Intravesical antimicrobial administration for urinary tract infections via a dedicated catheter

IF 3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
John Posner
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Immunoprophylaxis with oral OM-89, a bacterial lysate extract from <i>Escherichia coli</i> that is thought to stimulate the host immune system, is also generally supported.<span><sup>2</sup></span></p><p>Complicated UTIs, as distinct from recurrent UTIs, include those related to pregnancy, anatomical or functional abnormalities of the urinary tract, indwelling urinary catheters, renal disease and other immunocompromising diseases such as diabetes. Patients with chronic neuropathic conditions such as spinal injury or multiple sclerosis are at particular risk of recurrent infections and septicaemia. Use of indwelling Foley catheters, particularly in the elderly and patients with neuropathy, is widely practised, but they act as a source of repeated infection.</p><p>Treatment failure and recurrence of infections associated with increasing development of antimicrobial resistance (AMR) may partly be attributable to the way in which antibiotics are used including overuse, misuse and suboptimal infection prevention practices.<span><sup>3</sup></span> Whether administered by the oral or intravenous route only a fraction of the administered dose actually reaches the urine and bladder urothelium in concentrations that exceed the minimum inhibitory concentration (MIC) for adequate duration. While bactericidal efficacy in serum for systemic infections is dependent on the ratios between plasma C<sub>max</sub> and AUC to the MIC,<span><sup>4</sup></span> these data are far less applicable to infection localized to the bladder. Furthermore, the drug that does reach the bladder is diluted by urine, thereby reducing the probability of attaining and maintaining bactericidal concentrations. The importance of achieving and testing antimicrobial sensitivity based on urinary rather than serum concentrations is not new and was the subject of a paper published over 50 years ago.<span><sup>5</sup></span> Adverse effects are also a major consideration for some antibiotics administered by a systemic route.</p><p>These serious and common shortcomings in the treatment and prevention of cystitis with antibiotics may at least be partially overcome by direct intravesical administration (IVA) after voiding urine. Importantly, the permeability of the urothelium is very low so that drug permeation into the systemic circulation and the gut should be negligible.<span><sup>6</sup></span> IVA for treatment of bladder conditions is not novel. Intravesicular Bacillus Calmette–Guerin (BCG) has been used for many years for treatment of non-muscle invasive bladder cancer as have chemotherapies such as gemcitabine and mitomycin. Intravesical interferon gene therapy with adenoviral vector-based nadofaragene firadenovec has also been approved by the FDA for adult patients with high-risk BCG-resistant, non-muscle invasive bladder cancer. Severe cases of irritable bladder can also be treated with intravesical botulinum toxin.</p><p>The conduct of adequately powered, high-quality, prospective clinical trials of intravesical antimicrobials for cystitis has been limited to date and does not appear to have been of interest to drug regulatory authorities. In a review of five prophylactic and six treatment studies involving intravesical gentamicin, neomycin with polymyxin, neomycin or colistin a good reduction in symptomatic UTI was seen in 78% (120/168) of patients in the prophylaxis group and 88% (103/117) in the treatment groups. Treatments were tolerated well with few adverse effects, and discontinuation rates were less than 10%.<span><sup>7</sup></span> The authors concluded that IVA appeared to be safe and effective for both prophylaxis and treatment of rUTIs.</p><p>In a prospective study of intravesical instillations of gentamycin to 63 adult patients with rUTIs caused by multidrug resistant pathogens, overnight intravesical instillations of gentamicin were administered for 6 months.<span><sup>8</sup></span> The mean number of UTIs was reduced from 4.8 to 1.0 during treatment and the resistance rate of the uropathogens decreased from 78% to 23%. No systemic absorption or clinically relevant side effects were observed.</p><p>To summarize, of the antibiotics available for IVA, there are encouraging data with gentamycin, but it is clear that randomized, controlled clinical trials are needed to assess the acceptability and effectiveness of IVA with different antibiotics. IVA of non-antibiotic prophylactic agents has recently been reviewed.<span><sup>9</sup></span> Instillation of hyaluronic acid alone and combined with chondroitin sulphate targets adherence of bacteria to the bladder mucosa, which is attributable to a damaged glycosaminoglycan (GAG) layer. Recurrence of cystitis, urinary symptoms, quality of life and cystometric capacity have been shown to be superior to antibiotic prophylaxis with substantially longer times to recurrence.</p><p>The paucity of clinical trials of antibiotics or prophylactic agents by the intravesical route may partly be explained by the lack of suitable catheters. A catheter for dedicated intravesicular use that can be inserted into the urethra by the patient or carer without significant risk of introducing bacteria is of critical importance for treatment of cystitis. A single-use disposable narrow-gauge catheter would be appropriate for safe and painless IVA after application of antiseptic gel or possibly a rapidly acting prophylactic agent. Instillation of the antibiotic or other treatment should be through a lumen separate from that for urine drainage using an easily-attached pre-filled syringe with valves to prevent backflow of both urine and therapeutic agent.</p><p>Evaluation of treatments with such a device should proceed with high-quality randomized, controlled clinical trials using different antibiotics or other agents and a range of doses determined from the MIC in urine. The instillation should take place after emptying the bladder and should be retained in the bladder for at least an hour to maximize the chance of achieving eradication of the infection. The number of administrations will depend on the indication. As well as severity of symptoms including pyrexia, trials should compare rates of the four patterns of bacteriuria response: (i) cure, (ii) persistence of the same bacterium after treatment, (iii) relapse with the same microorganism after cessation of treatment and (iv) reinfection, that is, usually with a different bacterial species after initial successful sterilization of the urine.<span><sup>10</sup></span> Suitable populations for such trials should include various groups of patients with recurrent cystitis and those with complicating risk factors such as diabetes and neuropathic conditions including multiple sclerosis and spinal cord injuries. Such topical therapy has the potential to reduce the frequency and severity of recurrent UTIs and, if successful, could reduce the ever-present and increasing risk of AMR particularly in the elderly population.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 8","pages":"2184-2185"},"PeriodicalIF":3.0000,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70124","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"British journal of clinical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bcp.70124","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

The European Association of Urology (EAU) defines recurrent urinary tract infection (rUTI) as ‘two or more episodes of symptomatic UTI within 6 months, or three or more within 12 months’. Guidelines available for management of rUTIs in women have been reviewed and summarized.1 Most recommend treatment with short courses of antibiotics for acute episodes and prophylaxis with continuous or post-coital antibiotics, increased fluid intake and topical vaginal oestrogen for postmenopausal women. Strategies to prevent rUTIs in particular groups of patients include use of cranberry products containing proanthocyanidin and oral methenamine hippurate or mandelate. Immunoprophylaxis with oral OM-89, a bacterial lysate extract from Escherichia coli that is thought to stimulate the host immune system, is also generally supported.2

Complicated UTIs, as distinct from recurrent UTIs, include those related to pregnancy, anatomical or functional abnormalities of the urinary tract, indwelling urinary catheters, renal disease and other immunocompromising diseases such as diabetes. Patients with chronic neuropathic conditions such as spinal injury or multiple sclerosis are at particular risk of recurrent infections and septicaemia. Use of indwelling Foley catheters, particularly in the elderly and patients with neuropathy, is widely practised, but they act as a source of repeated infection.

Treatment failure and recurrence of infections associated with increasing development of antimicrobial resistance (AMR) may partly be attributable to the way in which antibiotics are used including overuse, misuse and suboptimal infection prevention practices.3 Whether administered by the oral or intravenous route only a fraction of the administered dose actually reaches the urine and bladder urothelium in concentrations that exceed the minimum inhibitory concentration (MIC) for adequate duration. While bactericidal efficacy in serum for systemic infections is dependent on the ratios between plasma Cmax and AUC to the MIC,4 these data are far less applicable to infection localized to the bladder. Furthermore, the drug that does reach the bladder is diluted by urine, thereby reducing the probability of attaining and maintaining bactericidal concentrations. The importance of achieving and testing antimicrobial sensitivity based on urinary rather than serum concentrations is not new and was the subject of a paper published over 50 years ago.5 Adverse effects are also a major consideration for some antibiotics administered by a systemic route.

These serious and common shortcomings in the treatment and prevention of cystitis with antibiotics may at least be partially overcome by direct intravesical administration (IVA) after voiding urine. Importantly, the permeability of the urothelium is very low so that drug permeation into the systemic circulation and the gut should be negligible.6 IVA for treatment of bladder conditions is not novel. Intravesicular Bacillus Calmette–Guerin (BCG) has been used for many years for treatment of non-muscle invasive bladder cancer as have chemotherapies such as gemcitabine and mitomycin. Intravesical interferon gene therapy with adenoviral vector-based nadofaragene firadenovec has also been approved by the FDA for adult patients with high-risk BCG-resistant, non-muscle invasive bladder cancer. Severe cases of irritable bladder can also be treated with intravesical botulinum toxin.

The conduct of adequately powered, high-quality, prospective clinical trials of intravesical antimicrobials for cystitis has been limited to date and does not appear to have been of interest to drug regulatory authorities. In a review of five prophylactic and six treatment studies involving intravesical gentamicin, neomycin with polymyxin, neomycin or colistin a good reduction in symptomatic UTI was seen in 78% (120/168) of patients in the prophylaxis group and 88% (103/117) in the treatment groups. Treatments were tolerated well with few adverse effects, and discontinuation rates were less than 10%.7 The authors concluded that IVA appeared to be safe and effective for both prophylaxis and treatment of rUTIs.

In a prospective study of intravesical instillations of gentamycin to 63 adult patients with rUTIs caused by multidrug resistant pathogens, overnight intravesical instillations of gentamicin were administered for 6 months.8 The mean number of UTIs was reduced from 4.8 to 1.0 during treatment and the resistance rate of the uropathogens decreased from 78% to 23%. No systemic absorption or clinically relevant side effects were observed.

To summarize, of the antibiotics available for IVA, there are encouraging data with gentamycin, but it is clear that randomized, controlled clinical trials are needed to assess the acceptability and effectiveness of IVA with different antibiotics. IVA of non-antibiotic prophylactic agents has recently been reviewed.9 Instillation of hyaluronic acid alone and combined with chondroitin sulphate targets adherence of bacteria to the bladder mucosa, which is attributable to a damaged glycosaminoglycan (GAG) layer. Recurrence of cystitis, urinary symptoms, quality of life and cystometric capacity have been shown to be superior to antibiotic prophylaxis with substantially longer times to recurrence.

The paucity of clinical trials of antibiotics or prophylactic agents by the intravesical route may partly be explained by the lack of suitable catheters. A catheter for dedicated intravesicular use that can be inserted into the urethra by the patient or carer without significant risk of introducing bacteria is of critical importance for treatment of cystitis. A single-use disposable narrow-gauge catheter would be appropriate for safe and painless IVA after application of antiseptic gel or possibly a rapidly acting prophylactic agent. Instillation of the antibiotic or other treatment should be through a lumen separate from that for urine drainage using an easily-attached pre-filled syringe with valves to prevent backflow of both urine and therapeutic agent.

Evaluation of treatments with such a device should proceed with high-quality randomized, controlled clinical trials using different antibiotics or other agents and a range of doses determined from the MIC in urine. The instillation should take place after emptying the bladder and should be retained in the bladder for at least an hour to maximize the chance of achieving eradication of the infection. The number of administrations will depend on the indication. As well as severity of symptoms including pyrexia, trials should compare rates of the four patterns of bacteriuria response: (i) cure, (ii) persistence of the same bacterium after treatment, (iii) relapse with the same microorganism after cessation of treatment and (iv) reinfection, that is, usually with a different bacterial species after initial successful sterilization of the urine.10 Suitable populations for such trials should include various groups of patients with recurrent cystitis and those with complicating risk factors such as diabetes and neuropathic conditions including multiple sclerosis and spinal cord injuries. Such topical therapy has the potential to reduce the frequency and severity of recurrent UTIs and, if successful, could reduce the ever-present and increasing risk of AMR particularly in the elderly population.

经专用导尿管膀胱内给药治疗尿路感染。
欧洲泌尿外科协会(EAU)将复发性尿路感染(rUTI)定义为“6个月内两次或两次以上有症状的尿路感染发作,或12个月内三次或三次以上”。现已审查和总结了妇女尿道感染管理的现有准则大多数人建议对急性发作进行短期抗生素治疗,对绝经后妇女进行持续或性交后抗生素预防,增加液体摄入量和局部阴道雌激素。在特定患者群体中预防ruti的策略包括使用含有原花青素的蔓越莓产品和口服甲基苯丙胺(马尿酸或扁桃酸)。口服OM-89的免疫预防也得到普遍支持,OM-89是从大肠杆菌中提取的细菌裂解物,被认为可以刺激宿主的免疫系统。复杂性尿路感染与复发性尿路感染不同,包括与妊娠、尿路解剖或功能异常、留置导尿管、肾脏疾病和其他免疫损害疾病(如糖尿病)有关的尿路感染。患有慢性神经性疾病(如脊髓损伤或多发性硬化症)的患者尤其容易发生复发性感染和败血症。留置Foley导尿管,特别是在老年人和神经病变患者中,被广泛应用,但它们是反复感染的来源。与抗菌素耐药性(AMR)日益发展相关的治疗失败和感染复发可能部分归因于抗生素的使用方式,包括过度使用、误用和不理想的感染预防做法无论是口服还是静脉给药,只有一小部分给药剂量在足够的时间内到达尿液和膀胱尿路上皮,其浓度超过最低抑制浓度。虽然血清对全身性感染的杀菌效果取决于血浆Cmax和AUC与MIC的比值,但这些数据远不适用于膀胱局部感染。此外,到达膀胱的药物被尿液稀释,从而降低了达到和维持杀菌浓度的可能性。基于尿液浓度而不是血清浓度来实现和测试抗菌药物敏感性的重要性并不新鲜,这是50多年前发表的一篇论文的主题对于一些全身给药的抗生素,不良反应也是一个主要的考虑因素。在用抗生素治疗和预防膀胱炎方面,这些严重和常见的缺点至少可以部分地通过排尿后直接膀胱内给药(IVA)来克服。重要的是,尿路上皮的渗透性很低,因此药物进入体循环和肠道的渗透性可以忽略不计体外循环治疗膀胱疾病并不新鲜。与化疗如吉西他滨和丝裂霉素一样,囊内卡介苗(BCG)已被用于治疗非肌肉浸润性膀胱癌多年。基于腺病毒载体的nadofaragene firadenovec膀胱内干扰素基因治疗也已被FDA批准用于成人高风险bcg耐药非肌肉浸润性膀胱癌患者。严重的膀胱易激症也可以用膀胱内肉毒杆菌毒素治疗。迄今为止,膀胱内抗菌剂治疗膀胱炎的充分有力、高质量、前瞻性临床试验的开展受到限制,药物监管当局似乎并未对此感兴趣。在一项涉及膀胱内使用庆大霉素、新霉素与多粘菌素、新霉素或粘菌素的5项预防性研究和6项治疗性研究的综述中,预防组78%(120/168)的患者和治疗组88%(103/117)的患者出现症状性尿路感染的良好减少。治疗耐受性好,不良反应少,停药率小于10%作者得出结论,IVA对于rUTIs的预防和治疗似乎是安全有效的。在一项对63例由多重耐药病原体引起的rUTIs的成人患者进行膀胱内滴注庆大霉素的前瞻性研究中,研究人员对患者进行了为期6个月的夜间膀胱内滴注庆大霉素治疗期间尿路感染平均数量由4.8个下降到1.0个,尿路病原菌耐药率由78%下降到23%。未观察到全身吸收或临床相关副作用。综上所述,在可用于IVA的抗生素中,庆大霉素的数据令人鼓舞,但很明显,需要随机对照临床试验来评估不同抗生素IVA的可接受性和有效性。近年来对非抗生素预防性药物的体外注射进行了综述。 单独滴注透明质酸和联合硫酸软骨素可靶向细菌对膀胱黏膜的粘附,这是由于糖胺聚糖(GAG)层受损。膀胱炎的复发、泌尿系统症状、生活质量和膀胱容量已被证明优于抗生素预防,且复发时间大大延长。缺乏经膀胱内途径使用抗生素或预防性药物的临床试验,部分原因可能是缺乏合适的导管。患者或护理人员可以将专用导管插入尿道内,而不会有引入细菌的重大风险,这对膀胱炎的治疗至关重要。在使用消毒凝胶或可能的速效预防药物后,一次性使用的一次性窄规导管适用于安全无痛的IVA。抗生素或其他治疗应通过与尿液引流管分离的管腔进行滴注,使用易于连接的预充式注射器,带有阀门,以防止尿液和治疗剂倒流。对这种装置的治疗评估应进行高质量的随机对照临床试验,使用不同的抗生素或其他药物,并根据尿液中的MIC确定剂量范围。应在排空膀胱后进行灌注,并应在膀胱中保留至少一个小时,以最大限度地消除感染。管理的次数将取决于指示。除了包括发热在内的症状的严重程度外,试验还应比较四种细菌尿反应模式的比率:(i)治愈;(ii)治疗后同一细菌的持续存在;(iii)停止治疗后同一微生物的复发;(iv)再感染,即在初步成功地对尿液进行灭菌后,通常感染不同的细菌种类适合此类试验的人群应包括各种复发性膀胱炎患者和具有并发症危险因素(如糖尿病和神经病变包括多发性硬化症和脊髓损伤)的患者。这种局部治疗有可能降低复发性尿路感染的频率和严重程度,如果成功,可以降低一直存在和不断增加的AMR风险,特别是在老年人中。
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来源期刊
CiteScore
6.30
自引率
8.80%
发文量
419
审稿时长
1 months
期刊介绍: Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.
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