Group Title: Critical Care
Title: Optimizing the use of carbapenems in the face of increasing Gram-negative resistance
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 Material Information
Title: Optimizing the use of carbapenems in the face of increasing Gram-negative resistance
Physical Description: Book
Language: English
Creator: Ramphal, Reuben
Publisher: Critical Care
Publication Date: 2008
General Note: Start page S1
General Note: M3: 10.1186/cc6817
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Bibliographic ID: UF00099974
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: Open Access:
Resource Identifier: issn - 1364-8535


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Optimizing the use of carbapenems in the face of increasing

Gram-negative resistance
Reuben Ramphal

Division of Infectious Diseases, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA

Corresponding author: Reuben Ramphal,

Published: 21 May 2008
This article is online at 2/S4/S1
C 2008 BioMed Central Ltd

Among the worrisome complications in the treatment of
serious bacterial infections is antibiotic resistance, both pre-
existing and emerging during therapy. The consequences of
this phenomenon have repeatedly been analyzed, with the
conclusion that infections with resistant pathogens generally
result in increased patient morbidity and mortality, and an
increase in the societal financial burden. Much of this
resistance, particularly among Gram-negative organisms, is
directed against often used classes of antibiotics, such as the
third-generation cephalosporins, fluoroquinolones, and broad-
spectrum penicillins. Thus, there has been increasing use of
carbapenems for empiric and definitive therapy in institutions
in which resistance among Gram-negative organisms is fre-
quently observed. The articles included in this supplement
review optimization of therapy, focusing on the following
issues: appropriate first-line therapy, de-escalation, antibiotic-
related adverse events, and pharmacokinetic-pharmaco-
dynamic principles of antibiotic infusion.

Thomas G Slama (Clinical Professor of Medicine at Indiana
University School of Medicine) reviews the clinical and
economic significance of antibiotic resistance [1]. The Anti-
microbial Availability Task Force, created by the Infectious
Diseases Society of America, identified six pathogenic micro-
organisms, including three key Gram-negative pathogens, as
being significant concerns. Dr Slama reviews the role of
these Gram-negative organisms in infections and the impact
that they have. Acinetobacter has now reared its head in
North America after being widely recognized as an important
problem in European and Asian intensive care units. It is now
considered to be a battlefield organism. He also briefly
reviews the prevalence, costs, and mortality associated with
infections caused by extended P-lactamase producing
bacteria, emphasizing that delays in appropriate therapy
result in increased mortality.

Dr Slama also discusses the real costs of antibiotic
resistance. In addition to patient care costs, there are costs
associated with surveillance, testing, and isolation

Critical Care 2008, 12(Suppl 4):S1 (doi:1 0.1186/cc681 7)

procedures. His commentary on new drug development is
worth a read.

Robert C Owens Jr (Co-Director of the Antimicrobial
Stewardship Program at Maine Medical Center in Portland,
Maine) focuses on the adverse events associated with
antimicrobial agents [2]. Antimicrobial agents lead all drug
classes in terms of associated adverse events. The adverse
events that are characteristic of a particular class of
antimicrobials, such as P-lactams, remain manageable.
However, the drug classes that contain unique, unpredictable
harms, such as the fluoroquinolones, must be viewed with
caution and subject to scrutiny. Importantly, although not
typically considered an adverse event, the emergence of
resistance plays an integral role in the process of deciding on
the initial therapeutic regimen. Emergence of resistance
becomes an even greater concern because carbapenems
(members of the P-lactam class with activity against a broad
spectrum of resistant pathogens) are increasingly being
utilized in first-line therapy protocols for the treatment of
serious bacterial infections.

James J Rahal (Professor of Medicine at Weill Medical
College of Cornell University and New York Hospital in New
York) reviews the importance of appropriate initial antibiotic
therapy and de-escalation [3]. Drawing on his lengthy and
broad experience in dealing with resistant Gram-negative
bacteria, he emphasizes the role of carbapenems in insti-
tutions that are plagued by extended-spectrum P-lactamase
producers, but he also points out the downside to carba-
penem use based on his first-hand published experience. He
also emphasizes careful de-escalation to a narrow spectrum
of antibiotic therapy after identification of the infecting
organism, and appropriate short-course therapy to limit the
emergence of resistance to carbapenems.

David P Nicolau (Director of the Center for Anti-Infective
Research and Development at the Hartford Hospital,
Hartford, Connecticut) discusses the pharmacokinetic-

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Critical Care Vol 12 Suppl 4 Ramphal

pharmacodynamic principles required to optimize antibiotic
administration and so improve clinical outcomes [4]. The
goals of antibiotic use are to achieve and maintain thera-
peutic drug levels that eradicate the pathogen, while
simultaneously preventing the emergence of resistance. He
suggests how both goals can be attained by targeting the
pathogen-specific minimum inhibitory concentration and
altering infusion strategies. Continuous infusion strategies, as
opposed to the commonly employed intermittent (1 hour)
infusion, have been reported in a few small studies to yield
enhanced clinical response rates. He points out that it is not
necessary to exceed the minimum inhibitory concentration for
the entire duration of the dosing regimen. An alternative
strategy uses the same dose at the same frequency of
administration but extends the period of infusion. The
extended infusion protocol appears to have almost identical
efficacy with a low dose as with a higher dose infused over a
shorter period of time, while also reducing cost, toxicity, and
the possibility of emergence of resistance.

These reviews should serve as starting points for optimal use
of carbapenems to prolong their useful life, given the demon-
strated need for carbapenems resulting from the emergence
of more resistant Gram-negative organisms. However, it
should be noted that no long-term data on some of the
strategies suggested in these reviews exist. The proof that
prolonging infusion times will minimize the development of
resistance is still lacking, and whether outcomes will be
better must still be demonstrated in large-scale studies. Thus,
careful data collection and reporting are needed if we are to
obtain a better appreciation of the utility of such strategies.

Competing interests
The author declares that they have no competing interests.

This article is published as part of Critical Care Volume 1 2 Supplement
4, 2008: Optimizing the use of carbapenems in the face of increas-
ing Gram-negative resistance. The full contents of the supplement
are available online at 2/S4

Publication of this supplement has been sponsored by Ortho-McNeil,

1. Slama TG: Gram-negative antibiotic resistance: there is a
price to pay. Crit Care 2008, 12(Suppl 4):S4.
2. Owens RC Jr: An overview of harms associated with P-lactam
antimicrobials: where do the carbapenems fit in? Crit Care
2008, 12(Suppl 4):S3.
3. Rahal JJ: The role of carbapenems in initial therapy for serious
Gram-negative infections. Crit Care 2008, 12(Suppl 4):S5.
4. Nicolau DP: Pharmacodynamic optimization of p-lactams in
the patient care setting. Crit Care 2008, 12(Suppl 4):S2.

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