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Editorials: Point and Counterpoint |

Rebuttal From Dr Kollef 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):744-745. doi:10.1016/j.chest.2016.11.005
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Antibiotic resistance in multidrug-resistant (MDR) bacteria has emerged as one of the most important determinants of outcome in patients with serious infections, including ventilator-associated pneumonia (VAP). In the United States, more than 700,000 health-care-associated infections, many of which are caused by antibiotic-resistant gram-negative bacteria (GNB), occur annually, with almost half of these occurrences in critically ill patients. In Europe, there is an increasing prevalence of carbapenemase-producing Enterobacteriaceae, in particular with the rapid spread of carbapenem-hydrolyzing oxacillinase-48 and New Delhi metallo-beta-lactamase-producing Enterobacteriaceae. Escalating rates of antibiotic resistance add substantially to the morbidity, mortality, and costs related to infection in hospitalized patients. Given these worrisome trends, it is appealing to consider the use of aerosolized antibiotics for the treatment of VAP, especially when dealing with highly resistant pathogens, inadequate delivery of systemic antibiotics to the lung, or toxicities related to the use of parenteral agents such as aminoglycosides and polymyxins. However, it is also important to consider the potential downside of the increasing use of aerosolized antibiotics for VAP.

A recent consensus statement from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy recommended as a key point for antibiotic use that clinicians “prescribe drugs at their optimal dose, mode of administration and for the appropriate length of time, adapted to each clinical situation and patient characteristics.” Unfortunately, many patients are treated with antibiotics for suspected VAP or tracheal colonization when pneumonia is not present. Additionally, inadequate delivery of antibiotic concentrations to the lung due to insufficient parenteral dosing or augmented renal clearance can result in a greater likelihood of treatment failures when VAP is present, as noted by Dr Wunderink. The indiscriminate use of aerosolized antibiotics in environments in which parenteral antibiotics are not optimally administered, especially without clear data indicating ideal aerosolized antibiotic selection, dosing, delivery mechanism, and duration of therapy, is likely to simply drive further resistance.

It is also important to consider the availability of new parenteral antibiotics for the treatment of VAP. Two new antibiotics targeting MDR GNB (ceftolozane-tazobactam, ceftazidime-avibactam) have recently been approved by the US Food and Drug Administration, and over the next 3 to 5 years, several other new antibiotics directed against MDR GNB are likely to become available including meropenem-vaborbactam, plazomicin, eravacycline, relebactam, brilacidin, BAL30072, aztreonam-avibactam, carbapenem combined with ME 1071, and S-649266, a novel siderophore cephalosporin. These agents will potentially provide enhanced activity against β-lactamase producers, carbapenem-resistant bacteria, and in some cases even metallo-β-lactamase-producing bacteria. Therefore, the use of aerosolized antibiotics needs to be considered against the backdrop of these novel agents. In addition to new antibiotics, there has been progress in the development of vaccines and immunotherapies directed against MDR GNB. A vaccine candidate targeting Pseudomonas aeruginosa is in clinical development, and the results from a phase II/III clinical trial in patients in the ICU who require mechanical ventilation should be available soon. Similarly, the development of monoclonal antibodies targeting virulence factors in MDR GNB, such as the type 3 secretion mechanism in P aeruginosa, hold promise for future nonantibiotic therapy for VAP.

In summary, aerosolized antibiotics for the treatment of VAP are likely to be a valuable addition to our therapeutic armamentarium, especially for the treatment of infections attributed to MDR GNB. However, the use and delivery of aerosolized antibiotics should be guided by indications supported by appropriately designed clinical trials and should only be used to treat salvageable patients with true infections given the variability of documented practices. Only in this way can we be sure to optimize the use of these new agents without further promotion of global antibiotic resistance (Fig 1).

Figure Jump LinkFigure 1 Circular nature of increasing antibiotic administration leading to greater resistance and higher rates of inappropriate antibiotic therapy, morbidity, and mortality attributed to bacterial infections.Grahic Jump Location

References

Magill S.S. .Edwards J.R. .Bamberg W. .et al Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198-1208 [PubMed]journal. [CrossRef] [PubMed]
 
Albiger B. .Glasner C. .Struelens M.J. .et al Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill. 2015;20:- [PubMed]journal
 
Maragakis L.L. .Perencevich E.N. .Cosgrove S.E. . Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008;6:751-763 [PubMed]journal. [CrossRef] [PubMed]
 
Levy Hara G. .Kanj S.S. .et al Ten key points for the appropriate use of antibiotics in hospitalised patients: a consensus from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy. Int J Antimicrob Agents. 2016;48:239-246 [PubMed]journal. [CrossRef] [PubMed]
 
Wunderink R.G. . Point: Should inhaled antibiotic therapy be used routinely for the treatment of bacterial lower respiratory tract infections in the ICU setting? Yes. Chest. 2017;151:737-739 [PubMed]journal
 
Knisely J.M. .Liu B. .Ranallo T.R. .Zou L. . Vaccines for healthcare-associated infections: promise and challenge. Clin Infect Dis. 2016;63:657-662 [PubMed]journal. [CrossRef] [PubMed]
 
François B. . New targets for new therapeutic approaches. Crit Care. 2014;18:669- [PubMed]journal. [CrossRef] [PubMed]
 
Solé-Lleonart C. .Rouby J.J. .Chastre J. .et al Intratracheal Administration of antimicrobial agents in mechanically ventilated adults: an international survey on delivery practices and safety. Respir Care. 2016;61:1008-1014 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Circular nature of increasing antibiotic administration leading to greater resistance and higher rates of inappropriate antibiotic therapy, morbidity, and mortality attributed to bacterial infections.Grahic Jump Location

Tables

References

Magill S.S. .Edwards J.R. .Bamberg W. .et al Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198-1208 [PubMed]journal. [CrossRef] [PubMed]
 
Albiger B. .Glasner C. .Struelens M.J. .et al Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill. 2015;20:- [PubMed]journal
 
Maragakis L.L. .Perencevich E.N. .Cosgrove S.E. . Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008;6:751-763 [PubMed]journal. [CrossRef] [PubMed]
 
Levy Hara G. .Kanj S.S. .et al Ten key points for the appropriate use of antibiotics in hospitalised patients: a consensus from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy. Int J Antimicrob Agents. 2016;48:239-246 [PubMed]journal. [CrossRef] [PubMed]
 
Wunderink R.G. . Point: Should inhaled antibiotic therapy be used routinely for the treatment of bacterial lower respiratory tract infections in the ICU setting? Yes. Chest. 2017;151:737-739 [PubMed]journal
 
Knisely J.M. .Liu B. .Ranallo T.R. .Zou L. . Vaccines for healthcare-associated infections: promise and challenge. Clin Infect Dis. 2016;63:657-662 [PubMed]journal. [CrossRef] [PubMed]
 
François B. . New targets for new therapeutic approaches. Crit Care. 2014;18:669- [PubMed]journal. [CrossRef] [PubMed]
 
Solé-Lleonart C. .Rouby J.J. .Chastre J. .et al Intratracheal Administration of antimicrobial agents in mechanically ventilated adults: an international survey on delivery practices and safety. Respir Care. 2016;61:1008-1014 [PubMed]journal. [CrossRef] [PubMed]
 
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