mcr-1 Gene in Latin America: How Is It Disseminated Among Humans, Animals, and the Environment?

Abstract

In the last decade, polymyxins have been reintroduced in the therapeutic arsenal to treat severe infections by carbapenem-resistant Enterobacterales. At that time, reports of polymyxin resistance were all due to chromosomal mutations (1). These mechanisms included (i) modifications of the lipopolysaccharides (LPSs) moiety via the addition of cationic groups; (ii) mutations that lead to the loss of the LPS; (iii) porin mutations and overexpression of efflux pump systems; (iv) overproduction of capsular polysaccharide (CPS) in some Gram-negative bacteria (GNB) that hide the polymyxin-binding sites and the release of CPS-trapping polymyxins; and (v) enzymatic inactivation of polymyxins (2). Although some chromosomal resistance mechanisms have been studied since the 1960's, it was in the late 1990's, after the reintroduction of polymyxins in the therapeutic arsenal, that this problem became more important (3). In fact, this information is supported by the first report of colistin resistance among Acinetobacter baumannii clinical isolates from the Czech Republic in 1999 and Klebsiella pneumoniae from Athens in 2004 (4). However, in 2015, the mcr-1 gene, associated with IncI2-type plasmid, was identified in Escherichia coli resistant to colistin obtained from food animals and humans in China (1). This finding promoted a great concern in the international scientific community since the last therapeutic option to treat serious infections by multidrug-resistant GNB could be exhausted. With the horizontal transfer, the rapid spread of the mcr-1 gene would be inevitable. The mcr-1 gene carried by different plasmid types has already been identified in all five continents from different sources and hosts (1, 5). Surprisingly, Shen and colleagues, in a retrospective study, characterized the early occurrence of the mcr-1 gene in chicken isolates from 1980's (6). So far, a total of 10 different variants (7) of the mcr gene have been described mainly among the Enterobacterales, but with the mcr-1 gene remaining the most prevalent (1). To date, the sequences of 30 mcr-1 mutations (mcr-1.2 to mcr-1.30) have already been deposited in the GenBank database, differing from mcr-1 by one or few amino acids. Besides that, 10 mcr gene variants (mcr-1 to mcr-10) were deposited, with amino acid identity ranging from 31 to 83% (8). These variants were identified at the beginning in Enterobacterales isolates, including E. coli (mcr-1, mcr-2, and mcr-3 genes), Salmonella enterica (mcr-4, mcr-5 and mcr-9 genes), K. pneumoniae (mcr-7 and mcr-8 genes), and Enterobacter roggenkampii (mcr-10 gene). The exception is due to mcr-6 gene that was first identified in Moraxella spp. After that, some variants were identified in non-fermenter Gram-negative rods, as Acinetobacter spp. (mcr-1 and mcr-4) and Pseudomonas spp. (mcr-1 only) (9, 10). In general, the isolates carrying mcr genes were first isolated from animals such as pigs (mcr-1, mcr-2, mcr-3, mcr-4, mcr-6, and mcr-8 genes) and chickens (mcr-5 and mcr-7 genes), but mcr-9 and mcr-10 genes were identified, for the first time, from human patients (8). The resistance to polymyxins was attributed mainly to chromosomal mutations and is rare in human clinical isolates (0.67–1.6%) (11). Nevertheless, this differs among bacteria species, being higher in K. pneumoniae and A. baumannii (20–80%) (4) in contrast to lower rates in E. coli (0.2–0.6%) (11). The polymyxin resistance rate associated to plasmid, as mcr-1, is also low in humans (~1%) (4). On the other hand, according to a large US surveillance study, the association between mcr-1 and other antibiotic resistance genes, such as extended-spectrum β-lactamase (ESBL) and carbapenemases, may reach 32% of prevalence in K. pneumoniae (11). Regarding the mortality associated with infections caused by colistin-resistant isolates in humans, the rate is variable, and it is higher in critically ill patients (30–37%) including those previously exposed to colistin (4). The mortality rate may reach 100% in patients with nosocomial infections caused by pan–drug-resistant K. pneumoniae. It is important to emphasize that the prevalence of mcr-1 gene is higher among production animals, mainly in pig and chicken isolates (5). The data show colistin resistance rates of ~70% in E. coli isolates from China and ~90% among Enterobacterales in some European countries (8). So, these data corroborate with the scientific evidence that the worldwide spread of the mcr-1 gene is mainly associated with the large amounts of colistin use in production animals, and its emergence is a particular threat to public health as colistin is considered the last-resort antimicrobial for treatment of severe human infections, and its use in livestock production contributes to emerging resistance globally (1). In Latin America, a systematic review analysis showed that the prevalence of mcr-1 gene is higher in isolates from animals (8.7%) than in food (5.4%) and humans (2.0%) (12). To the best of our knowledge, the first reports of mcr-1 gene in Latin America dated from July and October 2012 when this gene was identified in E. coli isolates from two inpatients in different hospitals in Argentina (Table 1) (13). Patients presented neurological disease and diabetes, and the mcr-1–positive isolates were obtained from blood and urine, respectively. In this study, the authors evaluated the presence of the mcr-1 gene in 87 colistin-resistant clinical human isolates from 2008 to 2016 (28 E. coli, 19 K. pneumoniae, 36 of other members of...