Diagnostica dell’allergia a β -lattamici: “up-to-date” Antonino Romano antoninoromano@h-columbus.it Complesso Integrato Columbus – Roma IRCCS Oasi Maria S.S. – Troina (EN)
PENICILLINS CEPHALOSPORINS O O S R-C-NH R 1 -C-NH N N O COOH O C-R 2 MONOBACTAMS CARBAPENEMS O R 1 R-C-NH S- R 2 N N O O SO 3 H C=O OH Structure of the four classes of betalactam antibiotics in use today
Diagnostic tests of hypersensitivity reactions to drugs Type of reaction Type of test In vitro Immediate Specific IgE assays Flow cytometric basophil activation tests In vivo Skin tests Provocation tests A Romano et al, J Allergy Clin Immunol 2011
Update on the evaluation of hypersensitivity reactions to betalactams • Immunoassays remain an important diagnostic method • The basophil activation test has emerged as a useful tool for the diagnosis of immediate allergic reactions to betalactams, especially cephalosporins, for most of which immunoassays are not available M Blanca et al, Allergy 2009
LONG ALGORITHM CLINICAL HISTORY AND BLOOD SAMPLE Prick PPL/MDM + + ID PPL/MDM ALLERGIC + In vitro test Non selective reactions + DPT with BP 1 week + ALLERGIC Prick ulprit drug selective reactions + ID culprit drug + NON ALLERGIC DPT culprit drug M Blanca et al, Allergy 2009
SHORT ALGORITHM CLINICAL HISTORY AND BLOOD SAMPLE Prick PPL/MDM/AX/Drug + + ID PPL/MDM/AX/Drug ALLERGIC + + In vitro test + In vitro test – DPT drug Repeat study in 2 to 4 w. NON ALLERGIC M Blanca et al, Allergy 2009
The diagnostic interpretation of basophil activation test in immediate allergic reactions to betalactams Of the 70 patients, 34 (48.6%) were positive to Basotest, 31 (44.3%) to CAP/RAST and 46 (65.7%) to either one or both MJ Torres et al, Clin Exp Allergy 2004
The diagnostic interpretation of basophil activation test (BAT) in immediate allergic reactions to betalactams No. of BAT- % patients positive Group A 53 27 50.9% (ST+) Group B 10 6 60% (ST- / CAP+) Group C 7 1 14.3% (ST- / CAP- / DPT+) MJ Torres et al, Clin Exp Allergy 2004
Haptens and the highest concentrations recommended for prick and intradermal tests HAPTEN DOSE UNIT 5x10 -5 PPL mMol/l 2x10 -2 MDM mMol/l AMOXICILLIN 20 mg/ml BENZYLPENICILLIN 10,000 IU/ml CULPRIT DRUG 2 mg/ml • Cephalosporin 20 mg/ml • Amoxicillin-clavulanic 20 mg/ml • Ampicillin M Blanca et al, Allergy 2009
Which is the major determinant? 100 80 60 Blanca M 1990 Torres MJ 2001 Blanca M 2007 40 20 0 PPL MDM AX AMP Benzylpenicilloil Benzylpenicillin Benzylpenicilloic acid Benzylpenilloic
Haptens and the highest concentrations recommended for prick and intradermal tests HAPTEN DOSE UNIT 5x10 -5 PPL mMol/l 2x10 -2 MDM mMol/l AMOXICILLIN 20 mg/ml BENZYLPENICILLIN 10,000 IU/ml CULPRIT DRUG 2 mg/ml • Cephalosporin 20 mg/ml • Amoxicillin-clavulanic 20 mg/ml • Ampicillin M Blanca et al, Allergy 2009
Haptens and the highest concentrations recommended for prick and intradermal tests HAPTEN DOSE UNIT 5x10 -5 PPL mMol/l 2x10 -2 MDM mMol/l AMOXICILLIN 20 mg/ml BENZYLPENICILLIN 10,000 IU/ml CULPRIT DRUG • Cephalosporin 2 mg/ml • Amoxicillin-clavulanic 20 mg/ml • Ampicillin 20 mg/ml M Blanca et al, Allergy 2009
Nonirritating concentrations for 15 commonly used antibiotics Antimicrobial Full-strength NIC (as dilution from No. of patients drug concentration full-strength concentration) tested Cefotaxime 100 mg/mL 10 -1 25 Cefuroxime 100 mg/mL 10 -1 25 Cefazolin 330 mg/mL 10 -1 25 Ceftazidime 100 mg/mL 10 -1 25 Ceftriaxone 100 mg/mL 10 -1 30 Tobramycin 80 mg/2 mL 10 -1 25 Ticarcillin 200 mg/mL 10 -1 25 Clindamycin 150 mg/mL 10 -1 25 R Empedrad et al, J Allergy Clin Immunol 2003
Skin tests with cephalosporins at a concentration of 20 mg/mL o Nonirritating 215 patients Cefuroxime Second-generation cephalosporin 31 patients Ceftriaxone Third-generation cephalosporin 24 patients Cefotaxime Third-generation cephalosporin 24 patients Ceftazidime Third-generation cephalosporin 5 patients Cefazolin First-generation cephalosporin o Irritating 7 control subjects Cefepime Fourth-generation cephalosporin S Testi et al, J Investig Allergol Clin Immunol 2010
Haptens and the highest concentrations recommended for prick and intradermal tests HAPTEN DOSE UNIT 5x10 -5 PPL mMol/l 2x10 -2 MDM mMol/l AMOXICILLIN 20 mg/ml BENZYLPENICILLIN 10,000 IU/ml CULPRIT DRUG • Cephalosporin 2 mg/ml • Amoxicillin-clavulanic 20 mg/ml • Ampicillin 20 mg/ml M Blanca et al, Allergy 2009
Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions HAPTEN DOSE UNIT 5x10 -5 PPL mMol/l 2x10 -2 MDM mMol/l CLV 20 mg/ml AMOXICILLIN 20 mg/ml AMOXICILLIN+CLV 20+4 mg/ml M J Torres et al, J Allergy Clin Immunol 2010
Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions 31 refused or did not complete the study 307 patients with a reaction with AX-CLV 5 positive to PPL or MDM 276 patients 55 with positive skin- 34 positive to AX (all tolerated DPT to BP) completed the study test results 16 positive to CLV (all tolerated DPT to BP and AX) 221 patients with negative skin tests 10 positive to AX-CLV to penicillin determinants 199 tolerated DPT to BP, AX and AX-CLV all patients 15 tolerated DPT to BP, but developed an immediate reaction to AX accepted DPT 7 tolerated DPT to AX, but developed an immediate reaction to AX-CLV M J Torres et al, J Allergy Clin Immunol 2010
LONG ALGORITHM CLINICAL HISTORY AND BLOOD SAMPLE Prick PPL/MDM + + ID PPL/MDM ALLERGIC + In vitro test Non selective reactions + DPT with BP 1 week + ALLERGIC Prick ulprit drug selective reactions + ID culprit drug + NON ALLERGIC DPT culprit drug M Blanca et al, Allergy 2009
SHORT ALGORITHM CLINICAL HISTORY AND BLOOD SAMPLE Prick PPL/MDM/AX/Drug + + ID PPL/MDM/AX/Drug ALLERGIC + + In vitro test + In vitro test – DPT drug Repeat study in 2 to 4 w. NON ALLERGIC M Blanca et al, Allergy 2009
Controlled administration of penicillin to patients with a positive history but negative skin and specific serum IgE tests • Positive skin tests to at least one determinant observed in 203 (61.5%) out of the 330 subjects evaluated • 38 (11.5%) out of the 330 subjects were skin test negative and had positive benzylpenicilloyl and/or amoxicilloyl in vitro tests (CAP-FEIA) • 49 (14.8%) out of the 330 subjects were skin test and CAP-FEIA negative and reacted to the controlled administration • 40 (12.1%) out of the 330 subjects were negative in allergologic workups, including challenges MJ Torres et al, Clin Exp Allergy 2002
Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions 31 refused or did not complete the study 307 patients with a reaction with AX-CLV 5 positive to PPL or MDM 276 patients 55 with positive skin- 34 positive to AX (all tolerated DPT to BP) completed the study test results 16 positive to CLV (all tolerated DPT to BP and AX) 221 patients with negative skin tests 10 positive to AX-CLV to penicillin determinants 199 tolerated DPT to BP, AX and AX-CLV all patients 15 tolerated DPT to BP, but developed an immediate reaction to AX accepted DPT 7 tolerated DPT to AX, but developed an immediate reaction to AX-CLV M J Torres et al, J Allergy Clin Immunol 2010
PENICILLINS CEPHALOSPORINS O O S R-C-NH R 1 -C-NH N N O COOH O C-R 2 MONOBACTAMS CARBAPENEMS O R 1 R-C-NH S- R 2 N N O O SO 3 H C=O OH
Clinical history, CAP-FEIA and sepharose-RIA 1 st day Skin tests with PPL, MDM and BP 3 positive only to penicillin reagents: group A (no. 1-3) 2 nd day 19 patients with skin-test and/or CAP-FEIA positivity to penicillin Skin tests with AM and AX reagents 16 positive to both penicillins and cephalosporins: group B (no. 4-19) 3 rd day 21 patients positive to more than one cephalosporin: group C (no. 20-40) Skin tests with cephalosporins 18 patients positive only to the culprit cephalosporin: group D (no. 41-58) 18 patients negative to 5 sepharose-RIA positive not challenged: group E (no. 59-63) skin tests and CAP-FEIA 13 sepharose-RIA negative 5 refused challenges: group E (no. 64-68) 1 group B patient (no. 69) 8 accepted challenges 2 reacted re-evaluation after 4 weeks 1 group D patient (no. 75) (no. 69-76) 3 group C patients (no. 70-72) 5 positive 2 group D patients (no. 73, 74) 6 tolerated challenges and re-evaluation one-week therapeutic courses after 4 weeks 1 negative in all allergologic tests: group E (no. 76) Romano A et al, Clin Exp Allergy 2005
Skin test, RAST, and BAT sensitivity over time 100- 1,0 P=0.0167 Nonselective reactions *p<0.0003 Log Rank= 5.73 Selective reactions 80- % survival of skin test positive Cumulative survival 0,8 60- RAST 0,6 40- 0,4 BAT 20- 0,2 0- 0,0 0 0 6 12 18 24 30 36 42 48 1 2 3 4 5 6 Years Negativization Time (months) M Blanca et al, J Allergy Clin Immunol 1999 TD Fernández et al, Clin Exp Allergy 2008
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