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546 PART 5: Infectious Disorders

Carbapenems provide the broadest gram-negative coverage of all In contrast to meropenem and imipenem, doripenem is stable for
β-lactams and unlike other β-lactams, carbapenems are stable against 12 hours at room temperature, making it a more suitable option for
extended-spectrum β-lactamases and AmpC β-lactamases. Resistance prolonged infusions. Another advantage of doripenem is enhanced
mechanisms such as ESBLs are of particular concern because they are in vitro activity against P aeruginosa compared with imipenem and
increasing worldwide, including in the United States, and current meropenem. Similar to meropenem, prolonging the infusion can
treatment options are very limited. Similar to other β-lactams, car- help optimize outcomes, especially in situations where the infecting
bapenems exhibit time-dependent bactericidal activity and require pathogen is likely to have a high MIC. For most infections, doses of
approximately 40% fT > MIC, and therefore administering these 500 to 1000 mg every 8 hours are used for patients with normal renal
agents as prolonged infusions can help increase fT > MIC and ulti- function. However, for cystic fibrosis patients, it has been shown that
mately efficacy. The pharmacokinetics of carbapenems in critically ill higher than recommended doses of doripenem and meropenem are
patients are likely to change in a similar pattern as other β-lactams likely needed as these patients are often infected with multidrug-resis-
with increases in volume of distribution and clearance. Currently, tant organisms and have a vastly different pharmacokinetic profile.
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there are four carbapenems available in the United States: imipenem, Doripenem doses such as 2 g every 8 hours are not uncommon in this
meropenem, ertapenem, and doripenem. Each of these differs slightly patient population.
in their spectrum of activity and pharmacologic properties. While Common indications for use include nosocomial pneumonia and
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carbapenems typically are well tolerated, the potential for seizures intra-abdominal infections. Of note, a recent study comparing a 10-day
have been reported with imipenem/cilastatin. Impaired renal func- course of imipenem-cilastatin versus a 7-day course of doripenem
tion, high doses, increased age, history of seizures, or preexisting CNS for the treatment of ventilator-associated pneumonia showed lower
diseases/infections are the most common risk factors for seizures. clinical cure and higher mortality in the doripenem arm. This was
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The documented incidence from phase III trials and post-marketing attributed to the short course of doripenem administered and there-
surveillance is 1.5% to 2%. Meropenem, doripenem, and ertapenem fore careful consideration is recommended when determining both
have a lower risk of seizures compared with imipenem. the adequacy of dosing regimen as well as the duration of therapy to
Imipenem was the first carbapenem approved in the United States optimize outcomes.
in the 1980s. Imipenem can be hydrolyzed and inactivated by dehydro- Ertapenem is the most unique among the four carbapenems.
peptidase I (DHP-1), an enzyme found at the renal brush border cells, Pharmacokinetically it has a longer half-life and is significantly more
therefore it must be coadministered in a 1 : 1 with a DHP-1 inhibitor, protein bound allowing for once daily administration. The most com-
cilastatin. Depending on the severity of infection and renal function monly utilized dose of ertapenem is 1 g every 24 hours as a 30-minute
typical dosing of imipenem is 250 to 1000 mg every 6 to 8 hours admin- infusion. While 1 g doses are generally sufficient for efficacy, in the
istered as a 30- to 60-minute infusion. At room temperature imipenem context of augmented renal function, dosing every 12 hours may be
is stable for only 4 hours, making it very difficult to administer as a required to produce adequately high exposures. While this agent has
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prolonged infusion. Additionally, the potential for seizures at higher good activity against Enterobacteriaceae and has shown good outcomes
doses may prevent the use of imipenem for infections that require relative to the Group 2 carbapenems (imipenem, meropenem) against
more aggressive dosing, especially in patient populations at greater ESBL-producing organisms, this compound has no appreciable activity
risk (ie, CNS infections, concomitant medications that lower seizure against P aeruginosa and Acinetobacter. Due to its limited spectrum of
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threshold, renal dysfunction) for seizures. Previous imipenem therapy activity against these prominent ICU pathogens ertapenem is not typi-
is an independent risk factor for the presence of imipenem-resistant cally used as empiric therapy in the critical care setting. However, use of
P aeruginosa. 19,20 Another study in febrile neutropenic patients showed this agent for de-escalated therapy against enzyme-producing bacteria
that relapses with Pseudomonas were more common with imipenem may reduce the antipseudomonal pressure exerted by the use of the
(2 g/d) compared with ceftazidime. Similar to other carbapenems, other Group 2 carbapenems. This strategy should be considered when
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imipenem is not active against methicillin-resistant staphylococci or possible as the increasing use of these Group 2 carbapenems (imipenem,
vancomycin-resistant enterococci. Among clinically relevant gram- meropenem, doripenem) has resulted in escalating levels of resistance
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negative bacteria, imipenem is not active against Burkholderia cepacia across the globe for P aeruginosa and Acinetobacter.
and Stenotrophomonas maltophilia.
Unlike imipenem, meropenem stability at room temperature is Cephalosporins: Cephalosporins as a class cover a broad range of
enhanced and therefore prolonged infusions are a more viable option. organisms and are fairly well tolerated. They are typically classi-
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Meropenem dosing ranges from 500 to 2000 mg every 8 hours as fied as first, second, third, fourth, and fifth generation with varying
a 15- to 30-minute infusion for patients with normal renal function. spectrum activity among the generations. First-generation cephalo-
Due to the overall stability, prolonged infusions of meropenem are sporins, such as cefazolin, have activity against most gram-positive
generally limited to 3 hours. Monte Carlo simulations have been used cocci except enterococci and methicillin-resistant S aureus. Gram-
to help optimize dosing of meropenem in critically ill patients based negative coverage includes most strains of Escherichia coli, Proteus
on renal function. Simulations comparing a 30-minute infusion with mirabilis, and Klebsiella pneumoniae, but there is no activity against
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a 3-hour prolonged infusion showed that prolonging the infusion organisms such as Acinetobacter spp and Pseudomonas aeruginosa.
increases the probability of achieving 40% fT > MIC and required Because of its narrow spectrum of activity, cefazolin is not typically
less total daily dose. Depending on the MIC of the pathogen, this used as empiric therapy in the critical care setting. Second-generation
can have substantial effects on clinical outcomes. Prolonged infusion cephalosporins (cefoxitin and cefuroxime) have slightly better gram-
meropenem at a dose of 2 g every 8 hours given as a 3-hour infusion in negative bacilli coverage compared with the first generation. Similar
patients with normal renal function has also been utilized in a clinical to cefazolin, these agents are not often used as empiric therapy due
pathway for patients with ventilator-associated pneumonia. Based on to their limited spectrum of activity. Third-generation cephalospo-
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the organizations’ unit-specific ICU data and pharmacodynamic mod- rins (cefotaxime, ceftriaxone, and ceftazidime) are much more active
eling approaches, prolonged infusion meropenem was incorporated against gram-negative bacilli such as Enterobacteriaceae, Neisseria,
in the empiric treatment of VAP. The implementation of this pathway and Haemophilus influenzae. Compared with first-generation ceph-
significantly reduced infection-related length of stay and mortality. alosporins, these agents have less activity against gram-positive
Meropenem has slightly better gram-negative coverage than imipenem organisms. Of the three parenteral third-generation cephalosporins,
as it is active against Burkholderia cepacia. Additionally, the chemical ceftazidime is slightly different in that it has activity against P aeru-
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structure of meropenem makes it more difficult for P aeruginosa to ginosa. Similar to ceftazidime, cefepime, a fourth-generation cepha-
develop resistance. losporin, also has activity against P aeruginosa. Cefepime also has

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