1. Antibiotics Shuaib Nasser Cambridge University Hospitals NHS Foundation Trust NAP6 Steering Committee member

2. Key Findings
Antibiotics most common cause of perioperative anaphylaxis in UK
35% of all cases (NMBAs ≈25% of cases)
Antibiotic anaphylaxis in 5.15 per 100,000 patients /yr receiving at least one antibiotic perioperatively
3.96 per 100,000 antibiotic administrations /yr develop antibiotic anaphylaxis
Co-amoxiclav caused17.3% and teicoplanin 13.5% of the 35% total ie 89% of all cases
Perioperative anaphylaxis incidence:
Teicoplanin per 100,000 administrations /yr, ie16-fold that of cefuroxime
Co-amoxiclav per 100,000 administrations /yr ie 9-fold that of cefuroxime
vancomycin was 3rd and piperacillin-tazobactam 4th place - distant
Most common first clinical feature was hypotension - 42% of all antibiotic cases
presented within 5 min of exposure in 76% of cases
Two fifths of the patients with a pre-operative history of penicillin allergy reacted to teicoplanin
Allergy clinics did not identify the antibiotic culprits in 25% cases due to incomplete investigations ie
skin tests and drug provocation challenges
In two thirds of cases inappropriate advice on future avoidance was given by allergy clinics
Allergy clinics may be underdiagnosing antibiotic allergy, potentially placing patients at risk
NMBAs, second leading cause, ≈25% of cases
The onset of anaphylaxis was within 5 minutes in 74% of cases, within 10 minutes in 92% and in all cases within 30 minutes
Previous history of penicillin allergy appears to be a risk factor for anaphyalxis to Teicoplanin and therefore:
This evidences the need for robust programmes to investigate and de-label, where appropriate, patients with reported history of penicillin allergy.

3. Antibiotic allergy reported pre-operatively
Allergy to
Penicillin
Cephalosporin
Other antibiotic 45 3 4 2 10
total 52 7 16
73 patients had pre-operative label of antibiotic allergy:
52 to penicillins (49 penicillin, 2 amoxicillin, 1 piperacillin-tazobactam), 3
3 also had a label of cephalosporin allergy.
7 had a label of cephalosporin allergy
16 - allergy to a variety of antibiotics including trimethoprim, co-trimoxazole, erythromycin, metronidazole, doxycycline or tetracycline.
Four of these also had a label of penicillin allergy.
One patient had a label of multiple antibiotic allergy

4. Demographics –antibiotic allergy
Only 12%<35yrs of age

5. Antibiotic culprits

6. Time interval from IV injection to first clinical feature
The onset of anaphylaxis was within 5 minutes in 74% of cases, within 10 minutes in 92% and in all cases within 30 minutes

7. First Clinical Feature

8. Clinical features
These are discussed in Chapter 10 Clinical features. The most common first clinical feature (42%) was hypotension followed by bronchospasm/high airway pressure (15%) and tachycardia (13%). During teicoplanin anaphylaxis hypotension was a dominant presenting feature with bronchospasm uncommon (Figure 5).
Considering clinical features present at any time during the episode, hypotension was universal and blood pressure was unrecordably low in a quarter of cases. Flushing/non-urticarial rash, bronchospasm/high airway pressure and tachycardia were the next most common features (67%, 53% and 50%, respectively). Bradycardia was present in 11% of cases. Table 6.

9. Grade of anaphylaxis for all antibiotics
Total
Co-amoxiclav 24 21 1 46
Teicoplanin 18 16 2 36
Cefuroxime 4
Gentamicin 3
Flucloxacillin
Piperacillin- tazobactam
Metronidazole
Vancomycin 48 43 94
*Two cases where teicoplanin and gentamicin were joint probable causes therefore 92 patients but 94 antibiotics
Severity
There were 46 (50%) grade 3 and 43 (47%) grade 4 reactions. Three (3%) cases were fatal of which two were due to teicoplanin and one co-amoxiclav.

10. Allergy clinic diagnosis of 92 cases of antibiotic anaphylaxis
92 cases of antibiotic-induced anaphylaxis were identified by the review panel
Allergy clinics considered 69 cases (50 definite) to have been caused by an antibiotic. But in some cases a single culprit was not confirmed and >2agents were recommended for avoidance
In 12 cases the review panel considered that an oral challenge had been omitted by the allergy clinic
In another 11 cases the review panel suggested IV drug provocation should have been considered
In 61 /92 cases(66%) of antibiotic allergy identified by the review panel appropriate advice on future avoidance was not provided by the allergy clinic either not given, inappropriate due to incomplete investigation of all culprits and/or no culprit identified, no safe alternatives clearly stated, excessive avoidance advice (e.g. multiple antibiotics) based on incomplete investigations
Ie. allergy clinics may be underdiagnosing antibiotic allergy potentially placing patients at risk
Culprit established by the review panel
Allergy clinic diagnosis of antibiotic allergy with high certainty
Allergy clinic diagnosis of antibiotic allergy with intermediate certainty or certainty not stated
Not investigated by Allergy clinic or culprit not identified
Antibiotic
number
% of cases established by the review panel
Co-amoxiclav 46 24
52.2% 8
17.4%
14a
30.4%
Flucloxacillin 2
100% 0%
Piperacillin-tazobactam 1
Cefuroxime 4
50.0%
Teicoplanin 36 19
52.8%
22.2% 9
25.0%
Vancomycin
Gentamicin 3
33.3%
66.7%
Metronidazole
Total 94 50
53.2%
20.2%
25.5%
In two cases both tecicoplanin and gentamicin were judged equally probable as culprits so there were 94 definite or probable antibiotic culprits

11. Antibiotic use & relative incidence of anaphylaxis
Exposure from activity survey
Use in NAP6
Cases suspected by anaesthetist
Allergic reactions in NAP6*
Incidence
Relative incidence
Estimated annual caseload
Total no
% of all cases
cases per 100,000 administrations per year
Cefuroxime = 1
Co-amoxiclav
532,580 71
26.7% 40 46
17.3%
8.64
9.16 
Flucloxacillin
211,973 12
4.5% 6 2
0.8%
0.94
1.0
Piperacillin-tazobactam
28,237 4
1.5% 3 1
0.4%
3.54
3.76
Cefuroxime
424,143 16
6.0%
Teicoplanin
219,621 62
23.3% 33 36
13.5%
16.39
17.38
Vancomycin
17,648
5.67
6.01
Gentamicin
616,899 56
21.1%
1.1%
0.49
0.52
Metronidazole
272,173 17
6.4%
0.37
0.39
Amoxicillin
Data not collected 0% -
Ceftriaxone
Ciprofloxacin
Clindamycin
Meropenem
Amikacin
Total
2,323,274
256 92
(94)#
34.6%
(35.3%)
3.96
(4.05)
4.20
(4.29)
Patients receiving at least one antibiotic
1,787,360
5.15 
5.46
The incidence of perioperative anaphylaxis to teicoplanin is considerably high at per 100,000 administrations per year, which 16-fold that of cefuroxime. Co-amoxiclav was the antibiotic with the second highest risk of perioperative anaphylaxis at 8.64 per 100,000 persons per year, 9-fold that of cefuroxime

12. RECOMMENDATIONS Institutional
Patients with reported allergy to a beta-lactam antibiotic and at least one other class of antibiotics should be referred for allergy investigation, before elective surgery, in line with NICE CG183: Drug allergy: diagnosis and management.
If antibiotic allergy is suspected despite negative skin tests, challenge testing should be considered
Broad beta lactam avoidance advice should be discouraged and patients should be further investigated to clarify the drug(s) to avoid and to identify safe alternatives.
Individual
Ninety per cent of anaphylaxis due to antibiotics presents within ten minutes of administration. When perioperative antibiotics are indicated they should be administered as early as possible, where practical at least 5-10 minutes before induction of anaesthesia, providing this does not interfere with their efficacy.
The anaesthetist should consider co- amoxiclav or teicoplanin amongst the likely culprits when anaphylaxis occurs after their administration.
Avoid test doses of antibiotic
A test dose of antibiotic should not be used, as it will not prevent or reduce the severity of anaphylaxis.
Administration of antibiotics several minutes before induction of anaesthesia will likely improve detection, may simplify treatment and will help investigation when reactions occur
Teicoplanin was administered frequently because of a history of penicillin allergy. With the knowledge that penicillin allergy is unfounded in >90% of cases, effective de-labelling of penicillin allergy would decrease overall risk of anaphylaxis.

13. Key Findings
Antibiotics most common cause of perioperative anaphylaxis in UK
35% of all cases (NMBAs ≈25% of cases)
Antibiotic anaphylaxis in 5.15 per 100,000 patients /yr receiving at least one antibiotic perioperatively
3.96 per 100,000 antibiotic administrations /yr develop antibiotic anaphylaxis
Co-amoxiclav caused17.3% and teicoplanin 13.5% of the 35% total ie 89% of all cases
Perioperative anaphylaxis incidence:
Teicoplanin per 100,000 administrations /yr, ie16-fold that of cefuroxime
Co-amoxiclav per 100,000 administrations /yr ie 9-fold that of cefuroxime
vancomycin was 3rd and piperacillin-tazobactam 4th place - distant
Most common first clinical feature was hypotension - 42% of all antibiotic cases
presented within 5 min of exposure in 76% of cases
Two fifths of the patients with a pre-operative history of penicillin allergy reacted to teicoplanin
Allergy clinics did not identify the antibiotic culprits in 25% cases due to incomplete investigations ie
skin tests and drug provocation challenges
In two thirds of cases inappropriate advice on future avoidance was given by allergy clinics
Allergy clinics may be underdiagnosing antibiotic allergy, potentially placing patients at risk
NMBAs, second leading cause, ≈25% of cases
The onset of anaphylaxis was within 5 minutes in 74% of cases, within 10 minutes in 92% and in all cases within 30 minutes
Previous history of penicillin allergy appears to be a risk factor for anaphyalxis to Teicoplanin and therefore:
This evidences the need for robust programmes to investigate and de-label, where appropriate, patients with reported history of penicillin allergy.

14. Thank you