Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
A 32-year-old AAF is referred to the Allergy & Immunology service of a tertiary care center for penicillin (PCN) allergy and desensitization. The patient is 15 weeks pregnant and at recent obstetrics visit tested positive for RPR.
In the beginning of her pregnancy, she was given a single antibiotic injection for UTI at another hospital and developed hives and swelling of the face the next day. She was told that the shot was penicillin.
Past medical and surgical history
Four miscarriages, tubal pregnancy, right salpingoophorectomy.
Medications
Prenatal multivitamin daily.
Social history (SH)
Negative.
Physical examination
VS: Temp. 98.4 F, pulse 84 bpm, BP 110/76 mm Hg, RR 16, SpO2 99% on RA.
Skin: No rash.
Ears: Normal.
Nose: Normal.
Chest: Clear to auscultation bilaterally.
Cardiovascular: Clear S1, S2.
Extremities: No edema or clubbing.
What diagnostic tests would you recommend?
Skin testing was done with major and minor determinants of PCN.
The percutaneous skin tests were negative but the patient reacted to one of the minor determinants on intradermal skin tests (penilloate).
What treatment would you recommend for this patient?
The patient was admitted to the obstetrics unit and oral PCN desensitization was started with the original protocol published by NEJM and CDC (http://www.cdc.gov/std/treatment/2006/penicillin-allergy.htm).
She complained of severe throat itching, voice hoarseness and difficulty breathing after the third dose (penicillin V 400 U). No stridor, wheezing or unstable vital signs were noticed at that time.
How would you treat these symptoms during PCN desensitization?
The patient had symptoms of anaphylaxis.
Epinephrine 1:1000, 0.3 ml IM with Benadryl 25 mg IV and prednisone 40mg IV were given. Her symptoms resolved, she was observed overnight in ICU and was discharged home the next day.
How would you approach PCN desensitization in this patient?
A week later, the patient was pretreated with H1 and H2 antihistamines and prednisone:
- Benadryl 50 mg po q8 hr
- Famotadine 20 mg po bid
- Prednisone 50 mg po daily starting one day before the PCN desensitization
She was admitted to ICU and the obstetrics team on call was notified.
PCN desensitization was started with a modified protocol (shown below). Fetal heart sounds were monitored periodically by the obstetrics team.
Modified Penicillin Desensitization Protocol from Wendel GO Jr, Stark BJ, Jamison RB, Melina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229–32: | ||||||
Penicillin V | Concentration | mL | Units | Cumulative | ||
suspension | Time | (units/mL) | dose (units) | Reaction/treatment | ||
dose | ||||||
1 | 10 | 0.1 | 1 | 1 | ||
2 | 10 | 0.2 | 2 | 3 | ||
3 | 10 | 0.4 | 4 | 7 | ||
4 | 10 | 0.8 | 8 | 15 | ||
5 | 10 | 1.6 | 16 | 31 | ||
6 | 10 | 2.4 | 24 | 55 | ||
7 | 10 | 5 | 50 | 105 | ||
8 | 10 | 8 | 80 | 185 | ||
9 | 10 | 8 | 80 | 265 | ||
10 | 10 | 8 | 80 | 345 | ||
11 | 10 | 8 | 80 | 425 | ||
12 | 10 | 8 | 80 | 505 | ||
13 | 10 | 8 | 80 | 585 | ||
14 | 10 | 8 | 80 | 665 | ||
15 | 10 | 8 | 80 | 745 | ||
16 | 10 | 8 | 80 | 825 | ||
17 | 10 | 8 | 80 | 905 | ||
18 | 10 | 8 | 80 | 985 | ||
19 | 10 | 8 | 80 | 1065 | ||
20 | 10 | 8 | 80 | 1145 | ||
21 | 10 | 8 | 80 | 1225 | ||
22 | 10 | 8 | 80 | 1305 | ||
23 | 1,000 | 0.1 | 100 | 1405 | ||
24 | 1,000 | 0.2 | 200 | 1605 | ||
25 | 1,000 | 0.4 | 400 | 2005 | ||
26 | 1,000 | 0.8 | 800 | 2805 | ||
27 | 1,000 | 1.6 | 1,600 | 4,405 | ||
28 | 1,000 | 3.2 | 3,200 | 7,605 | ||
29 | 1,000 | 6.4 | 6,400 | 14,005 | ||
30 | 10,000 | 1.2 | 12,000 | 26,005 | ||
31 | 10,000 | 2.4 | 24,000 | 50,005 | ||
32 | 10,000 | 4.8 | 48,000 | 98,005 | ||
33 | 80,000 | 1 | 80,000 | 178,005 | ||
34 | 80,000 | 2 | 160,000 | 338,005 | ||
35 | 80,000 | 4 | 320,000 | 658,005 | ||
36 | 80,000 | 8 | 640,000 | 1,298,005 | ||
Reference for the original protocol: Wendel GO Jr, Stark BJ, Jamison RB, Melina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229–32.
What happened?
After the 8th dose of oral penicillin V (80 U), she started to complain of throat itching. Benadryl 25 mg IV was given. At this point, the dose of penicillin V was kept at 80 U given at one hour intervals for the next 14 doses.
The patient again had throat itching and discomfort at dose #24, penicillin V (200 U). Benadryl 25 mg IV was given along with one dose of nebulized racemic epinephrine.
Penicillin V doses were increased according to the modified protocol. The patient received another treatment of nebulized racemic epinephrine and Benadryl 25 mg IV at dose #29, penicillin V (6400 U). No change in BP was noticed at any point.
At the end of the protocol, after receiving an accumulating dose of penicillin V of 1,298,005 U, the patient received and tolerated benzathine PCN G 1.2 million U IM.
The treatment of syphilis infection of more than one year duration or of unknown duration, is benzathine PCN G 2.4 million U IM once a week for 3 weeks. Our patient received benzathine PCN G 1.2 million U IM per the CDC guidelines because she had already taken oral penicillin V 1,298,005 U.
What happened next?
The patient had weekly injections of benzathine PCN G 2.4 million U IM for 2 more weeks. She tolerated the therapy well.
Summary
Manifestations of beta-lactams hypersensitivity can be remembered by the mnemonic MAUS:
Maculopapular exanthema, 19%
Anaphylaxis without shock, 19%
Urticaria, 36%
Shock, anaphylactic shock, 17%
Penicillins, cephalosporins, and carbapenems share a bicyclic nucleus (beta-lactam) which conveys a cross-reactivity in immune responses to these drugs. Cross-reactivity among penicillins is virtually complete.
Management of adverse drug reactions: PAD:
Premedication with antihistamines and steroids
Avoidance
Desensitization
Desensitization is used for patients with history of IgE-mediated allergic reactions to PCN who require PCN for serious infections, e.g. bacterial endocarditis or meningitis. Different PO or parenteral protocols have been proposed.
Minimum requirements for rapid desensitization: 1-on-1 RN, CPR/ACLS, crash cart, Epi at bedside, anesthesia/code team, allergist 3 minutes from bedside.
Desensitization protocols for a medication allergy
The patient should be in a monitored environment (at least on telemetry) with IV access, epinephrine, IV diphenhydramine, O2 and resuscitation equipment at the bedside. Obtain informed consent prior to the procedure because an anaphylactic reaction during the protocol administration may result in death.
Desensitization is based on incremental dosing of the antigen q 30 min. Oral or IV regimens can be used; SC or IM regimens are not recommended. A typical desensitization protocol for beta-lactam antibiotics involves starting at a dose which is 6-7 logs below the usual therapeutic dose and increasing the dose by 1 log every 30 minutes.
Dilute drug solution/suspension to 1–3 mg/ml. Prepare three tenfold dilutions.
The success depends on constant presence of drug in the serum and so must not be interrupted; desensitization is immediately followed by full therapeutic doses. Hypersensitivity typically returns 24-48 hours after discontinuation. Minor reactions (eg, itching, rash) are common during desensitization.
Desensitization protocols are considered only for drugs such as penicillin or insulin when the use of the drug could be absolutely life-saving and no alternative exists.
Desensitization should not be attempted in patients who have had Stevens-Johnson syndrome in the past.
Classification of adverse reactions to drugs: "SOAP III" mnemonic (click to enlarge the image):
Adverse drug reactions (ADRs) affect 10–20% of hospitalized patients and 25% of outpatients.
Rule of 10s in ADR
10% of patients develop ADR
10% of these are due to allergy
10% of these lead to anaphylaxis
10% of these lead to death
References
Management of Patients Who Have a History of Penicillin Allergy. CDC.
Wendel GO Jr, Stark BJ, Jamison RB, Melina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229–32.
Penicillin allergy. Mercedes E. Arroliga, MD, Cleveland Clinic Disease Management Project.
Penicillin allergy and desensitization in serious infections during pregnancy. GD Wendel, BJ Stark, RB Jamison, RD Molina, and TJ Sullivan. NEJM, Volume 312:1229-1232 May 9, 1985 Number 19.
Diagnosis and Management of Penicillin Allergy. M. Park, J. Li. Mayo Clin Proc. 2005;80:405-410.
Is This Patient Allergic to Penicillin? An Evidence-Based Analysis of the Likelihood of Penicillin Allergy. JAMA. 2001;285:2498-2505.
Adverse Reactions to Drugs: A Short Review. Allergy Cases.
Which Cephalosporins to Use in Penicillin Allergy? Allergy Notes.
Skin testing to penicillin. Ask the expert. AAAAI, 2009.
Non IgE-mediated reaction to penicillin - AAAAI - Ask the Expert, 2011.
Diagnosis and management of penicillin allergy. Mayo Clinic Proceedings, 2005 (PDF).
Penicillin and Cephalosporin allergy - Annals of Allergy, Asthma & Immunology, 2014 http://buff.ly/1ltZntr
Multiple choice questions
Chapter 57: Drug Allergy. Allergy and Immunology Review Corner: Chapter 57 of Pediatric Allergy: Principles & Practices, edited by Donald Y.M. Leung, et al.
Published: 10/08/2008
Updated: 03/15/2012
Diagnosis and management of penicillin allergy. Mayo Clinic Proceedings, 2005 (PDF).
Penicillin and Cephalosporin allergy - Annals of Allergy, Asthma & Immunology, 2014 http://buff.ly/1ltZntr
Multiple choice questions
Chapter 57: Drug Allergy. Allergy and Immunology Review Corner: Chapter 57 of Pediatric Allergy: Principles & Practices, edited by Donald Y.M. Leung, et al.
Published: 10/08/2008
Updated: 03/15/2012
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