This document discusses using penicillin in a patient with a reported penicillin allergy. It notes that most reported penicillin allergies are not true IgE-mediated allergies and many patients can safely receive penicillins. Skin testing helps identify patients with true IgE-mediated allergy and determines safer antibiotic options. For this patient, skin testing showed no reaction so cephalosporins would likely be safe to use given the low cross-reactivity risk.

1. Is it safe to use in a patient
with ?
臨床藥學與藥物科技研究所 陳秋縈
指導老師 李佳雯醫師 林妏娟藥師
2013. 10. 30

2. Age 83
Gender Female
HT/BW 150 cm/47.5 kg
BMI 21.1
2
Social History Negative
Family History Not contributory
Drug Allergy NKDA
Past medical history
• Type 2 DM (diagnosed for 1 year)
• Hypertension
• Osteoporosis, compression fracture
of spine
• Carpal tunnel syndrome
• Knee osteoarthritis
• Cataract s/p Phaco+PCIOL at 2008
Admission date 2013/02/18
Regular medication
• Raloxifene 60mg QD
• Flurbiprofen 40mg/patch
• Metformin 500mg BID
• Nifedipine 20mg QD
• Imipramine

3. 3
Chief complaint
• Right lower leg erythematous, painful and swelling for 2 days
• Pain got worse today so she could not walk
• She went to 官田衛生所 for help and then was referred to
NCKUH
• First episode
• Denied salt water exposure, animal bite, wound, crepitus
2/18 11:55
ED
Physical examination
• Consciousness: E4V5M6
• Vital sign:
TPR 36.8/82/18, BP 163/73mmHg, SpO2: 98%
• Extremities:
right lower leg painful, swelling with a wound with clear
discharge, local heat(+), erythema(+), bullae(-+), inguinal lymph
note(+)
• Tinea pedis was noted

4. 4
檢驗項目 參考值 2/18 2/25
WBC(10^3/μL) 3.4-9.1 10.7 5.9
RBC(10^6/μL) 4.26-5.56 3.37
Hb(g/dL) 13.5-17 11.5
Hct(%) 39.1-48.9 34.1
MCV(fl) 82.6-97.4 101.2
MCH(pg) 28.5-34 34.1
MCHC(g/dL) 33.8-35.6 33.7
RDW(%) 11.9-14.3 13.9
Plt(10^3/μL) 138-353 162
Blast(%) 0
Pro(%) 0
Myelo(%) 0
Meta(%) 0
Band(%) 22
Seg(%) 43-64 73 60.9
Eos(%) 0-1 0 0.2
Baso(%) 0-6 0 0.3
Mono(%) 3-9 1 7.1
Lymph(%) 27-47 4 31.5
檢驗項目 參考值 2/18 2/25
BUN(mg/dL) 7-21 45 13
CREA(mg/dL) 0.7-1.5 0.77 0.49
eGFR 72 ≧90
AST(U/L) 0-39 51
ALT(U/L) 0-54 55
NA(mmol/L) 135-148 132 136
K(mmol/L) 3.5-5 3.5 3.6
Glucose(mg/dL) <140 269
Impression
• Right leg cellulitis
• DM
• Hypertension
• Hyponatremia

5. 5
11:55 ED Diagnosis: right leg cellulitis
TPR 36.8/82/18, BP 163/73mmHg
12:20 Penicillin skin test: negative
12:50 Ampicillin/sulbactam 3g stat & q6h IVD
14:00 呼吸平順，無不適
18:00 Ampicillin/sulbactam 3g IVD
18:20 Chin rash and maculopapular leision
Periorbital erythematous swelling
TPR 38.1/100/20, BP 166/59mmHg
DC ampicillin/sulbactam
18:45 Diphenhydramine 30mg IVD
Acetaminophen 500mg stat
21:00 發燒改善(36.9)，臉部紅疹情形仍存，無發癢不適
Moxifloxacin 400mg qd IVD & stat
Withhold imipramine due to drug drug interaction
Keep monitoring hemodynamic status for severe anaphylaxis
2/18
Interaction Severity Warning
Moxifloxacin
Imipramine
Major
increased risk of cardiotoxicity
(QT prolongation, tdp, cardiac arrest)
day1

6. 6
Event Management
• Periorbital swelling improved
• Mild fever, BT: 37.9
• Hypertension, BP: 169/70 mmHg
• Diphenhydramine 30mg IVD
• Acetaminophen 500mg stat
• Amlodipine 5mg qd
• Metformin 500mg bid
• Periorbital swelling subsided
Chin and forehead wheal lesion resolved
• Fever subsided
• Leg swelling and bulla progressed,
Edema: 4+
• Neomycin/bacitracin/polymyxin B
skin oint
• Furosemide 20mg IVD stat
• Leg: aseptic pierced bulla
 discharge culture
• BP: 165/68 mmHg
• No stool passage for 4 days
• Shift amlodipine to
nifedipine 20mg qd
• Bisacodyl 10mg supp
2/19
2/20
2/21
day2
day3
day4

7. 7
Event Management
• Leg erythema, swelling and pain
improving
•
• BP: 165/73 mmHg
• Decreased urine amount
• Urinary incontinence
• Nifedipine 20mg bid
• Furosemide 20mg IVD stat
• Bethanechol 25mg bid AC
• Lorazepam 0.5mg stat
• Leg: local heat(-), erythema(-), bulla(-)
水泡傷口結痂，無分泌物
• Shift ABX to oral form
Moxifloxacin 400mg qd AC
Discharge medication x 7 days
• Moxifloxacin 400mg qd AC
• Metformin 500mg bid
• Nifedipine 20mg qd
2/24
2/25
2/28
2/18 blood culture (-)
2/21 discharge culture (-)
3/01
day7
day8
day11
day12

8. 8
3/03
Emergency Department
• CC: Right lower leg swelling,
erythema and pain developed on
03/02 night
• No fever, chills, cough
• Tinea pedis was also noted
• Diagnosis:
Right lower leg cellulitis
Admission
• Cefuroxime 1500 mg q8h IVD
• Miconazole cream
3/01 Discharge
3/02 N/V after moxifloxacin oral intake Suspect moxifloxacin related

9. Suspect moxifloxacin
induced NV
9
Admission
Rt leg cellulitis
Discharge
2/18 19 20 21 22 23 24 25 26 27 28 3/1 3/3
Ampicillin/sulbactam 3g q6h
Moxifloxacin 400mg 1bot IVD 1# PO QD AC
Diphenhydramine 30mg stat stat
Acetaminophen 500mg 1# q6h prn
Metformin 500mg 1# bid
Amlodipine 5mg 1# qd
Nifedipine 20mg 1# qd 1# bid
Furosemide 20mg stat stat stat
Bisacodyl 10mg stat
Bethanechol 25mg 1# bid AC
Lorazepam 0.5mg stat stat
Resolved
Admission
Rt leg cellulitis
Chin rash and maculopapular leision
Periorbital erythematous swelling
Fever

10.  Overview of Penicillin allergy
 Classification
 Pathogenesis
 Case Discussion
 What is the role of penicillin skin testing ?
 Is it safe to use cephalosporin in a patient with penicillin
allergy ?
 Choice of antibiotic for our patient ?
 Take home massage
10

11.  A specific immunologic reaction to a drug, no correlation with
known pharmacological properties
 Consists of two phases
 Induction of an immune response on initial exposure
 Election of symptoms on subsequent allergen exposure
 In the absence of prior exposure
 Allergic symptoms rarely appear before one weeks
 But after sensitization
 The reaction may be rapid triggered by a drug amount that is far
below the therapeutic range
11
J Am Pharm Assoc (2003). 2008 Jul-Aug;48(4):530-40.

12. 12
Type Onset Mediators Manifestations Comments
I < 1 h IgE
Anaphylaxis
Urticaria
Angioedema
Bronchospasm
Accelerated reactions
occurring 1-72 h after
exposure may be IgE
mediated
II
(cytotoxic)
> 72 h
IgG, IgM,
complement
Hemolytic anemia
Cytopenia
Intersitial nephritis
non IgE-mediated
III
(immune complex)
> 72 h IgG and IgM
immunomplex
Serum sickness
Vasculitis
Drug fever
non IgE-mediated
IV
(Delayed,
cell-mediated)
> 72 h T-lymphocytes,
cytokines
Contact dermatitis
exanthems
non IgE-mediated
Other
(Idiopathic)
Usually
> 72 h
Unknown
mechanism
Maculopapular or
morbilliform rash
SJS, TEN, DRESS
non IgE-mediated
Delayed
Immediate

13. Penicillin-induced anaphylaxis: IgE-mediated
 Incidence: 0.004–0.015%
 Fatality rate: 0.0015-0.02%
 The most concern: life-threatening
 Responsible for 75% of anaphylactic deaths in the United States
Classification problem
 Most penicillin class antibiotic reactions involve cutaneous eruptions
 Frequency of skin reactions
Amoxicillin: 5.1%, ampicillin: 4.5%, penicillin:1.6%
 Most of these reactions were macular, morbilliform, or urticarial
 Mechanism responsible for the reaction is not clear
13
1. Bull WHO. 1968;38:159–188. III. 2. Pharmacotherapy 2007;27:542-5 3. JAMA. 1986 Dec 26;256(24):3358-63.

14. 14
Trends Immunol. 2008 Dec;29(12):633-42.
2nd allergen
exposure
1st allergen
exposure

15.  Most anaphylaxis caused by minor determinant
15
N Engl J Med. Feb 9;346(6):601-609
Penicillin
Penicilloyl
Penicilloate Penilloate
Side chain β lactam
ring
Thiazolidine
ring
Degrades
Hapten-protein complex
Physiologic
condition
Minor Determinant Minor Determinant
Major Determinant
95%
5%
Minor Determinant
Type Onset Most common cause
Immediate reaction < 1 h Minor determinant
Accelerated reaction 1-72 h Major determinant
Late reaction Usually >72 h Physiopathological
mechanism is not known

16. 16

17. Utility of patient history
 5-10% of patients self-report a history of penicillin class antibiotic
allergy
17
1. Chest. 2000;118:1106-8. 2. J Allergy Clin Immunol. 1981;68(3):171. 3. J Allergy Clin Immunol. 1999;103(5 Pt 1):918.
4. Ann Allergy Asthma Immunol. 2006;97(2):169.
May be unreliable
True allergy
Q:
Only about 10% of patient with history of “penicillin allergy”
present positive skin tests
Drug-related side effects rather than a true allergic reaction
A:

18.  Patients labeled penicillin-allergic
 more likely to be treated with broader-spectrum antibiotics
 development and spread of multiple drug-resistant bacteria
18
1. Arch Intern Med. 2000 Oct 9;160(18):2819-22. 2. Ann Allergy Asthma Immunol. 2000 Mar;84(3):329-33.
Patients with
PCN allergy
Patients without
any ABX allergy
Vancomycin 39.7 % 17.4 %
P< .001
Levofloxacin 21.5 % 8 %
P< .001
Erythromycin
Quinolone
Vancomycin
Antibiotic choices in PCN allergy

19. 19
Clin Exp Allergy. 2003 Apr;33(4):501-6.
Objective
Estimated the costs and usage of antibiotic treatment of
'penicillin-allergic' patients in comparison to non-allergic patients
in a tertiary care hospital
Method
 Retrospective review of medical records in a hospital
 118 randomly chosen 'penicillin-allergic' patients who were
hospitalized due to infection
 Match with 118 non-allergic patients who were hospitalized due
to similar cause
 Antibiotic selection and cost of the patients were compared

20. 20
Clin Exp Allergy. 2003 Apr;33(4):501-6.
The mean antibiotic cost for patients
allergic to penicillin is 63% higher than
for those not allergic to penicillin

21. Why penicillin allergy testing?
 Improved antibiotic selection
 Combating drug resistance
 Reduced antibiotic costs
Detects the presence or absence of penicillin specific IgE antibodies
(type I reaction)
 Will not detect non-IgE-mediated reactions
 ex: SJS, TEN
 IgE antibodies decrease over time
 50% of patients with IgE-mediated penicillin allergy lose their
sensitivity 5 years after reacting, 80% in 10 years
 6-12 month most sensitive
21
1. Cleve Clin J Med. 2003 Apr;70(4):313-4, 317-8, 320-1. 2. J Allergy Clin Immunol. 1999;103(5 Pt 1):918.
3. Ann Allergy Asthma Immunol. 2006;97(2):169.

22. 22
Am J Med. 2008 Jul;121(7):572-6. doi: 10.1016/j.amjmed.2007.12.005.
History of PCN allergy
No need PSTImmunologic
reaction
Yes No
Nonpruritic late
mobilliform rash
No
IgE-mediated Non IgE-mediated
Avoid the drug
Yes
PST available PST not available
Use alternative drug
or desensitize
PST + PST -
Give drug
causiously
Use alternative drug
or desensitize
History of PCN allergy
Yes No
PST positive rate 65-93% 2%

23. 23
Reagent Concentration
Major determinant
Penicilloyl-polylysine
(PPL, Pre-Pen®)
6 x 10-5 M
Commercial available
The only FDA approved skin test
1974-2004, 2009-
Minor determinants
Penicillin G 10,000 units/mL
Penicilloate 0.01 M Not commercially available
Penilloate 0.01 M Not commercially available
Positive control
Histamine 1 mg/ml
Antihistamines, TCA can inhibit skin
tests results
Negative control
Saline
Minimal reagents required: PPL, penicillin G, positive & negative control
Ann Allergy Asthma Immunol. 2008 Mar;100(3 Suppl 3):S1-148.

24.  Skin prick test (SPT)
 Should be performed first
 Both major and minor determinant are used
 Read after 15-20 minutes
 Positive: wheal size ≥ 3 mm than negative
control
 Intradermal skin test (IDT)
 Performed only if skin prick test is negative
 May induce systemic reactions
 More sensitive than skin prick test
 Positive: wheal size ≥ 4 mm than control
24
1. Mayo Clin Proc 2005 Mar;80(3):405 2. Clin Infect Dis 2001 Jun 15;32(12):1685
Positive SPT

25.  Suspected IgE-mediated accelerated reactions (1-72 h)
 Non IgE-mediated reaction? Allergy to sulbactam?
 Imipramine can inhibit skin tests results
 Should be hold several days before the test
half life: 6-18 h (elderly 25-30h)
 Inappropriate testing reagent
 IgE-mediated reaction
75-90 % caused by major determinant
15-16% caused by minor determinant (serious reaction)
 Performed with both major and minor determinants are gold
standard
25

26. 26
1. JAMA. 1993;270(20):2456. 2. J Allergy Clin Immunol. 2005;115(6):1314.
Reagent Standard Practice in Taiwan
Major determinant
Penicilloyl-polylysine
(PPL, Pre-Pen®)
V X
Minor determinants
Penicillin G V V (1000 U/ml)
Penicilloate X X
Penilloate X X
Predictive value
NPV: 97-99 %
PPV: 40-100 %
75% of PST(+) patients react only to PPL
NPV is poor without PPL
No positive and negative control
Skin testing without PPL may fail to identify many penicillin-allergic individuals
會過敏 不會過敏
陽性
陰性 偽陰: 1-3% NPV: 97-99%
陰性預測值 Negative Predictive Value (NPV)
會過敏 不會過敏
陽性 PPV: 40-100% 偽陽: 0-60%
陰性
陽性預測值 Positive Predictive Value (PPV)

27. Who need PST ? PST (-) PST (+) or unavailable
US History of IgE-
mediated PCN allergy
Give drug
cautiously
Use alternative drug
or desensitize
Taiwan ???
27
Ann Allergy Asthma Immunol. 2008 Mar;100(3 Suppl 3):S1-148.
NCKUH

28. 28
B B
Cross reaction ?

29. Limitations of the studies
 Cephalosporins were contaminated with trace amounts of penicillin
(Before 1980s)
 Loosely defined ‘‘allergy’’ (based on patient history)
 Probably a selection bias: less likely to treat with cephalosporins if
patients had more severe or recent penicillin reaction histories
 Did not consider 3-fold increased risk of ADR to any unrelated drugs in
PCN allergic patients
29
1. J Antimicrob Chemother 1975;1(3 Suppl):107–118. 2. J Infect Dis. 1978;137(Supp):S74-79. 3. Clin Anesth. 2001;13:561-564.
4. J Allergy Clin Immunol. 2004;113:1220-1222. 5. N Engl JMed 274:998–1002.
Reference
History of
PCN allergy
No history of
PCN allergy
Cephalosporins administered
Dash CH (1975) 25/324 (7.7%) 140/17,216 (0.8%) Cephalexin, cephaloridine
Petz LD (1978) 57/701 (8.1%) 285/15,007 (1.9%) Cephalexin, cephaloridine,
cephalothin, cefazolin, cefamandole

30. 30
Am J Med. 2006; 119(4):354 e311-359 ALE = allergic-like event
Source population
3,375,165 patient use PCN
534,810 patient use cephalosporin
at least 60 days later
Study group
ALE within 30 days of
PCN: 3920
Comparison group
No ALE within 30 days
of PCN: 530,890
Cephalosporin
ALE within 30 days
43 (1%)
ALE within 30 days
581 (0.1%)
Penicillin
Retrospective cohort study
United kindom general practice research database
Risk of anaphylaxis is low

31. 31
1. Pediatrics 115: 1048-1057 2. Diagn Microbiol Infect Dis. 2007 Mar;57(3 Suppl):13S-18S.
6-position 7-position 3-position
Structural differences Penicillin Cephalosporin
Sulfur ring 5-membered
thiazolidine ring
6-membered
dihydrothiazine ring
Side chains
differentiate the activity
and metabolic parameters
6-position 7,3-position

32. 32
1. J Allergy Clin Immunol. 2006 Feb;117(2):404-10. 2. Diagn Microbiol Infect Dis. 2007 Mar;57(3 Suppl):13S-18S.
Cephalosporins undergo rapid fragmentation of the β-
lactam and dihydrothiazine rings
 The resultant compounds are extremely unstable
 Rapidly form simple degradation products that do not
function as haptens
Immunologic cross-reactivity between the b-lactam rings of
these compounds should be minimal

33. 33
Otolaryngology–Head and Neck Surgery (2007) 136, 340-347

34.  A considerable body of evidence has established that cross-
reactivity is dependent on the side chain structure of these
agents rather than the core ring structure
 Between cephalosporins and penicillins
 Between different cephalosporins
34
J Am Pharm Assoc (2003). 2008 Jul-Aug;48(4):530-40
6-position 7-position
3-position
R1
R1 & R2

35. 35

36. 36
Pediatrics 2005;115;1048

37. 37
Ampicillin
Cefuroxime

38. 38
Admission Discharge
2/18 19 20 21 22 23 24 25 26 27 28 3/1 3/3
Ampicillin/sulbactam 3g q6h
Moxifloxacin 400mg 1bot IVD 1# PO QD AC
Resolved
• Chin rash and maculopapular leision
• Periorbital erythematous swelling
• Fever
Suspect moxifloxacin
induced NV
Admission
Rt leg cellulitis
2/18 blood culture (-)
2/21 discharge culture (-)

39. 39
BMJ 2012;345:e4955
Denied salt water
exposure, animal bite,
wound, crepitus

40.  Gram (-), anaerobic (usually in the presence of an ulcer)
40
BMJ 2012;345:e4955
Clin Infect Dis. 2005 Nov 15;41(10):1373-406.
Likely organisms Source Empiric IV therapy Alternative
β-hemolytic streptococci
(most common)
S. aureus
(abscess or penetrating trauma)
(evaluate risk for MRSA)
Macerated or fissured
interdigital toe spaces
IV:
Cefazolin
Oxacillin
Oral:
Cephalexin
Dicloxacillin
Amoxicillin-clavulonate
Moxifloxacin
Clindamycin
Vancomycin
Risk: Tinea pedis
Lower extremity cellulitis without evidence of abscess
 Other consideration: Diabetes
健保給付規範
10.8.2.1.Moxifloxacin (如Avelox)：(91/2/1、92/11/1、94/3/1、97/9/1)
限用於成人(18歲以上)之慢性支氣管炎的急性惡化、社區性肺炎、複雜性腹腔內感染。

41. 41
3/03 Emergency Department
• Cefuroxime 1500 mg q8h IVD
• Miconazole cream
No further fever or chills developed
during admission
3/06 • Shift to oral cefuroxime 500 mg q12h
3/11 Discharge

42.  Predict value of PST without major determinant is poor in taiwan
 Fail to identify many penicillin-allergic individuals
 Whether to dispense cephalosporin to patient with penicillin
allergies should be based on
 The type of allergic manifestations
 The specific drug prescribed: side chain similarity as a major source of
cross-reactivity
42
PCN allergy
Use other class first
cephalosporin without
similar side chain
Desensitization or
graded challenge

43. 43