检索问题
治疗肺部疾病且通过静脉输注的抗生素有哪些？是否有必要改良为雾化吸入给药？
静脉输注抗生素在治疗肺部疾病中扮演着重要角色，尤其是在处理严重的肺部感染时。然而，随着对药物药代动力学和药效学理解的深入，以及多重耐药菌问题的日益突出，雾化吸入抗生素作为一种辅助或替代给药方式，其必要性也逐渐被提上日程。
一、通过静脉输注治疗肺部疾病的抗生素种类及应用
静脉输注抗生素广泛应用于治疗各种肺部疾病，特别是那些由细菌感染引起的、病情较重的疾病。这些疾病包括但不限于囊性纤维化（Cystic Fibrosis, CF）引起的肺部急性加重、呼吸机相关性肺炎（Ventilator-Associated Pneumonia, VAP）和其他慢性化脓性肺病。
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囊性纤维化肺部急性加重：
- 囊性纤维化是一种多系统疾病，其特征是产生浓稠分泌物，导致反复肺部感染，常伴有不寻常的细菌感染。
- 静脉输注抗生素通常用于治疗囊性纤维化的急性症状恶化（即肺部急性加重）。然而，近期有观点对“急性加重是由于细菌负荷增加”的假设提出了质疑。
- 在囊性纤维化患者中，比较单一抗生素与联合抗生素治疗方案时，接受联合抗生素治疗的患者在多项肺功能测量中表现出更大的改善，但证据质量非常低。
- 科克伦系统评价显示，对于囊性纤维化肺部急性加重，静脉抗生素与安慰剂、吸入或口服抗生素的对比，其证据质量普遍较差。没有证据表明某种特定的抗生素组合优于其他组合，也缺乏证据表明静脉途径优于吸入或口服途径。关于静脉抗生素治疗的最佳疗程尚无明确指南，通常根据单位政策和治疗反应进行10到21天的治疗，但通常为14天。
- 在治疗铜绿假单胞菌（Pseudomonas aeruginosa）引起的呼吸道感染时，抗生素的选择以及单药或联合治疗存在争议。科克伦系统评价未能得出单药与联合静脉抗假单胞菌抗生素治疗效果差异的结论，因为纳入研究的方法学质量较差且存在异质性。
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呼吸机相关性肺炎（VAP）：
- 在呼吸机相关性肺炎患者中，全身使用抗生素是医疗管理的核心。
- 然而，传统静脉抗生素治疗的局限性在于其肺部渗透性不佳和全身毒性。
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多重耐药革兰阴性菌感染：
- 革兰阴性菌是下呼吸道感染（特别是医院获得性感染）的主要病原体，并且这些菌株的耐药率持续上升。
- 全身性抗生素在治疗这些感染时，往往难以充分渗透到肺实质，且有效性和毒性之间的治疗窗口狭窄。
- 多黏菌素（Polymyxins）是一类重要的抗生素，用于对抗多重耐药革兰阴性菌，包括碳青霉烯类耐药革兰阴性菌（CR-GNB）。然而，多黏菌素的使用因其潜在的肾毒性而受到限制。临床试验和研究证实，在适当的配方和给药方式下，多黏菌素可以有效治疗CR-GNB感染，且肾毒性水平可接受。
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社区获得性细菌性肺炎（CABP）：
- Lefamulin是一种新型的口服和静脉用截短侧耳素类抗生素，被开发用于每日两次治疗社区获得性细菌性肺炎。
- Lefamulin对革兰阳性、革兰阴性需氧和厌氧菌以及引起CABP的非典型细菌具有广谱抗菌活性。
- 两项III期临床试验（LEAP 1和LEAP 2）证实了Lefamulin在口服和静脉剂型治疗CABP方面不劣于莫西沙星。
二、改良为雾化吸入给药的必要性
鉴于静脉输注抗生素在肺部穿透性、全身毒性和多重耐药菌感染治疗方面的挑战，雾化吸入抗生素作为一种局部给药方式，其必要性和优势日益凸显。
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药代动力学优势：
- 高局部浓度： 雾化吸入抗生素可以直接将药物输送到感染部位，从而在肺部实现更高的局部抗生素浓度，而全身暴露和毒性最小化。例如，在大型动物模型中，肺部给药的胶粘甲磺酸（CMS）在肺上皮衬液（ELF）中产生了高浓度的可林（colistin），而血浆浓度很低，这表明相对于静脉给药具有显著的靶向优势。
- 克服肺部穿透性差的问题： 全身性抗生素，尤其是在治疗下呼吸道感染时，常常难以充分渗透到肺实质。雾化吸入可以绕过肺泡毛细血管屏障，将抗生素直接输送到感染的肺实质。
- 快速清除： 雾化吸入抗生素在肺部具有快速清除的特点，可能有助于减少全身暴露。
- 潜在的生物膜相关耐药机制： 雾化吸入高浓度药物可能有助于克服生物膜相关的耐药机制。
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减少全身毒性和副作用：
- 通过减少全身吸收，雾化吸入抗生素可以显著降低全身副作用的风险。
- 例如，多黏菌素虽然对多重耐药革兰阴性菌有效，但其肾毒性限制了应用。通过雾化吸入，可以提高肺部疗效同时减少全身副作用。
- 一项系统评价和荟萃分析显示，雾化吸入抗生素降低了肺炎患者肾功能损害的风险。
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对抗多重耐药菌（MDR）的策略：
- 随着抗生素耐药率的上升，特别是革兰阴性菌的耐药性，开发新的治疗策略变得尤为重要。
- 雾化吸入抗生素通过增加局部抗生素浓度，可以增强抗菌效力，从而在治疗多重耐药病原体引起的肺炎方面具有特别的优势。
- 这对于缺乏新型抗革兰阴性抗生素的研发管线来说，鼓励对现有药物进行创新性使用，而吸入途径正是值得进一步研究和采纳的途径。
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临床应用的进展和证据：
- 囊性纤维化： 雾化吸入抗生素在囊性纤维化患者的肺炎治疗中已成为常见做法。有研究表明，吸入性抗生素能够有效治疗铜绿假单胞菌引起的慢性气道感染，如妥布霉素和氨曲南，因为它们在肺部的穿透性更好且全身暴露较低。然而，对于囊性纤维化肺部急性加重的治疗，吸入性抗生素的有效性证据仍然有限且质量不高。
- 呼吸机相关性肺炎（VAP）： 雾化吸入抗生素作为静脉抗生素的辅助治疗，在实验和临床研究中显示出药理学益处，包括药物到达感染肺实质、增加局部抗生素浓度以提高抗菌效力以及减少全身毒性。这对于治疗多重耐药病原体引起的肺炎可能特别有益。在机械通气患者中，雾化抗生素已被证明安全，并作为静脉治疗的辅助或单药疗法在治疗VAP或呼吸机相关气管支气管炎中显示出疗效，尤其是针对MDR或敏感病原体。
- 慢性化脓性肺病（如支气管扩张症）： 在囊性纤维化以外的慢性化脓性肺病患者中，雾化吸入抗生素作为辅助治疗与全身抗生素联合使用可能具有治疗优势。在非囊性纤维化支气管扩张症患者中，可能需要长期使用吸入性抗生素，特别是对于革兰阴性病原体定植的患者。妥布霉素和可林在临床实践中已广泛使用，尽管尚未被批准用于非囊性纤维化支气管扩张症；氨曲南、环丙沙星和庆大霉素的临床试验正在进行中。
- 整体疗效和安全性： 一项包括30项研究（12项随机对照试验和18项观察性研究）的荟萃分析发现，雾化吸入抗生素在肺炎患者中显著改善了临床治愈率和微生物治愈率，并降低了肾功能损害的风险。子组分析显示，雾化吸入抗生素与静脉给药联合使用，以及吸入性阿米卡星，在改善死亡率、临床治愈率和微生物治愈率方面表现更好。
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挑战与未来展望：
- 证据不足： 尽管药理学优势显著，但雾化吸入抗生素的临床数据仍相对有限。许多研究存在设计异质性，导致荟萃分析难以得出明确结论。
- 设备和给药技术： 肺部药物输送涉及多个因素，包括药物本身、制剂、吸入装置以及患者的生理和吸入操作。需要优化雾化器选择、回路配置和基本安全措施等实用实施指南。
- 生物等效性评估： 对于吸入性化合物的生物等效性评估比口服剂型更复杂，需要考虑患者-设备界面等因素。
- 患者依从性与耐受性： 在开始吸入治疗前，通常建议进行药物反应评估以评估支气管收缩和耐受性。一项研究发现，大多数患者（94%）通过了药物反应评估，干粉吸入抗生素的通过率高于雾化抗生素。
- 标准化和大型试验： 需要进行大规模、标准化的临床试验，以充分确定雾化吸入抗生素在所有情况下的临床疗效，并为临床实践指南的制定提供依据。未来的发展方向包括开发能够提高临床有效性、降低毒副作用并防止耐药菌株出现的新型多黏菌素递送系统。
总结：
静脉输注抗生素是治疗肺部感染（特别是严重感染）的基石。然而，其在肺部的渗透性不佳、全身毒性以及对抗多重耐药菌方面的局限性促使人们寻求更有效的给药途径。雾化吸入抗生素作为一种局部给药方式，通过在肺部提供高浓度药物、减少全身暴露和毒性，并可能克服生物膜耐药性，展现出显著的药代动力学优势和临床潜力。虽然目前缺乏高质量、大规模的证据来明确其在所有适应症中的优越性，但现有研究表明，雾化吸入抗生素在改善临床和微生物治愈率、降低肾功能损害风险方面具有积极作用，特别是在与静脉抗生素联合使用或针对多重耐药菌感染时。因此，改良为雾化吸入给药不仅必要，而且是未来治疗肺部感染，特别是多重耐药菌感染的重要发展方向，但仍需更多的研究来标准化技术和明确适应症。
References
1Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.PubMed
Matthew N Hurley, Andrew P Prayle, Patrick Flume
BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. OBJECTIVES: To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long-term clinical outcomes. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. SELECTION CRITERIA: Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and risk of bias and extracted data. MAIN RESULTS: We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and no studies in any comparison reported on quality of life. There were no effects on the secondary outcomes weight or adverse effects. When comparing specific antibiotic combinations there were no significant differences between groups on any measure. In the comparisons between intravenous and nebulised antibiotic or oral antibiotic (low quality evidence), there were no significant differences between groups on any measure. No studies in any comparison reported on quality of life. AUTHORS' CONCLUSIONS: The quality of evidence comparing intravenous antibiotics with placebo is poor. No specific antibiotic combination can be considered to be superior to any other, and neither is there evidence showing that the intravenous route is superior to the inhaled or oral routes. There remains a need to understand host-bacteria interactions and in particular to understand why many people fail to fully respond to treatment.
2Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model.PubMed
Cornelia B Landersdorfer, Tri-Hung Nguyen, Linh Thuy Lieu, et al.
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.
3Should Aerosolized Antibiotics Be Used to Treat Ventilator-Associated Pneumonia?PubMed
Changsheng Zhang, Lorenzo Berra, Michael Klompas
In patients with ventilator-associated pneumonia, systemic use of antibiotics is the cornerstone of medical management. Supplemental use of aerosolized antibiotics with intravenous antibiotics in both experimental and clinical studies has been shown to have the following pharmacologic benefits: (1) aerosolized antibiotics reach the infected lung parenchyma without crossing the pulmonary alveolar capillary barrier; (2) aerosolized antibiotics increase anti-bacterial efficacy through increased local antibiotic concentration; and (3) aerosolized antibiotics decrease systemic toxicity. These benefits may be particularly beneficial to treat pneumonia caused by multidrug-resistant pathogens. Clinical data on the benefits of aerosolized antibiotics are more limited. Studies to date have not clearly shown improvements in time to extubation, mortality, or other patient-centered outcomes. At present, amikacin, colistin, and ceftazidime are the most frequently used and studied aerosolized antibiotics. This review summarizes the characteristics of aerosolized antibiotics, reviews the advantages and disadvantages of using aerosolized antibiotics, and calls for future investigations based on animal study data.
4Inhaled Antibiotics for Gram-Negative Respiratory Infections.PubMed
Eric Wenzler, Dustin R Fraidenburg, Tonya Scardina, et al.
Gram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects, in vitro and microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.
5Considerations in establishing bioequivalence of inhaled compounds.PubMed
Irvin Mayers, Mohit Bhutani
INTRODUCTION: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds. AREAS COVERED: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds. EXPERT OPINION: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians' misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents.
6Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis.PubMed
Poppy Holland, Nikki Jahnke
BACKGROUND: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE. MAIN RESULTS: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination. There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores. AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.
7Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges.PubMed
G Poulakou, G Siakallis, S Tsiodras, et al.
Nebulized antibiotics use has become common practice in the therapeutics of pneumonia in cystic fibrosis patients. There is an increasing interest in their use for respiratory infections in mechanically ventilated (MV) patients in order to a) overcome pharmacokinetic issues in the lung compartment with traditional systemic antibiotic use and b) prevent the emergence of multi-drug-resistant (MDR) pathogens. Areas covered: The beneficial effects of antibiotic nebulization in MV patients e.g. increasing efficacy, reduced toxicity and prevention of resistance are described. Physicochemical parameters of optimal lung deposition, characteristics of currently available nebulizers, practical aspects of the procedure, including drug preparation and adjustments of ventilator and circuit parameter are presented. Antibiotics used in nebulized route, along with efficacy in various clinical indications and safety issues are reviewed. Expert commentary: The safety of nebulization of antibiotics has been proven in numerous studies; efficacy as adjunctive treatment to intravenous regimens or as monotherapy has been demonstrated in ventilator-associated pneumonia or ventilator-associated tracheobronchitis due to MDR or susceptible pathogens. However, due to the heterogeneity of studies, multiple meta-analyses fail to demonstrate a clear effect. Clarification of indications, standardization of technique and implementation of clinical practice guidelines, based on new large-scale trials will lead to the optimal use of nebulized antibiotics.
8Advances in the clinical treatment of multidrug-resistant pathogens using polymyxins.PubMed
Yizhen Huang, Mingrui Liao, Xuzhi Hu, et al.
OBJECTIVES: Polymyxins are a vital class of antibiotics used to combat multidrug-resistant Gram-negative bacteria. However, their use is limited due to potential nephrotoxicity and the availability of alternative antibiotics. This review aims to examine the properties of polymyxins and the clinical advances in their use for treating infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). METHODS: This review analyses literature on polymyxin properties and various clinical approaches, including intravenous drip infusion, nebulized or dry powder inhalation, and ointment application. Treatment efficacy in terms of bacterial eradication, cure rate and mortality rate are reviewed and evaluated. RESULTS: Polymyxins have been reintroduced to treat critical infections due to the increasing prevalence of CR-GNB. Clinical trials and studies have confirmed that polymyxins can effectively treat CR-GNB infections when the formulation and administration are appropriate, with acceptable levels of nephrotoxicity. CONCLUSIONS: In the future, the development of polymyxin formulations will aim to improve their clinical effectiveness while reducing toxicity and side effects and preventing the emergence of polymyxin-resistant strains. Enhanced efficacy and minimized potential side effects can be achieved by developing new polymyxin-delivery systems that provide a smart and controlled release or customized patient administration.
9MP-376 (Aeroquin) for chronic Pseudomonas aeruginosa infections.PubMed
Doina Azoicai, Sabina Antonela Antoniu
INTRODUCTION: The chronic airway infection with Pseudomonas aeruginosa (PA) is a risk factor for rapid disease progression in various chronic pulmonary diseases including cystic fibrosis or chronic obstructive pulmonary disease. Inhaled antibiotics are able to treat effectively such chronic airway infections, and MP-376 is currently in late-stage clinical development for such an indication. AREAS COVERED: Review of the existing preclinical and clinical data on MP-376, with a focus on the efficacy and safety of the compound on chronic airways infections due to PA. EXPERT OPINION: Chronic airways infection with PA represents a therapeutic challenge because of its own complex mechanisms of defense, because of the rapid development of antibiotic resistance and by the fact that systemic antibiotics are not always able to achieve appropriate concentrations at lung level. Inhaled antibiotics (tobramycin, aztreonam, etc.) represent optimal alternatives to their systemic homologs due to their better penetrability in the lungs and due to the lower systemic exposure. Inhaled levofloxacin which is currently investigated for chronic airways infection might be another possible antipseudomonal inhaled therapy.
10Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia.PubMed
George G Zhanel, Christina Deng, Sheryl Zelenitsky, et al.
Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (V) ranging from 82.9 to 202.8 L, total clearance (CL) of 19.5 to 21.4 L/h, and terminal elimination half-life (t) of 6.9-13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (C) of 1.2-1.5 mg/L with a time of maximum concentration (T) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC) of 8.5-8.8 mg h/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.
11The efficacy and safety of inhaled antibiotics for pneumonia: A systematic review and meta-analysis.PubMed
Zengzeng Zhang, Hong Li, Yutao Hu, et al.
OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of inhaled antibiotics for adults with pneumonia by meta-analysis. METHODS: Literature retrieval was completed through five databases (PubMed, Embase, Cochrane Library, Web of Science and Scopus) by the deadline of May 31, 2024. The process of study selection and data extraction were performed independently by two reviewers. The quality of observational studies and randomized controlled trial (RCT) studies were evaluated by Newcastle Ottawa scale and Jadad scale, respectively. The primary outcomes included mortality, clinical cure, and microbiological cure. Secondary outcomes were recurrence and renal impairment. RESULTS: There were 30 studies were analyzed, including 12 RCT studies and 18 observational studies. Inhaled antibiotics did not significantly reduce mortality in RCT studies (odds ratio (OR) = 1.06, 95 % confidence interval (CI): 0.80-1.41). Inhaled antibiotics were associated with higher rates of clinical cure (OR = 1.47 95%CI: 0.82-2.66 in RCT studies and OR = 2.09, 95%CI: 1.36-3.21 in observational studies) and microbiological cure (OR = 7.00 in RCT studies and OR = 2.20 in observational studies). Subgroup analysis showed patients received inhaled antibiotics combined with intravenous administration and inhaled amikacin had better improvements of mortality, clinical cure and microbiological cure. Inhaled antibiotics were not associated with recurrence. The pooled OR of renal impairment were 0.65 (95%CI: 0.27-1.13; I-squared = 43.5 %, P = 0.124) and 0.63(95%CI: 0.26-1.11; I-squared = 69.0 %, P = 0.110) in RCT studies and observational studies, respectively. CONCLUSIONS: Inhaled antibiotics decreased risk of renal impairment and achieved significant improvements of clinical and microbiological cure in patients with pneumoniae.
12Advances in Pulmonary Drug Delivery.PubMed
Ayca Yıldız-Peköz, Carsten Ehrhardt
Pulmonary drug delivery represents an attractive, non-invasive administration option. In addition to locally acting drugs, molecules that are intended to produce systemic effects can be delivered via the pulmonary route. Several factors need to be considered in the context of delivering drugs to or via the lungs-in addition to the drug itself, its formulation into an appropriate inhalable dosage form of sufficient stability is critical. It is also essential that this formulation is paired with a suitable inhaler device, which generates an aerosol of a particle/droplet size that ensures deposition in the desired region of the respiratory tract. Lastly, the patient's (patho-) physiology and inhalation manoeuvre are of importance. This Special Issue brings together recent advances in the areas of inhalation device testing, aerosol formulation development, use of in vitro and in silico models in pulmonary drug deposition and drug disposition studies, and pulmonary delivery of complex drugs, such as vaccines, antibiotics and peptides, to or via the lungs.
13Delivery of antibiotics to the respiratory tract: an update.PubMed
Daniela Traini, Paul M Young
The use of inhaled medications for the treatment of pulmonary diseases has become an increasingly popular drug delivery route over the past few decades. This delivery route allows for a drug to be delivered directly to the site of the disease, with a lower dose than more conventional oral or intravenous delivery methods, with reduced systemic absorption and consequently reduced risk of adverse effects. For asthma this delivery route has become the 'golden standard' of therapy. It is not unexpected therefore, that there has been great interest in the prospect of using inhaled antibiotics for the treatment of both chronic and recurrent respiratory infections. Since the early 1980s, several investigations have demonstrated that antibiotics could be delivered safely by means of inhalation, using nebulisers as their delivery systems. Lately, antibiotics delivery via inhalation have seen a 'revival' in interest and most of these studies have focused on delivering antibiotics to the lungs by means of a dry powder format. This review focuses on recent advances in antibiotic inhalation therapy.
14Duration of intravenous antibiotic therapy in people with cystic fibrosis.PubMed
Linsey Abbott, Amanda Plummer, Zhe Hui Hoo, et al.
BACKGROUND: Progressive lung damage from recurrent exacerbations is the major cause of mortality and morbidity in cystic fibrosis. Life expectancy of people with cystic fibrosis has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient. The risk of systemic side effects such as allergic reactions to antibiotics also increases with prolonged courses and the use of aminoglycosides requires frequent monitoring to minimise some of their side effects. However, some organisms which infect people with cystic fibrosis are known to be multi-resistant to antibiotics, and may require a longer course of treatment. This is an update of previously published reviews. OBJECTIVES: To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings. Most recent search of the Group's Cystic Fibrosis Trials Register: 30 May 2019.We also searched online trials registries. Most recent search of the ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) portal: 06 January 2019. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. DATA COLLECTION AND ANALYSIS: No eligible trials were identified for inclusion. A trial looking at the standardised treatment of pulmonary exacerbations is currently ongoing and will be included when the results are published. MAIN RESULTS: No eligible trials were included. AUTHORS' CONCLUSIONS: There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and adherence, result in a reduced incidence of drug reactions and be less costly. However, the shorter duration may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications. The currently ongoing STOP2 trial is expected to provide some guidance on these questions when published.
15Inhaled Antibiotics for Ventilator-Associated Pneumonia: A Turning Point.PubMed
Stephan Ehrmann
Ventilator-associated pneumonia remains a major challenge in critical care because of its high incidence, prolonged ICU and hospital stays, and escalating health care costs. Conventional intravenous antibiotic therapy is limited by suboptimal lung penetration and systemic toxicity. Inhaled antibiotic therapy offers a promising alternative by delivering high concentrations of drug directly to the site of infection, thereby potentially overcoming biofilm-related resistance mechanisms and improving bacterial eradication. This review examines the epidemiology and clinical burden of ventilator-associated pneumonia, its pathophysiology, and the pharmacokinetic advantages of the inhaled route. Three strategies for inhaled antibiotic therapy-substitutive, adjunctive, and preventive-are discussed. Data from key trials provide proof of concept for prophylactic inhaled therapy, whereas mixed results from adjunctive studies underscore the need for further research. Practical implementation guidelines, such as optimal nebulizer selection, circuit configuration, and essential safety measures, are discussed. Finally, future perspectives on inhaled anti-infectious therapies, including immunomodulators and biologics, are presented. Together, these data support the view that inhaled anti-infective therapy has the potential to transform the management of ventilator-associated pneumonia, although further standardized, large-scale trials are needed to fully establish its clinical efficacy in all situations.
16Bronchiectasis--diagnosis and treatment.PubMed
Jessica Rademacher, Tobias Welte
BACKGROUND: Radiologically evident bronchiectasis is seen in 30% to 50% of patients with advanced chronic obstructive pulmonary disease (COPD). As COPD is now becoming more common around the world, bronchiectasis is as well. METHODS: We review pertinent articles published before May 2011 that were retrieved by a selective PubMed search. RESULTS: The principles of treatment of bronchiectasis in patients who do not have cystic fibrosis ("non-CF bronchiectasis") are derived from the treatment of other diseases: secretolytic and anti-infectious treatment are given as in cystic fibrosis, while anti-obstructive treatment is given as in COPD. The few randomized trials of treatment for non-CF bronchiectasis that have been completed to date do not permit the formulation of any evidence-based recommendations. Many potential treatments are now under evaluation. Hypertonic saline is often used because of its demonstrated benefit in CF, even though no benefit has yet been shown for non-CF bronchiectasis. Phase II trials of inhaled mannitol have yielded promising results, leading to phase III trials that are now underway. There may be a future role for inhaled antibiotics, particularly in patients colonized with Gram-negative pathogens. Inhaled tobramycin and colistin are well established in clinical practice, though not approved for non-CF bronchiectasis; clinical trials of aztreonam, ciprofloxacin, and gentamicin are ongoing. Macrolides seem to bring an additional benefit, though the studies that documented this involved only small numbers of patients. Long-term treatment with inhaled antibiotics and/or macrolides is indicated only if a benefit is seen within three months of the start of treatment (less sputum, no exacerbations). CONCLUSION: A national registry of patients with bronchiectasis should be established to help us gain better knowledge of its prognostic factors and treatment options.
17Nebulizer therapy with antibiotics in chronic suppurative lung disease.PubMed
M A el-Din, L B Palmer, M N el-Tayeb, et al.
Aerosolized antibiotics have been shown to be a useful modality of treatment in patients with cystic fibrosis. In this investigation we examined the utility of this treatment in patients with other chronic suppurative lung disorders. These included forty patients, thirty men and ten women with chronic airway infection (27 with bronchiectasis, 6 with chronic abscess and 7 with chronic suppurative bronchitis). Pathogenic organisms were isolated from the affected part of the lung by a fiberoptic bronchoscopy using a sterile disposable bronchial microbiology brush. Cultures from these specimens were used to determine the appropriate antibiotic. A second control group of 20 patients was treated with systemic antibiotics alone. Both systemic and aerosolized antibiotics were administered in 20 patients. A statistically significant improvement in clinical, and ventilatory functions was recorded in the first group compared to the second. Nebulized antibiotics used as adjunctive therapy in association with systemic antibiotics may offer a therapeutic advantage in chronic suppurative lung diseases.
18Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis.PubMed
Sherie Smith, Nicola J Rowbotham, Edward Charbek
BACKGROUND: Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. This is an update of a previously published review. OBJECTIVES: To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work and improves their long-term survival. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 03 October 2018.We searched ClinicalTrials.gov, the Australia and New Zealand Clinical Trials Registry and WHO ICTRP for relevant trials. Date of last search: 09 October 2018. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. They assessed the quality of the evidence using the GRADE criteria. Authors of the included trials were contacted for more information. MAIN RESULTS: Four trials with 167 participants are included in the review. Two trials (77 participants) compared inhaled antibiotics alone to intravenous antibiotics alone and two trials (90 participants) compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone. Trials were heterogenous in design and two were only available in abstract form. Risk of bias was difficult to assess in most trials, but for all trials we judged there to be a high risk from lack of blinding and an unclear risk with regards to randomisation. Results were not fully reported and only limited data were available for analysis.Inhaled antibiotics alone versus intravenous antibiotics aloneOnly one trial (n = 18) reported a perceived improvement in lifestyle (quality of life) in both groups (very low-quality of evidence). Neither trial reported on time off work or school. Both trials measured lung function, but there was no difference reported between treatment groups (very low-quality evidence). With regards to our secondary outcomes, one trial (n = 18) reported no difference in the need for additional antibiotics and the second trial (n = 59) reported on the time to next exacerbation. In neither case was a difference between treatments identified (both very low-quality evidence). The single trial (n = 18) measuring adverse events and sputum microbiology did not observe any in either treatment group for either outcome (very low-quality evidence).Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics aloneNeither trial reported on quality of life or time off work or school. Both trials measured lung function, but found no difference between groups in forced expiratory volume in one second (one trial, n = 28, very low-quality evidence) or vital capacity (one trial, n = 62). Neither trial reported on the need for additional antibiotics or the time to the next exacerbation; however, one trial (n = 28) reported on hospital admissions and found no difference between groups. Both trials reported no difference between groups in adverse events (very low-quality evidence) and one trial (n = 62) reported no difference in the emergence of antibiotic-resistant organisms (very low-quality evidence). AUTHORS' CONCLUSIONS: There is little useful high-level evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations.
19Aerosolized antibiotics: do they add to the treatment of pneumonia?PubMed
Marin H Kollef, Cindy W Hamilton, A Bruce Montgomery
PURPOSE OF REVIEW: The increasing rate of ventilator-associated pneumonia (VAP) caused by multidrug-resistant pathogens warrants the development of new treatment strategies. Carefully engineered delivery systems are undergoing evaluation to test the hypothesis that aerosolized administration of antibiotics will provide high local concentrations and fast clearance, which in turn may improve efficacy and decrease the risk of microbial resistance. RECENT FINDINGS: Recent studies indicate that aerosolized delivery systems for specially formulated antibiotics yield high local concentrations with rapid clearance and low systemic exposure. Preliminary clinical studies reveal that aerosolized delivery of antibiotics is well tolerated and active, when combined with intravenous antibiotics. No single aerosolized antibiotic is likely to provide broad-spectrum activity against both Gram-negative and Gram-positive bacteria. SUMMARY: Large multicenter trials are needed to determine whether preliminary findings will translate to improved clinical activity and decreased microbial resistance in VAP patients, and to optimize the use of aerosolized antibiotics.
20The utility of drug reaction assessment trials for inhaled therapies in patients with chronic lung diseases.PubMed
Brittany B Dennis, Giulia Rinaldi, Georgie Housley, et al.
BACKGROUND: Current guidelines recommend a Drug Reaction Assessment (DRA) before beginning inhaled therapies to assess for bronchoconstriction and tolerability. There is limited evidence to support this recommendation. METHODS: In this study we aimed to establish the predictors of successful DRAs in different patient groups using a cohort of all DRAs performed in adults between 2011 and 2016 at the Royal Brompton Hospital. Spirometry, age, gender, height, and underlying lung disease were recorded. A multivariable logistic regression model was constructed to ascertain variables associated with successful DRAs. RESULTS: There were 1492 DRA trials using hypertonic saline (32%), antimicrobials (63%), or rhDNase (5%). The majority of patients (94%, n = 1408) passed the DRA. Mean FEV% predicted was 58.03 (SD 23.36). Female sex, type of inhaled product, and FEV% predicted were established as significant predictors for DRA success. An FEV% predicted > 55% was associated with greater probability of DRA success (Odds Ratio [OR]: 2.96 (1.80,4.86) p < 0.0001). Those receiving dry powder, inhaled antibiotics were more likely to pass the DRA compared to nebulised antibiotics (OR: 3.99 (1.38,11.51) p = 0.01)). CONCLUSION: This study classifies distinct patient groups with varying baseline risks which can be used to predict tolerability when adding an inhaled product to their management plan. Some "low risk" patients may in future be able to self-assess their tolerability for inhaled therapies at home to avoid unneeded hospital monitoring.