Allergy to semisynthetic penicillins in cystic fibrosis

Allergy to semisynthetic penicillins in cystic

fibrosis Allergic reactions to anti-Pseudomonal penicillin derivatives are an increasing problem in therapy o f cystic fibrosis lung disease. We evaluated 15 patients, ages 12 to 37 years, with documented allergic reactions to carbenicillin, ticarcillin, or piperacillin. Intradermal skin test reactions were positive for benzylpenicillin in seven patients, penicilloyl-polylysine in one, and ticarcillin or piperacillin in eight, for a total o f 11 o f 11 tested. Results o f radioallergosorbent testing to penicilloyl conjugates were positive in eight o f 14 patients and equivocal in four others. Overall, skin tests or R A S T results were positive in 13 o f 15 patients, till patients were desensitized with a semisynthetie penicillin by continuous serial intravenous infusion o f IO-fold dose increments, beginning with 10 -6 o f the therapeutic dose. Desensitization was successful in 25 o f 26 instances. After intravenously administered therapy, maintenance o f desensitization with dicloxacillin orally was unsuccessfid in four o f six patients. We conclude that (1) allergy to semisynthetic penicillins in cystic fibrosis usually is IgE mediated; (2) such allergy can be evaluated by skin testing; (3) it can be safely and in most cases successfully treated by intravenous desensitization; and (4) allergic patients should be desensitized on each subsequent admission for intravenously administered therapy. (J PEDIATR 104:460. 1984)

Richard B. Moss, M.D., Sarah Babin, R.N., M.S., Yao-Pi Hsu, M.S., Joann Blessing-Moore, M.D., and Norman J. Lewiston, M.D. Palo Alto, Calif.

ANTI-PSEUDOMONAL PENICILLIN DERIVATIVES are widely used to treat episodes of respiratory infection in colonized patients with cystic fibrosis? Although penicillin antibk3tics are remarkably nontoxic, a continuing clinical problem has been hypersensitivity reactions. 2 The incidence of allergic reactions during therapy with penicillin antibiotics (defined here as all antibiotics sharing the 6-aminopenicillanic acid nucleus) is probably about 5% in intravenously administered courses; approximately 10% of this large number of reactions are life threatening, and up to 10% of reported anaphylactie reactions are fatal? In the general patient population, most fatal reactions occur in patients without a prior history of allergic symptoms on previous exposure to penicillin. However, patients with cystic fibrosis represent a unique group of persons who

From the Ross Mosier Laboratory for Research in Cystic Fibrosis, Children's Hospital at Stal~ord, and the Department o f Pediatrics, Stanford University School o f Medicine. Reprint requests: Richard B. Moss, M.D., Children's llospital at Stanford. 520 Willow Rd., Palo Alto, CA 94304.

460

The Journal o f P E D I A T R I C S

receive enormously greater cumulative exposure, with multiple high-dose, intravenously administered courses of penicillins. This exposure represents a major risk factor in terms of both repetitive exposure and route of administration. In addition, patients with CF probably have other risk factors for lgE-mediated reactions to penicillin, including BPO CF PCN G PMPO PPL

Benzylpenicilloyl Cystic fibrosis Benzylpenicillin Phenoxymethylpenicilloyl Penicilloyl-polylysine

a high rate of generalized immune responsiveness and atopy?. 5 The immunochemistry of penicillin allergy has been well studied, and the use of skin test reagents for identification of patients at risk for allergic reactions has been described? 8 In addition, sporadic reports of successful desensitization of patients with anaphylactic sensitivity to penicillin have appeared in the literature? j~ In the past 2 years, 15 of our patients with CF with

Volume 104 Number 3

Allergy to semisynthetic penicillins in CF

461

Table I. Clinical data

Desensitization

Reaction

Date

Reaction-desensitization interval

4/83 3/83

6 yr 4 mo

12/82 4/83 6/82 10/82, 1/83, 2/83, 4/83,t 6/83 11/82 3/83 1/83t

41h yr 6d 14 mo 37 d

3/83, 5/83

9 yr

Piperacillin

8/82t

6 mo

Ticarcillin

12/82t

4 yr

3/83 2/82 11/82 2/83, 6/83t

13 d 14 mo 8 mo 14 mo

3/83, 7/83 6/83 6/83

8 yr 13 mo 6 mo

Drug

Patient

Drug

I 2

Carbcnicillin Ticarcillin Piperacillin Carbenicillin Piperacillin Carbenicillin Ticarcillin

5/77 10/82 i 2/82 4/78 4/83 4/81 9/82

Urticaria Urticaria Angioedema Angioedema Anaphylaxis Anaphylaxis Angioedema

Ticarcillin Ticarcillin

5 6 7

Ca rbenicillin Carbenicillin Ticarcillin

11/80 5/76 7/82

Piperacillin Piperacillin Ticarcillin

8 9

Carbenicillin Carbenicillin

2/74 9/81

Ticarcillin

2/82

10

Carbcnicillin Ticarcillin

1/79 2/83

II 12

Carbenicillin Ticarcillin Carbenicillin

12/80 3/82 12/81

13 14 15

Carbenicillin Carbenicillin Ticarcillin

1975 4/82 12/82

Urticaria Urticaria Urticaria Angioedema Anaphylaxis Urticaria Angioedcma Urticaria Angioedema Urticaria Angiocdema. Anaphylaxis Urticaria Urticaria Urticaria Angioe.dema Urticaria Anaphylaxis Angiocdema

3 4

IDate._lSign/symptom

Piperacillin Mezlocillin* Ticarcillin Piperacillin (•

Piperacillin (x2)

Piperacil!in Ticarcillin Piperacillin Piperacillin (• Ticarcillin (x2) PiperaciIlin Piperacillin

I

2 yr 7 yr 5 mo

*Desensitizationunsuccessful(see text). tRequired diphenh)dramineduring successfuldesensitization. immediate allergic reactions to intravenously administered penicillin derivatives subsequently required further treatment with these drugs for exacerbations of Pseudomonai endobronchitis. We therefore developed a protocol for skin testing and intravenous desensitization, which has led to safe and, in most cases (25/26), successful therapeutic drug administration: Also, inasmuch as it has been suggested that it may be possible to maintain tolerance to one penicillin derivative indefinitely after desensitization by continuing oral administration of another penicillin, ~" ~swe explored this possibility in several patients. MATERIALS

AND METHODS

Fifteen patients with cystic fibrosis,seen at the Stanford Cystic Fibrosis Center at Children's Hospital, Stanford, with allergic reactions to penicillin, were identified between 1980 and 1982 (Table I). Seven were male, and eight female, ages 12 through 3 7 years (mean ___ SD = 23.3 ___ 7.8 years). All patients had had a documented in-hospital reaction to one or more penicillin drugs, as follows: carbenicillin (12), ticarcillin (seven), and piperacillin (two). Reactions consisted of generalized urticaria

(12), angioedema (nine), and anaphylaxis with hypotension or bronchospasm (five). All patients had received prior intravenously administered courses of penicillin drugs (mean 5.8 prior courses, range two to 11) before the systemic reaction occurred. Subsequent to the generalized reactions,.these patients had a range of up to 19 further admissions, during which only aminoglycoside antibiotics were given before evaluation and desensitization were performed. The interval between allergic reaction a n d evaluation-desensitization ranged from several days to more than 9 years. Informed consent was obtained for diagnostic skin tests in 11 patients and for desensitization in all 15. Skin testing was performed prior to desensitization in 11 patients. The skin test reagents used were benzylpenicillin (Pfizer), penicilloyl-polylysine(Pre-Pen, Kremers-Urban), and either piperacillin (Pipracil, Lederle) or ticarcillin (Ticar, Beecham) (Table II). Penicillin G was used in concentrations of 10, 1000, and 100,000 U / m l for epicutaneous prick and intracutaneous testing. Penicilloyl-polylysine was used at a concentration of 6 X 10-SM. Ticarcillin or piperacillin, therapeutic drugs of choice during this

462

Moss et al.

The Journal of Pediatrics March 1984

Table II. Skin test protocol for penicillin derivatives

Reo eo, Benzylpenicillin (PCN G, Pfizer

I

A ,ico,ion

I

Prick* [ntraderrnalt (0.02 ml)

Penicilloyl polylysine (Pre-Pen, Kremers) Carbenicillin Ticarcillin Piperacillin Mezlocillin (ug/ml) Azlocillin

Prick Intradermal Prick

Phosphate-buffered saline

Prick Intradermal Prick

Histamine phosphate (Lilly)

lntradermal

O,,,,ioo

I

.oce.2,ro oo

10-~ 10-2 Stock 10-4 I0-~ Stock 6 • 10-3 M 6 • I0-3 M I0-~ 10-2 Stock 10-' 10-5 Stock

10 U/ml 103 U/ml 10s U/ml l0 U/ml 103 U/ml 103 U/ml

20 2 200 20 2 200

Stock

100 ug/ml

t~g/ml mg/ml mg/ml ,ug/ml mg/ml mg/ml

I T o,e o, n, 0 15 30 45 60 75 0 45 0 15 30 45 60 75 0 45 0

*Interpretationof prick skintest results:negative,whealsize < 2 mm > PBS; I+. >---2 mm> PBS;2+, 3 to 5 mm> PBS;3+. :> 6 mm > PBS. "l'lnterpretationof intradermaltest results:negative.< 3 mm> PBS; I+, >" 3 mm> PBS;2+, 8 to 12 mm> PBS; 3+. > 12 mm> PBS. period, were used in concentrations of 20 ug/ml and 2 and 200 mg/ml. All intracutaneous testing was done with an injected volume of 0.02 ml. Drugs were prepared fresh immediately before each test in phosphate-buffered saline. Positive and negative controls, using histamine phosphate and PBS (pH 7.4), respectively, were used for each individual tested. Prick test results were considered positive if the wheal diameter at 15 minutes was >__2 mm greater than the PBS control. A scoring system for progressively larger reactions was used. Positive intrader2 mal test results required a wheal diameter at 15 minutes >__3 mm larger than the PBS control wheal2 Specific lgE antibodies to benzylpenicilloyl-human serum albumin conjugates and phenoxymethylpenicilloylhumb.n serum albumin conjugates were performed in the standard radioallergosorbent test using Pharmacia reagents. ~9 Results (x) were expressed as the mean count rate for each antigen-coated disc as a percent of the mean count rate of the totalradi0activity added (a) minus the percentage nonspecific binding obtained with human serum albumin-coated discs (b). a - b = x. Values (x) >0.8 were considered positive, and values (x) between 0.6 and 0.8 were considered borderline or equivocal.:~ Thirtythree samples from 14 patients were assayed. Desensitization with ticarcillin or piperacillin was accomplished using the intravenous route. The full therapeutic dose of the drug to be administered (50 mg/kg IV every 4 hours) was calculated. Serial 10-fold dilutions, starting from the full therapeutic dose and decreasing to 10-6 of the full therapeutic dose, were prepared just before administration. All patients received continuous monitor-

ing in the hospital during desensitization, with emergency drugs and other life-support equipment at the bedside. Starting with the 10-6 concentration diluted in 50 ml D5/0.2% saline solution, progressively higher 10-fold drug concentrations were infused over 30 to 45 minutes each, without interruption between doses, until the full therapeutic dose was administered. Then the therapeutic schedule was begun. Probenecid 50 mg/kg/day in four divided doses given orally was added 24 hours after completion of desensitization. All patients received combination therapy of ticarcillin or piperacillin with tobramycin for courses of 10 to 21 days. Tobramycin doses and intervals Were individualized to maintain serum peak levels of 8 to 12 t~g/ml and trough levels of <2 t~g/ml obtained twice weekly. No premedication was given before desensitization. In six patients for whom maintenance of tolerance after desensitization treatment was attempted, therapy with dicloxacillin 250 to 500 mg Po two to four times daily was begun 24 hours before completion of intravenous therapy and discharge from the hospital. RESULTS Fifteen patients with generalized immediate reactions (Table I) were evaluated. Skin testing was done prior to desensitization in 11 patients; 33 serum assays for penicillin-specific lgE antibodies were performed in 14 patients. Skin test reactions were positive in all I 1 patients tested. However, no patients had positive epicutaneous (prick) test reactions. In fact, with three exceptions, all positive skin test drug reactions occurred only at the highest (stock)

Volume 104 Number 3 concentration for intradermal testing. Seven patients had a reaction to penicillin G, one to PPL, and eight to ticarcillin or piperacillin. Four patients had a reaction to one reagent, and seven to two reagents; none reacted to all three. In general, reactivity appeared to be to determinants specific for the semisynthetic penicillin side chain (I0 reactions) or the basic penicillin molecule (seven) rather than the penicilloylated metabolite antigen (Table III). R A S T tests for IgE antibodies to BPO or PMPO a n t i g e n s were positive in eight of 14 patients tested and yielded borderline values in another four patients (Table III). A total of 23 of 33 (70%) serum samples tested were equivocally (10) or definitely (13) positive. Use of both antigens enhanced the sensitivity of the test, as previously reported. 2t Persistence of lgE antibody after allergic reaction was variable and unpredictable; as expected, RAST results were most likely to be positive when serum was obtained close to the time of the reaction (data not shown). 22 Desensitization was carried out in 15 patients; in seven patients, multiple desensitization courses were given over the study period. Twenty-five of 26 desensitization attempts were successful, success being defined as completion of a full 10- to 21-day therapeutic course of combined penicillin-aminoglycoside therapy. The single treatment failure occurred in a 33-year-old man (patient 3) who had laryngeal edema caused by carbenicillin in April of 1978 and seven subsequent hospitalizations without receiving a penicillin. In August 1982 hepatitis type b was diagnosed. Liver function tests have shown persistent elevation of values with HbsAg carrier state, multiple organ involvement consistent with serum sickness (arthritis, myositis, hematuria, fever, adenopathy), and persistent circulating immune complexes. He was successfully desensitized to piperacillin in December 1982. On his next hospitalization in April 1983 he developed urticaria, angioedema, and bronchospasm during a first test dose (1 : I00 dilution) of piperacillin. Desensitization was attempted with mezlocillin. Laryngospasm developed during the desensitization process when the first full therapeutic dose was given. Mezlocillin was discontinued and the reaction reversed with epinephrine and diphenhydramine. H e has subsequently been successfully given cefotaxime using our desensitization protocol. Five patients developed urticaria during desensitization (five courses), which resolved after intravenous use of diphenhydramine, allowing continuation of desensitization and a successful treatment course. I n 20 courses no reactions were observed during the desensitization procedure and the full treatment course was tolerated without adverse reaction. No evidence of serum sickness was found in our patients.

Allergy to semisynthetic penicillins in CF

4 63

T a b l e IlL lntradermal skin test and serum RAST results

Patient [ I

2 3 4 5 6 7 8 9 10 II 12 13 14 15

Skin test (+) ND 1+ PCN 105 U/ml I+ TIC 200 mg/ml ND I+ TIC 2 mg/ml I+ PIP 200 mg/ml 2+ TIC 200 mg/ml I+ PIP 200 mg/ml I+ PCN I0~ U/ml ND I+ PPL 6 X 10-s M !+ PCN 105 U/ml I+ PIP 200 mg/ml I+ PCN 105 U/ml I+ TIC 2 mg/ml ND I+ PCN 105 U/ml I+ TIC 2 mg/ml I+ PCN 105 U/ml I+ PIP 200 rng/ml I+ PCN l0 s U/ml I+ PIP 200 mg/rnl

I

RAST* -+ BPO _+ BPO + BPO, + PMPO + BPO _+ BPO, + PMPO + BPO Negative --- PMPO + BPO, _+ PMPO ND + BPO, + PMPO + BPO, + PMPO +.+_BPO, -4- PMPO + BPO, + PMPO Negative

BPO. Benzylpenicilloyl;PCN, benzylpenicillin;PIP, piperacillin;PMPO. phenoxymeth)lpenicilloyl;PPL, penicilloyl-polylysine;TIC, ticareillin; ND. not done. *Interpretationof results:negative,< 0.6; borderline,0.6 to 0.8 (equivocal); positive> 0.8. For derivationof results,see Methods. Maintenance of desensitization by use of an oral course of penicillin was attempted in six patients. Dicloxacillin 250 or 500 mg vo was given two to four times per day. Two of these six patients had to discontinue dicloxacillin within 1 week of discharge because of recurrent symptoms of allergic i:eactivity (urticaria and laryngeal edema, respectively). Of the remaining four patients who tolerated dicloxacillin, three have since been readmitted and given challenge test doses of piperacillin at I:100 and ! : 1 0 dilutions followed by full therapeutic doses. In two of the three, Urticarial reactions occurred to the full therapeutic dose, and repeat desensitization according to our intravenous protocol was necessary. In both, desensitization was successful. The one patient who tolerated an intravenous rechallenge without need for repeat desensitization had been given maintenance therapy with the highest oral dose of dicloxacillin (500 mg four times a day). DISCUSSION Allergic reactions to semisynthetic anti-Pseudomonal penicillin derivatives are becoming a major problem in treatment in patients with cystic fibrosis.2J'24 At the Stanford Cystic Fibrosis Center in 1981-1982, II of 179 courses (6%) of intravenously administered anti-Pseudomonal therapy in eight of 74 patients with C F (11%)

464

Moss et al.

resulted in immediate onset of allergic reactions. These reactions occurred primarily in older patients (mean age in our series, 23tA years) with multiple prior courses of intravenously administered therapy. The need for continued treatment and lack of suitable alternatives led us to develop a uniform approach to diagnosis and treatment of peniciilin allergy in CF. Most persons who report a history of penicillin allergy are found on immunologic investigation not to have reaginic sensitivity (as defined by positive immediate skin test reactions) and tolerate drug rechaUenge without adverse effect. 6-gThis tolerance appears to be related in major part to incorrect diagnosis, but also to waning of true penicillin hypersensitivity over time. Conversely, most serious peniCillin reactions occur in patients with no prior history of penicillin allergy2 In the last two decades, a number of studies established the immunochemical basis of penicillin hypersensit.ivity and led to the proper selection of reagents fo~: skin tests predictive for rechallenge outcome. A study of nearly 3000 patients by the American Academy of Allergy established the usefulness of benzylpenicillin and a polymer of its major metabolite, penicilloyl-polylysine, in evaluating a history of penicillin allergy. Positive skin test reactions to one or both of these reagents are highly predictive of an allergic reaction on rechallenge, whereas negative reactions are excellent predictors of an uneventful outcome. 6 A marginal increment in skin test sensitivity has been found with addition of other minor penicillin metabolites, such as penicilloie acid or benzylpenicilloate (the "minor determinant mix"), 7's'z5 but this slight advantage is more than offset by the difficulty in obtaining a wellcharacterized standardized supply of such metabolites. Moreover, PCN G itself appears to be the most important single antigen in the minor determinant mix. 6.26 The increase of clinically available semisynthetic penicillin analogues With unpredictable allergenic cross-reactivity to pen!cillin G has substantially complicated the evaluation of allergic reactions to these drugs. ]lere, addition of specific semisynthetie penicillins to the skin test reagent battery has significantly increased the sehsitivity and resulting predictive value. 7'8"2~ In our series, addition of the proposed drug of rechallenge, either tiearcillin or piperacillin, to the PCN G / P P L skin test battery substantially improved the diagnostic yield in our patients, three of whom had a reaction only to the semisynthetic derivative on skin testing. This is not surprising, as our patients were originally sensitized to a semisynthetic penicillin derivati~'e rather than to PCN G, in contrast to most prior reported patients. This difference in the drug of sensitization probably also accounts for the low rate of reactivity to the major determinant, PPL, to which many persons with a history of allergy to PCN G are sensitized. Thus, these

The Journal of Pediatrics March 1984

patients with CF appear to be distinguished from most other patients allergic to penicillin by development of primarily derivative drug (side chain)-specific reaginic antibodies rather than antibodies tO drug metabolites of PCN G. The use of the radioallergosorbent test for penicillin allergy' was introduced in 1971.19 This test uses two major determinant haptens, benzylpenicilloyl and phenoxymethylpenicilloyl, coupled to human serum albumin as a protein carrier and then insolubilized on cyanogen bromideactivated Cellulose paper disks as a solid-phase matrix. The use of both reagents is based on the occasional finding of sensitivity to phenoxymethylpenicillin but not benzylpenicillin, z~ The IgE antibodies formed to a number of distinctly different penicillin-related antigens cross-react and bind to these disks, as demonstrated by RAST inhibition using different penicillin antigens, 19 by correlative studies showing 85% to 95% agreement between RAST and skin tests using a variety of antigens includ!ng minor determinants, ~9.z'.22.2~3~ a n d by minimal if any increase in RAST sensitivity with addition of other penicillin-related antigens to the BPO/PMPO disks24 In our series, RAST test results were unequivocally positive in eight of 14 patients and were borderline positive in another four patients. Skin tests are probably more sensitive than RAST, in that skin test reactions were positive when RAST was negative or equivocal in four of 14 patients. It is likely that RAST results were positive in our patients as a result of crossreactivity with penicillin analogue determinants rather than penicilloyl-specific IgE antibodies, because PPL skin test reactions were, with one exception, negative and RAST titers were generally lower than those reported in other patients allergic to penicillin. RAST thus appears to offer no significant advantage over skin testing for penicillin allergy so long as the latter is performed with a graded dose to avoid anaphylactic reaction. RAST is probably most useful when testing is desired immediately after a reaction occurs, z-''29as skin testing may give false negative results during this refractory period, which may last a week or longer before in vivo cellular sensitiv!ty is restored2 ~ Our data provide strong evidence for drug-specific lgE antibody formation in the majority (13 of 15) of these patients. In 1970 Rourk and Spock 36reported that four of 35 (11%) of their patients with CF had positive reactions to penicillin skin tests. Moiler et a127 did not find evidence of reaginic hypersensitivity by skin test or in vitro methods (RAST and leukocyte histamine release) in I6 patients with CF with a variety of skin reactions to carbenieillin. However, their study had a number of flaws: (1) Patients were selected on the basis of any cutaneous reaction; thus 10 of 16 patients had exanthems, which are typically not

Volume 104 Number 3

associated with reaginic penicillin hypersensitivity. (2) The time of onset of reaction with respect to drug administration was not given. (3) Skin testing was done with only one reagent (carbenicillin) at one concentration (I00 mg/ml) by one method (epicutaneous prick), which would not be expected to detect lesser levels of drug sensitization. (4) The failure to find any evidence of lgM or IgG antibodies to penicillin in all 16 patients contradicts general experience regarding penicillin immunogenicity?s Desensitization of penicillin allergic patients by the oral, intradermal, subcutaneous, and intravenous routes has been describedYt5 Its rarity is a testament to both the risks thought to be involved in the procedure and the availability of alternative antibiotics in most infections. Cystic fibrosis presents an unusual challenge because of the need for anti-Pseudomonal penicillin derivatives in ill patients. All methods of drug desensitization rely on giving initially infinitesimal doses with increments over time that are believed to allow gradual binding of allergen to reaginie cell-fixed antibody, leading to subsequent controlled (rather than massive) release of allergic mediator substances. Sullivan et al. '7 described an oral desensitization protocol using benzylpenicillin or carbenicillin. Although 30% of their patients developed mild allergic reactions, all were successfully treated. Comparison with prior published cases of parenteral desensitization in allergic patients (which showed a 58% cumulative allergic reaction rate including 16% anaphylaxis) led to their conclusion that oral desensitization was probably the safest route. We used the intravenous route primarily because of the unavailability of orally active newer anti-Pseudomonal penicillins and the undesirability of using any other agent for desensitization than the therapeutic drug. Others have questioned the variability of absorption in oral desensitization, contrasting it with the controlled dose and rate of intravenous infusion) ~ Our intravenous desensitization protocol was uniformly safe and therapeutically successful in 25 of 26 challenges. In 1982 Brown et al. 16reported intravenous desensitization of a patient with CF with ticarcillin followed by maintenance of tolerance with orally taken penicillin. Similarly, Naclerio et al. ~8desensitized a penicillin-allergic woman, with maintenance of tolerance with phenoxymethylpenicillin given orally. A dose dependency for tolerance maintenance was suggested in both these reports. We attempted a similar tolerance maintenance program by oral administration of dicloxacillin to six desensitized patients. We were disappointed to find recrudescence of allergic s.ymptoms in two of these patients, and repeated allergic reactions on intravenous rechallenge in another two patients with tolerance successfully maintained with dieloxacillin. We therefore recommend repeat desensitiza-

Allergy to semisynthetic penicillins in CF

465

tion for any patient with CF with documented immediate hypersensitivity each time use of such an agent is necessary. ADDENDUM Since submission of this manuscript, 13 successful desensitizations in 10 patients (including two new patients) have occurred, bringing the total to date (December 1983) to 38 of 39 challenges. REFERENCES I. Marks MI: The pathogenesis and treatment of pulmonary infections in cystic fibrosis. J PEOIA'rR98:173, 1981. 2. Erffmeyer JE: Adverse reactions to penicillin. Ann Allergy 47:288, 1981. 3. Idsoe O, Guthe T, Wilcos RR,de Week A: Nature and extent of penicillin side reactions with particular reference to fatalities from anaphylactie shock. Bull WllO 38:i59, 1968. 4. Adkinson NF, Wheeler B: Risk factors for lgE dependent reactions to penicillin. In Kerr JW, Ganderton MA, editors: Proceedings of Invited Symposia, XI International Congress of Allergology and Clinical Immunology. London, 1983, Macmillan, p 55. 5. Moss RB: Immunology of cystic fibrosis, h~ Lloyd-Still J, editor: Textbook of cystic fibrosis. Boston, 1983, John Wright-PSG, p 109. 6. Green GR, Rosenblum All, Sweet LC: Evaluation of penicillin hypersensitivity.J Allergy Clin Immunol 60:339, 1977. 7. Sullivan TJ, Wedner HJ, Shatz GS, Yecies LD, Parker CW: Skin testing to detect penicillin allergy. J Allergy Clin Immunol 68:171, 1981. 8. Solley GO, Gleich GJ, Van Dellen RG: Penicillin allergy: Clinical experience with a battery of skin test reagents. J Allergy Clin Immunol 69:238, 1982. 9. O'Donovan WJ, Klorfajn I: Sensitivity to penicillin:Anaphylaxis and desensitization. Lancet 2:444, 1946. 10. Reisman RE, Rose NR, Witebsky E, Arbesman CE: Penicillin allergy and desensitization. J Allergy 33:178, 1962. I I. Green GR, Peters GA, Geraci JE: Treatment of bacterial endocarditis in patients with penicillin hypersensitivity.Ann Intern Med 67:237, 1967. 12. Pedersen-Bjergaard J: Specific hyposensitization of patients with penicillin allergy. Aeta Allergol 24:333, 1969. 13. Parker CW: Allergic drug responses: Mechanisms and unsolved problems. CRC Crit Rev Toxicol 1:161, 1972. 14. Graybill JR, Sande MA, Reinarz JA, Shapiro SR: Controlled penicillinanaphylaxis leading to desensitization.South M'edJ 67:62, 1974. 15. Gorevie PD, Levine BB: Desensitization of anaphylactic hypersensitivity specific for the penicilloate minor determinant of penicillin and carbenicillin. J Allergy Clin lmmunol 68:267, 1981. 16. Brown I.A, Goldbert NB, Shearer WT: Long-term ticarcillin desensitization by the continuous oral administration of penicillin. J Allergy Clin lmmunol 69:51, 1982. 17. Sullivan TJ, Yecies LD, Shatz GS, Parker CW, Wedrez tlJ: Desensitization of patients allergic to penicillin using orally administered beta-lactam antibiotics. J Allergy Clin lmmunol 69:275, 1982. 18. Naclerio R, Mizrahi EA, Adkinson NF: Immunologicobser-

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vations during desensitization and maintenance of clinical tolerance to penicillin. J Allergy Clin Immunol 71:294, 1983. Wide L, Juhlin L: Detection of penicillin allergy of the immediate type by radioimmunoassay of reagins (lgE) to penicilloyl conjugates. Clin Allergy 1:171, 1971. Pharmacia Diagnostics: Manufacturer's package insert, July 1982. Juhlin L, Wide L: Detection of penicillin allergy by radioallergosorbent test. Lancet 2:261, 1979. Kraft D, Roth, Mischer P, Pichlcr tt, Ebner It: Specific and total serum IgE measurements in the diagnosis of penicillin allergy: A long-term follow-up study. Clin Allergy 7:21, 1977. Moiler NE: Side effects of carbenicillin treatment in patients with cystic fibrosis with chronic infections with Pseudomonas aeruginosa. Ugeskr Laeger 141:1649, 1979. tloiby N, Friis B, Jensen K, Koch C, Moiler NE, Stvring S, Szaff M: Antimicrobial chemotherapy in cystic fibrosis patients. Aeta Paediatr Scand 301:75, 1982. Lcvine BB, Zolov DM: Prediction of penicillin allergy with immunological tests. J Allergy 43:231, 1969. Levinc BB, Redmond AP: Minor haptenic determinantspecific reagins of penicillin hypersensitivity in man. Int Arch Allergy Appl Immunol 35:455, 1969. Van Dellen RG, Walsh WE, Peters GA, Gleich G J: Differing patterns of wheal and flare skin reactivity in patients allergic to the penieillins. J Allergy 47:230, 1971. Adkinson NF: Recent developments in the use of RAST for determining hypersensitivity to penicillin. In Evans R, editor: Advances in diagnosis of allergy: RAST. Symposia Specialist, Miami, 1975, p 125.

The Journal o f Pediatrics Alarch 1984

29. Kraft D, Wide L: Clinical patterns and results of radioallergosorbent test (RAST) and skin tests in penicillin allergy. Br J Dermatol 94:593, 1976. 30. Spath P, Huber H, Ludvan M, Roth A, Schwarz S, Zelger J: Determinations of penicilloyl specific IgE antibodies for the evaluation of hypersensitivity against penicillin. Allergy 34:405, 1979. 31. Basomba A, Villalmanzo IG, Campos A, Pelaez A, Berglund A: IgE antibodies against penicillin as determined by Phadebas RAST. Cfin Allergy 9:515, 1979. 32. Chandra RK, Joglekar SA, Toma E: Penicillin allergy: Antipenicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin. Arch Dis Child 55:857, 1980. 33. Jarisch R, Roth A, Boltz A, Sandor 1: Diagnosis of penicillin allergy by means of Phadebas RAST penicilloyl G and V and skin tests. Clin Allergy 11:155, 1981. 34. Kraft D, Berglund A, Rumpold tt, Roth A, Ebner 1t: Radioallergosorbent test with conjugates specific for minor haptenic determinants in the diagnosis of IgE-mediated penicillin allergy in man. Clin Allergy 11:579, 1981. 35. Bierman CW, Van Arsdale PP: Penicillin allergy in children: The role of immunological tests in its diagnosis. J Allergy 43:267, 1969. 36. Rourk MH, Spoek A: Incidence of atopy in patients with cystic fibrosis of the pancreas. Cystic Fibrosis Club Abstracts 11:20, 1970. 37. Moller NE, Ahlstedt S, Skov PS, Norn S: Allergological examination of cystic fibrosis patients with skin reactions during carbenicillin treatment. Allergy 35:135, 1980. 38. Levine BB: Immunologic mechanisms of penicillin allergy. N Engl J Med 275:1115, 1966.