalis has been confirmed.24
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Pharmacokinetics and pharmacodynamics |
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After single, 30-minute, ascending-dose intravenous infusions, peak plasma
concentrations (Cmax) were observed at the end of
infusion.33
Cmax and area under the concentration–time curve (AUC)
exhibit linear dose response up to the maximum dose studied (1000 mg). The
apparent volume of distribution at steady-state (Vss) is
18–20 L, which is approximately the volume of the extracellular fluid
compartment in adults. Plasma protein binding averages 16% to mostly albumin
and 
1-acid glycoprotein. The majority of ceftobiprole
is recovered in the urine as unchanged drug (83%) in addition to small amounts
of prodrug (0.3%) and open-ring metabolite
(0.8%).35
The mean total renal clearance (Clren) ranges from 68 to 85
mL/min and unbound fraction in plasma is 62%. Therefore,
Clren of the unbound fraction is 110–136 mL/min, which
equates to a normal glomerular filtration rate of 125 mL/min in adults.
Clren, Vss, and half-life
(t1/2) are all independent of dose (range 125–1000
mg).
A multiple-dose study was performed in 16 healthy men taking ceftobiprole medocaril at doses of 500 and 750 mg or placebo.34 Subjects were given one 30-minute infusion of ceftobiprole or placebo diluted to 200 mL in 5% dextrose on days 1 and 8, and two 30-minute infusions or placebo 12 hours apart on days 2–7. Single- and multiple-dose pharmacokinetics were similar. Drug accumulation was assessed by comparing AUC on day 1 with AUC on day 8. Mean ± SD accumulation levels (AUCday8/AUCday1) were minimal at 1.06 ± 0.18 for the 500-mg dose and 1.04 ± 0.09 for the 750-mg dose, suggesting no alteration in clearance during therapy. Again, linearity exists for Cmax and AUC, while Vss, plasma protein binding, Clren, and t1/2 are independent of dose. Similar pharmacokinetic results were replicated at ceftobiprole doses of 1000 mg every 8 hours as a 90-minute infusion37 and 500 mg every 8 hours as a 2-hour infusion.38
Ceftobiprole is similar to other β-lactam antibiotics in that the time above the MIC (T > MIC) correlates to clinical efficacy. A fraction of T > MIC (fT > MIC) of at least 40% is most commonly sought in gram-positive organisms, although maximal killing is achieved at 50%.38 Thirty-minute infusions of ceftobiprole medocaril at 500–1000 mg resulted in fT > MIC of 42–58% for a 12-hour dosing interval at an MIC of 4 µg/mL for MRSA.33 In the multiple-dose study, 30-minute infusions led to fT > MIC of 40–58% for 500 mg every 12 hours and 58–75% for 750 mg every 12 hours.34 Considering these data, 500 mg every 12 hours infused over 30 minutes may be an option in methicillin-resistant staphylococcal infections with an MIC up to 4 µg/mL, but 750 mg every 12 hours infused over 30 minutes is expected to achieve maximal killing.
Two studies utilized Monte Carlo simulation to predict target attainments
rates (TARs), or the probability of achieving a specific pharmacodynamic
value, and dosing regimens for Phase 3 clinical trials of
ceftobiprole.39,40
These results are summarized in Table
3 for the most applicable targets of fT > MIC of 40%, 50%, and
60%. TARs were predicted for dosing schedules of mostly 500 mg, either every 8
or 12 hours, over 30-minute to 2-hour infusions. An optimal dosing regimen is
close to 100% TAR. In summary, TARs greater than or equal to 90% at a maximal
bactericidal target of fT > MIC of 50% at an MIC of 2 µg/mL are
predicted to occur with all dosing regimens, with the exception of 500 mg
every 8 hours infused over 30 minutes with an estimated creatinine clearance
(Clcr) of 120 mL/min (TAR 88%) and 500 mg every 12 hours
infused over 1 hour with normal Clcr of 80–120 mL/min
(TAR 84–74%) in the Lodise et
al.39
analysis. However, Mouton et
al.40
determined that a 30-minute infusion of 500 mg every 12 hours provides 100%
TAR. A possible explanation for this discrepancy is the number and
characteristics of subjects from whom pharmacokinetic data were collected. The
Lodise et
al.39
analysis may be considered more robust considering that more subjects were
analyzed (150 vs 12) and subjects were diverse, including 22 intravenous drug
users. This is important because intravenous drug users often have higher
clearances, thus explaining lower TARs. From these Monte Carlo simulations,
maximum bactericidal activity at all susceptible gram-positive isolates (MIC
4 µg/mL) is likely to occur at 500 mg every 8 hours infused over
1–2 hours or at 30-minute infusions of 750 mg every 12 hours. Since the
majority of MRSA isolates have MICs less than or equal to 2 µg/mL and
ceftobiprole retains bacteriostatic activity at lower targets, 500 mg every 12
hours infused over 0.5–1 hour may still be clinically effective.
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Gram-negative pathogens have higher targets than gram-positive pathogens and higher doses or more frequent dosing is often required. The fT > MIC for bacteriostatic effect is 40% and, for bactericidal effect, is 60%. Utilizing the aforementioned Monte Carlo simulations, 500 mg every 8 hours (2-h infusion) is the dose with the highest TARs.39,40 These analyses demonstrate that 500 mg every 8 hours as a 2-hour infusion is expected to provide mostly bacteriostatic activity in susceptible gram-negative infections and bactericidal activity in susceptible gram-positive infections. This dosing scheme is expected to be used as empiric therapy and in polymicrobial infections such as diabetic foot infections and pneumonia.
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Patients were excluded if they had a cephalosporin or vancomycin allergy, Clcr less than 30 mL/min or oliguria less than 20 mL/h in response to fluid challenge, or alanine aminotransferase/aspartate aminotransferase levels 3 times the upper limit of normal. In addition, patients could not be pregnant or lactating, neutropenic, or HIV-infected with a CD4+ count less than 0.2 x 109/L; have diabetic foot infections or infections associated with bites; or have received antimicrobial therapy for more than 24 hours in the previous 7 days.42
Patients were randomized to receive either ceftobiprole 500 mg intravenously over 60 minutes every 12 hours or vancomycin 1 g intravenously over 60 minutes every 12 hours (serum concentrations were adjusted based on local practices) for 7–14 days. All abscesses were incised and drained within 48 hours. Empiric therapy with aztreonam or metronidazole was allowed for the first 48 hours pending organism identification. Patients were evaluated at baseline and followed up on days 4, 8, and 14. Additional evaluations included end-of-therapy or within 24 hours of last treatment dose, test-of-cure, or 7–14 days after end-of-therapy, and late follow-up, or 28–35 days after end-of-therapy in patients clinically cured at test-of-cure visit.42
The primary endpoint of this noninferiority study was clinical cure rate at the test-of-cure visit, where cure was resolution of infection or improvement not needing antimicrobial therapy. Noninferiority was defined as less than a 10% difference in the clinical cure rate. Secondary endpoints were microbiologic efficacy and safety.42
Demographics were comparable between treatment groups, with the most common
diagnosis being abscesses (48%). Approximately 80% of gram-positive isolates
in the modified intent-to-treat and microbiologically evaluable groups were
S. aureus. Of these, approximately 35% were MRSA. The second most
common gram-positive isolate identified was Streptococcus pyogenes
(
6%). MICs for MSSA in the modified intent-to-treat group were 0.5
µg/mL for ceftobiprole and 1 µg/mL for vancomycin. MICs for MRSA in the
modified intent-to-treat group were 2 µg/mL for ceftobiprole and 1 µg/mL
for
vancomycin.42
Clinical cure rates are found in Table 4. Overall, the ceftobiprole group was noninferior to the vancomycin group for all populations identified (intent-to-treat, modified intent-to-treat, clinically evaluable, microbiologically evaluable). Of patients with only gram-negative isolates identified at baseline, more patients were cured in the ceftobiprole group than in the vancomycin group (75% vs 50%). Clinical cure rates were also similar for the MSSA and MRSA groups; however, ceftobiprole had a higher cure rate compared with vancomycin in MRSA isolates positive for Panton-Valentine leukocidin (93.1% vs 84.6%; NS).42
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The second study also focused on cSSSIs, but inclusion criteria were broadened to include diabetic foot infections.43 In addition, ceftobiprole was compared with vancomycin plus ceftazidime for possible gram-negative pathogens. Patients were greater than 18 years of age with a diagnosis of a cSSSI, defined as an infection involving subcutaneous tissue or requiring significant surgical intervention, and one or more of the following: (1–3) infections as outlined in aforementioned study42 in addition to (4) a foot infection, in diabetic patients, consisting of a full-thickness skin ulcer, cellulitis, myositis, or tendonitis with 3 or more other signs of infection. Infections involving both gram-negative and gram-positive pathogens were included. Specific exclusion criteria were allergy to antimicrobials used in the study, severe hepatic and renal impairment, and infections requiring longer treatment duration (ie, foreign body infection and osteomyelitis).43
Patients were randomized (2:1) to receive intravenous infusions of ceftobiprole 500 mg over 120 minutes every 8 hours and placebo over 60 minutes every 12 hours, or vancomycin 1 g over 60 minutes every 12 hours plus ceftazidime 1 g over 120 minutes every 8 hours for 7–14 days. Vancomycin dose was adjusted based on serum concentrations according to local practices. In addition, metronidazole was allowed for up to 48 hours. Final assessment occurred 7–14 days after end-of-therapy.43
The primary endpoint was noninferiority of the ceftobiprole group compared with the vancomycin–ceftazidime group on clinical cure rates at the test-of-cure visit of clinically evaluable and intent-to-treat populations. Secondary endpoints were microbiologic efficacy of the microbiologically evaluable population and safety utilizing the intent-to-treat group. Noninferiority was determined if the lower limit of the 95% confidence interval of the treatment difference was –10% or more.43
Of the 828 patients enrolled, 547 were allocated to the ceftobiprole group and 281 to the vancomycin–ceftazidime group. Baseline characteristics were similar between groups. The most common infection types were diabetic foot (31%) and abscesses (30%), and S. aureus was the most common bacteria isolated, at approximately 63% of total isolates. Twenty-eight percent of the isolates were gram-negative pathogens. Of these isolates, E. coli was more common in the vancomycin–ceftazidime group (45% vs 36%), whereas P. aeruginosa was more common in the ceftobiprole group (29% vs 16%).43
Results of this study are shown in Table 4. In summary, clinical cure rates, microbiologic eradication rates, and adverse events were similar between ceftobiprole-treated patients compared with vancomycin plus ceftazidime–treated patients. Noninferiority of ceftobiprole was demonstrated in all endpoints. Although the results were nonsignificant, ceftobiprole-treated patients had higher clinical cure rates in diabetic foot infections and cellulitis, but lower cure rates for wound or abscesses compared with vancomycin plus ceftazidime–treated patients. In addition, the ceftobiprole group had nonsignificantly higher cure rates for MRSA infections, but lower cure rates for gram-negative infections compared with the vancomycin plus ceftazidime group.43
In summary, ceftobiprole appears to be equivalent in efficacy and safety to vancomycin in treatment of cSSSI involving gram-positive pathogens or vancomycin plus ceftazidime when gram-positive and gram-negative organisms are the source of infection. Limitations of these studies include the exclusion of patients with renal and hepatic impairment and of those with more severe infections requiring longer treatment. We await the results of other Phase 3 clinical trials for the treatment of hospital-acquired pneumonia, community-acquired pneumonia, and chemotherapy-induced neutropenia and fever.
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Phase 3 clinical trials have confirmed the relative safety of ceftobiprole. One trial found no significant differences between total adverse events (52% for ceftobiprole vs 51% for vancomycin), total serious adverse events (6% vs 6%), discontinuation of drug (4% vs 6%), or abnormal laboratory values between treatment groups.42 However, more patients in the ceftobiprole group experienced nausea (14% vs 8%; p < 0.05), vomiting (7% vs 4%; NS), and dysgeusia (8% vs 1%; NS), whereas more patients in the vancomycin group experienced pruritus (6% vs 3%; NS). Similar safety results were replicated in the other cSSSI clinical trial43 (Table 4). Laboratory values at baseline compared with those at the end of therapy were not significantly different in the ceftobiprole groups.42,43 There were 3 total deaths in the ceftobiprole groups, but none was considered to be related to the study drug.42,43
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Dosing and Administration |
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Two dosing regimens were used in clinical trials based on presumed pathogens in cSSSIs. In the latter clinical trial, a 2-hour infusion was utilized to maximize pharmacodynamic targets. A 2-hour infusion may complicate the administration of ceftobiprole with other intravenous medications. This may become problematic if Phase 3 clinical trials are positive for community-acquired and nosocomial pneumonia where combination therapy is the standard of care. In the Monte Carlo simulation by Mouton et al.,40 estimated ceftobiprole serum concentrations for additional dose and interval combinations were analyzed and presented in figure format. Unfortunately, TARs were not calculated for these combinations. As administration of ceftobiprole may create confusion and complicate administration, additional dosing schemes need to be explored.
Because ceftobiprole is a broad-spectrum antimicrobial, resistance induction and "collateral damage" are of concern. Although ceftobiprole was not shown to induce resistance in clinical trials, numerous abstracts demonstrate that low- and high-level ceftobiprole resistance develops when isolates are exposed to sub-MIC concentrations.44-48 No correlation has been identified between baseline MIC and development of resistance in staphylococci.45 Clinical trial data indicate that cure rates against P. aeruginosa infections are lower than in ceftazidime-treated patients. Although MICs were not reported in the ceftazidime group, ceftobiprole was effective against P. aeruginosa infections, with MICs 4 µg/mL or less. This suggests that optimizing pharmacodynamic parameters for MICs 8 µg/mL or more may increase activity against P. aeruginosa; however, the safety and tolerability of these regimens have not been evaluated. Comparing efficacy between antipseudomonal agents other than ceftazidime is difficult, as these data include in vitro and animal models. If ceftobiprole is used as an antipseudomonal cephalosporin, concern for resistance induction is real and limitations on widespread use must be considered. Overuse of ceftobiprole may also increase resistance in Enterobacteriaceae, particularly E. coli and K. pneumoniae, and may increase the rate of VRE colonization and C. difficile infection. As such, judicious use and proper monitoring of ceftobiprole will be necessary.
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Ceftobiprole is a broad-spectrum addition to our antimicrobial arsenal that is unique in its activity against MRSA and VRSA and is well tolerated. However, resistance induction in gram-negative pathogens and a complicated dosing regimen may limit ceftobiprole's use to empiric therapy in cSSSIs including diabetic foot infections and combination therapy for the treatment of nosocomial pneumonia.
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