Title: Clinical relevance of Pseudomonas aeruginosa hypermutation in cystic fibrosis chronic respiratory infection
Abstract: I read with great interest the recent publication by Auberbach and colleagues concerning the potential clinical implications of hypermutable Pseudomonas aeruginosa in chronic respiratory infections among patients with cystic fibrosis (CF) [[1]Aurbach A. Kerem E. Assous M.V. Picard E. Bar-Meir M. Is infection with hypermutable Pseudomonas aeruginosa clinically significant?.J Cyst Fibros. 2015; 14: 347-352Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. It is certainly a well-designed prospective clinical survey providing a large amount of very interesting information on this topic. However, while the main conclusion of the authors is that the presence of hypermutable P. aeruginosa is not associated with a worse clinical outcome, their interpretation of some of the presented data may lead, in my opinion, to an underestimation of the clinical relevance of hypermutation and antibiotic resistance. Indeed, we, and then others, have documented a high prevalence of hypermutable or mutator strains (i.e. those showing significantly enhanced spontaneous mutation rates) specifically linked to chronic respiratory infections, including those seen in CF and other chronic respiratory diseases such as bronchiectasis or chronic obstructive pulmonary disease [2Oliver A. Canton R. Campo P. Baquero F. Blázquez J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection.Science. 2000; 288: 1251-1254Crossref PubMed Scopus (1154) Google Scholar, 3Macià M.D. Blanquer D. Togores B. Sauleda J. Pérez J.L. Oliver A. Hypermutation is a key factor in development of multiple-antimicrobial resistance in Pseudomonas aeruginosa strains causing chronic lung infections.Antimicrob Agents Chemother. 2005; 49: 3382-3386Crossref PubMed Scopus (237) Google Scholar, 4Ciofu O. Riis B. Pressler T. Poulsen H.E. Hoiby N. Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation.Antimicrob Agents Chemother. 2005; 49: 2276-2282Crossref PubMed Scopus (203) Google Scholar, 5Henrichfreise B. Wiegand I. Pfister W. Wiedemann B. Resistance mechanisms of multiresistant Pseudomonas aeruginosa strains from Germany and correlation with hypermutation.Antimicrob Agents Chemother. 2007; 51: 4062-4070Crossref PubMed Scopus (143) Google Scholar, 6Waine D.J. Honeybourne D. Smith E.G. Whitehouse J.L. Dowson C.G. Association between hypermutator phenotype, clinical variables, mucoid phenotype, and antimicrobial resistance in Pseudomonas aeruginosa.J Clin Microbiol. 2008; 46: 3491-3493Crossref PubMed Scopus (50) Google Scholar, 7Ferroni A. Guillemot D. Moumile K. Bernede C. Le Bourgeois M. Waernessyckle S. et al.Effect of mutator P. aeruginosa on antibiotic resistance acquisition and respiratory function in cystic fibrosis.Pediatr Pulmonol. 2009; 44: 820-825Crossref PubMed Scopus (46) Google Scholar]; a strong association between mutator strains and antimicrobial resistance was invariably observed. In agreement with those studies, Auberbach and colleagues noted a high prevalence (30% of patients) of mutator strains, which were significantly associated with multidrug resistance (MDR) profiles, detected in 73% of the cases as compared to only 35% for nonmutator strains. However, the author's conclusions seem to trivialize this dramatic association with MDR, as an unavoidable consequence of the marked capacity of P. aeruginosa to adapt to the CF lung environment. Far from that, as claimed by the World Health Organization (WHO), antimicrobial resistance is a major evolving public health threat, which requires urgent strong efforts directed to the prevention of the emergence and transmission of resistant organisms, particularly those showing MDR profiles [[8]World Health Organization The evolving threat of antimicrobial resistance.Options for action. WHO Press. Word Health Organization, Switzerland2012Google Scholar]. Another likely underestimated aspect is the marked effect of the presence of mutator strains on the antimicrobial therapies established; colistin, which is a last-resource antimicrobial agent for the treatment of infections by MDR Gram-negative pathogens, was very frequently added to the standard antimicrobial therapy used only if a mutator strain was isolated. In my opinion these two facts, linkage to MDR and requirement of last-resource antimicrobial treatments should be considered per se as a clinically relevant issue, even if a major impact on patient's health is not easy to demonstrate given the complexity of the disease. Indeed, unlike other antipseudomonal agents, colistin seems to be quite effective for controlling infections by MDR hypermutable strains in vitro [[9]Maciá M.D. Mena A. Borrell N. Pérez J.L. Oliver A. Increased susceptibility to colistin in hypermutable Pseudomonas aeruginosa strains from chronic respiratory infections.Antimicrob Agents Chemother. 2007; 51: 4531-4532Crossref PubMed Scopus (8) Google Scholar], perhaps explaining the absence of a major impact on lung function or treatment failures in this cohort. Nevertheless, we shall not forget that in those cases we are depending only on one last-resource antimicrobial agent and that prolonged use could as well lead to resistance development, leaving us with no effective antimicrobial therapies. In other words, antimicrobial resistance might not seem clinically relevant when we still have more antibiotics to add, but such possibility is not expected to last forever. In addition to promoting antimicrobial resistance development, available evidence suggests that mutator phenotypes facilitate the genetic adaptation process required for the establishment of chronic infections [10Mena A. Smith E.E. Burns J.L. Speert D.P. Moskowitz S.M. Perez J.L. et al.Genetic adaptation of Pseudomonas aeruginosa to the airways of cystic fibrosis patients is catalyzed by hypermutation.J Bacteriol. 2008; 190: 7910-7917Crossref PubMed Scopus (187) Google Scholar, 11Rodríguez-Rojas A. Oliver A. Blázquez J. Intrinsic and environmental mutagenesis drive diversification and persistence of Pseudomonas aeruginosa in chronic lung infections.J Infect Dis. 2012; 205: 121-127Crossref PubMed Scopus (49) Google Scholar, 12Hogardt M. Heesemann J. Microevolution of Pseudomonas aeruginosa to a chronic pathogen of the cystic fibrosis lung.Curr Top Microbiol Immunol. 2013; 358: 91-118PubMed Google Scholar]. Interestingly, even if statistical significance was not reached, the data of Auerbach and colleagues show a certain tendency towards association of hypermutable strains with chronic infection (79% vs 53%) and the occurrence of pulmonary exacerbations in the preceding year (63% vs 41%); this information should also argue in favor of the conclusion that clinical relevance cannot be fully ruled out. On the contrary, all together these data indicate that further studies are still needed to fully elucidate the clinical impact of mutators. Moreover, these and previous evidences should alert us of the need to consider MDR as a primary negative clinical outcome and encourage the scientific community to develop therapeutic strategies directed to prevent or combat mutation-driven antimicrobial resistance in CF.