key: cord-031256-4mxt501d
authors: Van Der Poorten, Marie-Line M.; Van Gasse, Athina L.; Hagendorens, Margo M.; Faber, Margaretha A.; De Puysseleyr, Leander; Elst, Jessy; Mertens, Christel M.; Romano, Antonino; Ebo, Didier G.; Sabato, Vito
title: Non-irritating skin test concentrations for ceftazidime and aztreonam in patients with a documented beta-lactam allergy.
date: 2020-09-01
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.08.031
sha: 
doc_id: 31256
cord_uid: 4mxt501d

nan

Conflict of Interest Statement: All authors agree with the content of the manuscript and that none of 24 us has interests that might be interpreted as influencing the research. This manuscript represents 25 results of original work that have not been published elsewhere. This manuscript has not and will not 26 be submitted for publication elsewhere until a decision is made regarding its acceptability for 27 publication in The Journal of Allergy and Clinical Immunology in Practice. If accepted for publication, 28

it will not be published elsewhere. Furthermore, there are no perceived (financial) conflicts of 29 interest related to the research reported in the manuscript. 30

Our study shows that the maximal non-irritant concentration (NIC) for ceftazidime and for aztreonam 32 is as high as 20 mg/mL for immediate readings of intradermal skin tests (IDT). For delayed readings of 33 IDT the NIC is even a 10-fold higher, that is 200 mg/mL. 34 35 36 J o u r n a l P r e -p r o o f hypersensitivity reactions (henceforth designated as IDHRs and NIDHRs). At present, skin tests (STs) 38 with immediate and delayed readings occupy the first place to document such IDHRs and NIDHRs. 39 Therefore, optimising non-irritant concentrations (NICs) is critical to ascertain the best balance of 40 sensitivity and specificity. Avoiding under-and over-diagnosis should not only improve antibiotic 41 stewardship at the level of the individual patient, but also reduce the costs of our health systems. (1) 42 This study aims at assessing the NIC for ceftazidime, a third generation cephalosporin, and 43 aztreonam, a synthetic monobactam, both potential safe alternative β-LABs in patients with a 44 documented hypersensitivity reaction to penicillin G, amoxicillin (+/-clavulanic acid) or cefazolin. 45

For this purpose, we set up a prospective study. All patients were included by trained physicians via 46 the outpatients' clinic of Allergology of the Antwerp University Hospital between 2018 and 2020. The 47 local ethics committee approved this study (B300201524055) and patients provided an informed 48 consent in accordance with the declaration of Helsinki. 49

All patients had with an IDHR or NIDHR to Penicillin G or amoxicillin (+/-clavulanic acid) or an IDHR to 50 cefazolin, that was confirmed in our clinic between 2018 and 2020, were systematically offered to 51 participa in this study. Diagnosis of their Penicillin G, amoxicillin (+/-clavulanic acid) or cefazolin 52 hypersensitivity was based upon a history complemented by positive STs (immediate and delayed 53 readings), drug-reactive sIgE antibodies, a sIgE-to-tIgE ratio ≥ 0.002, or a graded drug challenge (DC). 54

(2) 55

In our hospital, it is standard practise to offer all patients with a beta-lactam allergy subsequent 56 testing for identification ofcross-reactive and safe alternative molecules. All patients that were 57 tested, chose to participate, hencealso had additional ST titrations with ceftazidime and aztreonam. 58

Skin testing included skin prick tests (SPTs) and intradermal tests (IDTs) with immediate and delayed 59 readings after 15 minutes and 48 hours, respectively. A 0.9% NaCl solution and histamine (10 mg/mL) 60 were used as negative and positive control. The drugs were diluted in 0.9% NaCl not more than 2 drop of the drug or the control solution. SPTs were considered positive when a wheal > 3 mm 63 surrounded by flare was observed. IDTs were performed only when SPTs were negative. For IDTs, 64 0.02 mL of the reagent solution was injected on the volar side of the forearm, using a disposable 1 65 mL syringe. Immediate IDT readings were considered positive when the diameter of the wheal, 66 accompanied by an erythema, was at least 3 mm greater than the injection bleb. Delayed IDT 67 readings were considered positive when an induration exceeding 5 mm, surrounded by an erythema, 68 was observed (3-5). All patients with negative ST results at the recommended end concentration of 2 69 mg/mL (3), had additional STs with 20 mg/mL and 200 mg/mL. Graded DCs (cumulative dose of 1 70 gram) were performed irrespective the outcome of STs with 20 mg/mL or 200 mg/mL. The DC 71 protocol is shown in Table E1 in article's online repository. Challenge tests were performed in our 72 hospital, under direct supervision of a physician and nurses having immediate access to emergency 73 medications and equipment. A DC was considered positive only when objective symptoms could be 74 observed. 75

As shown in Figure 1 , 31 patients with a documented IDHR or NIDHR to penicillin G, amoxicillin (+/-76 clavulanic acid), or cefazolin were eligible. Two patients had positive immediate ST readings for 77 aztreonam or ceftazidime at a concentration ≤ 2mg/mL. In these patients the ST was considered 78 diagnostic (3), leaving 29 patients for further evaluation. Twenty-one out of these patients had a 79 complete work-up for both aztreonam and ceftazidime, 4 patients were tested only for aztreonam 80 and another 4 patients only for ceftazidime. Table 1 shows the patients' characteristics, ST results 81 and DC outcomes. In 72.4% of our cases (21/29), an IDHR was diagnosed. Immediate ST readings 82 were positive in 2, 10 and 5 patients for penicillin G, amoxicillin (+/-clavulanic acid) and cefazoline, 83 respectively. Four patients displayed a positive sIgE result for one or more penicillin determinants. 84

Delayed IDT readings for amoxicillin (+/-clavulanic acid) were positive in 6 patients. Two patients (# 85 6, 13) had negative serological and STs but experienced a non-immediate maculopapular exanthema recommended at the start of this study (3) (6, 7), we 96 studied NICs in 29 patients with a documented β-LAB hypersensitivity and therefore being at risk for 97 potential cross-reactivity to other β-LABs. This is in line with clinical practice, where correct antibiotic 98 stewardship in patients with a particular β-LAB hypersensitivity implies exploration of cross-reactivity 99 and identification of safe alternatives for the future. Clinical practice does not require to 100 dichotomize between patients and asymptomatic control individuals. 101

Our results show that the NICs for ceftazidime and aztreonam, as recommended in the ENDA/EAACI 102 Drug Allergy Interest Group position paper (3) and its update by Romano et al (8) , can further benefit 103 from an assessment in patients who experienced an IDHR or NIDHR to penicillin G, amoxicillin (+/-104 clavulanic acid) or an IDHR to cefazolin. In such patients we endorse the recently proposed NIC of 20 105 mg/mL for immediate ceftazidime IDTs (8). For aztreonam, we show that the NIC for immediate IDT 106 readings can be increased up to 20 mg/mL, without false-positives in our series. 107 At present, same NICs are recommended for IDHRs and NIDHRs. However, this approach is rather 108 empirical and poorly substantiated. Exploring whether other NICs apply in NIDHRs, is an interesting 109 area of research and could improve diagnostic performance STs. Indeed, for intradermal testing for 110 many drugs, the NIC of the sterile intravenous preparation of drug with readings after 15 to 30 mg/mL, a tenfold higher than for the immediate readings. 114

Admittedly, increasing the NIC entails the risk of overdiagnosis. In this respect, a limitation of this 115 study is the small number of included subjects. However, offering a DC as reference test certainly 116 adds rigor to our results and increases confidence in our findings. 117

During the interpretation of our findings, one should keep in mind that, although skin tests are 118 extensively used, there are different methods and criteria for positivity worldwide. To establish a 119 positive intradermal test result, the increase in wheal can be compared to the negative control, to 120 the positive control or to the injection bleb (4). Whether our NICs apply to these other protocols, 121 remains to be established. 122

Finally, we show that, although uncommon, cross-reactivity between (amino)penicillins and 123 ceftazidime and aztreonam exists.. 124

In conclusion, by performing drug challenges irrespective of ST outcomes with 20 mg/mL and 200 125 mg/mL, we provide evidence for the NIC for ceftazidime and for aztreonam to be as high as 20 126 mg/mL for immediate readings. For delayed readings the NIC can be increased up to 200 mg/mL. 127

Although limited, the risk of cross-reactivity between (amino)penicillins and cefazolin and ceftazdim 128 and aztreonam cannot be neglected. A drug challenge is considered positive only when objective symptoms can be observed. If symptoms occur, an allergist is attending. Nurses prepare an appropriate dose of epinephrine and antihistamines for the patients' body weight. These emergency medications are readily available at bedside.

Emergency equipment is also available.

There is easy access to the Intensive Care Unit (< 1 minute) in case this is necessary.

Patients have to stay under observation for two hours after a negative drug challenge. Skin test positive ≤ 2 mg/mL (aztreonam or ceftazidime) n = 2

No drug challenge Patients with negative skin testing for 2 mg/mL for ceftazidime and/or aztreonam n = 29

Full work-up for aztreonam and ceftazidime n = 21

Full work-up for aztreonam only* n = 4

Full work-up for cefazidime only* n = 4 *Work-up incomplete due to measures reinforced by the government to address the COVID 19 crisis (6) or due to cancellation by the patient (2) 

Update on the 142 evaluation of hypersensitivity reactions to betalactams

High serum β-lactams 144 specific/total IgE ratio is associated with immediate reactions to β-lactams antibiotics

Skin 147 test concentrations for systemically administered drugs --an ENDA/EAACI Drug Allergy Interest 148 Group position paper

Allergy diagnostic testing: 150 an updated practice parameter

General considerations for skin 152 test procedures in the diagnosis of drug hypersensitivity

Nonirritating intradermal skin test 154 concentrations for commonly prescribed antibiotics

Nonirritating 156 concentration for skin testing with cephalosporins