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On a movie set in Jersey City, I am watching the actor and hip-hop artist Mos Def play the part of Chuck Berry in what might be described as a music-history mash-up. In the auditorium of the Create Charter High School—a room that looks as if it hasn't been touched since Ike was president—Def (real name: Dante Terrell Smith) glides about the stage channeling rock 'n' roll's most influential forefather, Chuck Berry, and doing a pretty spooky job of it. Regally turned out in a maroon-and-black brocade jacket, black button-down shirt, black pants, and a prosthetic pompadour that resembles the brilliantined prow of a cruise ship, Def swivels his narrow hips, bobs his glossy head, and duckwalks across the stage while mock-playing a blond, wide-body 1950 Gibson ES350 to the familiar start-and-stop cadence of Berry's "No Particular Place to Go."
At the foot of the stage, approximately 250 extras dressed in 1950s fashions—bobby socks, saddle shoes, penny loafers, and sweaters—move politely to the music in two distinct groups. Separated by skin color and a double row of velvet-rope-linked brass stanchions, they are meant to represent a concert audience, presumably somewhere in the South in mid-50s pre-civil-rights America. But this imposed order soon turns to chaos when one particularly enthusiastic white teen near the front of the crowd knocks over part of the barrier (as per the script) and the crowd, whipped into a joyous frenzy by the music and its performer's snake-hipped showmanship, surges together—blacks and whites mixing and then, scandalously, dancing together to the revolutionary strains of early rock 'n' roll.
Left, Chuck Berry at Leonard Chess's home in Chicago, circa 1950. Right, Mos Def as Chuck Berry in the Sony BMG film Cadillac Records. From Michael Ochs Archives/Getty Images (Berry). By Eric Liebowitz/Sony BMG Films (Mos Def).
The scene is one of the last to be shot for a film called Cadillac Records, slated to hit cineplexes in the coming months. Written and directed by Darnell Martin (I Like It Like That, Their Eyes Were Watching God) and produced by the film division of record label Sony BMG, Cadillac Records is actually one of two movies filmed this year that depict the rise of the Chicago blues and its musical spawn—rock 'n' roll and soul—via the lives and loves of the black artists and white record men at one of the most innovative and influential independent labels in modern music history: Chicago-based Chess Records, home to not only Berry but also Muddy Waters, Howlin' Wolf, Etta James, Bo Diddley, Little Walter, and dozens more. The second film, tentatively titled Chess, is directed by Jerry Zaks, best known for his Tony-winning work on Broadway (House of Blue Leaves, Six Degrees of Separation), and though the films cover overlapping territory, Cadillac Records can claim bigger star power. In addition to Mos Def, the picture stars Beyoncé Knowles, Jeffrey Wright, Adrien Brody, and Emmanuelle Chriqui. (The cast of Chess includes Alessandro Nivola and Robert Randolph.)
But for all the staged pandemonium in Jersey City, the Cadillac Records re-creation of the Berry concert is judged lacking. As Def works the increasingly integrated crowd into a dancing frenzy, the disembodied voice of first assistant director Jonathan Starch booms over a loudspeaker. "Cops, you've got to go crazy! You see people mixing. That is not right!" he says, and a handful of actors dressed as policemen bull through the audience, pulling and tugging at the revelers, attempting to return the room to its stratified state. Their efforts prove futile, however, and before long a ponytailed blonde has climbed onto the stage and is shimmying back-to-back with Def and his Gibson. "Ahhhhh, yeah! All right!" Berry's doppelgänger cries out with glee while his dance partner wears a look that borders on sexual arousal. The cops are clearly of a different mind, though, and they swarm the rocker and his admirers, shoving them, kicking and screaming, offstage. This is what Cadillac Records is meant to illustrate: a time when rock 'n' roll moved mountains and not just automobiles.
In 1947 a Polish Jew named Lejzor Czyz, who had immigrated to Chicago in 1928 and changed his name to the much more marketable Leonard Chess, was running a nightclub called the Macomba Lounge on the city's heavily black South Side. When Chess learned that someone wanted to record one of his acts, he decided to go into the record business himself, initially by investing in a Chicago-based label called Aristocrat. By 1950, however, Chess and his younger brother Phil (formerly Fiszel, a name that would make Snoop Dogg smile) had bought out the other owners and changed the label's name to their own.
That same year, a B-side issued by the label, a blues number called "Rollin' Stone" that consisted of a sole, sinewy electric guitar coiling and snaking along to the field-seasoned vocals of a Mississippi transplant nicknamed Muddy Waters (real name: McKinley Morganfield), made waves even if it didn't hit the charts. Waters was hardly new to the music business: he'd recorded for Columbia and Aristocrat, where he'd gotten his first taste of success, but as Peter Guralnick writes in his book Feel Like Going Home: Portraits in Blues and Rock 'n' Roll, the modest success of "Rollin' Stone" for Chess "set the tone" for the new label and "undoubtedly influenced the entire course of post-war blues recording."
Indeed, that summer, Waters would begin recording with members of a band he'd been gigging with in nightclubs for some time. Featuring Jimmy Rogers on guitar and the brilliant but hot-headed Little Walter on harmonica and, by the end of the year, expanding to include a drummer and a bassist, the group laid down some of the earliest examples of the genre of music now known as the Chicago blues, an electric, amplified version of the acoustic country blues that had flourished on the Mississippi plantations Waters and many of his fellow musicians had left in search of a better life up north. The Chicago blues was made for the rude, noisy city and its rowdy club crowds, and Chess's roster, along with its subsidiary labels, soon grew to include some of its most formidable practitioners, among them Howlin' Wolf (real name: Chester Arthur Bates), Sonny Boy Williamson II (Aleck "Rice" Miller), Little Walter and Jimmy Rogers (who both had solo careers subsequent to their work with Waters), and Willie Dixon, the bassist, producer, and staff songwriter at Chess, who is credited with writing many of the Chicago-blues era's most famous songs, including Muddy Waters's signature sex song, "Hoochie Coochie Man," as well as "I Just Want to Make Love to You" and "You Need Love."
According to Phil Chess, who currently lives in Tucson, Arizona, there's a perfectly logical explanation for his and his brother's affinity for the blues. "We'd been around it all our lives," he says. "We came from Poland in 1928. That was blues all the time." And yet, remarkably, putting out some of the most cherished and honored blues records ever released would not be the Chess brothers' only contribution to popular music. In 1951, the label released what is often called the first rock 'n' roll song (though not without debate): "Delta 88," by Jackie Brenston and His Delta Cats, which features a driving boogie-woogie piano by the late Ike Turner and was a harbinger of things to come. Four years later, an ambitious young guitar player and songwriter from St. Louis named Chuck Berry sought out Leonard Chess at Muddy Waters's suggestion, and in May of that year Chess released "Maybellene," the first of many seminal rock 'n' roll hits that Berry would record for the label. His music was faster, brighter, and less obviously sexual than that of the Chicago bluesmen, but there was no doubt it was related. As Waters himself sang: "The blues had a baby and they named it rock and roll."
Adrien Brody as Leonard Chess and Beyoncé Knowles as Etta James. By Eric Liebowitz/Sony BMG Films.
All this rich history presented Martin, the writer-director, with a dilemma when she sat down to write her script, forcing her to make hard choices in developing certain characters at the expense of others. Her focus on the friendship of Muddy Waters and Leonard Chess, who are played by, respectively, Jeffrey Wright (Basquiat, Syriana) and Oscar winner Adrien Brody (The Pianist, The Darjeeling Limited), meant that Phil Chess, who was a key contributor to the label's success, had to be reduced to what amounts to a cameo appearance. Nor was there room in the film for Williamson or pianist Otis Spann, who joined Waters's band later in the decade and was vital to his sound. Another casualty was Bo Diddley, who had his first hit for Chess the same year as Berry.
These are examples of compression and omission that will no doubt infuriate some historical purists, or "blues maniacs," as Martin calls them, but the director was interested in making a more subjective picture, like Lady Sings the Blues, in which Diana Ross starred as the inimitable but doomed jazz singer Billie Holiday. That 1972 film has been criticized for taking liberties with Holiday's life story. (Then again, Holiday was accused of similar sins when her autobiography, on which the film was loosely based, was published in the late 50s.) But despite lapses in accuracy, the film stood on its own as a harrowing, music-driven tale, and Ross's riveting portrayal of Holiday earned her an Oscar nomination for best actress.
Jeffrey Wright as Muddy Waters and Columbus Short as Little Walter. By Eric Liebowitz/Sony BMG Films.
Martin and her music director, Steve Jordan, also agreed that Lady Sings the Blues set a smart precedent for the way to approach Cadillac Records' many musical performances, which involve songs that, in some cases, have taken on an iconic importance in popular culture, much like the Holiday songs that Ross performed. In Martin's opinion, the reason Lady Sings the Blues works is that "Diana Ross was not doing an imitation of Billie Holiday. She was singing her songs but bringing them into a new time. She made those songs fresh and accessible, but without losing the integrity or the feel of Holiday's original performances."
And so, all of the Chess classics used in Cadillac Records were freshly recorded using a crack band of musicians put together by Jordan, with vocal performances by the actors playing the Chess recording artists in the film. The fact that Beyoncé Knowles, who played the Diana Ross equivalent in Dreamgirls, stars as Etta James, the singer who starred for Chess in the 1960s, will no doubt generate some publicity and soundtrack sales.
Mos Def will also help the film resonate with contemporary audiences. "Mos Def is Chuck Berry," says Jordan, who has spent some time around the real man. (He played the drums in the Berry documentary-concert film Hail! Hail! Rock 'n' Roll.) "Chuck's sarcasm, his wit, and his naïveté—Mos displays it all at some point in this film." If anybody can take the syncopated wordplay of Berry's music to new places, Jordan says, "it's a world-class rapper."
Martin, 44, grew up in the rough-and-tumble Grand Concourse neighborhood in the Bronx. She says that when she was first approached by Sony BMG to take on the project, she already knew a little bit about the music of the period and liked the character of Leonard Chess, but wasn't sure she was the right filmmaker for the job. Before signing on, she took several weeks to immerse herself in the Chicago-blues world, reading "every book I could get my hands on about the subject," cross-referencing the stories and anecdotes, and even talking to people who had been on the scene, who volunteered more stories. "It was a lot of work before getting the job," the director says with a laugh.
She came to see the film as an ensemble story that depicted the intersecting lives of some of Chess's biggest stars. "I started to see these guys with each other," she says. "It's like GoodFellas. It's like a Western. The blues is about machismo." "And these guys were coming out of Capone's Chicago, so everybody carried a gun. And people were getting shot and killed left and right."
Not that Cadillac Records is primarily about gunplay. There is violence and a subplot involving a psychopath with a grudge against harmonica players, but Martin's script is more ambitious than that. Her story covers approximately 25 years, beginning in the late 40s, when Leonard Chess bought into the record business, and extending through 1969, when he sold the company. He subsequently died of a massive heart attack behind the wheel of his car—a demise that, in Cadillac Records, is conflated with the sale of the company, although in actuality they occurred almost a year apart. Under the new ownership, Phil Chess was only nominally involved, but Leonard's son, Marshall, briefly ran the label after his father's death. He quit in 1970, but Chess and its subsidiary labels limped on until mid-decade when their master tapes were sold off. Marshall, who served as a consultant on both films, subsequently helped the Rolling Stones start their own record label and, currently, runs Arc Music, the music publishing company his father and uncle co-founded, which still controls the rights to a number of Chess classics.
Judging from Martin's script, Leonard Chess is the catalyst of Cadillac Records, the no-nonsense businessman who did what he needed to do to keep his artists producing and their records selling. (The film's title refers to the brand of cars that Chess and his artists got as status symbols of their success.)
But if Chess is a constant presence in Cadillac Records, Waters's story provides the film's backbone. The movie begins and ends with him, depicting his rise as the father of the electrified Chicago blues, his decline in Berry's flashy wake, and his lionization by the British lads who came to dominate rock 'n' roll in the 60s and 70s by first aping and then building upon the riffs and chord progressions that the Chicago bluesmen and Berry pioneered. Indeed, the Rolling Stones—who took their name from Waters's first Chess single and recorded at Chess studios in 1964 (their instrumental "2120 S. Michigan" is named for the studio's address)—figure in the film, as do Elvis Presley and California's Beach Boys, who spun Berry's primitive chords into pure pop floss.
Another pivotal character in the film is Little Walter (born Marion Walter Jacobs), the star-crossed harmonica genius who played harp in Waters's band before striking out on his own. Walter, who was posthumously inducted into the Rock and Roll Hall of Fame this year, is remembered today for the R&B hits "Juke" and "My Babe," but in the 1950s he was a Chess phenomenon, helping to define the Chicago-blues sound and elevating the humble harmonica to exalted status. His life story is also one of the great tragedies of the blues. He died in his sleep in 1968 after getting involved in a street fight, and though he was only 37, alcoholism had ravaged his matinee-idol looks, making him look decades older.
Martin describes the Little Walter character in Cadillac Records as a mixture of Johnny Boy, Robert De Niro's character in Mean Streets; Tommy DeVito, Joe Pesci's character in GoodFellas; and Piano Man, Richard Pryor's character in Lady Sings the Blues. As portrayed by actor Columbus Short (Stomp the Yard, Whiteout), who dropped 25 pounds to get the job, Walter is the movie's loose cannon but also its most emotionally naked character, and through his interactions with Waters and some of the other Chess all-stars, his strand of the film's plot opens a window onto the often fraught bonds and fragile dynamics behind a kick-ass band. "You know, there was this real love story," says Martin. "There were two things that Muddy Waters actually said about Little Walter. He said, 'He fitted me.' And he said, 'When he left me, it was like somebody took away my oxygen.' Those are really things you say about a woman you're in love with—the big love of your life."
Left, Etta James, circa 1970. Right, Beyoncé Knowles as Etta James. From Michael Ochs Archives/Getty Images (James). By Eric Liebowitz/Sony BMG Films (Knowles).
Cadillac Records depicts another, more typical love story, albeit one that might kindle controversy among pop-music purists. In 1960, Etta James (born Jamesetta Hawkins), a moody singer with a contralto voice as striking as the platinum-blond beehive hairdo she wore in one iconic publicity shot, joined the Chess roster and became its resident queen of soul, years before Atlantic's Aretha Franklin ended up with the title. (Ironically, a teenaged Franklin briefly recorded for Chess's subsidiary Checker label at the beginning of her career.) In the first four years James was at the label, she racked up nine Top 10 hits on the R&B charts, with at least one crossing over onto the pop charts. As the voice behind such standards as "At Last" and "I'd Rather Go Blind," James would become one of Chess's most successful artists, but her talent and success came with baggage, including a stubborn drug habit.
In Martin's screenplay, romantic sparks fly between James and Leonard Chess, something Martin acknowledges has never been documented, but the director says the notion isn't beyond the pale given the bond the two shared. She points out that another scene in the movie, in which Chess bolts from the studio where James is singing "I'd Rather Go Blind" because the raw emotion she conveys is too much for him, actually occurred. "And he wasn't an emotional man," Martin says, adding that James, who is also known for her tough exterior, once said that Leonard Chess "was the only man who knew that she was vulnerable." (James declined to be interviewed for this piece.)
Martin says she wrote the role with Knowles in mind: "I couldn't conceive of anybody else who could play Etta James." When Knowles signed on, as both a star and an executive producer, Martin says the singer really went to work, sometimes spending hours rehearsing her lines after a full day of shooting. Via e-mail, Knowles writes that taking the part of James was "a challenge for me as an actor." To prepare, she explains, "I spent hours on YouTube learning to imitate [James's] expressions and body language." Knowles also studied the singer's autobiography Rage to Survive: The Etta James Story, which she calls "the most open" memoir she's ever read. "It was so unfiltered and real," Beyonce writes, adding that she did not have the opportunity to meet James, "but I really look forward to it."
"Beyoncé really wanted to go to that dark place," the director says. "She doesn't look like Beyoncé. You forget who she is. She didn't want to be pretty. She didn't want to look too comfortable. I think people are going to be really, really surprised with what she did in this movie."
As the man in charge of both evoking the Chess sound for Cadillac Records and updating it for modern ears, Steve Jordan says he operated from the standpoint that "you can't beat" the originals. Still, he had to come somewhat close, or at least try. That meant putting together a group of musicians who, he says, "really know the genre inside out—live it, breathe it—so that when you're playing with them, they're not just imitating, they're swinging."
The musicians, all of them respected session players and many with deep Chicago roots, gathered at Avatar Studios in Manhattan for eight days in February to lay down instrumental versions of the tracks that are slated to be heard in the movie, including Waters's "Mannish Boy," Walter's "My Babe," Wolf's "Smokestack Lightnin'," James's "I'd Rather Go Blind," and Berry's "Nadine."
Leonard Chess's address book, circa 1959. Courtesy of the Chess Family Archives.
Among those who stopped by to watch the musicians work was Bruce Springsteen, who was recording upstairs, and Marshall Chess, who liked what he heard. "This band blew me away," Chess says. "I've been making blues records my whole life, and Steve put together what, to me, was one of the finest electric-blues bands I've ever heard." He also gave high marks to Knowles's portrayal of James, based on the recordings he's heard and the scene he watched being filmed. Interestingly, that scene involved the imagined kiss between a heroin-addicted James and Chess's father, which occurs when he comes to tell her that her single "At Last" has crossed over onto the pop charts. "I was shocked at how good Beyoncé was," Chess says. "I've been around enough junkies in my life to tell you it was real."
As for the veracity of that kiss, Chess says he called up James, with whom he has remained friends, and asked her about it. "She said, 'All your daddy ever did was kiss me on the cheek.'"
But there are other things about Cadillac Records that bother Chess more, such as the minimal role given his uncle Phil. "I had a lot of trouble with the Sony movie at first, because I kept comparing it mentally to the real thing," Chess says. For his part, Phil Chess says he doesn't mind the snub, and Marshall adds that he has come to accept that both Chess Records films are not documentaries, but, rather, movies "based on reality," and he is rooting for each.
In some respects the two movies are strangely complementary. Andrea Baynes, a producer of Chess, says the Jerry Zaks–directed film spans the years from 1931 to 1955, which could almost qualify it as a prequel to Cadillac Records. The film opens and closes at Brooklyn's Paramount Theater, during one of the seminal rock 'n' roll concerts that took place there in the 50s. Oddly enough, Bo Diddley, played by slide guitarist Robert Randolph, is the rocker featured in this movie. (Berry is not depicted, according to Baynes, but Muddy Waters, Jimmy Rogers, and Little Walter are.) And though this film also focuses on Leonard, the character of Phil Chess is given much more prominence. Marshall is also portrayed as a young boy. "The producers of both films hate me when I say this," he says with a laugh. "They want me to say one is shit, you know? But the thing is, I want them both to be great because, unfortunately, they're going to represent how a lot of people see my family."
Still, as Willie Dixon's character says in Cadillac Records, the blues "are made up of legends and truth," and Marshall Chess acknowledges that during his time on the set he witnessed some moments that were spookily real. The last day he was on location in Newark, New Jersey, Jeffrey Wright walked up to him in full character. "He had the big hair," Chess says, "and he had on the bathrobe, the slippers, just like I'd seen Muddy [wear]." When Chess was a kid hanging out at the studios, or when Waters and the other artists were hanging out at his home, he says, they would always ask him about his sex life. "'Did you get any yet?' That was the main topic when I was young," Chess says. And on that day in Newark, Wright sidled up to Chess in full Muddy regalia and asked him, "You get any yet?"
"Man, I swear to you, it was like living in a science-fiction book," Chess says. Presumably it's a story about time travel in which rock 'n' roll never dies and the blues go on forever.
Frank DiGiacomo is a Vanity Fair contributing editor.


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Print Media
We are living in a digital world where everything is moving with a pace. Advertising is very important for marketers in order to attract more audience or buyers. Print media is recognized as one of the best and inexpensive way of advertising and announcing something. This includes magazines, newspapers and other important medium. When it comes to the promotion of a company's product and service then print media is one of the best medium for this.
Businesses can pursue a number of avenues in order to attract potential buyers for their products or services. In order to advertise, they may go for television and radio advertising or can use social media and internet. But, print media do not need anything as it can reach there where radio, television, and internet cannot reach. It is an inexpensive method of advertising and makes people aware of your services or products and its wide coverage make it more special and beneficial for marketers. Print media is able to target all types of audiences as it can attract high class with the help of magazines. It can also attract middle and lower class people with the help of roadside banners, newspapers, and pamphlets. This helps marketers to explain their product or service in a better and simple way.

subset: commoncrawl


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What year did the israeli-palestinian conflict begin?
On Nov. 29, 1947, the United Nations established a plan to divide Palestine between Arabs and Jews. Rioting among Palestinians began almost immediately. Israel officially came into existence on Ma...
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How to Understand the Israeli Palestinian Conflict?
The Israeli-Palestinian conflict is an ongoing conflict between Israel and Palestine. Lots of deliberately misleading opinions are propagated, but actual events and statistics can sometimes be less...
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What is America's perspective on the Israeli-Palestinian conflict?
This question does not discriminate between the two Americas, that is to say the Government of the United States of America and the Prevailing Opinions of its Citizens. Government: Israel and the ...
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Why should we as Americans care about the Israeli-Palestinian conflict?
The issue is one of compassion and of the human condition. The people of both sides suffer psychologically and physically at the brutality, and desperate measures taken to extremes. This ongoing cr...
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The Arab-Israeli conflict began at the beginning of the 20th century. In 1917, Britain issued the Balfour Declaration, which stated that Palestine would be viewed as the national home of the Jewish...
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Land Arae:
Hinigaran is a coastal town of Negros Occidental, located 54 kilometers south of Bacolod City. It has a land area of 15,492 hectares .surrounded by sugarcane plantations, fish ponds and rich fields. It has a coordinate of 122 degrees 50'12" east longitude and 10 degrees 16'20" north latitude. It is bounded on the north by the town of Pontevedra, La Castellana-Pontevedra on the north-east, Isabela on the east, Binalbagan on the north and Guimaras Strait on the west.
Administratively, Hinigaran is composed of 24 barangays, four of which are coastal barangays, namely:
Of the total land area 15,492 hectares, 34.24% is classified as rolling hills, 9.93% is low mass of hydrosol area and 55.83% plain. The highest elevation is approximately 174 meters above sea level which can be located in the inland portion of the town's Barangay Camalobalo, while the lowest elevation ranges from 2 to 10 meters above sea level. There are areas which are characterized as rolling to gently rolling areas. Most of these are located in Brgy. Tuguis, Camalobalo, Himaya, Bato Aranda, Candumarao and Calapi. It is on these areas where contour framing and strip cropping are commonly observed.
- Anahaw
- Aranda
- Brgy. I
- Brgy II
- Brgy III
- Quiwi
- Tagda
- Tuguis
- Baga-as
- Nanunga
- Narauis
- Palayog
- Paticui
- Pilar
- Cambugsa
- Candumarao
- Gargato
- Himaya
- Miranda
- Brgy. IV
- Bato
- Calapi
- Camalobalo
- Camba-og


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In the 1980s, Gram-negative pathogens appeared to have been beaten by oxyimino-cephalosporins, carbapenems, and fluoroquinolones. Yet these pathogens have fought back, aided by their membrane organization, which promotes the exclusion and efflux of antibiotics, and by a remarkable propensity to recruit, transfer, and modify the expression of resistance genes, including those for extended-spectrum β-lactamases (ESBLs), carbapenemases, aminoglycoside-blocking 16S rRNA methylases, and even a quinolone-modifying variant of an aminoglycoside-modifying enzyme. Gram-negative isolates -both fermenters and non-fermenters-susceptible only to colistin and, more variably, fosfomycin and tigecycline, are encountered with increasing frequency, including in Korea. Some ESBLs and carbapenemases have become associated with strains that have great epidemic potential, spreading across countries and continents; examples include Escherichia coli sequence type (ST)131 with CTX-M-15 ESBL and Klebsiella pneumoniae ST258 with KPC carbapenemases. Both of these high-risk lineages have reached Korea. In other cases, notably New Delhi Metallo carbapenemase, the relevant gene is carried by promiscuous plasmids that readily transfer among strains and species. Unless antibiotic stewardship is reinforced, microbiological diagnosis accelerated, and antibiotic development reinvigorated, there is a real prospect that the antibiotic revolution of the 20th century will crumble.
The ability to treat bacterial infection is critical to modern medicine, from abdominal surgery to transplants to cancer management. Without antibiotics, these procedures would be unthinkable owing to the infection risk. Yet this ability to beat infection has existed for only a brief fraction of human history, beginning with the introduction of sulfonamides in the 1930s. The 'antibiotic revolution' gathered pace from the late 1940s to the 1960s, with a golden age of natural product discovery. This period was followed by two decades of repeated successes in modifying natural antibiotics to enhance their activity. Subsequently, the flow of new antibiotics has dwindled, with diminishing numbers licensed in the 1990s and the first decade of this century [1,2]. The reasons are threefold: first, the technical difficulty of discovering new antibiotics, especially those able to penetrate Gram-negative bacteria [3,4]; second, the regulatory hurdles to new antibiotics which have become increasingly complex [5]; and, third, the brutal fact that antibiotics, as short-course treatments, are less lucrative for the pharmaceutical industry than are long-term therapies for chronic conditions [6,7].
The lack of new antibiotics is critically important, given the continued accumulation of resistance favored by Darwinian selection, which erodes the utility of existing antibiotics. Once a pathogen has been cultured some antibiotic retaining activity can usually be identified, at least in vitro. The greater problem is for empirical therapy, where growing resistance increases the risk that the antibiotic used will prove inactive. In severely ill patients, this ineffectiveness leads to increased mortality, length of hospital stay, and cost [8,9].
This review considers the extent of emerging and proliferating resistance in Gram-negative bacteria-where the problem is most acute-and discusses strategies that may be deployed to counter the threat.
The defining feature of Gram-negative bacteria, distinguishing them from Gram-positive species, is a double membrane wall (Fig. 1). The outer membrane excludes large or hydrophobic molecules, including glycopeptides, daptomycin, and rifampicin, and slows the entry of drugs that can cross it, augmenting the effectiveness of the next line of defense. These defenses include periplasmic-β-lactamases and cytoplasmic membrane efflux pumps, which scavenge amphipathic molecules-including antibiotics-that enter the membrane, pumping them back out of the cell [10]. The combination of impermeability and clearance explains why Gram-negative bacteria are inherently more resistant than Gram-positive species, and why new antibiotics active against them are harder to find [3]. Efflux is especially important in Pseudomonas aeruginosa, which has multiple pumps that render it resistant to many drug families active against other Gram-negative species [11,12].
Both Enterobacteriaceae (Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus spp., Serratia spp.) and non-fermenters (Pseudomonas, Acinetobacter, and related genera) are important opportunist pathogens. E. coli is-by a large margin-the most common agent of community and hospital urinary tract infections and the main aerobic component of the mixed flora in intra-abdominal infections. P. aeruginosa, Klebsiella, and Enterobacter are important in nosocomial pneumonia, especially in patients with prolonged hospitalization. Acinetobacter baumannii is less pathogenic, but notoriously causes outbreaks in the most vulnerable patients in intensive care units (ICUs). Gram-negative pathogens account for around half of all bacteremias, most of which arise due to bacterial overspill from other primary infection sites. In the UK, E. coli is the most common agent of bacteremia, causing 30% of all cases, whereas P. aeruginosa, Klebsiella spp., Enterobacter spp., and Proteeae each account for 4-8% of cases [13]. A few Gram-negative species are important classical pathogens; those remaining important in developed countries include Salmonella spp., Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and N. gonorrhoeae. Others ranging from Vibrio cholenzae, to Burkholderia pseudomallei remain important in developing countries, but lie beyond the scope of this review.
The first anti-Gram-negative antibiotics were sulfonamides, introduced in the 1930s; tetracyclines, first-generation aminoglycosides, and chloramphenicol then became available in the late 1940s and early 1950s, respectively. Two quantum leaps followed. The first delivered semi-synthetic penicillins and first-generation cephalosporins in the early 1960s, along with more potent and less toxic aminoglycosides such as gentamicin and amikacin. The second, in the 1980s, led to the development of third- and fourth-generation oxyimino-cephalosporins, β-lactamase-inhibitor combinations, carbapenems, and fluoroquinolones. These drug families are now standard therapies for severe Gram-negative infections, but growing resistance has created the present problem, as few new agents have been developed to replace them.
Resistance in Enterobacteriaceae, internationally and in Korea
At launch, third-generation cephalosporins were almost universally active against Enterobacteriaceae; ceftazidime was also active against P. aeruginosa and, often, A. baumannii. Resistance emerged first in Enterobacter spp. (especially), Citrobacter freundii, and Serratia spp., all of which have inducibly-expressed chromosomal AmpC β-lactamases. Third-generation cephalosporins are labile to these enzymes but are weak inducers of their synthesis. The result is that cephalosporins kill the AmpC-inducible cells but confer an advantage upon spontaneous 'derepressed' variants that express AmpC activity without induction [14]. These variants arise by spontaneous mutation in inducible (i.e., normal) strains, and the likelihood of their selection during therapy, with consequent treatment failure, is as high as 20-30% when third-generation cephalosporin is used to treat an Enterobacter bacteraemia [15]. Selection is associated with a doubling of mortality and a 50% increase in hospital stay and doubling of cost for survivors (Table 1) [16]. Piperacillin-tazobactam is also compromised, but seems to be less often associated with selection than are third-generation cephalosporins, although the reasons for this difference remain uncertain and one analysis did find similar selectivity [17]. Fourth-generation cephalosporins (cefepime and cefpirome) and carbapenems are more stable and less selective (Table 2).
Genes encoding AmpC β-lactamases have escaped from the chromosomes of Citrobacter and other genera to plasmids and are now circulating in E. coli and Klebsiella pneumoniae [18]. The enzymes they encode are variously called CMY, FOX, MOX and MIR types or, more usefully, 'plasmid AmpC.' Extended-spectrum β-lactamases (ESBLs) represent the second and greater plasmid-mediated threat to oxyimino-cephalosporins, affecting fourth- as well as third-generation analogues (Table 2). The earliest ESBLs, first identified in the 1980s, were mutants of the plasmid-borne TEM and SHV penicillinases that had disseminated in E. coli and other Enterobacteriaceae in the 1960s and 1970s [19]. Although third-generation cephalosporins are stable to classical TEM and SHV enzymes, over 200 ESBL mutants have been identified, with sequence changes that expand the active site, allowing attack on oxyimino-cephalosporins (see http://www.lahey.org/studies for a list). Many variants have been described only once or twice, but SHV-2, -5, -11, and -12 and TEM-3, -10, -26, -52, and -116 are widespread in many countries [20,21].
TEM and SHV ESBLs spread during the 1980s and 1990s, largely in Klebsiella spp. and particularly in ICUs [19,22]. Some strains caused major outbreaks, but did not substantially penetrate E. coli strains or spread in the community. This is surprising because E. coli strains with the progenitor TEM-1 enzyme are frequent in the human gut and must have been exposed to huge amounts of ceftriaxone, which was long the most widely used injectable antibiotic and has biliary excretion. These ESBLs may thus present a burden to E. coli, but this aspect remains to be properly explored.
A massive shift in the distribution of ESBLs has occurred since 2000 with the spread of CTX-M types-a decade earlier in Argentina [23]. Unlike TEM and SHV variants, these ESBLS are not mutants of old plasmid-mediated penicillinases. Rather, their genes originated in the chromosomes of Kluyvera spp., a genus of no direct clinical importance, and were mobilized to plasmids by insertion sequences, notably ISEcp1 [24,25]. Plasmids encoding these CTX-M enzymes then reached human opportunists, where they have proliferated in community E. coli and hospital Klebsiella spp. Gene escape has occurred repeatedly, with five CTX-M families (groups 1, 2, 8, 9, and 25) circulating. Different CTX-M families dominate in different places: CTX-M-15 (group 1) is predominant in most of Europe, North America, the Middle East, and India, but CTX-M-14 (group 9) is most common in China, Southeast Asia, and Spain, and CTX-M-2 (group 2) is predominant in Argentina, Israel, and Japan [20,22].
The prevalence of ESBLs (CTX-M and other types) differs among patient groups and clinical and geographic settings. In the UK, around 10% of E. coli from bacteremias now have ESBLs -90% of them CTX-M types [26]- and producers are frequent in urinary isolates from geriatric patients, although denominators are poor, precluding accurate prevalence estimates. By contrast, their prevalence is ≤ 1% in community cystitis. Gut carriage of ESBL E. coli was seen in 40% of nursing home residents in Belfast (Northern Ireland), providing a reservoir for future urinary or intra-abdominal infections-which are frequent in these vulnerable patients-but in only 1-2% of other outpatients whose stools were examined by the clinical laboratory [27]. Many studies have shown that community infections with ESBL E. coli predominantly affect older (> 65 years) patients with recent hospitalization and antimicrobial treatment, especially with cephalosporins or quinolones [28]. Travel in high-prevalence countries is a risk factor for gut colonization by ESBL E. coli, with travel-associated-strains sometimes causing later urinary infections [29].
The variability in ESBL rates among population groups should prompt caution when viewing national prevalence rates; these benchmark values are of less clinical importance than local rates in different patient groups. Despite this caveat, a rough international picture can be drawn. Multiple surveys have shown that the highest ESBL rates for E. coli and Klebsiella spp. occur in India (≥ 80%) and China (≥ 60%), [30-32], with rates ≥ 30% elsewhere in East and Southeast Asia, Latin America, and southern Europe vs. 5-10% in Australasia, northern Europe, and North America [30]. Some studies have suggested that ESBL prevalence in India is equally high in community and hospital E. coli isolates [31], probably reflecting unregulated antibiotic use coupled with recycling of gut bacteria by an overloaded sewage infrastructure [33,34]. In Hong Kong, ESBLs were found in 7.3% of E. coli from uncomplicated community cystitis, including in 11/219 isolates from women aged 18-35 years, a much younger age group than typically affected by ESBL E. coli elsewhere [35]. A growing number of ESBL outbreaks has also been reported in neonatal units, likely due to the transfer of E. coli from the gut flora of one mother to her infant at birth, followed by spread among other infants in the unit [36,37].
The epidemiology of CTX-M ESBLs involves both plasmid dissemination and clonal success. CTX-M-15-the most prevalent enzyme-is most often encoded by IncF plasmids that are prone to multiple rearrangements [38]. In the case of K. pneumoniae, these plasmids are carried by diverse strains; some strains cause local outbreaks but none has achieved wider success [39]. In E. coli, however, CTX-M-15-encoding IncF plasmids are strongly associated with a sequence type (ST)131 lineage, now widespread globally [25,40] (Fig. 2). It remains unclear whether a progenitor ST131 strain acquired an original IncF-CTX-M-15 plasmid and then spread while diversifying, or whether ST131-a lineage that dates back to the 1980s-has repeatedly acquired IncF-CTX-M-15 plasmids at different times in different places, perhaps with considerable exchange to and from Klebsiella. E. coli ST131 occasionally hosts other ESBLs besides CTX-M-15: in Belfast (Northern Ireland, UK) it often has the IncI1 plasmid, pEK203, encoding CTX-M-3. CTX-M-3 differs from CTX-M-15 by only a single amino acid change and the two enzymes can interconvert by mutation: nevertheless, the sequences flanking blaCTX-M-3 in pEK203 differ from those flanking blaCTX-M-15 in its typical IncF plasmid hosts, e.g., pEK499 and pEK516 [41,42], showing that they reflect separate gene escapes from Kluyvera. CTX-M-14 ESBL, which dominates in the Far East, is not strongly associated with ST131 or other successful clones, and its accumulation largely entails plasmid spread among strains.
ESBLs achieved a high prevalence before 2000 in Korea; otherwise, the pattern appears similar to that elsewhere, with CTX-M ESBL types replacing TEM and SHV. In a review of studies published before 1998, Pai [43] estimated ESBL prevalence rates of 4.8-7.5% in E. coli and 22.5-22.8% in K. pneumoniae, with TEM-52 dominant in E. coli and SHV-2 and -12 in K. pneumoniae. Plasmid-mediated CMY-1 (AmpC) was estimated to occur in 15% of Enterobacteriaceae-an exceptionally high rate [43]. These results were broadly supported by a survey of 13 hospitals by Jeong et al. [44] in 2002, which found SHV-2a and -12 and TEM-19, -20, -52, and -116 to be the main ESBLs, although the prevalence of CMY-1 was much lower than Pai [43] had suggested. CTX-M ESBLs were first reported in Korea in 2005 [45] and are now predominant [46]: CTX-M-14 and -15 are both widespread [46,47]. As elsewhere, CTX-M-15 is strongly associated with E. coli ST131 [48], whereas CTX-M-14 is disseminated among strains [47]. Infection risk factors for ESBL producers resemble those found internationally, including prior healthcare and antibiotics [49,50]. More exceptional-but recapitulating the Hong Kong data [35]-is a 2006 multicenter survey finding of ESBLs in 11.8% of E. coli from uncomplicated cystitis [51]. A subsequent study of isolates collected in 2008-2009 found a lower (6.4%) rate of cephalosporin resistance in E. coli from cystitis, although the authors noted that ciprofloxacin resistance continued to increase from 15.2% in 2002 to 23.4% in 2006 and 24.8% in 2008-2009 [52].
Many ESBL producers in Korea and elsewhere are multiresistant to non-β-lactam antibiotics, including fluoroquinolones and aminoglycosides [20,23,53]. The main factors in quinolone resistance are combinations of mutations affecting the chromosomal topoisomerase genes gyrA and parC. Resistance to other antibiotics, including trimethoprim, tetracyclines, sulfonamides, and chloramphenicol as well as aminoglycosides is often encoded by the same plasmids that determine the ESBL. IncF plasmids encoding CTX-M-15 ESBL often also determine AAC(6')-Ib-cr, which inactivates amikacin and tobramycin (not gentamicin) and also deactivates ciprofloxacin, augmenting resistance [54]. These plasmids also often encode OXA-1, an inhibitor-resistant penicillinase, conferring resistance to piperacillin-tazobactam and amoxicillin-clavulanate, even though these inhibitors inactivate CTX-M-15 [41,55].
Most aminoglycoside resistance among Enterobacteriaceae in the West is determined by aminoglycoside-modifying enzymes like AAC(6')-1b. These enzymes are also common in Asia, but wide circulation of the ArmA and RmtA-C 16S ribosomal RNA (rRNA) methylases is also found in Asia, unlike in Europe and the US [56-58]. These methylases modify bacterial ribosomes to block binding of all key aminoglycosides, including the new analogue ACHN-490 [59]. They are widespread in Korea and are commonly carried by plasmids that also encode SHV-12 and CTX-M-14 ESBLs, but have not been associated with CTX-M-15 or E. coli ST131 [60,61].
Carbapenem resistance
The growing prevalence of cephalosporin-resistant Enterobacteriaceae is driving the directed and empirical use of carbapenems, as the only widely marketed β-lactams stable to ESBLs and AmpC enzymes (Table 2).
Carbapenems retained near-universal activity against Enterobacteriaceae for around 20 years after the introduction of imipenem in 1985, but resistance is now accumulating. It can evolve by porin loss, reducing drug entry in strains already containing high levels of AmpC or an ESBL [62]. This is a common source of low-level resistance to ertapenem, especially in Enterobacter and Klebsiella, with resistant variants sometimes selected during carbapenem therapy [63]. However, this problem is limited because these variants are often unstable and tend to revert to susceptibility, rarely spreading among patients [64,65]. Their porin deficiency likely impedes nutrition, reducing competitiveness.
Much more concerning is the gradual proliferation of carbapenemases, which are biochemically diverse and include members of three of the four β-lactamase classes (A, B, D).
KPC enzymes (class A, non-metallo) are currently the predominant carbapenemases emerging in Enterobacteriaceae [66]. They were first recorded in North Carolina (USA) in 1997, with outbreaks in New York by 2005. Since 2006, KPC+ K. pneumoniae have spread across the USA and in Israel, Greece, and, latterly, Italy, with growing outbreaks in China, Brazil, and several European countries. The highest national prevalence rate (to 40%) is for K. pneumoniae from bacteremias in Greece [67]. Much of this spread reflects an association of KPC enzymes with a successful clone, K. pneumoniae, ST258 (Fig. 3) [68]. Members of this lineage are typically resistant to all antibiotics except colistin, tigecycline, and gentamicin. A colistin-resistant variant of ST258 is circulating in Greece [69], with cases also seen, possibly via import, in Hungary and the UK [70]. The reasons for the particular success of ST258 are uncertain, but its ability to spread swiftly is beyond dispute. In addition, KPC enzymes have spread considerably via plasmids among different K. pneumoniae strains and other Enterobacteriaceae, principally E. coli and Enterobacter spp.
Metallo-carbapenemases (class B) are biochemically very different from KPC, and include IMP, VIM, and New Delhi Metallo (NDM) enzymes, along with less frequently occurring families. IMP was recognized in Japan at the end of the 1980s [71] and has gradually spread worldwide, although it has not achieved great prevalence anywhere. VIM is more important; it was first recorded in P. aeruginosa in Verona (Italy) in 1997 [72] and then spread into Enterobacteriaceae, principally K. pneumoniae. By 2005, it was present in 40% of bloodstream K. pneumoniae from Greece, where it has subsequently been partly displaced by KPC enzymes [73].
Clusters of K. pneumoniae with VIM carbapenemases are increasingly being reported worldwide, although they are less numerous than isolates with KPC enzymes. A further distinction is that VIM enzymes are not associated with any particular clone, whereas KPC enzymes are associated with ST258 K. pneumoniae. Although local outbreaks occur, the larger issue is the dissemination of blaVIM among K. pneumoniae, largely by IncN plasmids [73,74].
NDM-the most publicized metallo-carbapenemase-is epicentered in India, where it occurs in 2-8% of Enterobacteriaceae at teaching hospitals [75,76], and in Pakistan, where 27% of inpatients at two military hospitals were carriers. blaNDM-1, encoding the enzyme, is wide-spread in surface-water bacteria in New Delhi, implying community circulation. Enterobacteriaceae (and occasionally Acinetobacter spp.) with NDM carbapenemase have repeatedly been imported into Europe, Asia, North America, and Australasia by those who have travelled or been hospitalized in the Indian subcontinent [77]. As with VIM metallo-carbapenemases, spread is largely by plasmid transfer, not clonal dissemination [77].
The final and very different-emerging carbapenemase of Enterobacteriaceae is OXA-48, reported in Turkey since 2001, mostly in K. pneumoniae. It has disseminated in the Middle East and North Africa since 2007-2008, with repeated import into Europe; outbreaks have occurred in the UK, Belgium, Ireland, France, Spain, and The Netherlands (Fig. 4) [78,79]. The main factor in its spread is dissemination of 50- and 70-kb plasmids carrying the blaOXA-48 transposon Tn1999 among Klebsiella strains [80]. A related enzyme, OXA-181, is circulating in India, where it seems less frequent than NDM-1 [81]. OXA-48 and -181 originated by separate mobilizations of chromosomal β-lactamase genes from Shewenella, a genus otherwise lacking clinical importance [79].
To date, carbapenemase-producing Enterobacteriaceae have shown little circulation in Korea, although C. freundii and S. marcescens with VIM-2 [82] and K. pneumoniae [83] with KPC enzymes have been reported, and a very recent report described an outbreak cluster of K. pneumoniae with the NDM-1 enzyme [84]. Unusually, an S. marcescens strain with AmpC and impermeability caused an outbreak involving nine patients at a hospital in Seoul [65]. Most disturbing is the recent appearance of KPC+ K. pneumoniae ST258. Only one producer has been reported to date [85], from a urinary infection in Seoul, but this development should raise concern, given the strain's dramatic success elsewhere.
KPC carbapenemases inactivate all β-lactams. Aztreonam is stable to the IMP, VIM, and NDM types, but these are often accompanied by aztreonam-hydrolyzing ESBLs. Similarly, although OXA-48 spares ceftazidime, it is often accompanied by ceftazidime-hydrolyzing ESBLs (Table 2). Resistance to non-β-lactams is variable, but many carbapenemase producers are susceptible only to colistin, tigecycline, and/or fosfomycin, none of which is an 'ideal' antibiotic. NDM carbapenemases are often accompanied by the 16S rRNA methylases mentioned earlier, compromising the widest range of aminoglycosides [59,81].
The prevalence of resistance in P. aeruginosa varies widely among countries. In Europe, resistance rates to aminoglycosides, carbapenems, cephalosporins, and fluoroquinolones are lowest (< 10%) in the northwest, particularly in Scandinavia, and highest (25-50%) in the southeast, particularly in Greece [86]. Rates are high in Latin America and Southeast Asia, and intermediate in the US [87].
Most resistance among P. aeruginosa in Europe and North America involves mutations that restrict drug entry (the most common cause of carbapenem resistance), derepress chromosomal AmpC (as in Enterobacter, above) and up-regulate efflux [88,89]. Acquired mechanisms are more important in resistance in Asia and Latin America and include different ESBLs to those most prevalent in Enterobacteriaceae, notably PER-1, which is widespread in Turkey [90], and VEB-1, which first proliferated in Southeast Asia [91]. Metallo-β-lactamases are scattered and single-hospital outbreaks due to producers have occurred worldwide (Fig. 5) [92,93]. These outbreaks are often prolonged, with cases scattered over long periods, probably owing to persistence in the hospital structure, e.g., in sink traps. In Brazil, a clone with São Paolo Metallo (SPM)-β-lactamase has disseminated among hospitals, achieving national distribution [94]. Elsewhere, P. aeruginosa ST111, which corresponds to serotype O12 and 'burst group 4,' is now a common host to VIM metallo-carbapenemases [68]. This lineage has a long history of acquiring resistance -20 years ago it often carried the PSE-1 carbenicillinase [95]. ST235 (serotype 11) is also a successful accumulator of resistance, frequently hosting IMP and VIM carbapenemases [68].
A 2005 survey of 23 hospitals in Korea found carbapenemases in 10% of carbapenem-resistant P. aeruginosa, with VIM types 2.5-fold more common than IMP types [96]. The remaining 90% of carbapenem-resistant P. aeruginosa were inferred to have impermeability-type resistance. Subsequently, an ST235 clone with the IMP-6 enzyme has disseminated nationally [97]. In a 2009 survey of 21 hospitals, this strain accounted for 30/386 (7.8%) isolates and was recovered in 14 sites. As with NDM-1 in Enterobacteriaceae, blaIMP-6 in Korean P. aeruginosa is often associated with the ArmA rRNA methylase [98].
The molecular epidemiology of A. baumannii, another important opportunistic non-fermenter, contrasts to that of P. aeruginosa, with resistance largely originating from the up-regulation of inherent chromosomal AmpC and carbapenemase (blaOXA-51) genes by insertion sequences, critically ISAba1, which migrate within the chromosome [99,100]. The insertion of ISAba1 in front of one of these β-lactamase genes provides an efficient promoter, allowing expression and resistance. Alternatively, resistance can be caused by acquired OXA-23, -40, and -58 carbapenemases [99]. OXA-23 originated as a chromosomal carbapenemase in Acinetobacter radioresistens [101], a species with no direct clinical importance.
OXA carbapenemases account for most carbapenem resistance in A. baumannii worldwide, including in Korea, where the resistant proportion reportedly grew from 13% in 2003 to 51% in 2008-2009, and where two carbapenemase-producing clones are in wide circulation among hospitals, one with OXA-23 and frequent colistin resistance, the other with up-regulated OXA-51 [102].
Metallo-carbapenemases also occur, with NDM recorded in A. baumannii (although not yet in Korea) and IMP in non-baumannii species, but these are extremely rare compared with OXA types [103]. A unique metallo-type, Seoul imipenemase (SIM-1), has been described from A. baumannii in Korea, but it has not disseminated [104].
As in Enterobacteriaceae, most resistance to non-β-lactams depends on acquired genes-not on mutation, as in P. aeruginosa. Acquired genes may be carried by plasmids or by massive 'resistance islands' inserted into the chromosome [105,106]. Colistin resistance, as in one of the prevalent Korean clones, can arise via changes to membrane phospholipids and lipopolysaccharides [107,108], and resistance to tigecycline by up-regulation of the chromosomal AdeB efflux pump is sometimes selected for during therapy [109].
Fastidious Gram-negative bacteria
A few N. meningitidis and H. influenzae isolates have low-level resistance to fluoroquinolones, whereas resistance to third-generation cephalosporins has not been seen in either species. N. meningitidis shows only slightly reduced susceptibility to penicillin, even after 70 years of use.
N. gonorrhoeae, by contrast, has sequentially developed resistance to low-level penicillin, high-level penicillin, and ciprofloxacin, with borderline non-susceptibility to cefixime (MICs, 0.12-0.5 mg/L) now proliferating [110], including in Korea [111,112]. This development is driving a treatment shift to high-dose ceftriaxone, sometimes (as in the UK) combined with azithromycin [113]. Few other options are available if substantial resistance to these treatments emerges and, disturbingly, two reports have described gonococci with resistance to ceftriaxone and cefixime: one from Japan [114] and the other from France [115]. The first patient developed an oropharyngeal infection and recovered-perhaps spontaneously-during a second course of ceftriaxone; the second developed a urethral infection that was cured with gentamicin.
The range of antibiotic options to treat Gram-positive infections, particularly those due to MRSA, has expanded in the past decade with the introduction of quinupristin-dalfopristin, linezolid, daptomycin, tigecycline, and, in some markets, telavancin and ceftaroline. Additional agents, including oritavancin, dalbavancin, and tedizolid (torezolid), are in phase III development and are anticipated in the next 2-3 years. Among these new anti-MRSA agents, only tigecycline shows any increase in in vitro anti-Gram-negative activity compared with previous members of its chemical family (tetracyclines), and its efficacy in severe infections is variable, with low serum levels and disappointing results in nosocomial pneumonia [116]. The only other anti-Gram-negative agent launched in the past decade is doripenem, which represents an incremental improvement over meropenem in anti-Pseudomonas activity, but is otherwise similar [117].
In short, little progress against Gram-negative bacteria has been made for a long time. Nevertheless, several new anti-Gram-negative agents are in phase III development and show promise. CXA-201, a cephalosorin (ceftolozane)-tazobactam combination, is four-fold more active than ceftazidime-still the best anti-pseudomonal cephalosporin-against P. aeruginosa [118,119]. Ceftazidime-avibactam, another new inhibitor combination, is active against strains with AmpC, ESBLs, and KPC or OXA-48 carbapenemases [120], and the neoglycoside plazomicin overcomes nearly all aminoglycoside-modifying-enzyme-mediated resistance [121].
Nevertheless, each of these agents has gaps in its spectrum, and none provides such complete coverage as ceftazidime, imipenem, and ciprofloxacin did when they were introduced 20-30 years ago. CXA-201 lacks activity against Enterobacteriaceae with metallo- and KPC carbapenemases and shows borderline activity against some ESBL and AmpC producers [122]; ceftazidime-avibactam lacks activity against strains with metallo-carbapenemases, such as VIM and NDM [120]; and plazomicin fails to overcome resistance mediated by ArmA and Rmt rRNA methylases [59].
Other antibiotics in earlier developmental stages may offer a more comprehensive solution. The most promising are 1) boron-based protein synthesis inhibitors (GSK-Anacor partnership) [123]-though their development was recently suspended, 2) fluorine-containing tetracyclines ('fluorocyclines,' Tetraphase) [124], and 3) novel protein synthesis inhibitors (RibX-Sanofi partnership). Aztreonam-avibactam shows the potential to overcome both metallo- and non-metallo-carbapenemases [120]; it is not yet under formal development but would be relatively easy to progress, following experience with ceftazidime-avibactam and ceftaroline-avibactam.
However, these drugs will only be available in the future, and licensing success is not guaranteed. Therefore, as much as possible must be done through good stewardship and infection control to prolong the life of existing antibiotics. Improvements in laboratory microbiology and its interaction with patient management are also critical. Currently, a 48-hour interval-at the very best-remains between the clinical diagnosis of a patient's infection and the clinician's acquisition of laboratory results indicating the isolate's susceptibility. During this interval the patient is treated empirically based on the likely pathogens and local resistance rates. Such treatment becomes more difficult as resistance increases, and multiple studies have shown that resistance to the empirical regimen leads to a near doubling of mortality in bacteremias [8]. One response is to start patients on the most powerful empirical antibiotic, typically a carbapenem combined with an anti-MRSA agent, and to 'de-escalate' once laboratory microbiology results are available [125,126]. Although this strategy improves initial coverage, which may benefit the patient [127], it has two pitfalls: first, hospitals frequently fail to enforce de-escalation when a susceptible pathogen is isolated; second, the approach does not specify the appropriate response when the patient still shows symptoms of infection but no pathogen is isolated. Both factors potentially lead to unnecessarily prolonged use of the broadest-spectrum agents, increasing the selection of resistance. The situation would be improved if microbiology could be accelerated, identifying pathogens and their resistances in hours rather than days, and without the need for culture [128]. Potential methods exist, including polymerase chain reaction or DNA arrays to seek species- and resistance-specific genes [129,130]. Nevertheless, great challenges remain, especially with non-sterile-site specimens, in which DNA extracted from the pathogen becomes mixed with that from commensals.
If these challenges can be overcome-perhaps first for blood and other sterile-site specimens-results can be delivered to the ward far more swiftly. Such development would reduce the conflict between the individual, who currently may benefit from receiving the most powerful antibiotics, and society, which benefits if they are conserved. This goal is surely worthwhile because the alternative is a world where high-tech medicine becomes ever more hazardous as-owing to proliferating resistance-it becomes increasingly more difficult to treat infection empirically.
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Table 1
Cases exhibited selection of AmpC-derepressed mutants during cephalosporin treatment of Enterobacter infections; controls are those in whom cephalosporins were used successfully, without selection of resistance [16].
Table 2
RRR, high-level resistance always seen; RR, resistance usually clear; R, MICs raised but may or may not exceed breakpoint; -, resistance not normally seen.
ESBL, extended-spectrum β-lactamase.
aResistance arises if combined with impermeability.
bResistance widespread as producers often also have ESBLs.


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Do you long to make a difference in this world? Does your heart feel pain for the souls of women today?
So much is happening around us. Women everywhere are feeling angst. Some are fearful. Some are angry. Some are passionate. They are marching. They are hoping. They are calling for change for their lives and for the lives of those around them. They hunger to feel valued. They desire a meaningful purpose. Meanwhile, too many are burdened by bitterness and weighed down by guilt and shame. Women across the world are desperate for meaningful relationships…longing to matter. Longing for love.
Myriad are the issues, but the one solid solution lies only in the person of Jesus. Only through his loving, life-giving message can the hearts of everywoman—those we don't know as well as those we do know—find true acceptance, freedom from guilt, forgiveness, and hope. Jesus alone can give confidence, security, and purpose to all. He turned the world upside down with his culture-changing value of women when he walked this earth, and he has no desire to stop now.
To be bold for spiritual change we must start somewhere. What can we do?
Look around. Really see the lives behind each face. Will you pray for them? Will you act on their behalf?
Wednesday, March 8 is the annual International Women's Day. This year's world theme is "Be Bold for Change." What a fitting message for disciples of Jesus!
The need is great. We need courage and boldness to offer the mighty things God has done for us to those around us. We must act in compassion, for without love our words are no more than clanging symbols (1 Cor. 13).
Words can be many. We can post, we can tweet, we can carry signs…but the question remains—what will we do? As the Scriptures state, Dear children, let us not love with words or tongue, but with actions and in truth. (1 John 3:18)
On Tuesday, March 7, we are asking all sisters around the world to join together for a day of prayer and fasting.
For what? For boldness to change the world for Jesus. We will send specific scriptures and prayer requests via the website.
On Wednesday, March 8, we are asking all sisters to "be bold for spiritual change." Act. Be bold. Through faith let us call on God to unleash the power of his Spirit in our lives as we share the powerful message of Jesus. And remember that we are not alone.
Prepare your hearts. Stay tuned. Tune in to: beboldforspiritualchange.wordpress.com. Sign up and you will receive updates. We will send ideas and would love to hear yours. Spread the word. Share. Post.
Let us call on God together, and through faith wait in grateful expectation for his mighty works.


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18 Free Comic Book Day Previews Available Now
Headline - Press release
Posted by Richard Boom on Feb 27, 2010
From cool kids comics to the greatest super-hero fare, from classic reprints to the latest stories, it's a wide spectrum of comics covered in the Gold and Silver comic books available for Free Comic Book Day 2010, taking place Saturday, May 1, 2010!
No you can go the Comics Page of the www.freecomicbookday.com website and view six-page Previews of eighteen of the Gold and Silver titles.
Books you now have the opportunity to preview are:
Gold Titles
* Archaia Entertainment's Mouse Guard/Fraggle Rock Flip Book
* Archie Comics' Archie's Summer Splash! #1
* Boom Studios' Toy Story
* Drawn & Quarterly's YOW! The John Stanley Library
* IDW Publishing's G.I. JOE #155 1/2
* Image Comics' Fractured Fables
Silver Titles
* Archie's Sonic the Hedgehog: Hide & Seek & Destroy!
* Aspen Comics' Worlds of Aspen
* Asylum Press' Fearless Dawn/Asylum Press Sampler
* BOOM! Studio's Irredeemable #1 FCBD Edition
* Del Rey Comics' Del Rey Showcase
* IDW's Library of American Comics #0
* Marvel Comics' Iron Man: Supernova
* New England Comics' The Tick #1
* Radical Publishing's Radical: Bigger Books! Bigger Value!
* Red 5 Comics' Atomic Robo & Friends
* Storm Lion's Freedome Formula: Speed Metal Overtures
* Th3rd World Studios' The Stuff of Legend: Mortal Instruments Preview
Don't forget to also become an FCBD fan at Facebook and follow us on Twitter at www.Twitter.com/FCBD10.
As we add the sponsor book previews we'll be "tweeting" their arrival on the FCBD website!
Related content
Related Headlines
- Preview: Fearless Dawn FCBD Sampler - written by Richard Boom on Jan 26, 2010
- The Comic Bug Celebrates FCBD With Big Creator Line-Up - written by Richard Boom on Apr 21, 2010
- FCBD At Collector's Paradise With TopCow And More - written by Richard Boom on Apr 26, 2010
- FCBD 2005 Success Report - written by Frederik Hautain on May 8, 2005
- Niles' City of Dust - written by Frederik Hautain on Apr 30, 2008
Related Lowdowns
- Everyone Loves a Party - written by Sam Moyerman on May 11, 2006
- FCBD 2007: Atomic Comics - written by Jake Bell on May 5, 2007
Related Reviews
- FCBD 2010: Fractured Fables - written by Jason Wilkins on May 4, 2010
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text:
If you are experiencing any type of grief due to events in your life, you may feel low-energy. The holiday season may fill you with feelings of stress and overwhelm. How can you re-fill your tank?
There are 4 areas to consider in managing your energy- physical, mental, emotional and spiritual.
Sleep and movement are critical to a sense of well-being. When you are anxious or in grief, sleep can be elusive and exercise may get dropped in favor of collapsing on the couch. Even if you don't feel like it, doing small things such as going for a walk, or playing with the dog will boost your energy level and help get your emotions back on track by releasing chemicals in your brain that promote a sense of well-being and reduce stress.
What is your belief about what has happened in your life? Are you accepting life circumstances or spending energy resisting them? Stress is caused by resisting what is. Resistance sounds like this.
"I shouldn't have to struggle."
"My partner shouldn't have left."
"My boss shouldn't have fired me."
Removing the word should removes judgment about the situation, leaving only the situation to deal with. Once resistance is cleared, there is energy available to engage what is present in your life, and move forward.
Stressful thoughts trigger stressful emotions. We can't choose which feelings come to us. They're automatic. They are an immediate reaction to the situation we are experiencing. And many times they are triggered from feelings that haven't been dealt with in the past. Trying to stuff your emotions in order to avoid their unpleasant intensity will sap your energy and is toxic. It is important to realize that you have emotions, you aren't your emotions.
Dealing with your emotions by expressing them will give you the energy you need to move forward. As you acknowledge them, try and correctly identify them.
For example, if you feel angry, are you really afraid? If you feel depressed, are you really angry?
What gives you meaning and purpose? Knowing this will sustain you through some very hard times of grief. If you have wanted to reconnect to your faith, this is the time to do it. If walks in nature nourish your soul, then program time to do that. Reading about others' spiritual paths can also be inspiring.
As the four areas of energy are integrated, you will discover that nourishing one area also feeds the others. Notice the next time you go for a walk what happens. Does your perspective about your situation shift? How does that change the way you feel about it? What possibilities emerge that have meaning for you?


text:
Fridays in Playa d'en Bossa belong to Glitterbox. Defected's sparkly love-child, Glitterbox has found its forever home at Hï Ibiza. Love it or hate it, you simply cannot deny it, 21st Century disco is here to stay. Twinkly house anthems, gleaming disco-classics and extravagant performances come from the over-the-top dancers, and every year sees more and more seemingly serious DJs succumb to the glitter madness and don their sequins with glee.
Head honcho Simon Dunmore is joined by a phenomenal selection of household names of house music, along with PAs, guest singers and a uniquely faithful and exuberant Ibiza crowd that love nothing more than a good shimmy. Go on! Resistance is futile – just give it up and get on down.