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Drug-Induced Pigmentary Disorders
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Part III
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Special Drug Categories
Immediate andDelayed Reactions
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toBeta-Lactams
MaríaJoséTorresJaén andAdrianaArizaVeguillas
1 Introduction
Beta-lactams (BLs) are the most widely used
antibiotics in the treatment of bacterial infections and are also the drugs most frequently
involved in drug reactions. Such reactions are induced by specic immunological
mechanisms (Dona et al. 2014), occur in both
adults and children (Rubio et al. 2012; Gomes
etal. 2016) and presentas eitherimmediate (IRs)
or nonimmediate reactions (NIRs) (Torres and
Blanca 2010).
All BL compounds can potentially induce a specic immunological response due to the widespread prescription of these antibiotics. BL allergy
and its associated implicationsis now a worldwide
health problem. Almost half of all hospitalized
patients would require antibiotic treatment, and
around 10–15% of these patients are considered
M. J. TorresJaén (*)
Allergy Research Group, Instituto de Investigación
Biomédica de Málaga-IBIMA, Málaga, Spain
Allergy Unit, Hospital Regional Universitario de
Málaga, Málaga, Spain
Centro Andaluz de Nanomedicina
y Biotecnología- BIONAND, Málaga, Spain
Departamento de Medicina, Universidad de Málaga,
Málaga, Spain
A. ArizaVeguillas
Allergy Research Group, Instituto de Investigación
Biomédica de Málaga-IBIMA, Málaga, Spain
e-mail: adriana.ariza@ibima.eu
allergic to BLs and have to receive an alternative
treatment that is not the rst therapeutic choice
(Thong et al. 2003; Gomes and Demoly 2005).
These second-line drugs are usually less effective,
more toxic, more expensive, and contributes to the
increase inbacterial resistance (Dona etal. 2012;
Jeffres etal. 2016; Macy etal. 2009; Picard etal.
2013). It is estimated that 70–90% of patients
“labelled” as allergic to BL may not havetrue allergies(Sastre et al. 2012; Lee etal. 2000). Hospital
admission and treatment of patients “labelled” as
allergic to BL are more expensive compared to
“unlabelled patients” ($14,193 and $609 respectively) (Antunez etal. 2006). Therefore, an accurate evaluation and diagnosis of BL allergy (Rubio
et al. 2012; Gomes and Demoly 2005; Demoly
etal. 2010; Torres and Blanca 2006) have a relevant
impact on health systems and should be included as
a strategy in antibioticstewardship programmes,as
bacterial resistance is an important global problem,
with the majority of pharmaceutical companies no
longer interested in the development of new antibiotics (Fernandez etal. 2017).
2 BL Consumption
andSensitization Patterns
over Time
In general, BL antibiotics include different
chemical compounds with a common structure
(Table 1), and the patterns of prescription and
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_22
263
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M. J. TorresJaén and A. ArizaVeguillas
consumption have evolved over time and differ
among countries (Versporten et al. 2011a, b;
Torres et al. 2019, 2016; Lazaro Bengoa et al.
2002). Following the discovery of benzylpenicil-
lin (BP) in 1929, new semisynthetic penicillins
were developed and introduced, such as
penicillin V (PV), ampicillin (AMP), and amoxi-
Table 1 Chemical structure of β-lactam antibiotics
Beta-lactam groups Chemical structures
Penicillins
Natural penicillins (R)
Benzylpenicillin (penicillin G) Penicillin V
Semisynthetic penicillins (R)
Amoxicillin Ampicillin Carbenicillin Cloxacillin Dicloxacillin
Flucloxacillin Methicillin Oxacillin Piperacillin Ticarcillin
cillin (AX) (Versporten et al. 2011b).
Cephalosporins constitute the second most consumed BL antibiotic after penicillins and consist
of different generations of cephalosporins with
different chemical structures and antibacterial
properties (Versporten et al. 2011a) developed over time. In addition to penicillins and
Cephalosporins 1st generation
1
R
Cefadroxil Cefalotine
Cefalexin Cefprozil
2nd generation
1
R
Cefaclor Cefonicid
Cefamandole Cefuroxime
2
R
2
R
1
R
1
R
2
R
2
R
Immediate andDelayed Reactions toBeta-Lactams
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Table 1 (continued)
Beta-lactam groups Chemical structures
3rd generation
1
R
2
R
Cefodizime Ceftizoxime
Cefotaxime Ceftriaxone
4th generation
1
R
2
R
Cefepime
265
1
R
1
R
2
R
2
R
Carbapenems R
1
2
R
3
R
Imipenem Ertapenem
Meropenem Doripenem
Clavams
Clavulanic acid
Monobactams Aztreonam
cephalosporins, other BL compounds with
β-lactamase inhibitory activity are frequently
prescribed in combination with penicillins to
maintain their antimicrobial activity due to the
increase in bacterial resistance (Dona et al.
2012). Clavulanic acid (CLV) is a potent and the
most relevant β-lactamase inhibitor administered
in combination with AX (Torres etal. 2016), but
there are other inhibitors applied in clinical prac-
1
R
2
R
3
R
tice, such as sulbactam and tazobactam which
are prescribed along with other BL antibiotics.
All these changes not only resulted in the
evolution of sensitization patterns but also
affected the sensitivity of available diagnostic
tests.Since the 1970s, BP has been gradually
replaced by new BLs (Torres and Blanca 2010;
Levine and Ovary 1961) and the progressive
decreased consumption of BP has resulted in
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M. J. TorresJaén and A. ArizaVeguillas
reactions falling steadily from 20% to 5% of
reported clinical cases.Consequently,the determinant benzylpenicilloyl (BPO) has become a
less relevant sensitizer (Macy etal. 2009). The
progressive use of semisynthetic penicillins has
caused a progressive increase in the appearance
of selective reactions to these compounds
(Silviu-Dan et al. 1993). Data published in
2001 showed that the most common antibiotics
used in Europe were broad-spectrum penicillins, ranging from 56% in Spain to 20% in
Germany (Cars et al. 2001). In 2003, similar
values were reported for Austria, Belgium,
Hungary, Luxemburg, Portugal, and Spain,
with AX alone or in combination with CLV as
the main elicitor for allergic reactions to BL in
Europe (Torres and Blanca 2010; Bousquet
etal. 2005; Ferech etal. 2006) and the most fre-
quent cause of anaphylaxis to BL (Blanca
1995). On the other hand, narrow-spectrum
penicillins, mainly PV, still represented more
than 60% of the total penicillin use in Norway,
Sweden, and Denmark, whereas in Belgium,
France, Italy, Luxemburg, Portugal, and Spain,
they represented less than 2% (Ferech et al.
2006). As mentioned, cephalosporins have been
the second most highly prescribed BL antibiotic (Van Boeckel et al. 2014) and between
1997 and 2009, their consumption was higher
in Southern and Eastern European countries
compared toNorthern Europe. In general, their
administration has increased over time in
Europe, mainly due to the increased use of second-, third-, and fourth-generation cephalosporins (Versporten et al. 2011a). Regarding the
β-lactamase inhibitor CLV, the combination
AX-CLV is nowadays the most frequently prescribed antimicrobial treatment (Lazaro Bengoa
etal. 2002) and its consumption is still increasing (Mayorga et al. 2016), especially in
Southern Europe (Fernandez etal. 2017).
3 Clinical Manifestations
Drug hypersensitivity reactions are usually classied as immediate or nonimmediate/delayed
based on the time interval between the drug expo-
sure and the onset of the symptoms (Levine
1966). The cut-off point between immediate and
nonimmediate reactions remains controversial. A
new cut-off point that classied these reactions
into immediate (<1–6h after drug exposure) and
nonimmediate (>1 h after drug exposure) has
been proposed (Demoly et al. 2014), with an
overlapping group of IRs and NIRs that occurred
between 1 h and 6 h (Levine 1966; Montanez
et al. 2017). These overlapping reactions were
originally dened by Levine (1966) as “accelerated reactions.” Clinical manifestations of immediate and nonimmediate reactions are
heterogeneous and are described below.
3.1 Cutaneous Immediate
Adverse Reactions
Two main clinical entities are associated with
immediate adverse reactions: urticaria, with or
without angioedema, and anaphylaxis. Urticaria
is characterized by rapidly evolving transient
pruritic wheals occurring at different sites of the
body. Urticaria may represent the rst stage of an
anaphylactic reaction (Blanca etal. 2009). On the
other hand, anaphylaxis is dened as “a serious
allergic reaction with a rapid onset that may
cause death” (Sampson etal. 2006).
3.2 Cutaneous Nonimmediate
Adverse Reactions
NIRs to BLs are characterized by the heterogeneity of the clinical manifestations. These reactions
may be precipitated by a concomitant viral infection (Shiohara and Kano 2007). Ahigh proportion of such subjects with exanthematous
reactionsmayhave good tolerance to the culprit
BLa few weeks after resolution of the viral infection (Romano et al. 1995); This is in contrast
toothers whodevelop a new reaction after BL reexposure in the absence of the viral disease
(Padial etal. 2008).Such individualsare dened
as true allergic patients.
The most common nonimmediate cutaneous
adverse reactions are maculopapular exanthema
Immediate andDelayed Reactions toBeta-Lactams
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267
(MPE) and delayed urticaria/angioedema, which
have been reported to be induced by the administration of penicillins and cephalosporins
(Hunziker etal. 1997; Bigby 2001; Stern 2012;
Roujeau etal. 2014; Romano etal. 2002, 2010,
2012, 2013, 2016; Lammintausta and
Kortekangas-Savolainen 2005; Macy and Ngor
2013; Pinho et al. 2017; Ponvert et al. 2011;
Atanaskovic-Markovic et al. 2016). Moreover,
BLs are also involved less commonly in other
nonsevere reactions such as xed drug eruption
(FDE), palmar exfoliative exanthema, and symmetrical drug-related intertriginous and exural
exanthema (SDRIFE), as well as severe reactions
such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia
and systemic symptoms (DRESS), StevensJohnson syndrome (SJS), and toxic epidermal
necrolysis (TEN) (Lammintausta and
Kortekangas-Savolainen 2005; Romano et al.
2010, 2013; Pinho et al. 2017; Ponvert et al.
2011; Atanaskovic-Markovic et al. 2016;
Gastaminza etal. 2000; Hausermann etal. 2004;
Andrade etal. 2011; Sidoroff 2012; Papay etal.
2012; Kardaun etal. 2013; Lin etal. 2014).
4 Diagnostic Procedure
The diagnostic approach in suspected hypersensitivity reactions to BLs is based on a complex
allergological workup that includes: (1) detailed
clinical history, (2) skin tests (STs), and (3) drug
provocation tests (DPTs). These tests are long,
expensive, and not risk-free procedures. For this
reason, complementary invitro tests are usually
recommended in high-risk patients before ST in
order to reduce the risk of systemic reactions
(Demoly etal. 2010; Romano etal. 2020; Torres
etal. 2002).
4.1 Clinical History
The clinical history is the starting point for the
diagnosis of patients with allergic reactions to
BLs, allowing both differentiation of IRs from
NIRs as well as risk assessment.Riskstratica-
tion involves classifaction of patients into high
and low risk based on the morphology and chronology of the index reaction, the reaction severity, and the underlying characteristics of the
patient (beta-blocker treatments, cardiac disease,
and so on) (Romano et al. 2020). However the
clinical history alone is not diagnostic even when
mathematical models are used (Hierro Santurino
etal. 2016; Soria etal. 2017; Chiriac etal. 2018).
In addition, the sensitivity of ST is not optimal;
therefore DPT may be required to establish diagnosis in many cases (Demoly etal. 2010; Romano
etal. 2020; Torres etal. 2002).
4.2 Skin Tests
Skin testing is used for the diagnosis of both IR
and NIR and is considered the best validated
invivo method for diagnosing IR to BLs (Blanca
et al. 2009). In IRs, STs are usually performed
using skin prick test, consisting of pricking the
skin with a needle through an allergen solution. If
the skin prick test isnegative, an intradermal test
(IDT) is performed, by the injection of 0.02–
0.05ml of the drug solution, raising a small bleb
that is marked initially (Torres et al. 2003). STs
should include a panel of reagents composed of
the traditional major and minor BP determinants
(described below), as well as semisynthetic compounds with different side chains such as AX,
AMP, cephalosporins, CLV, or any other suspected BL since selective reactions to these compounds have been reported over time (Blanca
etal. 2009; Gadde etal. 1993; Green etal. 1977).
Currently, benzylpenicilloyl-octa--lysine
(0.04 mg/ml, DAP®) is the commercially available BP major determinant, whereas sodium benzylpenilloate (0.5mg/ml, DAP®) and BP are the
commercially available minor determinants in
Europe (Torres et al. 2019). However, a recent
study showed that the inclusion of BP in STs is
not clearly useful for the diagnostic algorithm as
the determinants penicilloyl-polylysine (PPL)
and minor determinant (MD) are already included
and the population is mainly sensitized to AX/
AX-CLV (Lacombe-Barrios et al. 2016; Dona
etal. 2019) (Table2).
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M. J. TorresJaén and A. ArizaVeguillas
Table 2 Beta-lactam determinants and highest concentrations recommended for skin tests
Haptens Concentration
Benzylpenicillin-octa--lysine
(BP-OL)
Minor determinant (MD) 0.5mg/ml
Amoxicillin (AX) 20mg/ml
Clavulanic acid (CLV) 20mg/ml
Cephalosporins 20mg/ml
0.04mg/ml
In the evaluation of NIR, both patch tests (PT)
and delayed-reading IDTs can be used, although
the latter are not as standardized as for IR and the
usefulness of BP determinants is limited (Torres
etal. 2019; Dona etal. 2019). However, ST sensitivity in NIR is low especially in children and
therefore it is not mandatory to perform STs in
children with mild exanthema before DPT
(Caubet etal. 2011).
Remarkably, for evaluating patients who suffered severe anaphylactic reactions (Co Minh
etal. 2006) and severe cutaneous NIR (Barbaud
et al. 2001), starting concentrations of reagents
should be lower, at least 1/10 dilution of the highest nonirritating concentration (Torres etal. 2019;
Sacco etal. 2017).
4.3 Drug Provocation Test
DPT is recommended by the European Network
of Drug Allergy (ENDA) to conrm the allergy
diagnosis (Aberer etal. 2003) when (1) STs are
negative and (2) to assess the tolerance of potentially cross-reactive BLs (Torres et al. 2019;
Sacco etal. 2017; Chiriac etal. 2017), due to the
excellent negative predictive value reported in
both adults and children (Mirakian etal. 2009;
Misirlioglu et al. 2014; Kuruvilla and Khan
2015). DPT consists in the single blind con-
trolled administration of escalating doses of the
drug, which are administered at intervals of
30–90min up to reach the full therapeutic dose.
Starting doses are lower in the evaluation of IR
compared with NIR (Chiriac etal. 2017) and a
lower starting dose should be administered in
patients with a history of prior severe reactions.
Similarly, the cumulative dose has to be adapted
for children or subjects with kidney or liver diseases (Dona et al. 2019). DPTs are timeconsuming and costly tests and they are not
risk-free. Therefore, DPTs should only be performed by trained personnel after a risk/benet
evaluation. If symptoms manifest during the test,
the procedure must be stopped. DPT is contraindicated in cases with severe life-threatening
reactions (Aberer et al. 2003; Chiriac et al.
2017). On the contrary, it may be recommended
in children with a clinical history of mild cutaneous reactions since most of them are not allergic
reactions but viral exanthemas (Gomes et al.
2016). Most of the prescribed BL antibiotics can
beused in DPT.In the case of AX-CLV allergy,
DPT can be used to assess AX allergy/tolerance
directly. However, CLV allergy must be conrmed indirectly by determining AX tolerance in
patients with positive DPT to the combination
AX-CLV, as CLV not combined with AX is not
available (Roujeau etal. 2014).
4.4 In Vitro Tests
In vitro tests can be used as complementary diagnostic tests, especially to avoid invivo assays in
the diagnosis of severe and life-threatening reactions. However, limitations of in vitro tests
include suboptimal sensitivity, certain BL structures are not readily tested by commercial assays,
or the short time interval from blood extraction to
perform the test in the case of cellular methods. It
is therefore crucial to improve our existing
invitro tests for the diagnosis of drug allergy, and
specically for BL allergy, through the search
and inclusion of new antigenic determinants, the
use of nano-engineered solid phases, or the modication and optimization of currently methods
(Fernandez etal. 2017).
Immediate Reactions
Two main invitro methods are used for the diagnosis of IR to BLs: specic IgE determination
and basophil activation test (BAT), although
other tests can be applied.
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269
Detection andQuantication
ofSpecic IgE
Specic IgE is quantied by different immunochemical methods, although FEIA-ImmunoCAP®
(ThermoFisher, Uppsala, Sweden) system is
nowadays the commercially available method
more suitable for routine analysis (Torres etal.
2003). The specic IgE ranges from 0.01–
100kUA/l, witha cut-off value of 0.35kUA/l for
positive results, and levels higher than 0.10kUA/l
indicating sensitization. Unfortunately, the
ImmunoCAP® is only available for some BL
antibiotics, including BP, PV, AX, AMP, and
cefaclor, and the sensitivity is low and variable
depending on the drug involved (Fontaine et al.
2007; Blanca et al. 2001; Torres et al. 2001).
Other detection methods can be performed, such
as enzymoimmunoassay and in-house radioimmunoassay, which can be customized to use the
more adequate solid phase and carrier molecule
to detect specic IgE against the interest drug;
however these methods are not always available
for routine diagnosis (Fernandez etal. 2017).
Basophil Activation Test
The basophil activation test (BAT) is based on the
detection by ow cytometry of basophil activation in the presence of specic stimulus, being
CD63 and CD203c the most common molecules
to determine basophil activation (Mayorga et al.
2019a). BAT is recommended for the diagnostic
evaluation of IgE-mediated reactions to BLs,
with the advantage of including drugs with no
other in vitro test available, such as CLV
(Mayorga etal. 2019b; Sanz etal. 2002; Torres
etal. 2004). The potential use of BAT as a complementary tool has been reported in different
studies, with reported values of 55% sensitivity,
89% specicity, and 96% positive predictive
value (PPV) (Torres etal. 2011, 2010; De Week
etal. 2009; Eberlein et al. 2010; Garcia-Ortega
and Marin 2010). A strategy to improve the sensitivity of invitro tests could be the inclusion of
drug metabolites besides the native drug (Ariza
etal. 2016). Indeed, a recent study has shown that
the use of one CLV synthetic determinant,
together with CLV itself, improves signicantly
the sensitivity from 41% to 69% in patients with
hypersensitivity reaction to AX-CLV (Barbero
etal. 2019). It has to be noted that BAT should be
performed in a short interval time since the allergic episode to reduce false-negative results due to
the negativization rates of BAT over time (Salas
et al. 2018; Fernandez et al. 2009). In a study
published by Fernandez et al. (2009) it was
shown that BAT results for AX allergic patients
became negative for more than 50% of cases in
tests performed over 18months after the allergic
reactions (Mayorga etal. 2019a).
Histamine Release Test
Regarding the determination of basophil activation, histamine release test (HRT) is based on the
detection of histamine release by basophils after
stimulation with the drug. The method uses
glass- microber plates where released histamine
is adsorbed and detected by uorometric methods (Stahl Skov et al. 1984; Wenande et al.
2013). Although this assay is not widely used, it
has shown promising preliminary results for the
diagnosis of allergic reactions to CLV (Pineda
etal. 2015), with the possibility of using patients’
basophils (direct HRT) as well as IgE-stripped
donors’ basophils combined with patients’ sera
(passive HRT). Sensitivity and specicity values
reported in this study were 55% and 85%,
respectively, for both direct and passive
HRT.Interestingly, passive HRT is useful to conrm by indirect methods the presence of specic
IgE when no direct methods are available, as is
the case of CLV.
Nonimmediate Reactions
Lymphocyte Transformation Test
Lymphocyte transformation test (LTT) is the
most widely used invitro test to conrm drugspecic cellular sensitization (Fernandez et al.
2017; Mayorga et al. 2019a; Kano et al. 2007;
Pichler and Tilch 2004; Beeler et al. 2008).
Different studies have shown differences in the
values of sensitivity and specicity related with
the clinical manifestations and the selection criteria, and there is no consensus regarding the best
time to perform the test (Mayorga et al. 2016;
Kano etal. 2007; Polak etal. 2013). LTTwith the
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