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COUNTERPOINT: Should Inhaled Antibiotic Therapy Be Used Routinely for the Treatment of Bacterial Lower Respiratory Tract Infections in the ICU Setting? No FREE TO VIEW

Marin H. Kollef, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: This work was supported by the Barnes-Jewish Hospital Foundation. M. H. K. was a principal investigator in the Cardeas study.

Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO

CORRESPONDENCE TO: Marin H. Kollef, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 4523 Clayton Ave, Campus Box 8052, St. Louis, MO 63110


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(4):740-743. doi:10.1016/j.chest.2016.11.007
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Published online

The use of antimicrobial agents is a relatively new phenomenon that arose at the start of the 20th century. In critically ill patients with microbiologically confirmed infections, the timely administration of appropriate antibiotic therapy (ie, an antibiotic regimen with activity against the causative bacterial pathogen based on in vitro testing) is associated with a lower risk of mortality. Unfortunately, antibiotics are frequently prescribed to patients devoid of bacterial infection. The emergence of antibiotic resistance shortly followed the introduction of these agents, and the steady escalation of resistance up to the present has been directly associated with increasing antibiotic consumption. The impact of antibiotic resistance on health care and global economics is highlighted by a recent Wellcome Trust report estimating that by 2050, > 10 million deaths will be attributed to antimicrobial resistance, greater than the number of deaths attributed to cancer. Given the rise in antibiotic resistance and its link to consumption, we must carefully consider whether any new indication for antibiotics is justifiable.

Bacterial lower respiratory tract infection (BLRTI) is relatively common in patients requiring mechanical ventilation. Antibiotics have been used prophylactically and therapeutically for BLRTIs, including for ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT)., The pulmonary concentration of antibiotics is an important factor influencing clinical outcomes and the emergence of resistance. Meta-analyses of trials evaluating tigecycline have shown increased mortality relative to comparator antibiotics, including studies of hospital-associated pneumonia. The use of off-label high-dose tigecycline (100 mg every 12 hours) has been shown to achieve greater clinical cure rates when compared with both approved dosing and the comparator imipenem-cilastin, suggesting that underdosing of tigecycline contributed to the poor outcomes observed in prior studies. Similarly, ceftobiprole was compared with linezolid and ceftazidime in patients with hospital-acquired pneumonia/VAP and was found to be inferior, which was thought in large part to be due to underdosing in critically ill patients. Moreover, in vitro studies suggest that antibiotic concentrations less than a specific threshold, termed the mutation prevention concentration (MPC), can be associated with greater emergence of antibiotic resistance, which is particularly important in the lung, given the variable penetration of antibiotics into the epithelial lining fluid (Fig 1)., Taken together, these data support the premise that antibiotic delivery to the lung is a key determinant of clinical cure and emergence of resistance.

Figure Jump LinkFigure 1 Serum or tissue antibiotic concentration assessed over time after delivery. Drug concentrations less than the minimum inhibitory concentration (MIC) suggest that the pathogen is not susceptible, and first-step resistant mutants will not be inhibited. Drug concentrations between the MIC and the mutation prevention concentration (MPC) suggest that the pathogen is susceptible but that first-step resistant mutants will not be inhibited. Antibiotic concentrations greater than the MPC will achieve susceptibility for the pathogen as well as inhibit first-step mutant strains. The table provides estimates of the epithelial lining fluid antibiotic concentrations after parenteral administration). ELF = epithelial lining fluid.Grahic Jump Location

The rise in BLRTI attributed to multidrug-resistant (MDR) bacteria and the inadequacy of pulmonary penetration of systemically administered antibiotics have served as the main rationale for the development of aerosolized antibiotics. Most nebulizers are designed to deliver drugs to the proximal airways and not to the lung parenchyma. Deposition location in the lung is a function of particle size, usually expressed as mass median aerodynamic diameter (MMAD) (Fig 2). Typical jet nebulizers have a variable particle size of about 5 μm MMAD. To reach distal lung units, the optimal size is about 1 to 3 μm MMAD, but no available jet nebulizer can consistently produce such a small particle size. Additionally, delivery to distal lung units is impeded by humidity in the ventilator circuit, which can cause hydroscopic growth and a rainout effect in the endotracheal tube. Moreover, inherent differences in delivered aerosol between commercial nebulizer systems are significant, with differences between devices exceeding 10-fold. Vibrating mesh-aperture plate nebulizers use a fixed aperture size to produce consistent particle sizes of 2 to 3 μm MMAD and an aerosol output two to three times greater than a jet nebulizer. Moreover, vibrating mesh nebulizers can be used without changing ventilator settings. Given that increasing numbers of MDR bacteria have minimum inhibitory concentrations (MICs) to carbapenems and β-lactams greater than or equal to 256 mg/L, achievable antibiotic concentrations of at least 6,400 mg/L in the lung are required to overcome the influence of sputum antagonism. Large comparative studies of various aerosol antibiotic delivery devices are currently lacking and are needed, with appropriate outcome assessments.

Figure Jump LinkFigure 2 Aerosol deposition in the oropulmonary space according to generated particle size.Grahic Jump Location

The evidence in support of the routine use of aerosolized antibiotics for the treatment of VAP and VAT is lacking. A recent meta-analysis concluded that there is insufficient evidence for inhaled antibiotic therapy as primary or adjuvant treatment of VAP or VAT. However, only six studies with a total of 305 patients were identified as meeting full criteria for inclusion in the analysis. The authors concluded that additional better-powered randomized controlled trials are needed to assess the efficacy of inhaled antibiotic therapy for VAP and VAT. However, another meta-analysis reviewed 16 studies for the treatment of VAP with aerosolized colistin. Despite the quality of evidence being graded as “very low” to “low,” this meta-analysis found that clinical cure and microbiological eradication were greater with aerosolized colistin, whereas overall mortality was unaffected. Despite lacking evidence, the use of aerosolized antibiotics for BLRTI has increased over the past decade in many parts of the world, especially in countries like China and India, which have experienced dramatic increases in BLRTI attributable to MDR bacteria. Unfortunately, the expanding use of colistin in these countries for the treatment and eradication of MDR bacteria has been associated with the emergence of plasmid-mediated colistin resistance. The development of colistin resistance in carbapenem-resistant Enterobacteriaceae, including New Delhi metallo-β-lactamase-1 strains, brings a renewed sense of urgency to minimize any further emergence of resistance and to prevent the spread of these extremely drug-resistant (XDR) bacteria.

It can be argued that any new indication for antibiotics needs careful scrutiny, especially in environments in which MDR and XDR pathogens are already endemic. This has been the argument for restricting the routine use of selective digestive decontamination to prevent BLRTI due to concerns of further emergence of resistance. For a new pharmaceutical agent to be licensed by the US Food and Drug Administration (FDA), sufficient data must be presented on preclinical safety, appropriate dose and formulation, and a defined clinical indication showing efficacy. These standards are to protect the safety of patients and to prevent the use of agents for which these parameters have not been proved. Not one currently or previously tested aerosolized antibiotic for adjunctive use in VAP or VAT has yet to meet all these criteria. Aerosol toxicology studies have been conducted only on tobramycin solution and aztreonam lysine, both approved for use in cystic fibrosis. Aerosolized colistin has been associated with respiratory failure and can cause direct damage to lung tissue when not administered correctly, leading to potentially serious and life-threatening side effects. Potential indications for the approval of adjunctive aerosol antibiotics in the treatment of BLRTI could potentially include decreased time to recovery in patients with BLRTIs sensitive to the parenterally administered antibiotic, the treatment of patients with MDR and XDR pathogens, or a decrease in the emergence of resistant bacteria. The latter may be difficult to obtain FDA approval for, as it may not have any direct benefit to the treated patient but might be an effective antibiotic stewardship tool.

Table 1 outlines the important questions that need to be addressed prior to accepting the routine use of aerosolized antibiotics for the treatment of BLRTI. It is imperative to determine whether aerosolized antibiotics are effective in treating VAP and VAT as well as determining what outcomes can be used to determine their clinical utility. We also need to understand which classes of antibiotics are most effective when administered as aerosols and whether combination aerosol therapy offers advantages over single agents. The duration of treatment is also important, especially if adjunctive aerosolized antibiotics can reduce the overall duration of treatment and the emergence of resistant bacteria. Two pharmaceutical companies are currently conducting programs that are attempting to meet the FDA standards for approval (NCT01969799, NCT01799993). In Scotland, there are three possible verdicts in a criminal trial: guilty, not guilty, and not proven. I ask readers acting as the jury on the use of aerosolized adjunctive antibiotics for BLRTIs to return a verdict of “not proven.” Hopefully, the ongoing clinical trials will allow a more definitive answer soon.

Table Graphic Jump Location
Table 1 Outstanding Questions Regarding Aerosolized Antibiotics for the Treatment of Bacterial Lower Respiratory Tract Infections

BLRTI = bacterial lower respiratory tract infection.

Kollef M.H. .Sherman G. .Ward S. .Fraser V.J. . Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462-474 [PubMed]journal. [CrossRef] [PubMed]
 
Bell B.G. .Schellevis F. .Stobberingh E. .Goossens H. .Pringle M. . A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014;14:13- [PubMed]journal. [CrossRef] [PubMed]
 
Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance. Chaired by Jim O'Neill. December 2014.https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf. Accessed April 13, 2016.
 
Solé-Lleonart C. .Roberts J.A. .Chastre J. .et al Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines. Clin Microbiol Infect. 2016;22:359-364 [PubMed]journal. [CrossRef] [PubMed]
 
Martin-Loeches I. .Povoa P. .Rodríguez A. .et al Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study. Lancet Respir Med. 2015;3:859-868 [PubMed]journal. [CrossRef] [PubMed]
 
Prasad P. .Sun J. .Danner R.L. .Natanson C. . Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis. 2012;54:1699-1709 [PubMed]journal. [CrossRef] [PubMed]
 
Ramirez J. .Dartois N. .Gandjini H. .Yan J.L. .Korth-Bradley J. .McGovern P.C. . Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013;57:1756-1762 [PubMed]journal. [CrossRef] [PubMed]
 
Awad S.S. .Rodriguez A.H. .Chuang Y.C. .et al A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis. 2014;59:51-61 [PubMed]journal. [CrossRef] [PubMed]
 
Rodvold K.A. .George J.M. .Yoo L. . Penetration of anti-infective agents into pulmonary epithelial lining fluid. Clin Pharmacokinet. 2011;50:637-664 [PubMed]journal. [CrossRef] [PubMed]
 
Olofsson S.K. .Cars O. . Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis. 2007;45:S129-S136 [PubMed]journal. [CrossRef] [PubMed]
 
Kollef M.H. .Hamilton C.W. .Montgomery A.B. . Aerosolized antibiotics: do they add to the treatment of pneumonia? Curr Opin Infect Dis. 2013;26:538-544 [PubMed]journal. [CrossRef] [PubMed]
 
Boe J. .Dennis J.H. .O'Driscoll B.R. .et al European Respiratory Society Guidelines on the use of nebulizers. Eur Respir J. 2001;18:228-242 [PubMed]journal. [CrossRef] [PubMed]
 
Le J. .Ashley E.D. .Neuhauser M.M. .et al Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010;30:562-584 [PubMed]journal. [CrossRef] [PubMed]
 
Russell C.J. .Shiroishi M.S. .Siantz E. .Wu B.W. .Patino C.M. . The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and tracheobronchitis: a systematic review. BMC Pulm Med. 2016;16:40- [PubMed]journal. [CrossRef] [PubMed]
 
Valachis A. .Samonis G. .Kofteridis D.P. . The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med. 2015;43:527-533 [PubMed]journal. [CrossRef] [PubMed]
 
Hsieh T.C. .Chen F.L. .Ou T.Y. .Jean S.S. .Lee W.S. . Role of aerosolized colistin methanesulfonate therapy for extensively-drug-resistant Acinetobacter baumannii complex pneumonia and airway colonization. J Microbiol Immunol Infect. 2014;49:523-530 [PubMed]journal. [PubMed]
 
Liu Y.Y. .Wang Y. .Walsh T.R. .et al Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16:161-168 [PubMed]journal. [CrossRef] [PubMed]
 
van Duin D. .Doi Y. . Outbreak of colistin-resistant, carbapenemase-producing Klebsiella pneumoniae: are we at the end of the road? J Clin Microbiol. 2015;53:3116-3117 [PubMed]journal. [CrossRef] [PubMed]
 
Wunderink R.G. . Welkommen to our world. Emergence of antibiotic resistance with selective decontamination of the digestive tract. Am J Respir Crit Care Med. 2010;181:426-427 [PubMed]journal. [CrossRef] [PubMed]
 
McCoy K.S. . Compounded colistimethate as possible cause of fatal acute respiratory distress syndrome. N Engl J Med. 2007;357:2310-2311 [PubMed]journal
 

Figures

Figure Jump LinkFigure 1 Serum or tissue antibiotic concentration assessed over time after delivery. Drug concentrations less than the minimum inhibitory concentration (MIC) suggest that the pathogen is not susceptible, and first-step resistant mutants will not be inhibited. Drug concentrations between the MIC and the mutation prevention concentration (MPC) suggest that the pathogen is susceptible but that first-step resistant mutants will not be inhibited. Antibiotic concentrations greater than the MPC will achieve susceptibility for the pathogen as well as inhibit first-step mutant strains. The table provides estimates of the epithelial lining fluid antibiotic concentrations after parenteral administration). ELF = epithelial lining fluid.Grahic Jump Location
Figure Jump LinkFigure 2 Aerosol deposition in the oropulmonary space according to generated particle size.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Outstanding Questions Regarding Aerosolized Antibiotics for the Treatment of Bacterial Lower Respiratory Tract Infections

BLRTI = bacterial lower respiratory tract infection.

References

Kollef M.H. .Sherman G. .Ward S. .Fraser V.J. . Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462-474 [PubMed]journal. [CrossRef] [PubMed]
 
Bell B.G. .Schellevis F. .Stobberingh E. .Goossens H. .Pringle M. . A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014;14:13- [PubMed]journal. [CrossRef] [PubMed]
 
Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance. Chaired by Jim O'Neill. December 2014.https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf. Accessed April 13, 2016.
 
Solé-Lleonart C. .Roberts J.A. .Chastre J. .et al Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines. Clin Microbiol Infect. 2016;22:359-364 [PubMed]journal. [CrossRef] [PubMed]
 
Martin-Loeches I. .Povoa P. .Rodríguez A. .et al Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study. Lancet Respir Med. 2015;3:859-868 [PubMed]journal. [CrossRef] [PubMed]
 
Prasad P. .Sun J. .Danner R.L. .Natanson C. . Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis. 2012;54:1699-1709 [PubMed]journal. [CrossRef] [PubMed]
 
Ramirez J. .Dartois N. .Gandjini H. .Yan J.L. .Korth-Bradley J. .McGovern P.C. . Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013;57:1756-1762 [PubMed]journal. [CrossRef] [PubMed]
 
Awad S.S. .Rodriguez A.H. .Chuang Y.C. .et al A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis. 2014;59:51-61 [PubMed]journal. [CrossRef] [PubMed]
 
Rodvold K.A. .George J.M. .Yoo L. . Penetration of anti-infective agents into pulmonary epithelial lining fluid. Clin Pharmacokinet. 2011;50:637-664 [PubMed]journal. [CrossRef] [PubMed]
 
Olofsson S.K. .Cars O. . Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis. 2007;45:S129-S136 [PubMed]journal. [CrossRef] [PubMed]
 
Kollef M.H. .Hamilton C.W. .Montgomery A.B. . Aerosolized antibiotics: do they add to the treatment of pneumonia? Curr Opin Infect Dis. 2013;26:538-544 [PubMed]journal. [CrossRef] [PubMed]
 
Boe J. .Dennis J.H. .O'Driscoll B.R. .et al European Respiratory Society Guidelines on the use of nebulizers. Eur Respir J. 2001;18:228-242 [PubMed]journal. [CrossRef] [PubMed]
 
Le J. .Ashley E.D. .Neuhauser M.M. .et al Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010;30:562-584 [PubMed]journal. [CrossRef] [PubMed]
 
Russell C.J. .Shiroishi M.S. .Siantz E. .Wu B.W. .Patino C.M. . The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and tracheobronchitis: a systematic review. BMC Pulm Med. 2016;16:40- [PubMed]journal. [CrossRef] [PubMed]
 
Valachis A. .Samonis G. .Kofteridis D.P. . The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med. 2015;43:527-533 [PubMed]journal. [CrossRef] [PubMed]
 
Hsieh T.C. .Chen F.L. .Ou T.Y. .Jean S.S. .Lee W.S. . Role of aerosolized colistin methanesulfonate therapy for extensively-drug-resistant Acinetobacter baumannii complex pneumonia and airway colonization. J Microbiol Immunol Infect. 2014;49:523-530 [PubMed]journal. [PubMed]
 
Liu Y.Y. .Wang Y. .Walsh T.R. .et al Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16:161-168 [PubMed]journal. [CrossRef] [PubMed]
 
van Duin D. .Doi Y. . Outbreak of colistin-resistant, carbapenemase-producing Klebsiella pneumoniae: are we at the end of the road? J Clin Microbiol. 2015;53:3116-3117 [PubMed]journal. [CrossRef] [PubMed]
 
Wunderink R.G. . Welkommen to our world. Emergence of antibiotic resistance with selective decontamination of the digestive tract. Am J Respir Crit Care Med. 2010;181:426-427 [PubMed]journal. [CrossRef] [PubMed]
 
McCoy K.S. . Compounded colistimethate as possible cause of fatal acute respiratory distress syndrome. N Engl J Med. 2007;357:2310-2311 [PubMed]journal
 
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