An#bio#c hypersensi#vity
(Other than beta-lactams and
Sulfa)
Dr. Natasorn Lekuthai
Allergy fellowship year 1

• Fluoroquinolones inhibit DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-
positive bacteria, promoting the DNA cleavage and rapid killing of susceptible bacteria.
• Excellent tissue and intracellular penetration, high bioavailability, and generally good oral
tolerability.
Fluoroquinolones
Zhu, L.J., Liu, A.Y., Wong, P.H. et al. Road Less Traveled: Drug Hypersensitivity to
Fluoroquinolones, Vancomycin, Tetracyclines, and Macrolides. Clinic Rev Allerg
Immunol62, 505–518 (2022)

• Quinolones are potent, synthetic antibiotics composed of a bicyclic skeleton with carboxylic acid and ketone
groups
• The fifth most common antibiotic associated with anaphylaxis in the United States (US),
• Moxifloxacin is the most frequently implicated fluoroquinolone in immediate HSRs and anaphylaxis
• For delayed reactions, ciprofloxacin and moxifloxacin were the most frequent offenders
• The most frequent reactions were anaphylaxis (62.5–64.3%), followed by urticaria (30.4–35.7%), and
angioedema (7.1%) . Anaphylaxis has occurred upon first fluoroquinolone exposure.
Fluoroquinolones
Zhu, L.J., Liu, A.Y., Wong, P.H. et al. Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin,
Tetracyclines, and Macrolides. Clinic Rev Allerg Immunol62, 505–518 (2022)

Doña I, Moreno E, Pérez-Sánchez N, Andreu I, Hernández Fernandez de Rojas D, Torres MJ. Update on Quinolone Allergy. Cu
Allergy Asthma Rep. 2017;17(8):56

• The most common quinolone allergies are immediate reaction and ~70% of those cases are
severe.
• An estimated incidence of quinolone-induced anaphylaxis is 1.8–2.3 per 10,000,000 days of
treatment. Quinolones were reported to be responsible for 4.5% of 333 drug-induced
anaphylaxis cases.
• The risk of anaphylaxis may be different among quinolones. An in vitro laboratory evaluation and
spontaneous adverse drug reaction reports in Europe has shown that moxifloxacin was most
frequently involved in anaphylaxis (52.1–63%) >levofloxacin (13–35.7%) > ciprofloxacin (7.1–
28.9%).
• Whereas the highest incidence of DRs has been observed with ciprofloxacin (33.3–34.9%),
>levofloxacin (19.9–32.3%) > moxifloxacin (13.5–20.4%).
Fluoroquinolones
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• Previous history of beta-lactam allergy as a strong risk factor (OR:4.571; 95% CI: 0.987–21.171; adjusted OR:
23.654; 95% CI: 1.529–365.853)
Ø A study displayed that 21% of patients with a history of IgE-mediated penicillin allergy reported
allergic reactions to non-beta-lactams, compared to only 1% of patients with no drug allergy history
• Underlying disease : mastocytosis
Fluoroquinolones : Risk factors
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• Immediate-type reactions ;There is evidence for both IgE-mediated and non-IgE–mediated
mechanisms, because fluoroquinolones may cause nonspecific mast cell degranulation via
interaction with the surface receptor MRGPRX2.
• Unlike IgE-mediated reactions, non-IgE–mediated reactions may occur with first exposure
because prior sensitization is unnecessary.
• The rate of fluoroquinolone-related anaphylaxis has been reported to be 1-5 per 100,000
prescriptions and moxifloxacin is implicated most often; this rate is comparable to
cephalosporins but lower than penicillins.
• Consequently, studies have shown that about 65%-75% of patients with convincing histories of
immediate-type reactions to fluoroquinolones tolerate the culprit antibiotic when rechallenged.
Fluoroquinolones: Immediate type reac8on
A 2022 practice parameter update. The Journal of allergy and clinical
immunology, 150(6), 1333–1393.

Porebski, Grzegorz, et al. "Mas-related G protein-coupled receptor-X2 (MRGPRX2) in
drug hypersensitivity reactions." Frontiers in immunology 9 (2018): 3027.
Quinolone-specific IgE has
been previously detected in
30/55 (54.5%) patients who
reported an immediate HSR
to a quinolone.
Manfredi M, Severino M, Testi S, Macchia D, Ermini G, Pichler WJ et al (2004) Detection of
specific IgE to quinolones. J Allergy Clin Immunol 113:155–160

Fluoroquinolones : Delayed type reaction
• The most common type of delayed type allergic reaction to fluoroquinolones is a delayed onset
maculopapular exanthem, which is generally benign and self-limited.
• These rashes occur in 2%-3% of patients treated, although the rate varies among different agents
and appears to be highest for Gemifloxacin.
• Allergic cross-reactivity among fluoroquinolones for delayed cutaneous rashes appears to be low.
• When patients with history of fluoroquinolone-associated rashes undergo evaluation with
rechallenge with the culprit agent, there is a high chance of success, because only about 5%
develop recurrence.
A 2022 practice parameter update. The Journal of allergy and clinical
immunology, 150(6), 1333–1393.

• Drug reacon with eosinophilia and systemic symptoms (DRESS), each accounng for 3 of the 69 cases.
• Reports of acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syn- drome (SJS), toxic
epidermal necrolysis (TEN), symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), and
leukocytoclasc vasculis have also been described.
Fluoroquinolones: Delayed type reaction
Zhu, L.J., Liu, A.Y., Wong, P.H. et al. Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin,
Tetracyclines, and Macrolides. Clinic Rev Allerg Immunol62, 505–518 (2022)

• Highest incidence of immediate allergic reactions, specifically anaphylaxis
• Urticaria or anaphylaxis is most common presentation.
• Delayed type can be occurred.
• Kulthanan and colleagues where three of 151 (2%) patients developed a reaction to moxifloxacin,
two developed DRs, with one developing SJS-TEN and the other a maculopapular rash.
Fluoroquinolones : Moxifloxacin
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• SJS-TENs, eczema, FDE, erythroderma, erythema multiforme and maculopapular rash
• Kulthanan and colleagues described IRs due to ciprofloxacin in 20 of 151 (13%) patients, with urticaria being
the most common, as observed in 12 of 20 (60%) patients .
Fluoroquinolones : Ciprofloxacin
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• The Thailand retrospective review noted that five of the 151 (3%) patients had an IR to levofloxacin with
symptoms of urticaria, and nine of the 151 (6%) had a DR with a maculopapular rash and SJS/TEN.
Fluoroquinolones : Levofloxacin
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• Case report
Ø Ciprofloxacin and ofloxacin ( Similarity in structures)
Ø Ciprofloxacin and levofloxacin
Ø 3 case reports of Moxifloxacin immediate reaction but can use ciprofloxacin.
• However, most of the ciprofloxacin-reactive patients tolerated levofloxacin and the majority of the
levofloxacin-reactive patients tolerated ciprofloxacin.
Fluoroquinolones: Cross-reactivity
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• Skin tests for immediate reactions
• Most studies show that quinolones can induce false-positive results, probably because of the capacity of
some quinolones to directly induce histamine release because of mast cell activation.
• Skin testing with fluoroquinolones is not validated or standardized.
• Nonirritating concentrations are difficult or impossible to determine due to the antibiotics’ propensity to
cause nonspecific mast cell degranulation.
• Low sensitivity, Low specificity
• In vitro test
• Basophil activation testing has been described in the research setting , may increased sensitivity
• RIA has been shown to have low sensitivity for quinolones, varying from 31.6% to 54.5%, and high specificity
Fluoroquinolones : Evalua8on and Diagnosis
A 2022 practice parameter update. The Journal of allergy and clinical immunology, 150(6), 1333–1393.
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3 97. 19
Jul. 2019.

Fluoroquinolones : Evaluation and Diagnosis
Doña I, Moreno E, Pérez-Sánchez N, Andreu I, Hernández Fernandez de Rojas D, Torres MJ. Update on Quinolone
Allergy. Curr Allergy Asthma Rep. 2017;17(8):56

• Drug provocation test
• “Gold standard” for establishing or excluding diagnosis of quinolone allergy.
• Milder reactions, such as MDE and urticaria, that occurred longer than 5 years ago may be most amenable
for a 1- or 2-step graded challenge with the implicated fluoroquinolone.
• For more severe or recent reactions, single-dose or 2-step graded challenge with a different fluoroquinolone
than the one implicated in the historical reaction (because they may not cross-react) may be considered.
Fluoroquinolones : Evaluation and Diagnosis
A 2022 practice parameter update. The Journal of allergy and clinical
immunology, 150(6), 1333–1393.

Krantz MS, Stone CA Jr, Yu R, Adams SN, Phillips EJ. Criteria for intradermal skin tescng and oral
challenge in pacents labeled as fluoroquinolone allergic. J Allergy Clin Immunol Pract.
2021;9(2):1024-1028.e3.
Skin prick test 0.1 mg/ml
IDT 0.005 mg/ml , 0.025 mg/ml

Skin test concentration
McGee, Edoabasi U et al. “Quinolone Allergy.” Pharmacy (Basel, Switzerland) vol. 7,3
97. 19 Jul. 2019, doi:10.3390/pharmacy7030097

• Macrolides consist of a macrocyclic lactone ring that contains 14, 15, or 16 carbon atoms with 1 or more
sugar attached and were first isolated from Streptomyces venezuelae.
• The prevalence of reported macrolide-induced anaphylaxis was 3.8 per 10,000 patients in one large US
healthcare system, with erythromycin accounting for the majority of cases.
Macrolides

- Large lactone ring that varies in size
from 12 to 18 atoms.
- Sugar molecules are attached to the
lactone ring with glycosidic bonds.
Ø 14-membered lactones (erythromycin and
clarithromycin),
Ø 15-membered lactones (azithromycin),
ketolide (telithromycin)
Ø 18-membered lactone (fidaxomicin)

• Macrolides with a 14- membered lactone ring such as erythromycin and clarithromycin have been reported
to express cross-reacvity in single case reports.
• Azithromycin is a semisynthec derivave of erythromycin with a 15-membered lactone ring in its structure.
Owing to azithromycin’s structural similarity to erythromycin, cross-reacvity with erythromycin has also
been reported.
• However, There is a lack of scienfic evidence to support cross sensizaon between various macrolide
derivaves.
• The exact mechanism of hypersensivity due to macrolides is not clearly understood.
Macrolides
Shaeer, Kristy M., et al. "Macrolide allergic reactions." Pharmacy 7.3 (2019): 135.

Macrolides
• The most common macrolide-related allergic reactions are delayed cutaneous reactions, and they occur in
about 1% of patients.
• When patients with convincing histories of allergic reactions undergo formal evaluation, only about 5% are
confirmed to be allergic.
• IgE-mediated reactions are uncommon, limited to case series, and anaphylactic reactions are extremely
rare.
• Direct challenge appears to be the most appropriate diagnostic approach for patients with a history of
nonanaphylactic reactions.
A 2022 practice parameter update. The Journal of allergy and clinical
immunology, 150(6), 1333–1393.

• Urticaria is the most commonly reported immediate HSR to macrolides, followed by urticaria/angioedema.
Anaphylaxis is rare.
Macrolides : Immediate reactions
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• The most common delayed reaction to macrolides is a maculopapular exanthem or undefined rash . Other
more severe delayed HSRs include FDE, DRESS, SJS/TENS, and bullous skin reaction.
• HLA-A*02:07 allele is associated with clarithromycin- induced cutaneous ADRs in Han Chinese patients and
may be a genetic risk factor.
Macrolides : Delayed type reaction
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• Sensitivity of all skin tests was 0.0% (95% confidence interval [CI], 0.00%-19.51%)
• Specificity was 85.00% (95% CI, 62.11%-96.79%)
• Positive predictive value was 0%
• Negative predictive value was 50% (95% CI, 45.41%-54.59%),
• False-positive results were 3%
• False-negative results were 17%
DPT is the only reliable method to
predict macrolide hypersensitivity as
well as to detect cross-reactivity
between macrolides.

Macrolides : Skin test concentration

• Patients reporting purely benign cutaneous reactions (ie, MDE or urticaria) to macrolides are candidates for
1- or 2-step drug challenge. Using this approach allows 95% of patients to safely reintroduce macrolides.
Macrolides
A 2022 practice parameter update. The Journal of allergy and clinical
immunology, 150(6), 1333–1393.

Macrolides : Cross-reactivity
Ünal, Derya, et al. "Diagnostic value of oral challenge testing in the diagnosis of
macrolide hypersensitivity." The Journal of Allergy and Clinical Immunology: In
Practice 6.2 (2018): 521-527.

• Tetracyclines classify as protein synthesis inhibitor antibiotics and are considered to be broad-spectrum.
• Naturally occurring drugs in this class are tetracycline, chlortetracycline, oxytetracycline, and
demeclocycline. Semi-synthetic tetracyclines are lymecycline, methacycline, minocycline, rolitetracycline,
and doxycycline.
Tetracyclines

• Adverse reactions involving IgE-mediated mechanisms to these medications are rarely reported.
• Immediate HSRs are infrequent, anaphylaxis to minocycline , tetracycline , and doxycycline have been
reported.
• Most reactions occurred within 1 h of drug intake and consisted of urticaria, angioedema, dyspnea,
wheezing, tachycardia, and/or hypotension
• In a few cases, patients were subsequently confirmed to have an IgE-mediated hypersensitivity by either
positive skin testing or oral challenge.
Tetracyclines : Immediate reactions
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• Delayed reactions to tetracyclines include erythematous rash, DRESS, SJS/TEN, serum sickness like reaction
(SSLR), FDE, hypersensitivity pneumonitis, drug-induced lupus, hepatitis, and myocarditis with cutaneous
reactions being the most common.
• FDEs occur most frequently with tetracycline and doxycycline, and typically appear within 24 h and in
various locations, including genitals. Minocycline poses the highest risk for DRESS amongst tetracyclines and
can manifest with pneumonitis and myocarditis in addition to hepatic and renal involvement.
• Minocycline-induced DRESS may have a prolonged course, particularly in patients with darker skin.
Tetracyclines : Delayed type reactions
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

Tetracyclines
• The rate of cross-reactivity between tetracycline antimicrobials has not yet been established, but co-allergy
to doxycycline and minocycline has been reported.
• In general, HSRs are more commonly attributed to minocycline than to doxycycline.
• Skin testing protocols and minimum nonirritating concentrations for doxycycline, minocycline, and tige-
cycline have not been established.
• Furthermore, there have only been a few single-case reports of doxycycline desensitization protocols, and
these were all in adult patients.
• There are no previously reported validated desensitization protocols for use in pediatric patients.
Maciag, Michelle C., et al. "Hypersensitivity to tetracyclines: skin testing, graded challenge, and
desensitization regimens." Annals of Allergy, Asthma & Immunology 124.6 (2020): 589-593.

Maciag, Michelle C., et al. "Hypersensitivity to tetracyclines: skin testing, graded challenge, and
desensitization regimens." Annals of Allergy, Asthma & Immunology 124.6 (2020): 589-593.
Tetracyclines : Skin tes8ng Regimens
Skin testing regimens for
tetracyclines are not standardized,
and their negative and positive
predictive values are unknown
DPT remains the gold standard
for diagnosis.

Maciag, Michelle C., et al. "Hypersensitivity to tetracyclines: skin testing, graded challenge, and
desensitization regimens." Annals of Allergy, Asthma & Immunology 124.6 (2020): 589-593.

Maciag, Michelle C., et al. "Hypersensitivity to tetracyclines: skin testing, graded challenge, and
desensitization regimens." Annals of Allergy, Asthma & Immunology 124.6 (2020): 589-593.
Tetracyclines: Desenstization protocol

Maciag, Michelle C., et al. "Hypersensitivity to tetracyclines: skin testing, graded challenge, and
desensitization regimens." Annals of Allergy, Asthma & Immunology 124.6 (2020): 589-593.
Tetracyclines: Desenstization protocol

Vancomycin
• Vancomycin, a tricyclic glycopepde, is one of the oldest anmicrobials against Gram-posive cocci bacteria.
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• The most common immediate vancomycin-induced reacon in both pediatric and adult populaons has
historically been called “red man syndrome,” a term with racist undertones that some have called to replace
with “vancomycin infusion reacSon (VIR)
• VIR is mediated by infusion rate–dependent direct mast cell degranulaon, resulng in a rise of plasma
histamine levels and symptoms of flushing, pruris, and/or erythematous rash, typically on the face, neck,
and upper torso
• Nine of 11 healthy, vancomycin-naïve volunteers developed VIR with vancomycin 1 g/h,
• The severity of their symptoms were proporonal to the amount of histamine released. The incidence of VIR
in infected paents appears to be lower, ranging from 3.4 to 47% in small prospecve studies.
• Rapid symptom onset, rapid resoluSon of symptoms with drug withdrawal, and appearance on first
exposure to vancomycin favor VIR over IgE-mediated HSR.
• Serum tryptase has been proposed as a method to disSnguish between VIR and IgE- mediated anaphylaxis,
but the data are conflicSng
Vancomycin : Immediate reaction (VIR)
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• Immediate reactions to vancomycin are mediated by non-IgE mechanisms such as VIR and, less commonly,
IgE mechanisms. MRGPRX2 has been implicated via in vitro studies in which vancomycin- triggered mast
cell degranulation of human mast cells was reduced in mast cells with decreased MRGPRX2 expression.
Vancomycin : Immediate reaction
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• SCARs are uncommon, accounng for 3.5% of delayed HSRs.
• DRESS is the most frequent EHR- documented vancomycin-associated SCAR.
• Vancomycin is one of the most common anbioc culprits of DRESS, accounng for 39–60% of the cases
depending on the study and the second most common culprit of DRESS reported in the FDA Adverse Event
ReporSng System.
• Moreover, vancomycin is the most common culprit in drug-induced linear IgA bullous dermatosis (LABD), a
rare autoimmune disease characterized by linear IgA deposion in the basement membrane zone .
• LABD symptoms occur, on average, 7 days aqer vancomycin iniaon and typically consists of tense bullae in
an older, predominantly male populaon.
• SJS/TEN , acute intersal nephris, fixed drug erupon (FDE), and AGEP
Vancomycin: Delayed type reaction
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

Drug-induced linear IgA bullous dermatosis
(LABD)
Annular macules, and papules with
surrounding erythematous base with
urticarial plaques and excoriation.
Numerous clustered 5 mm to 2 cm clear
smooth vesicles and tense bullae on the
palmar surface with no nail involvement
appreciated
Kim MM, Baquerizo K, Srivastava P, Lankalapalli D, Ullah A. Vancomycin-induced bullous
dermatosis. Int J Case Rep Images 2016;7(7):476–480.

An SY, Hwang EK, Kim JH, et al. Vancomycin-associated spontaneous
cutaneous adverse drug reactions. Allergy Asthma Immunol Res.
2011;3(3):194-198.

Minhas JS, Wickner PG, Long AA, Banerji A, Blumenthal KG. Immune-
mediated reaccons to vancomycin: A systemacc case review and
analysis. Ann Allergy Asthma Immunol. 2016;116(6):544-553.

• HLA-A*32:01 is strongly associated with vancomycin- induced DRESS among patients with European
ancestry. In a cohort of 23 patients diagnosed with probable DRESS, 19 had HLA-A*32:01 allele compared to
0 of 45 vancomycin-tolerant–matched controls . For those carrying the HLA-A*32:01 allele, the risk for DRESS
approaches 20% at 4 weeks of vancomycin therapy .
Vancomycin: HLA-A*32:01
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin, Tetracyclines, and
Macrolides." Clinical Reviews in Allergy & Immunology 62.3 (2022): 505-518.
Konvinse KC, Trubiano JA, Pavlos R, et al. HLA-A*32:01 is
strongly associated with vancomycin-induced drug
reaction with eosinophilia and systemic symptoms. J
Allergy Clin Immunol. 2019;144(1):183-192.

• Skin testing to vancomycin has high false positivity rates, likely due to direct cutaneous mast cell activation.
Vancomycin
Unknown PPV, NPV
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

• In vitro testing, such as BAT for immediate reactions and IFN-γ cytokine release assay or lymphocyte
transformation tests for delayed reaction, has been performed but is not commercially available.
• For vancomycin-induced DRESS, a rapid allele-specific assay for HLA-A*32:01 has 100% sensitivity and 100%
specificity, but it is not commercially available, and the test characteristics can change if the methods are
modified. Based on the 6.8% prevalence of HLA- A*32:01 in individuals with European ancestry, Rwanda-
muriye et al. estimate that 75 patients will need to be tested to prevent 1 case of DRESS.
• DPT with a slower infusion rate and/or antihistamine pre-medications remains the gold standard for
differentiating between VIR and type I HSR, but is generally avoided in the setting of severe symptoms,
positive skin testing, or elevated tryptase levels .
Vancomycin
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.

Vancomycin cross reactivity
• In the largest study, 58 of the 304 hospitalized patients who received teicoplanin for the first time had an
adverse reaction to teicoplanin and 55 demonstrated adverse reactions to both teicoplanin and vancomycin.
• The incidence of teicoplanin adverse reactions was higher in patients with prior vancomycin adverse
reactions compared to those who did not (23.1% vs. 5.1%, p < 0.001) .
• S.-H. Hsiao et al. found that thirty-eight of 170 patients (22.4%) treated with vancomycin developed ADRs.
Twenty-four patients were switched to teicoplanin. However, 14 of those 24 patients (58.3%) developed
ADRs.
Zhu, Linda J., et al. "Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones,
Vancomycin, Tetracyclines, and Macrolides." Clinical Reviews in Allergy & Immunology 62.3
(2022): 505-518.
Hsiao SH, Chou CH, Lin WL, et al. High risk of cross-reactivity between vancomycin and sequential
teicoplanin therapy. J Clin Pharm Ther. 2012;37(3):296-300

Wazny LD, Daghigh B. Desensiczacon protocols for vancomycin hypersensicvity. Ann
Pharmacother. 2001;35(11):1458-1464. doi:10.1345/aph.1A002

Mycobacterium therapy

• Tuberculosis (TB) is the most common cause of death by a single infecous agent globally, and it is one of
the top 10 overall causes of death worldwide.
• It is esmated that 10 million paents developed TB in 2019, resulng in 1.4m deaths, including over 0.2 m
in those with human immunodeficiency virus (HIV) infecon.
• Early diagnosis and effecve treatment of TB are key pillars of the World Health Organisaon (WHO) End
Tuberculosis global strategy.
• Effecve first-line treatment of TB requires mulple agents to be administered concomitantly, typically
isoniazid, rifampicin, pyrazinamide and ethambutol.
• Esmates vary, but up to 60% of paents report ADRs to TB treatment.
• The majority of these are likely to be type A reacons, either pharmacological side effects or due to ‘drug-
drug’ interacons.
Mycobacterium therapy
Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

• Immediate or type I HSRs are also relatively rare, most are mild-moderate and seldom meet diagnostic
criteria for anaphylaxis.
• Most manifest as nonimmediate maculopapular exanthemata, morbilliform rash, urticaria and lichenoid
eruptions, probably representing a T-cell-mediated HSR.
• SCARs such as SJS/TEN ,DRESS are rare events.
• Some case reports is that some patients develop non- immediate HSRs to structurally unrelated anti-TB
drugs during the re-challenge process, and it has been hypothesised that persistent T-cell activation and
cytokine dysregulation in the immediate aftermath of a SCAR may predispose to such reactions.
Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.
Mycobacterium therapy

Risk factors
• Reduction in glomelular filtration rate
• Concomitant therapy with cotrimoxazole
• Hx of previous HSRs as risk factors for HSRs to anti-TB drugs in patients with concomitant HIV infection
• Breen et al. reported an incidence of cutaneous reactions (vesiculation, moist desquamation or
ulceration) during treatment as 8% in HIV-negative patients and 20% in patients with coexisting HIV
infection.
• No specific association has however been shown with absolute CD4+ cell count
Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. PracLcal management of suspected
hypersensiLvity reacLons to anL-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

Skin testing
• Skin prick tests (SPTs) and intradermal tests (IDTs) are performed for isoniazid and rifampicin, as these are
available in parenteral formulations.
• The non-irritant concentrations for skin tests have not been well established.
• Ethambutol and pyrazinamide, not available in parenteral formulation.
• A concentration of 0.006 mg/ml has been employed for IDTs for rifampicin, but positive and negative
predictive values remain uncertain.
In vitro testing
• There is limited experience in the use of basophil activation tests for type I HSRs to anti-TB drugs.
• lymphocyte transformation test(LTT) ; expensive test , limited experience , low sensitivity and high specificity
• IFN-gamma ,IL-4 release assays have shown better than LTT.
Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.
Mycobacterium therapy

Adverse drug reactions
แนวทางการรักษาและควบคุมวัณโรคในประเทศไทย พ.ศ. 2564

Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. PracLcal management of suspected
hypersensiLvity reacLons to anL-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

แนวทางการรักษาและควบคุมวัณโรคในประเทศไทย พ.ศ. 2564

• In cases of DHR caused by first-line anti-tuberculosis drugs, the occurrence of MDHS may be substantially
high, even in the non-severe forms.
• Physicians should consider the possibility of MDHS in patients with suspected anti-tuberculosis drugs-
induced DHR.
• We recommend performing allergy tests, including drug provocation test, for the 4 first-line drugs.
• Among the 4 drugs, ethambutol and rifampin could be the common culprit drugs, and the combination
of these 1 may be the most frequent culprit in inducing MDHS.
• Further investigations including higher numbers of patients will be needed to elucidate the mechanism
why the occurrence of MDHS to first-line anti-tuberculosis drugs may be higher in tuberculosis patients.

Readmistration protocol

Desensitisation protocol
Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

Bermingham WH, Bhogal R, Arudi Nagarajan S, et al. Practical management of suspected
hypersensitivity reactions to anti-tuberculosis drugs. Clin Exp Allergy. 2022;52:375–386.

Thong BY, Chia FL, Tan SC, et al. A retrospec9ve study on sequen9al desensi9za9on-rechallenge for
an9tuberculosis drug allergy. Asia Pac Allergy. 2014;4(3):156-163.

Thong BY, Chia FL, Tan SC, et al. A retrospective study on sequential desensitization-rechallenge for
antituberculosis drug allergy. Asia Pac Allergy. 2014;4(3):156-163.

Pyrazinamide desensi8za8on protocol
Bavbek, Sevim, et al. "Pyrazinamide-induced anaphylaxis: diagnosed by
skin test and successful desensitization." International archives of allergy
and immunology 157.2 (2012): 209-212.

Ethambutol desensitization protocol
Cernadas, Josefina Rodrigues, et al. "Hypersensitivity reaction
and tolerance induction to ethambutol." Case Reports in
Medicine 2013 (2013).

• Sensitivity of ELISpot at a threshold >=50 SFUs was 33% for rifampicin, 13% for isoniazid, 11%
for pyrazinamide, and 0% for ethambutol, respectively .
• Specificity was 100% for all the four FLTB drugs, and positive predictive values were 100% for
rifampicin, isoniazid, and pyrazinamide.
• In DRESS phenotype, rifampicin ELISpot sensitivity was 30% and 0% for the other FLTB drugs.
• In SJS/TEN phenotype, the sensitivities were 50, 33, 25, and 0% for rifampicin, isoniazid,
pyrazinamide, and ethambutol, respectively.
• No difference was seen in sensitivity and specificity of IFN-g ELISpot assay for each of the four
FLTB drugs when DRESS phenotype was stratified into groups of possible, probable, or definite.