布鲁氏菌病

如果存在急性非特异性特征但无局灶性感染，布鲁氏菌病被视为非复杂疾病。接受单药治疗的患者多达 30% 会出现复发，因而通常建议使用抗生素联合治疗。

WHO 建议患有布鲁氏菌病的成人和青少年接受 6 周的口服多西环素加 6 周的口服利福平或加 2 周的链霉素肌肉注射。[60]World Health Organization. Brucellosis in humans and animals. 2006. http://www.who.int/ (last accessed 26 August 2016).http://www.who.int/csr/resources/publications/Brucellosis.pdf

最佳治疗方案仍有争议，但下列原则越来越清晰：[103]Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med. 2007;4:e317.http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0040317http://www.ncbi.nlm.nih.gov/pubmed/18162038?tool=bestpractice.com[104]Skalsky K, Yahav D, Bishara J, et al. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008;336:701-704.http://www.bmj.com/content/336/7646/701http://www.ncbi.nlm.nih.gov/pubmed/18321957?tool=bestpractice.com[105]Solís García del Pozo J, Solera J. Systematic review and meta-analysis of randomized clinical trials in the treatment of human brucellosis. PLoS One. 2012;7:e32090.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032090http://www.ncbi.nlm.nih.gov/pubmed/22393379?tool=bestpractice.com[106]Yousefi-Nooraie R, Mortaz-Hejri S, Mehrani M, et al. Antibiotics for treating human brucellosis. Cochrane Database Syst Rev. 2012;(10):CD007179.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007179.pub2/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23076931?tool=bestpractice.com[107]Hashemi SH, Gachkar L, Keramat F, et al. Comparison of doxycycline-streptomycin, doxycycline-rifampin, and ofloxacin-rifampin in the treatment of brucellosis: a randomized clinical trial. Int J Infect Dis. 2012;16:e247-e251.http://www.ncbi.nlm.nih.gov/pubmed/22296864?tool=bestpractice.com含有一种可注射氨基糖苷类药物的方案优于 2 种口服药物方案，主要优势是可以减少后续复发；庆大霉素可以作为首选氨基糖苷类药物取代链霉素；氨基糖苷类药物的用药持续时间应当超过 7 天（很可能是 10～14 天）；6 周口服治疗优于 4 周；喹诺酮类药物很可能不适合加入一线治疗方案，因为其有效性低于上述方案，通常不推荐；然而，喹诺酮-利福平方案的耐受性优于多西环素-利福平方案；三联治疗方案（包括一种氨基糖苷类药物）很可能优于二联抗菌药物方案，在复杂疾病中可以是首选。[103]Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med. 2007;4:e317.http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0040317http://www.ncbi.nlm.nih.gov/pubmed/18162038?tool=bestpractice.com[104]Skalsky K, Yahav D, Bishara J, et al. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008;336:701-704.http://www.bmj.com/content/336/7646/701http://www.ncbi.nlm.nih.gov/pubmed/18321957?tool=bestpractice.com[105]Solís García del Pozo J, Solera J. Systematic review and meta-analysis of randomized clinical trials in the treatment of human brucellosis. PLoS One. 2012;7:e32090.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032090http://www.ncbi.nlm.nih.gov/pubmed/22393379?tool=bestpractice.com[106]Yousefi-Nooraie R, Mortaz-Hejri S, Mehrani M, et al. Antibiotics for treating human brucellosis. Cochrane Database Syst Rev. 2012;(10):CD007179.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007179.pub2/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23076931?tool=bestpractice.com[108]Pappas G, Christou L, Akritidis N, et al. Quinolones for brucellosis: treating old diseases with new drugs. Clin Microbiol Infect. 2006;12:823-825.http://www.ncbi.nlm.nih.gov/pubmed/16882286?tool=bestpractice.com[109]Bosilkovski M, Kirova V, Grozdanovski K, et al. Doxycycline-rifampin versus doxycycline-rifampin-gentamicin in treatment of human brucellosis. Trop Doct. 2012;42:13-17.http://www.ncbi.nlm.nih.gov/pubmed/22290107?tool=bestpractice.com[110]Vrioni G, Bourdakis A, Pappas G, et al. Administration of a triple versus a standard double antimicrobial regimen for human brucellosis more efficiently eliminates bacterial DNA load. Antimicrob Agents Chemother. 2014;58:7541-7544.http://aac.asm.org/content/58/12/7541.fullhttp://www.ncbi.nlm.nih.gov/pubmed/25246401?tool=bestpractice.com

治疗复发的方案通常与最初使用的方案相同，因为对抗菌药物耐药很少是复发的原因。

如果存在急性非特异性特征但无局灶性感染，布鲁氏菌病被视为非复杂疾病。

对孕妇和母乳喂养妇女的最佳治疗是基于无对照的个案报告。[46]Khan MY, Mah WM, Memish ZA. Brucellosis in pregnant women. Clin Infect Dis. 2001;32:1172-1177.http://cid.oxfordjournals.org/content/32/8/1172.fullhttp://www.ncbi.nlm.nih.gov/pubmed/11283806?tool=bestpractice.com一般建议口服利福平一个疗程。[30]Beeching NJ, Whatmore AM, Corbel MJ. Brucellosis. In: Fauci AS, Braunwald E, Kasper DL,et al, eds. Harrison’s principles of internal medicine. 19th ed. New York, NY: McGraw-Hill; 2014: chap 192.[31]Beeching NJ, Madkour MM. Brucellosis. In: Farrar J, Hotez P, Junghanss T, et al, eds. Manson’s tropical diseases. 23rd ed. London: Elsevier; 2013:371-378, 378.e1.利福平加甲氧苄啶/磺胺甲噁唑是一种可接受的替代方案。[46]Khan MY, Mah WM, Memish ZA. Brucellosis in pregnant women. Clin Infect Dis. 2001;32:1172-1177.http://cid.oxfordjournals.org/content/32/8/1172.fullhttp://www.ncbi.nlm.nih.gov/pubmed/11283806?tool=bestpractice.com

不建议在妊娠早期使用甲氧苄啶/磺胺甲噁唑，因为其与先天性畸形的风险增加相关。只有治疗获益超过风险时才应当使用建议的方案。

疗程：6 周（利福平单药治疗）；4 周（联合治疗）。

如果存在急性非特异性特征但无局灶性感染，布鲁氏菌病被视为非复杂疾病。

回顾性研究提示，对儿童的治疗可以缩短到 3 周联合治疗，但是尚未在前瞻性比较研究中评估。[111]Lubani MM, Dudin KI, Sharda DC, et al. A multicenter therapeutic study of 1100 children with brucellosis. Pediatr Infect Dis J. 1989;8:75-78.http://www.ncbi.nlm.nih.gov/pubmed/2649867?tool=bestpractice.com在儿童中，可以使用甲氧苄啶/磺胺甲噁唑取代四环素类药物。[112]Roushan MR, Mohraz M, Janmohammadi N, et al. Efficacy of cotrimoxazole and rifampin for 6 or 8 weeks of therapy in childhood brucellosis. Pediatr Infect Dis J. 2006;25:544-545.http://www.ncbi.nlm.nih.gov/pubmed/16732154?tool=bestpractice.com

疗程：至少 6 周。

通常建议使用三联抗生素方案治疗复杂感染，可以根据临床和放射学应答延长治疗时间。[116]Ulu-Kilic A, Karakas A, Erdem H, et al. Update on treatment options for spinal brucellosis. Clin Microbiol Infect. 2014;20:O75-O82.http://www.ncbi.nlm.nih.gov/pubmed/24118178?tool=bestpractice.com

关于复杂或局灶性疾病（睾丸炎、骶髂关节炎、脊椎炎、心内膜炎）病例的最佳治疗持续时间，证据很少，但大多数作者偏好使用三联抗生素疗法用于成人或青少年，其中包含多西环素、利福平和一种氨基糖苷。[30]Beeching NJ, Whatmore AM, Corbel MJ. Brucellosis. In: Fauci AS, Braunwald E, Kasper DL,et al, eds. Harrison’s principles of internal medicine. 19th ed. New York, NY: McGraw-Hill; 2014: chap 192.[31]Beeching NJ, Madkour MM. Brucellosis. In: Farrar J, Hotez P, Junghanss T, et al, eds. Manson’s tropical diseases. 23rd ed. London: Elsevier; 2013:371-378, 378.e1.[60]World Health Organization. Brucellosis in humans and animals. 2006. http://www.who.int/ (last accessed 26 August 2016).http://www.who.int/csr/resources/publications/Brucellosis.pdf[103]Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med. 2007;4:e317.http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0040317http://www.ncbi.nlm.nih.gov/pubmed/18162038?tool=bestpractice.com[104]Skalsky K, Yahav D, Bishara J, et al. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008;336:701-704.http://www.bmj.com/content/336/7646/701http://www.ncbi.nlm.nih.gov/pubmed/18321957?tool=bestpractice.com

治疗复发的方案通常与最初使用的方案相同，因为对抗菌药物耐药很少是复发的原因。

对于儿童，如果没有证据，可以应用类似的考量；对于孕妇或母乳喂养妇女，应当根据具体情况评估。因此在开始治疗孕妇或母乳喂养妇女以及治疗儿童之前，建议请传染病专科医生会诊。

一般不建议对孕妇使用多西环素，因为担心影响到胎儿骨骼发育和骨骼生长。不建议对孕妇使用氨基糖苷类药物，因为担心胎儿耳毒性和肾毒性。只有治疗获益超过风险时才应当使用建议的方案。

疗程：3 至 6 个月；氨基糖苷仅给药 2 周。

布鲁氏菌心内膜炎通常影响主动脉瓣，布鲁氏菌病 1% 至 5% 的死亡率中，有很大一部分是心内膜炎所导致。[71]Uddin MJ, Sanyal SC, Mustafa AS, et al. The role of aggressive medical therapy along with early surgical intervention in the cure of Brucella endocarditis. Ann Thorac Cardiovasc Surg. 1998;4:209-213.http://www.ncbi.nlm.nih.gov/pubmed/9738123?tool=bestpractice.com

大多数感染性心内膜炎患者，尽管接受 6 个月或更长时间的抗生素治疗，但最后仍需要瓣膜替换。[5]Pappas G, Papadimitriou P, Akritidis N, et al. The new global map of human brucellosis. Lancet Infect Dis. 2006;6:91-99.http://www.ncbi.nlm.nih.gov/pubmed/16439329?tool=bestpractice.com[30]Beeching NJ, Whatmore AM, Corbel MJ. Brucellosis. In: Fauci AS, Braunwald E, Kasper DL,et al, eds. Harrison’s principles of internal medicine. 19th ed. New York, NY: McGraw-Hill; 2014: chap 192.[31]Beeching NJ, Madkour MM. Brucellosis. In: Farrar J, Hotez P, Junghanss T, et al, eds. Manson’s tropical diseases. 23rd ed. London: Elsevier; 2013:371-378, 378.e1.有证据表明早期手术可降低死亡率。[113]Keshtkar-Jahromi M, Razavi SM, Gholamin S, et al. Medical versus medical and surgical treatment for brucella endocarditis. Ann Thorac Surg. 2012;94:2141-2146.http://www.ncbi.nlm.nih.gov/pubmed/23102495?tool=bestpractice.com

通常建议使用三联抗生素方案治疗复杂感染，可以根据临床和放射学应答延长治疗时间。[116]Ulu-Kilic A, Karakas A, Erdem H, et al. Update on treatment options for spinal brucellosis. Clin Microbiol Infect. 2014;20:O75-O82.http://www.ncbi.nlm.nih.gov/pubmed/24118178?tool=bestpractice.com

在有神经系统表现（脑膜脑炎、局灶性脑或颅神经损伤）的病例中，通常不鼓励使用链霉素或庆大霉素，因为氨基糖苷类药物进入脑脊液的能力不确定，并且可能有神经毒性，会进一步使临床表现更复杂。[114]Pappas G, Akritidis N, Christou L. Treatment of neurobrucellosis: what is known and what remains to be answered. Expert Rev Anti Infect Ther. 2007;5:983-990.http://www.ncbi.nlm.nih.gov/pubmed/18039082?tool=bestpractice.com可以添加头孢曲松或甲氧苄啶/磺胺甲噁唑作为第三种药物，因为其 CNS 渗透性较好。[30]Beeching NJ, Whatmore AM, Corbel MJ. Brucellosis. In: Fauci AS, Braunwald E, Kasper DL,et al, eds. Harrison’s principles of internal medicine. 19th ed. New York, NY: McGraw-Hill; 2014: chap 192.[31]Beeching NJ, Madkour MM. Brucellosis. In: Farrar J, Hotez P, Junghanss T, et al, eds. Manson’s tropical diseases. 23rd ed. London: Elsevier; 2013:371-378, 378.e1.[37]Beeching NJ, Erdem H. Brucellosis. In: Cohen J, Powderly WG, Opal SM, eds. Infectious diseases. 4th ed. London: Elsevier Science; 2016:1098-1101.[114]Pappas G, Akritidis N, Christou L. Treatment of neurobrucellosis: what is known and what remains to be answered. Expert Rev Anti Infect Ther. 2007;5:983-990.http://www.ncbi.nlm.nih.gov/pubmed/18039082?tool=bestpractice.com[115]Erdem H, Ulu-Kilic A, Kilic S, et al. Efficacy and tolerability of antibiotic combinations in neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother. 2012;56:1523-1528.http://aac.asm.org/content/56/3/1523.longhttp://www.ncbi.nlm.nih.gov/pubmed/22155822?tool=bestpractice.com

治疗复发的方案通常与最初使用的方案相同，因为对抗菌药物耐药很少是复发的原因。

对于儿童，如果没有证据，可以应用类似的考量；对于孕妇或母乳喂养妇女，应当根据具体情况评估。因此在开始治疗孕妇或母乳喂养妇女以及治疗儿童之前，建议请传染病专科医生会诊。

一般不建议对孕妇使用多西环素，因为担心影响到胎儿骨骼发育和骨骼生长。不建议在妊娠早期使用甲氧苄啶/磺胺甲噁唑，因为其与先天性畸形的风险增加相关。只有治疗获益超过风险时才应当使用建议的方案。

疗程：3 至 6 个月。