原文全文
Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics
2021-09-25 20:44
先是在 AAAAI 網站看到磺胺類抗生素與非抗生素磺胺交叉反應的文章, 裡面提到2003年NEJM這篇. 所以把這篇也看一看, 做做筆記.
先說簡單的結論, 發生過磺胺類抗生素過敏的人, 當然也可以對非抗生素磺胺過敏, 但醫師應該要知道, 這類患者其實對任何所有藥物都可能過敏, 甚至發生 penicillin 過敏機率還超過非抗生素磺胺類(例如丹木斯), 所以磺胺類抗生素過敏, 並不是丹木斯過敏的好指標
過去認為磺胺類抗生素過敏, 會發生非抗生素磺胺過敏, 是基於理論推導, 並非真實的數據
底下的中文使用google自動翻譯
Abstract
BACKGROUND
The safety of sulfonamide nonantibiotics is unclear in patients with prior allergic reactions to sulfonamide antibiotics.
方法：
我們利用英國全科醫學研究資料庫進行了回顧性隊列研究，評估了服用磺胺類非抗生素藥物後30天內發生過敏反應的風險。研究對象為服用磺胺類抗生素後出現過敏反應證據的患者，與未出現此類證據的患者進行了比較。此外，我們也對使用青黴素取代磺胺類藥物的情況進行了類似的分析，以確定是否存在特定於磺胺類藥物交叉反應的風險。
結果：
969位服用磺胺類抗生素後出現過敏反應的患者中，96位（9.9%）在隨後服用磺胺類非抗生素藥物後出現過敏反應。 19,257位服用磺胺類抗生素後未出現過敏反應的患者中，315位（1.6%）在服用磺胺類非抗生素藥物後出現過敏反應（校正比值比為2.8；95%信賴區間為2.1-3.7）。然而，與此病史的患者相比，曾對磺胺類抗生素出現過敏反應的患者在服用青黴素後出現過敏反應的風險更高（校正比值比為3.9；95%置信區間為3.5-4.3）。此外，對於曾服用磺胺類抗生素後出現過敏反應的患者，後續服用磺胺類非抗生素後發生過敏反應的風險低於後續服用青黴素後發生過敏反應的風險（校正比值比為0.7；95%信賴區間為0.5-0.9）。最後，對於曾有磺胺類抗生素過敏史的患者，後續服用磺胺類非抗生素後發生過敏反應的風險低於對青黴素過敏史的患者（校正比值比為0.6；95%信賴區間為0.5-0.8）。
結論
服用磺胺類抗生素後的超敏反應與服用磺胺類非抗生素後的過敏反應之間存在關聯，但這種關聯似乎是由於易發生過敏反應，而不是與磺胺類藥物的交叉反應。
結果
：總體而言，使用廣義定義，4.8% 的患者（20,226 例中的 969 例）在初始使用磺胺類抗生素後 30 天內出現明顯過敏反應；使用狹義定義，0.4% 的患者（20,279 例中的 86 例）出現過敏反應。 （這些分母略有不同，因為我們使用廣義定義排除了更多既往疾病患者，而不是使用狹義定義。）兩組中，67.5% 的患者為女性，43.5% 的患者在接觸藥物時年齡在 65 歲及以上。
總體而言，根據廣義定義，2.0% 的患者（20,301 例中的 411 例）在隨後使用磺胺類非抗生素藥物後出現明顯的過敏反應，而根據狹義定義，0.1% 的患者（20,391 例中的 19 例）出現過敏反應。在全科醫學研究資料庫中，先前使用磺胺類抗生素後出現過敏反應的患者與此病史的患者在年齡（P=0.24）、性別（P=0.94）和追蹤時間長度（P=0.62）相似。
磺胺類非抗生素治療後，共9.7%的過敏反應（411例中的40例）嚴重到需要住院治療。我們複合終點中最常見的診斷是氣喘（411例中的288例，佔70.1%）、濕疹（411例中的58例，佔14.1%）和藥物不良反應（411例中的47例，佔11.4%）。根據我們對結果的狹義定義，比較結果並無實質差異。因此，除非另有說明，我們對所有後續結果均採用廣義定義。
使用磺胺類非抗生素藥物後發生超敏反應或過敏反應，與無此類病史相比，使用廣義定義（表2）時，未校正比值比為6.6（95%信賴區間，5.2-8.4），使用狹義定義時，未校正比值比為13.2（95%信賴區間，1.7-99.9）。僅納入症狀符合I型超敏反應或IgE介導反應（即過敏反應、支氣管痙攣、蕁麻疹、喉痙攣或血管性水腫）的患者亞組，結果實質上相同，但不精確，因為只有18例患者出現此類反應。
由於大多數患者（98.4%）的初始用藥為甲氧芐啶-磺胺甲噁唑，因此整體組與以甲氧芐啶-磺胺甲噁唑作為初始磺胺類抗生素的患者亞組的結果相同。根據後續處方的磺胺類非抗生素藥物對亞組進行分類時，結果也未發生顯著變化：單用噻嗪類利尿劑的未校正比值比為 5.7（95% 置信區間，4.0 至 8.3），單用袢利尿劑的未校正比值比為 7.0（95% 置信區間，單用袢利尿劑的未校正比素比為 7.0（95% 置信區間，5.5. 6.9（95% 信賴區間，3.0 至 15.9），其他磺胺類非抗生素的未校正比值比為 3.6（95% 信賴區間，0.2 至 72.3）。
在調查的大量潛在混雜因素中，我們發現唯一使比值比至少改變 15% 的變數是既往氣喘病史以及既往使用氣喘藥物和皮質類固醇的情況。校正後的比值比（校正性別、結果年齡、先前氣喘病史、先前使用氣喘藥物和皮質類固醇的情況後）為 2.8（95% 信賴區間，2.1 至 3.7）。 65 歲以下族群的比值比為 2.9（95% 信賴區間，1.9 至 4.2），65 歲及以上族群的比值比為 2.6（95% 信賴區間，1.7 至 4.0）。以停止磺胺類非抗生素治療（而非過敏反應）作為結果，先前對磺胺類抗生素的超敏反應並不是停止使用磺胺類非抗生素治療的預測因子（未調整的優勢比為 1.1；95% 信賴區間為 0.9 至 1.2）。
最後，為了正確看待上述結果（表2），對於先前服用磺胺類抗生素後出現過敏反應的患者，與未出現過敏反應的患者相比，服用青黴素後發生過敏反應的未調整比值比為7.8（95%置信區間，7.1-8.5），調整後的比值比為3.9（95%置信區間，7.1-8.5），調整後的比值比為3.9（95%置信區間，3.5-4.4.4.4.4%）。對於服用磺胺類抗生素後出現過敏反應的患者，與未出現過敏反應的患者相比，服用後續磺胺類非抗生素藥物後發生過敏反應的未調整比值比為0.7（95%置信區間，0.5-0.9），調整後的比值比為0.7（95%置信區間，0.5-0.9）。事實上，將曾經使用磺胺類抗生素後出現過敏症狀的患者與曾經使用青黴素後出現過敏症狀的患者進行比較，結果表明，在他們隨後使用磺胺類非抗生素藥物後 30 天內，過敏反應的發生率分別為 9.1%（889 人中的 81 人）和 14.6%（47363 人中的 69696%（47363 人的 6.信賴區間，0.4 至 0.7]；調整優勢比，0.6 [95% 信賴區間，0.5 至 0.8]）（表 2）。
討論
我們的研究結果表明，雖然對磺胺類抗生素過敏確實是隨後對磺胺類非抗生素藥物發生過敏反應的危險因素，但青黴素過敏史至少也是同樣重要的危險因素。在初步分析中最初發現的與磺胺類非抗生素藥物的關聯可能是透過某些患者普遍易患過敏反應來解釋的，而不是透過與含磺胺類藥物的特定交叉反應。因此，我們的結果表明，如果對既往有磺胺類過敏史的患者避免使用磺胺類非抗生素藥物，那麼對既往有青黴素過敏史的患者也必須避免使用。或者，也許更合理的是，處方人員應該簡單地理解，在服用磺胺類藥物或青黴素後有任何類型的過敏反應史的患者對其他藥物的反應風險可能會增加，而不是將磺胺類藥物視為特定的禁忌症。事實上，先前的數據已經表明，有藥物不良反應史會增加後續藥物不良反應的風險。 1,22 一些數據表明，過敏症患者對青黴素、23 放射性造影劑、24,25 麻醉劑、22 肌肉鬆弛劑、22 巴比妥類藥物、22 對乙醯氨基酚、26 非類固醇類抗發炎藥、27 和多種抗生素的反應風險更高。 28 其他數據表明，過敏症患者不會增加藥物超敏反應的風險，1,29,30 但他們的反應可能更嚴重。 1,22,31
儘管磺胺類藥物過敏難以預測且可能危及生命，但針對此類反應的系統研究卻很少，關於後續服用非抗生素磺胺類藥物後發生超敏反應風險的研究更是少之又少。了解這些風險尤其重要，因為磺胺類藥物過敏很常見。此外，磺胺類非抗生素藥物包含許多極為重要的藥理學類別。先前數據表明，對磺胺類非抗生素的過敏反應與對磺胺類抗生素的反應史之間存在關聯，但主要限於病例報告。 6,32-34 一篇統合分析對塞來昔布（一種含有芳基磺胺部分的抗發炎藥物）的臨床試驗數據進行分析，發現磺胺類藥物敏感性相關的過敏反應風險並未增加。 6 在兩家教學醫院進行的一項小型隊列研究未發現甲氧芐啶-磺胺甲噁唑與氨苯砜之間存在交叉反應。 35 我們採用了更大規模的世代研究，系統性地探討了有磺胺類藥物過敏史的患者對所有磺胺類非抗生素藥物發生過敏反應的風險。然而，我們無法納入一些較新藥物（包括塞來昔布）的使用數據。由於磺胺類藥物超敏反應的過敏原、半抗原和其他免疫機制尚未確定，因此無法使用免疫學方法研究這種風險。
一些限制可能影響了我們的結果。如果兩個研究組在結局資訊的完整性方面不對稱，則可能導致資訊偏差。然而，由於資訊來自電腦化的醫療記錄，結局評估並不依賴患者的回憶或訪談員。此外，我們也不依賴醫師對藥物不良反應的歸因分析。儘管全科醫學研究資料庫中有藥物誘發疾病的代碼，但我們無法確保全科醫生使用的是此類代碼，而不是結局本身的代碼（例如蕁麻疹）。因此，我們不願意做出這樣的區分。此外，此類病例報告中歸因關聯的有效性在許多情況下值得懷疑，因為臨床醫生無法確定蕁麻疹是由於患者接觸磺胺類抗生素引起的，還是與其他誘因有關，或者是特發性的。這種主觀判斷的有效性不確定，正是我們這樣的比較流行病學研究的必要性所在。
如果對有相關暴露的患者進行更密切的結局監測，而不是對未存在相關暴露的患者進行更密切的結局監測，即如果醫生更有可能在給予有磺胺類過敏史的患者使用非抗生素磺胺類藥物後監測其是否出現過敏反應，則可能出現所謂的診斷懷疑偏倚。然而，這種偏差會增加磺胺類藥物與青黴素類藥物比較時出現正相關性的風險，而我們發現的結果是負相關性。
如果結果未引起醫學關注，則可能會發生結果分類錯誤。但是，在我們的分析中，如果停用磺胺類非抗生素藥物是結果變量，則可能會發現這些錯誤。如果醫生沒有使用正式診斷來記錄較輕微的門診藥物反應（例如斑丘疹），也可能出現結果分類錯誤。由於我們依賴原始病歷，而不是理賠數據，因此這種可能性不太可能成為問題。此外，沒有理由認為這個因素在各研究組之間應該有所不同。如果患者有慢性過敏症狀（例如氣喘）並且恰好服用了磺胺類藥物，也可能發生結果分類錯誤。但是，我們在分析中控制了先前存在的過敏反應。
入組後病患流失（無論是因死亡或轉出診所）可能會引入選擇偏差。在英國全科醫生的病歷資料庫中，這種流失不太可能發生，而且兩個研究組的流失情況也不太可能不相等。
如果曾有磺胺類抗生素過敏反應的患者被開立非抗生素磺胺類藥物的可能性小於無此病史的患者，則也可能引入了選擇偏差。但是，當我們將服用初始磺胺類抗生素後 30 天內出現過敏反應的患者與未出現過敏反應的患者進行比較，檢查至少 60 天後被開具後續磺胺類非抗生素藥物的可能性時，我們發現相對風險為 1.13（95% 置信區間為 1.06 至 1.21）。換句話說，服用磺胺類抗生素後出現過敏反應的患者被開立後續磺胺類非抗生素藥物的可能性略高於無此病史的患者（17.0% 對 15.3%）。但是，有可能那些有某些類型初始反應的患者會優先避免後續接觸藥物。但是，無論初始反應是否符合我們的嚴格定義，或初始反應是否導致住院，我們的結果並沒有實質差異。因此，這樣的選擇過程似乎不太可能影響我們的結果。
最後，我們在分析中控制了大量潛在的混雜因素，發現先前存在的氣喘及其治療有顯著的混雜因素，這當然可能與後續氣喘以及抗生素和其他藥物的使用有關。我們也無法確定是否存在其他我們無法控制的變數。
因此，儘管磺胺類抗生素過敏史是後續接觸磺胺類非抗生素藥物風險增加的一個標誌，但我們的研究結果表明，這種風險並非磺胺類抗生素所獨有。事實上，有磺胺類抗生素過敏史的患者，後續對青黴素（一種生化性質不同的藥物）發生反應的風險甚至高於對非抗生素磺胺類藥物反應的風險。處方醫生應理解，有藥物過敏史的患者發生所有看似過敏性質的藥物引起的不良事件的風險都可能增加。
Abstract
BACKGROUND
The safety of sulfonamide nonantibiotics is unclear in patients with prior allergic reactions to sulfonamide antibiotics.
METHODS
We conducted a retrospective cohort study using the General Practice Research Database in the United Kingdom, examining the risk of allergic reactions within 30 days after the receipt of a sulfonamide nonantibiotic. Patients with evidence of prior hypersensitivity after the receipt of a sulfonamide antibiotic were compared with those without such evidence. Similar analyses were also performed with the use of penicillins instead of sulfonamides, to determine whether any risk was specific to sulfonamide cross-reactivity.
RESULTS
Of 969 patients with an allergic reaction after a sulfonamide antibiotic, 96 (9.9 percent) had an allergic reaction after subsequently receiving a sulfonamide nonantibiotic. Of 19,257 who had no allergic reaction after a sulfonamide antibiotic, 315 (1.6 percent) had an allergic reaction after receiving a sulfonamide nonantibiotic (adjusted odds ratio, 2.8; 95 percent confidence interval, 2.1 to 3.7). However, the risk of allergic reactions was even greater after the receipt of a penicillin among patients with a prior hypersensitivity reaction to a sulfonamide antibiotic, as compared with patients with no such history (adjusted odds ratio, 3.9; 95 percent confidence interval, 3.5 to 4.3). Furthermore, among those with a prior hypersensitivity reaction after the receipt of a sulfonamide antibiotic, the risk of an allergic reaction after the subsequent receipt of a sulfonamide nonantibiotic was lower than the risk of an allergic reaction after the subsequent receipt of a penicillin (adjusted odds ratio, 0.7; 95 percent confidence interval, 0.5 to 0.9). Finally, the risk of an allergic reaction after the receipt of a sulfonamide nonantibiotic was lower among patients with a history of hypersensitivity to sulfonamide antibiotics than among patients with a history of hypersensitivity to penicillins (adjusted odds ratio, 0.6; 95 percent confidence interval, 0.5 to 0.8).
CONCLUSIONS
There is an association between hypersensitivity after the receipt of sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a sulfonamide nonantibiotic, but this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.
Results
Overall, 4.8 percent of patients (969 of 20,226) had an apparent allergic reaction within 30 days after receiving the initial sulfonamide antibiotic with use of the broad definition, and 0.4 percent (86 of 20,279) had an allergic reaction with use of the narrow definition. (These denominators differ slightly, because we excluded more patients with prior disease using the broad definition than using the narrow definition.) In both groups, 67.5 percent of patients were female and 43.5 percent of patients were 65 years of age or older at the time of exposure.
Overall, 2.0 percent of patients (411 of 20,301) had an apparent allergic reaction after subsequently receiving a sulfonamide nonantibiotic with use of the broad definition, and 0.1 percent (19 of 20,391) did so with use of the narrow definition. Patients with prior hypersensitivity after sulfonamide antibiotics and those without such a history were similar with respect to age (P=0.24), sex (P=0.94), and duration of follow-up in the General Practice Research Database (P=0.62).
A total of 9.7 percent of allergic reactions after the sulfonamide nonantibiotics (40 of 411) were serious enough to require hospitalization. The most common diagnoses included in our composite end point were asthma (288 of 411, or 70.1 percent), eczema (58 of 411, or 14.1 percent), and adverse drug reactions (47 of 411, or 11.4 percent). With the use of our narrow definition of outcome, the comparative results were not substantively different. Therefore, we used the broad definition for all subsequently presented results, unless specified otherwise.
The unadjusted odds ratio for the association between hypersensitivity or allergic reactions after receipt of a sulfonamide nonantibiotic and a history of hypersensitivity or allergic reactions to sulfonamide antibiotics, as compared with no such history, was 6.6 (95 percent confidence interval, 5.2 to 8.4) with use of the broad definition (Table 2) and 13.2 (95 percent confidence interval, 1.7 to 99.9) with use of the narrow definition. Results that included only the subgroup of patients whose symptoms were consistent with those of type I hypersensitivity or IgE-mediated reaction (i.e., anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) were substantively the same but imprecise, since only 18 patients had such reactions.
Since the majority of patients (98.4 percent) received trimethoprim–sulfamethoxazole as the initial drug, the results were identical between the group as a whole and the subgroup of patients who received trimethoprim–sulfamethoxazole as their initial sulfonamide antibiotic. The results also did not change substantively when the subgroups were classified according to the subsequent sulfonamide nonantibiotic that was prescribed: the unadjusted odds ratio was 5.7 (95 percent confidence interval, 4.0 to 8.3) for thiazides alone, 7.0 (95 percent confidence interval, 5.1 to 9.3) for loop diuretics alone, 6.9 (95 percent confidence interval, 3.0 to 15.9) for sulfonylureas alone, and 3.6 (95 percent confidence interval, 0.2 to 72.3) for other sulfonamide nonantibiotics.
Of the large number of potential confounders investigated, we found that the only variables that changed the odds ratio by at least 15 percent were preexisting asthma and prior use of asthma medications and corticosteroids. The adjusted odds ratio (after controlling for sex, age at outcome, and the presence or absence of preexisting asthma, prior use of asthma medications, and prior use of corticosteroids) was 2.8 (95 percent confidence interval, 2.1 to 3.7). The odds ratio was 2.9 (95 percent confidence interval, 1.9 to 4.2) for those younger than 65 years old and 2.6 (95 percent confidence interval, 1.7 to 4.0) for those 65 years of age or older. With the use of cessation of the sulfonamide nonantibiotic therapy (instead of allergic reactions) as the outcome, prior hypersensitivity to sulfonamide antibiotics was not a predictor for stopping therapy with a sulfonamide nonantibiotic (unadjusted odds ratio, 1.1; 95 percent confidence interval, 0.9 to 1.2).
Finally, to place the above results in perspective (Table 2), the unadjusted odds ratio for an allergic reaction after the receipt of a prescription for a penicillin for those with a prior reaction after a sulfonamide antibiotic, as compared with those without such a reaction, was 7.8 (95 percent confidence interval, 7.1 to 8.5), with an adjusted odds ratio of 3.9 (95 percent confidence interval, 3.5 to 4.3). Among those with an allergic reaction after receiving a sulfonamide antibiotic, the unadjusted odds ratio for an allergic reaction to a subsequent sulfonamide nonantibiotic, as compared with a subsequent penicillin, was 0.7 (95 percent confidence interval, 0.5 to 0.9), and the adjusted odds ratio was 0.7 (95 percent confidence interval, 0.5 to 0.9). Indeed, comparing patients with prior evidence of hypersensitivity after sulfonamide antibiotics with patients with prior evidence of hypersensitivity after penicillins showed that an allergic reaction occurred in 9.1 percent (81 of 889) and 14.6 percent (693 of 4736), respectively, within 30 days after they had received a subsequent sulfonamide nonantibiotic drug (unadjusted odds ratio, 0.6 [95 percent confidence interval, 0.4 to 0.7]; adjusted odds ratio, 0.6 [95 percent confidence interval, 0.5 to 0.8]) (Table 2).
Discussion
Our results suggest that, although allergy to a sulfonamide antibiotic is indeed a risk factor for a subsequent allergic reaction to a sulfonamide nonantibiotic, a history of penicillin allergy is at least as strong a risk factor. The association initially seen in the primary analysis with the sulfonamide nonantibiotics might be explainable by a general predisposition to allergic reactions among certain patients rather than a specific cross-reactivity with drugs containing the sulfa moiety. Thus, our results suggest that, if sulfonamide-based nonantibiotics were to be avoided in those with a prior sulfa allergy, they would also have to be avoided in those with a prior penicillin allergy. Alternatively, and perhaps more rationally, prescribers should simply understand that patients with a history of any type of allergic reaction after the receipt of sulfonamides or penicillins may be at increased risk for reactions to other drugs, rather than consider sulfonamides a specific contraindication. Indeed, previous data have indicated that a history of an adverse drug reaction increases the risk of a subsequent adverse drug reaction.1,22 Some data suggest that persons with atopy are at higher risk for reactions to penicillin,23 radiocontrast dye,24,25 anesthetics,22 muscle relaxants,22 barbiturates,22 acetaminophen,26 nonsteroidal antiinflammatory drugs,27 and multiple antibiotics.28 Other data indicate that persons with atopy are not at increased risk for a drug hypersensitivity reaction,1,29,30 but that they may have more severe reactions.1,22,31
Although sulfonamide allergy is unpredictable and potentially life-threatening, there are few systematic investigations of these reactions and even fewer studies of the risk of hypersensitivity reactions after the subsequent receipt of a nonantibiotic sulfonamide. Understanding these risks is especially important, because sulfonamide allergy is common. In addition, sulfonamide nonantibiotics include members of many extremely important pharmacologic classes. Previous data indicating a link between an allergic reaction to a sulfonamide nonantibiotic and a history of a reaction to a sulfonamide antibiotic are limited primarily to case reports.6,32-34 One meta-analysis of data from clinical trials of celecoxib, an antiinflammatory agent containing an arylsulfonamide moiety, found no increased risk of an allergic reaction related to sulfonamide sensitivity.6 A small cohort study at two teaching hospitals did not find cross-reactivity between trimethoprim–sulfamethoxazole and dapsone.35 We used a much larger cohort to explore systematically the risk of allergic reactions to all sulfonamide nonantibiotics in patients with a history of sulfonamide allergy. However, we could not include data on the use of some newer drugs, including celecoxib. Because allergens, haptens, and other immune mechanisms for sulfonamide hypersensitivity have not been identified, this risk could not be studied with the use of immunologic methods.
Several limitations may have influenced our results. Information bias could have resulted if the two study groups were asymmetric with respect to the completeness of the information on outcomes. However, the assessment of outcome was not dependent on the patients' recall or on interviewers, since the information was obtained from computerized medical records. Furthermore, we did not rely on physicians' attribution of adverse drug reactions. Although there are codes in the General Practice Research Database for drug-induced disease, we have no way of ensuring that the general practitioners used such a code rather than a code for the outcome itself (e.g., urticaria). Therefore, we were hesitant to make such a distinction. In addition, the validity of the attributed link in such case reports is questionable in many instances, because a clinician cannot always determine whether urticaria is due to a patient's exposure to a sulfonamide antibiotic, is related to another precipitant, or is idiopathic. The uncertain validity of such subjective judgments is why comparative epidemiologic studies such as ours are needed.
So-called diagnostic suspicion bias could have occurred if patients who had the exposure of interest were more closely monitored for the outcome of interest than those without this exposure; that is, if physicians were more likely to monitor patients with a history of sulfa allergies for allergic reactions after administering a nonantibiotic sulfonamide. However, such bias would have increased the risk of a positive association in the comparison of sulfonamides with penicillins, in contrast to the inverse association that we found.
Outcome misclassification might have occurred if the outcomes did not come to medical attention. However, they would have been detected in our analyses in which cessation of sulfonamide nonantibiotics was the outcome variable. Outcome misclassification could also have occurred if physicians did not use a formal diagnosis to document milder outpatient drug reactions, such as maculopapular rashes. Since we relied on primary medical records, not on claims data, this possibility is less likely to have been a problem. In addition, there is no reason why this factor should have differed between the study groups. Outcome misclassification could also have occurred if a patient had chronic allergic symptoms (e.g., asthma) and coincidentally took a sulfonamide. However, we controlled for preexisting allergic reactions in the analysis.
A selection bias might be introduced from the loss of patients after enrollment (either due to death or to transfer out of the practice). Such a loss is unlikely in a medical-record data base of general practitioners in the United Kingdom and was unlikely to be unequal in the two study groups.
Selection bias could also have been introduced if a patient with a prior sulfonamide antibiotic reaction were less likely to be prescribed a nonantibiotic sulfonamide than a patient with no such history. However, when we compared those with an allergic reaction within 30 days after receipt of the initial sulfonamide antibiotic with those without such a reaction, examining the probability of being prescribed a subsequent sulfonamide nonantibiotic at least 60 days later, we found a relative risk of 1.13 (95 percent confidence interval, 1.06 to 1.21). In other words, those with an allergic reaction after a sulfonamide antibiotic were slightly more likely to receive a subsequent sulfonamide nonantibiotic than those without such a history (17.0 percent vs. 15.3 percent). It is possible, however, that those with certain types of initial reactions were preferentially steered away from subsequent exposures. However, our results did not differ substantively according to whether the initial reaction did or did not meet our strict definition or whether the initial reaction did or did not result in hospitalization. Thus, it seems very unlikely that such a selection process could have affected our results.
Finally, we controlled for a large number of potential confounders in the analyses, and substantial confounding was seen from preexisting asthma and its treatment, which can, of course, be related both to subsequent asthma and to the use of antibiotics and other medications. We also cannot be certain that there were no other variables for which we could not control.
Thus, although a history of allergy to sulfonamide antibiotics is a marker of increased risk on subsequent exposure to sulfonamide nonantibiotics, our results suggest that this risk is not unique to sulfonamide antibiotics. Indeed, patients with a history of hypersensitivity to sulfonamide antibiotics are at even greater risk for subsequent reactions to penicillins, a biochemically distinct group, than to nonantibiotic sulfonamides. Prescribers should understand that patients with a history of allergic reactions to drugs may be at increased risk for all drug-induced adverse events that appear to be allergic in nature.
