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      The New Incurable Wound

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          Giovanni Paolo Panini (1691–1765), Alexander the Great Cutting the Gordian Knot (ca. 1718–1719). Oil on canvas, 28 7/8 in × 23 1/2 in/ 73.3 cm × 59.7 cm. Public domain digital image courtesy of The Walters Art Museum, 600 N Charles St, Baltimore, Maryland, USA. According to ancient mythology, the peasant Gordius, who married the fertility goddess Cybele, became king of Phrygia. He then dedicated his chariot to Zeus in the city Gordium and fastened it to a column with a large, complicated knot that became known as the Gordian knot. An oracle predicted that the future king of Asia would be the only person who could disentangle this knot. Many individuals who traveled to Gordium attempted to untie the knot and thereby lay their claim to the throne, but their attempts proved futile. Then the Greek conqueror, Alexander the Great, whose actual name was Alexander III of Macedon, visited the city in 333 bce. He, too, was perplexed as he studied the knot, searching for its hidden ends. Whether prompted by impatience or insight, Alexander unexpectedly unsheathed his sword and sliced through the strands of rope, thereby severing and removing the knot. He subsequently conquered Asia, fulfilling the prophecy. He founded more than 70 cities and created a vast empire across three continents before his death in Babylon in June 323 bce. Alexander’s bold, unexpected resolution gave rise to the oft-repeated saying, “cutting the Gordian knot.” That saying—now ubiquitously and inevitably linked to the shopworn notion of “thinking outside the box”—continues, however, to help codify thorny conundrums in multiple disciplines, including law, commerce, technology, education, economics, warfare, medicine, and health. The depiction of Alexander’s eureka moment on this month’s cover was imagined by Giovanni Paolo Panini, “the most celebrated and popular view painter in eighteenth-century Rome,” according to the National Gallery of Art. Panini not only excelled as a vedutisti, he was also an architect and a professor of perspective and optics at the French Academy in Rome. He was considered a master of perspective, and his vistas of Rome, which featured many of the city’s antiquities, may have inspired creation of the Panini projection, a mathematical rule for constructing images with very wide fields of view, which was recently rediscovered and is now used in software for creating and viewing panoramic photographs. Panini places Alexander in the center right of the bottom third of the painting, among a scattered group of onlookers. Some in the crowd, as well as a dog, watch with interest; others stand stiff and cross-armed—they have seen this act before. A child behind him holds his shield. The rows of columns and patterned floor add drama and perspective; the angled shadow cast by the balcony leads to Alexander, his sword glinting in the sunlight as he raises his left hand to warn away anyone who might step in for a closer look. A sculpture depicts Zeus perched on his stone throne, gripping his thunderbolt and peering directly at the viewer as if to say, “I knew this day would come.” The interrelated, complex issues that have joined to create the current public health crisis of antimicrobial drug resistance constitute a Gordian knot as well. The question of whether we could see the rise of a postantibiotic period of infectious diseases that could mirror conditions of the preantibiotic and prevaccine period is not theoretical. Another Alexander, Sir Alexander Fleming, noted while accepting the 1945 Nobel Prize awarded for his 1928 discovery of penicillin that “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.” Howard Walter Florey, Ernst Boris Chain, and Norman Heatley subsequently recognized the potential of Fleming’s discovery and developed an effective drug from penicillin. Since the 1940s, antibiotics have greatly reduced illness and death from infectious diseases. But their widespread, and often inappropriate, use has come at a price: the infectious organisms have adapted to the antibiotics, making the drugs less effective. Current events confirm Fleming’s prescience: bacterial infections incurable by antibiotics are now possible. Researchers found that a high proportion of swine-pathogenic Escherichia coli in Japan are resistant to colistin and noted concern for “a risk for transmission of mcr-1 from these strains to human-pathogenic bacteria.” A recently published report describes a patient in the United States infected with E. coli containing the mcr-1 resistance gene on a plasmid conferring resistance to colistin, the current antibiotic of last resort for treating patients with infections caused by some multidrug-resistant bacteria. Like Zeus, Fleming knew this day would come. Some of the overlapping strands woven into the Gordian knot of antimicrobial resistance are myriad mutations and adaptations of various infectious organisms, lack of development of new antimicrobial agents, modern agricultural practice, and ineffective antibiotic stewardship. Tackling individual problems such as multidrug-resistant Shigella sp. infections, antibiotic overuse, or the transition of Clostridium difficile and Staphylococcus aureus from institutionally acquired to community-acquired infections is vital because an all-encompassing solution to the puzzle, such as that found by Alexander the Great, does not seem to be on our horizon.

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          Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States

          LETTER The recent discovery of a plasmid-borne colistin resistance gene, mcr-1, in China heralds the emergence of truly pan-drug-resistant bacteria (1). The gene has been found primarily in Escherichia coli but has also been identified in other members of the Enterobacteriaceae in human, animal, food, and environmental samples on every continent (2 – 5). In response to this threat, starting in May 2016, all extended-spectrum-β-lactamase (ESBL)-producing E. coli clinical isolates submitted to the clinical microbiology laboratory at the Walter Reed National Military Medical Center (WRNMMC) have been tested for resistance to colistin by Etest. Here we report the presence of mcr-1 in an E. coli strain cultured from a patient with a urinary tract infection (UTI) in the United States. The strain was resistant to colistin, but it remained susceptible to several other agents, including amikacin, piperacillin-tazobactam, all carbapenems, and nitrofurantoin (Table 1). E. coli MRSN 388634 was cultured from the urine of a 49-year-old female who presented to a clinic in Pennsylvania on 26 April 2016 with symptoms indicative of a UTI. The isolate was forwarded to WRNMMC, where susceptibility testing indicated an ESBL phenotype (Table 1). The isolate was included in the first 6 ESBL-producing E. coli isolates selected for colistin susceptibility testing, and it was the only isolate to have a MIC of colistin of 4 μg/ml (all of the others had MICs of ≤0.25 μ/ml). The colistin MIC was confirmed by broth microdilution, and mcr-1 was detected by real-time PCR (6). Whole-genome sequencing (WGS) of MRSN 388634 was performed using a PacBio RS II system and a MiSeq benchtop sequencer. TABLE 1 Antibiotic resistance profile of MRSN 388634 Antibiotic(s) MIC(s) (μg/ml) a Amikacin ≤8, S Amoxicillin/clavulanate 16/8, I Ampicillin >16, R Aztreonam >16, R Cefazolin >16, R Cefepime >16, R Ceftazidime >16, R Ceftriaxone >32, R Ciprofloxacin >2, R Colistin 4, R Ertapenem ≤0.25, S Gentamicin >8, R Imipenem ≤0.25, S Levofloxacin >4, R Meropenem ≤0.25, S Nitrofurantoin ≤16, S Piperacillin-tazobactam 4/4, S Tetracycline >8, R Tobramycin >8, R Trimethoprim-sulfamethoxazole >2/38, R a MICs were determined using BD Phoenix (BD Diagnostics Systems, Hunt Valley, MD, USA) with panels NMIC/ID 133, except for colistin, for which determinations were performed using Etest and manual broth microdilution; both gave MICs of colistin of 4 μg/ml. R = resistant, I = intermediate, and S = susceptible, based on CLSI guidelines (except for colistin, where EUCAST breakpoints are used). E. coli MRSN 388634 belonged to sequence type 457 (ST457), a rare E. coli ST first identified in 2008 from a urine culture in the United Kingdom (7). It was subsequently identified from a bloodstream culture in Italy, where it was found to harbor the carbapenemase genes bla KPC-3 and bla CTX-M-55 (8). MRSN 388634 carried 15 antibiotic resistance genes, which were harbored on two plasmids, but no carbapenemases (Table 2). TABLE 2 Characteristics of plasmids in E. coli MRSN 388634 Plasmid name Size (kb) Inc a Copy no. b Antibiotic resistance genes c pMR0516mcr 225.7 F18:A-:B1 2 strA, strB, bla CTX-M-55, bla TEM-1B, mcr-1 , sul2, tet(A), dfrA14 pMR0416ctx 47 N 1 aac(3)-IVa, aph(4)-Ia, bla CTX-M-14, fosA3, mph(A), floR, sul2 a Data represent plasmid incompatibility (Inc) group designations, as determined by Plasmid Finder version 1.2 (10). b Data represent average numbers of copies per cell, normalized to the chromosomal read coverage. c The gene of interest is indicated in bold. The first plasmid, pMR0516mcr, was 225,707 bp in size and belonged to incompatibility group F18:A-:B1 (9). BLAST analysis indicated that pMR0516mcr represented a novel IncF plasmid. Notably, it shares 89 kb of homologous sequence with pHNSHP45-2, a mcr-1-carrying IncHI2 plasmid described by Liu and colleagues (1). This shared sequence contains mcr-1 in association with ISApl1 (1), but in pMR0516mcr it is in a different location and orientation (Fig. 1). pMR0516mcr also carried 7 additional antibiotic resistance genes, including the ESBL gene bla CTX-M-55 (Table 2). The second plasmid, pMR0416ctx, was ∼47 kb in size and was assigned to IncN (Table 2). It carried 7 antibiotic resistance genes, including bla CTX-M-14. A complete description of both plasmids is under preparation. FIG 1 Comparison of the homologous regions containing mcr-1 shared by pMR0516mcr and pHNSHP45-2. Open arrows represent coding sequences (green arrows, mcr-1; white arrows, ISapl1; purple arrows, metabolic function; blue arrows, plasmid replication and maintenance; gray arrows, hypothetical and unclassified) and indicate direction of transcription. The arrow size is proportional to the gene length. The gray and blue areas between pMR0516mcr and pHNSHP45-2 indicate nucleotide identity of >99.9% by BLASTN. To the best of our knowledge, this is the first report of mcr-1 in the United States. The epidemiology of MRSN 388634 is noteworthy; the isolate was submitted from a clinic in Pennsylvania, and the patient reported no travel history within the prior 5 months. To date, a further 20 ESBL-producing E. coli isolates from patients at the WRNMMC have tested negative for mcr-1 and have been colistin sensitive. However, as testing has been ongoing for only 3 weeks, it remains unclear what the true prevalence of mcr-1 is in the population. The association between mcr-1 and IncF plasmids is concerning, as these plasmids are vehicles for the dissemination of antibiotic resistance and virulence genes among the Enterobacteriaceae (9). Continued surveillance to determine the true frequency for this gene in the United States is critical. Nucleotide sequence accession numbers. The Short Read Archive (SRA) file for MRSN 388623 has been deposited at GenBank with accession number SRP075674. The complete sequence of pMR0516mcr has been deposited at GenBank with accession no. KX276657.
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            Colistin-Resistant mcr-1–Positive Pathogenic Escherichia coli in Swine, Japan, 2007−2014

            To the Editor: Colistin is an old-generation antimicrobial agent; however, because it is one of the few agents that remain effective against multidrug-resistant gram-negative bacteria (e.g., carbapenem-resistant Pseudomonas aeruginosa and Enterobacteriaceae), its clinical usefulness is being increasingly recognized ( 1 ). Previous reports have described the mechanisms of colistin resistance ( 2 ) as being chromosomally mediated and not associated with horizontal gene transfer. However, from 2011 through 2014, a plasmid-encoded colistin-resistance gene, mcr-1, was identified in colistin-resistant Escherichia coli isolated in China, particularly from animals. Specifically, mcr-1–positive isolates were found in 21% of healthy swine at slaughter, 15% of marketed pork and chicken meat, and 1% of hospitalized human patients ( 3 ). A study of E. coli isolated from healthy cattle, swine, and chickens in Japan during 2000–2014 found only 2 (0.02%) of 9,308 isolates positive for mcr-1 ( 4 ). We report the rates at which mcr-1 was detected in our stored collection of E. coli isolates from diseased swine (swine with diarrhea or edema disease), hereafter referred to as swine-pathogenic E. coli. We recently analyzed swine-pathogenic E. coli strains isolated from diseased swine throughout Japan during 1991–2014 ( 5 ). We analyzed all swine disease-associated E. coli strains isolated from the 23 Livestock Hygiene Service Centers in Japan (including prefectures that covered 75% of total swine production in Japan in 2014) and sent to the National Institute of Animal Health for diagnostic purposes during 1991–2014. Among the 967 strains examined, 684 (71%) belonged to E. coli serogroup O139, O149, O116, or OSB9. In the study reported here, we investigated these 684 strains for susceptibility to colistin and for mcr-1 carriage. The strains from the 4 predominant serogroups (Technical Appendix Table) can be considered representative of swine-pathogenic E. coli strains isolated from farm animals, but not food products, in Japan. MICs were determined by using the agar dilution method according to the recommendations of the Clinical and Laboratory Standards Institute ( 6 ). The presence of mcr-1 was detected by PCR ( 3 ). Among the 684 strains examined, colistin MICs exhibited a bimodal distribution of 0.25–128 μg/mL and peaked at 0.5 and 16 μg/mL (Technical Appendix Figure). According to the European Committee on Antimicrobial Susceptibility Testing criterion ( 7 ), in which isolates with an MIC of >4 μg/mL are considered colistin resistant, 309 (45%) of the 684 strains were classified as colistin resistant. The gene mcr-1 was detected in 90 (13%) strains, and the MICs for these mcr-1–positive strains ranged from 8 to 128 μg/mL (Technical Appendix Figure). Among the 309 colistin-resistant strains, mcr-1–positive and mcr-1–negative isolates had the same 50% and 90% MICs, 16 and 32 μg/mL, respectively. These results indicate that a high proportion of swine-pathogenic E. coli in Japan are resistant to colistin, that mcr-1 has already been widely disseminated among these strains, and that the level of colistin resistance mediated by mcr-1 is similar to that mediated by mcr-1–independent mechanisms. In 2004, colistin-resistant E. coli already represented 77% of the isolates, and the positivity rates varied from year to year (26%–82%) (Figure). First detection of mcr-1–positive strains was in 2007, and the proportion of mcr-1 positivity has risen, especially since 2009 (Figure). During 2013–2014, approximately half of the strains isolated were mcr-1 positive (Figure), and most colistin-resistant strains isolated during these 2 years carried mcr-1 (85% and 62% in 2013 and 2014, respectively). Of note, the rates of mcr-1–positive strains among the 4 serogroups isolated from 2010 through 2014 did not differ significantly (χ2 test): 22 (20%) of 110 in O139, 38 (38%) of 100 in O149, 19 (26%) of 73 in O116, and 6 (32%) of 19 in OSB9. This finding suggests that the sharp rise in the proportion of mcr-1–positive strains has been driven by plasmid-mediated horizontal gene transfer, not by the expansion of a specific clone. Figure Changes in the numbers of colistin-susceptible and colistin-resistant Escherichia coli isolated from swine with diarrhea or edema disease, Japan, 2004–2014. The line shows the changes in proportion of mcr-1–positive isolates among the total isolates for each year. In Japan, rates of isolation of colistin-resistant and mcr-1–positive E. coli strains from healthy animals are low, 1.00% and 0.02% of 9,308 strains examined, respectively ( 4 ). These low rates may be the result of the prudent use of colistin in Japan. During 2000–2007 in Japan, colistin use in swine did not increase significantly ( 8 ). However, our data show that mcr-1 has recently been disseminated among swine-pathogenic E. coli in Japan, which might be associated with the use of colistin to treat disease in swine. Although mcr-1–positive bacteria have not yet been isolated from humans in Japan ( 4 ), the sharp increase in swine-pathogenic E. coli in animal strains implies a risk for transmission of mcr-1 from these strains to human-pathogenic bacteria, a serious concern for human medicine. More active surveillance of mcr-1–positive colistin-resistant bacteria in human and animal environments is needed. Technical Appendix Information about isolates used in study of mcr-1–positive colistin-resistant pathogenic Escherichia coli in swine, Japan, 2007–2014, and MICs of colistin for E. coli isolated from diseased swine in Japan 1991–2014.

              Author and article information

              Emerg Infect Dis
              Emerging Infect. Dis
              Emerging Infectious Diseases
              Centers for Disease Control and Prevention
              September 2016
              : 22
              : 9
              : 1696-1697
              Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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              The New Incurable Wound


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