Immediate hypersensitivity to moxifloxacin with tolerance to ciprofloxacin: report of three cases and review of the literature.

OBJECTIVE: To report 3 cases of immediate hypersensitivity reactions to moxifloxacin in patients who tolerated ciprofloxacin. CASE SUMMARIES: A 71-year-old man, a 44-year-old woman, and a 70-year-old woman with a history of a moxifloxacin reaction developed an immediate hypersensitivity reaction upon oral challenge with moxifloxacin in our Drug Safety Clinic. The reaction was mainly characterized by pruritus and urticaria, although dyspnea and hypotension were noted in the first and second patient, respectively. Two of the patients had negative oral challenge tests with ciprofloxacin and all 3 patients tolerated full treatment courses of oral ciprofloxacin. In all 3 cases, use of the Naranjo probability scale indicated a highly probable adverse drug reaction. DISCUSSION: Moxifloxacin, similar to other fluoroquinolones, can cause immediate hypersensitivity reactions. Previous publications have reported both cross-reactivity and a lack of cross-reactivity among various fluoroquinolones. The 3 patients discussed demonstrated a lack of cross-reactivity between moxifloxacin and ciprofloxacin since they tolerated oral challenge tests and full treatment courses of ciprofloxacin. Moxifloxacin has unique side chains at positions 7 and 8 on its bicyclic ring structure. Antigenic specificity to particular side chains at positions 7 and 8 on the bicyclic ring structure of moxifloxacin may explain this lack of cross-reactivity. Higher reporting rates of anaphylaxis to moxifloxacin compared to other fluoroquinolones may also be related to side chain specificity, although definitive evidence for this is lacking. CONCLUSIONS: Based on our experience, patients who develop immediate hypersensitivity reactions to moxifloxacin may receive ciprofloxacin therapy in an appropriately monitored setting if they have previously tolerated full treatment courses of ciprofloxacin. Research into whether there is a specific side chain reaction unique to moxifloxacin is warranted.

Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review.

Anticonvulsant hypersensitivity syndrome (AHS), also known by the other names drug rash (reaction) with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS), is a rare and potentially fatal reaction that occurs in susceptible patients after exposure to certain drugs, including aromatic anticonvulsants. Because of its ill-defined clinical picture and resemblance to other diseases, the diagnosis of AHS is often difficult and requires a safe and reliable diagnostic test. The skin patch test has been proven to be very useful for prediction and diagnosis of some types of hypersensitivity reactions such as delayed drug eruptions to beta-lactam antibacterials. However, the diagnostic value of patch testing for AHS is yet to be determined and its negative predictive values (NPVs) and positive predictive values (PPVs) are still unknown. This systematic review attempts to evaluate the usefulness of patch tests in the diagnosis of AHS and to examine different technical aspects of patch testing that may contribute to its performance. We included studies in which aromatic anticonvulsant drugs are the likely causes of the hypersensitivity reaction. Analysis of original publications from 1950 to August 2008 and cited in PubMed, MEDLINE and EMBASE has revealed contradictory findings, possibly due mainly to the use of unstandardized methods. Numerous factors have been suggested to affect the final result of the test, including the following: type of drug tested; concentration of drug and vehicle used; timing of the test after exposure; and the clinical picture of the reaction. The PPV of the test in optimal conditions was as high as 80-90% depending on the drug tested. On the other hand, this value is around 10-20% in many other published studies. Although patch testing may be a useful diagnostic test for AHS, accurate determination of its sensitivity and specificity is yet to be achievable due to the lack of a gold standard test against which the performance of patch testing can be measured. Its PPV appears to be higher than its NPV, a matter that necessitates the use of other confirmatory tests in case of negative patch tests (e.g. careful systemic rechallenge). The benefit of testing appears to be maximal with certain drugs (i.e. carbamazepine and phenytoin) and for specific clinical manifestations (strong reactions). It should be performed 2-6 months after recovery from the date of the ADR for best results, with adequate vehicle control.

Sulfonamide Hypersensitivity: Fact and Fiction.

Sulfonamide antimicrobials are commonly reported as causing drug allergy and have been implicated in a variety of hypersensitivity reactions including immediate IgE-mediated reactions, benign T-cell-mediated rashes, and severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Cross-reactivity is unlikely between sulfonamide antimicrobials and sulfonamide non-antimicrobials. In patients who develop reactions to a sulfonamide non-antimicrobial, there is no evidence to suggest that sulfonamide antimicrobials and other sulfonamide non-antimicrobials would cross-react. Although immediate skin testing can be performed in patients with histories of immediate reactions, they are infrequently positive and wane over time. Delayed skin testing including patch tests to sulfonamides is rarely positive. Drug challenges are a useful tool for patients with both immediate and delayed reactions to sulfonamides. The role of sulfamethoxazole desensitization is controversial as rates of hypersensitivity reactions are similar between desensitization and drug challenge.

Management options for patients with aspirin and nonsteroidal antiinflammatory drug sensitivity.

OBJECTIVE: To evaluate and provide management strategies for patients with aspirin or nonselective nonsteroidal antiinflammatory drug (NSAID) sensitivity. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-March 2007) using the terms acetaminophen, aspirin, antiinflammatory agents nonsteroidal, urticaria, angioedema, asthma, leukotriene antagonists, desensitization, and tacrolimus. Article references retrieved were hand-searched for other relevant articles. STUDY SELECTION AND DATA EXTRACTION: All studies published in English were evaluated. Studies, review articles, and commentaries on aspirin-induced asthma and aspirin- or NSAID-induced urticaria/angioedema were included in the review. DATA SYNTHESIS: Aspirin sensitivity is most often manifested as respiratory reactions (eg, bronchospasm, profuse rhinorrhea, conjunctival injection) or urticaria/angioedema. The primary mechanism is believed to be inhibition of the cyclooxygenase 1 (COX-1) enzyme; as such, patients with aspirin sensitivity often display cross-reactions to nonselective NSAIDs that inhibit the COX-1 enzyme. Management strategies include avoidance of aspirin and cross-reacting nonselective NSAIDs. However, desensitization to aspirin is a viable option for patients with aspirin-induced respiratory reactions, especially for those who require aspirin for thromboembolic prophylaxis. Aspirin desensitization is maintained indefinitely with a daily aspirin dose. There is limited evidence of the use of leukotriene modifiers in preventing aspirin-induced asthma. COX-2 selective NSAIDs, especially in patients with aspirin-induced asthma, have not been found to cross-react. However, approximately 4% of patients with a history of aspirin-induced skin reactions may experience a cutaneous reaction following a challenge to a COX-2 selective NSAID. Since acetaminophen is a weak inhibitor of the COX-1 enzyme, patients with aspirin-induced asthma should not take more than 1000 mg of acetaminophen in a single dose. CONCLUSIONS: Management of patients with aspirin/NSAID sensitivity includes avoidance of aspirin/nonselective NSAIDs, use of COX-2 selective NSAIDs, acetaminophen in doses less than 1000 mg, and desensitization. The role of leukotriene modifiers requires further study before they can be recommended for patients.

Recognition and management of severe cutaneous drug reactions.

Cutaneous drug reactions are among the most common types of adverse drug reactions. This article focuses on the recognition and management of severe cutaneous drug eruptions, including the drug-hypersensitivity syndrome, serum sickness-like reaction, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Cutaneous reactions are considered severe when they can result in serious skin damage or involve multiple organs. Some of these reactions can cause significant morbidity or death. Each may be confounded by diagnostic difficulties, confusion in ascertaining causality, and treatment challenges.

Allergic reaction to fluorescein dye: successful one-day desensitization.

CASE REPORT: An 86-year-old woman developed IgE-mediated generalized urticaria after a second fluorescein injection. A one-day desensitization protocol was successfully administered that permitted continuation of angiography for deteriorating vision. COMMENTS: We review the literature on adverse events associated with administration of fluorescein and suggest guidelines for testing and desensitization.

Self-Monitoring of Blood Glucose: Impact of Quantity Limits in Public Drug Formularies on Provincial Costs Across Canada.

OBJECTIVES: For most patients with diabetes, routine use of blood glucose test strips (BGTS) has not been shown to be beneficial, yet the economic implications of broad publicly funded reimbursement for BGTS are substantial. We assessed the potential impact of BGTS quantity limits on utilization and costs for 6 publicly funded drug plans across Canada. METHODS: A cross-sectional analysis was conducted in 6 provinces (Alberta, Saskatchewan, Manitoba, Nova Scotia, Newfoundland and Labrador and Prince Edward Island) for patients who received at least 1 prescription for BGTS in 2014 through the public drug program. We determined the number of BGTS that would have exceeded the quantity limits and the associated costs to the provincial drug program. RESULTS: A total of $38,051,026 was spent on BGTS reimbursed through public drug programs among the 6 provinces. In provinces where BGTS use is largely restricted to patients using insulin, the potential annual savings were minimal, ranging from 0.4% to 2.3%, whereas in provinces with more liberal listings, potential savings ranged from 12.4% to 19.8%. Combining these results with data from a previous analysis in Ontario and British Columbia, the cost savings associated with BGTS quantity limits for 8 provinces across Canada (capturing approximately three-quarters of the Canadian population) is estimated to be $30.3 million annually. CONCLUSIONS: The national implementation of a quantity limit policy for BGTS that aligns with evidence of efficacy, optimal prescribing and patient safety can lead to considerable savings for most public drug plans across Canada.

Povidone-iodine-induced burn: case report and review of the literature.

Burns are a rare but potentially serious complication of povidone-iodine use. This rare adverse drug reaction developed in a 38-year-old woman who underwent laparoscopic right ovarian cystectomy and endometrial ablation as a day procedure involving application of the topical antiseptic 10% povidone-iodine solution. Two days later, the patient was admitted to the hospital with burning, pain, itching, marked redness, and blistering extending from her midback to buttocks. A stain on her back also was evident. Partial-thickness chemical burn was diagnosed. Review of the literature yielded 13 other cases of povidone-iodine-induced burn. This underrecognized adverse effect of povidone-iodine application typically occurs when the povidone-iodine has not been allowed to dry or has been trapped under the body of a patient in a pooled dependent position. The burn is usually seen immediately after the procedure or on the next day, and typically heals with minimum scarring within 3-4 weeks with conservative treatment. The commonly postulated mechanism is a chemical burn due to irritation coupled with maceration, friction, and pressure. Given the widespread use of povidone-iodine and the potential for development of infection after a burn, clinicians need to be aware of this possible povidone-iodine-associated adverse drug reaction, and of preventive measures.

Unintended medication discrepancies at the time of hospital admission.

BACKGROUND: Prior studies suggest that unintended medication discrepancies that represent errors are common at the time of hospital admission. These errors are particularly worthy of attention because they are not likely to be detected by computerized physician order entry systems. METHODS: We prospectively studied patients reporting the use of at least 4 regular prescription medications who were admitted to general internal medicine clinical teaching units. The primary outcome was unintended discrepancies (errors) between the physicians' admission medication orders and a comprehensive medication history obtained through interview. We also evaluated the potential seriousness of these discrepancies. All discrepancies were reviewed with the medical team to determine if they were intentional or unintentional. All unintended discrepancies were rated for their potential to cause patient harm. RESULTS: After screening 523 admissions, 151 patients were enrolled based on the inclusion criteria. Eighty-one patients (53.6%; 95% confidence interval, 45.7%-61.6%) had at least 1 unintended discrepancy. The most common error (46.4%) was omission of a regularly used medication. Most (61.4%) of the discrepancies were judged to have no potential to cause serious harm. However, 38.6% of the discrepancies had the potential to cause moderate to severe discomfort or clinical deterioration. CONCLUSIONS: Medication errors at the time of hospital admission are common, and some have the potential to cause harm. Better methods of ensuring an accurate medication history at the time of hospital admission are needed.

Clinical and immunogenetic correlates of abacavir hypersensitivity.

A patch test (PT) may be useful in defining true abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.

Hydrochlorothiazide-induced noncardiogenic pulmonary edema: an underrecognized yet serious adverse drug reaction.

Noncardiogenic pulmonary edema is a rare but potentially life-threatening complication of hydrochlorothiazide therapy. We describe three patients who developed this serious adverse reaction. A 64-year-old woman developed dypsnea and hypotension within 60 minutes of taking a single dose of hydrochlorothiazide 25 mg. She was admitted to the critical care unit with acute respiratory failure and subsequent multiple-organ dysfunction. The second patient was a 56-year-old woman who experienced sudden onset of shortness of breath that developed 10 minutes after taking a single dose of hydrochlorothiazide 25 mg. The third was a 59-year-old woman who developed sudden onset of shortness of breath, nausea, vomiting, and diarrhea after her first dose of hydrochlorothiazide-triamterene. All three women had a history of a similar, albeit minor, reaction to a thiazide diuretic. Review of the literature identified 36 additional cases of noncardiogenic pulmonary edema after thiazide use. The patients developed symptoms 10-150 minutes after ingestion of hydrochlorothiazide or another thiazide. Symptoms can occur on first exposure to the drug or in patients taking the drug intermittently. Of interest, 90% of documented cases occurred in women. With the increasing use of thiazide diuretics in the treatment of hypertension, clinicians need to be aware of the possible association of these drugs with the development of noncardiogenic pulmonary edema.

Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review.

BACKGROUND: Over a quarter of hospital prescribing errors are attributable to incomplete medication histories being obtained at the time of admission. We undertook a systematic review of studies describing the frequency, type and clinical importance of medication history errors at hospital admission. METHODS: We searched MEDLINE, EMBASE and CINAHL for articles published from 1966 through April 2005 and bibliographies of papers subsequently retrieved from the search. We reviewed all published studies with quantitative results that compared prescription medication histories obtained by physicians at the time of hospital admission with comprehensive medication histories. Three reviewers independently abstracted data on methodologic features and results. RESULTS: We identified 22 studies involving a total of 3755 patients (range 33-1053, median 104). Errors in prescription medication histories occurred in up to 67% of cases: 10%- 61% had at least 1 omission error (deletion of a drug used before admission), and 13%- 22% had at least 1 commission error (addition of a drug not used before admission); 60%- 67% had at least 1 omission or commission error. Only 5 studies (n = 545 patients) explicitly distinguished between unintentional discrepancies and intentional therapeutic changes through discussions with ordering physicians. These studies found that 27%- 54% of patients had at least 1 medication history error and that 19%- 75% of the discrepancies were unintentional. In 6 of the studies (n = 588 patients), the investigators estimated that 11%-59% of the medication history errors were clinically important. INTERPRETATION: Medication history errors at the time of hospital admission are common and potentially clinically important. Improved physician training, accessible community pharmacy databases and closer teamwork between patients, physicians and pharmacists could reduce the frequency of these errors.

Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada.

Although information on efficacy and adverse drug reactions is lacking, ribavirin has been used empirically for the treatment of severe acute respiratory syndrome (SARS). We report common adverse events in 110 patients with suspected or probable SARS who were treated with ribavirin. Sixty-one percent of the patients had evidence of hemolytic anemia, and hypocalcemia and hypomagnesmia were reported in 58% and 46% of patients, respectively.

Evaluation of the extent of under-reporting of serious adverse drug reactions: the case of toxic epidermal necrolysis.

INTRODUCTION: Toxic epidermal necrolysis (TEN) is a life-threatening adverse drug reaction (ADR) that is primarily the result of drug exposure (incidence 0.4-1.3 per million person-years). Life-threatening ADRs such as TEN should be reported to ADR monitoring programmes, which collect reports for suspected ADRs and alert the public and medical practitioners to new drug hazards. In Canada, reports are made to the Canadian Adverse Drug Reaction Monitoring Program (CADRMP). OBJECTIVE: To examine the extent of under-reporting for TEN in Canada. DESIGN: A retrospective case series design was used to collect all TEN cases for the period January 1995 to December 2000. METHODS: The CADRMP and 22 burn centres across Canada were contacted for all TEN patients treated during the specified time period. PATIENT GROUPS STUDIED: The study population consisted of patients admitted to burn treatment sites across Canada, patient cases reported to the CADRMP and patient cases recorded by the Canadian Institute for Health Information (CIHI) hospital discharge summaries as the International Classification of Diseases Version 9 Clinical Modification (ICD-9-CM) code 695.1. RESULTS: Twenty-five TEN cases (six fatal) were reported to CADRMP from January 1995 to December 2000. During this period, 14 (63.6%) burn treatment sites reported admission of 250 TEN cases. Hospital discharge summaries using the ICD-9-CM code 695.1 indicated that 4349 cases were admitted to hospital during this time period and it was estimated that 15.5% (n = 674) of these cases were TEN. Using the burn facility data as the denominator, 10% (25 of 250) of TEN cases were reported to CADRMP. Using CIHI data as a denominator, only 4% (25 of 674) of TEN cases were reported to CADRMP. CONCLUSIONS: There is serious under-reporting of TEN. Lack of reporting of life-threatening ADRs can compromise population safety. There is a need to increase awareness of ADR reporting programmes.

Safety of celecoxib in individuals allergic to sulfonamide: a pilot study.

OBJECTIVE: To evaluate cross reactivity between sulfonamide antimicrobials and celecoxib in patients with histories of allergies to sulfonamide antimicrobials. METHODS: Immunocompetent patients with a history of sulfonamide antimicrobial allergy who were being considered for therapy with celecoxib were prospectively enrolled. Sulfamethoxazole and trimethoprim skin prick and intradermal testing and/or an in vitro lymphocyte toxicity assay were performed. If skin testing was negative, an oral challenge with sulfamethoxazole and trimethoprim was performed. Oral challenges with celecoxib were administered to all patients. RESULTS: Twenty-eight immunocompetent patients (26 female; mean age 60 years) were evaluated. History of sulfonamide antimicrobial allergy included urticaria (n = 7), cutaneous eruptions (n = 9), and other (n = 12). Four of the 28 patients who were skin prick tested were positive to sulfamethoxazole and two of the ten patients who underwent in vitro testing were positive to sulfamethoxazole. All 28 patients were administered celecoxib and tolerated the medication. Phone call follow up in 25 patients disclosed that 15 patients continued to take celecoxib, while five patients did not take celecoxib following the oral challenge, and five discontinued celecoxib due to adverse effects, lack of drug efficacy or physician preference. CONCLUSIONS: Confusion exists regarding the potential for cross reactivity between sulfonamide antimicrobials and other sulfonamide-containing compounds. The six sulfonamide-allergic patients tolerated celecoxib uneventfully. This pilot study supports the hypothesis that the potential for cross-reactivity between celecoxib and sulfonamide antimicrobials appears to be low. However, further investigations are required to confirm this.

Reactive metabolites and adverse drug reactions: clinical considerations.

Idiosyncratic reactions can affect many different organ systems, either as -an isolated event (e.g., hepatitis) or as part of a syndrome (e.g., drug hypersensitivity syndrome). Formation of reactive metabolites of drugs in conjunction with a decreased ability for detoxification is believed to be the initiating step in many idiosyncratic reactions. The drug hypersensitivity syndrome, defined by the presence of fever, rash and internal organ involvement, is estimated to occur in approx 1 in 1000 to 1 in 10,000 exposures with drugs such as anticonvulsants sulfonamide antibiotics, allopurinol, and dapsone. Symptoms usually start within 2-8 wk of drug initiation. Serum sicknesslike reaction, most frequently found after 7-14 d of drug exposure, is distinguished by a fever, cutaneous eruption and arthralgias. Medications such as cefaclor, minocycline and bupropion are most frequently implicated in this reaction. In contrast, drug-induced lupus can occur l-2 yr after initiation of medication. Drug-induced lupus is characterized by musculoskeletal complaints and fever and weight loss. Drugs most commonly associated with drug-induced lupus include procainamide, hydralazine, chlorpromazine, isoniazid, and minocycline. Management of patients who develop idiosyncratic reactions includes discontinuation of the implicated drug, initiation of corticosteroids (when appropriate), and symptomatic relief as required. Internal organ involvement, which may initially be asymptomatic, should be monitored. Confirmatory or diagnostic tests are not readily available in most areas, except for research purposes.

Confirming false adverse reactions to drugs by performing individualized, randomized trials.

One-patient, randomized, double-blind, controlled trials (N-of-1 RCTs) have traditionally been used to assess the efficacy of treatment. At the Drug Safety Clinic, Toronto, this methodology is used to evaluate adverse effects related to medication use, specifically when the symptoms are vague and are in response to more than one medication. Two patients are described with histories of drug allergies to multiple medications; as well, guidelines for conducting N-of-1 trials are summarized. The first patient had a history of prolonged periorbital and generalized weakness lasting up to one week after exposure to a variety of drugs. Because of the ambiguous results of local anesthetic skin testing, an N-of-1 trial was performed using lidocaine without preservative. Two short-lived episodes of blepharospasm and lethargy were observed with placebo; no subjective or objective reaction occurred with active drug. The second patient had a history of prolonged weakness and drowsiness after exposure to many medications; she had been told that she was allergic to all drugs with a benzene ring. During the first N-of-1 trial, generalized weakness was observed with 10 mg of dimenhydrinate and all four placebo doses. During the second N-of-1 challenge using codeine, no unwarranted reactions occurred with either active or placebo drug. Traditional testing of these patients to disprove the clinical symptoms is often difficult because of the anxiety level associated with the patients' past experiences. N-of-1 trials provide a useful alternative for the management of patients with nonspecific symptomatology attributed to drug ingestion.

Skin eruption following the use of two Chinese herbal preparations: a case report.

OBJECTIVE: To describe a patient who developed a widespread skin eruption following the use of two Chinese herbal medications, Fang Feng Tong Sheng Wan and Bi Yan Pian. CASE SUMMARY: A 34-year-old man developed widespread erythematous papules that coalesced into plaques after five days of therapy with two Chinese herbal preparations. There was no lymphadenopathy or hepatosplenomegaly, and the patient denied any fever, chills or malaise. The skin biopsy was compatible with a drug eruption. When the patient's oral medications, including the herbal medications, were discontinued, the skin eruption resolved over the next few weeks. All of the regular long term medications were restarted without any sequalae. DISCUSSION: This case, once again, emphasizes that, although herbal medications are marketed as natural products, these products can be associated with adverse drug effects. Other adverse effects that have been implicated with the use of Chinese herbal medications include interstitial fibrosis, renal failure, liver toxicity and severe dermatitis. In addition, there are several cases of adulteration of Chinese herbal products with synthetic medications. CONCLUSION: Although rare, Chinese herbal medications can be associated with serious adverse effects. Clinicians should question patients about the use of herbal products whenever an adverse drug effect is suspected.

Drug eruptions: approaching the diagnosis of drug-induced skin diseases.

Adverse drug reactions are a major problem in drug therapy, and cutaneous drug reactions account for a large proportion of all adverse drug reactions. Cutaneous drug reactions are also a challenging diagnostic problem since they can mimic a large variety of skin diseases, including viral exanthema, collagen vascular disease, neoplasia, bacterial infection, psoriasis, and autoimmune blistering disease, among others. Furthermore, determining that a particular medication caused an eruption is often difficult when the patient is taking multiple drugs. In this review, we will describe and illustrate a thoughtful, comprehensive, and clinical approach to the diagnosis and management of adverse cutaneous drug reactions. A morphologic approach to drug eruption includes those that are classified as maculopapular, urticarial, blistering or pustular with or without systemic manifestations. Exanthematous drug eruptions, drug hypersensitivity syndrome, urticaria and angioedema, serum sickness-like reactions, fixed drug eruptions, drug-induced autoimmune blistering diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced acne, acute generalized exanthematous pustulosis, lichenoid drug eruptions and photosensitivity eruptions will be discussed.