替加环素单药疗法成功治愈多药耐药大肠杆菌引起的急性前列腺炎

Elia Lo Priore, David M Livermore, Niccolo Buetti, Philipp Jent, Niklas Pelzer, Carlo Casanova,  Hansjakob Furrer, and Baharak Babouee Flury

(1 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland, 2 Norwich Medical School, University of East Anglia, Norwich, United Kingdom, 3 UroSwiss AG, Department of Urology, Oberaargau Regional Hospital, Langenthal, Switzerland, and 4 Institute for Infectious Diseases, University of Bern, Bern, Switzerland）

（1瑞士伯尔尼大学附属医院传染病科，2英国东英吉利大学诺里奇医学院，3 瑞士伯尔尼大学朗根塔尔奥伯阿默高地区医院泌尿科，4瑞士伯尔尼传染病研究所）

2018年3月，一名79岁的患者在伯恩大学医院泌尿科就诊，该患者患有膀胱颈硬化症、慢性多尿症和夜尿症。患者在就诊前两周症状逐渐恶化，有新发性排尿前膀胱疼痛，但没有发热。该患者在2017年接受尿道前列腺电切术，治疗了前列腺腺瘤，并自2015年以来患有慢性肾功能不全。

临床检查中，患者前列腺压痛明显。患者入院时经前列腺按摩后获得的尿液中，亚硝酸盐呈阳性，白细胞> 40/ hpf，C反应蛋白和白细胞计数正常。尿液培养产生的大肠杆菌为104 CFU / mL，病菌对β-内酰胺/β-内酰胺酶抑制剂组合、头孢菌素、氨基糖苷、经典四环素、抗叶酸药、磷霉素和喹诺酮类药物耐药（表1）。微阵列分析检测到NDM-1碳青霉烯酶、CMY-2型质粒AmpC酶和TEM 164H超广谱β-内酰胺酶基因。

患者病症确诊为急性前列腺炎。因为该患者多药耐药且缺乏能够合理替代相关药物的天然药物，开始接受替加环素治疗。治疗持续了四周。初始的负荷剂量为100毫克，随后的剂量为每次50毫克，每天两次。在接受治疗的第6天，患者的顽固性脓尿消失。在接受治疗的第8天，该患者的早尿疼痛得到完全缓解，且夜尿症和多尿症得到改善。治疗后4个月进行的前列腺按摩后尿液分析未显示顽固性脓尿，长达7个月的后续疗程中均未检测出多药耐药性大肠杆菌的再生。

讨论

在本案例之前，已经有3例使用替加环素治愈的前列腺炎患者的报告。这些报告均支持使用替加环素及MDR大肠杆菌联合疗法治疗前列腺炎的有效性。

当前研究显示，影响方案有效性的因素是多方面的，但采用替加环素的最主要原因是缺乏其它较好的替代选择。出于耐药性方面的考虑，治疗方案排除了氟喹诺酮类，复方新诺明和磷霉素。由于存在bla NDM基因,亚胺培南和美罗培南被排除在方案之外。即使保持最低抑制浓度，这两种药物也无法发挥预期的效果。排除氨曲南的原因与排除亚胺培南和美罗培南类似。氨曲南是CMY-2的基质，且是可能具有ESBL活性的TEM 164H酶的基质。不推荐使用β-内酰胺的原因是它们在前列腺组织中的渗透性很差，且使用氨曲南和阿维巴坦时应避免使用β-内酰胺。排除使用粘菌素的原因则是患者的肾脏受损，存在较高的肾毒性增加风险。以及，粘菌素在前列腺组织中的渗透性尚不确定。Eravacycline是一种新型的四环素，这一药物的肠杆菌科MIC低于替加环素，可能已经成为一些医生的临床选择。但是，当前缺乏该药物在前列腺组织中渗透性的数据，且瑞士还没有这种抗生素。

前列腺炎治疗的机制与泌尿道感染不同。对于泌尿道感染来说，任何经肾脏排泄的抗生素都可能具有治疗作用。然而，对于前列腺来说，抗生素通过血浆的被动扩散来渗透到前列腺中，且渗透性取决于脂质的溶解度、解离常数和蛋白质结合。替加环素通常具有良好的前列腺组织和液体渗透性，但不适用于泌尿道感染。当前，关于替加环素的数据很少。在结构上与替加环素相关的米诺环素在前列腺组织和血清中比率为0.94±0.39。基于当前研究，且考虑到稳态血清水平为0.6 mg/L,本研究认为替加环素疗法达到曲线/MIC比值下足够的面积。作为参考的指标是欧洲抗菌药物委员会的敏感性临界点，在药敏试验中为0.5 mg / L。在与核糖体30S亚基结合方面，替加环素比早期的四环素具有更高的亲和力，并且可以避开获得性溢出和糖体保护蛋白导致的抗性。 

据了解，目前为止，公开医学报告中仅有3例患者使用替加环素单药治疗的前列腺炎病例。三例患者的治疗时间分为2周，6周，以及22周，全部都与产生ESBL的大肠杆菌相关。本次研究中，我们使用替加环素（MIC 0.38 mg/L）根除了微生物，且在患者患有膀胱颈硬化症的情况下调理了患者的后遗症，即夜尿症和多尿症。

美国食品和药物管理局对替加环素发出黑箱警告。且由于主要依赖胆汁排出，该药不适用于UTI.

作为临床试验中的单一疗法，替加环素的使用历史较长。在皮肤和软组织感染，复杂的腹腔内感染，以及社区获得性细菌性肺炎等疾病的治疗方面，均有显著成效。但是，在糖尿病足感染，呼吸机相关的肺炎/医院获得性细菌性肺炎的VAP臂中，未能有良好表现。替加环素最常用作抗MDR病原体组合疗法中的一种用药。尽管还需要更大样本的试验及病例研究，当前的研究支持将前列腺炎添加到可以合理使用替加环素作为单一疗法的感染清单中，尤其是针对MDR大肠杆菌。

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We present a successful treatment, with tigecycline monotherapy, of acute prostatitis caused by multidrug-resistant Escherichia coli harboring an NDM-1 carbapemenase along with a CMY-2 cephalosporinase and a TEM ESBL. 

【Key words】CMY-2；NDM-1；prostatitis；TEM ESBL；tigecyclin；

CASE

A 79-year-old patient with known bladder neck sclerosis and subsequent chronic polyuria and nocturia presented to the Department of Urology at Bern University Hospital in March 2018 with progressive worsening of symptoms over the preceding 2 weeks and new-onset premicturition pain without fever. The history was notable for a prostate adenoma treated 

with transurethral resection of the prostate in 2017 and for chronic renal insufficiency (CKD IIIb) since 2015. Clinical examination revealed marked prostatic tenderness. Urine, obtained after prostate massage at admission, was nitrite positive, and >40 leucocytes/hpf C-reactive protein and white blood cell count were normal. Culture of urine yielded Escherichia coli at 104  CFU/mL, resistant to β-lactam/β-lactamase inhibitor combinations, cephalosporins, aminoglycosides, classical tetracyclines, antifolates, fosfomycin, and quinolones (Table  1). Microarray analysis (Check-MDR CT103XL, CheckPoints, Wageningen, the Netherlands) detected genes for an NDM-1 carbapenemase, CMY-2-acquired AmpC, and a TEM 164H  extended-spectrum β-lactamase (ESBL).

A diagnosis of acute prostatitis was established. Due to its multidrug resistance (MDR) and the lack of reasonable alternatives (discussed below), tigecycline therapy was started with a loading dose of 100 mg, followed by 50 mg twice daily, and continued for 4 weeks. Full relief from the premicturition pain and improvement of nocturia and polyuria were apparent at day 8 of treatment. Follow-up cultures up to 7 months post- treatment did not detect regrowth of the MDR E. coli. Urinalysis after prostate massage, 4  months post-treatment, revealed no persistent pyuria; this had disappeared at treatment day 6.

DISCUSSION

This case complements 3 previous reports of prostatitis treated with tigecycline [1]; all support the drug’s effectiveness as monotherapy for prostatitis with MDR E. coli.

For the present case, the choice of this regimen reflected several factors, but primarily the lack of good alternatives. Fluoroquinolones, co-trimoxazole, and fosfomycin—as conventional agents for prostatitis—were precluded by resistance. Imipenem and meropenem were avoided, despite low minimum inhibitory concentrations (MICs), owing to presence of the blaNDM gene. Similar considerations applied for aztreonam (MIC 1.5 mg/L), which is a substrate for CMY-2 and a likely substrate for TEM 164H enzyme that is expected to have ESBL activity [2]. Furthermore, penetration of β-lactams into prostatic tissue is poor, suggesting against their use (and that of aztreonam/avibactam, which would evade all the β-lactamases present). We avoided colistin because of the patient’s renal impairment, enhancing the risk of nephrotoxicity, [3] and because of this drug’s uncertain prostatic tissue penetration [4]. 

Eravacycline, a novel tetracycline, has lower MICs than tigecycline for Enterobacteriaceae [5] and might have been an alternative; however, data on prostatic penetration are lacking, and this antibiotic is not yet available in Switzerland.

Prostatitis presents a different challenge to urinary tract infections (UTIs), where any renally excreted antibiotic is potentially therapeutic. Penetration of antibiotics to the prostate occurs by passive diffusion from plasma and depends upon lipid solubility, dissociation constant, and protein binding [6]. Tetracyclines generally have good prostatic tissue and fluid penetration, but they are not appropriate for UTIs [6]. Although there are few data for tigecycline, minocycline, to which it is structurally related, achieves a prostatic tissue/serum ratio of 0.94 ± 0.39 [7]. Such considerations, coupled with a steady-state serum level of c. 0.6 mg/L, suggest that adequate area under the curve/MIC ratios (the critical pharmacodynamic parameter for tigecycline [8]) should be achievable, as related to the susceptibility breakpoint (0.5 mg/L) of the European Committee on Antimicrobial Susceptibility Testing [9]. Tigecycline binds to ribosomal 30S subunits with greater affinity than earlier tetracyclines and evades the resistance conferred by acquired efflux and ribosomal protection [8].

To our knowledge, only 3 previous cases of prostatitis treated with tigecycline monotherapy have been reported [1, 10, 11]. All involved ESBL-producing E. coli, and, despite significant differences in treatment duration (2, 6, and 22 weeks, respectively), all showed favorable outcomes. Here we achieved microbiological eradication with tigecycline (MIC 0.38  mg/L). Residual nocturia and polyuria after treatment were interpreted in the context of known bladder neck sclerosis.

Tigecycline has a black box warning from the US Food and Drug Administration and is unsuitable for UTIs owing to largely biliary excretion. It has a mixed history as monotherapy in clinical trials, achieving noninferiority to comparators in skin and soft tissue infection (SSTI) [12], complicated Intraabdominal Infection (cIAI) [13], and community-acquired bacterial pneumonia (CABP) [14], but failing to do so in diabetic foot infection [15] and in the VAP arm of a ventilatorassociated penumonia/Hospital-aquired bacterial penumonia (VAP/HABP) trial [16]. It is most often used as a combination agent against MDR pathogens. Although larger trials or case series studies are needed, the present results support the view that prostatitis might be added to the list of infections where use as monotherapy can reasonably be considered, particularly against MDR E. coli.

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