Original Paper
Int Arch Allergy Immunol 2006;140:20–26
DOI: 10.1159/000091839
Immediate Hypersensitivity to Rifampicin in 3
Patients: Diagnostic Procedures and Induction
of Clinical Tolerance
Stephan Buergin a Kathrin Scherer b Peter Häusermann b
Andreas J. Bircher b
a
Department of Rheumatology, and b Allergy Unit, Department of Dermatology, University Hospital Basel,
Basel, Switzerland
Key Words
Desensitization
Drug hypersensitivity
Immediate
hypersensitivity
Leukotriene stimulation test

Lymphocyte transformation test
Rifampicin
Skin
tests
Urticaria
Abstract
Background: Desensitization with drugs may be indicat-
ed in some clinical situations. Apart from large experi-
ences with
-lactam antibiotics and cotrimoxazole in HIV
infection, experience with other drugs is limited. Rifam-
picin may elicit exanthema and urticaria, and their
pathomechanisms are not known in detail. Since therapy
with rifampicin may be indispensable in mycobacterial
infections or against multiresistant Staphylococcus au-
reus, desensitization may be indicated in some patients.
Objective: Report of immediate hypersensitivity to ri-
fampicin and description of diagnostic and desensitiza-
tion procedures. Methods: We report 3 patients with im-
mediate urticarial reactions to rifampicin. Diagnostic
procedures included skin and in vitro tests (specific IgE,
lymphocyte transformation test, LTT, and CAST®). The
non-irritant cutoff concentration was evaluated in 24 vol-
unteers. A 7-day desensitization procedure was used.
Results: Only intradermal tests at a dilution of at least
© 2006 S. Karger AG, Basel
1018–2438/06/1401–0020$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: October 5, 2005
Accepted after revision: December 29, 2005
Published online: March 2, 2006
1: 10,000 (concentration of rifampicin approximately
0.006 mg/ml) were true positive, whereas in vitro tests
(IgE, LTT and CAST) did not correctly identify hypersen-
sitive patients. Two patients had positive accidental re-
exposure. All patients were successfully desensitized
with rifampicin according to a slow 7-day protocol. Con-
clusions: Rifampicin rarely elicits immediate hypersen-
sitivity symptoms which may be diagnosed by intrader-
mal skin tests. In vitro tests did not contribute to the
diagnosis. Therefore, an IgE-mediated mechanism re-
mains to be proven. Desensitization with rifampicin
using different protocols has been reported. In our 3
cases, clinical tolerance to rifampicin was achieved using
a 7-day protocol.
Copyright © 2006 S. Karger AG, Basel
Introduction
Desensitization with drugs may be indicated in pa-
tients with vital indications, if there is no treatment alter-
native [1]. There is considerable experience with cotri-
moxazole in HIV patients and with
-lactam antibiotics
[2, 3]. However, for many drugs, only small case series or
single cases have been reported. Most patients have suf-
fered from immediate symptoms such as urticaria or ana-
Correspondence to: Dr. Andreas J. Bircher
Allergy Unit, Department of Dermatology
University Hospital, Petersgraben 4
CH–4031 Basel (Switzerland)
Tel. +41 61 265 2525, Fax +41 61 265 4885, E-Mail Andreas.Bircher@unibas.ch
phylaxis or from different types of exanthema. Knowl-
edge on mechanisms of drug desensitization is limited
[4–6].
Rifampicin is a semisynthetic agent belonging to the
group of rifamycin antibiotics. It has a bactericidal action
and is primarily used in the treatment of mycobacterial
infections. It is well absorbed from the gastrointestinal
tract, peak plasma concentrations are reached within 2–
4 h, and it is widely distributed in most body tissues and
fluids, with a plasma half-life of approximately 3 h. Due
to hepatic enzyme induction, the metabolization rate of
many other medications is increased [7].
We report on 3 patients who suffered from urticarial
reactions while being treated with rifampicin for different
conditions, and results of diagnostic tests and induction
of tolerance are described.
Patients and Methods
Case 1 (N.R.)
Four years ago, a 29-year-old patient had a car accident with an
open fracture of the right knee. After osteosynthesis, he suffered
from recurrent septic arthritis. As a consequence, he had been treat-
ed with repeated courses of different antibiotics at other hospitals.
Previous exposure to rifampicin could not be identified from his
available charts and reports.
Finally, arthrodesis of the knee joint was performed. One month
later, osteomyelitis with oxacillin-sensitive Staphylococcus aureus
recurred. Two large abscesses were drained while the osteosynthe-
sis was left in situ. Despite a history of a rash to amoxicillin, ther-
apy with intravenous amoxicillin-clavulanic acid was started. On
day 7, a maculopapular exanthema developed, and treatment was
changed to intravenous flucloxacillin (Floxapen®) 2 g q.i.d. and oral
rifampicin (Rimactan®) 450 mg b.i.d. Nine days later, he was
switched from flucloxacillin to oral ciprofloxacin (Ciproxin®)
750 mg b.i.d. After the first dose, the patient suffered from acute
urticaria, gastrointestinal cramps and diarrhea. The reaction was
attributed to ciprofloxacin, which was stopped. On the following
day, 30 min after the next dose of 450 mg Rimactan, again urti-
caria and gastrointestinal cramps occurred. Two days later, intake
of rifampicin from another provider with a different galenic for-
mulation (Rifampicin Lactab®) resulted in an identical reaction.
Respiratory or cardiovascular symptoms did not occur. All
symptoms rapidly responded to intravenous clemastine (Tavegyl®)
and hydrocortisone (SoluCortef®). At that point, all antibiotics
were discontinued and an allergological investigation was initiated.
Due to the recommendation to treat S.-aureus-infected metallic
implants with a combination of rifampicin and ciprofloxacin, these
antibiotics were considered essential to circumvent amputation
[8].
Case 2 (B.C.)
The 73-year-old female patient was hospitalized with monar-
thritis of her right knee. Four years ago, she had received a knee
joint prosthesis. A puncture revealed oxacillin-sensitive S. aureus.
Immediate Hypersensitivity to Rifampicin
Therapy with intravenous flucloxacillin (Floxapen) 2 g q.i.d. and
oral rifampicin (Rimactan) 450 mg b.i.d. was begun. The therapy
was initially well tolerated, but after 2 weeks she developed an acute
pruritic urticaria which responded to antiallergic therapy, and ri-
fampicin was stopped. Five days later, upon an accidental reexpo-
sure to rifampicin, an anaphylactoid reaction with urticaria, high
fever, shivering and vomitus occurred within 15 min. She respond-
ed again to antiallergic treatment and was discharged with cefazo-
lin 2 g t.i.d.
Case 3 (F.R.)
A 51-year-old female patient was treated with several courses
of anti-tuberculous agents. In 1992, she was first diagnosed with
tuberculous meningitis; Mycobacterium bovis was identified in her
cerebrospinal fluid. Later she developed occlusive hydrocephalus
and required ventriculoperitoneal shunting. Ten years later, she
had a relapse of tuberculous meningitis. She developed severe hep-
atitis from isoniazid. After the hepatopathy had resolved, therapy
was switched to rifampicin (Rimactan) 450 mg b.i.d. and levoflox-
acillin (Tavanic®) 500 mg q.i.d, and after 3 weeks she suffered from
acute urticaria with intensive pruritus 30 min after the 450-mg ri-
fampicin dose, without having yet taken levofloxacillin this day.
The allergic reaction responded to oral corticosteroids and cetiri-
zine (Zyrtec®).
Methods
In all 3 cases, allergologic investigations were performed at base-
line and after tolerance induction with rifampicin (table 1). For all
in vivo and in vitro tests Rimactan (60 mg/ml) was used. The vial
contains sodium rifampicin, sodium hydroxymethanesulfinate di-
hydrate and water, and the pH of the solution is 8.21.
Investigations started with a prick test with undiluted Rimac-
tan, and, if negative, were followed by intradermal tests at various
dilutions of rifampicin (from 1:100 up to 1:100,000), starting at the
highest dilution. A non-irritant intradermal cutoff concentration of
rifampicin was established in 24 healthy volunteers at a dilution of
1:10,000, which corresponds to approximately 0.006 mg/ml [9]. In
2 patients, patch tests with undiluted rifampicin were done.
In vitro tests included the determination of total IgE, SX-1 for
atopy screening, mast cell tryptase (Pharmacia, Sweden) and spe-
cific IgE to rifampicin (by courtesy of Mariangela Manfredi and
Paolo Campi, Florence, Italy). These drug-specific serum IgE were
determined using a radioimmunoassay described earlier [10]. Brief-
ly, the solid phase was obtained by coupling the drug to Sepharose-
epoxy-activated 6B through a spacer arm. Rabbit-mouse anti-hu-
man IgE antiserum labeled with iodine-125 (Pharmacia, Uppsala,
Sweden) was used as the detecting antibody. Results are expressed
as the percentage of the radioactivity bound to the solid phase in
relation to the total radioactivity introduced. Values of at least 3
times the level of normal serum (pool of 2 sera of healthy, non-
atopic individuals) are considered positive.
Cellular tests with rifampicin included the lymphocyte transfor-
mation test (LTT) [11], sulfidoleukotriene stimulation (CAST®
2000) and CD63 expression (Flow CAST®) [12].
In 24 healthy, consenting volunteers with no preexposure to the
drug, intradermal tests were performed with six different Rimactan
concentrations (1: 103, 1: 104, 1: 105, 1: 3 ! 103, 1: 3 ! 104 and 1:
3 ! 105) on the upper back to establish a non-irritant threshold
concentration. The different concentrations were consecutively in-
jected in approximately 1-min intervals starting with the highest
Int Arch Allergy Immunol 2006;140:20–26 21
Table 1. Results of diagnostic and therapeutic procedures with rifampicin

Patients Case 1 (N.R.) Case 2 (B.C.) Case 3 (F.R.)

Age, years/sex 29/male 80/female 51/female

Clinical diagnosis septic arthritis osteosynthesis monarthritis after knee prosthesis tuberculous meningitis
Bacteria S. aureus S. aureus Mycobacterium bovis
Allergic symptoms urticaria and gastrointestinal cramps urticaria urticaria
nausea
fever
Prick test equivocal equivocal negative
Intradermal tests, ø mm erythema/weal (before, after tolerance)
1:100 14/20, 14/40 12/20, ND ND, ND
1:1,000 14/20, 10/30 7/12, 10/20 10/40, 8/25
1:10,000 10/40 positive, 5/5 7/8, 7/10 positive ND, 5/10 negative
1:100,000 ND, ND 0/0, ND 7/10 positive, 3/3
1:1 ! 106 ND, ND ND, ND 0/0, ND
LTT negative negative ND
CAST 2000® positive, positive negative negative
Flow CAST® ND negative positive
Patch tests (undiluted) –/– (day 2/3) –/– (day 2/3) ND
Total IgE, kU/l 167 342 9.7
SX-1 (atopy screen), kU/l <0.35 <0.35 <0.35
Rifampicin-specific IgE negative negative ND
Tryptase baseline, g/l (<13.5. g/l) 4.4 5.4 4.08
Reexposure positive positive ND
Tolerance induction
Rapid unsuccessful ND ND
Slow successful successful successful

ND = Not done.

dilution. 15 min after injecting 0.03–0.04 ml of the solution, a
digital image of the resulting weal was taken using a Coolpix 5000
with an optical device with integrated scale to allow contact pho-
tography. The images were then analyzed using the freeware Image
J software (NIH, version 1.3). The perimeter of the weal was taken
in triplicate, and the corresponding area of the weal was calculated.
The differences in the weal sizes were then compared to the nega-
tive control (0.03 ml of 0.9% NaCl). The attempt to establish valid
threshold concentrations for Rimactan in intradermal tests was dif-
ficult, possibly due to irritant reactions to the additive. A dilution
of 1:10,000 of the stock solution of Rimactan was negative in all
volunteers. Therefore, it was considered as the threshold concentra-
tion [13].
Results
Skin prick tests were negative or equivocal in all pa-
tients. Intradermal tests were positive at a dilution of
1:10,000 or higher (table 1). Patch tests in patients 1 and
2 gave negative readings on days 2 and 3. Total IgE was
not contributing, SX-1 was negative, and an attempt to
measure specific IgE in patients 1 and 2 did not show
specific binding. Mast cell tryptase was within normal
limits in all cases. LTT was performed in 2 patients with
three concentrations of rifampicin and selected other an-
tibiotics and was negative in both [12].
CAST 2000 measures the formation of sulfidoleuko-
trienes mainly from basophils upon incubation with a
suspected allergen. In case 1 only, the test was positive
before and remained positive after tolerance induction.
Flow CAST, which measures the CD63 expression on
basophils, was negative in patient 2 and positive in pa-
tient 3.
An IgE-mediated hypersensitivity reaction was sus-
pected on the basis of non/irritant intradermal skin test
positivity as well as on positive responses to reexposure
in 2 patients. Several weeks after induction of tolerance,
diagnostic tests were repeated with similar results, except
in cases 1 and 3 where weal/flare was smaller following
the highest positive test dilution compared to before tol-
erance induction (table 1).

22 Int Arch Allergy Immunol 2006;140:20–26 Buergin /Scherer /Häusermann /Bircher

Table 2. Oral 7-day desensitization scheme with rifampicin (Rimac- Case 1 (N.R.). After obtaining informed consent, a 1-
tan®) day combined intravenous and oral rush desensitization
was attempted in an intensive surveillance unit. Briefly,
Day Dose Time Single dose Cumulative dose, mg
No. h mg three intravenous doses (0.06. 0.6 and 6 mg) were admin-
daily total istered in 20-min intervals followed by 5, 10, 20, 30, 50,
100 and 150 mg of Rimactan in gelatin capsules in 30- to
1 1 8:00 5.00 5 5
2 11:00 5.00 10 10 45-min intervals. After 5.25 h, a single dose of 150 mg
3 14:00 5.00 15 15 (cumulative 521.66 mg) was tolerated. After another
4 17:00 5.00 20 20 hour, a 300-mg Rimactan tablet was given, and 60 min
5 20:00 5.00 25 25 later the patient had generalized urticaria and abdominal
6 23:00 5.00 30 30
cramps which responded to intravenous clemastine and
2 7 8:00 10.00 10 40 hydrocortisone. After evaluating treatment alternatives
8 11:00 10.00 20 50 and to circumvent amputation, a second desensitization
9 14:00 10.00 30 60
attempt was considered for which the patient again gave
10 17:00 10.00 40 70
11 20:00 10.00 50 80 informed consent. A desensitization schedule during 7
12 23:00 10.00 60 90 days with slow dose increases was performed (table 2).
From day 7 on, the patient tolerated Rimactan 300 mg
3 13 8:00 20.00 20 110
14 11:00 20.00 40 130 t.i.d. orally with minor gastrointestinal complaints which
15 14:00 20.00 60 150 were suppressed with 10 mg Zyrtec. Oral ciprofloxacin
16 17:00 20.00 80 170 was added, and both drugs were continued for another
17 20:00 20.00 100 190 24 weeks and then stopped. The patient presented 1
18 23:00 20.00 120 210
month later in good clinical condition without evidence
4 19 8:00 50.00 50 260 of infection, but was then lost to further follow-up. After
20 11:00 50.00 100 310 5 weeks, diagnostic tests were again performed. Cetiri-
21 14:00 50.00 150 360
22 17:00 50.00 200 410
zine was stopped for 48 h, again resulting in minor gas-
23 20:00 50.00 250 460 trointestinal complaints after taking 300 mg of Rimac-
24 23:00 50.00 300 510 tan, which spontaneously resolved after 2 h. The repeat-
5 25 8:00 100.00 100 610
ed intradermal tests did not show any differences
26 11:00 100.00 200 710 compared to the baseline test results before tolerance in-
27 14:00 100.00 300 810 duction, despite a smaller test reaction in the 1:10,000
28 17:00 100.00 400 910 dilution, which was considered positive before desensi-
29 20:00 100.00 500 1,010 tization.
30 23:00 100.00 600 1,110
Case 2 (B.C.). After slow tolerance induction with
6 31 8:00 150.00 150 1,260 Rimactan, ciprofloxacin was added and Rimactan was
32 11:00 150.00 300 1,410 tolerated for another 6 months. One month after desen-
33 14:00 150.00 450 1,560
34 17:00 150.00 600 1,710
sitization, there was an exanthematous reaction that was
35 20:00 150.00 750 1,860 clinically attributed to ciprofloxacin. Ciprofloxacin was
36 23:00 150.00 900 2,010 changed to fusidinic acid (Fucidin®) and the rash disap-
7 300 ! 3 peared. At week 4, tests were repeated, and the results
corresponded to those found at baseline.
Case 3 (F.R.). During tolerance induction with Rimac-
tan, Tavanic was continued and ethambutol (Myambu-
tol®) was added to prevent resistance. Despite a brief ur-
Tolerance Induction ticarial rash which was controlled by Zyrtec and Tavegyl,
In case 1, a first attempt with a rapid 1-day desensiti- desensitization was successful. Finally, she took rifampi-
zation regimen with rifampicin [14–18] resulted in recur- cin 450 mg b.i.d. with no further reactions. The antihis-
rence of urticaria and abdominal pain. A second attempt tamines were stopped 2 months later, tuberculostatic
with a slow oral protocol over 1 week (table 2) resulted in treatment was continued for another 6 months with good
clinical tolerance and anti-infectious efficacy. Patients 2 clinical response. After 8 weeks, diagnostic tests were per-
and 3 were then treated with the same slow protocol. formed with results similar to those at baseline, however

Immediate Hypersensitivity to Rifampicin Int Arch Allergy Immunol 2006;140:20–26 23

with a smaller test reaction in the intradermal test at the
highest dilution considered positive before induction of
tolerance.
Discussion
In up to 20% of patients, there are adverse effects
from rifampicin. Most often a ‘flu’-like syndrome has
been reported. This syndrome presents with fever, shiv-
ering, faintness, headache, myalgia and arthralgia, skin
reactions like exanthema and urticaria, abdominal pain
and cramps, dyspnea or rarely shock [19, 20]. There is
some evidence that the ‘flu’-like syndrome is due to cir-
culating antibodies complexing with rifampicin. Rifam-
picin may form conjugates with proteins, and immuno-
genicity has been demonstrated by the detection of ri-
fampicin-specific antibodies in animal experiments and
in humans [21]. Rifampicin-specific antibodies of vari-
ous isotypes, including IgE, have been associated with a
variety of clinical syndromes [22]. O’Mahony and Kar
[22] considered a relationship between rifampicin-de-
pendent antibodies and adverse reactions to intermit-
tent rifampicin treatment. They showed that the lower
the concentration of the drug, the higher the concentra-
tion of the antibodies. The ‘flu’-like syndrome, however,
was not directly linked to the antibody titer; therefore,
a toxic effect of the drug was discussed. In agreement
with Ohta et al. [23], IgE could not be measured in our
cases, although skin tests were positive, but from our
experience these may have been irritant reactions. Our
investigations in 24 healthy volunteers showed that
Rimactan is irritant in intradermal tests up to a concen-
tration of 1:3,000, which means that positive intrader-
mal tests can be considered truly positive only at a dilu-
tion of 1:10,000 or higher.
Mild cutaneous reactions such as pruritus, erythema
or maculopapular eruptions, which may be self-limiting,
have been observed in 0.5–5% of patients [21, 24, 25].
There are case reports of more severe reactions such as
erythema multiforme, pemphigus vulgaris, porphyria cu-
tanea tarda, hypersensitivity vasculitis and Lyell’s syn-
drome [20]. Other adverse reactions particularly associ-
ated with intermittent therapy are dyspnea and shock,
acute hemolytic anemia, renal failure and thrombocyto-
penic purpura [21, 24, 26]. Furthermore, there are sev-
eral case reports of anaphylaxis from rifampicin [27–30].
With respect to other drugs [2], HIV-infected patients
suffer more often (up to 47%) from adverse reactions to
rifampicin [27].
24 Int Arch Allergy Immunol 2006;140:20–26
In a number of patients with a variety of adverse reac-
tions, desensitization has been attempted. Alonso et al.
[15] successfully applied a rapid protocol in 1 patient who
had reacted with generalized urticaria. Premedication
with oral antihistamines was given. Five cases having
mostly cutaneous reactions were reported by Abong and
Andutan [14] with tolerance of rifampicin after a fast
protocol. One case with an adverse reaction to rifampicin
was successfully desensitized using a 4-day protocol [31].
Pech et al. [18] reported a patient with colonic tubercu-
losis who presented a maculopapular rash after rifampi-
cin. They performed a fast 1-day protocol with success.
Holland et al. [16] and Matz et al. [17] studied desensiti-
zation in a group of 10 patients and 1 patient, respec-
tively. They presented a revised protocol for desensitiza-
tion with rifampicin, which was modified for our cases.
In a case of pulmonary tuberculosis, successful desen-
sitization over 3 weeks with rifampicin (Rifater®) and
other tuberculostatic therapy was reported by Driria et al.
[32]. Mild side effects were controlled with antihista-
mines. Dutau et al. [33] reported 1 patient with an unsuc-
cessful fast intravenous desensitization attempt. They
speculated that a non-IgE-mediated pathomechanism
was responsible, and warned to perform desensitization
in patients with rifampicin-associated hepatitis or ne-
phritis.
It is mandatory that desensitization attempts should
only be performed for vital indications by specialized and
experienced physicians and under intensive surveillance.
In every patient, the risks and benefits have to be bal-
anced against the risks and the severity of possible ad-
verse reactions and the necessity to treat the underlying
disease.
So far, little is known about the mechanism of drug
desensitization. Methods for desensitization rely on alter-
ing the host response by introducing minute quantities of
a substance and gradually increasing the concentration
until the required dose is reached. The fast protocol we
first used was modified from that reported for penicillin
[16, 17, 35]. The modification of the intervals stems from
the longer half-life of rifampicin. The successful slow pro-
tocol was adapted from reports in the literature [16, 17].
Diagnostic tests for immediate-type reactions to ri-
fampicin have been rarely evaluated. Some of the report-
ed cases with positive skin tests may have been false pos-
itive due to the irritant characteristics of Rimactan. In
our test setting, Rimactan had to be diluted to 1:10,000
to obtain a non-irritant test solution, therefore a cutoff
concentration of 1:10,000 seems to be adequate to iden-
tify true-sensitive patients. Although we did not provoke
Buergin /Scherer /Häusermann /Bircher
our patients, accidental reexposure resulted in the relapse
of symptoms in 2 patients, indicating true clinical hyper-
sensitivity. Therefore, a predictive value of adequately
performed intradermal skin tests is possible. On the oth-
er hand, in vitro test systems did not contribute to the
diagnosis. Specific IgE was negative, CAST was positive
in only 1 patient and Flow CAST in another patient, and
LTT was false negative. Therefore, the exact pathogenesis
of these reactions remains unresolved. Our patients could
have suffered from an IgE-mediated reaction, as suggest-
ed by the severity of the clinical manifestation and pos-
sibly the positive skin test, or a so-called pseudoallergic
or non-allergic hypersensitivity reaction with direct mast
cell and basophil activation. This is supported, at least in
part, by the positive sulfidoleukotriene stimulation test.
However, the sensitivity of in vitro tests in drug hyper-
sensitivity is generally rather low due to the problems of
coupling haptens to a solid phase, for example, which may
explain false-negative results.
The initially positive skin tests remained reactive after
tolerance induction in patient 2 but decreased in cases 1
and 3. This supports the clinical observation that desen-
sitization in drug hypersensitivity induces clinical toler-
ance only as long as the treatment is continuously main-
tained and does not necessarily change immunologic pa-
rameters, being in agreement with an observation in a
patient allergic to penicillin [4]. On the other hand, in 3
desensitized penicillin-allergic patients skin tests became
negative, whereas non-specific reactions to histamine
were not affected [36]. Therefore, it appears that in some
hypersensitivity reactions to some drugs a status of clini-
cal tolerance but not true immunologic desensitization
can be achieved.
Acknowledgment
We thank Drs. M. Manfredi and P. Campi, Allergy Clinic and
Laboratory, Nuovo Ospedale San Giovanni di Dio, Florence, Italy,
for the measurement of specific IgE to rifampicin, and Buhlmann
Laboratories, Allschwil, Switzerland, for the performance of CAST
and Flow CAST.

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