Diabetes Mellitus
Diabetes Mellitus
Diabetes Mellitus
com/content/12/S4/S3
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
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].
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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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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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