Ivan Dobrić

Ivica Grgurević

Jadranka Morović-Vergles

Neven Tudorić

Vladimir Gašparović

Vlatko Pejša

English

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133Acta Dermatovenerol Croat                   2008;16(3):133-137                           CASE REPORTFatal Toxic Epidermal Necrolysis and Severe Granulocytopenia Following Therapy with Cefuroxime Ivica Grgurević1, Vlatko Pejša1, Jadranka Morović-Vergles1, Ivan Dobrić2, Vladimir Gašparović3, Neven Tudorić1 1University Department of Medicine, Dubrava University Hospital; 2University Department of Dermatology and Venereology, and 3Department of Emergency and Intensive Care Medicine, University Department of Medicine, Zagreb University Hospital Center and School of Medicine, Zagreb, CroatiaCorresponding author: Ivica Grgurević, MDUniversity Department of MedicineDubrava University HospitalAvenija Gojka Šuška 6HR-10000 ZagrebCroatia ivica.grgurevic@zg.htnet.hrReceived: December 27, 2007Accepted: July 21, 2008SUMMARY Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure. KeY woRdS: epidermal necrolysis, toxic; Stevens-Johnson syndrome; cefuroxime; furosemide; kidney failure, chronic; neutropeniaIntRodUCtIonToxic epidermal necrolysis (TEN) or Lyell’s syndrome is a life threatening cutaneous reaction most commonly induced by various drugs (1-4). The incidence of TEN and Stevens-Johnson syn-drome (SJS) has been estimated to 0.4-1.2 cases per million per year based on retrospective stud-ies (5-8). In a prospective study from Germany the incidence of SJS and TEN was calculated to be 1.89 cases per million per year (3). The domi-nant causative agents are various drugs although association with some other conditions has also been described (e.g., graft versus host reac-tion, malignant disorders, infections, etc.) (1-4). Drugs most frequently associated with TEN are 134 ACTA DERMATOVENEROLOGICA CROATICAsulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, chlormezanone and allopurinol (9). Among recently marketed drugs, nevirapine, lamotrigine and sertraline have been significantly associated with TEN (10). Con-troversies regarding the possible role of cortico-steroids as causative agents in several cases of TEN (9) have not yet been resolved as they have been usually prescribed along with some other drugs with a known potential for TEN induction (10). Although the pathogenetic mechanisms re-sponsible for TEN have not yet been fully clarified, it is widely accepted that it is a hypersensitivity reaction mediated dominantly by cytotoxic CD8+ lymphocytes (11).The onset of the disease usually occurs within 4 weeks of the initiation of causative agent therapy and manifests with general symptoms such as fe-ver, malaise and arthralgias, which are followed by mucocutaneous eruptions that appear 1-3 days later (12) and progress rapidly to bullous formation and detachment of large areas of the epidermis (1-4,10). Etiologic diagnosis is based on the dynam-ics of events that occur within a typical period of time after particular drug exposure. In vitro hyper-sensitivity tests are neither specific nor sensitive enough, whereas in vivo provocation tests confer high risk since re-exposure is likely to elicit a new episode of TEN of increased severity (4,13). Medi-cations and procedures reported to be efficacious in the treatment of TEN include corticosteroids (14), cyclophosphamide (15), cyclosporine A (16), plasmapheresis (17), and intravenous immuno-globulins (IVIG) (18). Despite all these measures the mortality is still high and reaches 30%-40% (1,2). In a certain number of cases granulocyto-penia occurs along with TEN. Based on the anal-ysis of cases and series of patients reported so far, granulocytopenia, impaired renal function and older age have been recognized as variables as-sociated with worse prognosis (19,20).  Cefuroxime induced TEN is an extremely rare condition anecdotally registered by the manufac-turer during the post-marketing follow up. In medi-cal literature only a single case report has been published so far (21). However, no case of simul-taneous occurrence of TEN and severe granulo-cytopenia following the treatment with cefuroxime has been described until now. Furthermore, the possible unfavorable influence of concomitantly prescribed medications through different path-ways of interactions on the development of these threatening conditions is emphasized.CASe RepoRtA 73-year-old woman with a history of partial strumectomy in her youth, arterial hypertension, chronic renal failure (CRF) (grade II/IV) and no previous history of allergic diathesis had been treated with cefuroxime axetil (2x500 mg/day per os for 10 days) for urinary tract infection caused by Escherichia coli. Her previous medication for hypertension and CRF included lisinopril, furose-mide and CaCO3. Eight days following the com-pletion of cefuroxime therapy, fever, malaise, ar-thralgias, skin rash and pruritus developed. The patient was prescribed antihistaminics (loratadine tablets) by her family physician. Because this therapy proved inefficient, the patient presented to the Emergency Department of our hospital. The patient was subfebrile, complaining of arthralgias, malaise and itching. Physical examination re-vealed atypical target lesions densely distributed over her face and truncal region, and to a lesser extent over extremities. Several blisters filled with serous to sanguinolent fluid as well as areas of scaled epidermis were already formed on her face, dorsal regions, hands and feet (Fig. 1). Nikolsky’s sign (dislodgement of epidermis by lateral pres-sure) was positive. Buccal mucosa and lips were affected with ulcerations, along with bilateral se-vere keratoconjunctivitis. There were no lesions of genital mucosa. The patient was hypertensive (180/90 mm Hg), with otherwise normal cardiocir-culatory and respiratory status at that time. Com-plete blood count as well as cytologic analysis of bone marrow specimen obtained by sternal punc-ture indicated leukopenia (leukocytes 1.09x109/L) with severe granulocytopenia (absolute number Figure 1. The patient in the initial stage of the dis-ease. Areas of scaled, necrotic epidermis on the skin of the face and forehead, with bilateral con-junctival involvement.Grgurević et al.      Acta Dermatovenerol CroatCefuroxime-induced TEN and granulocytopenia      2008;16(3):133-137135ACTA DERMATOVENEROLOGICA CROATICAof granulocytes 480/μL). The relevant results of blood tests obtained 3 months prior to hospital admission during routine check-up and compara-tive results at hospital admission on day +19 fol-lowing exposure to cefuroxime are presented in Table 1. The diagnosis of Lyell’s syndrome was confirmed by skin biopsy, which revealed necrotic epidermis, subepidermal separation of the epider-mis and pronounced edema of the dermis with sparse mononuclear infiltrate and no neutrophils. Direct immunofluorescence showed no immune deposits in these specimens. All medications pre-viously used were withdrawn. Treatment with cor-ticosteroid (methyl prednisolone 125 mg/day intra-venously (iv)), antimicrobial agents (ciprofloxacin 400 mg/day iv), fluid replacement with crystalloids and colloids, along with local corticosteroid thera-py, fish oil and topical antimicrobial agents (genta-micin) was started. Despite these measures, skin lesions progressed, leading to detachment of the epidermis from the entire face, hand dorsa and a large part of her back (>30% of the body surface area) (22). During the next period the condition was complicated by sepsis caused by methicillin resistant Staphylococcus epidermidis (MRSE) and gastrointestinal hemorrhage (hemorrhagic esoph-agitis). After transient improvement, leukopenia recurred and persisted throughout the course of the disease, and total serum proteins fell to 37 g/L as the result of protein loss through denuded skin. Despite intensive medical treatment at Intensive Care Unit, the patient’s condition steadily wors-ened, with the development of multiple organ fail-ure (MOF) syndrome, and she died 38 days from the disease onset.discussionOur case report shows that cefuroxime, other-wise an efficacious and widely used antimicrobial (23,24), is an agent capable to induce fatal ad-verse effects such as TEN and severe granulocy-topenia. To the best of our knowledge, this is the first description of their simultaneous occurrence following the treatment with cefuroxime. Only a single case of TEN believed to be caused by ce-furoxime has been published in the literature until now (21). In that case, therapy with cefuroxime (3x1.5 g/day iv) was initiated for urinary tract in-fection in a cirrhotic patient that had been treated with furosemide and spironolactone for several years. Twenty-four hours later, TEN developed, followed by ischemic hepatitis on day 6, and the patient died. In our patient, TEN developed 18 days of the initiation of treatment with cefuroxime axetil. Before that, the patient had been treated with lisinopril, furosemide, acetylsalicylic acid and CaCO3 for 3 months for CRF. Although all these drugs (except for CaCO3) have previously been reported as causative agents in several cases of TEN (3) and no hypersensitivity testing was per-formed in our patient because of the known limita-tions and hazards of these tests, we believe that in our case the association of cefuroxime and TEN development is obvious. Namely, the development of the clinical picture upon initiation of cefuroxime therapy followed a time pattern characteristic of TEN induced by drugs. It is interesting to note that in both these cases of cefuroxime induced TEN, patients were also taking furosemide. One could hypothesize that it is probably not a coincidence that both patients went on to develop TEN. In our case, there are some additional reasons to believe so. First, drug interactions can be facilitated in conditions of their altered pharmacokinetics (and renal failure as in case of our patient is one of the best examples of such a condition). Second, the manufacturer of cefuroxime warns against simul-taneous use of furosemide because of potenti-ated nephrotoxicity (23). And finally, in our case the dose of cefuroxime was not adjusted to the renal function. All these facts taken together al-low us to conclude that cefuroxime is an agent table 1. Values of blood tests obtained 72 days prior and 19 days after cefuroxime introduction in therapy 3 months before hospital admission (72 days before cefuroxime introduction)At hospital admission (day 19 of cefuroxime  introduction)Serum creatinine (μmol/L) 300 213WBC (Nx109) 7.1 1.09Granulocytes (N/mm3) 5100 480Hemoglobin (g/L) 88 83Total protein (g/L) 66 67C-reactive protein (mg/L) 2.1 102Grgurević et al.      Acta Dermatovenerol CroatCefuroxime-induced TEN and granulocytopenia      2008;16(3):133-137136capable to induce these threatening adverse ef-fects; for this scenario the interaction with furose-mide might be a facilitating event (especially when occurring in a patient with impaired renal function). Along with TEN, severe granulocytopenia devel-oped in our patient and this is the first description of such an association (following the cefuroxime ingestion). According to the manufacturer’s infor-mation, granulocytopenia itself has been identi-fied during the post-marketing follow up as one of the rare adverse events to cefuroxime, but the exact incidence could not been estimated due to insufficient data (23). Neither of these two cases of cefuroxime induced TEN was treated by IVIG, a therapeutic modality that could be efficacious in stopping the progression of the disease according to some reports (18). However, Bachot et al. found no benefit of IVIG treatment on either mortality or disease progression (25). Even more, the use of IVIG was associated with worse outcome, espe-cially in patients with previously impaired renal function. Corticosteroids that were used as part of the therapeutic regimen in our patient did not stop progression of the disease, which is consistent with the reports of several authors (26,27). Accord-ing to the same sources, corticosteroids may play a limited role in the very beginning of the patho-logic process, but their protracted use is probably harmful rather than beneficial. It also appears that corticosteroids cannot prevent the development of SJS/TEN, the observation derived from the stud-ies in patients that had been placed on long-term corticosteroid treatment for some other systemic disease (28). In a recently published retrospective analysis of 281 patients included in the EuroS-CAR study, the authors found no strong evidence for the benefit for any specific treatment (IVIG vs. IVIG + corticosteroids vs. corticosteroids) in com-parison to only supportive care (29). Only a trend of a beneficial effect of corticosteroids has been observed in that study. In conclusion, cefuroxime is an agent capable to simultaneously induce fatal adverse reactions such as TEN and severe granulocytopenia. Inter-action with furosemide might be a facilitating event for this scenario. This warns of precaution when considering drug combinations, especially in a setting of CRF. References1.   Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Toxic epidermal necrolysis. In: Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Dermatology, 2nd edition. Berlin: Springer; 2000. pp. 414-6.2.   Becker DS. Toxic epidermal necrolysis. Lan-cet 1998;351:1417-22.3.   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Fatal Toxic Epidermal Necrolysis and Severe Granulocytopenia Following Therapy with Cefuroxime

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