A Breath of Fresh Air in the Fog of Antimicrobial Resistance: Inhaled Polymyxins for Gram-Negative Pneumonia

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Abstract

Despite advancements in therapy, pneumonia remains the leading cause of death due to infectious diseases. Novel treatment strategies are desperately needed to optimize the antimicrobial therapy of patients suffering from this disease. One such strategy that has recently garnered significant attention is the use of inhaled antibiotics to rapidly achieve therapeutic concentrations directly at the site of infection. In particular, there is significant interest in the role of inhaled polymyxins for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia, due to their retained activity against multi-drug resistant Gram-negative pathogens, including Acinetobacter baumannii and Pseudomonas aeruginosa. This review will provide a comprehensive overview of the pharmacokinetic/pharmacodynamic profile, clinical outcomes, safety, and potential role of inhaled polymyxins in clinical practice.

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Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.

Matthew E. Falagas, Sofia Kasiakou (2005)

The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.

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Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

Matthew E. Falagas, Sofia Kasiakou (2006)

Background The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity. Methods We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005). Results It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature. Conclusion New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.

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Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database.

Michael Joannidis, Barbara Metnitz, Peter Bauer … (2009)

Acute kidney injury (AKI) is associated with significantly increased morbidity and mortality. To provide a uniformly accepted definition, the RIFLE classification was introduced by the Acute Dialysis Quality Initiative, recently modified by the Acute Kidney Injury Network (AKIN), suggesting staging of AKI based on dynamic changes within 48 h. This study compares these two classification systems with regard to outcome. Cohort analysis of SAPS 3 database. Sixteen thousand seven hundred and eighty-four ICU patients from 303 ICUs were analysed. Classification was performed according to RIFLE (Risk, Injury, Failure) or according to AKIN (stage 1, 2, 3) without including a requirement of renal replacement therapy in the analysis. Changes of serum creatinine as well as urinary output were assessed for both AKIN and RIFLE during the first 48 h of ICU admission. Primary endpoint was hospital mortality. Incidence of AKI in our population of critically ill patients was found to range between 28.5 and 35.5% when applying AKIN and RIFLE criteria, respectively, associated with increased hospital mortality averaging 36.4%. Observed-to-expected mortality ratios revealed excess mortality conferred by any degree of AKI increasing from 0.81 for patients classified as non-AKI up to 1.31 and 1.23 with AKIN stage 3 or RIFLE Failure, respectively. AKIN misclassified 1,504 patients as non-AKI compared to RIFLE which misclassified 504 patients. Acute kidney injury classified by either RIFLE or AKIN is associated with increased hospital mortality. Despite presumed increased sensitivity by the AKIN classification, RIFLE shows better robustness and a higher detection rate of AKI during the first 48 h of ICU admission.

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Journal

Journal ID (nlm-ta): Antibiotics (Basel)

Journal ID (iso-abbrev): Antibiotics (Basel)

Journal ID (publisher-id): antibiotics

Title: Antibiotics

Publisher: MDPI

ISSN (Electronic): 2079-6382

Publication date (Electronic): 16 March 2019

Publication date Collection: March 2019

Volume: 8

Issue: 1

Electronic Location Identifier: 27

Affiliations

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 164 (M/C 886), Chicago, IL 60612, USA; mbiagi2@ 123456uic.edu (M.B.); dbutler1@ 123456uic.edu (D.B.); xt9@ 123456uic.edu (X.T.); sqasmieh@ 123456uic.edu (S.Q.)

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[* ]Correspondence: wenzler@ 123456uic.edu ; Tel.: +1-312-996-7440; Fax: +1-312-413-1797

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Eric Wenzler https://orcid.org/0000-0003-3914-8400

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Publisher ID: antibiotics-08-00027

DOI: 10.3390/antibiotics8010027

PMC ID: 6466860

PubMed ID: 30884839

SO-VID: 4c3c6468-6122-460a-8189-ef62988414aa

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

A Breath of Fresh Air in the Fog of Antimicrobial Resistance: Inhaled Polymyxins for Gram-Negative Pneumonia

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Pneumonia, sex, and the environment

Most cited references 125

Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.

Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database.

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