Anaphylactic Reaction to Penicillin Case File

Anaphylactic Reaction to Penicillin Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 35

An 18-year-old primigravida at term is admitted to labor and delivery with regular uterine contractions and a history of rupture of the fetal membranes 2 hours prior to admission. She has a positive vaginal culture for group B β-hemolytic Streptococcus (GBS) noted at 36 weeks gestation and denies allergies to medications. On examination, she is afebrile, blood pressure is 110/70 mm Hg, pulse is 88 beats per minute, and she is having regular contractions every 3 to 4 minutes. Examination reveals a term size uterus with vertex presentation, fetal heart tones are detected at 140 beats per minute, and cervix is dilated to 6 cm. Amniotic fluid pooling is noted in the vagina at the time of the examination.

An IV is started, and penicillin G, 5 million units is administered intravenously for GBS prophylaxis. As the infusion of penicillin is begun, the patient complains of itching on her arms and head, and hives are noted by her nurse. Within 30 seconds, the patient becomes restless and complains of shortness of breath and dizziness. Her lungs are clear to auscultation and a diffuse urticarial rash is noted. Her pulse is noted to be 160 beats per minute and her blood pressure is noted to be 90/60 mm Hg. The fetal heart rate slows to a rate of 70 beats per minute.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 35:

Anaphylactic Reaction to Penicillin

Summary: This is a healthy 18-year-old primigravida at term gestation in labor with the acute onset of urticaria, tachycardia, and hypotension upon administration of penicillin.

➤ Most likely diagnosis: Anaphylaxis to penicillin.

➤ Next step: Discontinue penicillin infusion, begin supportive measures, and administer epinephrine.

➤ Potential complications: Maternal death, fetal anoxic injury, and death.

ANALYSIS

Objectives

1. Describe the pathophysiology of anaphylaxis.
2. Describe the clinical presentation of acute allergic reactions and anaphylaxis.
3. Describe the treatment of anaphylaxis.

Considerations

This healthy 18-year-old woman experienced the acute onset of urticaria, tachycardia, and hypotension upon intrapartum administration of penicillin. While other obstetric emergencies may cause hypotension and tachycardia (such as amniotic fluid embolism, massive pulmonary embolism, or uterine rupture), the combination of rapid appearance of cutaneous manifestations and hemodynamic compromise immediately after penicillin infusion makes anaphylaxis highly likely. 

Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. It is caused by the interaction of a specific antigen with IgE. The subsequent release of inflammatory mediators results in the acute onset of symptoms, usually within minutes of antigen exposure, including wheezing, urticaria, angioedema, flushing, itching, diarrhea and abdominal pain, hypotension, rhinorrhea, and bronchorrhea. The inciting agent may be a food, drug, latex, or insect sting. In up to 50% of cases the culprit allergen is never identified. Antibiotics are arguably the most common cause of druginduced anaphylaxis, and β-lactams account for roughly 20% of all drugrelated episodes. Anaphylaxis occurs in approximately 1 in 5000 to 10,000 courses of penicillin therapy.

Immediate intervention is similar to that in the nonpregnant patient and consists of discontinuation of penicillin infusion and provision of supportive care. An adequate airway and intravenous access are secured, aggressive fluid resuscitation begun, and the mother positioned in left lateral decubitus with

Trendelenburg in an effort to maximize venous return. Epinephrine should then be administered (0.2-0.5 mg of a 1:1000 solution intramuscularly every 5 min as needed). Second-line therapy includes diphenhydramine, ranitidine, and glucocorticoids.

In pregnancy, vasoconstriction associated with maternal anaphylaxis may precipitate fetal bradycardia. The first priority is to stabilize the mother; once this is accomplished it is likely that the fetal heart rate will recover, and labor may be allowed to continue. Emergent cesarean delivery has been described,

with varying maternal and neonatal outcomes. Successful supportive management with delayed delivery has also been reported. The optimal delivery plan will involve an assessment of the entire clinical picture once all measures have been undertaken to stabilize the mother.

APPROACH TO

Anaphylactic Reaction to Penicillin

Diagnosis

In 2006, the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium set forth clinical criteria for diagnosing anaphylaxis. Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both, and at least one of the following:

a. Respiratory compromise

b. Hypotension or associated evidence of end-organ dysfunction

2. Two or more of the following that occur rapidly after exposure to a likely allergen:

a. Involvement of the skin-mucosal tissue

b. Respiratory compromise

c. Hypotension or associated evidence of end-organ dysfunction

d. Persistent gastrointestinal symptoms

3. Hypotension after exposure to a known allergen (for adults, systolic BP < 90 mm Hg or > 30% decrease from that person’s baseline).

Pathophysiology

Anaphylactic reactions are mediated through antigen-induced IgE mast cell and basophil degranulation. Release of histamine and other inflammatory mediators causes spasm of the bronchial, gastrointestinal, and coronary artery smooth muscle, vasodilation, increased vascular permeability, and tachycardia. Wheezing, nausea, vomiting, diarrhea, myocardial ischemia, flushing, hypotension, urticaria, and angioedema may result. Intravascular fluid can be transferred to the extravascular space at a rapid rate (50% within 10 min), so aggressive volume resuscitation is imperative. The loss of intravascular volume invokes compensatory responses, which seem to have variable effects; in some patients, peripheral resistance is elevated to an exaggerated degree, and in others it falls inappropriately despite catecholamine release. From a therapeutic standpoint, it is important to remember that patients in later stages of anaphylactic shock may not respond to pressors if they are already maximally vasoconstricted. Intravenous fluid resuscitation and volume expansion is the treatment of choice in such cases.

Anaphylaxis in pregnancy has been described following laminaria insertion, exercise, induction of general anesthesia, and exposure to latex, antibiotics, iron, ranitidine, local anesthesia, insect stings, and snake antivenom. Strictly speaking, only IgE-dependent events can be termed anaphylaxis. Such a reaction to penicillin occurs when the β-lactam ring is opened and bound to protein in the penicilloyl configuration, forming an antigenic hapten called the major determinant, or when protein binds a minor product of penicillin metabolism (penicilloate or penilloate).

Immediate Management

When faced with a patient with an anaphylactic reaction to penicillin, the obstetrician’s first concern is maternal stabilization. The drug infusion should be stopped immediately, and help sought to secure an adequate airway. As described earlier, rapid fluid shifts may deplete intravascular volumes such that massive infusions of crystalloid (up to 7 L) may be necessary. Accordingly, a large (1-2 L) bolus of normal saline should be administered as quickly as possible, and multiple wide-bore intravenous access sites obtained. The gravida should be placed in the left lateral decubitus position with Trendelenburg as tolerated to promote venous return and maximize cardiac output. Oxygen may be administered by face mask or endotracheal tube as necessary, and monitors applied to assess pulse oximetry and maternal and fetal heart rates continuously. 

Aqueous epinephrine 1:1000 dilution (1 mg/mL) 0.2 to 0.5 mL intramuscularly or subcutaneously is given every 5 minutes as necessary to control symptoms and increase blood pressure. Available data suggest that the intramuscular route results in faster absorption. The preferred site is the anterior lateral thigh. In patients who do not respond, it may be given intravenously. It may be dosed intermittently (0.1-0.3 mL of 1:1000 concentration diluted in 10 mL of normal saline and given over several minutes), or as a continuous infusion. For a continuous infusion, 1 mg of a 1:1000 solution may be mixed in 250 mL of normal saline and infused at a rate of 1 μg/min to a maximum of 10 μg/min. This technique has been used in pregnancy with success.

Continuous cardiac monitoring is essential in this situation due to the risk for cardiac arrhythmia. Some controversy exists regarding the effect of epinephrine on the pregnant uterus.

Adjunctive measures include histamine receptor antagonists, inhaled β-agonists, and glucocorticoids. The combination of an H1 and H2 antagonist is superior to either one alone, but note that these are considered second-line therapy for anaphylaxis and should never be used in isolation. Diphenhydramine 25 to 50 mg and ranitidine 50 mg may be given parenterally. If bronchospasm unresponsive to epinephrine occurs, inhaled β-agonist (nebulized albuterol 2.5-5 mg in 3 mL saline) should be considered. Glucocorticoids are not usually acutely helpful, but in theory may prevent recurrent or prolonged anaphylaxis and should be used in patients with asthma or severe or prolonged anaphylaxis (methylprednisolone 1-2 mg/kg or its equivalent IV every 6 h). 

Individuals taking beta-blockers may be refractory to treatment if their response to epinephrine is blunted. Though unproven, glucagon may be helpful in such patients by independently activating adenylate cyclase to alleviate hypotension and bronchospasm. It is given in a dosage of 1 to 5 mg IV over 5 minutes, then infused (5-15 g/min titrated to clinical response). Vasopressors may be necessary to maintain blood pressure if epinephrine and fluid resuscitation fail. In the event of cardiac arrest, high-dose intravenous epinephrine is used (1-3 mg [1:10,000 dilution] administered over 3 min, 3-5 mg administered over 3 min, and then a 4-10 mg/min infusion).

Fetal Considerations

Maternal vasodilation and hypoxia will predictably lead to fetal bradycardia and eventually hypoxemia and death. Efforts should primarily be focused on stabilization of the mother, since successful maternal resuscitation will make in utero resuscitation more likely. Adverse neonatal outcomes including anoxic injury and death have been described following both emergent cesarean delivery and delayed delivery. If maternal cardiac arrest occurs, management should include continued efforts at maternal cardiopulmonary resuscitation, followed by delivery of the viable fetus within an appropriate amount of time.

Prevention of Anaphylaxis to Penicillin

It is clear that penicillin should not be given to individuals with a documented history of anaphylaxis to penicillin. Because anaphylaxis can occur in patients with no prior reaction or no prior exposure to penicillin, history alone cannot prevent all serious allergic reactions. However, since penicillin allergy is often overdiagnosed and situations arise in pregnancy where penicillins are the most appropriate or the only treatment option, it is incumbent upon the clinician to take a detailed history of the nature of past reactions to penicillin. This history should include the patient’s age at the time of the reaction and whether the patient actually recalls the reaction or was told of it by a reliable informant, the duration from penicillin exposure to onset of symptoms, the nature of the reaction, route of and reason for penicillin administration, concurrent medications, and reactions to penicillin-like medications (see diagnostic criteria for anaphylaxis earlier). It is rare for lifethreatening reactions to penicillin to present more than 1 hour following exposure.

Because of its narrow spectrum of antimicrobial activity and effectiveness against GBS, penicillin is the drug of choice for intrapartum prophylaxis. The Centers for Disease Control and Prevention guidelines for prophylaxis against GBS were revised in 2002 in the face of increasing resistance to clindamycin and erythromycin. Adherence to these guidelines now requires knowledge of the nature of a past reaction to penicillin. Penicillin and cefazolin are withheld from patients with history of immediate hypersensitivity to penicillin and those in whom anaphylaxis would be more difficult to treat (ie, asthmatics or individuals on beta-blockers). In patients who have a history of penicillin allergy but do not meet these conditions, cefazolin is given.

Skin Testing

Approximately 10% of the US population reports allergy to penicillin. It is estimated that 80% to 90% of these patients are not truly allergic. A detailed history suggesting penicillin allergy approximately doubles the likelihood that an individual will have positive skin testing to penicillin; its absence reduces this likelihood by roughly half. Skin testing is highly accurate for identification of penicillin allergy; at least 98% of individuals with a negative skin test result can tolerate penicillin without sequelae. 

Skin testing is appropriate for those patients with a history of immediate hypersensitivity reaction who require penicillin therapy. It has been performed safely during pregnancy. If an initial skin-prick test with the major determinant penicilloyl polylysine (PPL) and either penicillin G or a mixture of minor determinants is negative after 15 minutes, then intracutaneous testing is performed. A positive result is an increase in the wheal diameter of at least 3 mm compared to negative control. Negative skin testing only implies the absence of an IgE-mediated reaction and does not predict IgEindependent allergy. Patients with a history of serious but non-IgE-related allergy (Stevens-Johnson syndrome, toxic epidermal necrolysis, hemolytic anemia, hepatitis, or interstitial nephritis) are not appropriate candidates for skin testing and should continue to avoid penicillins. 

The major limitation of skin testing is that PPL has not been manufactured in the United States since 2004, and it is unclear whether or when production will resume. An alternative radioallergosorbent test (RAST) correlates only with the major determinant. A combination approach involving RAST with minor determinant skin testing may be accurate but has not been tested.

Therefore, those individuals with a history suggesting immediate hypersensitivity to penicillin who require its use (notably pregnant women with syphilis) should undergo desensitization if skin testing reagents are not available.

Desensitization

In patients with IgE-mediated penicillin allergy who require penicillin therapy, immune tolerance can be produced by administering successively increasing doses of penicillin. This process takes approximately 4 hours and should be performed in a setting where close observation and immediate intensive care are available, because adverse reactions occur in approximately 30% of patients. Tolerance lasts only for as long as the drug is given; the risk of an immediate hypersensitivity reaction returns after 24 hours and repeat desensitization is necessary. Both oral and intravenous desensitization protocols have been used in pregnancy with good results. It is important that the patient understands she is still allergic to penicillin after undergoing desensitization.

Comprehension Questions

35.1 Which of the following histories is highly suggestive of anaphylaxis?

A. Maculopapular rash beginning 5 days after PCN exposure

B. Nausea and vomiting without rash, respiratory symptoms, or hypotension

C. Urticaria and wheezing beginning 30 minutes after penicillin infusion

D. Fever and epidermal necrosis with skin sloughing requiring intensive care

35.2 All of the following are appropriate initial steps in the management of severe anaphylaxis EXCEPT:

A. Intravenous fluid bolus

B. Oxygen by face mask

C. Epinephrine 0.2 mL of 1:1000 aqueous solution IM

D. Diphenhydramine 25 mg po

35.3 A 30-year-old G1P0 at 36 weeks’ gestation arrives by ambulance, having become unresponsive 40 minutes after a bee sting. She is tachycardic, hypotensive, and stridorous. She had IV lines placed in the ambulance and is receiving fluids. The fetal heart rate is 70 beats per minute. Which of the following is the best initial step?

A. Perform an emergent cesarean delivery.

B. Give methylprednisolone 100 mg IV.

C. Position her in left lateral decubitus with Trendelenburg.

D. Begin an epinephrine drip.

35.4 A 17-year-old G1P0 is diagnosed with primary syphilis at 26 weeks’ gestation. Her mother reports she developed hives and wheezing shortly after taking penicillin as a child. Which of the following is the most appropriate next step?

A. Benzathine penicillin G 2.4 million units IM single dose

B. Doxycycline 100 mg po bid for 14 days

C. Azithromycin 2 g po single dose

D. Desensitization to penicillin and treatment with penicillin

ANSWERS

35.1 C. Idiopathic maculopapular eruptions occur in 1% to 4% of patients receiving penicillin but have many other causes, and cutaneous manifestations of anaphylaxis typically arise within minutes to hours of exposure. Gastrointestinal symptoms must be accompanied by cutaneous, respiratory, or hemodynamic signs in order to constitute an anaphylactic reaction. Fever with skin sloughing suggests a severe IgE-independent allergic reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis. 

35.2 D. Although histamine receptor antagonists may be helpful in counteracting the effects of mast cell degranulation, they are considered a second-line therapy and should not be given in isolation. The combination of an H1 and an H2 blocker is superior to either one alone. In severe cases they should be given parenterally. 

35.3 C. While this patient may require emergent delivery, the fetal heart rate may respond to efforts at maternal resuscitation, and the potential harm from emergency anesthesia and blood loss with surgery will only add further insult to her condition. Steroids may be helpful in preventing prolonged or biphasic anaphylaxis but are not useful in the acute management. Maternal stabilization with positioning to maximize venous return will make in utero resuscitation more likely. Epinephrine drip has been used successfully in pregnancy with anaphylaxis, but intramuscular injection should be tried first. 

35.4 D. This patient has a history suggestive of anaphylaxis to penicillin. Ideally, she should undergo skin testing to determine whether she can tolerate penicillin; however, since skin testing reagents are unavailable, she should undergo desensitization and treatment with penicillin. Doxycycline is not used in pregnancy because offspring exposed to tetracyclines in utero may have permanently discolored teeth. Treatment failure and resistance to azithromycin has been reported, so this is not an appropriate choice.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ The following measures constitute an appropriate response to anaphylaxis to penicillin in pregnancy:

    ➤ Discontinue penicillin infusion.

    ➤ Assess airway, breathing, circulation, and position gravida to maximize venous return (Level III).

    ➤ Give intravenous fluid bolus (1-2 L normal saline) (Level III).

    ➤ Administer epinephrine (Level II-2) or ephedrine (Level III).

    ➤ Consider histamine receptor antagonists, inhaled β2-agonists, and glucocorticoids (Level III).

    ➤ Assess response to maternal resuscitative efforts and consider delivery.

➤ Epinephrine should be given intramuscularly in the anterior lateral thigh (Level II-2).

➤ The vast majority (80%-90%) of patients who report penicillin allergy have negative skin testing, and 98% of these patients can tolerate penicillin without serious adverse effects (Level II-2).

➤ Penicillin skin testing may be performed safely in pregnancy (Level III).

➤ Since skin testing reagents are currently unavailable, desensitization is necessary if a pregnant penicillin-allergic woman requires penicillin therapy (Level III).

CONTROVERSIES

Epinephrine versus Ephedrine

Concern has been raised regarding the potential for the alpha-adrenergic stimulation associated with epinephrine to cause uterine vessel constriction, contributing to uteroplacental insufficiency and fetal hypoxia. Some authors argue that ephedrine should be the first-line therapy for anaphylaxis in pregnancy; since it is a less potent α-agonist, it may spare uterine blood flow by increasing cardiac output through β1-agonist activity. Given its popularity for treating post-anesthesia hypotension, ephedrine is readily available and familiar in the obstetric suite. For these reasons it may be appropriate to try ephedrine as initial therapy in the pregnant woman experiencing anaphylaxis. However, since epinephrine is the mainstay of treatment in severe anaphylaxis, epinephrine should be used if ephedrine does not bring about a favorable response quickly.

Steroids

The use of corticosteroids in anaphylaxis is extrapolated from their utility in treating other allergic disorders, but has not been tested in placebo-controlled trials. Biphasic anaphylactic reactions have been described, and experts postulate that steroids might prevent a prolonged or biphasic reaction. Like most aspects of anaphylaxis therapy, data demonstrating the effectiveness of steroids are lacking.

Overdiagnosis of Penicillin Allergy

It is commonplace for clinicians to accept a diagnosis of penicillin allergy without taking a history regarding the details of the reaction, thereby unnecessarily withholding penicillin from patients without a true allergy. Through careful history-taking, patients in whom anaphylaxis is highly likely may be identified. Those without such a history could probably receive penicillin safely. However, the current lack of availability of skin testing reagents makes this issue difficult to approach and may contribute to the overdiagnosis of penicillin allergy, since there is no logical next step except to choose an alternative antibiotic. In those cases for which penicillin is the only acceptable treatment, it is likely that many subjects reporting a history of penicillin allergy will undergo unnecessary, costly, and time-consuming desensitization procedures.

Cephalosporins

Although the cross-reactivity rate for penicillin and cephalosporins has been reported as 10%, the true figure is unknown. In a review of studies documenting penicillin allergy with skin testing, only 4% of skin-test positive subjects experienced cephalosporin reactions. Again, the lack of availability of skin testing means that those with a history of penicillin allergy will need to receive an alternate antibiotic, a graded challenge to cephalosporin, or desensitization.

REFERENCES

1. Chisholm CA, Katz VL, McDonald TL, Bowes WA Jr. Penicillin desensitization in the treatment of syphilis during pregnancy. Am J Perinatol. 1997;14(9):553-554. 

2. Entman SS, Moise KJ. Anaphylaxis in pregnancy. South Med J. 1984;77(3):402. This case report describes a pregnant woman who experienced anaphylaxis after receiving snake antivenin at 28 weeks. She was given multiple doses of epinephrine and other therapies. Six weeks later she delivered; the infant had evidence of intracranial hemorrhage and died at 4 days of age. The argument is made that epinephrine compromised uteroplacental perfusion, and that ephedrine is a better choice. 

3. Gei AF, Pacheco LD, Vanhook JW, Hankins GDV. The use of a continuous infusion of epinephrine for anaphylactic shock during labor. Obstet Gynecol. 2003;102(6):1332-1335. Case report of anaphylaxis to intrapartum ampicillin, treated with epinephrine in intermittent doses followed by a continuous infusion. Pharmacology of epinephrine and ephedrine are reviewed. 

4. Gruchalla RS, Pirmohamed M. Antibiotic allergy. N Engl J Med. 2006;354:601-609. 

5. Lieberman PL. Anaphylaxis and anaphylactoid reactions. In: Adkinson NF Jr, Yunginger J, Busse W, Bochner B, Holgate S, Simons F, eds. Middleton’s Allergy: Principles and Practice. Philadelphia, PA: Mosby; 2003:1497-1518. 

6. Lieberman P, Kemp S, Oppenheimer J, Lang D, Bernstein I, Nicklas R. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115(Suppl):483S-523S. An extensive, evidence-based review of anaphylaxis management with accessible algorithms. 

7. Salkind AR, Cuddy PG, Foxworth JW. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498-2505. A good review of history-taking tips, as well as the utility and limitations of history and skin testing. 

8. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-397. Latest guidelines for diagnosis of anaphylaxis, critique of the evidence behind current management, and suggested avenues for further research. 

9. Wendel GD Jr, Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med. 1985;312(19):1229-1232.

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