Associations of HLA and drug-metabolizing enzyme genes in co-trimoxazole-induced severe cutaneous adverse reactions

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B¹13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66–26.77, P = 2.94 × 10⁻⁴, Pc = 0.0126). Moreover, the HLA-C¹08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18–33.14, P = 8.60 × 10⁻⁴, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.     

OUTBREAK OF CO-TRIMOXAZOLE- and GENTAMICIN-RESISTANT KLEBSIELLA AEROGENES BACTEREMIA IN NEUTROPENIC PATIENTS RECEIVING ORAL CO-TRIMOXAZOLE PROPHYLAXIS

Over a five-day period, three neutropenic patients developed bacteremia with an identical strain of Klebsiella aerogenes (serotype K16) resistant to co-trimoxazole and gentamicin. All three patients had received prophylaxis with oral co-trimoxazole before the onset of bacteremia. This report outlines some of the problems associated with co-trimoxazole prophylaxis. (Aust NZ J Med 1983; 13: 636–638.)     

Is SAPHO syndrome a target for antibiotic therapy?

The etiology of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome remains unclear. Infectious factors are proposed to be relevant in the etiopathogenesis of the disease. To our knowledge, this is the first reported case of a proposed relationship between Staphylococcus aureus cultured from plantar pustule and SAPHO syndrome, which was successfully treated with co-trimoxazole (CTM) (sulfamethoxazole/trimetoprim). CTM might be the drug of choice for therapy for SAPHO syndrome because of combined antibiotic and immunomodulatory properties. Hypersensitivity testing of the medication in vitro was performed to identify, in the preclinical stage, the hypersensitivity reaction to CTM, which may have been severe.     

复方新诺明预防治疗对艾滋病患者生存状况的影响

目的 了解复方新诺明（CTX）预防治疗对河南省接受国家免费抗病毒治疗（ART）的艾滋病患者生存状况的影响。方法 利用“中国疾病预防控制系统-艾滋病综合防治信息系统”收集的河南省2007－2011 年加入国家免费ART艾滋病患者资料,根据开始接受ART时既往CTX使用情况,将研究对象分为既往未服用、既往服用过现仍服用和既往服用过现未服用3 组,采用Kaplan-Meier 法绘制生存曲线,运用Cox比例风险回归模型分析CTX预防治疗对艾滋病患者生存状况的影响。结果 13 103 名艾滋病患者中共有1 702 名死亡,死亡率为4.46/100 人年,开始治疗3 个月和12 个月内分别死亡455 人和970 人,死亡率分别为14.15/100 人年和7.78/100 人年。开始ART时既往未服用、既往服用过现仍服用和既往服用过现未服用CTX三组中以既往服用过现仍服用组的生存期（M＝0.98 年,IQR：0.25～2.16）最长,Kaplan-Meier 生存曲线显示,开始治疗时既往服用过现仍服用CTX 组生存时间长于既往未服用CTX 组,死亡率低于既往未服用CTX 组,log-rank 检验显示,开始治疗12 个月内的两组间差异有统计学意义（log-rank＝5.15,P＝0.02）。多因素分析发现,研究对象开始治疗时年龄、性别、婚姻状况、传播途径、确认阳性到开始治疗的时间、基线CD₄^＋T 淋巴细胞计数、临床分期、初始治疗方案、CTX服用情况、开始治疗时年份、基线症状数、最近7 d 是否漏服与生存时间存在统计学关联,其中既往使用过现仍服用CTX组的死亡风险低于既往未服用CTX组（调整HR＝0.71,95%CI：0.63～0.80,P＝0.00）。结论 艾滋病ART开始时既往CTX预防治疗可以降低艾滋病患者的死亡风险,特别是在开始治疗的第1 年内效果明显。     

非水滴定法测定双嘧啶片和复方新诺明片中TMP、SD和SMZ的含量

先将样品乙酰化以消除主药之间的干扰,再用单纯形最优化法选择实验条件,不经分离提取,直接测定双嘧啶和复方新诺明片中TMP、SD、SMZ的含量。TMP回收率分别是99.68±0.17％,100.0±0.03％。双嘧啶片中SD和复方新诺明片中SMZ的回收率各为:99.97±0.10％,100.0±0.04％。     

The comeback of trimethoprim in France

Already used in various countries, trimethoprim (TMP) was withdrawn from the French market in 1990, but should be soon available again. This article reviews the experience of TMP use around the world and its current use in Europe. Label use and guidelines only recommend the use of TMP for the treatment of urinary tract infections (UTI). Compared with co-trimoxazole (Co-T), a combination of TMP and sulfamethoxazole (SMX), TMP has (a) a similar resistance rate among Escherichia coli strains (estimated between 10 and 20% in uncomplicated cystitis), (b) a similar clinical efficacy for cystitis prevention and treatment, (c) a lower toxicity (as severe toxicity adverse effects of Co-T come from its sulfonamide component), (d) limited data for the treatment of pyelonephritis and male UTIs, and (e) an important impact on the microbiota. TMP should thus be indicated in the third-line empirical treatment of acute uncomplicated cystitis (sparing fluoroquinolones and nitrofurantoin), in the prevention of recurrent acute cystitis when an antibiotic prophylaxis is required (possibly in first line), and in the treatment of documented acute cystitis at risk of complications. Updated data on the epidemiology of resistance to TMP per clinical pictures is now required. The bactericidal effect of TMP should also be confirmed on recent strains (although limited recent data suggests a bactericidia similar to that of Co-T) and its clinical efficacy should be evaluated in pyelonephritis and male UTI.     

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction

Objective The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. Methods A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. Results The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01–0.51] and 0.09 (95% CI: 0.01–0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. Conclusion PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs.     

The dosage of Co-trimoxazole in childhood

Summary Co-trimoxazole, a mixture of one part trimethoprim (TMP) and five parts of sulphamethoxazole (SMX) in fixed ratio was given to 48 children aged between one and 48 months twice daily for up to seven days. Twenty were relatively healthy and 28 were very ill. Dosage was based on age. Plasma concentrations of both drugs were measured just before a dose was due and some three hours later. They were in the effective but not toxic range and serve to justify the simple regimen which generated them.     

Incidence of neutropenia in HIV-infected African adults receiving co-trimoxazole prophylaxis: a 6-year cohort study in Abidjan, Côte d'Ivoire

In a placebo-controlled trial of co-trimoxazole prophylaxis in C?te d'Ivoire, neutropenia was the most frequent short-term side effect. The long-term incidence of neutropenia in sub-Saharan African adults receiving co-trimoxazole has never been reported. We followed a prospective cohort of HIV-infected adults receiving co-trimoxazole (sulphamethoxazole 800 mg/trimethoprim 160 mg daily) in Abidjan. Grades of neutropenia were successively defined as at least one absolute neutrophil count (ANC) of: <1500/mm(3) (severity grade >/=1), <1000/mm(3) (grade >/=2), <750/mm(3) (grade >/=3) or <500/mm(3) (grade 4). In total, 533 adults were followed-up during 1450 person-years, with a total of 3154 ANCs. The probability of remaining free of neutropenia at 48 months was 0.29 (95% CI 0.23-0.34) for grade >/=1, 0.64 (95% CI 0.60-0.71) for grade >/=2, 0.82 (95% CI 0.77-0.86) for grade >/=3 and 0.96 (95% CI 0.93-0.99) for grade 4. The only factor significantly associated with a higher rate of all grades of neutropenia was a low baseline CD4 count. There was no association between any grade of neutropenia and the global risk of serious morbidity during the study period. In adults receiving co-trimoxazole in Abidjan, mild neutropenia is a common observation with no evidence of negative clinical consequences. The consequences of associating co-trimoxazole with other haematotoxic drugs should be carefully assessed.     

Level of understanding of co-trimoxazole use among HIV infected,recurrent pulmonary tuberculosis suspects at a national referral tuberculosis clinic in Kampala,Uganda: a qualitative analysis

BackgroundCo-trimoxazole use is the standard of care for preventing Pneumocystis jirovecii pneumonia in sub-Saharan Africa but implementation remains slow. Co-trimoxazole is self- administered with uncertain adherence. Knowledge of co-trimoxazole use among HIV infected persons is unknown.ObjectivesTo assess knowledge, attitudes and practices of co-trimoxazole use among HIV infected adults evaluated for recurrent PTB in Kampala, Uganda.MethodsA qualitative study utilizing 5 focus group discussions among 30 HIV infected PTB suspects at the national referral tuberculosis treatment centre in Kampala.ResultsMales and females had similar median ages. 80% were currently on co-trimoxazole and 50% of participants were on HAART. Majority of participants defined co-trimoxazole as an analgesic. Few noted co-trimoxazole was a drug to treat cough and chest pain. However, few responses revealed that co-trimoxazole prevents opportunistic diseases among PLHIV. Most of participants believed HAART and anti-TB drugs work as co-trimoxazole thus it should not be taken together with them. This belief may lead to increased risk of opportunistic infections, morbidity and mortality.ConclusionsWe revealed gaps in understanding of co-trimoxazole use among study participants. We therefore recommend that more facts about co-trimoxazle as prophylaxis against P. jirovecii, bacterial and diarrheal pathogens should be incorporated in VCT fact sheets.