Drug allergy in cystic fibrosis

Drug Allergy in Cystic Fibrosis

Richard B. Moss

Allergy~Pulmonary Division, Department of Pediatrics, Stanford University School of Medicine, Children's Hospital at Stanford,

520 Sand Hill Road, Palo Alto, CA 95304

INTRODUCTION

In the absence of a rational therapeutic approach to the basic molecu- lar defect in cystic fibrosis (CF), contemporary therapy remains an amal- gam of variably effective empiric treatments aimed at various clinical manifestations and components of this complex and protean disease. The result is a remarkable polypharmaceutical regimen of antibiotics, pancreatic enzymes, nutritional supplements, bronchodilators, and assorted other medications. In this chapter, I will review the two components of this polypharmacy that have resulted in significant problems with allergic reactions, not only in CF patients, but also (in some cases) in their caretakers. These two components are antibiotic and pancreatic enzyme therapy. Among the antibiotics used to treat pulmonary infection in CF, antipseudomonal semisynthetic penicillin derivative and cephalosporin ~-lactam drugs have caused most of the allergic problems found in patients; accordingly, the major focus of this review will be on these com- pounds.

ANTIMICROBIALS

Beta-Lactam Antibiotics

Antimicrobial therapy is an essential component of therapy for CF lung disease, that is characterized by chronic respiratory mucosal bacterial colonization and repeated episodes ofendobronchial infection. The typi-

Clinical Reviews in Allergy, voL 9: Cystic Fibrosis Ed: E. Gershwin �9 1991 The Humana Press Inc.

211

212 Moss

cal patient receives numerous courses of oral, parenteral, or inhaled antibiotics directed against colonizing bacteria; in addition, many patients are main ta ined on long-term or continuous "suppressive" regimes of oral or inhaled antibiotics after ineradicable colonization with Pseudomonas aeruginosa. It is not surprising that given this enormous exposure a substantial problem with allergic reactions has arisen. Most reactions and reports of sensitization have been to antipseudomonal ~-lactarn antibiotics (Table 1). Immediate, IgE-mediated systemic allergic reactions to ~-lactam antibiotics occur in 1-10% of subjects during a given course of treatment, with the variation in incidence dependent upon several factors such as the subject population, drugs involved, and ascer ta inment methodology. The vast majority of these early reactions are l imited to cutaneous or subcutaneous tissues, with 2-10% involving life-threatening respiratory tract or cardiovascular system tissues. Up to 9% of the l ife-threatening reactions actually result in death, yielding a final fatality rate est imated at =1/50,000 treated subjects (1).

Reviews of penicillin allergy in general population samples consistently emphasize the inaccuracy of historical information. Anywhere from 10-73% of patients giving a history of penicillin allergy are reactive to penicillin reagents on skin test evaluation, depending upon time elapsed since the reported reaction, nature of the reaction, age of subject, and possibly other factors (1,2). Evaluation of penicillin allergy with jus t two commercially available reagents, benzylpenicillin and its majormetabolite, benzylpenicilloyl-polylysine [PPL; available at 6 • 105M concentration as Pre-Pen | Kremers-Urban, Milwaukee, WI], detects 65-93% of sensitized individuals. The remainder of allergic subjects are reactive only to minor penicillin metabolites benzylpenicilloate and/or benzylpenilloate, which are unstable and not commercially available (Fig. 1). Unfortunately, those sensitized to these minor penicillin metabolites appear to be at h igher risk of anaphylactic reactions i f reexposed to penicillin (3).

For individuals sensitized to one or more [3-1actam drugs other than benzylpenicillin, skin test evaluation and prediction of subsequent clinical reactivity becomes considerably more difficult. Major and minor metabolites of these drugs are not commercially available and oi~en are not well characterized; cross-reactivity studies between various ~-lactams yield disparate results; and clinical responses are often not predictable from skin test responses (4-9). Thus, the safest course is usually to avoid ~-lactam antibiotics and choose an alternate class of drug if at all possible (10). Un- fortunately, t reatment ofP. aeruginosa infection does not usual ly offer

Drug Allergy in CF 213

Table 1 Antipseudomonal Beta-Lactams

Penicillins

Cephalosporins

Carbapenems

Monobactams

Carbenicillin Ticarcillin Piperacillin Azlocillin

Ceftazidime

Imipenem

Aztreonam

this choice; usually, a ~-lactam antipseudomonal drug is essential and some method of evaluation and t reatment in the subject with a history of allergy to any penicillin or cephalosporin must be considered.

The following typical case report illustrates the complexity and difficulty of unders tanding and treating ~-lactam allergy in patients with CF.

Case Report J. J. is a 21-yr-old male whose CF was diagnosed at age 41/2 too. His

f irst Stanford Children's Hospital admission for respiratory symptoms of CF was in December 1968; since then, he has been seen intermittently, w i th outpatient visits and hospitalizations also occurring nearer his home, that is several hours away from Stanford. According to his mother, sometime during 1971-72 he had a cutaneous reaction to oral penicillin; this reaction was not observed or documented by a physician. In 1979, he developed a morbil l i form macula r erythematous rash while on tri- methoprim-sulfamethaxazole; the drug was stopped, the rash resolved, and he has not taken sulfa drugs since then. Between 1972 and 1986 he was treated with several ~-lactam agents, including oral cloxacillin, and at least 11 courses of intravenous carbenicillin, ticarcillin, or piperacillin, in combination with aminoglycosides without adverse reactions.

In March 1986, he developed pruri tus and urticaria on the chest and extremities during the initial infusion dose of his fii~h lifetime exposure to piperacillin. The reaction resolved with discontinuation of the drug; tobramycin was continued. The following day, he underwent intravenous desensitization to piperacillin without adverse reaction. Over the next 2 -

214 Moss

O H / ~ k . /S.~. / . C 3 & //k-- CH2-C-N H-CH-- C H C... t _ ~ I I I CH3

O=C--N CH-CO2H

0 II / S ~ /CH3

CH2-C-NH-CH--CH C I I I "cH3

HO2C NH--CH-CO2H

Benzylpenicill in

10 -2 M

Benzylpenicil loate

10 -2 M

~ / S ~ /CH3 CH2-C-NH-CH-- CH C

I I I "CH~ C=O N H--CH-CO2H

.... Jr .... NH I

(CH2)4 I

- N H - C H - C -

Be nzylpenicilloyl- polylysine

6 x 10 - 5 M (penlcilloyl)

O II .S /CH 3

CH2-C-NH-CH2--CH ~'C~

- I 1 -c'~ NH --CH -CO2H

8enzylpenil loate 10 . 2 M

Fig 1 Structural relationships of penicillin-derived reagents used for skin testing.

3 d, however, he complained of intermittent pruritus without visible urticaria which was treated with diphenhydramine, allowing him to fin- ish the treatment course.

On his next admission in November 1986, he was desensitized without incident to ticarcillin (his first lifetime course); he also received tobramycin. However, pruritus occurred the day after desensitization that required treatment for 24 h with diphenhydramine. After 10 d, a fixed macular eruption appeared on his abdomen. Ticarcillin was stopped. He was again treated with diphenhydramine and the rash resolved within 24 h. Tobramycin was given throughout.

His next admission was March 1987. At this time, he was desensitized to Timentin| (ticarcillin-clavulonate); he also received tobramycin. Upon infusion of the last and highest desensitizating dose of Timentin, he developed wheezing and urticaria on the legs. Timentin was stopped and diphenhydramine given. Two days later, he was desensitized to cef~azidime without adverse reaction and received ceftazidime and tobramycin for a full treatment course. He received a second course of tobramycin and ceftazidime after desensitization in October 1987.


In August 1988, he was evaluated by skin testing. Prick tests to PPL and minor determinant mixture were both positive with a 3.5 m m mean wheal diameter at 15 rain for each; there was a 1.5 m m wheal with buff- ered saline negative control. Intradermal testing with ticarcillin (20 ~tg/ mL) was also positive with a 9 m m wheal compared to a 5.5 m m wheal with the negative control. Intradermal tests with four aztreonam reagents (fresh native aztreonam in 0.21% arginine buffer, an open ring hydrolysis metabolite of aztreonam, the polylysine conjugate of this metabolite, all at 6 x 10-3M, and buffer alone) were negative. He was treated with aztreonan, tobramycin, clindamycin, and ciprofloxacin without adverse reactions. He received a second course of aztreonam and tobramcyin without incident in July 1989.

Incidence and Diagnosis Sensitization to penicillin in CF patients was first reported in 1970

by Rourk and Spock, who found positive skin tests to pencillin in 4/35 (11%) of their CF patients. No information regarding clinical allergies or other evaluation was given (11). Patterson and Snyder reported that 15% of CF patients treated with dicloxacillin had unspecified rashes (12).

In 1980, Moller et al. noted that 16 of 84 CF patients (19%) treated repeatedly with carbenicillin developed rashes, mostly pruritic exanthems with or without urticaria. Immunologic evaluation included immunoas says for IgG, IgM, and IgE antibodies against carbenicillin; leukocyte histamine release by carbenicillin; prick skin testing with 100 mg/mL carbenicillin; and RAST using hapten-carrier conjugates of benzylpenicilloyl-human serum albumin [HSA], phenoymethylpenicilloyl-HSA, carbenicilloyl-HSA, ampicilloyl-E, coli acylase, and benzylpenicillin fermentation products as allergens coupled to the solid phase. All these tests were negative. All the patients had negative prick tests and subsequent oral challenges with phenoxymethyl-penicillin. The authors concluded that the carbenicillin rashes were not because of IgE- or IgG-mediated reactions (13). There are a number of problems with this paper, however. First, it is not clear when reactions began in relation to the t reatment course, except for two patients reacting during the first and second infusions, respectively. This leaves open the possibility that delayed reactions, which are less likely to be mediated by antibodies, were being studied. Second, the use of only one reagent, native carbenicillin, at one epicutaneous concentration, may have missed other specificities of IgE antibodies or low levels of carbeni-

216 Moss

cillin-specific IgE. Third, the lack of IgG or IgM antibodies is puzzling because most studies show that intravenous expo sure to penicillin results in a detectable immune response in most subjects. Fourth, other inves- tigators have consistently demonstrated positive skin tests in clinically allergic and even nonallergic CF patients.

Indeed, in 1982, Brown et al. described an 11 yr-old boy with CF who reacted to a first dose reexposure infusion ofticarcillin. In t radermal skin tests to PPL, a 1:10,000 dilution of minor determinant mix, and 1:10,000 ticarcillin were strongly positive. He was treated successfully with intravenous desensitization, and skin test reactivity reverted to negative with desensitization (14).

In a retrospective survey in 1982, we documented immedia te systemic allergic reactions during 11 of 179 courses (6%) of intravenous ant ipseudomonal penicill in therapy with carbenicillin, ticarcillin, or piperacillin in 8 of 74 (10.8%) patients hospitalized at the Stanford CF Center (15). Reactions were usual ly seen in older patients with a history of mult iple prior exposures. Reactions always included cutaneous components (pruritic erythema, urticaria, and/or angioedema); respiratory tract involvement occurred in a minority of systemic reactions, but could be quite severe with bronchospasm or laryngeal edema. Cardiovascular symptoms and signs were rare.

Prick and in t radermal skin tests were later performed in all clini- ically allergic Stanford CF patients with benzylpenicillin, PPL, and the pr imary drug causing the reaction. All 11 patients tested were skin test- positive, four at 1:100 drug dilution, and seven with undiluted drug. Nine were positive to the primary drug (three to the primary drug only), whereas one patient was skin test-positive only to PPL and the last pat ient was skin test-positive only to benzylpenicillin. RAST tests to benzylpenicilloyl HSA and phenoxyme-thylpenicilloyl-HSA were positive in eight of 14 patients tested (15).

Our study had a number of shortcomings. First, we did not perform skin tests on a control group of CF patients who were not clinically allergic to semisynthetic penicillins. Thus, some of the skin test positive results could have been caused by nonspecific irritative reactions. However, the pat tern of reactivity as well as the classic wheal-and-flare nature of the skin test reactions make us doubtful that this is the case. Second, we did not perform RAST inhibition assays to prove the specificity of the RAST reactivity. However, control RASTs onnonallergic subjects with or without CF were consistently negative.


In preliminary reports, Hilman and Rao noted allergic reactions in seven of 31 (22.5%) of CF patients treated repeatedly with azlocillin. Prick and intradermal skin tests with PPL were negative (16). Galant et al. conducted a study of 23 CF patients, eight of whom had a history of systemic allergic reactions to semisynthetic penicillins, and 18 nonCF controls. Prick and intradermal skin tests with PPL and 10-2M benzylpenicillin, penicilloate, penilloate, ticarcillin, and cefoperazone were performed. Reaction rates were higher in CF patients than controls (30 vs 5.6%) with benzylpenicillin yielding the greatest number of skin test reactions. However, there was no significant difference in the incidence of skin test reactivity between the CF patients with a history of reactions and those without such a history (17). The study of Galant et al. seems to confirm the propensity of CF patients to mount IgE antibody responses to ~-lactam drugs as it questions the pathogenic role of these antibodies.

Earl and Sullivan reported an unusual case of multiple drug allergy in a 15-yr-old girl with CF who had urticarial reactions to tobramycin, gentamicin, cefaclor, and cefoperazone, and an anaphylactic reaction to ticarcillin. Skin test evaluation showed positive intradermal reactions to tobramycin (40 pg/mL) and PPL, with negative-reactions to benzylpenicillin, penicilloate, cephalothin, and ticarcillin. Tobramycin at concentrations up to 4000 pg/mL did not cause whealing responses in four nonallergic subjects (18). This is the only reported case of apparent IgE- mediated aminoglycoside allergyin a CF patient and highlights a tendency for subjects who are allergic to a ~-lactam drug to have an increased rate of sensitization (by IgE-mediated or other mechanisms) to immuno- chemically non-related drugs (2,19).

To further investigate the basis for ~-lactam allergy in CF patients, we recently conducted a multicenter evaluation of the allergenicity, immunogenicity, and crossreactivity of aztreonam in 19 CF patients with a history of allergy to other ~-lactam agents (20). Aztreonamis a monobactam antibiotic and shares the basic ~-lactam ring with antipseudomonal carboxy- and ureidopenicillins. It also contains a large aminothiazole side chain similar to that of the antipseudomonal cephalosporin ceftazidime (Fig. 2) (21). Studies in animals and in patients without CF have indicated that aztreonam may be less immunogenic than other ~-lactam antibiotics (22,23). On the basis of in vitro studies demonstrating a. weak immunogenicity ofaztreonam, b. noncrossreactivity of IgE antibodies raised against other ~-lactam drugs with aztreonam, and c. selective induction ofnon- crossreactive side-chain specific antibodies by aztreonam, it has been

218 Moss

Penicdlins

CeDhalosoonns

MonoDactams

0 It

R--C--NH . S - ~

0 / ~ N ~" COOH

0 II

R--C - - N H ~ , S~

o ~"---- N ~ R' COOH

0 II

R--C--NH%

C ~ C ~ N S

NH O u::~--'N----UCOOH I C=@ I

o

.m7-i--!--..--_-/\ a,/ H~N ~ o i H~ o - - - --coo~ ~ooe I

CEFTAZIDIME c.~

C~3

c,~:j o-.mc --coo.

I AZTREONAM zH:~

Fig. 2. Structural relationships of penicillin, cephalosporin, and monobactam antipseudomonal ~-Iactam antibiotics.

proposed that aztreonam may be suitable for use in patients clinically allergic to other ~-lactam antibiotics (24). In several patients without CF who were allergic to another ~-lactam drug, aztreonam was safely administered without formal desensitization, suggesting that aztreonam may not be crossreactive in Vivo (25,26).

In our study, prick and intradermal skin tests with PPL, minor determinant mixture, and 20 pg/mL and two mg/mL concentrations of the drug responsible for the most recent previous allergic reaction (piperacillin, azlocillin, or ceftazidime) were positive in 26, 53, and 79% of these 19 subjects, respectively. The overall 89% rate of skin test positivity was higher than in other series and is almost certainly the result of the unique character of the history of drug allergy in CF patients. These reactions are almost always in-hospital, physician-observed, well-characterized and documented generalized immediate-onset cutaneou.~+respiratory tract hypersensitivity reactions. The two skin test-negative cases most likely represented time-dependent waning of drug hypersensitivity rather than false-positive history. Eighteen of the 19 patients had negative aztreonam reagent skin tests (see case report above), but one patient who had never received aztreonam had positive skin tests to determinants of this drug.


Three of 18 patients who were initially skin test-negative to aztreonam became clinically sensitized by subsequent treatment with aztreonam and were skin test-positive on repeat testing. We thus found a 5.3% rate of preexisting crossreactivity between IgE antibodies to aztreonam and other ~-lactam drugs in vivo in CF patients, and a 16.7% incidence of clinical sensitization to aztreonamin CF patients allergic to other ~-lactam drugs (20).

The skin test evaluation pattern showed that 15 ofl 7 (88%) skin test- positive patients reacted to the primary drug responsible for the most recent allergic reaction. In five cases, the primary drug produced the only positive skin test reaction. Ten patients were positive to the minor determinant mixture, whereas only five were positive to PPL. These results suggest that ~-lactam allergy in CF is mainly drug-specific, perhaps caused by side chain epitope immunodominance. This situation differs radically from other penicillin allergic patients in the literature, whose reaginic hypersensitivity appears mainly directed to determinants on the bicyclic PPL nucleus. It is essential to remember, when pondering this difference, that the exposure history of CF patients also greatly differs from most non-CF patients previously reported and is the most likely source of the differing pattern of reactivity, although intrinsic differences in immuno- reactivity cannot be excluded.

At present, the mechanism of clinical sensitization to ~-lactam antibio tics in CFpatientsis still unclear. The pattern and nature ofreactivity suggest induction of drug-specific IgE antibodies in most cases, but formal proof via detection of circulating drug-specific IgE antibodies is lacking. We were unable to demonstrate PPL- or aztreonyl-specific IgE antibodies in multiple blood samples from these patients when RAST was combined with RAST inhibition, although we did find PPL-speciflc IgG in sera from a majority of the patients (20). Certainly, the possibility of increased tissue mast cell releasibility triggered by low levels of drug-specific (and variably cross-reactive) IgE antibodies is suggested by most studies conducted to date. It is clear that crossreactivity between various [3-1actam drugs occurs in vivo, and that any ~-lactam including monobactams like aztreonam may induce clinical hypersensitivity in CF patients. It is not currently possible to predict which CF patients will become sensitized, although it is clear that multiple courses, high doses, and the intravenous route of drug exposure are key elements in sensitization. Finally, the pattern of skin test reactivity at a given time cannot be used as a guide to the safety of choosing a particular ~-lactam drug for therapy. Patients

220 Moss

may become sensitized during or between any given course of antibiotic therapy.

Table 1 gives a suggested protocol for the diagnostic skin test evaluation of patients with a history of an allergic reaction to any ~-lactam agent. Skin tests are useful in determining the validity of a past history of~-lactam drug allergy and the necessity for desensitization prior to treatment. Unless conducted for research reasons, skin tests should be performed immediately prior to contemplated treatment, since the results represent only a static snapshot in a dynamic process of sensitization and tolerance.

Treatment

Acute. Penicillin has long been successfully given to high-risk, history-positive, skin test-positive patients by parenteral (intra-dermal, subcutaneous, and/or intravenous) administration of gradually increasing doses under close observation for adverse effects, a process termed desensitization (27). Chiarmonte and Pinsker described application of this approach to P. aeruginosa infection using the semi-synthetic penicillin derivative carbenicillin (28). Problems with allergic reactions during or shortly after completion ofparenteral desensitization in some patients led Sullivan and colleagues to develop an alternative oral route of desensitization. In the first 30 patients so treated, 21 received oral benzylpenicillin prior to therapy with intravenous benzylp enicillin or oxacillin, and eight were desensitized with oral carbenicillin prior to iv carbenicillin therapy. Adverse reactions were limited to pruritic cutaneous rashes in 30% of patients 6-48 h after onset of therapy (29). Further reports on oral desensitization by Sullivan's group broadened successful application to pregnant women, critically ill patients, and patients with serious, but not life-threatening, infections (30,31).

The immunologic mechanisms involved in clinical desensitization are still unclear. Gorevic and Levine showed that iv desensitization with carbenicillinin a patient allergic to benzylpenicilloate and the penicilloate derivative of carbenicillin antigens resulted in loss of circulating peni- ciUoate-specific IgE antibodies as well as skin test reactivity (32). Pro- duction ofspecific'%locking" IgG antibodies occurs in desensitized patients, but kinetics and magnitude of response can lag behind or dissociate from induction of clinical tolerance (32). Using abatteryofdrugandaeroallergen antigens, as well as nonimmunologic mast cell degranulating agents, Sullivan showed that oral desensitization with benzylpenicillin, nafcillin, and carbenicillin in three patients was associated with an antigen-spe-


cific loss of skin test reactivity, whereas reactivity to heterologous antigens and nonspecific mast cell degranulating stimuli remained intact (33). Thus, tachyphylaxis to mediators, mast cell mediator depletion, or unresponsiveness to generalized IgE-mediated signals could be excluded, leaving either interference with specific cell-fixed IgE antibody-drug in- teraction and/or delivery of the antigen-antibody crosslinking signal to the mast cell, as potential mechanisms. This could occur via cellular desensitization or via competition by free drug or univalent noncross- linking drug-carrier conjugates with multivalent (crosslinking) conjugates for cell-fixed IgE antibodies on the mast cell surface.

However, caution in extrapolating from skin test responses to clinical tolerance is necessary, as divergence of skin test and clinical responses has been noted. For example, a penicillin allergic patient clinically tol- erant to maintenance oral penicillin following parenteral desensitization showed reemergence of skin test-positivity to penicilloate antigen (34). Such discrepancies apparently indicate a dynamic balance between sensitization and tolerance that appears to be dose-dependent.

A fascinating recent study by Pienkowski and colleagues shows that the desensitization phenomenon is even more complex and less well understood than previously supposed. Blood basophils from a PPL-allergic patient obtained after clinically effective iv desensitization showed no reduction in either nonspecific or PPL-specific histamine release in vitro, despite loss of skin test reactivity to PPL. Moreover, PPL-specific IgE antibodies persisted in serum, and PPL-specific IgG antibodies did not rise significantly after desensitization. Hapten inhibition and loss of circulating drug allergen in blood were ruled out. In fact, the patient's serum was able to release histamine from nonallergic donor basophils passively sensitized with anti-PPL IgE in vitro (35).

When considering the question of desensitization in CF patients, we continue to be impressed by several advantages of iv desensitization compared to the oral route (36). First, as stressedby several others (32,37), only the iv route allows control of the dose and rapidity by which the drug enters the circulation. After oral, subcutaneous, or intradermal administration of drug antigen, variable and unpredictable further absorption will occur after a reaction has begun. During iv desensitization, the earliest signs of a reaction can be, at least in part, immediately managed by slowing or stopping the infusion. Second, oral absorption of penicillin or other drugs may be altered in CF patients by pancreatic insufficiency, intestinal mucosal transport abnormalities, or other gastrointestinal

222 Moss

pathology. Third, the pattern of skin test responses in [3-1actam-allergic CF patients suggests that the most effective desensitizing agent can be none other than the homologous drug itself. For most antipseudomonal [3-1actam antibiotics, only iv preparations are available for homologous desensitization. Finally, we must consider that the only reported failure of oral desensitization employing Sullivan's protocol in a total of 71 patients occurred in the single CF patient treated in this fashion (18, 29--31).

We therefore continue to desensitize allergic CF patients intravenously according to a specifically designed protocol (Tables 2 and 3). Ex- perience with >125 such procedures since 1983 has shown that pruritic cutaneous rashes occur in -25-30% of cases, often during or just after the last and highest desensitizing dose. Such mild reactions are treated with slowed infusion rates and parenteral diphenhydramine. Nonlife threatening systemic reactions involving subcutaneous and/or respiratory tract tissues are treated similarly, with a case-by-case addition of adrenergic agents and ongoing diphenhydramine administration prior to each dose oflactam antibiotic appropriate to the individual problem.

Life-threatening anaphylactic reactions occur in 1-2% of cases and require immediate appropriate management and discontinuation of desensitization. In virtually all cases,iv desensitizationwith another ~-lactam antibiotic has been successfully performed 24 48 h after the patient has been stabilized. In one recent case, a woman who had twice failed desensitization with azlocillin, and who was very ill from severe pneumonia with P. aeruginosa and resistant to all other ~-lactam antibiotics, was successfully desensitized and treated with azlocillin after pretreatment with iv methylprednisolone, diphenhydramine, and cimetidine. The pro- phylactic drugs were successfully tapered and stopped 3-5 d after desensitization without adverse reactions. However, further experience is necessary before conclusions regarding the potential efficacy of combined HI-, H2-receptor blockade and corticosteroid drug prophylaxis for patients with histories of desensitization failure can be made.

Chronic. Brown et al. reported that partial clinical tolerance and antigen-specific skin test desensitization was maintained for several months in an 11-yr-old boy with CF by treatment with continuous oral penicillin (250 mg b.i.d.-t.i.d.) after successful iv desensitization with ticarcillin (14). Naclerio et al. confirmed that such long-term tolerance could be maintained, and also that such tolerance appears to be partial at best and dependent on the dose of the tolerogenic drug (34). We at- tempted to reproduce these encouraging results in six intravenously de-

Drug Allergy in CF

Table 2 Beta-Lactam Drug Allergy Skin Test Reagents and Procedure

223

A. Reagents and concentrations

1. Major penicillin metabolite: benzylpenicilloyl (Pre-pen| Kremers-Urban, Milwaukee WI) at 6 • 10-5M.

2. Minor penicillin determinant mixture: Penicilloate and penilloate, each at 10-2M. �9

3. The [~-lactam drug to be used for t rea tment at 20 ~g/mL and, if negative at this dose, 2 mg/mL.

4. Negative control: Physiologic saline pH 7.4. 5. Positive control: Histamine phosphate 2.75 mg/mL (Lilly, Indianapolis,IN). 6. Optional (for documentation): ~-lactam drug causing previous allergic re-

action, as in #3. 7. I f any ~-lactam tests are positive, t reat by iv desensitization."

B. Procedure

1. Perform skin tests on volar forearms to allow tourniqueting if necessary. 2. Test all reagents with epicutaneous prick test first. If prick test is negative,

proceed to intradermat test with that reagent. If prick test is positive, do not do intradermal test. Multiple tests may be applied concurrently but only prick tests should be placed as a group.

3. Read and record results at 15 min by measur ing largest and orthogonal wheal diameters and averaging the two values. Wheals >3 ram>negative control with erythema are considered positive.

4. Have equipment, medication and personnel available to t reat systemic reactions.

5. Skin testing is of greatest utili ty just prior to contemplated drug t rea tment , and diminishes as time lapses between testing and t reatment .

6. Skin tests may yield false-negative results up to two wk following a systemic allergic reaction ("refractory period").

"Not commercially available. Fresh benzylpenicillin may be substituted with 5-10% loss of diagnostic sensitivity.

"'Negative skin tests to the treatment drug does not rule out a reaction if penicillin metabolite test(s) are positive. Negative skin tests to all drug reagents does not rule out a reaction but re- duces risk of immediate systemic reaction to general population background (3-5%), obviating need for desensitization.

sensitized CFpatients using oral dicloxacillin (250-500 mgb.i.d.-t.i.d.) for maintenance of tolerance. In two patients, allergic reactions requiring discontinuation of dicloxacillin occurred with one wk; in two others, subsequent allergic reactions to iv piperacillin required repeat iv desensitization (15). Stark et al. successfully maintained tolerance in seven desensitized allergic patients with >b.i.d. oral phenoxymethyl penicillin or cloxacillin for three wk to over 24 mo, stating that"no lapses in therapy

224 Moss

Table 3 Cystic Fibrosis Intravenous Desensitization Protocol

for Treatment of Exacerbated Pseudomonas Endobronchitis

1. Begin aminoglycoside therapy 24 h prior to desensitization and observe for any reactions.

2. Obtain properly documented informed consent. 3. Indicate desired treatment drug. 4. Indicate full therapeutic dose and interval to be administered after desensi-

tization. 5. Assign 1:1 nursing care with assessment of vital signs q 15 min through

procedure; assure immediate MD coverage for t reatment of reactions during procedure.

6. Order resuscitation equipment and drugs at bedside, including epinephrine 1:1000 subcutaneously 0.01 cc/kg, diphenhydramine intravenously 1 mg/kg, and oxygen 4-6 L/min.*

7. Infuse following drug doses continuously over 30 min each by secured intravenous line:

Syringe #1: 2 pg/50 cc D5/0.2 NS, then Syringe #2: 20 pg/50 cc D5/0.2 NS, then Syringe #3: 200 pg/50 cc D5/0.2 NS, then Syringe #4: 2 mg/50 cc D5/0.2 NS, then Syringe #5: 20 mg/50 cc D5/0.2 NS, then Syringe #6: 200 mg/50 cc D5/0.2 NS, then Syringe #7: full therapeutic dose (if full dose >2 mg, give 2 mgin

syringe #7, then full dose in syringe #8).

8. Following desensitization, nursing assessment q 2 hr x 2, then as previously ordered unless otherwise indicated.

9. Ifprobenecid is desired, begin >24 h after desensitization is completed.

*Reactions occur in 25-30% of lactam rush IV desensitization procedures; most are mild cutaneous reactions that can be managed by slowing the infusion and administering diphenydra- mine. Ongoing mild reactions can be prophylaxed with oral or IV diphenhydramine pretreatment. Respiratory tract or circulatory system reactions (1-2%)require discontinuation of the drug and appropriate intervention.

were permitted" (31). Despite this statement, it is not clear how one maintains 100% compliance (which may be necessary to maintain tolerance) indefinitely in nonhospitalized CF patients. Thus, maintenance of tolerance in desensitized patients with a heterologous oral ~-lactarn antibiotic seems insufficiently effective for routine use. We prefer the routine iv desensitization of an allergic patient each time he or she re- quires antipseudomonal ~-lactam antibiotic treatment.


Nonimmediate Hypersensitivity Reactions A number of physicians treating CF patients have noted increasing

rates ofnonimmediate reactions to ~-lactam antibiotics. Typically, these serum sickness4ike reactions consist of drug fever, malaise, myalgia, morbilliform rashes, and/or arthalgias with or without frank arthritis. Less often, lymphadenopathy, organomegaly, and vasculitic dermal involvement may occur. Such reactions may or may not involve IgE-dependent mechanisms. An immunologic mechanism is indicated by acceler- ated reactions following reexposure, that suggests anamnestic immune responses to the drug.

There appear to be real differences in the propensity of ~-lactam antibiotics to cause nonimmediate allergic reactions, but the basis for these differences is unclear. In a comparative study of seven antipseudomonal J3-1actam antibiotics in treatment of CF, Mastella et al. found that piperacillin caused fever and rashes in 18.7% of patients treated, compared to < 3% for the other drugs (38). Moller et al. reported that seven of 20 patients treated with azlocillin, and 14 of 30 treated with piperacillin developed serum sickness-like syndromes, contrasted with only one similar episode among >300 historical controls treated with carbenicillin (39). These delayed reactions may be related to increasing in vivo druglevels. Thus, some have ascribed the increased rate of serum sickness-like reactions to concomitant use of probenecid to raise serum druglevels (40). Others have implicated the higher doses ofsemisynthetic penicillins recently investigated to treat CF P. aeruginosa endobronchial exacerbations (41). Still others believe intrinsic differences in ~-lactam reactogenicity may be involved (42,43). Finally, the possibility of drug- induced bacterial antigen release with a Jarisch-Herxheimer mechanism cannot be excluded (40).

Aminoglycosides

Ifaminoglyco side reactivity is suspected, the reader is referred to the case report by Earl and Sullivan for a suggested approach (18). There are no other published case reports ofaminoglycoside allergy in CF patients. We have been unable to document aminoglycoside allergy by skin testing in any of our ~-lactam allergic patients. However, sulfite sensitivity can masquerade as drug allergy. We have identified one patient who was sensitive to sulfites, including those used as preservatives in one formu- lation of tobramycin.

226 Moss

The increasing use of long-term aerosol therapy with aminoglycosides, particularly tobramycin, raises the possibility of increased rates of sensitization to these antibiotics in CF patients. As yet, however, no reports ofbronchosplastic or other allergic reactions specifically attribut- able to aerosolized aminoglycosides have appeared.

Other Antimicrobials

Sulfonamides, particularlytrimethoprim-sulfamethoxazole [T/S], and the tetracyclines, particularly vibramycin and doxycycline, remain popu- lar classes of antibiotic therapy for outpatient management of CF patients. Rates of allergic sensitization to these and other less frequently employed classes of antibiotics in patients with CF have not been reported. It is our impression that immediate systemic allergic reactions to non ~-lactam antibiotics are quite rare in CF patients, as they are in other subjects. Nonimmediate morbilliiform or exfoliative cutaneous reactions to T/S have occurred somewhat more frequently, perhaps up to 5-6% of courses administered. Because of the risk of Stevens-Johnson syndrome, such reactions usually require permanent discontinuation of treatment.

Pancreatic Extracts

Therapy with exogenous porcine or bovine pancreatic extracts con- taininglipase, amylase, and protease activity is a mainstay of treatment for pancreatic exocrine insufficiency affecting -90% of CF patient. In the mid-1970s several reports were published noting immediate hypersensitivity respiratory reactions inparents of CF patients following exposure and presumptive inhalation of pancreatin-containing powders (44--49). Positive skin tests (including late-phase reactions), positive passive transfer of cutaneous reactivity, and positive bronchial provocation tests have been noted, indicating involvement of IgE antibodies (45,46). In vitro evidence of IgE-mediated hypersensitivity was obtained by antigen-specific leukocyte histamine release and PAST (47,49).

Examination of the antigenic specificity of the extracts implicates trypsin as the dominant allergen, although porcine pancreatic elastase was also found to be immnogenic (50), and in one study soluble trypsin failed to inhibit RAST binding ofsera from four pancreatic extract-allergic subjects (49). However, immunogenicity ofxeno geneic trypsin was con- clusively demonstrated by Romeo and colleagues, who found antitrypsin IgG antibodiesin 80% of CF patients and 30% oftheir mothers (51). Similar antibodies are found in <3 % of controls not expos ed to pancreatin powders


(50). The s tudy of Romeo et al. offers a clue as to why the CF pa t ien t s themselves rarely, i f ever, have adverse reactions to pancrea t in powder: possibly some of the IgG antibodies induced by therapeut ic ingest ion of the pancreat ic extract are capable of suppressing IgE-mediated react ions (i.e., are blocking antibodies).

The in t roduct ion of various enteric-coated microsphere pancrea t in formulat ions in the las t several years has great ly lessened the l ikel ihood of aerosolization of extract const i tuents and resul ted in a corresponding decline of reported reactions. However, the cont inued use of powdered pancreat ic extract formulations, par t icular ly in infants wi th CF, provides a potent ia l source of sensi t izat ion to care-takers (who are not also being immunized enterally). Thus, a recent report cited respi ra tory symptoms in six of 11 nurses caring for CF infants (52). Cont inued caut ion when us ing pancreat ic extract powders seems prudent .

REFERENCES

1. Sullivan, T. J. (1982), Pediatr. Infect. Dis. 1,344-350. 2. Saxon,A.,Beall, G.N.,Rohr, A.S.,andAdelman, D.C.(1987),Ann. Int. Med. 107,

204-215. 3. Ressler, C. and Mendelson, L. M. (1987), Ann. Allergy 59, 167-170. 4. Van Dellen, R. G., Walsh, W. E., Peters, G. A., and Gleich, G. J. (1971), J. Allergy

47, 230- 236. 5. Petz, L. D. (1978), J. Infect. Dis. 137,$74-$79. 6. Sullivan,T. J., Wedner, H. J., Shatz, G. S., Yecies, L D., and Parker, C. W. (1981),

J. Allergy Clin. Immunol. 68, 171-180. 7. Solley, G. 0., Gleich, G. J., andVan Dellen, R. G. (1982), J. Allergy Clin. Immunol.

69, 238-244. 8. Saxon,A.,Adelman, D. C.,Patel,A.,Hajdu, R.,and Calandra, G.B.(1988),J.Allergy

Clin. Immunol. 82, 213-217. 9. Blanca, M., Fernandez, J., Miranda, A., Terrados, S., Torres, M. J., Vega, J. M.,

Avila, M. J., Perez, E., Garcia, J. J., and Suau, R. (1989), J. Allergy Clin. Immunol. 83, 381-385.

10. Sogn, D. (1984), J. Allergy Clin. Imrnunol. 74, 589-593. 11. Rourk, M. and Spock, A. (1970), CF Club Abstr. 19,20. 12. Patterson, P. and Snyder, K. (1976), CF Club Abstr. 25, 54. 13. Moller, N., Ahlstedt, S., Skov, S., and Norm, S. (1980), Allergy 35, 135-138. 14. Brown, L. A., Goldberg, N. D., and Shearer, W. T. (1982), J. Allergy Clin. Im-

munol. 69, 51-54. 15. Moss, R. B., Babin, S., Blessing, J., and Lewiston, N. J. (1984), J. Pediatr. 104,

460-466. 16. Hilman, B. C. and Rao, K (1986), J. Allergy Clin. Immunol. 77, 167.

228 Moss

17. Galant, S., Posner, L., Lee, N., Hicks, D., WiIkinson, B., and Ellis, M. (1987), J. Allergy Clin. Immunol. 79, 199.

18. Earl, H. S. and Sullivan, T. J. (1987), J. Allergy Clin. Immunol. 79, 477-483. 19. Sullivan, T. J., Ong, R. C., and Gilliam, L. K. (1989), J. Allergy Clin. Immunol.

83, 270. 20. Moss, R. B., McClelland, E., Rubio, T., Hillman, B., Williams, R., and Adkinson,

N. F. Rev. Infect. Dis., in press. 21. Neu, H. C. (1986), Rev. Infect. Dis. 8, $237-$259. 22. Adkinson, N. F., Swabb, E. A., and Sugarman, A. A. (1984),Antimicrob. Agents

Chemother. 25, 93-97. 23. Saxon, A., Hassner, A., Swabb, E. A., Wheeler, B., and Adkinson, N. F. (1984), J.

Infect. Dis. 149, 16-22. 24. Adkinson, N. F., Saxon, A., Spence, M. R., and Swabb, E. ,4. (1985), Rev. Infect.

Dis. 7, $613-$621. 25. Saxon, A., Swabb, E. A., and Adkinson, N. F. (1985), Am. J. Med. 78 (suppl 2A),

19-26. 26. Loria, R. C., Finnerty, N., and Wedner, H. J. (1989), J. Allergy Clin. Immunol. 83,

735-737. 27. O'Donovan, W. J. and Klorfajn, I. (1946), Lancet 2, 444-446. 28. Chiarmonte, J. S. and Pinsker, W. (1978), Ann. Allergy 41,111,112. 29. Sullivan, T. J., Yecies, L. D., Shatz, G. S., Parker, C. W., and Wedner, H. J. (1982),

J. Allergy Clin. Immunol. 69, 275-282. 30. Wendel, G. D., Stark, B. J., Jamison, R. B., Molina, R. D., and Sullivan, T. J.

(1985), N. Engl. J. Med. 312, 1229-1232. 31. Stark, B. J., Earl, H. S., Gross, G. N., Lumry,W. R., Goodman, E. L., and Sullivan,

T. J. (1987), J. Allergy Clin. Immunol. 79, 523-532. 32. Gorevic, P. D. and Levine, B. B. (1981), J. Allergy Clin. Immunol. 68, 267-272. 33. Sullivan, T. J. (1982), J. Allergy Clin. Immunol. 69, 500-508. 34. Naclerio, R., Mizrahi, E. A., and Adkinson, N. F.(1983), J. Allergy Clin. Immunol.

71,294--301. 35. Pienkowski, M. M., Kazmier, J., and Adkinson, N. F. (1988), J. Allergy Clin.

Immunol. 82, 171-178. 36. Moss, R. B. (1989), J. Allergy Clin. Immunol. 83, 1138. 37. Borish, L., Tamir, R., and Rosenwasser, L. J. (1987), J. Allergy Clin. Immunol.

80, 314-319. 38. Mastella, G., Agostini, M., Bar]occo, G., Bonomi, U., Borgo, G., Bozzino, L., Cabrini,

G., Capelletti, L. M., Castellani, L., Confort, M., Marazzani, S., Martini, N., Montemezzi, P., Paulon, G., Pederzini, F., Sancassani, L., and Scroccaro, G. (1983), J. Antimicrob. Chemother. 12 Suppl A, 297-311.

39. Mr N. E., Eriksen, K. R., Feddersen, C., Flensb0rg, E. W., H0iby, N., Norn, S., Rosendal, K., Schiotz, P. O., and Skov, P. S. (1982),Eur. J. Resp. Dis. 63, 130- 139.

40. Discussion. (1981), Scand. J. Infect. Dis. (Suppl) 29, 102,103. 41. Reed, M. D., Stern, R. C., Myers, C. M., Yamashita, T. S., and Blumer, J. L. (1984),

Abstr. Int. Congress Antimicrob. Agent Chemother. (abstract 15849), p. 238. 42. Strandvik, B. (1984),Lancet 1,857,858.


43. Stead, R. J., Kennedy, H. G., Hodson, M. E., and Batten, J. C. (1985), Thorax 40, 184-186.

44. Dolan, T. F. and Meyers, A. (1974), Am. Rev. Respir. Dis. 110,812,813. 45. Bergner, A. and Bergner, R. K. (1975), Pediatrics 55, 814-817. 46. Hill, D. (1975), Med. J. Aust. 2, 553-555. 47. Twarog, F., Weinstein, S. F., Khaw, K T., Strieder, D. J., and Colten, H. R. (1977),

J. Allergy Clin. Immunol. 59, 35-40. 48. Sakula, A. (1977), Br. J. Dis. Chest 71,295-299. 49. Ganier, M. and Lieberman, P. (1979), Clin. Allergy 9, 125-132. 50. Parsons, M.(1980),TrypsinbindingPlasmaProteinsinCysticFibrosis,(Doctorial

Thesis), Stanford University, Palo Alto, CA. 51. Romeo, G., Parsons, M., Bossen, A., Blessing-Moore, J., and Cavalli-Sforza, L.

(1978), Nature 274, 909-911.

Documents

Drug allergy in cystic fibrosis