Is it the end of the road for inhaled antibiotics in ventilator-associated pneumonia?

Ventilator-associated pneumonia (VAP) caused by multidrug-resistant bacteria continues to be a major cause of morbidity and mortality in our ICUs. We have a limited choice of antibiotics to combat the resistant bacterial flora prevalent in many units. Besides, most systemically administered antibiotics fail to attain therapeutic concentrations in the lung. This has led many clinicians to resort to aerosolized antibiotics, often as an adjuvant to systemic therapy in the treatment of VAP. The use of inhaled antibiotics is based on a sound rationale, with the possibility of delivering a high concentration of the drug to the target site. Furthermore, the emergence of resistant organisms may also be reduced with the preservation of the gut flora. An added advantage may be to cut down the duration of systemic antibiotics, and perhaps, even use inhaled antibiotics are monotherapy.

Inhaled antibiotic therapy is by no means a new therapeutic modality; a 1975 study of ICU patients used polymyxin B in the atomized form or by endotracheal instillation in intubated patients as prophylaxis against pneumonia (1). Predictably, such unlimited, universal, largely prophylactic therapy resulted in a high level of polymyxin resistance and high mortality. A global survey conducted in 2017 revealed that 63.4% of 261 ICUs used inhaled antibiotics, mainly for VAP and ventilator-associated tracheobronchitis (VAT) (2). 

Why the inhaled route?

High levels of antibiotics concentration are attained in the lung when administered through the inhaled route. Animal studies have demonstrated substantially higher pulmonary concentrations in the lung by the inhaled compared with the intravenous route (3). Studies among patients with VAP have also revealed concentrations considerably higher than the minimum inhibitory concentration (MIC) of the causative pathogen. Besides, as systemic absorption is limited, the plasma levels remain much lower compared with intravenous administration (4). Low systemic concentrations might reduce overall antibiotic exposure and minimize the emergence of resistant strains (5). Toxic effects resulting from intravenous administration may also be lower with inhaled administration. The incidence of acute kidney injury may be lower with inhaled compared to intravenous administration of colistin (6). 

There are several potential drawbacks and limitations of inhaled antibiotic therapy. Respiratory complications, including bronchospasm and worsening of hypoxia may occur. Pneumonia may lead to bacteremia; the relative lack of a systemic effect would render inhaled therapy ineffective in this situation. Besides, the efficacy of aerosol delivery to the less ventilated regions of the lung including areas of consolidation or collapse may be suboptimal. The filter at the expiratory port of the ventilator may occlude, leading to interference with ventilation and serious complications, including hypoxia and cardiac arrest. Although adverse effects are often highlighted in clinical guidelines (7,8), the actual incidence may be less than 1%, with most events being mild and easily reversible (9). Intravenous formulations, in general, are unsuitable for inhalational delivery. Inhalational preparations must be nonpyrogenic, and preservative-free, with a pH between 4–8, and osmolality of 150–200 mOsm/l (10). 

Mode of delivery 

Particle size, nebulizer type

Larger particles tend to impact against the lumen of the respiratory tract as the direction of gas flow changes along the proximal airways. Such impaction leads to the deposition of particles in the large proximal airways leading to a lack of effectiveness. The optimal particle size for enhanced distal deposition ranges between 0.5–5 μm (11). Jet, ultrasonic, and vibrating mesh nebulizers are commonly used in clinical practice. Jet nebulizers are the least preferred as they require an external source of compressed gas that interferes with ventilator settings. Besides, a substantial residual volume of the solution remains in the nebulizing chamber at the end of treatment, rendering it inefficient. Ultrasonic nebulizers are effective; however, they generate heat that may cause the degradation of heat-sensitive drugs. Vibrating mesh nebulizers are generally preferred for the delivery of inhaled antibiotics. A high-frequency (150 – 300,000 cycles per second) vibrating mesh pumps the solution through conical outlets. Mesh nebulizers are easy to use, do not interfere with ventilator settings, and leave behind the least residual volume. Vibrating mesh nebulizers may be breath-activated with nebulization synchronized to the inspiratory phase. This mechanism prevents the ventilator bias flow from carrying the aerosol into the expiratory limb during the expiratory phase, with wasteful drug deposition in the circuit (12) (Figure 1). Ultrasonic and jet nebulizers are placed in the inspiratory limb, about 15–40 cm upstream to the Y-piece of the circuit; vibrating mesh nebulizers are placed immediately proximal to the Y-piece or distal to the Y-piece in a breath-activated device. 

Circuit and ventilator setup 

Humidification of gas flow increases particle size of the aerosol due to water absorption, leading to reduced efficacy. Heat and moisture exchanger filters completely occlude aerosol delivery and hence, must be removed prior to nebulization. It may be ideal to assign a separate “dry” circuit for the duration of nebulization, provided the duration of nebulization is less than 30 min (7). A low, constant flow ventilation mode is preferred to optimize aerosolization. Volume control-assist control mode with a tidal volume of 7–9 ml/kg, respiratory rate of 12/min, and inspiratory: expiratory ratio of 1:1, with the addition of an end-inspiratory pause enables efficient aerosolization (13). Pressure-controlled ventilation with a decelerating flow pattern is not ideal for effective nebulization. Patient-ventilator asynchrony may lead to inefficient therapy; hence, an appropriate level of sedation may be required prior to nebulization to control asynchronous breaths. The duration of nebulization should be restricted to <60 min to prevent adverse events arising from interruption of heating and humidification of the inspired gas for a protracted period (14).

Figure 1. Ventilator setup for nebulization. A dedicated “dry” circuit in a constant flow mode, long inspiratory time, and an inspiratory pause is preferred. The nebulizer is placed in the inspiratory limb. Breath-activated delivery, synchronized with the inspiratory phase, will prevent aerosol passage into the expiratory limb and wasteful deposition of particles in the circuit 

What does evidence suggest regarding the efficacy of inhaled therapy?

Randomized controlled trials 

Do inhaled antibiotics really work? There is scant, often conflicting evidence on their efficacy from controlled trials. 

The INHALE prospective, double-blind RCT included mechanically ventilated patients with pneumonia diagnosed by chest radiography. The etiology was documented to be due to multidrug-resistant (MDR) gram negative organisms, or the patient had two risk factors for such infection. The clinical pulmonary infection score (CPIS) was ≥6, and impaired oxygenation was present in the 48-hour period prior to screening. Patients were randomly assigned to receive 400 mg amikacin or saline by the inhaled route twice daily for 10 days, in addition to standard intravenous antibiotic therapy. A breath-activated, vibrating mesh nebulizer that aerosolizes the drug during the initial 75% of the inspiratory cycle was used in this study. A total of 725 patients were randomized, 362 to receive amikacin and 363 to placebo. Among these patients, 712 received at least one dose of the study drug. The primary endpoint, survival at 28–32 days, was analyzed in 508 patients; there was no significant difference between the inhaled administration of amikacin compared with placebo (amikacin vs. saline: 75% vs. 77%; odds ratio 0·841, 95% CI 0·554–1·277; p = 0·43). Treatment-related adverse events were also similar between the two groups (15).

Kollef et al. conducted a randomized controlled trial (RCT) in patients with VAP due to gram-negative bacteria. Inhalational antibiotic therapy was carried out with amikacin, 300 mg, and fosfomycin, 120 mg delivered twice daily for 10 days or until extubation, using a vibrating mesh nebulizer (16). Nebulization was carried out for 12 min, with a special formulation suitable for aerosol delivery. The control group received a placebo. Both groups of patients also received intravenous meropenem or imipenem as gram-negative cover for 7 days. A total of 143 patients were included in the study, with 71 in the inhalational and 72 in the placebo group. Change in the CPIS from baseline, the primary outcome, was not significantly different between the two groups. The hierarchical secondary endpoint of being alive with clinical cure, and alive and ventilator-free at day 14 were similar between groups. Compared to the placebo group, the inhaled therapy group had fewer positive cultures on days 3 and 7, although this did not translate to a clinical benefit. This RCT did not reveal any clinical benefit or improvement in the CPIS using adjuvant inhaled therapy with amikacin and fosfomycin compared with standard intravenous antibiotic therapy alone. 

Would inhaled antibiotics be effective in cardiothoracic surgical patients who develop hospital-acquired pneumonia or VAP in the postoperative period? 

Hassan et al. evaluated patients with nosocomial pneumonia caused by MDR gram-negative bacilli following cardiothoracic surgery in an RCT (17). Patients were diagnosed as having hospital-acquired pneumonia, or VAP using predefined criteria. Intravenous piperacillin-tazobactam was administered to all patients. In the inhalational therapy group, amikacin 400 mg twice daily was administered as nebulization; in the control group, amikacin 20 mg/kg was administered intravenously. The primary outcome was clinical cure on day 7, defined as normalization of temperature, WBC count <10,000/ml, absence of purulent secretions, improved radiological infiltrates, and a PaO2/FiOratio of >250 in patients with VAP. Clinical cure on day 7 was significantly higher with inhaled therapy. Inhaled therapy was associated with a shorter ICU stay, fewer days on mechanical ventilation, and a more rapid clinical cure. Nephrotoxicity was also lower in the inhaled therapy group. This study revealed improvement in clinical outcomes with the use of aerosolized compared with intravenous amikacin in combination with intravenous piperacillin/tazobactam in nosocomial pneumonia post-cardiothoracic surgery. Table 1 summarizes main RCTs that evaluated the efficacy of inhaled antibiotic therapy in VAP. 

Table 1. Main RCTs that have evaluated the efficacy of inhaled antibiotics 

Study/yearInhalational antibiotic groupControl group Outcomes
Niederman et al.12    (INHALE, 2020)Amikacin, 400 mg twice daily for 10 d, combined with standard intravenous antibiotics Standard intravenous antibiotics alone Survival at 28–32 days not different; adverse events similar 
Kollef et al.13            (2017)Amikacin, 300 mg, and fosfomycin, 120 mg twice daily for 10 days or until extubation + intravenous meropenem or imipenemPlacebo + intravenous meropenem or imipenemChange in the CPIS similar; clinical cure, and alive and ventilator-free similar at day 14; fewer positive cultures at days 3 and 7 in the inhalational group
Hassan et al.14.                (2018)Amikacin 400 mg twice daily. Intravenous piperacillin-tazobactamIntravenous piperacillin-tazobactam aloneClinical cure on day 7 significantly higher, nephrotoxicity lower, with inhalational therapy

Abbreviation: CPIS, Clinical Pulmonary Infection Score

In contrast to the equivocal results in VAP, the use of inhaled antibiotics has met with relative success in ventilator-associated tracheobronchitis (VAT). In a double-blind RCT, mechanically ventilated patients with VAT, defined as the production of  ≥2 ml of purulent secretions during a 4-hour period, with a positive gram stain, were assigned to inhaled antibiotic or placebo. Compared with the placebo group, the inhaled group had reduced signs of ongoing respiratory infection by the Centers for Disease Control National Nosocomial Infection Survey VAP criteria and the CPIS. Besides, bacterial resistance was also lower with inhaled therapy (18). In another RCT, mechanically ventilated patients with evidence of respiratory infection based on purulent secretions and a CPIS ≥6 were included. The use of inhaled antibiotics resulted in significantly greater elimination of the pathogen based on culture and gram stain, compared with placebo. The emergence of bacterial resistance was higher in the placebo arm. The use of inhaled antibiotics also led to a reduction in the Clinical Pulmonary Infection Score (5).  

Meta-analyses 

Zampieri et al. performed a meta-analysis comparing the combination of intravenous and aerosolized antibiotics with intravenous administration alone in the treatment of VAP (19). The antibiotics used included gentamicin, amikacin, tobramycin, ceftazidime, and colistin. The likelihood of clinical cure was significantly higher with combined therapy; however, there was no significant difference in microbiological cure rates, ICU or hospital mortality, ventilation days, and ICU length of stay. In another meta-analysis, intravenous colistin was compared with adjunctive inhaled colistin therapy. This study reported a significantly higher clinical response, microbiological eradication, and infection-related mortality. There was no difference in the overall mortality or nephrotoxicity (20). Liu et al. compared the efficacy of intravenous-inhaled combination of colistin with IV colistin alone in their meta-analysis. They observed a greater clinical response, a higher rate of eradication of the pathogen, and reduced all-cause mortality with the inhaled-intravenous combination (21). 

The future

Considering the lack of evidence to support inhaled therapy, should we persist with this treatment modality? The Infectious Diseases Society of America and the American Thoracic Society recommend the use of inhaled antibiotics only as a last resort to treat refractory VAP, unresponsive to conventional systemic antibiotic therapy (8). Perhaps we need to reassess the endpoints of inhalational therapy. It is plausible that the use of the inhaled route could potentially reduce the duration of systemic therapy, thereby reducing the emergence of resistant strains. The dosing needs standardization; the currently employed dosing may well be inadequate, and a higher dose, particularly of colistin, may be required for an optimal response (22). Patients with more severe illness may potentially benefit; future studies should specifically target subgroups of patients based on the severity of illness. The ideal mode of aerosol delivery needs further research; vibrating mesh nebulizers, synchronized with the inspiratory phase, may be superior compared to jet and ultrasonic nebulizers. It may also be appropriate to target drug levels by distal lung lavage to ensure adequate drug delivery at the site of infection (23). 

Key points

  • The use of inhaled antibiotics is based on a sound physiological rationale, with the potential to deliver a high concentration of the drug to the site of infection. Besides, delivery by nebulization may alleviate systemic adverse effects, including nephrotoxicity
  • Inhalational therapy is likely to fail in the presence of bacteremia, considering the lack of a systemic effect. Besides, adverse effects may occur, including respiratory complications and prolongation of the duration of mechanical ventilation 
  • Although the optimal modality of delivery is not established, vibrating mesh nebulizers may offer optimal particle size. Besides, in contrast to jet nebulizers, the residual, unused volume is significantly reduced. Synchronization with the inspiratory phase prevents the passage of aerosol into the expiratory limb and wasteful deposition in the ventilator circuit
  • RCTs and meta-analyses on the topic provide conflicting results regarding the efficacy of inhaled therapy; considering the lack of robust evidence, most guidelines recommend inhaled antibiotics only as a last resort in intractable cases and infection with MDR organisms 
  • Future research should focus on the optimal dosing; more meaningful endpoints, including efficacy in subgroups of patients with more severe illness, and the likelihood of reducing the emergence of resistant strains should also be considered  

References

1.   Feeley TW, Du Moulin GC, Hedley-Whyte J, Bushnell LS, Gilbert JP, Feingold DS. Aerosol polymyxin and pneumonia in seriously ill patients. N Engl J Med. 1975 Sep 4;293(10):471–5. 

2.   Alves J, Alp E, Koulenti D, Zhang Z, Ehrmann S, Blot S, et al. Nebulization of antimicrobial agents in mechanically ventilated adults in 2017: an international cross-sectional survey. Eur J Clin Microbiol Infect Dis. 2018 Apr;37(4):785–94. 

3.   Goldstein I, Wallet F, Nicolas-Robin A, Ferrari F, Marquette CH, Rouby JJ. Lung deposition and efficiency of nebulized amikacin during Escherichia coli pneumonia in ventilated piglets. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1375–81. 

4.   Boisson M, Jacobs M, Grégoire N, Gobin P, Marchand S, Couet W, et al. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother. 2014 Dec;58(12):7331–9. 

5.   Palmer LB, Smaldone GC. Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med. 2014 May 15;189(10):1225–33. 

6.   Abdellatif S, Trifi A, Daly F, Mahjoub K, Nasri R, Ben Lakhal S. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care. 2016 Dec;6(1):26. 

7.   Ehrmann S, Chastre J, Diot P, Lu Q. Nebulized antibiotics in mechanically ventilated patients: a challenge for translational research from technology to clinical care. Ann Intensive Care. 2017 Dec;7(1):78. 

8.   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 Sep 1;63(5):e61–111. 

9.   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 Feb;42(2):192–201. 

10. Bassetti M, Luyt CE, Nicolau DP, Pugin J. Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient. Ann Intensive Care. 2016 Dec;6(1):35. 

11. Brain JD, Valberg PA. Deposition of aerosol in the respiratory tract. Am Rev Respir Dis. 1979 Dec;120(6):1325–73. 

12. Gowda AA, Cuccia AD, Smaldone GC. Reliability of Vibrating Mesh Technology. Respir Care. 2017 Jan;62(1):65–9.

13. Dhand R. Maximizing aerosol delivery during mechanical ventilation: go with the flow and go slow. Intensive Care Med. 2003 Jul;29(7):1041–2. 

14. Rello J, Rouby JJ, Sole-Lleonart C, Chastre J, Blot S, Luyt CE, et al. Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients. Clin Microbiol Infect. 2017 Sep;23(9):640–6. 

15. Niederman MS, Alder J, Bassetti M, Boateng F, Cao B, Corkery K, et al. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis. 2020 Mar;20(3):330–40. 

16. Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, et al. A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial. Chest. 2017 Jun;151(6):1239–46. 

17. Hassan NA, Awdallah FF, Abbassi MM, Sabry NA. Nebulized Versus IV Amikacin as Adjunctive Antibiotic for Hospital and Ventilator-Acquired Pneumonia Postcardiac Surgeries: A Randomized Controlled Trial. Crit Care Med. 2018 Jan;46(1):45–52. 

18. Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T, Monteforte M, et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008 Jul;36(7):2008–13. 

19. Zampieri FG, Nassar AP, Gusmao-Flores D, Taniguchi LU, Torres A, Ranzani OT. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care. 2015 Apr 7;19:150. 

20. 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 Mar;43(3):527–33. 

21. Liu D, Zhang J, Liu HX, Zhu YG, Qu JM. Intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis. Int J Antimicrob Agents. 2015 Dec;46(6):603–9. 

22. Honore PM, Redant S, Stoll T, Preseau T, Moorthamers S, Kaefer K, et al. Study conclude that adjunctive inhaled antibiotics were not associated with reduced mortality: We are not sure! J Crit Care. 2022 Feb;67:227–8. 

23. Niederman MS. Adjunctive Nebulized Antibiotics: What Is Their Place in ICU Infections? Front Med. 2019 May 8;6:99. 

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