Reviewing drug hypersensitivity and cross-reactivity in ID treatment

January 2004

When it comes to reporting their own drug allergies, patients are notoriously bad historians. Often an allergy occurred years ago, patients cannot remember the details of their reaction and they are mistaken for adverse reactions to a drug. There is no therapeutic area in which drug allergies present a greater challenge than in the treatment of infectious diseases.

Health care providers commonly contribute to this allergy confusion, often over-diagnosing antibiotic allergies without performing an adequate history of the patient’s reaction.

ß-lactam antibiotics

It has been reported that up to 10% of the United States population reports an allergy to penicillin. However, studies have shown that when “penicillin allergic” patients are skin tested, only 10% of these have IgE antibodies to penicillin. An immediate reaction to penicillin, considered a type 1 reaction, typically occurs in less than one hour of exposure with parenteral treatment, and six hours if given orally. Penicillin or its metabolites bind to IgE antibodies and the anaphylaxis process is stimulated. Common signs include laryngeal edema, angioedema, bronchospasm, urticaria, and hypotension. Death due to anaphylaxis is estimated to occur with one out of 50,000 to 100,000 administrations and is more common with parenteral use. True hypersensitivity reactions to penicillin are rare. Large studies have consistently shown anaphylaxis with penicillin to occur in one to four people per 10,000 treated.

When choosing an antibiotic for a patient with a likely history of penicillin allergy, there are several options. First, if there is an equally efficacious antibiotic with no cross-over to penicillin, there is no reason to not use that therapy. There are rare situations that warrant using penicillin even with a questionable history of allergy. An example of this would be the treatment of syphilis, where penicillin is still the drug of choice and should be used unless a history of a well-documented type 1 reaction exists. If the benefits of using a penicillin derivative outweigh the risks, a desensitization protocol can be used. Finally, if a penicillin allergy history is questionable, and is impeding therapy, skin testing for penicillin allergy can be done. This practice is not currently done on a wide scale; however its results can be highly predictive of a hypersensitivity reaction. A study of 6,739 patients reported patients with a penicillin allergy history and negative skin test results have an IgE mediated reaction only 1.5% of the time upon readministration. Although re-challenging these patients with a penicillin derivative is presumably safe, it is best to do so via the oral route and with medical supervision.

The management of a patient with a history of a cutaneous rash with penicillin is much less clear. Rashes to penicillin tend to occur greater than 72 hours after drug administration and have been reported to occur in 1% to 4% of treated patients. Rash to ampicillin has been reported as high as 9.5%. Small studies have suggested it is unlikely patients with only a history of rash with penicillin will have adverse reactions to a rechallenge. However, if other alternatives exist, administering penicillin to a patient with a history of rash is not recommended unless skin testing proves to be negative.

A common question in penicillin-allergic patients is whether a cephalosporin can be administered safely. Cephalosporins share structural similarities including the ß-lactam ring of penicillin and in vitro testing has suggested high cross-reactivity between the two classes. In practice, reactivity has been relatively low. A review of almost 16,000 patients treated with cephalosporins found that 8.1% of patients with a history of penicillin allergy had allergic reactions to this class of antibiotics and only 1.9% of patients with no reported penicillin allergy history reacted. Skin testing for allergy to cephalosporins is much less standardized than with penicillins and is of questionable clinical benefit. Patients with a well-documented history of only a maculopapular rash with penicillin are considered to be unlikely to react to cephalosporin antibiotics.

The carbapenems, including imipenem (Primaxin, Merck) and meropenem, (Merrem, AstraZeneca) are used for their broad spectrum of activity. These ß-lactam antibiotics have a ring structure similar to that of penicillin. One small study reported that 50% of confirmed penicillin allergic patients reacted to a skin test for imipenem. A review of 63 patients with reported penicillin allergy showed that 9.5% of patients who received imipenem had allergic reactions. However, it is important to note that these penicillin allergies were reported and unconfirmed by skin testing. If alternatives are available, carbapenems should be avoided in patients with a history of penicillin allergy. However, it is felt that patients with a negative skin test to penicillin can be safely treated with carbapenems.

A less immunogenic alternative to the ß-lactam antibiotics is aztreonam. Aztreonam is considered a monobactam antibiotic, which is distinguished by its monobactam ring. In vitro and human studies have shown that there is almost no cross-reactivity between aztreonam, penicillins, and cephalosporins. Ceftazidime, the only exception, shares an identical side chain and has shown some cross-reactivity potential.

Non-ß-lactam antibiotics

Sulfa allergies are another commonly reported allergy among patients. Trimethoprim-sulfamethoxazole (TMP/SMX) is still commonly used in urinary tract infections and is the drug of choice for pneumocystis carinii. Most adverse reactions with TMP/SMX are dermatologic in nature. In the general population, dermatologic adverse effects occur in about 2% to 4% of treated patients. HIV patients have the highest reported incidence of cutaneous adverse reactions to sulfonamides, with up to 60% of those treated reporting reactions. Photosensitivity is also associated with TMP/SMX and is sometimes confused for an allergy. Anaphylactic reactions to TMP/SMX are rare, however other serious reactions can occur. Patients on TMP/SMX can also develop a hypersensitivity syndrome, typically occurring after seven to 10 days, consisting of a classic triad of fever, rash, and organ toxicity. The organ most commonly involved is the liver, however renal, hematologic, and pulmonary effects can be seen. Although extremely rare, TMP/SMX remains a large cause of Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN).

Hypersensitivity reactions to macrolides, fluoroquinolones, vancomycin, and antivirals are rare and not as well documented. They are not known to share cross-reactivity with ß–lactam antibiotics.

Assessment of patient allergy

The key to assessing the relevance of a reported patient allergy is a thorough history. Questions that should be asked about an allergic reaction are shown in table 1.

The answers to these questions can assist the health care professional in determining whether the allergy was a hypersensitivity reaction, a rash, or an adverse effect of the drug.

Conclusions

In patients with one or more reported allergies to antibiotics, antibiotic selection can be challenging. Although studies have suggested that most reported allergies are not real, the possibility of fatal hypersensitivity reactions still exists. When the situation warrants, skin testing can reliably predict the risk of IgE mediated reactions to penicillin. Patients who have negative results are unlikely to have serious reactions to penicillin. The importance of taking a thorough history of a reported allergy cannot be overstated. Once an allergy is on a patient’s record, health care providers are reluctant to remove it.

For more information:

• 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.
• Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allergy Immunol. 2003;24(3):201-220.
• Segreti J, Trenholme GM, Levin S. Antibiotic therapy in the allergic patient. Med Clin North Am. 1995;79(4):935-942.
• Gruchalla RS. Drug allergy. J Allergy Clin Immunol. 2003;11:S548-S559.
• Suresh A, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol. 1995;74:167-170.
• Tilles SA, Slatore CG. Hypersensitivity reactions to non-beta-lactam antibiotics. Clin Rev Allergy Immunol. 2003;24(3):221-228.
• Gruchalla RS. Approach to the patient with multiple antibiotic sensitivities. Allergy Asthma Proc. 2000;21(1): 39-44.

• Brian C. Crandell, PharmD, is an oncology pharmacy specialty resident at the University of Colorado in Denver.