Ceftobiprole: A New Option for Treatment of Skin and Soft

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E D I T O R I A L C O M M E N TA R Y
Ceftobiprole: A New Option for Treatment of Skin
and Soft-Tissue Infections due to Methicillin-Resistant
Staphylococcus aureus
Andreas F. Widmer
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland
(See the article by Noel et al. on pages 647–55)
Methicillin-resistant Staphylococcus aureus
(MRSA) has emerged as an important
nosocomial pathogen, accounting for
150% of all bloodstream S. aureus isolates
recovered from 49 representative US hospitals [1], with similar trends in Europe
[2]. MRSA infection has also become
common in outpatients [3]. Even more
worrisome is the fact that MRSA was identified as the most common pathogen in
patients presenting with acute, purulent
skin and soft-tissue infections to emergency departments in the United States
[4]. Such infections are associated with
longer hospital stays, longer durations of
antibiotic use, higher costs, and, probably,
greater mortality rates, compared with infections caused by methicillin-susceptible
S. aureus [5, 6]. The emergence of community-onset MRSA infection aggravates
control of MRSA infection; a validated
guideline for control of community-onset
MRSA infection has not yet been pubReceived 5 November 2007; accepted 5 November 2007;
electronically published 25 January 2008.
Reprints or correspondence: Dr. Andreas F. Widmer, Div.
of Infectious Diseases and Hospital Epidemiology, University
Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
([email protected]).
Clinical Infectious Diseases 2008; 46:656–8
2008 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2008/4605-0002$15.00
DOI: 10.1086/526528
lished, and community-onset MRSA infection adds to the overall burden of
MRSA infection [7], even in countries
where a “search and destroy” policy is in
place [8]. From the United States, the predominant community-onset MRSA clone,
USA300 (ST8), can rapidly be spread by
travelers and health care workers in different parts of the world [9, 10]. Therefore,
new antimicrobial agents are urgently
needed [11].
The role of vancomycin as the reference
standard for treatment of MRSA infection
has been recently challenged [12]. In fact,
efficacy data have never been submitted
to the US Food and Drug Administration,
and breakpoints have recently been lowered by the Clinical and Laboratory Standards Institute to improve the correlation
between in vitro susceptibility and clinical
outcome. Many new drugs against grampositive pathogens—recently reviewed in
Clinical Infectious Diseases [13]—have
been developed, and some of them have
even been approved by the US Food and
Drug Administration (e.g., daptomycin,
tigecycline, and linezolid). However, tigecycline and linezolid are bacteriostatic
rather than bactericidal. Bactericidal activity is important for therapeutic efficacy in
certain infections, such as endocarditis,
meningitis, and infections in neutropenic
656 • CID 2008:46 (1 March) • EDITORIAL COMMENTARY
patients. Although once-daily daptomycin
is bactericidal and approved for S. aureus
bacteremia, including endocarditis, it is
not active against S. aureus pneumonia
[14]. Other not yet approved drugs, such
as second-generation glycopeptides, have
a smaller spectrum of antimicrobial activity. Iclaprim, a folate inhibitor with bactericidal activity against MRSA and gramnegative pathogens, is still being studied
in clinical trials [15].
In infectious diseases, survival is significantly improved when the initial choice
of antibiotics is “appropriate,” which is
defined as all isolated pathogens being susceptible to 11 of the antimicrobial agents
administered [16]. In addition, multiple
studies provide strong evidence that rapid
therapy improves outcome, including that
of MRSA infection [6, 17, 18].
Complicated skin and skin-structure
infections and pneumonia are the most
frequently observed infections due to
community-onset MRSA. Currently, the
Infectious Diseases Society of America
guidelines recommend vancomycin or linezolid for empirical treatment if MRSA
is suspected [19]. Microbiological results
require several days, and expensive PCR
tests must be performed to rule out MRSA
infection. Therefore, empirical coverage
for serious complicated skin and skin-
structure infections requires coverage
against MRSA infection in hospitals and
in areas where MRSA infection is highly
endemic.
The carefully conducted randomized,
controlled clinical trial by Noel et al. [20]
provides strong evidence for noninferiority of ceftobiprole, compared with the
combination of vancomycin and ceftazidime, for treatment of complicated skin
and skin-structure infections. A similar
trial comparing ceftobiprole with vancomycin alone supports the results of this
trial, with similar outcomes in both regimens [21]. Other b-lactam antibiotics
with activity against MRSA are under development, but no other agent is as advanced in clinical trial testing as ceftobiprole [22]. Ceftobiprole has an increased
binding to penicillin-binding protein 2a
from methicillin-resistant staphylococci
and to penicillin-binding protein 2x in a
penicillin-resistant Streptococcus pneumoniae strain, resulting in bactericidal activity against these emerging pathogens. In
addition, ceftobiprole demonstrates activity against vancomycin-intermediate and
-resistant S. aureus [22]. Polymicrobial infections are common in complicated skin
and skin-structure infections in patients
with diabetes; S. aureus, including MRSA,
and, less commonly, Pseudomonas aeruginosa are most frequently identified as
causes of such infections. Culture findings
of swab specimens from an ulcer are difficult to interpret, but S. aureus and P.
aeruginosa should be covered for treatment if found on culture of tissue specimens or, preferably, bone biopsy specimens. Ceftobiprole has in vitro activity
similar to that of ceftazidime or cefepime
against Enterobacteriaceae but is more active towards AmpC-mediated b-lactam resistance than is ceftriaxone or ceftazidime
[22]. Therefore, a single agent is now available for treatment that previously required
combinations of antibiotics. In such infections, ceftobiprole may become the
drug of choice—if currently unknown ad-
verse effects do not limit its use in the
future.
Activity against enterococci is another
advantage of ceftobiprole. Enterococci are
frequent colonizers of foot ulcers in patients with diabetes but rarely require
treatment. However, serious infections are
encountered in the immunocompromised
host, in whom resistance to ampicillin and
vancomycin has emerged [23].
Ceftobiprole demonstrated a low potential to select for resistance; the highest
MIC found in the presence of prolonged
serial passages with ceftobiprole at subinhibitory concentrations was 8 mg/mL in
1 of 10 strains after 50 passages [24]. However, resistance will most likely emerge if
the drug is not used wisely. The adverse
effects associated with ceftobiprole are
similar to those associated with comparators, with nausea and taste disturbance
(dysgeusia) being the most common.
Ceftobiprole may become an important
new antibiotic for complicated skin and
skin-structure infections before microbiological results allow streamlining of antimicrobial therapy. MRSA coverage with
ceftobiprole may improve outcome by enabling early bactericidal therapy in patients admitted to emergency departments
because of complicated skin and skinstructure infections not yet identified as
being due to MRSA. In addition, mixed
infections involving MRSA could be
treated with ceftobiprole, replacing vancomycin-based combination therapy.
Available data do not allow clinical statements against anaerobic infections. In vitro activity indicates lower ceftobiprole
MICs for Acinetobacter and Alcaligenes
species, compared with ceftriaxone and
even cefepime [25], but ceftobiprole is not
likely to be suitable for gram-negative
pathogens expressing extended-spectrum
b-lactamases. Ceftobiprole has shown superiority to vancomycin in a rat model of
left-side MRSA endocarditis [26].
This promising new agent may be regarded as the first clinically effective cephalosporin against MRSA for treatment of
complicated skin and skin-structure infections, with 2 randomized clinical trials
supporting its efficacy [20, 21]. Its additional activity against ampicillin-susceptible enterococci, penicillin-resistant
pneumococci, and most Enterobacteriaceae may allow ceftobiprole to be categorized as a new class of cephalosporins;
it may be considered to be a member of
the fifth-generation cephalosporins.
Acknowledgments
Potential conflicts of interest. A.F.W. has been
a member of an expert group for Novartis and
has served on the advisory board for Arpida.
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