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Review
An overview of harms associated with β-lactam antimicrobials:
where do the carbapenems fit in?
Robert C Owens Jr

Department of Clinical Pharmacy and Infectious Diseases, Maine Medical Center, Bramhall Street, Portland, Maine 04102, USA

Corresponding author: Robert C Owens, [email protected]

Published: 21 May 2008 Critical Care 2008, 12(Suppl 4):S3 (doi:10.1186/cc6819)


This article is online at http://ccforum.com/content/12/S4/S3
© 2008 BioMed Central Ltd

Abstract practicing today. Although these agents are generally safe,


The US Institute of Medicine’s focus on patient safety has certain class effects exist that include serious hypersensitivity-
motivated hospital administrators to facilitate a culture of safety. As related harms, bone marrow suppression, and seizures. These
a result, subcommittees of the pharmacy and therapeutics and other antimicrobial harms are discussed here.
committee have emerged in many hospitals to focus on adverse
events and patient safety. Antimicrobial harms have gained the General classification of adverse events
attention of practicing clinicians and hospital formulary committees,
Type A events are predictable events that represent either an
because they top the list of drugs that are associated with adverse
events and because of certain serious harms that have ultimately excess of the drug’s primary pharmacologic effect (for
led to the withdrawal of some antimicrobial agents. In the near example, hypotension with a vasodilator) or a secondary
future, several antimicrobials in the late phase of development will pharmacologic property (for example, anticholinergic effects
become available for clinical use (ceftobiprole, ceftaroline, and with tricyclic antidepressants) [2]. These events are typically
telavancin), and others (doripenem and dalbavancin) have recently dose related, usually identified before marketing, and
joined the armamentarium. Because new antimicrobials will
generally listed in the product’s labeling. Although common
become part of the treatment armamentarium, it is important to
discuss our current understanding of antimicrobial harms in and capable of producing significant morbidity, they are rarely
general. Although not thought of as traditional adverse events, fatal. In contrast, type B events are not an extension of the
Clostridium difficile infection and development of resistance during known pharmacologic properties of a drug. These events,
therapy are adverse events that occur as a result of antimicrobial which include idiosyncratic, immunologic/allergic, and
exposure and therefore are discussed. In addition, a distillation of carcinogenic/teratogenic events, are generally unpredictable,
our current understanding of β-lactam specific adverse events will
be provided. Finally, new methods of administration are being unrelated to dosing or route of administration, and are more
evaluated that may influence peak concentration-related anti- or less a function of the patient’s susceptibility to the effect
microbial adverse events. rather than intrinsic drug toxicity. Type B events can present
late, long after drug therapy has been discontinued, and
consequently they may not be recognized or attributed to the
Introduction drug because of the temporal disassociation. Although they
The safety of antibiotics has attracted attention lately in both are the least common, type B events are among the most
the scientific and regulatory communities. For example, in serious and potentially life-threatening of the adverse events
2001, the Interscience Conference on Antimicrobial Agents [2].
and Chemotherapy held a symposium entitled ‘Antibiotics to
die for’. In addition, the US Food and Drug Administration Adverse immunologic events can also be classified on the
(FDA) recently mandated a second change in the labeling of basis of their pathophysiology into types 1 through 4 and
telithromycin in less than a year because of safety concerns, idiopathic events [3,4]. Type 1 events are immunoglobulin
and has updated the language of antimicrobials regarding the IgE-mediated, immediate hypersensitivity reactions that
risk for Clostridium difficile infection [1]. Antibiotic safety is produce urticaria, hives, or anaphylaxis. Events of types 2 and
an important component of both patient care and formulary 3 are IgG-mediated or IgM-mediated delayed reactions. Type
decision making. β-Lactams are typically considered to be 2 events present as anemia, cytopenia, or interstitial nephritis,
among the safest classes of antibiotics available to clinicians whereas type 3 events present as serum sickness or drug

CDI = Clostridium difficile infection; CYP = cytochrome P450; FDA = Food and Drug Administration; IKr, delayed rectifier potassium channel; MIC =
minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; VAP = ventilator-associated pneumonia.

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fever. Type 4 events are T-cell-mediated, delayed reactions end-point of noninferiority compared with imipenem for
that present as contact dermatitis. All other events are deemed patients with VAP [6]. Therefore, we can find ourselves
idiopathic. These idiopathic events can present as eosinophilia, feeling that we need to use a new antimicrobial for a
a maculopapular rash, or Stevens-Johnson syndrome. particular indication before clinical studies support such a
use. Having antibiotics available with enough data to support
The type and severity of adverse events associated with a a wide range of indications to assess properly their utility for a
particular drug are influenced by a multitude of pharmaco- yet wider range of indications does not necessarily go hand
logic and clinical factors. These include the drug’s pharmaco- in hand in the current regulatory climate. Gone are the days
kinetic properties (absorption, distribution, metabolism, and when an antimicrobial came to the marketplace with 14
elimination); the dose, route, and duration of therapy; the indications (for instance, trovafloxacin). The trend, especially
patient’s age and genetic composition; the presence of for antimicrobials, is to request FDA approval for one or two
concomitant disorders; and concurrent drug administration. indications and leave the clinician to determine whether the
drug may or may not work for other infectious diseases. As
Sources of information for we have learned (for example, from daptomycin and
antibiotic-associated adverse events tigecycline), it should not be assumed that an antimicrobial
Data regarding a drug’s safety profile can be difficult to approved for skin and skin structure infections will be
obtain, because negative data are rarely published; moreover, effective for other indications. Clinicians typically must wait
there is typically a delay in the availability of published for 1 year for results from phase III trials to be published in a
information for new drugs. Several sources can be explored, respectable peer-reviewed journal. Interestingly, about half of
however, depending on where the drug is in its life cycle. all drug withdrawals from the market occur within approxi-
Data can of course be found in the product labeling and from mately 2 years of approval [7]. So, the first 2 years of the
meeting abstracts at the time of drug approval. If an advisory antimicrobial’s time in the marketplace is very telling.
committee hearing has taken place, then data may be found
at the FDA’s website [5]. This website is an underutilized As mentioned above, antimicrobials lead all drug classes in
source of data for the formulary decision maker and even for terms of numbers of adverse events [8]. Some adverse
practicing clinicians who desire to know more about the events are class specific, but even within a class of anti-
drugs they prescribe. Good examples exist of presentations microbials some agents may not be associated with the
and accompanying discussions held at the FDA’s Advisory adverse event at all. Examples include epileptogenic capa-
Committee meetings, which are posted on the website in a bilities among the various β-lactams. All β-lactams have some
downloadable format (PDF files and PowerPoint slides). potential to cause seizures, some more so than others.
Examples include the discussion of cardiac and renal Among the carbapenems, imipenem is most frequently
concerns related to the cyclo-oxygenase-2 inhibitors and associated with seizures, whereas meropenem, ertapenem,
specific toxicities of voriconazole, telitromycin, moxifloxacin, and doripenem are at the opposite end of the spectrum in
and newer generation antipsychotics. Although some of this terms of risk for seizures. Similarly, macrolides/ketolides and
information has made its way into the published literature, fluoroquinolones are associated with QT liability, but
some of it remains unpublished and is only available on the azithromycin and ciprofloxacin stand out as not being
FDA’s website. In addition, if the drug has already been associated with the potential for causing QT prolongation.
approved in other countries, postmarketing studies may be For these reasons, new drugs should be viewed skeptically
available in those countries. when they are first approved for use and introduced for
formulary discussion.
Another factor has an impact on the availability of safety data.
Companies sometimes seek initial FDA approval for two For some antimicrobial classes, safety can be inferred from
indications, particularly for antimicrobials. These indications previously introduced class members. For example, the β-
are usually skin and skin structure infections, acute lactams have an established safety profile, with few if any
exacerbations of chronic bronchitis, acute bacterial sinusitis, surprises when a new class member is introduced for clinical
or urinary tract infections - indications for which it is easy to use. Moxalactam is a well known exception to this long track
enroll patients over a short period of time. Unfortunately, this record of safety. Other than the moxalactam example, which
often leaves the clinician without data on other infections for occurred several decades ago, the β-lactam family that
which the drug may be used. For example, tigecycline has includes the penicillins, cephalosporins, cephamycins, mono-
been on the market for a couple of years, but its initial bactams, and carbapenems has not had a class member
indications were for the treatment of complicated skin and withdrawn from the marketplace because of an unexpected
soft tissue infections and complicated intra-abdominal and serious adverse event. For this reason, given adequate
infections. Pneumonia studies have only recently been safety data during a clinical development program, novel β-
conducted. Although tigecycline may have been used off- lactams have been well accepted by hospital formularies
label for the treatment of hospital-acquired pneumonia or upon their release to the market so long as other
ventilator-associated pneumonia (VAP), it failed to meet its considerations, such as pricing and efficacy, are favorable

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relative to existing class members. On the flip side, the including the carbapenems, have not been associated with
opposite is true for the fluoroquinolones. In addition to the QT liability to date. In addition, preclinical screening tools are
known class effects, unusual and serious adverse events with now used to detect the potential for QT liability, so that it can
these agents have emerged shortly after their introduction to be assessed early in development (moxifloxacin) rather than
the market. Examples include drugs that were actually with- waiting for postmarketing studies to elucidate this finding
drawn from the market (for example, temafloxacin [hemolytic- (droperidol).
uremic syndrome] and trovafloxacin [hepatotoxicity resulting
in death or transplantation]). For this reason, formulary com- Dysglycemias
mittees have been conservative in their adoption of new Dysglycemias (hypoglycemia and hyperglycemia) are un-
fluoroquinolones until a proven track record has been common adverse events associated with some antimicrobials,
established. including certain fluoroquinolones, particularly gatifloxacin
[13,15]. Historically, quinine has been associated with
Cardiac toxicity dysglycemias. The quinolones, which are structurally related
Prolongation of the QT interval is an increasingly important to quinine vis à vis quinoline rings, have a penchant to
adverse event that has led to the withdrawal of certain drugs influence the release of insulin (gatifloxacin, temafloxacin, and
from the market, many of them antimicrobials. Although clinafloxacin more so than others) [13,15]. Other anti-
prolonged QT interval rarely has consequences (such as life- microbial classes appear to be devoid of the potential to
threatening ventricular arrhythmias, specifically torsades de disrupt glucose homeostasis. The purported pathophysiology
pointes), they are severe [9-11]. The fluoroquinolones (except of perturbations in glucose homeostasis (specifically
for ciprofloxacin), macrolides/ketolides, and azoles have been hypoglycemia) is mechanistically similar to that observed with
shown to prolong the QT interval [9,11-13]. QT interval prolongation. A potassium channel exists within
pancreatic β cells that is genetically similar to the one present
QTc prolongation occurs as a result of a drug’s affinity in cardiac myocytes. Fluoroquinolones (particularly gatifloxa-
toward binding to a particular potassium channel in the cin, temafloxacin, and clinafloxacin) have a collateral affinity
cardiac myocyte (delayed rectifier potassium channel; IKr). toward this channel, resulting in partial blockade and leading
The prevalence and risk associated with this prolongation to an accumulation of intracellular glucose within these β
depends on drug-related and patient-related factors, cells, and insulin is secreted in response to this artificially
including the dose and route of administration, the drug’s elevated glucose concentration [16]. For example, clinafloxa-
individual propensity for binding to IKr channels, the number cin exposure resulted in a substantial increase in insulin
of channels present in an individual patient (reduced numbers release (from 165% to 235%) that triggered a reduction in
exist in patients with congestive heart failure and in women), blood glucose by 47% to 51% [13,15]. This is an extreme
and genetic anomalies within these and other cardiac example within the fluoroquinolone class. Substantially
channels. In addition, organ dysfunction or the concomitant smaller disturbances in blood glucose have been determined
administration of other medications can increase this risk by with other class members.
delaying metabolism of the QT interval prolonging drug or
enhancing drug exposure, or by causing electrolyte derange- The reason why this is clinically unnoticed in patients is
ments [9,10]. Furthermore, concurrently administered medi- explained by the fact that the body is remarkable in its ability
cations may have direct effects of their own on these to compensate physiologically for small fluctuations in glucose
channels, augmenting the overall effect on the QT interval. regulation [13,15]. However, symptomatic hypoglycemia can
develop in susceptible individuals who lack these compen-
The affinity of various antibiotics for these channels varies satory mechanisms (for example, patients with underlying
substantially. For example, 50% inhibition of the IKr channel is diagnosed or undiagnosed diabetes and those receiving
produced by a 33 μmol/l concentration of clarithromycin, a corticosteroids) [15]. Gatifloxacin gained notoriety for
42.5 μmol/l concentration of telithromycin, a 72 μmol/l complications that were detected in postmarketing studies.
concentration of erythromycin, a 129 to 353 μmol/l concen- Clinafloxacin’s proclivity for this rare but serious adverse
tration of moxifloxacin, and a 966 μmol/l concentration of event was determined during its clinical development program
ciprofloxacin [10]. In contrast, less than a 1 μmol/l concen- and may be among the reasons why its submission to the
tration of sotalol or terfenadine is required to produce 50% FDA was withdrawn by the company after completion of its
inhibition [11]. phase III studies [13,15].

Overall duration of exposure also plays an important role [14]. Clostridium difficile infection
Single doses of a drug are not likely to cause torsades de C. difficile infection (CDI) is an emerging, complex, and
pointes; however, the probability that this particular adverse important patient safety issue; it is an adverse event almost
event will occur rises sharply when a full course of therapy is exclusively associated with antibiotic administration. Acquisition
administered. In general, the median time to torsades de of CDI is a multifactorial process that involves antibiotic use,
pointes is typically 4 to 5 days into therapy. β-Lactams, exposure to the organism, and a variety of host factors,

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Figure 1

Pooled odds ratios and 95% confidence intervals for Clostridium difficile infection by antibiotic type. Adapted with permission from Bignardi.
Reprinted with permission [23]. Copyright © 1998 The Hospital Infection Society.

including age, immune status, and gastric acid suppression ranged from 1.3 to 36.2, depending upon the antibiotic
[13,17]. Consequently, the risk for CDI can be substantially employed (Figure 1) [23]. Given the limitations inherent in
reduced through good antimicrobial stewardship, compliance meta-analyses of trials with vastly different protocols, these
with infection control practices, and appropriate odds ratios are not listed for comparative purposes; however,
environmental intervention [17,18]. A number of reasons for they illustrate the fact that all antibiotics are associated with
the increased incidence of CDI have been proposed and are an increased risk for CDI [24]. Although carbapenems were
discussed in detail elsewhere [19]. In brief, the appearance of not included in this analysis, recent data demonstrate that this
a previously uncommon, toxin gene variant of C. difficile that class of antibiotics, like almost all others, carries a risk for CDI
possesses additional resistance characteristics (to [25,26]. And, a review of the newer literature evaluating
fluoroquinolones) has emerged as a predominant cause of antimicrobial risk for CDI suggests that identified odds ratios
CDI throughout North America and as far away as Japan [20]. fall within the previously identified range, including carba-
Because of the virulence associated with this new strain of C. penems [20]. Finally, it is important to remember that
difficile, careful attention to antimicrobial selection and although the risk for CDI increases with increasing duration of
duration of therapy has become an important tool in antibiotic therapy, only a single dose is needed to increase
combating this infection. this risk [20,25,27].

The individual risk associated with each antimicrobial is Metabolic liability


probably different. Studies to date have been unable to Drugs that rely on cytochrome P450 (CYP) enzymes for
distinguish antimicrobial risk at the ‘micro’ level but they were metabolism or inhibit these enzymes possess what is termed
able to elucidate differences at the ‘macro’ level. For example, ‘metabolic liability’. Of the various CYP isoenzymes, CYP
the cephalosporins, fluoroquinolones, and variably clinda- 3A4 is the most important because it is responsible for the
mycin have topped the list of antimicrobials that have been biotransformation of nearly 60% of all oxidized drugs [11].
associated with the emerging toxin gene variant strain of C. Inhibiting the metabolism of a drug that relies on CYP 3A4
difficile known as BI/NAP1. This is due, in part, to the fact magnifies any associated toxicities inherent to that drug,
that the aforementioned drug classes possess no or variable because most are dose (exposure)-dependent (for example,
activity against C. difficile. Antimicrobials with activity against hepatotoxicity, QT interval prolongation, and rhabdomyolysis).
C. difficile (for example, metronidazole, piperacillin-tazobactam, Because polypharmacy plagues patients with HIV disease
tetracyclines including tigecycline, and to some extent the and the elderly, the risk for drug interactions is increased
carbapenems) have been associated with CDI less often than significantly in these populations [28]. In addition, patients
those classes of drugs to which in vitro resistance is routinely may be at risk for certain toxicities when they receive drugs
observed in clinical isolates [21,22]. In a review of the that carry metabolic liability, even in the absence of a direct
literature, the odds ratios for C. difficile-associated disease drug-drug interaction. The reason for this is that some

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patients are characterized genetically as poor metabolizer Figure 2


phenotypes (typically more common with CYP 2C9 and CYP
2C19, which have specific impacts on the azole antifungals).
Patients with these poor metabolizer phenotypes are at risk
for dramatically reduced drug clearance when they are given
drugs that are metabolized through these CYP isoforms [11].
In general, antimicrobials that carry metabolic liability include
macrolides, ketolides, imidazole/triazole antifungals, and (to a
lesser degree) trimethoprim-sulfamethoxazole and ciprofloxa-
cin. To date, β-lactams, most fluoroquinolones, clindamycin,
and aminoglycoside antimicrobials do not possess metabolic
liability, making them safe to use in patients receiving
concurrent CYP P450 inhibitors and substrates.

A recent example demonstrates the ongoing importance of


unrecognized metabolic liability. A large population of
outpatients in a Medicaid claims database were evaluated
[29]. Patients who were receiving an antimicrobial (erythro- Approach to antibiotic selection in patients with a history of penicillin
mycin) concurrently with CYP 3A4 inhibitors were compared allergy. aIt is often difficult to obtain an accurate history; if in doubt,
assume that reaction could have been an urticarial rash. bAvoid use of
with patients receiving CYP 3A4 inhibitors and/or β-lactam first-generation cephalosporins. Stevens-Johnson syndrome and toxic
antibiotics. A fivefold increase in cardiac sudden death was epidermal necrolysis are not IgE mediated. If the suspected drug
reported in patients taking erythromycin-CYP 3A4 combina- reaction was either of these, then avoid skin testing and use of
tions compared with recipients of CYP 3A4 inhibitors and/or penicillins. cSkin testing with amoxicillin is sometimes used if the
reaction was to amoxicillin, but the incidence of false negatives is
amoxicillin.
unknown. dIf the reaction was serious, then one may challenge in a
supervised setting using a ‘graded challenge’ with escalating oral
Immune-mediated adverse events doses followed by intravenous administration, if applicable. Reprinted
Immune-related antimicrobial harms are a common with permission [3]. Copyright © 2002 the Infectious Diseases Society
of America.
complication of many antibiotics, including β-lactams, fluoro-
quinolones, glycopeptides, and sulfa drugs [4,13,30,31].
Hypersensitivity reactions producing rash, pruritus, and/or
urticaria are the most frequent and occur in up to 8% of historical information is in error; only 10% to 20% of patients
patients who receive a penicillin and up to 3% of patients reporting a penicillin allergy are truly allergic based on skin
who receive a cephalosporin [32,33]. In contrast, anaphylaxis testing [35]. Most of these ‘alleged’ allergic reactions to
develops in only 0.004% to 0.015%, and fatality due to this penicillin represent predictable side effects of the drug or are
anaphylaxis occurs in only 0.001% to 0.003% of penicillin due to the infectious agent itself rather than the drug and do
treatment courses [4]. not represent true type 1 hypersensitivity reactions [3,36].
Penicillin skin testing has a negative predictive value in
Cross-reactivity occurs within the various classes of antibiotics. excess of 99% and is a safe and effective means of
For example, patients who have had an allergic reaction to determining which of these reactions represent a true IgE-
penicillin have a fourfold to sixfold increased risk for a reaction mediated response. In more than 2,000 patients who stated
upon exposure to other β-lactams [4]. Thus, a history of an that they were allergic to penicillin but had a negative skin
allergic reaction to penicillin has traditionally been sufficient to test, no life-threatening immediate reactions occurred during
exclude further therapy with all members of the β-lactam class penicillin therapy [36]. In 2002, Robinson and coworkers [3]
[4]. However, recent evidence suggests that this broad-based reported a useful algorithm to guide antibiotic selection in
exclusion is too conservative and prevents patients from patients with a history of penicillin allergy (Figure 2). When
receiving first-line therapy, and often results in the patient using this algorithm it must be remembered that skin testing
receiving a marginally effective therapy. It is important to is predictive only of IgE-mediated events; a negative skin test
remember that patients should receive the most effective does not decrease the probability of non-IgE-mediated events
agent, not a second-line or third-line treatment (unless [3]. However, these non-IgE-mediated events are frequently
absolutely necessary). In some cases (for example, in patients related to side chains on the β-lactam ring [3], and so
with cystic fibrosis) there are no second-line therapies for affected patients may be less susceptible to cross-reactivity
certain pathogens; in these situations desensitization protocols with other members of the class or other classes of β-
are used to facilitate the use of a first-line antimicrobial [34]. lactams.

Between 5% and 20% of patients claim to have a history of Cross-reactivity between penicillins and carbapenems would
an allergic reaction to penicillin [3,4]. However, much of this be expected on the basis of structural similarity. However,

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data evaluating the frequency of hypersensitive reactions in Hepatotoxicity has been associated with amoxicillin/clavu-
penicillin allergic patients who receive a carbapenem are limited lanate, oxacillin, and trovafloxacin [40-43]. In a series of
to skin testing and retrospective evaluations [35]. In three patients being treated as outpatients with intravenous
separate chart reviews, the prevalence rates of carbapenem therapy, oxacillin was associated with a significantly increased
hypersensitivity in patients with a history of penicillin allergy were prevalence of hepatotoxicity (22%) as compared with nafcillin
9.5% [37], 11% [38], and 9.2% [39]. However, in only one of (0%), clindamycin (1.4%), or other antimicrobials (1.4%; all
these evaluations [38] was this risk significantly increased P < 0.001 versus oxacillin) [41]. Trovafloxacin was removed
relative to patients without a history of penicillin allergy. Because from the market secondary to several deaths related to
precise and complete documentation is essential to differentiate hepatotoxicity [13,44].
between allergic and nonallergic reactions and to establish the
temporal relationship of these reactions to therapy, the Bone marrow suppression resulting in thrombocytopenia,
retrospective nature of these evaluations substantially influences anemia, and/or neutropenia can develop when IgG or IgM
the accuracy of these risk assessments. antibodies bind to antimicrobial antigens on the surface of
circulating cells, leading to lysis or opsonization of these cells
Pending more definitive data, patients with a self-reported [4]. β-Lactams, including imipenem, linezolid, and glyco-
history of a penicillin allergy that is not IgE mediated are peptides, have all been associated with various forms of bone
assumed to be at moderate risk for an associated adverse marrow suppression [30,41,45,46].
event. These patients may receive a cephalosporin or
carbapenem if other treatment options are lacking and a Central nervous system adverse events
cephalosporin or carbapenem is deemed the most β-Lactams, fluoroquinolones, and isoniazid are associated
appropriate option. Skin testing can be considered in patients with increased risk for seizures [13,47,48]. In fact, β-lactams
with suspected IgE-mediated penicillin allergy. In general, are frequently used to induce seizures in animal models [49].
patients with a positive skin test or other documented type 1 At high enough doses, all β-lactams can induce seizures.
hypersensitivity to penicillin should avoid carbapenems However, because the problem is recognized and because of
unless justified by the clinical circumstances. In the setting of use of appropriate dosing regimens, seizures as a complica-
administering a cephalosporin or carbapenem to a patient tion of β-lactam use had almost fallen into obscurity before
with a documented anaphylactic reaction to penicillin, the the launch of imipenem [50]. Because high-dose (4 g/day)
patient should be desensitized using a published protocol in imipenem was thought to be more effective than a 2 g/day
the intensive care unit setting [3,35]. dosing regimen in certain infections, and because early
clinical trails suggested that 4 g/day was safe [51,52], the
For example, my colleagues and I reported the successful higher dosing regimen was evaluated. As a result, imipenem
treatment of an acute pulmonary exacerbation due to multi- was approved by the FDA for use at a dose of up to 4 g/day
drug-resistant Burkholderia cepacia and methicillin-resistant (1 g every 6 hours). However, subsequent analysis of phase
Staphylococcus aureus (MRSA) in a patient with cystic III dose-ranging studies showed that imipenem was asso-
fibrosis [34]. We documented hypersensitivity by skin testing ciated with a dose-dependent risk for seizures, with a risk of
to multiple antibiotics, including carbapenems, and a clinical 3.6% associated with daily doses exceeding 2 g/day [47]. In
history of hypersensitivity after receiving imipenem. We addition, a trial for the treatment of bacterial meningitis had to
utilized a regimen of meropenem, tobramycin, and vanco- be halted prematurely when 33% of the patients receiving
mycin after meropenem desensitization using a 12-dose imipenem developed seizures [53]. This risk for seizure has
escalation protocol. A number of our patients with cystic led to extensive revision of the recommended dosing regimen
fibrosis and histories of serious and life-threatening carba- for imipenem. The new scheme, which involves type and
penem or penicillin hypersensitivities have been desensitized severity of infection, susceptibility of the organism, six cate-
to carbapenems. Desensitization has worked in these gories of patient size, and five categories of renal function, is
patients with little trouble. In some cases the patient reacted among the most complicated for any pharmaceutical agent
upon receiving the third or fourth escalating desensitization approved for use in the USA [54]. This complicated dosing
dose; we returned to the previous concentration of drug to regimen, coupled with a fear of inducing seizures, has
which the patient did not react and infused that dose over a resulted in the underdosing of imipenem in clinical settings,
longer time period (for example, from >20 to >40 minutes) ‘just to be safe’. Suboptimal dosing of imipenem may reduce
and then continued with 40-minute consecutive infusions its efficacy for difficult infections and contribute to the rapid
rather than the standard 20-minute infusions. It is important emergence of resistance in Pseudomonas aeruginosa, which
that the patient does not miss any of the doses and that the is of particular concern for carbapenems (see below).
dose is administered on time (and not late). We often supply
extra doses on the nursing unit in case something happens to Although FDA-approved labeling warns of a seizure risk with
one of the doses. Another important caveat is that patients all carbapenems, this risk appears to be most significant with
with Stevens-Johnson syndrome or exfoliative reactions imipenem. The seizure rate in pivotal trials of newer
should not be challenged via desensitization. carbapenems is reported to be 0.7% or less [55,56]. The

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epileptogenic activity of β-lactams occurs as a direct result of Figure 3


their ability to bind to and competitively inhibit the γ-amino-
butyric acid receptor in the brain [57], and the affinity of
imipenem for this receptor is substantially greater than that of
meropenem. In an animal model, the concentration of
meropenem required to achieve 50% inhibition of γ-amino-
butyric acid receptors in cerebral cortical membranes was
more than 20-fold greater than that required with imipenem
(Figure 3) [57]. Consistent with this, intracerebroventricular
injection of 100 μg of imipenem into dogs induced facial
spasms, twitching, falling back, and clonic convulsions,
whereas a similar dose of meropenem had no effect on
behavior [57]. Ertapenem and doripenem appear to behave
similarly to meropenem rather than to imipenem. The central
nervous system safety of meropenem can be highlighted by
the fact that it is approved for the treatment of meningitis, Concentrations of various penems and their displacement of GABA
whereas for imipenem one-third of all patients with meningitis from their receptor sites. Illustrated is the concentration-dependent
suffered from seizures. displacement of muscimol by meropenem, panipenem, and imipenem
at the γ-aminobutyric acid (GABA) receptor in mouse cerebral cortical
membranes [66].
Other, and sometimes subclinical, neurologic effects can be
elicited by beta-lactams. This has been noted for nearly if not
all members of this class. Of late, a paper or two has
highlighted these effects with the use of the now generic involving more than 14,000 patients and 225 individual treat-
cefepime. While true, cefepime can cause subclinical and ment regimens, emergence of resistance occurred in 4% of
clinical neurologic effects which may manifest as delirium, all organisms and complicated 5.6% of all infections treated
psychosis, aphasia, somnolence, and insomnia, a myriad of [63]. Emergence of resistance was greatest for P. aeruginosa
other causes for these effects can be culprits. In one case infections and appeared to be associated with β-lactams,
report and review of the literature, cefepime was concluded aminoglycosides, and fluoroquinolones [63]. Currently,
to be similar to ceftazidime with respect to neurologic carbapenems retain a broad spectrum of activity that includes
adverse events [58]. One common theme tying together most β-lactamase producing organisms [64]. However,
these case reports were the fact that nearly all of the patients preserving this activity will require good antimicrobial
unequivocally had kidney disease or were on some form of stewardship that involves using them appropriately, at the
hemodialysis or filtration modality, yet were given unadjusted correct dose, and for the correct duration [24]. For example,
doses of cefepime. In modern times, we would call these studies have demonstrated that VAP can be treated for as
“medical errors”. Unlike most institutions where renal dosing few as 7 to 8 days of therapy, as long as the patient initially
takes place, one paper reported extreme overdoses, so much received effective antimicrobials (specifically, the pathogen
so it is not any wonder why the patients did not demonstrate eventually isolated turns out to be susceptible to the initially
frank seizures resulting in litigious action [59]. One of these selected empirical treatment choice) [65]. It is important to
patients with end stage kidney disease received, on average, note that patients with life-threatening infections, such as
almost 9 grams per day for five days [59]! The only health care associated pneumonia or sepsis, must receive
cephalosporin, monobactam, or carbapenem that does not initially appropriate therapy, because observations in clinical
require attention to renal dosing is ceftriaxone. For all other practice have demonstrated that this does not routinely occur
aforementioned antimicrobial classes, the clinician needs to in some centers. One can take the recommended approach
be cognizant of renal dosage adjustment in the context of the that reflects a Chinese menu, whereby one selects a drug
infection being treated [60]. Otherwise, one can be from column A (carbapenem, piperacillin-tazobactam, or
castigated, at minimum, for such a great responsibility which cefepime) and one from column B (an aminoglycoside or an
cannot be ignored, as happened in the paper in question. It antipseudomonal fluoroquinolone) plus or minus one from
also should be remembered that the fluoroquinolones exhibit column C (an anti-MRSA treatment option). The individual
neurologic adverse events as well, manifesting similarly to choices should be dictated by the hospital’s anibiogram.
beta-lactams [61]. A heightened awareness of this issue is These broad-spectrum regimens will ensure that the patient
warranted for these classes of drugs. receives adequate therapy initially.

Emergence of resistance Although some are fearful of this broad-spectrum approach,


Although not typically thought of as an adverse event, the key is to de-escalate therapy on day 3, when the results of
emergence of resistance is a major adverse sequela of the culture return, and to stop therapy in 7 to 8 days as long
antibiotic use [62]. In a retrospective review of 173 studies as the patient has clinically responded to the regimen.

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Critical Care Vol 12 Suppl 4 Owens

Figure 4 problematic pathogens should dictate which one is selected


for an individual formulary.

Prolonged infusion as a means to optimize


patient safety and enhance potential efficacy
Carbapenems are characterized pharmacodynamically as time-
dependent killers. In other words, bacterial killing is optimized
when the duration of time that the antibiotic concentration
exceeds the minimum inhibitory concentration (MIC) of the
infecting pathogen for a given period of the dosing interval
[24]. The time above MIC requirements for optimal efficacy of
carbapenems varies by pathogen and happens to be the least
amount of time required compared with other β-lactam
antimicrobials [75]. Certain adverse events are dose-
Cumulative risk for emergence of Gram-negative resistant organisms dependent or concentration-dependent, including seizures,
by treatment and duration of hospitalization. Adapted with permission
[70]. Copyright © 2001 the Infectious Diseases Society of America. nausea, and vomiting. Consequently, extending the duration of
the carbapenem infusion can maximize time above MIC and
can be a particularly useful tool when dealing with pathogens
Therapy for P. aeruginosa or Acinetobacter spp. may be such as P. aeruginosa, which have higher MIC values but
extended for up to 10 days, but the longer the patient receives remain within the susceptible or potentially intermediate
antimicrobials, the more likely the patient is to develop resistant breakpoint range. In some cases, in which high MIC
resistance to the antimicrobials being administered. Unfor- values are noted for the infecting organism, both increasing the
tunately, clinical guidelines that some clinicians consider a dose and prolonging the infusion interval can result in an
‘bible’ for antimicrobial information contain ‘random’ and non- optimized time above MIC and improve the probability of a
evidence-based statements. For example, for pneumonias clinical response. Selecting a drug within the class that
caused by P. aeruginosa or other Enterobacteriaceae, the possesses the lowest MIC value for a particular pathogen also
Sanford Guide 2007 [66] recommends ‘21 days, often up to helps in resolving the pharmacodynamic equation, in simple
42 days’ as the duration of therapy. Discrepancies between terms, because lower MIC values require less drug to maintain
quick pocket guides and randomized controlled trials an adequate time above MIC. This is commonly done in clinical
sometimes contribute to confusion in the trenches. practice, but for concentration-dependent killing agents such
as the aminoglycosides. Tobramycin typically possesses
Numerous evaluations have demonstrated that imipenem can twofold to fourfold lower MIC values than gentamicin for strains
select for emergence of resistant Gram-negative organisms of P. aeruginosa. In this case, the magnitude of the ratio
such as P. aeruginosa (Figure 4) [67-72]. In an early meta- between the peak concentration and the MIC value is an
analysis [67], 18% of P. aeruginosa isolates developed resis- important determinant of bacterial killing. Given that tobramycin
tance to imipenem during therapy for a variety of infections. and gentamicin have identical pharmacokinetic properties and
Furthermore, the incidence was 32.8% (41/125) in achievable peak concentrations, simply choosing the
respiratory tract infections. In a cohort evaluation, the hazard aminoglycoside with the lowest MIC can double or quadruple
ratio for the emergence of resistant P. aeruginosa was the ratio of peak concentration to MIC.
greater for imipenem therapy (44; P = 0.001) than for pipera-
cillin (5.2; P = 0.01), ciprofloxacin (9.2; P = 0.04), or ceftazi- Monte Carlo simulations have been performed for various
dime (0.8; P = 0.7) therapy [68]. In a subsequent, open-label carbapenem-pathogen combinations and dosing regimens.
prospective evaluation [69], this hazard ratio was greater for Meropenem 500 mg infused over a 3-hour period every
imipenem therapy (7.8; 95% confidence interval 3.4 to 18.1) 8 hours yielded a time above MIC comparable to 1 g
than for piperacillin-tazobactam (3.9; 95% confidence interval meropenem infused over 1 hour every 8 hours or 500 mg imi-
1.3 to 11.9) or cefotaxime (9.3; 95% confidence interval 2.9 penem infused over 1 hour every 6 hours [76]. In addition, the
to 30.2) therapy. blunted peak concentrations observed with prolonged infusion
times have been shown to be beneficial in terms of reducing
A single mutation in P. aeruginosa confers resistance to the gastrointestinal adverse effects associated with imipenem
imipenem; in contrast, resistance to newer carbapenems, therapy [72,77]. Prolonged or extended infusion of β-lactam
such as meropenem, requires two separate and distinct therapy is preferred to continuous infusion, because intra-
mutations [62,73]. As a result, emergence of resistant P. venous therapy can be administered more frequently and the
aeruginosa appears to be less likely with the newer intravenous catheter is not tied up for the entire 24-hour day.
carbapenems than with imipenem [74]. The clinical
significance of this may vary from center to center, and the The ability to extend infusion durations in the clinic can be
percentage susceptibility of each carbapenem to various impeded by the duration of stability once the solution is

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prepared. In this regard, imipenem is slightly less stable than Publication of this supplement has been sponsored by Ortho-McNeil,
Inc.
meropenem, limiting its practical utility in clinical practice. In a
comparative evaluation of the stability of both carbapenems in References
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