EDITORIAL COMMENTARY

How Can Understanding the Phenotype of Pseudomonas aeruginosa Lead to More Successful Eradication Strategies in Cystic Fibrosis? Valerie Waters Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada

(See the Major Article by Mayer-Hamblett et al on pages 624–31.)

cystic fibrosis; Pseudomonas; eradication.

As children with cystic fibrosis (CF) age, an increasing number are infected with Pseudomonas aeruginosa in their lungs. Persistent, mucoid P. aeruginosa pulmonary infection is associated with more rapid lung function decline and increased mortality in CF [1–3]. The standard of care is therefore to try to eradicate new P. aeruginosa acquisition, usually with inhaled tobramycin treatment, to prevent its long-term deleterious effects [4, 5]. However, in 10%–40% of patients, eradication treatment fails [6, 7]. The reasons for these failures are poorly understood. The in-depth study by MayerHamblett et al in this issue of Clinical Infectious Diseases sheds some light on the subject. Using a cross-sectional cohort study design that elegantly leverages the large number of first-time P. aeruginosa isolates collected as part of the Early

Received 2 May 2014; accepted 16 May 2014; electronically published 26 May 2014. Correspondence: Valerie Waters, MD, MSc, Department of Pediatrics, Division of Infectious Diseases, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada ([email protected]). Clinical Infectious Diseases 2014;59(5):632–4 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected] DOI: 10.1093/cid/ciu388

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Pseudomonas Infection Control (EPIC) trial, the authors identified wrinkly colony surface and irregular colony edges as P. aeruginosa phenotypes independently associated with eradication failure. These 2 colony phenotypes have previously been associated with altered quorum sensing and increased biofilm formation [8, 9]. A surprising number of baseline isolates were also mucoid and had defects in motility and protease production, reflecting more of a chronic, adapted CF strain, rather than an initial, presumably environmentally acquired strain, which typically possesses the virulence factors frequently seen with acute infections. These findings are consistent with those of a previous study of 92 initial infecting P. aeruginosa isolates from children diagnosed with CF by newborn screening; in a multivariate regression model, persistent strains showed significantly lower pyoverdine, rhamnolipid, hemolysin, total protease, and swimming and twitching motility compared with strains successfully eradicated by aggressive antibiotic treatment [10]. Outside of early eradication and newborn screening studies, it is difficult to obtain large collections of initial P. aeruginosa isolates given the unpredictable nature of firsttime P. aeruginosa colonization in CF. Unlike other studies that were limited

EDITORIAL COMMENTARY

by a small number of isolates [11], the study by Mayer-Hamblett et al was able to identify bacterial characteristics significantly associated with eradication failure because they had the largest published collection to date (N = 284). The natural question arising from these results is why are some children with CF infected with P. aeruginosa isolates that have a chronic phenotype? It is unlikely that certain environmental strains have this specific phenotype, as it is known to occur as an adaptation to the CF lung environment [12]. It is possible that the initial P. aeruginosa infection occurred a significant time period prior to first detection, especially given that, according to this trial design, there could have been an interval of up to 12 months since the last P. aeruginosa–negative respiratory tract culture [13]. Longitudinal cohort studies have shown that P. aeruginosa antibody titers can rise, indicative of infection, up to 12 months prior to firsttime isolation of the organism in respiratory specimen cultures [14]. Aggressive lower airway sampling in the form of routine bronchoscopic alveolar lavages in young children with CF, however, has not been shown to improve the culture rate of P. aeruginosa or improve the success rate of eradication therapy [15]. Culture-independent molecular methods

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Keywords.

antibiotics are known to be more effective against bacterial biofilms than others. Macrolides such as azithromycin have been shown to have bactericidal activity against P. aeruginosa biofilms; however, there are conflicting data as to whether azithromycin potentiates or actually antagonizes the effect of tobramycin [19–22]. Inhaled aztreonam is also being studied as an eradication therapy in pediatric patients with CF, but may not be as effective as tobramycin against P. aeruginosa biofilms, as certain CF P. aeruginosa isolates have been shown to be tolerant to aztreonam in vitro, likely due to their exopolysaccharide production [23, 24]. In addition, P. aeruginosa isolates with chronic phenotypes, against which eradication therapy fails, may have higher minimum inhibitory concentrations to tobramycin; it is not known whether initial treatment with tobramycin inhalation powder, which can achieve higher intrapulmonary concentrations of drug, would result in more successful eradication [25]. Although there may be an inclination to treat an initial P. aeruginosa infection with a chronic phenotype using intravenous antimicrobial therapy, there are no studies comparing intravenous with inhaled eradication treatments to demonstrate its superiority. Intravenous administration of antibiotics generally does not achieve as high intrapulmonary concentrations as does nebulized drug administration. The development of newer aerosolized formulations may thus be required to effectively penetrate the biofilm structure and allow eradication of organisms with a chronic phenotype. Bacterial characteristics are clearly not the only factor to influence the success of P. aeruginosa eradication in CF. Host factors are likely to play a role in the patient’s capacity to clear the bacteria. Although the EPIC trial did not identify any baseline patient characteristics as significant predictors of P. aeruginosa eradication success, previous studies have shown genetic determinants, related to degree of cystic fibrosis transmembrane conductance regulator

function, and female sex to be implicated in earlier time to first P. aeruginosa acquisition [5, 26–28]. Unfortunately, these factors are not modifiable. Additionally, the pulmonary microbiome, into which P. aeruginosa is introduced at the time of first infection, may also influence its ability to establish chronic infection. Antimicrobial treatment of other coinfecting organisms within this polymicrobial community may improve the success of eradication attempts and deserves further study. To conclude, given the lasting negative effects of P. aeruginosa infection on clinical outcomes in CF, an eradication failure rate of >30% in young children with CF is too high to accept. To develop better treatment strategies to improve eradication success rates, we must first understand why these efforts fail in the first place. To that end, the study by Mayer-Hamblett and colleagues is a significant step in the right direction. Note Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References 1. Pamukcu A, Bush A, Buchdahl R. Effects of Pseudomonas aeruginosa colonization on lung function and anthropometric variables in children with cystic fibrosis. Pediatr Pulmonol 1995; 19:10–5. 2. Kosorok MR, Zeng L, West SE, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol 2001; 32:277–87. 3. Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992; 12:158–61. 4. Schelstraete P, Haerynck F, Van daele S, Deseyne S, De Baets F. Eradication therapy for Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients not chronically colonized by P. aeruginosa. J Cyst Fibros 2013; 12:1–8. 5. Mayer-Hamblett N, Kronmal RA, Gibson RL, et al. Initial Pseudomonas aeruginosa treatment failure is associated with exacerbations in cystic fibrosis. Pediatr Pulmonol 2012; 47:125–34.

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may be a more sensitive way of detecting initial P. aeruginosa infection, although this has yet to be established [16]. Another possible explanation for first-time infection with a chronic phenotype, as pointed out by the current authors, is that initial infection may have occurred due to transmission from another CF patient with persistent P. aeruginosa infection. Potential transmission, in shared clinic space, of P. aeruginosa from older CF patients to infants and young children with CF identified through newborn screening, for example, has been previously described [17]. The enhanced infection control precautions recently recommended by the US Cystic Fibrosis Foundation may aid to address some of these concerns. Can the knowledge that specific P. aeruginosa phenotypes are associated with eradication failure help us to develop better treatment strategies? In the study by Mayer-Hamblett et al, 34% of cases of incident P. aeruginosa infection failed eradication therapy with high-dose inhaled tobramycin. The addition of oral ciprofloxacin to tobramycin inhalation solution did not influence the prevalence of P. aeruginosa positivity in those subjects randomized to this treatment arm during the EPIC trial [13]. Prolonging antibiotic treatment course does not improve P. aeruginosa eradication rates either, as demonstrated in the Early Inhaled Tobramycin for Eradication trial, which showed similar efficacy for 28 days compared with 56 days of inhaled tobramycin treatment of early-onset P. aeruginosa infection in patients with CF [18]. Although the authors of the current study examined biofilm formation in only 20% of their isolates, the study data did show that phenotypes previously known to have increased biofilm formation were associated with eradication failure. If their highthroughput system could identify this phenotype in a timely fashion in a clinical microbiology laboratory, would this information change how we would approach eradication in a child with CF and firsttime P. aeruginosa infection? Certain

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children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA 2002; 287:2958–67. Jain K, Wainwright C, Smyth AR. Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. Cochrane Database Syst Rev 2013; 12:CD009530. Maughan H, Wang PW, Diaz Caballero J, et al. Analysis of the cystic fibrosis lung microbiota via serial Illumina sequencing of bacterial 16S rRNA hypervariable regions. PLoS One 2012; 7:e45791. Kosorok MR, Jalaluddin M, Farrell PM, et al. Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol 1998; 26:81–8. Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 2010; 65:286–91. Nick JA, Moskowitz SM, Chmiel JF, et al. Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. Ann Am Thorac Soc 2014; 11:342–50. Tre-Hardy M, Nagant C, El Manssouri N, et al. Efficacy of the combination of tobramycin and a macrolide in an in vitro Pseudomonas aeruginosa mature biofilm model. Antimicrob Agents Chemother 2010; 54: 4409–15. Mulet X, Macia MD, Mena A, Juan C, Perez JL, Oliver A. Azithromycin in Pseudomonas aeruginosa biofilms: bactericidal activity and selection of nfxB mutants. Antimicrob Agents Chemother 2009; 53:1552–60.

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22. Lutz L, Pereira DC, Paiva RM, Zavascki AP, Barth AL. Macrolides decrease the minimal inhibitory concentration of anti-pseudomonal agents against Pseudomonas aeruginosa from cystic fibrosis patients in biofilm. BMC Microbiol 2012; 12:196. 23. Aztreonam Lysine for Pseudomonas Infection Eradication Study (ALPINE). Available at: Clinicaltrials.gov. NCT01375049. Accessed 30 April 2014. 24. Yu Q, Griffin EF, Moreau-Marquis S, Schwartzman JD, Stanton BA, O’Toole GA. In vitro evaluation of tobramycin and aztreonam versus Pseudomonas aeruginosa biofilms on cystic fibrosis-derived human airway epithelial cells. J Antimicrob Chemother 2012; 67:2673–81. 25. Konstan MW, Flume PA, Kappler M, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros 2011; 10:54–61. 26. Rosenfeld M, Emerson J, McNamara S, et al. Risk factors for age at initial Pseudomonas acquisition in the cystic fibrosis epic observational cohort. J Cyst Fibros 2012; 11:446–53. 27. Green DM, McDougal KE, Blackman SM, et al. Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res 2010; 11:140. 28. Maselli JH, Sontag MK, Norris JM, MacKenzie T, Wagener JS, Accurso FJ. Risk factors for initial acquisition of Pseudomonas aeruginosa in children with cystic fibrosis identified by newborn screening. Pediatr Pulmonol 2003; 35:257–62.

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6. Ratjen F. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis. Curr Opin Pulm Med 2006; 12:428–32. 7. Jones AM. Eradication therapy for early Pseudomonas aeruginosa infection in CF: many questions still unanswered. Eur Respir J 2005; 26:373–5. 8. Gupta R, Schuster M. Quorum sensing modulates colony morphology through alkyl quinolones in Pseudomonas aeruginosa. BMC Microbiol 2012; 12:30. 9. D’Argenio DA, Calfee MW, Rainey PB, Pesci EC. Autolysis and autoaggregation in Pseudomonas aeruginosa colony morphology mutants. J Bacteriol 2002; 184:6481–9. 10. Manos J, Hu H, Rose BR, et al. Virulence factor expression patterns in Pseudomonas aeruginosa strains from infants with cystic fibrosis. Eur J Clin Microbiol Infect Dis 2013; 32:1583–92. 11. Tramper-Stranders GA, van der Ent CK, Molin S, et al. Initial Pseudomonas aeruginosa infection in patients with cystic fibrosis: characteristics of eradicated and persistent isolates. Clin Microbiol Infect 2012; 18:567–74. 12. Hogardt M, Heesemann J. Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung. Int J Med Microbiol 2010; 300:557–62. 13. Treggiari MM, Retsch-Bogart G, MayerHamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011; 165:847–56. 14. West SE, Zeng L, Lee BL, et al. Respiratory infections with Pseudomonas aeruginosa in

Editorial commentary: how can understanding the phenotype of Pseudomonas aeruginosa lead to more successful eradication strategies in cystic fibrosis?

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