Penicillin Hypersensitivity—A Review

Symposium on Anti-Infective Therapy

Penicillin Hypersensitivity-A Review Theodore H. Sher, M.D.*

Penicillin is probably one of the most commonly prescribed drugs in the world, and since the first reported death in 1949 it has been estimated to be responsible for 75 per cent of anaphylactic deaths. 21 Anaphylactic reactions to penicillin have been reported to occur in about one to five per 10,000 patient courses of treatment. 52 The incidence of anaphylactic reactions ranges between 10 to 40 per 100,000 injections, and fatal anaphylaxis occurs in approximately 2 in 100,000. 42 This may be compared with an incidence of 0.6 cases per 1000 patients of drug-induced anaphylaxis in a large group of medical inpatients.l6 A previous history of drug exposure was not always obtained, and a prior atopic condition may often be absent. Allergic reactions to penicillin range from 1 to 10 per cent, with the lower estimate reflecting the incidence in a general ambulatory population, and the higher figure reflecting select groups of high-risk patients, such as chronically ill hospitalized patients who receive frequent courses of antibiotics. 82 Adults between the ages of 20 to 49 years have been found to be at a higher risk of developing anaphylaxis, but reactions have occurred in both older age groups and infancy. 42 • 57 The decreased frequency of allergic drug reactions in children may be secondary to several factors, including fewer drug exposures, generally reduced allergic reactivity, less vigorous antibody response, and differences in drug metabolism. 61 Anaphylaxis has been reported to occur following parenteral, oral, topical, or inhalation routes.87 Parenteral administration appears the most likely route to induce anaphylaxis in man. 61 · 87 The likelihood that anaphylaxis will occur decreases as the time interval from the initial drug administration increases. 25 As many as 85 per cent of patients who previously reacted to penicillin may be able to tolerate the drug on readministration, indicating the potential transient nature of the condition. 22 In addition, many reportedly allergic reactions may in fact be nonallergic, and may be due to other etiologies such as viral exanthems. The relationship between atopic disease and penicillin allergy is unclear.38· 68, 76, 78 In one study, a history of hay fever or asthma may have been significantly more frequent in patients with penicillin reactions, al*Assistant Professor of Pediatrics, Case Western Reserve University School of Medicine; Director, Division of Pediatric Allergy, Rainbow Babies and Children's Hospital Cleveland, Ohio ·

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though the number of patients reported with this history was small. 76 More importantly, a history of prior drug reactions was more common in patients reacting to penicillin than in those who did not react, suggesting the possibility that patients who experienced reactions were more likely to do so to multiple drugs. 76 Recent reviews suggest that there is no correlation between atopic disease and penicillin allergy. In a large multicenter study of the Penicillin Study Group of the American Academy of Allergy, no correlation was found between positive skin tests and either a family or personal history of allergy. 38 Similar results were obtained by another group which found no increased prevalence of penicillin hypersensitivity in asthmatic or ragweed rhinitis subjects relative to nonallergic controls. In view of the conflicting data available, 58• 59 sex probably has no effect on the incidence of penicillin reactions. No correlation has been found between race, HLA phenotype, and penicillin allergy. 25· 58 The problem of penicillin hypersensitivity in both children and adults is probably one of the more significant health problems physicians must face. A large number of patients have been labeled penicillin allergic, and may be denied optimal antibiotic therapy for serious infection if the history alone is relied upon. The purpose of this article is to summarize the currently available information and offer an approach to the penicillin allergic patient, with special emphasis on diagnosis and management. Antigenicity Penicillin administration in man potentially may induce the synthesis of several antibody classes with distinct haptenic specificities. 10• 5 1 It may also induce a delayed-type hypersensitivity reaction, but the clinical importance of this response is somewhat unclear. 50· 69 Penicillin is a lowmolecular-weight compound, and, like most drugs, is unable to elicit an immune response unless it can combine with a large-molecular-weight carrier such as a protein, polysaccharide, or cell membrane.22, 61 The penicillin molecule contains a 6-aminopenicillanic acid nucleus, consisting of a beta-lactam structure on which antimicrobial activity depends, and a thiazolidine ring. Penicillin is unable to bind firmly enough with proteins to form an immunogenic complex, but does become immunologically active in the body when degraded into its highly reactive metabolic breakdown products. 61 When benzylpenicillin is degraded, the betalactam ring opens and reacts with tissue proteins to form the benzylpenicilloyl group (BPO), which is the major haptenic determinant. It is referred to as the "major determinant" because approximately 95 per cent of benzylpenicillin reacts in this manner. 50· 61 BPO conjugates for skin testing have been synthesized in the laboratory, by combining penicillin with polylysine (which lacks immunogenicity), acting as a carrier to form penicilloyl-polylysine (PPL). This reagent has allowed the clinical detection of BPO-specific lgE by wheal and flare reaction. 62 Since it consists of multiple penicilloyl groups coupled to a polylysine backbone, it can elicit an allergic response without having to conjugate with cutaneous proteins. 61 Benzylpenicillin can also be degraded by other metabolic pathways to form additional antigenic determinants. These derivatives are formed in relatively small quantities and are termed the "minor antigenic determinants," which account for less than 5 per cent of the breakdowns pro-

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duced.22, 50· 85 The terms major and minor refer only to the relative quantity of hapten available, and not to their immunologic importance. The minor determinants are responsible for most immediate reactions and are of considerable clinical significance. 22· 50· 51 · 52 Unlike BPO, there is no commercially available mixture for skin testing, although penicillin G has been used in several large studies as a "minor determinant mixture" (MOM)J3. 20, 38, 39 It has been postulated that the side-chain structure of the semisynthetic penicillins may add additional antigenic determinants to the penicillin molecule, but the clinical significance is unclear. 22 One study suggested that antibodies adapted to the penicilloyl nucleus would display greater cross-reactivity among semisynthetic penicillins than antibody adapted to the side chains. 8 Positive skin tests to one penicillin drug are not necessarily associated with reactions to all the penicillin drugs, indicating the heterogeneity of the immune response to penicillin in man. 84 · 85 In general, the BPO and MOM antigens will detect most but not all penicillin hypersensitivity, and lgE-mediated reactions may occur occasionally in patients with negative skin tests. Immunology Penicillin is capable of eliciting an antibody response involving all major classes (IgG, lgM, lgA, IgO, and IgE), although not all classes may participate in hypersensitivity reactions. 84 Antibodies may be detected in almost 100 per cent of individuals whether a prior history of penicillin therapy is obtainable or not and are usually of low titer, BPO-specific lgM. 50• 52 Therapeutic and prophylactic administration of penicillin constitute "known" sources of potential sensitization, but there are many "hidden" sources, such as foods treated with penicillin as a preservative, cattle treated with penicillin for infection and subsequently ingested by man, or medical personnel sensitized by penicillin particles in the air. 42 The presence of antipenicillin antibodies of any class does not necessarily indicate that an allergic response will occur upon penicillin administration. Such factors as quantity of antibody synthesized, haptenic specificity, class, and relative affinity of the synthesized antibody all reflect the marked heterogeneity of the immune response in man and help determine whether a hypersensitivity reaction will occur. 50 Immediate hypersensitivity reactions to penicillin are mediated by IgE antibody (reagin) directed against the minor determinants (MOMspecific lgE), although on rare occasions the major determinant may be responsible (BPO-specific IgE). 22· 29· 50-52 BPO-specific IgE antibodies occur approximately five times more frequently than MOM-specific lgE antibodies among patients recently treated with penicillin. 50 The rarity of BPOspecific, lgE-mediated, immediate-type reactions can be explained by several factors. In virtually all patients with BPO-specific IgE, there is also the production of BPO-specific IgG, which can act as a "blocking antibody" and compete successfully for antigen, thereby preventing or modulating antigen-antibody (IgE) binding and subsequent release of mediators. 50· 52 No such blocking antibodies have been detected for the minor determinants that could act in a similar manner. This inability to synthesize "blocking antibody" to the minor determinants has been postulated to occur be-

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cause of the relatively large antigen dose required to induce IgG synthesis. The minor determinants, which are produced in smaller quantities than the major determinant, may be incapable of inducing such a response. 25• 52 MDM-specific IgE may have unusually high binding affinity (the ability of antibody to bind antigen when a low concentration of antigen limits binding), which may explain the preferential association of immediate allergic reactions and MDM-specific IgE.l In the BPO model, the binding affinity of blocking antibody (BPO-specific IgG) may be relatively high when compared with the binding affinity of BPO-specific lgE, which may be relatively low, thereby allowing it to compete successfully. 52 Accelerated and later allergic reactions are mediated by BPO-specific IgE, which may be modified by the presence of BPO-specific IgG, especially if in sufficiently high concentrations and binding affinities. 61 Evidence for this type of interaction has been demonstrated in patients with accelerated and late urticarial reactions, where a sharp rise in lgG titer occurs within several days following the onset of the reaction, which corresponds temporally with the disappearance of the urticaria. This occurs despite continued administration of the drug and persistently positive BPO-PPL skin tests. 50· 51 Accelerated reactors have BPO-specific IgG present prior to therapy, while late reactors develop these antibodies during the course of therapy. so Other immunologic mechanisms have been implicated in penicillin reactions, but their clinical significance is not clear. Elevated titers of lgM of unusually high values (1:2000 to 1:16000) have been found in patients with maculopapular eruptions, although other immune mechanisms for the rash have been postulated. 26 This may be helpful in differentiating infectious exanthems from penicillin reactions, especially if the BPO-specific lgM titer is greater than 1:1000. 22 • 50 High titers of BPO-specific IgG and IgM have been associated with hemolytic anemia and may be of some predictive value. 22• 52 The syndrome of recurrent urticaria and arthralgia, an unusual late reaction to penicillin, has been associated with MDM-specific IgE. 50 Serum sickness-like reactions have been attributed to BPO-IgG immune complexes, and BPO-specific IgE may allow for greater immune complex deposition by release of vasoactive amines. 61 Delayed reactions in the skin have been produced by penicillin on the basis of activated lymphocytes. Approximately 15 per cent of patients with penicillin allergy have positive delayed skin tests, although the clinical significance is uncertain. 69 Delayed hypersensitivity has been suggested in mediating such reactions as drug fever, maculopapular eruptions, and local reactions as well as allergic eczematous dermatitis. 61 Clinical Manifestations Hypersensitivity reactions to penicillin have been classified generally either by time of onset or immunologic mechanism. Drs. Cell and Coombs, two British immunologists, have divided hypersensitivity reactions into four major classifications, and, although some types of immune tissue damage do not fit, they nevertheless provide a basic approach to immune mechanisms. 31 • 64 Penicillin has been implicated in eliciting hypersensitivity reactions in man corresponding to all four major classificationsnamely, anaphylactic, cytotoxic, immune complex, and lymphocyte me-

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diated. 19• 26 (Table 1). Some reactions following penicillin administration such as erythema multiforme and the Stevens-Johnson syndrome, exfoliative dermatitis, fixed drug eruptions, and erythema nodosum have not been well defined immunologically. 25 Delayed skin test reactions have been observed in penicillin-sensitive patients; in fact, cellular immunity may be responsible for clinical reactions such as drug fever, direct organ toxicity, and the late maculopapular eruptions. 61 • 69 Classification of penicillin reactions in relation to time of onset has also been used by some authors. 50 (Table 2) Hypotension and death has been reported to occur without accompanying symptoms immediately after penicillin administration. 22 There are several late reactions that involve the skin, kidneys, and blood for which the immunologic mechanism is unclear. The maculopapular rash following penicillin administration has been the subject of much speculation. The rash develops while the patient is still receiving penicillin therapy, usually between 6 to 11 days, although it may occur as early as three days or as late as 58 days. The eruption typically clears with 21 days of discontinuation of the drug, and scaling may occur. There is no accompanying evidence of fever, lymphadenopathy, or renal or cardiac involvement, unlike the syndrome of serum sickness. 51 Several mechanisms have been postulated to explain the rash, and it is possible that several mechanisms may produce the same reaction. 26 Elevated lgM antibody titers of penicilloyl specificity have been detected in approximately 25 per cent of patients with the eruptions, which suggest toxic antigen-antibody complexes. 51 Antiepithelial antibodies of the lgG class have been detected in these patients resulting from penicillin altering the epidermal proteins in a Type-11 reaction. 27 Delayed positive skin tests have been detected in some patients with maculopapular eruptions; the reaction may, in fact, be toxic and nonimmunologic in nature. 26 Penicillin is one of the more common causes of serum sickness-like reactions. The typical clinical manifestations, which include fever, rash, arthralgia, renal involvement, and lymphadenopathy usually appear 6 to 21 days following administration of penicillin and is thought to be secondary to circulating antigen-antibody complexes. 22 The responsible antibodies are largely of the lgG class, and possibly lgM, although lgE may also play a role through release of vasoactive amines which may facilitate antigenantibody deposition. 61 Patients with penicillin-specific IgE may therefore be at increased risk of developing serum sickness. When long-acting penicillin preparations are used, clinical manifestations may be delayed up to three weeks and symptoms may be prolonged several weeks rather than a Table 1. TYPE

I II

III

IV

Penicillin Reactions Accordiflg to Cell and Coombs Classification

NAME

Anaphylactic Cytotoxic

IMMUNE MECHANISM

IgE IgG

Immune complex IgG IgM Delayed Lymphocyte

IMMEDIATE SKIN TYPE OF REACTION

TEST PREDICTIVE

Anaphylaxis urticaria Coombs-positive, hemolytic anemia Serum sickness

Yes No

Contact dermatitis

No

No

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Penicillin Reactions According to Time of Onset ANTIBODY

TYPE

ONSET

ANTIGEN

CLASS

Immediate

0-1 hr

lgE

Accelerated Delayed

1-72 hr 72 hr

lgE lgE lgG

MOM BPO (rarely) BPO BPO BPO-red cell membrane

lgM/cellular

BPO

CLINICAL REACTION

Anaphylaxis, urticaria Urticaria, asthma Urticaria Coombs-positive, hemolytic anemia Maculopapular eruption

few days to a week. 61 A syndrome of recurrent urticaria and arthralgia has been described that persists from 2 to 15 weeks after the penicillin is discontinued. The syndrome may occur after either oral or parenteral therapy, and there is no evidence of fever, lymphadenopathy, or cardiac or renal involvement. Typically, the syndrome begins 3 to 21 days after penicillin is discontinued, and lgE directed against both major and minor determinants has been detected, although the minor determinants responsible for the reaction differ from those responsible for immediate allergic reactions. 50· 51 A Coombs-positive hemolytic anemia has been described in patients receiving massive intravenous doses of penicillin for one week or more. 30• 66• 71 The hemolysis is usually not acute, but if unrecognized may be life-threatening unless penicillin is discontinued. Discontinuation of the penicillin therapy is followed by complete recovery, although hemolysis may continue for several weeks to a lesser degree. Other manifestations of penicillin allergy are usually not present. The hemolysis is generally extravascular and results when antipenicillin antibodies of the IgG class interact with penicillin adsorbed on the red cell membrane; the antibodies are subsequently removed by the reticuloendothelial system. Approximately 3 per cent of patients who receive intravenous penicillin develop a direct Coombs test, although hemolysis will occur in only a small percentage of these patients. Complement components have been detected on red cells in patients with intravascular hemolysis, which is more uncommon. 71 Other reported hematologic reactions include leukopenia41 and rarely thrombocytopenia. 7 Penicillin and its semisynthetic derivatives, especially methicillin, have been responsible for acute interstitial nephritis in some patients. The clinical syndrome begins between several days to weeks after methicillin therapy is started, and consists of fever, rash, arthralgia, and renal insufficiency. Laboratory abnormalities include hematuria, eosinophilia, eosinophiluria, pyuria, proteinuria, and elevated IgE levels. 5 • 22 · 23 • 54 The overall prognosis is good if the suspected drug is discontinued, with complete recovery eventually occurring in 90 per cent of cases. 23 The exact immunologic mechanism responsible for the disease is unclear, but both humoral and cellular abnormalities have been detected, including elevated lgE; 60 deposition of IgG, C 3 , and methicillin antigen present in linear pattern against tubular basement membrane; 14 positive delayed skin tests; 14 and positive lymphocyte transformation to methicillin. 23

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SKIN TESTING FOR PENICILLIN HYPERSENSITIVITY Skin Reactions There have been numerous studies demonstrating the value of skin testing with penicillin antigens in detection of penicillin hypersensitivity in clinical practice. 3· 13· 38· 39· 52· 80· 84 Reagin-mediated hypersensitivity reactions (Type 1-Gell and Coombs Classification) can be demonstrated by immediate wheal and erythema skin tests, and are responsible for both immediate and accelerated reactions occurring after penicillin administration. Skin tests are of no predictive value in non-lgE mediated reactions, such as serum sickness, hemolytic anemia, contact dermatitis, drug fever, or maculopapular rashes. 2· 22 Newly synthesized lgE that occurs as part of an anamnestic immune response during the course of therapy and not present prior to the initiation of therapy would also not be detected during a skin test screen for penicillin hypersensitivity ..s2 The entire skin test procedure can usually be successfully and safely accomplished in a short period of time with minimal risk to the patient if simple precautions are observed. 17 · 76 There is a small but present risk in the skin-test procedure, and fatalities have been reported following both scratch and intradermal testing. 24· 42 Despite this slight risk of reaction, multiple studies have confirmed the safety of the procedure when performed by those experienced in the technique. Indications for Skin Testing The skin test procedure is not indicated in all patients who have histories of presumed penicillin allergy. Substitution of an equally effective antibiotic which is non-crossreacting is the preferred approach. Only if there is no suitable alternative drug should skin testing be performed. Skin testing must be performed immediately prior to penicillin therapy, because negative skin test results may not be valid in predicting the safety of penicillin administration months or years later. Skin Test Evaluation When the decision to administer penicillin in a patient with a history of penicillin allergy is reached, skin testing with both the major and minor determinants must be performed to detect IgE activity. The determinant, linked onto a polylysine chain to form penicilloyl-polylysine (PPL), is available from Kremers-Urban (PRE-PEN). An important minor determinant, benzylpenicillin, can be prepared in the office by the physician, although some of the other potentially important minor determinants, such as benzylpenicilloate, benzylpenilloate, and benzylpenicylloylamine resulting from the alkaline hydrolysis of penicillin, are not commercially available. 51· 52 Technique This skin test is not difficult to perform when done properly.2. 3, 13, 22· 38 · 39· 52 · 84 Benzylpenicilloyl-polylysine (PPL) is available as PRE-PEN at a concentration of 6 X 10- 5M. Certain precautions should be taken prior to and during the skin test. The physician or trained technician performing the test should be at the bedside to treat any systemic reaction or problem that arises during the

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procedure. Emergency medication and equipment to treat anaphylaxis should be prepared and available. An intravenous line is generally not necessary, although this has been recommended. 25 Antihistamines should be withheld 24 to 48 hours prior to the procedure because of their potential to ablate or blunt a wheal and erythema reaction. Moderate (less than 60 mg/day) corticosteroid therapy will not interfere in evaluating the skin tests. 2· 84 Scratch tests should precede intradermal tests to minimize the risk of severe reactions. A buffered saline control should always be placed in addition to the penicillin reagents to avoid the confusion of nonspecific dermal reactions in certain patients. The technique of scratch testing is quite simple. Several small (1 em) scratches are made through a drop of each skin test reagent on the volar surface of the forearm. Care is taken not to break the skin and induce bleeding. A 26 g tuberculin syringe needle may be quite useful in this regard. The site is then observed over the next 15 minutes for wheal and erythema formation. The solution may in some patients cause a nonspecific irritative response, but this will generally disappear by 15 minutes. If a reaction occurs, or if the result is markedly positive, the reagent should be wiped off immediately. A wheal of 3 mm or more with surrounding erythema is considered positive. If the scratch test results are negative, intradermal tests are then placed.2. 84 An intradermal bleb of 1 to 3 mm in diameter is raised that will require approximately .02 to . 04 ml of reagent. Caution should be exercised in avoiding subcutaneous administration of the reagents, which will invalidate the test. If the initial bleb is too large, a nonspecific positive result may occur. A test is considered positive if the diameter of induration is greater than 5 mm, regardless of the presence or absence of erythema, 84 or if the mean diameter of the wheal is three times the control wheal or greater. 39 Occasionally, a technical problem of classification arises in patients who develop borderline or ambiguous reactions, such as erythema, without wheal formation. Skin tests should be considered negative if no reaction occurs with both PRE-PEN and PEN G (10,000 unit/ml) when placed intradermally. Prediction Several studies have shown that penicillin skin tests are valuable in predicting patients at risk for hypersensitivity reaction to penicillin. 3• 38, 39, 52, 84 Patients with positive skin tests to Pre-Pen (PPL) have been shown to be at increased risk of developing an accelerated reaction with penicillin administration, 50, 52 although on rare occasion anaphylaxis has been reported in patients positive to the PPL skin test reagent only. 22· 28· 74 Positive skin tests to penicillin G (or the minor determinants) indicate an increased risk of immediate or anaphylactic reactions occurring with penicillin administration.S0-52 Testing with PPL and Pen G will screen out approximately 95 per cent of potential immediate and accelerated reactors; if the other minor determinants were available, this figure would approach 100 per cent. 22 Skin testing has been effective in both children and adults. 13 In patients with a prior history of penicillin allergy, the incidence of positive skin tests has ranged from 10.6 per cent to 91 per cent, depending on

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population studied, skin test reagents used, validity of history, type of reaction, onset of reaction after penicillin administration, and time interval between the reaction and testing. lB. 25, 39 Semisynthetic Penicillins Skin testing with the semisynthetic penicillins has not been as well defined as with penicillin G. The nucleus of the penicillin molecule, 6 amino-penicillanic, is present in all semisynthetic penicillins, which accounts for their cross-allergenicity. Semisynthetic penicillin administration is contraindicated in patients allergic to penicillin, and the same indications for skin testing apply. Skin tests can be performed assuming 125 mg of the semisynthetic penicillins as being equivalent to approximately 200,000 units of penicillin G. 22 Van Dellen and coworkers found a marked variability in the patterns of reactivity between the penicillins, and concluded that a positive reaction to one penicillin drug is not necessarily associated with positive reactions to all the penicillins. Skin tests with the actual semisynthetic penicillin as well as the standard reagents was found to be useful. 85 Contrary to this view, Warrington reported in his study that all patients who had positive skin tests to minor determinants of ampicillin, cloxacillin, and methicillin also reacted to benzylpenicillin minor determinant mixture, and there was no need to use antigenic determinants other than those derived from benzylpenicillin. 86 In general, skin testing performed with the actual drug to be administered may increase the likelihood of detecting a positive skin reactor. 34 Radioallergosorbent Test There have been efforts to replace skin testing with an in vitro test that would involve no risk to the patient. The RAST (radioallergosorbent test) is a very sensitive solid-phase radioimmunoassay that can detect allergen-specific IgE antibodies. 86 Specific allergen is coupled with an insoluble matrix and incubated with unknown serum. A second incubation is performed with radiolabeled antibody to IgE, and the sample is then placed under a gamma-counter where it is compared with a reference serum to determine the antigen-specific IgE in the test serum. The RAST is generally less sensitive than direct skin tests, and its specificity is limited by the specificity of the available antigens. 56 The RAST has compared favorably with benzylpenicilloyl-polylysine skin tests, but there is no available RAST for the minor determinants because of their instability. Ampicillin Penicillin and its semisynthetic derivatives all share the 6-aminopenicillanic acid nucleus, which is antigenic, and it is not unexpected that further modification in the side chain of penicillin fails to abolish the crossallergenicity of the penicillins. 78 Ampicillin was introduced into clinical medicine in 1961, and it has probably become one of the more widely used synthetic penicillins. In general, sensitivity to penicillin is a contraindication to administer any of the semisynthetic analogs. 25• 36 Ampicillin is responsible for both urticarial and maculopapular eruptions, which must be differentiated because of their therapeutic and prognostic significance. The

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incidence of urticaria from ampicillin is no higher than with other penicillins, and in two large series of patients, was found to be 1 per cent. 9 · 75 Urticarial eruptions represent true penicillin allergy, mediated by reaginic antibodies, and carry the same potential risks as do penicillin administration in a sensitive individual. The maculopapular eruption, which is much more common, has an incidence of between 5 to 10 per cent, affects females more than males, and does not correlate with a prior history of penicillin therapy, skin disease, or atopic illness in patient or family. 45 • 70• 75 Patients receiving allopurinol are at increased risk of developing the rash (22.4 per cent), 15 as are patients with viral infections, such as mononucleosis (95 to 100 per cent)63 • 67 and cytomegalovirus (100 per cent). 46 The relation between viral infections and ampicillin is not clear, and it has been suggested that the virus might alter the immunologic competence of lymphocytes involved in the reaction. 70 The eruption usually begins over the trunk and spreads to the face and extremities, particularly the extensor portions of the knees and elbows. It is described as dull, red, mildly pruritic, generally but not always sparing the palms, soles, and mucosal areas. 12• 43 • 70 Systemic manifestations typically are not present, although the rash may be more severe with coalescence of lesions, purpura, and slight fever. 4 · 70 The rash may appear within 24 hours or as late as 28 days after initiation of therapy, and remain from 90 minutes to 7 days. The rash may occur even after the drug has been discontinued. 4, 12. 45 The mechanism underlying the reaction is uncertain. Immediate skin tests to penicillin determinants have been negative, suggesting a non-lgE immunologic mechanism. 12· 43 · 45 The relatively short incubation period, negative lymphocyte transformation tests, 73 infrequency of anaphylaxis, inability to demonstrate reaginic antibodies, and the fact that patients do not necessarily develop further rash when they are subsequently given penicillin all mitigate against allergy as a cause. 4 In addition, there are no increases in lgG or lgM antibodies either during or after the eruption, making it difficult to implicate these antibodies in the pathogenesis of the rash. 45 · 49 Other theories have been advanced to explain the rash, including protein impurities produced in the manufacturing process, 47 and release of bacterial endotoxin during ampicillin therapy, 12 but these have not been proven. The maculopapular eruption caused by ampicillin is not necessarily an indication to discontinue the drug, and in itself, is not a contraindication for subsequent administration of the drug. 12 · 70 When ampicillin has been continued in the presence of the eruption, no additional adverse effects have been reported by a number of investigators, and the rash may resolve despite continued therapy. 4 · 45• 70 It is critical for the clinician to distinguish between the two types of rashes in order to avoid falsely labeling patients "allergic" to penicillin, or exposing them to the unnecessary risk of hypersensitivity reactions. Cephalosporins Cephalosporin administration to a patient with a history of penicillin allergy may potentially be dangerous because of immunologic cross-reac-

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tivity between the drugs. The drugs resemble each other chemically, being of low molecular weight, highly substituted, and possessing a betalactam ring. The drugs differ in that the five-membered thiazolidine ring of the penicillin molecule is replaced by a six-membered dihydrothiazine ring in the cephalosporin molecule. 20· 65 It is not clear whether cephalosporins form minor haptenic determinants homologous to the minor determinants of penicillin. 55 In addition, cephaloyl groups are more labile than penicilloyl groups, and may not be important determinants of hypersensitivity.22 Primary allergic reactions to the cephalosporins, including anaphylaxis, urticaria, fever, eosinophilia, and serum sickness, have been estimated to occur in 5 per cent of cases. 59 In a study of 15,708 patients treated with cephalosporins, 4. 5 per cent had a history of penicillin allergy and 8.1 per cent had an allergic reaction to cephalosporin administration. There were 15,007 patients with no history of penicillin allergy, and only 1.9 per cent had an allergic reaction to a cephalosporin, indicating a fourfold risk of developing an allergic reaction to the cephalosporins for those with a history of penicillin allergy. 65 It is difficult to determine whether the higher rate is due to cross-reactivity between the antibiotics or to some other undetermined factor. In general, patients allergic to penicillin have an increased incidence of allergy to drugs immunologically unrelated to penicillin and many have an unreliable history, which add to the difficulty of assessing the true frequency of immunologic cross-reactivity. 59 · 76 Several studies have been performed using cephalosporins as skin-test reagents. 6 • 33 · 40 Positive skin tests have been demonstrated in patients allergic to penicillin who have never received a cephalosporin. 40 Patients with a positive history and PPL skin test have an incidence of allergic reactions to cephalosporins approaching 50 per cent. 81 In patients with a clinical diagnosis of penicillin allergy, approximately one third developed positive skin tests to cephalosporins when tested. 33 If a cephalosporin must be administered in a patient allergic to penicillin, skin testing may be performed by adding 4 ml of sterile water to 1 gm of cephalothin (250 mg/ml). Concentrations of 25, 2.5 and 0.25 mg/ml are prepared using saline as a diluent. Skin tests are placed using prick technique, beginning with the most dilute solution and progressing to the most concentrated. If negative results are obtained, intradermal tests are placed until the final concentration of 25 mg/ml is achieved. If negative, administration of cephalothin can be initiated cautiously. 22 Anaphylaxis has been reported in patients allergic to penicillin who have received a cephalosporin. 74 In summary, allergic cross-reactivity between the drugs does exist, although it is quite variable and probably not extensive. 48 In a patient with penicillin allergy, cephalosporins should probably be avoided, especially if the reaction is of the immediate type, such as anaphylaxis. If the history shows less severe reactions, such as drug fever, eosinophilia, or rash, cephalosporins may be cautiously administered, and in all likelihood will be tolerated without major sequelae.22, 58, 65 Management of Patients Allergic to Penicillin When a history of penicillin allergy is present, and the drug of choice remains penicillin, skin tests should be placed. If negative results are obtained, penicillin may be cautiously administered, remembering that until

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a minor determinant mixture is commercially available, the posibility of a generalized reaction does exist, albeit small. If allergy is present or cannot be excluded by immunologic testing, some other drug without immunologic cross-reactivity should be used. Penicillin administration may be mandatory in certain cases in which there are no alternative antibiotics to treat potentially fatal disease, or when an alternative antibiotic has failed to eradicate the infection. In such cases, penicillin desensitization should be considered, although it is a potentially dangerous procedure in itself. Penicillin desensitization refers to a procedure in which a patient with penicillin allergy receives gradually increasing doses of penicillin that ultimately result in full therapeutic doses without allergic reactions. Two different mechanisms have been demonstrated by which penicillin may be administered safely to patients with lgE to drug haptens. The first mechanism involves removal of specific lgE antibody from both tissues and plasma, evidenced as loss of passively transferable IgE antibody and immediate skin reactivity. 34· 35 This is actually true immunologic desensitization, and occurs by binding of lgE antibody to the antigen derived from the administered drug. The other mechanism involves the presence of BPO-specific lgE, which act as "blocking" antibodies to prevent the interaction of antigen with cell-bound IgE. Patients may tolerate penicillin therapy for several hours despite the presence of BPO-specific IgE, only to develop urticaria as the concentration of IgG decreases with continued therapy. However, within several days, urticaria will cease when a striking anamnestic rise in IgG begins.29, 32, 34, 52 The actual procedure of penicillin desensitization varies with the level of sensitivity and route of drug administration. Desensitization has been successfully accomplished using the oral, subcutaneous, and intravenous routes. It is mandatory that trained medical personnel be present to treat any allergic emergency that might arise. At our institution, desensitization is performed in an intensive care unit, with all emergency equipment and medications available for prompt administration. Premedication with antihistamines or corticosteroids should be avoided because of the potential risk of suppressing otherwise easily treated milder allergic reactions. 22 • 25 After full doses are achieved, these medications may be helpful in managing mild or even more severe reactions. A severe reaction dictates immediate intervention. 44• 55 Once penicillin has been interrupted or stopped for more than 48 hours, the patient is no longer considered "desensitized," and future administration will require similar precautions. The subcutaneous route of desensitization described by Green has been used by many clinicians. 37 Basically, subcutaneous administration of penicillin is begun at a very low dose, depending on the sensitivity, and increased until full therapeutic doses are achieved, at which point intravenous therapy is begun. One potential disadvantage to subcutaneous desensitization is the potential sequestration of penicillin at multiple tissue sites, which will not allow systemic distribution. When intravenous therapy is begun, a systemic reaction may occur. 32 The oral route has been used by some investigators, because of the rarity of fatal anaphylaxis occurring by this route. 53· 77 One recommended technique is to begin with a very small dose of penicillin (1000 units), which is then increased over the ensuing several hours until full therapeutic levels are achieved. Parenteral

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therapy is then begun at low doses and increased as oral therapy is continued. When full parenteral doses are reached, the oral penicillin is discontinued. 61 The rate of absorption may make this route potentially dangerous. Intravenous administration has recently been recommended, allowing absolute control over rate and concentration. 32• 83 A starting dose of 5 units of penicillin or its equivalent is administered in 50 ml of 5 per cent glucose in saline over approximately 20 minutes, with the dose increased tenfold until full therapeutic doses are tolerated. 83 If a reaction occurs with this route of administration, it potentially may be more severe and difficult to control. A systemic reaction is not necessarily an indication to discontinue the desensitization. Once the patient is stabilized, a reevaluation of the situation must be made. If deemed absolutely necessary, the desensitization may be reinstituted, but at a lower concentration and slower rate of administration. Pretreatment with epinephrine, antihistamines, and corticosteroids should be considered in a patient who has experienced a major reaction during the procedure. 25 Conclusion The immunologic mechanisms responsible for penicillin hypersensitivity have been defined over the last 15 years and have permitted the clinician to use a more rational approach in both diagnosis and management. Multiple studies have demonstrated the inaccuracy of history alone in defining the at-risk patient. Skin testing allows detection or confirmation of penicillin hypersensitivity prior to drug administration and subsequent reaction. It is clearly predictive of lgE-mediated reactions in patients. PREPEN and PEN G allow detection of most, but certainly not all potential reactors, but this could be increased if the minor determinants were commercially available to all clinicians. Finally, only physicians experienced in skin testing with penicillin and desensitization should perform the procedures on patients with penicillin hypersensitivity.

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