One-week Oral Challenge with Penicillin in Diagnosis of Penicillin Allergy

Transcription

1 Acta Derm Veereol 2012; 92: INVESTIGATIVE REPORT Oe-week Oral Challege with Peicilli i Diagosis of Peicilli Allergy Jai Hjortlud, Charlotte Gotthard Mortz, Per Stahl Skov, Esbe Eller, Joha Millig Holk Poulse, Jakob Eli Borch ad Carste Bidslev-Jese Departmet of Dermatology ad Allergy Cetre, Odese Uiversity Hospital, Odese, Demark May patiets experiece reactios durig peicilli treatmet. The diagosis may be difficult ad is maily based o short-term tests. The Europea Network for Drug Allergy (ENDA) guidelies proposed for diagosig peicilli allergy do ot iclude log-term challege. I this study a total of 405 patiets were evaluated. The ENDA guidelies were exteded, to iclude a 7-day oral treatmet (p.o.7) with peicilli for all patiets who were egative i the ENDA programme. Amog the 405 patiets; 85 had a immediate reactio to peicilli, ad a further 13 reacted durig p.o.7. Amog the 307 patiets with a egative outcome, 88 had a case history of reactio to other β-lactam atibiotics ad were subsequetly tested with the culprit drug. Thirtee patiets had a positive outcome: 3 o sigle-dose challege ad 10 durig p.o.7. The exteded peicilli diagostic work-up was positive i 111 patiets, 30.0% showed immediate reactios ad 5.7% reacted durig p.o.7. Approximately 20% of all patiets with positive outcome durig peicilli challege are detected by addig p.o.7 with peicilli to the origial ENDA guidelies. Key words: ENDA guidelies; oe week challege; peicilli allergy. (Accepted August 17, 2011.) Acta Derm Veereol 2012; 92: Jai Hjortlud, Departmet of Dermatology ad Allergy Cetre, Odese Uiversity Hospital, Sdr. Boulevard 29, DK 5000 Odese C, Demark. jai.hjortlud@ ouh.regiosyddamark.dk The diagosis of immediate allergic reactios to β-lactam atibiotics is based o the Europea Network for Drug Allergy (ENDA) guidelies (1). No-immediate maifestatios, particularly maculopapular eruptios, are commo durig β-lactam treatmet. Patch test, delayedreadig itradermal testig ad lymphocyte trasformatio test have bee suggested i the diagostic work-up of o-immediate reactios, followed by itraveous ad oral challege i egative cases. However, a systematic evaluatio of the diagostic work-up of peicilli allergy accordig to ENDA guidelies supplemeted with (whe egative), evaluatio with prologed oral treatmet with peicilli has bee published oly i a prelimiary study from our group (2) The Authors. doi: / Joural Compilatio 2012 Acta Dermato-Veereologica. ISSN MATERIALS AND METHODS Patiet selectio At the Allergy Cetre, Odese Uiversity Hospital, Demark, a total of 405 adult patiets (278 wome (68.6%) ad 127 me (31.4%)) with a history of hypersesitivity reactios to β-lactam atibiotics were evaluated durig the period 2007 to Peicilli was the culprit drug i 72% of the case histories. The mea age of the females was 46 years (rage years) ad, of males, 45 years (rage years). I 12.1% of patiets the reported time iterval betwee the iitial reactio ad ivestigatio was less tha oe year, 12.1% betwee oe ad 5 years, ad 10.4% more tha 5 years, whereas 65.4% did ot recall the time of reactio. The reported symptoms were almost exclusively cutaeous, maily urticaria ( = 144), agioedema ( = 30) ad uclassified cutaeous rash (UCR) ( = 182). Aaphylaxis was reported by ie patiets, whereas 37 did ot recall the ature of their iitial reactio. Three patiets had other symptoms. Diagostic work-up All patiets were ivestigated accordig to the ENDA guidelies (1), except usig the peicillis for itracutaeous test (ICT) at a cocetratio of 1.25 mg/ml, because false positive reactios were see usig higher cocetratios (3). If the ENDA programme proved egative, the ivestigatios cotiued with a prologed oral (7 day) treatmet (p.o.7) with peicilli. O the first ad secod evaluatio days, case history, cliical examiatio, specific IgE-atibodies agaist peicilli, stadard prick test (SPT) ad ICT were carried out (Part A). The ICT was carried out oly if SPT was egative. O day 3 all patiets with egative results uderwet peicilli challege (see below: Peicilli challege (part B)) ad the exteded protocol. IgE aalysis (part A) Specific IgE-atibodies agaist peicilli V, G, ampicilli ad amoxicilli were measured usig CAP-FEIA (Phadia, Uppsala, Swede). Ski testig (part A) SPT with bezylpeicilli, ampicilli ad amoxicilli (1.25 mg/ml) was performed together with SPT with the culprit drug accordig to patiet case history, Histamie 10 mg/ml (ALK- Abello, Hørsholm, Demark) ad isotoic sodium chloride were used as cotrols. ICT was carried out with bezylpeicilli ad ampicilli (1.25 mg/ml). Freshly prepared peicillis diluted with salie were used for SPT ad ICT. SPT ad ICT were performed o the volar forearm ad read after 20 mi. SPT wheal s largest diameter > 3 mm was cosidered positive. ICT was performed by ijectio of 0.05 ml of each hapte ad was cosidered positive if the wheal s largest diameter was greater tha the diameter of the immediate ijectio papule ad accompaied by erythema, cocordat with iteratioal guidelies (4 7). Acta Derm Veereol 92

2 308 J. Hjortlud et al. Peicilli challege (part B) The challeges were performed uder aaphylaxis surveillace. The procedure was divided ito the followig cosecutive steps: Itraveous challege with bezylpeicilli. The iitial dose was 100 IE followed by 1,000, 10,000, 100,000 ad 1,000,000 IU at 20 mi iterval. Challege was stopped whe a cliical reactio occurred. If egative, a oral challege with 400 mg of pheoxymethylpeicilli was admiistered 20 mi after the last itraveous ijectio ad the patiet was observed i the cliic for a further 2 h. If egative, the patiet was treated at home with a prologed oral treatmet (p.o.7), cosistig of 800 mg pheoxymethylpeicilli 3 times a day for 7 days. Challege with other culprit drugs (part C) All the 405 patiets participated i parts A ad B. Case histories of reactios to other β-lactam atibiotics were see i 88 patiets, ad they were subsequetly challeged with the culprit drug, iitially i a sigle p.o. challege protocol, followed by a 7-day repeated p.o with the culprit drug (iitial dose: amoxicilli, ampicilli ad dicloxacilli 500 mg, followed by p.o.7: 500 mg twice a day (amoxicilli ad ampicilli), ad dicloxacilli 500 mg three times a day). Statistical aalysis Statistical aalyses were performed usig Fisher s exact test. The sigificace level was set at 5%. RESULTS The algorithm of the diagostic work-up of the 405 patiets ad the outcome of the allergy tests are described i Fig. 1a. Part A Forty-four of the 405 patiets were IgE-sesitized to peicilli ad oe was positive i SPT. ICT was performed i the remaiig 360 patiets ad was positive i 20 patiets. The remaiig 340 patiets were subsequetly challeged with peicilli (part B) accordig to Fig. 1a (1, 8, 9). Part B Durig i.v. challege 5 patiets were positive; the remaiig 335 received oral challege (sigle dose) with pheoxymethylpeicilli, where 15 proved positive. The remaiig 320 patiets received a prologed oral (7 day) treatmet with pheoxymethylpeicilli (p.o.7); 13 had a positive reactio. Part C I parts A ad B 307 patiets had a egative outcome. Amog these, 88 had a case history of reactios to other β-lactam atibiotics ad were subsequetly a ( = 405) IgE to peicilli b Case History of other β-lactam atibiotics ( = 88 of 307) Positive IgE ( = 361) ( = 44) Pos. sigle p.o. Ampicilli ( = 1/23) PART A Immediate reactios SPT Positive SPT ( = 360) ( = 1) ICT Positive ICT ( = 340) ( = 20) IV challege (pec. G) PART C Sigle PO ( = 85 of 307) Pos. sigle p.o. Amoxicilli ( = 1/21) Pos. sigle p.o. Dicloxacilli ( = 1/30) Pos. sigle p.o. other ( = 0/14) Positive I.V ( = 335) ( = 5) Pos. p.o. 7 Ampicilli ( = 4/22) PART B Late Sigle PO (pec. V) Positive Sigle PO ( = 320) ( = 15) 7-day repeated PO (pec. V) Positive p.o. 7 (=13) (=307) 7-day repeated PO ( = 75 of 307) Pos. p.o. 7 Amoxicilli ( = 4/20) Pos. p.o. 7 Dicloxacilli ( = 2/29) Pos. p.o. 7 other ( = 0/14) Fig. 1. Diagostic work-up for peicilli allergy at the Allergy Cetre, Odese Uiversity Hospital i the period 2007 to (a) Parts A ad B. (b) Part C. Other β-lactam atibiotics (icludig meropeem, cefuroxime ad pivmecilliam). IV: itraveous; PO: oral; p.o.7: 7-day oral treatmet with peicilli; IgE: immuoglobuli E; SPT: stadard prick test; ICT: itracutaeous test. Acta Derm Veereol 92

3 Diagosis of peicilli allergy 309 Table I. Patters of IgE sesitizatio ad ski testig. Dicloxacilli was icluded oly i cases ( = 30) with dicloxacilli as the culprit drug Peicilli V aloe Ampicilli + Dicloxacilli Peicilli G + Ampicilli + Amoxicilli Ampicilli + Amoxicilli Peicilli G + Ampicilli Dicloxacilli Amoxicilli Ampicilli Peicilli G Part A. Positive reactios i IgE, SPT ad ICT IgE ( = 44) Peicilli V positive d d 17 Peicilli V egative d d SPT ( = 1) d ICT ( = 20) 5 9 d d: ot doe; IgE: immuoglobuli E; SPT: stadard prick test; ICT: itracutaeous test. Table II. Relatioship betwee case history ad peicilli challege with respect to type of reactio. Grey cells idicate cocordace of type of reactios elicitig primary reactio ad challege Case history i.v/p.o positive (=23) p.o.7 positive (=23) Had eczema Maculopapulous exathema Urticaria/agioedema Severe gastric symptoms Erythema fixum Maculopapulous exathema Urticaria/agioedema Parts B ad C. Challege Urticaria/agioedema Uclassified cutaeous rash Erythema fixum 1 i.v./p.o.: itraveous/oral; p.o.7: 7-day oral treatmet with peicilli. tested accordig to Fig. 1b. I all, 13 out of 88 patiets with a egative challege with peicilli were positive to other β-lactam atibiotics. Fourtee patiets were challeged with other culprit drugs ad all were egative. The exteded peicilli diagostic evaluatio (parts A, B ad C) was positive i 111 patiets (27.4%). Out of the 405 patiets 88 (21.7%) showed immediate reactios accordig to the ENDA guidelies. I additio, 23 patiets (5.7%) reacted durig p.o.7. Patters of IgE sesitizatio IgE-sesitizatio to peicilli was demostrated i 44 patiets, where 34 had specific IgE to peicilli V. Moo-sesitizatio to peicilli V was see i 17 patiets, 15 had specific IgE to both peicilli G ad V. IgEsesitizatio to ampicilli was foud i 19 patiets ad i 10 cases to ampicilli aloe. Noe had specific IgE to amoxicilli oly. Sevetee patiets were sesitized to more tha oe of the four peicillis (Table I). All patiets sesitized to peicilli V ad/ or peicilli G were treated with peicilli durig their primary reactio, except for two cases where the culprit drugs were amoxicilli ad cefuroxime, respectively. I the 10 cases with IgE to ampicilli aloe oly oe reported ampicilli as the culprit drug. Patters of ski testig Oe of 405 patiets demostrated a positive SPT to peicilli G without beig IgE sesitized (Table I). Amog the 20 patiets positive i ICT, 8 reacted to peicilli G, 13 to ampicilli ad 3 to dicloxacilli. I 4 cases the patiet had a positive reactio to two drugs. Reactios i challege positive patiets. Urticaria/agioedema were the most commoly reported reactio both i the 23 patiets positive o i.v. or sigle p.o. challege ad the 23 patiets i p.o.7 group. A high correlatio was foud betwee case history ad the reactios elicited durig challege (Tables II ad III). This was primarily see i 17 of the 23 patiets with immediate reactios (13 cases of urticaria/agioedema, three cases of UCR ad oe case of ery thema fixum), whereas 13 out of 23 reproduced their case history durig the p.o.7 (9 cases of urticaria/agioedema ad 4 cases of ma- Acta Derm Veereol 92

4 310 J. Hjortlud et al. Table III. Distributio of symptoms accordig to case history ad diagostic evaluatio Total ( = 405) Part A ( = 405) Parts B ( = 340) ad C ( = 88) IgE positive ( = 44) SPT positive ( = 1) ICT positive ( = 20) i.v. positiv ( = 5) p.o. positive ( = 18) p.o.7 positive ( = 23) Ay positive ( = 111) (%) ( = 294) (%) Case history symptoms Aaphylaxis, urticaria, (36.2) 118 (63.8) agioedema Uclassified cutaeous rash, (19.4) 175 (80.6) ukow Sweet s sydrome (100) Erythema fixum (100) Respiratory symptoms 1 1 (100) Peicilli was the culprit drug i 72% of the case histories. I 87.4% peicilli was the resposible drug regardig itraveous (i.v.)/oral (p.o.)-positive patiets ad 56.5% i the subgroup p.o.7 positive. I most cases the other culprit drugs were equally distributed. p.o.7: 7-day oral treatmet with peicilli; IgE: immuoglobuli E; SPT: stadard prick test; ICT: itracutaeous test. culopapulous rash. No sigificat differece was foud betwee the two subgroups (p > 0.05). Niety-oe of the 111 patiets with a positive challege remembered the ature ad timig of their iitial reactio. This fidig is i cotrast to the egative patiets, where oly 48 of 294 patiets could describe their iitial reactio (p < 0.05). Patiets with a case history of aaphylaxis, urticaria or agioedema were sigificatly more likely to be positive i the tests (part A, B or C) tha patiets reportig UCR or those ot rememberig the ature of their iitial reactio (36.2% vs. 19.4% positive) (p < 0.05) (Table III). Peicilli was the resposible drug i 20 of the 23 patiets positive i either i.v. or sigle-dose p.o. challege. I all patiets except oe the culprit drug was idetical to the resposible drug durig challege. Thirtee of the 23 patiets respodig durig p.o.7 had a positive reactio to peicilli, the remaiig reactig to dicloxacilli ( = 2), amoxicilli ( = 4) or ampicilli ( = 4). I 20 of the 23 patiets the culprit drug was idetical to the resposible drug durig challege (Table IV). Time iterval betwee p.o.7 ad cliical reactio The reactios i the 23 patiets i most cases appeared later tha reported i case history. Noe of the patiets reacted durig the first day of p.o.7. The latest day of reactio i case history was day 16. Latest positive challege was see at day 10, 3 days after completed p.o.7. Time iterval betwee self-reported reactio ad diagostic work-up. The time iterval betwee the allergic reactio durig treatmet ad the diagostic work-up is illustrated i Fig. 2. Patiets with positive IgE to peicillis were foud almost exclusively i the group of patiets with a iitial reactio withi a year before the ivestigatio. Patiets positive i ski tests or challege were more evely distributed, differig sigificatly from the patiets with egative peicilli challege (83.7%) oly rarely rememberig the ature ad time of their iitial reactio (p < 0.05). DISCUSSION The preset study icludes 405 cosecutive patiets with a case history of peicilli reactio referred to the Allergy Cetre, Odese Uiversity Hospital durig a 2-year period. All patiets were tested accordig to the ENDA guidelies for hypersesitivity reactios to β-lactam atibiotics ad, if egative, a 7-day oral treatmet was added. Accordig to ENDA guidelies 88 were positive (immediate reactios). I additio, 23 patiets were Table IV. Relatioship betwee case history ad peicilli challege with respect to type of culprit drug. Grey cells idicate cocordace of atibiotics elicitig primary reactio ad challege Case history i.v./p.o. positive ( = 23) p.o.7 positive ( = 23) Peicilli Dicloxacilli Ampicilli Amoxicilli Peicilli Dicloxacilli Ampicilli Parts B ad C. Challege Peicilli Dicloxacilli Ampicilli Amoxicilli 1 2 i.v./p.o.: itraveous/oral; p.o.7: 7-day oral treatmet with peicilli. Acta Derm Veereol 92 Amoxicilli

5 Diagosis of peicilli allergy 311 Patiets (%) < 1 year 1 5 years > 5 years Not recall =44 =21 =23 =23 =294 0 IgE pos. SPT/ICT pos. i.v/p.o pos. p.o 7 Patiet groups Fig. 2. Time iterval betwee primary reactio ad diagostic work-up at the Allergy Cetre accordig to the five differet patiet groups. i.v.: itraveous; p.o.: oral; p.o.7: 7-day oral treatmet with peicilli; IgE: immuoglobuli E; SPT: stadard prick test; ICT: itracutaeous test. foud to develop a reactio durig the subsequet 7-day challege with oral peicilli. This exteded peicilli diagostic work-up thus provides a sigificat diagostic improvemet. I total, 27.4% of the patiets had a positive outcome i our diagostic evaluatio, icludig the 5.7% havig a positive outcome durig p.o.7. Two other studies followig ENDA guidelies have published similar results (10, 11). I aother large study followig iteratioal guidelies oly 8.4% of patiets with possible β-lactam allergy were positive durig challege (12). Apart from the fact that childre were icluded i the study by Messaad, there are o obvious reasos for this discrepacy whe lookig at iclusio criteria, age ad sex distributio, diagostic work-up (excludig p.o.7) or patiet case histories. Torres et al. (13, 14) reported a eve higher frequecy (88%) of a positive outcome, maily due to positive ski tests. Whether these fidigs reflect differeces i testig procedures (icludig major ad mior peicilloyl determiats) or regioal differeces are ukow. However, they also show a sigificat proportio of cases with a clear positive history of immediate allergic reactio ad with both egative ski tests ad specific IgE to be positive durig drug challege. Immediate reactios Hypersesitivity reactios to β-lactam atibiotics are classified as immediate or o-immediate reactios. Previous studies have demostrated the presece of IgE-atibodies to peicillis i patiets with immediate reactios, ad the ivolvemet of these atibodies i urticaria, agioedema ad aaphylaxis is well kow (1, 8, 15). Five of 9 patiets with aaphylaxis had positive IgE, but oly two proved positive i ski tests (ICT). Noe of the 44 patiets with IgE-sesitizatio towards peicilli had a positive ski test, either SPT or ICT. I cotrast to what is ormally observed i patiets with type 1 allergy, there is a total lack of correlatio betwee IgE ad ski testig. Torres et al. (14) foud the same patters of egative ski tests i patiets with IgE-sesitizatio, reportig 11.5% to be ski test egative ad IgE positive. Patiets with immediate cliical reactios to β-lactam atibiotics may thus be positive or egative i IgE- ad/ or ski testig. The reaso for this is ukow, but it emphasizes the importace of cotrolled challege. Accordig to ENDA guidelies, ski testig with peicilloyl-polylysie (PPL) ad mior determiat mixture (MDM) represets the first-lie method for evaluatig immediate reactios to β-lactam atibiotics. Because of the uavailability of PPL ad MDM i Demark durig this ivestigatio, these peicilli reagets were ot used i our evaluatio. Ski testig with PPL ad MDM i proportio to peicillis has bee illustrated by Romao et al. (7). Accordig to their study, ski testig with bezylpeicilli may compesate for PPL ad MDM uavailability. Torres et al. (13) foud, i a large study, a equal distributio betwee patiets positive i ski testig with bezylpeicilli ad MDM. Time iterval I the preset study the time iterval betwee selfreported reactio ad diagostic work-up was importat. Most patiets with IgE-sesitizatio are diagosed withi oe year, idicatig that the level of IgE decreases over time, as has bee reported i other studies (1, 8, 9, 16 18). The diagostic sigificace of a trasiet IgE to peicilli is uclear. Patiets should therefore preferetially be examied withi oe year after the iitial reactio. Predictive factors May patiets (65.7%) are uable to give a detailed case history, ad there is a sigificat iverse correlatio betwee time iterval betwee the self-reported reactio ad the diagostic work-up. The ature of symptoms costitutes a statistically sigificat factor predictig test outcome. If the case history idicates symptoms such as aaphylaxis, agioedema or urticaria there is a icreased probability of positive test outcome, i cotrast to case histories such as UCR or ukow symptoms. A short time iterval betwee reactio ad diagostic work-up ad severity of symptoms idicates a higher hit-rate for establishig a positive outcome. Furthermore, positive patiets are foud almost exclusively amog patiets reportig cutaeous symptoms i the case history (all except oe, Acta Derm Veereol 92

6 312 J. Hjortlud et al. who had respiratory reactios oly). Positive outcome of allergy testig is, however, also see amog the patiets with symptoms such as UCR or ukow symptoms. Complete diagostic evaluatio is therefore ecessary i each patiet. Patters of culprit drug Peicilli was the culprit drug i 72% of the primary reactios. The majority of studies o peicilli allergy i Europe origiate from the Mediterraea area, where the distributio of β-lactam use differs from that i the Scadiavia coutries. A Europea Surveillace of Atimicrobial Cosumptio (ESAC) project moitored the use of peicillis i 25 coutries i Europe, ad foud that arrow-spectrum peicilli (maily pheoxymethylpeicilli) represeted more tha 60% of peicilli use i Scadiavia, whereas arrow-spectrum peicilli represeted less tha 2% of use the Mediterraea area. Broad-spectrum peicillis (maily amoxicilli) were most frequetly prescribed i the Mediterraea coutries (19). I accordace with their self-reported culprit drug reactio, some patiets i our study showed a egative challege with bezylpeicilli ad pheoxymethylpeicilli ad a positive challege with other β-lactam atibiotics. This is i agreemet with a previous study idicatig that cross-reactivity amog peicillis is ot a geeral rule (20). Amog the 23 patiets respodig durig p.o.7, oe reacted o day oe. It is therefore safe to discharge the patiet after a egative challege with peicilli for use at home for the ext 7 days. ENDA guidelies for ivestigatio of hypersesitivity reactios to β-lactam atibiotics are the gold stadard for a defiitive diagosis of peicilli allergy. At its preset level of developmet, however, there is still room for improvemet, sice we have demostrated that approximately 20% (23/111 patiets) of all the patiets with positive outcome o peicilli challege are detected by icludig a prologed oral treatmet with peicilli. The authors declare o coflicts of iterest. REFERENCES 1. Blaca M, Romao A, Torres MJ, Feradez J, Mayorga C, Rodriguez J, et al. Update o the evaluatio of hypersesitivity reactios to betalactams. Allergy 2009; 64: Borch JE, Bidslev-Jese C. Full-Course Drug challege test i the diagosis of delayed allergic reactios to peicilli. It Arch Allergy Immuol 2011; 155: Borch JE, Aderse KE, Bidslev-Jese C. The prevalece of acute cutaeous drug eactios i a Scadiavia uiversity hospital. Acta Derm Veereol 2006; 86: Brockow K, Romao A, Blaca M, Rig J, Pichler W, Demoly P. Geeral cosideratios for ski test procedures i the diagosis of drug hypersesitivity. Allergy 2002; 57: Dreborg S. Ski test used i type I allergy testig. Allergy 1989; 44: Dreborg S. Allerge stadardizatio ad ski tests. Allergy 1993; 48: Romao A, Bousquet-Rouaet L, Viola M, Gaeta F, Demoly P, Bousquet PJ. Bezylpeicilli ski testig is still importat i diagosig immediate hypersesitivity reactios to peicillis. Allergy 2009; 64: Romao A, Blaca M, Torres MJ, Bircher A, Aberer W, Brockow K, et al. Diagosis of oimmediate reactios to beta-lactam atibiotics. Allergy 2004; 59: Torres MJ, Blaca M, Feradez J, Romao A, Weck A, Aberer W, et al. Diagosis of immediate allergic reactios to beta-lactam atibiotics. Allergy 2003; 58: Bousquet PJ, Pipet A, Bousquet-Rouaet L, Demoly P. Oral challeges are eeded i the diagosis of beta-lactam hypersesitivity. Cli Exp Allergy 2008; 38: Silva R, Cruz L, Botelho C, Cadiha S, Castro E, Rodrigues J, et al. Work up of patiets with history of beta-lactam hypersesitivity. Allergol Immuopathol 2009; 37: Messaad D, Sahla H, Beahmed S, Godard P, Bousquet J, Demoly P. Drug provocatio tests i patiets with a history suggestig a immediate drug hypersesitivity reactio. A Iter Med 2004; 140: Torres MJ, Romao A, Mayorga C, Moya MC, Guzma AE, Reche M, et al. Diagostic evaluatio of a large group of patiets with immediate allergy to peicillis: the role of ski testig. Allergy 2001; 56: Torres MJ, Mayorga C, Leyva L, Guzma AE, Corejo-Garcia JA, Juarez C, et al. Cotrolled admiistratio of peicilli to patiets with a positive history but egative ski ad specific serum IgE tests. Cli Exp Allergy 2002; 32: Torres MJ, Sachez-Sabate E, Alvarez J, Mayorga C, Feradez J, Padial A, et al. Ski test evaluatio i oimmediate allergic reactios to peicillis. Allergy 2004; 59: Borch JE, Aderse KE, Bidslev-Jese C. The prevalece of suspected ad challege-verified peicilli allergy i a uiversity hospital populatio. Basic Cli Pharmacol Toxicol 2006; 98: Feradez TD, Torres MJ, Blaca-Lopez N, Rodriguez- Bada JL, Gomez E, Cato G, et al. Negativizatio rates of IgE radioimmuoassay ad basophil activatio test i immediate reactios to peicillis. Allergy 2009; 64: Mayorga C, Saz ML, Gamboa PM, Garcia BE, Caballero MT, Garcia JM, et al. I vitro diagosis of immediate allergic reactios to drugs: a update. J Ivestig Allergol Cli Immuol 2010; 20: Ferech M, Coee S, Dvorakova K, Hedrickx E, Suetes C, Goosses H. Europea Surveillace of Atimicrobial Cosumptio (ESAC): outpatiet peicilli use i Europe. J Atimicrob Chemother 2006; 58: Blaca M, Vega JM, Garcia J, Carmoa MJ, Terados S, Avila MJ, et al. Allergy to peicilli with good tolerace to other peicillis; study of the icidece i subjects allergic to beta-lactams. Cli Exp Allergy 1990; 20: Acta Derm Veereol 92