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Robin J Green, PhD
D epartm ent of Paediatrics and Child H ealth, U niversity
of Pretoria, South Africa
Paul C Potter, M D
U CT Lung Institute, Cape Tow n, South Africa
The incidence of adverse drug reactions is w idely quot-
ed as about 15% of all hospitalised patients.
H ow ever, this total includes m any non-allergic reac-
tions in both susceptible and non-susceptible individu-
als. A t m ost 5% of individuals have allergic drug reac-
tions, of w hich antibiotic allergy is by far the m ost fre-
quent event. Few studies of the incidence of adverse
drug reactions in intensive care units (IC U s) are avail-
able. H ow ever, a recent report of cutaneous adverse
drug reactions in an IC U has been published.
authors report on an 8-m onth period in an adult IC U .
The incidence of adverse drug reactions of a cutaneous
nature w as 11.6% . R isk factors identified w ere fem ale
gender, obesity, age over 60 and im m une dysregula-
tion (system ic lupus, dysthyroidism and anti-phospho-
lipid antibody syndrom e). A ntibiotics w ere the m ain
drug involved and few patients had a previous history
of drug reaction. Patients w ho had anaphylactic events
had a poor prognosis. The risk factors are com m only
reported (Table I).
O f all drug and antibiotic allergic reactions, allergy to
beta-lactam s is the m ost com m on reaction.
reactions are usually explained by either IgE or T-cell
dependent responses. B enzylpenicillin is no longer the
m ost frequently prescribed antibiotic, especially in the
IC U , and therefore new er antibiotic allergies have
Im m ediate hypersensitivity reactions to antibiotics are
IgE m ediated and characterised by the im m ediate
release of inflam m atory m ediators from m ast cells
resulting in anaphylaxis, urticaria and angio-oedem a.
B eta-lactam allergy is com m on enough for m ost clini-
cians to have an approach to this condition but other
drug allergies are less com m on, less often diagnosed,
often lack validated diagnostic tests and are usually
m anaged poorly.
This review focuses on the various diagnostic tests as
w ell as therapeutic strategies to deal w ith antibiotic
allergy in the IC U setting.
SUSPECTING ANTIBIOTIC ALLERGY
B ased on the risk factors, the m ost im portant state-
m ent regarding clinical presentation of drug allergy is
that a high index of suspicion is the m ost useful clue.
N early every clinical sign or abnorm al laboratory test
has drug allergy in its differential. A useful clinical guide
is that IgE-m ediated reactions usually present w ithin
30 m inutes of drug adm inistration and usually have
skin (urticarial, angio-oedem a), gastro-intestinal (diar-
rhoea or vom iting), respiratory (bronchospasm ) or sys-
tem ic (shock, hypotension) features. D elayed reactions
suggest another im m une m echanism for allergy.
Testing for suspected antibiotic allergy
M any clinical features of drug allergy in patients in an
IC U setting m ay be attributable to other causes, or
drugs other than antibiotics, and hence the approach of
trying to confirm allergy is useful. W ohrl and col-
reported on a cohort of 291 individuals w ith
suspected drug allergy. A ll patients had a detailed his-
tory, skin-prick testing (SPT) or specific IgE and provo-
cation testing. A lthough this w as not an IC U study they
w ere able to offer clear-cut recom m endations on drug
allergy, avoidance and alternatives to 82.1% of
patients, clearly show ing the usefulness of testing
strategies. In addition the IC U patient frequently har-
bours an organism that has m ultiple antibiotic resis-
tance patterns and dem ands use of a drug despite sus-
pected allergy. In addition som e disease states have
few or no alternative drug selections.
ANTIBIOTIC ALLERGY IN THE INTENSIVE
C orrespondence: Prof R G reen, PO B ox 67, Pretoria 0001. E-m ail
D rug allergy in an intensive care unit (IC U ) m ay be
m ore com m on than realised. A ntibiotics are the
m ain drug involved and few patients have a previous
history of drug reaction. O f all drug and antibiotic
allergic reactions, allergy to beta-lactam s is the m ost
com m on reaction. B eta-lactam allergy is com m on
enough for m ost clinicians to have an approach to
this condition but since other drug allergies are less
com m on, less often diagnosed, and often lack vali-
dated diagnostic tests, they are usually m anaged
poorly. B ased on the risk factors, the m ost im portant
statem ent regarding clinical presentation of drug
allergy is that a high index of suspicion is the m ost
useful clue to suspected allergy. Testing strategies
need to confirm allergy and skin-prick testing is use-
ful in m any circum stances. Treatm ent of a proven
antibiotic allergy m ay include avoidance, but
because the IC U patient frequently harbours an
organism that has m ultiple antibiotic resistance pat-
terns and dem ands use of a drug despite suspected
allergy, m ethods of desensitisation should be
Table I. Risk factors for antibiotic allergy
Increasing age –uncom m on in children
Fem ale sex
Intravenous adm inistration
Im m une disorders including H IV-positive individuals
C ystic fibrosis
M ultiple adverse events to m any drugs
A topy is not generally a risk factor
Previous reactions are uncom m on
Today a w ider selection of tests are available for testing
for antibiotic allergy. The four m ain tests are specific
R A ST testing, specific C A ST testing, skin-prick testing
and m easurem ent of serum tryptase.
Specific radio-allergosorbent test (RAST)
W hile R A STs are available to a w ide range of inhalant
and food allergens only a few antibiotic tests are
offered. They are reflected in Table II.
U nfortunately the R A STs for penicillin m easure only the
m ajor determ inant of penicillin. The m inor determ inant
is an im portant cause of anaphylaxis and therefore ana-
phylactic reactions cannot be excluded by negative
penicillin R A ST. R A ST testing has a useful negative pre-
dictive value in excluding future allergic reactions in
negative patients. H ow ever positive predictive value is
Cellular antigen stimulation test (CAST)
The C A ST is useful for detecting non-IgE-m ediated
sensitivity to certain drugs. It can also confirm IgE-
m ediated sensitivity, but in general, specific IgE tests,
such as SPTs and the C A P R A STs are m ore efficient in
Principle of the CAST
The C A ST depends on the exposure of interleukin-3
prim ed fresh basophils to different concentrations of
an allergen, drug or chem ical. B asophils w hich are sen-
sitive to such exposure release sulphido leukotrienes
into the m edia. These released leukotrienes are m ea-
sured by an enzym e-linked im m unosorbent assay
(ELISA ). The C A ST thus m easures both IgE- and non-
IgE-m ediated leukotriene release in the ELISA .
C ut-off values for non-specific leukotriene release have
been determ ined by exposing (± 20) healthy (non-aller-
gic and non-sensitive) adult individuals to the agents,
determ ining background release in this w ay. Patients
w ho are clinically sensitive release leukotrienes in lev-
els above the norm al controls.
The technical cut-off values are listed in Table III.
Requesting a CAST
A lim ited num ber of laboratories conduct the C A ST in
South A frica. For a C A ST a full history of specific expo-
sure in relation to clinical sym ptom s should be provid-
ed to the laboratory to assist selection of the m ost like-
ly ‘allergen’in a cost-effective w ay.
A fresh sam ple of ED TA blood is required (2 x 4 m l
specim ens) and this should reach the laboratory in the
m orning on w hich the test is to be conducted, prefer-
ably w ithin 3 hours of taking the blood sam ple. Patients
should be off all oral steroids for 48 hours prior to the
test. It is also preferable to investigate the patients 3
w eeks after a severe adverse reaction.
Patients m ay be brought to the laboratory w here blood
is taken freshly and the patient can also be interview ed
to assist intelligent selection of the m ost appropriate
C A ST reagent. It is also im portant to ensure that
patients are not on oral or injected steroids w ithin 2
w eeks of conducting a C A ST on their basophils.
The result of a C A ST is usually available w ithin 24
hours and it is our policy to discuss each result w ith the
patient and to provide specific w ritten inform ation to
facilitate avoidance of the allergen/preservative/addi-
tive/drug to w hich the patient is found to be sensitive.
This form of testing is becom ing increasingly useful for
patients w ith antibiotic reactions; how ever borderline
or low values m ay not exclude patients w ith potential
life-threatening reactions on challenge testing.
Skin-prick testing (SPT)
SPT is available only for beta-lactam antibiotics. B oth
m ajor and m inor determ inants of penicillin should be
C urrently the tem porary com m ercial unavail-
ability of Pre-Pen (penicilloyl polylysine) m akes SPT to
this m ajor determ inant difficult. M inor determ inant
C urrent A llergy & C linical Im m unology, A ugust 2007 Vol 20, N o. 3 131
Table II. Antibiotic RASTs
Penicilloyl G c1
Penicilloyl V c2
A m oxicilloyl c6
A m picilloyl c5
C efachlor R c7
Table III. Technical cut-off values for CAST
Code Allergen Conc. in cell stimulation Technical cut-off
B A G 2-C 1 Penicillin G 500 µg 50
B A G 2-C 2 Penicillin V 500 µg 40
B A G 2-C 11 PPL (B enzylpenicilloyl-polylysine) 5 µg 110
B A G 2-C 12 M D M (M inor determ inant m ixture) 100 µg 100
B A G 2-C 203 A m picillin 2 m g 70
B A G 2-C 204 A m oxicillin 200 µg 100
B A G 2-C 3 C ephalosporin C 20 µg 40
B A G 2-C 31 C efam andole 500 µg 80
B A G 2-C 32 C efazolin 500 µg 80
B A G 2-C 33 C efuroxim e 500 µg 40
B A G 2-C 61 Sulfam ethoxazole 20 µg 50
B A G 2-C 62 Trim ethoprim 20 µg 40
B A G 2-C 75 Tetracycline 20 µg 90
B A G 2-C 81 C iprofloxacin 20 µg 90
testing is also im portant. M D M can be m ade by diluting
fresh Penicillin G w ith 2-w eek-old penicillin, 10 000
U /m l. A protocol for penicillin SPT is described in Table
IV. O ther protocols are available from the authors.
The patient w ho has a sudden severe episode of shock
in the IC U or theatre is often considered to have had an
anaphylactic reaction to a drug. H ow ever, m any causes
exist and these com plicate the diagnosis especially in
patients w ho have been ill w ith various conditions prior
to drug adm inistration. A useful test to separate out ana-
phylactic from other 'anaphylactoid' events is serum
tryptase. This m easurem ent should be done im m edi-
ately follow ing the reaction, w hen a peak in levels is
expected, and then som e 6 hours later w hen return to
baseline should occur. Tryptase seem s not to be a use-
ful m easure after drug-provocation test reactions.
Oral provocation testing
Som e antibiotics have no gold-standard diagnostic test-
ing available and oral provocation m ay serve as the gold
standard. Such agents include m etronidazole and
TREATING ANTIBIOTIC ALLERGY IN THE
The diagnostic w ork-up suggested above is im portant
for the IC U patient w ith suspected antibiotic allergy
because often that antibiotic is the last antibiotic to
w hich highly resistant organism s m ay still be sensitive
or alternatives m ay not be available.
G eneral principles of m anagem ent of anaphylactic drug
reactions are listed in Table V.
A frequent question in practice is the use of
cephalosporins in patients w ith penicillin allergy. This
topic w as the subject of a recent m eta-analysis.
These authors review ed 219 articles and com m ented
on 9. A lthough the description of penicillin allergy diag-
nosis varied am ong studies they found a significant
cross-allergy betw een penicillins and first-generation
cephalosporins but this is negligible w ith second- and
third-generation cephalosporins. They concluded w ith
the statem ent that in selecting such a substitute antibi-
otic, particular em phasis should be placed on the chem -
ical structure sim ilarities betw een the reacting drug and
proposed substitute. A third- or fourth-generation
cephalosporin m ay be an acceptable substitute in the
IC U setting for penicillin-allergic patients w ho have
m inor reactions but should be considered only in spe-
cial situations in individuals w ho have had a docum ent-
ed anaphylactic reaction to penicillin. A recom m enda-
tion is that before using any cephalosporin in a peni-
cllin-sensitive patient, SPT to the proposed
cephalosporin should be used at concentrations of
25 m g/m l (w ith positive and negative controls) to con-
firm that the patient is not sensitive. There is a 95%
negative predictive value to this test. This could have
m edicolegal significance as som e w ould argue that no
patient w ith penicillin allergy is com pletely safe from
reactions to any generation of cephalosporin.
O ther antibiotics containing beta-lactam rings, such as
m onobactam s (aztreonam ), have no significant cross-
reactivity w ith penicillins, and recently im ipenem has
been show n to be tolerated by penicillin and beta-lac-
tam allergic patients.
Desensitisation for antibiotic allergy
D esensitisation for drug allergy is the induction of tem -
porary clinical unresponsiveness to drug allergens.
G radual re-introduction of sm all doses of drug allergen
at fixed tim e intervals allow s the delivery of full thera-
peutic doses protecting against anaphylaxis. The cellu-
lar and m olecular inhibitory m echanism s are not w ell
understood but the suggestion is that intracellular sig-
nalling pathw ays w ithin m ast cells and basophils
becom e inhibited.
Such protocols are available for com m on drugs (Tables
VI-IX) including penicillin, cephalosporins, carbapen-
em s, vancom ycin and sulphas. M ost of these protocols
apply to adult patients w hile the techniques are seldom
em ployed in children.
O nly im m ediate type I reactions to penicillin and beta-
lactam s are am enable to rapid desensitisation. O ther
reactions such as m aculopapular rashes, erythem a
m ultiform e, Stevens Johnson syndrom e, toxic epider-
m al necrolysis, bullous erythem a, erythroderm a, serum
sickness, haem olytic anaem ia, neutropenia, throm bo-
cytopenia, and acute interstitial nephropathy are not
am enable to rapid desensitisations.
132 C urrent A llergy & C linical Im m unology, A ugust 2007 Vol 20, N o. 3
Table IV. Penicillin SPT protocol
1. Pre-Pen in increasing quantities of diluted concen-
trations 1:1 000, 1:100, 1:10 follow ed, if negative,
by intraderm al test
2. M D M in increasing quantities of diluted concentra-
tions as above
3. R eaction m easurem ent: positive if > 5 m m w heal
4. A lw ays use a positive (histam ine) and negative
5. SPT should be perform ed in an IC U setting even for
non-IC U patients
Table V. Principles of managing anaphylactic
1. Stop the antibiotic adm inistration im m ediately
2. Treat the patient for the circulatory collapse and
bronchospasm by standard m eans.
3. Intram uscular or intravenous adrenaline rem ains
the m ainstay of treatm ent.
4. A dvise drug avoidance w here possible
5. A dvise cross-reacting drug avoidance w here possi-
6. O n discharge the patient should receive a M edic-
7. D esensitise if the drug is absolutely required
Table VI. Penicillin desensitisation protocol
A typical protocol for desensitisation to intravenous
penicillin and cephalosporins starts at 1:10 000 to
1:100 the target dose, and doubling doses are deliv-
ered every 15-20 m inutes over the course of several
hours until the target dose is reached.
A ll patients should be given an H 1-antihistam ine during
the desensitisation process. The role of steroids is con-
Sulfa hypersensitivity in patients with HIV
Sulfam ethoxazole/trim ethoprim (SM X-TM P) is the
m ost effective m edication for treatm ent and preven-
tion of Pneum ocystis jerovicii pneum onia (PC P) in
patients w ith A ID S. In m any sectors of practice in
South A frica it is the only available agent. H ow ever,
adverse events are frequently reported. In m ost
patients using SM X/TM P skin reactions occur. In m ost
patients the drug is stopped but there is new evidence
that this drug needs to be stopped only in severe cases
In patients w ith defined allergy, desensitisation can be
perform ed. In IC U s that treat PC P in H IV-positive chil-
dren this m ethod is som etim es im portant to be able to
continue life-saving therapy (Table XI). D esensitisation
can restore tolerability in approxim ately tw o-thirds of
patients w ho use it.
C urrent A llergy & C linical Im m unology, A ugust 2007 Vol 20, N o. 3 133
Table VII. Ceftazidime desensitisation protocol
1. 50 m g over 6-8 hours IV infusion
2. 750 m g over 6-8 hours IV infusion
3. 1 g over 6-8 hours IV infusion
4. Full dose (100 m g/kg/day) over 24 hours
Table VIII. Piperacillin/tazobactam desensitisation
1. 100 m g over 6 hours IV infusion
2. 500 m g over 6 hours IV infusion
3. 2 g over 6 hours IV infusion
4. Full dose (10 m g/kg/day) over 24 hours
Table IX. Vancomycin desensitisation protocol
Day Time Concentration Infusion rate Cumulative dose from
(min) (mg/ml) (mg/min) the start (mg)
1 0-10 0.0001 0.0001 0.001
10-20 0,001 0.00033 0.004
20-30 0.001 0.001 0.014
30-40 0.01 0.0033 0.047
40-50 0.01 0.01 0.15
50-60 0.1 0.033 0.48
60-70 0.1 0.1 1.48
70-80 1 0.33 4.8
80-90 1 1 14.8
90-100 10 2.2 36.8
100-110 10 4.4 80.8
1 110-215 10 4.4 500
2 0-300 1 1.7 500
3 0-300 1 1.7 500
4 0-300 1 1.7 500
5 0-300 1 1.7 500
6 0-300 2 3.3 1000
7 0-300 2 3.3 1000
8 0-300 2 3.3 1000
9 0-300 3 5.0 1500
10 0-300 3 5.0 1500
11 0-300 3 5.0 1500
12 0-300 3 5.0 1500
13 0-300 3 5.0 1500
14 0-300 4 6.7 2000
15 0-300 4 6.7 2000
16 0-300 4 6.7 2000
17 0-300 4 6.7 2000
18 0-300 4 6.7 2000
19 0-300 4 6.7 2000
20 0-300 4 6.7 2000
21 0-300 4 6.7 2000
22 0-300 4 6.7 2000
23 0-300 4 6.7 2000
24 0-300 4 6.7 2000
25 0-300 4 6.7 2000
26 0-300 4 6.7 2000
27 0-300 4 6.7 2000
28 0-300 4 6.7 2000
A ntibiotic allergy in the IC U is becom ing an im portant
topic w ith the em ergence of m ultiresistant organism s
and lim itations in antibiotic selections. W e should have
an approach to confirm ing suspected allergy and not
sim ply stop or change antibiotics w ithout proof. In addi-
tion protocols are now available to restore tolerance to
antibiotics in patients w ith severe allergic reactions.
These how ever should in the m ain be em ployed in an
IC U setting to lim it the possibility of adverse reactions.
Declaration of conflict of interest
The authors declare no conflict of interest.
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Allergy. 2nd ed. C ape Tow n: A LLSA , 2001.
2. Sullivan TJ. D rug allergy. In: M iddleton E, R eed C , Ellis E, A dkinson
N F, Yunginger JW , eds. Allergy, Principles and Practice. 3rd ed, vol
2, C hapter 65. St Louis: C M osby, 1998: 1523-1533.
3. C am pos-Fernandez M del M , Ponce-D e-Leon-R osales S, A rcher-
D ubon C , O rozco-Topete R . Incidence and risk factors for cuta-
neous adverse drug reactions in an intensive care unit. Rev Invest
Clin 2005; 57: 770-774.
4. R odriques-Pena R , A ntunez C , M artin E, B lanca-Lopez N , M ayorga
C , Torres M J. A llergic reactions to beta-lactam s. Expert O pin D rug
Saf2006; 5: 31-48.
5. A ntunez C , M artin E, C ornejo-G arcia JA , et al. Im m ediate hyper-
sensitivity reactions to penicillins and other betalactam s. Curr
Pharm D es 2006; 12: 3327-3333.
6. W ohrl S, Vigl K, Stingl G . Patients w ith drug reactions –is it w orth
testing? Allergy 2006; 61: 928-934.
7. Potter PC . C linical indications and interpretation of the C A ST.
Current Allergy & Clinical Im m unology 2006; 19: 14-17.
8. Schafer JA , M ateo N , Parlier G L, R otschafer JC . Penicillin allergy
skin testing: w hat do w e do now ? Pharm acotherapy 2007; 27: 542-
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severity m arker in drug provocation tests. Int Arch Allergy Im m unol
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134 C urrent A llergy & C linical Im m unology, A ugust 2007 Vol 20, N o. 3
Table X. Indications to stop SMX-TMP
Persistent rash or fever > 5 days
A bsolute neutrophil count < 500/m m
B listering desquam ation/m ucus m em brane involve-
Table XI. SMX-TMP desensitisation
Day Dose SMX-TMP
1 1 m l of 1:20 paediatric suspension of SM X-
TM P 0.4 m g/2 m g
2 2 m l of 1:20 paediatric suspension of SM X-
TM P 0.8 m g/4 m g
3 4 m l of 1:20 paediatric suspension of SM X-
TM P 1.6 m g/8 m g
4 8 m l of 1:20 paediatric suspension of SM X-
TM P 3.2 m g/16 m g
5 1 m l of paediatric suspension of SM X-TM P
8 m g/40 m g
6 2 m l of paediatric suspension of SM X-TM P
16 m g/80 m g
7 4 m l of paediatric suspension of SM X-TM P
32 m g/160 m g
8 8 m l of paediatric suspension of SM X-TM P
64 m g/320 m g
9 1 tablet of SM X-TM P 80 m g/400 m g
10 1 tablet of double-strength (D S) SM X-TM P
160 m g/800 m g
Thereafter 1 tablet of D S SM X-TM P on M onday,
W ednesday, and Friday for PC P prophylaxis or 2
tablets a day for the treatm ent of isosporiasis.
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Accurately confrm sensitizing
allergens and use quantitative
IgE antibody levels to
identify and evaluate the
behind the symptom(s).
Early sensitization can predict future
allergies. For example, IgE antibodies
to food early in life may be linked
with a high risk of developing
symptoms to inhalants later.
Furthermore, the higher
the level, the greater
to symptoms also
ImmunoCAP helps monitor the effect
of avoidance and treatment. Quantita-
tive IgE antibody levels let you follow
changes in in patients` allergic status.
In addition, test results help evaluate
persistency or tolerance development
of disease conditions.
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