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 AUC_ss,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 (C_ss,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).

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

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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).

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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• Received: 22 September 2024

• Accepted: 24 September 2024

• Published: 04 October 2024

• DOI: https://doi.org/10.1186/s13054-024-05111-x

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