J Occup Health 2000; 42: 338Ð340

Case Study in a pharmaceutical factory for 2 yr. The worker was exposed to the product in a powder state, while controlling Occupational Rhinitis and Bronchospastic the mixing of both N-formimidoyl-thienamicyn and cilistatin in a sterile room. One year after starting her Reaction in a Worker Exposed to Imipenem job the patient developed conjunctivitis, infections, dry and irritating cough, itchy nose, rhinorrea and headache. Paolo MARRACCINI1, Rossana SALIMBENI1, Lorenzo LODOLA2, The patient underwent a physical check up, routine tests Laura FARIOLI1 and Mario PREVIDI1 and a check for respiratory symptoms and rhinitis, that 1Occupational and Community Health Centre CEMOC, Istituti consisted of: Clinici di Perfezionamento, Milano and 2Policlinico S. Matteo - Skin tests for a panel of common commercial allergens IRCCS, Pavia, Italy such as grass, tree and weed pollens, animal danders, moulds, yeast and house dust mite. All tests were Key words: Imipenem, Occupational asthma, read at 15 min and a wheal with a diameter of 3 mm Occupational rhinitis, Rhinomanometry or more was regarded as positive. - Skin and intradermal tests for penicillins according Hypersensitive reactions to drugs are poorly to a standardised diagnostic methods for antibiotics, understood. Most are believed to be immunological, often testing both the determinants, major and minor β- expressions of Gel and Coombs Type I reactions mediated lactam antibiotics, G penicillin, ampicillin and by IgE1). The immune mechanism and the amoxicillin4). Evaluation was assessed after 20 min, immunochemistry of these reactions, especially to and again 48 h later. Histamine as a positive control common offending agents, such as penicillin and other and saline as a negative control were employed. β-lactam antibiotics, have been extensively Reactions at least 3 mm > than controls for skin test characterised2). Hence skin testing procedures and and 5 mm for intradermal test were considered standardisation of intradermal allergens for confirmation positive5). Serum total IgE and specific IgE for of a suspected IgE-mediated allergy to such agents have penicilloyl G, penicilloyl V, ampicillin and been validated and are in common use3Ð6). Although amoxicilline, but not imipenem, which is not adverse drug reactions are commonly observed in patients commercialized, were detected by the commercial after the administration of antibiotics, occupational CAP-SYSTEM (Pharmacia Upjhon Uppsala Sweden) asthma due to penicillins has been described in healthcare following the manufacturer’s methods. and in pharmaceutical factory workers7). Imipenem is a - Basal respiratory function and bronchial challenge β-lactam broad spectrum antibiotic, used in treatment for with methacoline9). Gram positive and negative, aerobic and anaerobic - Aspecific nasal challenge with distilled water (5 ml bacteria8). Occupational exposure can also occur via in each nostril). inhalation in the manufacturing of the compound. The - Specific nasal challenge with thienamycin and commercialised antibiotic is a 1:1 mixture of N- cilistatin directly instilled into the nose (2 mg in each formimidoyl-thienamicyn, a proximate principle, and nostril mixed with 2 mg of lactose). cilistatin, an inhibitor of dehydropeptidase enzyme, which Before each nasal challenge baseline function was enhances urinary concentrations of an active drug. In assessed (within 10% of that on control days). this report we describe the case of a worker who presented The anterior nasal airflow resistence and the measure with respiratory symptoms which were initially of FEV-1 by spirometer, as a control of respiratory underestimated. The symptoms seemed to be related to function, were recorded at: 5, 15, 30, 60, 240, 300, 360 the activity in the workplace (on-off test positive). Our min after the nasal challenge. The nasal challenge was goal was to establish the cause of such symptoms. The considered positive if anterior nasal airflow resistence human study was conducted in accordance with the increase was >100% of the baseline. The symptoms recommendations outlined in the Declaration of Helsinki. (rhinorrea, nasal irritation, stuffy nose and sneezing) were The authors obtained informed consent from the study assessed from a scale of severity which was recorded by subject. either the patient or the observer10). Our observation showed: Case - the on-off test was positive, A 33 year-old female has been employed as a technician - specific inhalation challenge with imipenem revealed bronchoconstriction and a positive nasal response, Received Mar 3, 2000; Accepted Sept 1, 2000 whereas cilistatin challenge and lactose challenge Correspondence to: P. Marraccini, UOOML CEMOC, Istituti (control test) were negative. Clinici di Perfezionamento, Via Riva Villasanta, 11 20145 Milano, Only the nasal challenge with imipenem provoked a Italy rapid increase in anterior nasal airflow resistance after 5 Paolo MARRACCINI, et al.: Occupational Exposure to Imipenem 339

Fig. 1. Changes in nasal airflow resistance and FEV-1 after the challenge with imipenem (N-Formimidoyl-thienamycin).

min, which persisted for 4 h together with positive literature11). Nevertheless, it does not result in very symptoms. The measurement of FEV-1 (forced sensitive detection of eosinophils, whose number is expiratory volume-1) also showed a significant fall extremely variable: it seems reasonable that eosinophils (>20%) in the first hour (Fig. 1). All other tests were at least betray a hyperreactive state12). negative. It was possible to remove the worker from the No response to cutaneous and intradermal test and risk site (she spent two weeks at home). At the following specific IgE for the antigenic determinants of penicillins check up the nasal symptoms had disappeared nor did was observed, even if it is suggested that cross reactivity she have bronchospastic reactions. and allergic reactions to imipenem could occur in patients known to be allergic to penicillin as determined Discussion by the IgE antibodies titre13). We cannot exclude a To date, no cases of occupational rhinitis and/or asthma possible IgE mediated mechanism. Indeed, it should due to imipenem have been described in the literature, be considered that there is a different sensibility and even if penicillins are selected amongst the major causes specificity between the radioallergosorbent test (RAST) of occupational respiratory diseases7). and the CAP SYSTEM (Pharmacia Upjhon Uppsala The symptoms improved in this case when the worker Sweden). was removed from the specific inhalatory risk. The Saxon et al. found that close to 50% of individuals increase in nasal resistance and the rhinitis symptoms who had penicillin-positive skin tests demonstrated have been associated with a specific bronchial reactivity to one or more of the imipenem determinants14), obstructive reaction. These data suggest that imipenem but Patriarca has recently considered it safe to administer specifically acts on the respiratory tract, even though carbapenems to patients with previous adverse reactions we are not able to identify the mechanism. The to β-lactams15). Nevertheless, in our opinion, negative diagnosis of occupational rhinitis due to imipenem has specific IgE antibodies do not exclude allergy to been supported by a clinical history and by a positive penicillins, and a correct diagnostic approach, other than nasal challenge, oculo-rhinitis symptoms after the skin tests, is often due to the challenge test. Moreover challenge, associated with a bronchospastic reaction. occupational challenge tests have a medico-legal value16). We could not asses the eosinophilic leukocytes in nasal Our observation is probably due to the different discharge in the nasal challenge test because the structure of the antigenic nucleus. In fact imipenem is a recovery of secretions by lavage did not permit carbopenem β-lactam antibiotic, differing from the simultaneous, objective measures of the physiological molecular structure of penicillins, in that the 5-membered response to the challenge, as also reported in the ring is unsaturated and contains a carbon (-CH2-) other 340 J Occup Health, Vol. 42, 2000

References 1) Blanca M, Torres MJ, Garcia JJ, et al. Natural evolution of skin test sensitivity in patients allergic to β-lactam antibiotics. J Allergy Clin Immunol 1999: 103: 918Ð 924. 2) Saxon A, Beall GN, Rohr AS, et al. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107: 204Ð215. 3) De Leo VA. Skin testing in systemic cutaneous drug reactions. Lancet 1998; 352: 1488Ð1490. 4) Memorandum SIAIC sulla diagnosi di allergia/ intolleranza a farmaci. Giorn Ital Allergol Immunol Clin 1998; 8: 568Ð595. 5) Romano A, Di Fonso M, Papa G, et al. Evaluation of adverse cutaneous reactions to aminopenicillin with emphasis on those manifested by maculopapular rashes. Allergy 1995; 50: 113Ð118. 6) Sullivan TJ, Wedner Hj, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol 1981, 68: 171Ð180. Fig. 2. Structure of imipenem and penicillins. 7) Venables M, Chang Yeung M. Occupational asthma. Lancet 1997; 349: 1465Ð1469. 8) Remington JS. Carbapenem: a new class of antibiotics. than a sulphur atom. Even the antigenic determinants Am J Med 1985; 78 (suppl 6a): 1Ð167. made up of the side chains are notably different in 9) Eiser NM, Kerrebijn KF, Quanjer PH. Gudelines for imipenem (eg. the p-hydroxy group is missing) and the standardization of bronchial challenges with (non hydroxyethylic side chain is joined to the β-lactamic ring specific) bronchocostricting agents. Bull Eur in the trans position (Fig. 2). The cases in the literature Physiopath Respir 1983; 19: 495Ð514. 10) Van Cauwenberge PB, Specific diagnostic tests: of cross reactivity of imipenem and penicillin suggest 14) immuno-allergic diagnostic assays: provocation tests. that they exist, in vivo, in homologous conformations . In: de Campora E, ed. Rhinology today. Roma: Primary prevention (elimination of the agent from the Medicon Italia, 1990; 167Ð175. workplace by substitution or process change) was 11) Naclerio RM, Norman PS, Fish JE. In vivo methods obviously not possible, but a reduction in exposure has for the study of allergy. In: Middleton E, Reed CE, been achieved through isolation, enclosure and improved Ellis E et al., eds. Allergy principles and practice. local exhaust. Mosby Year Book Inc., 1993; vol I: 595Ð625. The periodic examination of workers in high risk 12) Ingels K, Durdurez JP, Cuvelier C, et al. Nasal biopsy industries can lead to early recognition and early removal is superior to nasal smear for finding eosinophil in from exposure sources. The relocation of the patient in nonallergic rhinitis. Allergy 1997; 52: 338Ð341. order to reduce exposure and the provision of respiratory 13) Hantson P, de Corninck B, Horn JL, et al. Immediate hypersensitivity to atrezonam and imipenem. BMJ protection can help to reach low or occasional exposure 1991; 302: 294Ð295. levels, although the worker would remain under medical 14) Saxon A, Adelman DC, Patel A, et al. Imipenem cross- supervision. This was the solution for the patient reactivity with penicillin in humans. J Allergy Clin investigated in this study, who was employed in a Immunol 1988; 82: 213Ð217. monitored work place, not directly exposed to the 15) Patriarca G, D’Ambrosio C, Schiavino D. Clinical compound, and protected by a positive pressure helmet usefulness of patch and challenge tests in the diagnosis respirator. of cell-mediated allergy to betalactams. Ann Allergy Further epidemiological studies are needed to evaluate Asthma Immunol 1999; 83: 257Ð266. the prevalence of the respiratory symptoms among 16) Gruppo di lavoro della Società Italiana di Allergologia workers in pharmaceutical industries, and to obtain better e Immunologia Clinica. Diagnosi delle malattie knowledge of the immunological mechanism. professionali da ipersensibilità: patologie respiratorie. Giorn It Allergol Immunol Clin 1991; 1: 625Ð653.