Polymyxin-containing regimens for treating of pneumonia caused by multidrug-resistant gram-negative bacteria: Mind the breakpoints and the standardization of nebulization therapy

IF 8.8 1区 医学 Q1 CRITICAL CARE MEDICINE
Lihui Wang, Chunhui Xu, Lining Si, Guifen Gan, Bin Lin, Yuetian Yu
{"title":"Polymyxin-containing regimens for treating of pneumonia caused by multidrug-resistant gram-negative bacteria: Mind the breakpoints and the standardization of nebulization therapy","authors":"Lihui Wang, Chunhui Xu, Lining Si, Guifen Gan, Bin Lin, Yuetian Yu","doi":"10.1186/s13054-024-05111-x","DOIUrl":null,"url":null,"abstract":"<p>With great interest we read the recent network meta-analysis by Zhou et al. which found that the intravenous plus inhaled polymyxin-containing regimen could reduce the all-cause mortality of patients with pneumonia caused by multidrug-resistant gram-negative bacterial (MDRGNB) [1]. This is undoubtedly an encouraging result and provides evidence for the subsequent clinical implementation of such regimens. However, there are still some issues that need further attention.</p><p>Pneumonia caused by MDRGNB remains a huge challenge in the intensive care unit (ICU). Currently, the available effective antibiotics are limited, and polymyxins are still the cornerstones for treatment. However, with the introduction of new antibiotics into clinical practice (especially new beta-lactam and beta-lactamase inhibitor combination) and the potential renal toxicity of polymyxins, since 2020, the performance standards for antimicrobial susceptibility testing of the Clinical and Laboratory Standards Institute (CLSI) have canceled the susceptibility breakpoints of polymyxins for <i>Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii</i>. It defines a minimal inhibitory concentration (MIC) of ≤ 2 ug/mL as intermediate (https://clsi.org). At present, the newly available antibiotics for the treatment of MDRGNB pneumonia in China is limited. Therefore, Chinese Medical Association (CMA) still define MIC ≤ 2 ug/mL as susceptible according to the previous versions of CLSI before 2020 or the 10th version of European Committee on Antimicrobial Susceptibility Testing (EUCAST), to guide clinical treatment. The international approved and recognized method for susceptibility testing of polymyxins is broth microdilution (BMD), but its manual operation is complex and time-consuming, making it difficult for laboratories to routinely carry out. Thus, most laboratories still use automated or semi-automated instruments nowadays to detect the susceptibility, and the accuracy of the results still needs further evaluation.</p><p>In addition, the clinical pharmacokinetic/pharmacodynamic (PK/PD) target of polymyxins for efficacy is unclear [2]. Some guidelines recommended that for polymyxin B the AUC<sub>ss,24h</sub> should be about 50 mg h/L and possibly 50–100 mg h/L, with the latter corresponding to an average steady-state concentration across 24 h (C<sub>ss,avg</sub>) of 2–4 ug/mL for pathogens with MIC of ≤ 2 ug/mL [3]. Therefore, careful interpretation is needed for the susceptible judgment of polymyxins, the optimal PK/PD index, and the effectiveness of antibiotic therapy.</p><p>The presence of the blood-alveolar barrier prevents satisfactory concentrations of antibiotics in the epithelial lining fluid (ELF) when antibiotics are administered intravenously, and increasing the dosage of intravenous administration may lead to high rate of side effects such as acute kidney injury. Nebulization therapy can convert liquid antibiotic preparations into particles of 3–5 um, allowing them to deposit in the alveoli, thereby effectively increasing the concentration at the site of infection and improving clinical outcomes.</p><p>One early meta-analysis included eight studies on intravenous combined nebulized colistin. Due to significant differences in patient inclusion criteria, colistin dosage, and nebulization procedures, the quality of evidence presented for each outcome ranged from “very low” to “low.” It suggested that intravenous combined with nebulized colistin could enhance clinical response and microbiological eradication in patients with ventilator-associated pneumonia (VAP) while reducing infection-related mortality. However, it did not affect overall mortality (odds ratio, 0.74; 95% CI 0.54–1.01; <i>p</i> = 0.06; I<sup>2</sup> = 25%) [4]. Another meta-analysis included 11 randomized controlled trials (RCTs) comparing the safety and efficacy of nebulized combined with intravenous antibiotics (colistin, amikacin and tobramycin) for the treatment of VAP. It also found that the combined treatment strategy did not reduce the mortality (relative risk 1.00; 95% CI 0.82–1.21; I<sup>2</sup> = 45%) [5].</p><p>Physicians in the field of critical care medicine have been attempting to treat VAP with a regimen of nebulized antibiotics since 1985. After nearly 40 years of development, the efficacy of the regimen has significantly improved [6]. However, we still need to further standardize the procedure.</p><p>A 2-week cross-sectional study analyzed the process of nebulization therapy in 2808 patients undergoing mechanical ventilation in the ICU. The study found that 77% of physicians did not adjust the mechanical ventilation parameters during nebulization therapy, only 65% of the nebulization processes included the addition of a filter at the expiratory end, and 28% had not replaced the filter [7]. Another questionnaire-based cross-sectional survey from China enrolled 2203 medical staff who regularly worked in the ICU. It indicated that ventilator settings were never changed by 32.7% of respondents during nebulization. The usage rate of mesh nebulizers in ICUs in China was less than 1% [8]. In addition, polymyxin B was launched in China in September 2017. Due to its relatively low price (approximately $30 for 50 mg), it has become one of the preferred medications for nebulized therapy in patients with VAP. However, it is important to note that it may cause airway hyper-reactivity such as coughing and asthma after nebulization, which requires further attention. The high cost of colistimethate sodium (approximately $300 for 150 mg) prevents its widespread use in nebulized therapy in China. It is one of the combination therapies more commonly used for MDRGNB treatment. Therefore, it is recommended an urgent need for high-quality education to bring practice into line with evidence-based guidelines.</p><p>We have integrated published research and recommendation from various associations to develop a protocol suitable for nebulized therapy in mechanically ventilated patients in Chinese ICUs. Clear guidance is provided for the adjustments of relevant ventilator parameters before, during, and after nebulization. We hope that the implementation of standardized procedures will enhance the effectiveness of nebulization therapy and ultimately improve patient outcomes (Fig. 1).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13054-024-05111-x/MediaObjects/13054_2024_5111_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"363\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13054-024-05111-x/MediaObjects/13054_2024_5111_Fig1_HTML.png\" width=\"685\"/></picture><p>Process and precautions for nebulizing antibiotics in mechanically ventilated patients (drawn by Chunhui Xu)</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>We usually combine nebulized antibiotics with intravenous antibiotics for treatment VAP which makes it difficult to accurately evaluate the true efficacy of this strategy. In patients with VAP, the lung lesions are almost always heterogeneous, resulting in better ventilation in non-infected areas while infected regions suffer from inflammatory exudates, sputum obstruction, and local atelectasis, leading to poor ventilation. Therefore, in the context of mechanical ventilation, nebulized antibiotic particles are more likely to deposit in healthy lung tissue rather than in the damaged lung [9]. However, due to the excessive concentration of antibiotics deposited in healthy lung tissue, it remains unclear whether this will further damage the alveolar mucosal tissue and subsequently promote the occurrence of pneumonia, which requires further related research in the future.</p><p>Many studies have measured the concentration of antibiotics in bronchoalveolar lavage fluid (BALF) after nebulization therapy by using urea as an internal reference. After calibration with a formula ([Antibiotics]<sub>ELF</sub> = [Antibiotics]<sub>BALF</sub> × Plasma Urea value/BALF Urea value), the concentration of antibiotics in the ELF is reported. However, the antibiotic concentration obtained through the urea calibration method is 100-fold higher than that determined by the gold standard microdialysis probe detection method. This could be due to bronchial contamination during the bronchoalveolar sampling [10].</p><p>In summary, there are still many issues that cannot be clearly resolved regarding the treatment of VAP with intravenous combined nebulized therapy, and the actual efficacy remains unclear. Although the previous guidelines had lower-level antibiotic nebulization therapy, the latest guidelines, considering the lack of uniformity in the nebulization process and the high heterogeneity of VAP patients, currently do not recommend this strategy [11,12,13,14,15]. It is suggested that subsequent large-sample RCTs should be conducted under the premise of a standardized protocol, while also clarifying the actual concentration of antibiotics in the ELF after nebulization, in order to provide better evidence for clinical treatment.</p><p>Not applicable.</p><dl><dt style=\"min-width:50px;\"><dfn>MDRGNB:</dfn></dt><dd>\n<p>Multidrug-resistant gram-negative bacterial</p>\n</dd><dt style=\"min-width:50px;\"><dfn>ICU:</dfn></dt><dd>\n<p>Intensive care unit</p>\n</dd><dt style=\"min-width:50px;\"><dfn>CLSI:</dfn></dt><dd>\n<p>Clinical and Laboratory Standards Institute</p>\n</dd><dt style=\"min-width:50px;\"><dfn>MIC:</dfn></dt><dd>\n<p>Minimal inhibitory concentration</p>\n</dd><dt style=\"min-width:50px;\"><dfn>CMA:</dfn></dt><dd>\n<p>Chinese Medical Association</p>\n</dd><dt style=\"min-width:50px;\"><dfn>EUCAST:</dfn></dt><dd>\n<p>European Committee on Antimicrobial Susceptibility Testing</p>\n</dd><dt style=\"min-width:50px;\"><dfn>BMD:</dfn></dt><dd>\n<p>Broth microdilution</p>\n</dd><dt style=\"min-width:50px;\"><dfn>PK/PD:</dfn></dt><dd>\n<p>Pharmacokinetic/pharmacodynamic</p>\n</dd><dt style=\"min-width:50px;\"><dfn>ELF:</dfn></dt><dd>\n<p>Epithelial lining fluid</p>\n</dd><dt style=\"min-width:50px;\"><dfn>VAP:</dfn></dt><dd>\n<p>Ventilator-associated pneumonia</p>\n</dd><dt style=\"min-width:50px;\"><dfn>RCT:</dfn></dt><dd>\n<p>Randomized controlled trial</p>\n</dd><dt style=\"min-width:50px;\"><dfn>BALF:</dfn></dt><dd>\n<p>Bronchoalveolar lavage fluid</p>\n</dd></dl><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Zhou Y, Wang G, Zhao Y, Chen W, Chen X, Qiu Y, et al. Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis. Crit Care. 2024;28(1):239.</p><p>Article PubMed PubMed Central Google Scholar </p></li><li data-counter=\"2.\"><p>Abdul-Aziz MH, Alffenaar JC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med. 2020;46(6):1127–53.</p><p>Article PubMed PubMed Central Google Scholar </p></li><li data-counter=\"3.\"><p>Liu X, Huang C, Bergen PJ, Li J, Zhang J, Chen Y, et al. Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. J Zhejiang Univ Sci B. 2023;24(2):130–42.</p><p>Article PubMed Google Scholar </p></li><li data-counter=\"4.\"><p>Valachis A, Samonis G, Kofteridis DP. The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med. 2015;43(3):527–33.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"5.\"><p>Tang R, Luo R, Wu B, Wang F, Song H, Chen X. Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis of randomized controlled trials. J Crit Care. 2021;65:133–9.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"6.\"><p>Dugernier J, Ehrmann S, Sottiaux T, Roeseler J, Wittebole X, Dugernier T, et al. Aerosol delivery during invasive mechanical ventilation: a systematic review. Crit Care. 2017;21(1):264.</p><p>Article PubMed PubMed Central Google Scholar </p></li><li data-counter=\"7.\"><p>Ehrmann S, Roche-Campo F, Bodet-Contentin L, Razazi K, Dugernier J, Trenado-Alvarez J, et al. Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients. Intensive Care Med. 2016;42(2):192–201.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"8.\"><p>Sun Q, Chang W, Liu X, Xie J, Qiu H, Yang Y, et al. Aerosol therapy during mechanical ventilation in intensive care units: a questionnaire-based survey of 2203 ICU medical staff in China. J Intensive Med. 2022;2(3):189–94.</p><p>Article PubMed PubMed Central Google Scholar </p></li><li data-counter=\"9.\"><p>Ambrosio AM, Luo R, Fantoni DT, Gutierres C, Lu Q, Gu WJ, et al. Effects of positive end-expiratory pressure titration and recruitment maneuver on lung inflammation and hyperinflation in experimental acid aspiration-induced lung injury. Anesthesiology. 2012;117(6):1322–34.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"10.\"><p>Dhanani JA, Diab S, Chaudhary J, Cohen J, Parker SL, Wallis SC, et al. Lung pharmacokinetics of tobramycin by intravenous and nebulized dosing in a mechanically ventilated healthy ovine model. Anesthesiology. 2019;131(2):344–55.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"11.\"><p>Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–111.</p><p>Article PubMed PubMed Central Google Scholar </p></li><li data-counter=\"12.\"><p>Rello J, Solé-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;23(9):629–39.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"13.\"><p>Paul M, Carrara E, Retamar P, Tängdén T, Bitterman R, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. 2022;28(4):521–47.</p><p>Article CAS PubMed Google Scholar </p></li><li data-counter=\"14.\"><p>Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. 2023:ciad428.</p></li><li data-counter=\"15.\"><p>Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 2024:ciae403.</p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><p>Not applicable.</p><p>This work was supported by the Project of the Key Laboratory of Multiple Organ Failure, Ministry of Education (2023KF07), the Key Laboratory of Intelligent Pharmacy and Individualized Treatment in Huzhou City (HZKF-20240101).</p><span>Author notes</span><ol><li><p>Lihui Wang and Chunhui Xu have contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Critical Care Medicine, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200001, China</p><p>Lihui Wang &amp; Yuetian Yu</p></li><li><p>State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China</p><p>Chunhui Xu</p></li><li><p>Department of Critical Care Medicine, Affiliated Hospital of Qinghai University, Xining, 810001, China</p><p>Lining Si &amp; Guifen Gan</p></li><li><p>Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Huzhou, 313100, China</p><p>Bin Lin &amp; Yuetian Yu</p></li><li><p>Department of Pharmacy, Changxing People’s Hospital; Changxing Branch, Second Affiliated Hospital of Zhejiang University School of Medicine, Huzhou, 313100, China</p><p>Bin Lin</p></li></ol><span>Authors</span><ol><li><span>Lihui Wang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Chunhui Xu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Lining Si</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Guifen Gan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Bin Lin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yuetian Yu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Contributions</h3><p>LW and YY wrote the main manuscript text, CX prepared the figure. All authors reviewed the manuscript.</p><h3>Corresponding authors</h3><p>Correspondence to Bin Lin or Yuetian Yu.</p><h3>Ethics approval and consent to participate</h3>\n<p>Not applicable.</p>\n<h3>Consent for publication</h3>\n<p>Not applicable.</p>\n<h3>Competing interests</h3>\n<p>The authors declare that they have no competing interests.</p><h3>Publisher's Note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.</p>\n<p>Reprints and permissions</p><img alt=\"Check for updates. 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Abstract

With great interest we read the recent network meta-analysis by Zhou et al. which found that the intravenous plus inhaled polymyxin-containing regimen could reduce the all-cause mortality of patients with pneumonia caused by multidrug-resistant gram-negative bacterial (MDRGNB) [1]. This is undoubtedly an encouraging result and provides evidence for the subsequent clinical implementation of such regimens. However, there are still some issues that need further attention.

Pneumonia caused by MDRGNB remains a huge challenge in the intensive care unit (ICU). Currently, the available effective antibiotics are limited, and polymyxins are still the cornerstones for treatment. However, with the introduction of new antibiotics into clinical practice (especially new beta-lactam and beta-lactamase inhibitor combination) and the potential renal toxicity of polymyxins, since 2020, the performance standards for antimicrobial susceptibility testing of the Clinical and Laboratory Standards Institute (CLSI) have canceled the susceptibility breakpoints of polymyxins for Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. It defines a minimal inhibitory concentration (MIC) of ≤ 2 ug/mL as intermediate (https://clsi.org). At present, the newly available antibiotics for the treatment of MDRGNB pneumonia in China is limited. Therefore, Chinese Medical Association (CMA) still define MIC ≤ 2 ug/mL as susceptible according to the previous versions of CLSI before 2020 or the 10th version of European Committee on Antimicrobial Susceptibility Testing (EUCAST), to guide clinical treatment. The international approved and recognized method for susceptibility testing of polymyxins is broth microdilution (BMD), but its manual operation is complex and time-consuming, making it difficult for laboratories to routinely carry out. Thus, most laboratories still use automated or semi-automated instruments nowadays to detect the susceptibility, and the accuracy of the results still needs further evaluation.

In addition, the clinical pharmacokinetic/pharmacodynamic (PK/PD) target of polymyxins for efficacy is unclear [2]. Some guidelines recommended that for polymyxin B the AUCss,24h should be about 50 mg h/L and possibly 50–100 mg h/L, with the latter corresponding to an average steady-state concentration across 24 h (Css,avg) of 2–4 ug/mL for pathogens with MIC of ≤ 2 ug/mL [3]. Therefore, careful interpretation is needed for the susceptible judgment of polymyxins, the optimal PK/PD index, and the effectiveness of antibiotic therapy.

The presence of the blood-alveolar barrier prevents satisfactory concentrations of antibiotics in the epithelial lining fluid (ELF) when antibiotics are administered intravenously, and increasing the dosage of intravenous administration may lead to high rate of side effects such as acute kidney injury. Nebulization therapy can convert liquid antibiotic preparations into particles of 3–5 um, allowing them to deposit in the alveoli, thereby effectively increasing the concentration at the site of infection and improving clinical outcomes.

One early meta-analysis included eight studies on intravenous combined nebulized colistin. Due to significant differences in patient inclusion criteria, colistin dosage, and nebulization procedures, the quality of evidence presented for each outcome ranged from “very low” to “low.” It suggested that intravenous combined with nebulized colistin could enhance clinical response and microbiological eradication in patients with ventilator-associated pneumonia (VAP) while reducing infection-related mortality. However, it did not affect overall mortality (odds ratio, 0.74; 95% CI 0.54–1.01; p = 0.06; I2 = 25%) [4]. Another meta-analysis included 11 randomized controlled trials (RCTs) comparing the safety and efficacy of nebulized combined with intravenous antibiotics (colistin, amikacin and tobramycin) for the treatment of VAP. It also found that the combined treatment strategy did not reduce the mortality (relative risk 1.00; 95% CI 0.82–1.21; I2 = 45%) [5].

Physicians in the field of critical care medicine have been attempting to treat VAP with a regimen of nebulized antibiotics since 1985. After nearly 40 years of development, the efficacy of the regimen has significantly improved [6]. However, we still need to further standardize the procedure.

A 2-week cross-sectional study analyzed the process of nebulization therapy in 2808 patients undergoing mechanical ventilation in the ICU. The study found that 77% of physicians did not adjust the mechanical ventilation parameters during nebulization therapy, only 65% of the nebulization processes included the addition of a filter at the expiratory end, and 28% had not replaced the filter [7]. Another questionnaire-based cross-sectional survey from China enrolled 2203 medical staff who regularly worked in the ICU. It indicated that ventilator settings were never changed by 32.7% of respondents during nebulization. The usage rate of mesh nebulizers in ICUs in China was less than 1% [8]. In addition, polymyxin B was launched in China in September 2017. Due to its relatively low price (approximately $30 for 50 mg), it has become one of the preferred medications for nebulized therapy in patients with VAP. However, it is important to note that it may cause airway hyper-reactivity such as coughing and asthma after nebulization, which requires further attention. The high cost of colistimethate sodium (approximately $300 for 150 mg) prevents its widespread use in nebulized therapy in China. It is one of the combination therapies more commonly used for MDRGNB treatment. Therefore, it is recommended an urgent need for high-quality education to bring practice into line with evidence-based guidelines.

We have integrated published research and recommendation from various associations to develop a protocol suitable for nebulized therapy in mechanically ventilated patients in Chinese ICUs. Clear guidance is provided for the adjustments of relevant ventilator parameters before, during, and after nebulization. We hope that the implementation of standardized procedures will enhance the effectiveness of nebulization therapy and ultimately improve patient outcomes (Fig. 1).

Fig. 1
Abstract Image

Process and precautions for nebulizing antibiotics in mechanically ventilated patients (drawn by Chunhui Xu)

Full size image

We usually combine nebulized antibiotics with intravenous antibiotics for treatment VAP which makes it difficult to accurately evaluate the true efficacy of this strategy. In patients with VAP, the lung lesions are almost always heterogeneous, resulting in better ventilation in non-infected areas while infected regions suffer from inflammatory exudates, sputum obstruction, and local atelectasis, leading to poor ventilation. Therefore, in the context of mechanical ventilation, nebulized antibiotic particles are more likely to deposit in healthy lung tissue rather than in the damaged lung [9]. However, due to the excessive concentration of antibiotics deposited in healthy lung tissue, it remains unclear whether this will further damage the alveolar mucosal tissue and subsequently promote the occurrence of pneumonia, which requires further related research in the future.

Many studies have measured the concentration of antibiotics in bronchoalveolar lavage fluid (BALF) after nebulization therapy by using urea as an internal reference. After calibration with a formula ([Antibiotics]ELF = [Antibiotics]BALF × Plasma Urea value/BALF Urea value), the concentration of antibiotics in the ELF is reported. However, the antibiotic concentration obtained through the urea calibration method is 100-fold higher than that determined by the gold standard microdialysis probe detection method. This could be due to bronchial contamination during the bronchoalveolar sampling [10].

In summary, there are still many issues that cannot be clearly resolved regarding the treatment of VAP with intravenous combined nebulized therapy, and the actual efficacy remains unclear. Although the previous guidelines had lower-level antibiotic nebulization therapy, the latest guidelines, considering the lack of uniformity in the nebulization process and the high heterogeneity of VAP patients, currently do not recommend this strategy [11,12,13,14,15]. It is suggested that subsequent large-sample RCTs should be conducted under the premise of a standardized protocol, while also clarifying the actual concentration of antibiotics in the ELF after nebulization, in order to provide better evidence for clinical treatment.

Not applicable.

MDRGNB:

Multidrug-resistant gram-negative bacterial

ICU:

Intensive care unit

CLSI:

Clinical and Laboratory Standards Institute

MIC:

Minimal inhibitory concentration

CMA:

Chinese Medical Association

EUCAST:

European Committee on Antimicrobial Susceptibility Testing

BMD:

Broth microdilution

PK/PD:

Pharmacokinetic/pharmacodynamic

ELF:

Epithelial lining fluid

VAP:

Ventilator-associated pneumonia

RCT:

Randomized controlled trial

BALF:

Bronchoalveolar lavage fluid

  1. Zhou Y, Wang G, Zhao Y, Chen W, Chen X, Qiu Y, et al. Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis. Crit Care. 2024;28(1):239.

    Article PubMed PubMed Central Google Scholar

  2. Abdul-Aziz MH, Alffenaar JC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med. 2020;46(6):1127–53.

    Article PubMed PubMed Central Google Scholar

  3. Liu X, Huang C, Bergen PJ, Li J, Zhang J, Chen Y, et al. Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. J Zhejiang Univ Sci B. 2023;24(2):130–42.

    Article PubMed Google Scholar

  4. Valachis A, Samonis G, Kofteridis DP. The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med. 2015;43(3):527–33.

    Article CAS PubMed Google Scholar

  5. Tang R, Luo R, Wu B, Wang F, Song H, Chen X. Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis of randomized controlled trials. J Crit Care. 2021;65:133–9.

    Article CAS PubMed Google Scholar

  6. Dugernier J, Ehrmann S, Sottiaux T, Roeseler J, Wittebole X, Dugernier T, et al. Aerosol delivery during invasive mechanical ventilation: a systematic review. Crit Care. 2017;21(1):264.

    Article PubMed PubMed Central Google Scholar

  7. Ehrmann S, Roche-Campo F, Bodet-Contentin L, Razazi K, Dugernier J, Trenado-Alvarez J, et al. Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients. Intensive Care Med. 2016;42(2):192–201.

    Article CAS PubMed Google Scholar

  8. Sun Q, Chang W, Liu X, Xie J, Qiu H, Yang Y, et al. Aerosol therapy during mechanical ventilation in intensive care units: a questionnaire-based survey of 2203 ICU medical staff in China. J Intensive Med. 2022;2(3):189–94.

    Article PubMed PubMed Central Google Scholar

  9. Ambrosio AM, Luo R, Fantoni DT, Gutierres C, Lu Q, Gu WJ, et al. Effects of positive end-expiratory pressure titration and recruitment maneuver on lung inflammation and hyperinflation in experimental acid aspiration-induced lung injury. Anesthesiology. 2012;117(6):1322–34.

    Article CAS PubMed Google Scholar

  10. Dhanani JA, Diab S, Chaudhary J, Cohen J, Parker SL, Wallis SC, et al. Lung pharmacokinetics of tobramycin by intravenous and nebulized dosing in a mechanically ventilated healthy ovine model. Anesthesiology. 2019;131(2):344–55.

    Article CAS PubMed Google Scholar

  11. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–111.

    Article PubMed PubMed Central Google Scholar

  12. Rello J, Solé-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;23(9):629–39.

    Article CAS PubMed Google Scholar

  13. Paul M, Carrara E, Retamar P, Tängdén T, Bitterman R, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. 2022;28(4):521–47.

    Article CAS PubMed Google Scholar

  14. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. 2023:ciad428.

  15. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 2024:ciae403.

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This work was supported by the Project of the Key Laboratory of Multiple Organ Failure, Ministry of Education (2023KF07), the Key Laboratory of Intelligent Pharmacy and Individualized Treatment in Huzhou City (HZKF-20240101).

Author notes
  1. Lihui Wang and Chunhui Xu have contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200001, China

    Lihui Wang & Yuetian Yu

  2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China

    Chunhui Xu

  3. Department of Critical Care Medicine, Affiliated Hospital of Qinghai University, Xining, 810001, China

    Lining Si & Guifen Gan

  4. Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Huzhou, 313100, China

    Bin Lin & Yuetian Yu

  5. Department of Pharmacy, Changxing People’s Hospital; Changxing Branch, Second Affiliated Hospital of Zhejiang University School of Medicine, Huzhou, 313100, China

    Bin Lin

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LW and YY wrote the main manuscript text, CX prepared the figure. All authors reviewed the manuscript.

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Wang, L., Xu, C., Si, L. et al. Polymyxin-containing regimens for treating of pneumonia caused by multidrug-resistant gram-negative bacteria: Mind the breakpoints and the standardization of nebulization therapy. Crit Care 28, 324 (2024). https://doi.org/10.1186/s13054-024-05111-x

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治疗耐多药革兰氏阴性菌引起的肺炎的含多粘菌素方案:注意断点和雾化治疗的标准化
我们饶有兴趣地阅读了 Zhou 等人最近进行的网络荟萃分析,结果发现静脉注射加吸入含多粘菌素的治疗方案可降低耐多药革兰氏阴性菌(MDRGNB)引起的肺炎患者的全因死亡率[1]。这无疑是一个令人鼓舞的结果,并为随后在临床上实施此类治疗方案提供了证据。然而,仍有一些问题需要进一步关注。由 MDRGNB 引起的肺炎仍是重症监护室(ICU)面临的巨大挑战。目前,可用的有效抗生素有限,多粘菌素仍是治疗的基石。然而,随着新型抗生素(尤其是新型β-内酰胺与β-内酰胺酶抑制剂复方制剂)被引入临床实践,以及多粘菌素潜在的肾毒性,自 2020 年起,美国临床与实验室标准协会(CLSI)的抗菌药物药敏试验性能标准取消了多粘菌素对肠杆菌科、铜绿假单胞菌和鲍曼不动杆菌的药敏断点。它将最小抑菌浓度(MIC)≤ 2 ug/mL 定义为中间值(https://clsi.org)。目前,中国用于治疗 MDRGNB 肺炎的新抗生素有限。因此,中华医学会(CMA)仍根据2020年前CLSI的旧版本或欧洲抗菌药物敏感性检测委员会(EUCAST)的第10版将MIC≤2 ug/mL定义为易感,以指导临床治疗。国际上批准和认可的多粘菌素药敏试验方法是肉汤微量稀释法(BMD),但其手工操作复杂耗时,实验室难以常规开展。因此,目前大多数实验室仍使用自动化或半自动化仪器检测药敏性,其结果的准确性仍需进一步评估。此外,多粘菌素的临床药代动力学/药效学(PK/PD)疗效目标尚不明确[2]。一些指南建议,多粘菌素 B 的 AUCss,24h 应为约 50 毫克/小时/升,也可能为 50-100 毫克/小时/升,对于 MIC ≤ 2 微克/毫升的病原体,后者相当于 24 小时内的平均稳态浓度(Css,avg)为 2-4 微克/毫升[3]。由于血肺泡屏障的存在,静脉注射抗生素时上皮内衬液(ELF)中的抗生素浓度无法达到令人满意的水平,而增加静脉注射的剂量可能会导致急性肾损伤等副作用的高发。雾化疗法可将液体抗生素制剂转化为 3-5 微米的颗粒,使其沉积在肺泡中,从而有效提高感染部位的浓度,改善临床疗效。由于患者纳入标准、可乐定剂量和雾化程序存在显著差异,每项结果的证据质量从 "非常低 "到 "低 "不等。研究表明,静脉注射联合雾化吸入可乐定可提高呼吸机相关性肺炎(VAP)患者的临床反应和微生物根除率,同时降低感染相关死亡率。然而,这并不影响总死亡率(几率比,0.74;95% CI 0.54-1.01;P = 0.06;I2 = 25%)[4]。另一项荟萃分析纳入了 11 项随机对照试验(RCT),比较了雾化联合静脉注射抗生素(可乐定、阿米卡星和妥布霉素)治疗 VAP 的安全性和有效性。研究还发现,联合治疗策略并未降低死亡率(相对风险为 1.00;95% CI 为 0.82-1.21;I2 = 45%)[5]。经过近 40 年的发展,该疗法的疗效已显著提高[6]。一项为期两周的横断面研究分析了在重症监护室接受机械通气的 2808 名患者的雾化治疗过程。研究发现,77% 的医生在雾化治疗过程中没有调整机械通气参数,只有 65% 的雾化过程包括在呼气末添加过滤器,28% 的医生没有更换过滤器[7]。中国的另一项基于问卷的横断面调查招募了 2203 名经常在重症监护室工作的医务人员。调查显示,32.7% 的受访者在雾化过程中从未改变过呼吸机的设置。
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来源期刊
Critical Care
Critical Care 医学-危重病医学
CiteScore
20.60
自引率
3.30%
发文量
348
审稿时长
1.5 months
期刊介绍: Critical Care is an esteemed international medical journal that undergoes a rigorous peer-review process to maintain its high quality standards. Its primary objective is to enhance the healthcare services offered to critically ill patients. To achieve this, the journal focuses on gathering, exchanging, disseminating, and endorsing evidence-based information that is highly relevant to intensivists. By doing so, Critical Care seeks to provide a thorough and inclusive examination of the intensive care field.
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