Carbapenemase-producing Gram-negative bacteria - Future Medicine

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(2015) 10(3), 407–425 part of ... 4Departments of Laboratory Medicine & Internal Medicine, National Taiwan .... in China [19], Taiwan [26] and Singapore [45],.
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Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options Shio-Shin Jean1, Wen-Sen Lee2, Carlos Lam1, Chin-Wang Hsu3, Ray-Jade Chen3 & Po-Ren Hsueh*,4

ABSTRACT Carbapenemases, with versatile hydrolytic capacity against β-lactams, are now an important cause of resistance of Gram-negative bacteria. The genes encoding for the acquired carbapenemases are associated with a high potential for dissemination. In addition, infections due to Gram-negative bacteria with acquired carbapenemase production would lead to high clinical mortality rates. Of the acquired carbapenemases, Klebsiella pneumoniae carbapenemase (Ambler class A), Verona integron-encoded metallo-β-lactamase (Ambler class B), New Delhi metallo-β-lactamase (Ambler class B) and many OXA enzymes (OXA23-like, OXA-24-like, OXA-48-like, OXA-58-like, class D) are considered to be responsible for the worldwide resistance epidemics. As compared with monotherapy with colistin or tigecycline, combination therapy has been shown to effectively lower case-fatality rates. However, development of new antibiotics is crucial in the present pandrug-resistant era. Carbapenemases are β-lactamases with versatile hydrolytic capacity against β-lactam agents (including carbapenem agents) [1] . The β-lactamases are classified according to their functional groups (Bush-Jacoby-Medeiros, groups 1–4, with many subgroups) or molecular schemes (Ambler, class A–D). Currently, carbapenemases mainly fall under functional group 2d, 2f or 3. According to the Ambler classification system, they are categorized as class A, B or D [2] . Of them, molecular class-B β-lactamases are metallic ion-dependent enzymes, such as metallo-β-lactamases [MβL], which possess divalent cations (usually zinc) in the active site that are essential for hydrolysis of the β-lactam ring, whereas class A and D β-lactamases have serine at their active sites. Most of the genes encoding for these carbapenemases are associated with high potential for intra- and interhospital dissemination [1,3–14] . The prevalence of a variety of carbapenemases in Gram-negative bacteria (GNB) has increased markedly during the previous 10 years [1,15] . These carbapenemases compromise the efficacies of all carbapenem-class drugs, which are often the last resort against serious infections in hospitals, long-term acute care hospitals and long-term care facilities [16] . In this review, we summarize the genetic background, epidemiology and nonsusceptibility profiles of carbapenemase-producing GNB (Enterobacteriaceae and Acinetobacter spp.), and the clinical outcome of patients with infections caused by carbapenemase-producing GNB after various therapies.

KEYWORDS 

• carbapenemase • combination therapy • dissemination • Gram-negative bacteria • resistance

Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Division of infectious Diseases, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 3 Department of Emergency & Critical Medicine, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan 4 Departments of Laboratory Medicine & Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan *Author for correspondence: [email protected] 1 2

10.2217/FMB.14.135  © 2015 Future Medicine Ltd

Future Microbiol. (2015) 10(3), 407–425

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Review  Jean, Lee, Lam, Hsu, Chen & Hsueh Molecular class A carbapenemases The class A group of serine carbapenemases include not metalloenzyme carbapenemase (NMC)/imipenem-hydrolyzing β-lactamase (IMI), Serratia marcescens enzyme (SME), Klebsiella pneumoniae carbapenemase (KPC) and Guiana extended spectrum (GES) enzymes. ●●KPC

The blaKPC genes reside on transferable plasmids, thereby posing a formidable threat to infection control and survival of critically ill patients [3,17– 19] . The bla KPC-2 gene has been found to share high degrees of amino-acid sequence identity with blaKPC-3 [20] . Analysis of genetic sequences flanking blaKPC genes on plasmids of K. pneumoniae has revealed that transposase (tnpA), resolvase (tnpR) and two unrelated insertion sequences (IS; ISKpn6, ISKpn7; or a substitution of ISKpn8 for ISKpn7) are all invariable components on mobile transposons (a 10 kilobase, Tn3-based transposon, Tn4401) [3,21] . The facts that transposons are only located on a few different Inc groups of plasmid during the replicative process, and that there is limited diversity of transposon structure, corresponded well with few epidemic clones of KPC producers with distinct sequence types (STs; predominantly ST258 and ST11) being identified [1,21,22] . It is noteworthy that ST11 and ST258 are phylogenetically related [19] . The results of recent in vitro conjugation experiments showed that blaKPC-2 could be transferred with the assistance of flanking IS26 (in the form of composite transposon) and the transfer operon (locus tra-trb) in Escherichia coli but not in K. pneumoniae [23] . The cross-species transmission of the blaKPC-2 gene is, therefore, a worrisome reality. However, the other molecular investigation has also proven that the horizontal transfers of plasmid (IncFIA type) have also contributed to disseminations of the bla KPC genes between different Enterobacteriaceae spp. of diverse STs, as observed in NJ and NY, USA [24] . KPC enzymes possess highly conserved active-site motifs, including S-X-X-K, S-D-N and K-T-G in class A β-lactamases  [1] . These KPC enzymes, in contrast with other class-A β-lactamases, possibly have a catalytic serine in a more shallow position of the active-site cleft according to structural analysis [25] . This specific structure might allow carbapenem agents greater access to the catalytic site, thereby likely facilitating acylation and deacylation processes [25] .

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KPC enzymes are only weakly inhibited by clavulanate  [3] . However, studies showed that KPC-positive K. pneumoniae isolates coharbor plasmidic genes encoding for AmpC cephalosporinase (bla DHA and blaCMY ), extendedspectrum β-lactamase (ESBL ; mainly blaCTX-M) [26–28] and MβLs [26,29] . Furthermore, bla KPC -bearing plasmids likely also carry quinolone-resistant (qnrA, qnrB)  [30] , and aminoglycoside-modifying genetic determinants (ArmA and RmtB)  [31] . Unsurprisingly, KPCproducing GNB frequently exhibit multidrugresistant (MDR) phenotypes [17,20] , severely limiting antimicrobial options. In addition, studies have shown that KPC-K. pneumoniae isolates have impermeable outer membranes (deficiency of OmpK36, a porin of carbapenem entry), which further amplifies the resistance level to carbapenem agents [3,32] . The blaKPC genes have also been detected in Pseudomonas aeruginosa isolates obtained from patients in Colombia [33] and in Acinetobacter spp. obtained from patients in Puerto Rico [34] . KPC-producing K. pneumoniae causes a wide variety of infections including bacteremia, pneumonia and urinary tract infections [17] . The severity of those infections is highest in high-risk patient populations, such as patients with prolonged hospitalization courses, those who stay in intensive care units, and patients who receive immunosuppressive drugs or multiple antibiotic agents [3,17] . It is noteworthy that only a minority (4 mg/l have a higher mortality rate (60%) than those with infections due to VIM-1-producing K. pneumoniae that has an imipenem MIC ≤4 mg/l (14.3%) or those infected with non-blaVIM K. pneumoniae  [99] . They also noted that patients with rapidly fatal underlying diseases or higher degrees of clinical severity are more likely to die in the hospital setting [99,100] . ●●NDM

NDM enzymes were first detected in 2010 in patients transferred from the Indian subcontinent, an overcrowded region where antimicrobial usage is poorly regulated [11,48] . Accumulated evidence has pointed out that dissemination of the bla NDM traits is difficult to be predicted. For instance, it is noteworthy that the in vivo transfer of bla NDM-1 determinants was proven between different Enterobacteriaceae spp. (K. pneumoniae and E. coli) in the same patient, as described by Yong et al.  [101] . Furthermore, one survey exploring the genetic environments of bla NDM-1-carrying E. coli strains in China showed that the blaNDM-1 genes were flanked by some unique elements (IS3000, ISAba125, IS26 and a transposase gene), which suggests that a horizontal blaNDM-1 transfer potentially assisted by mobile transposons likely happened between E. coli and possibly environmental Acinetobacter spp. [102] . In addition, the other important investigation by Kumarasamy et al. revealed that the bla NDM-1 genes on Enterobacteriaceae spp. from the northern India were not conjugated, with these resistant isolates being of an identical clonality, which posed a significant contrast with the NDM-1 genes being readily transferable on clonally few diverse isolates (with plasmids of various sizes) collected from the southern part of India (as well as from the UK) [11] . The household contacts also likely facilitate to spread the bla NDM-1 alleles, as seen in an Australian child never traveling abroad [103] . In New Delhi, many other blaNDM-1-harboring bacteria were discovered from the drinkable tap water [48,104] , rendering them listed as potentially community-acquired pathogens. Consequently, the pattern about dissemination of NDM-1 genes is apparently complex, thereby posing an immense challenge on infection control [105] .

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Unlike blaVIM and blaIMP, the spread of blaNDM genes is not assisted by integrons [1,105] . The possible mechanisms governing plasmid-induced spread of the blaNDM traits include the reshuffling of blaNDM-bearing cassettes on various integrons of plasmids, and the en bloc mobilization of blaNDMassociated segments in a manner involving recombination or transposition, with probable assistance by some insertion elements, such as IS26, ISEc33 or ISSen4 [1,11,106–108] . Thus, the blaNDM-1 genes virtually move with a slow pace on plasmids [15,109,110] . Recently, bla NDM-1 genes, via spread of Tn125, have also been identified in clinical isolates of A. baumannii [111] . In striking contrast to blaVIM and blaIMP genes, blaNDM-1 genes were rarely detected in clinical isolates of P. aeruginosa [112] . Plasmids carrying blaNDM-1 genes also coharbor other resistance genes encoding for other carbapenemases such as class D oxacillinases (e.g., OXA48-like β-lactamases and VIM types), plasmidic AmpC cephalosporinase, ESBL enzymes (mostly CTX-M), qnrA6, qnrB1 and the genes responsible for resistance to macrolide (esterase), sulfamethoxazole, rifampicin and aminoglycoside [11,15,109] . Unsurprisingly, most bla NDM-1-bearing GNB exhibit an MDR profile. One in vitro study showed that aztreonam-avibactam (formerly known as NXL104) combination has promising potential against some Enterobacteriaceae species producing MβLs [113] . Nevertheless, the therapeutic regimens proven effective against NDM-producing organisms are unknown nowadays [11,114] . NDM-1 enteric GNB producers have been reported in most continents, except the Central and South America [15,115,116] . The number of reports on patients carrying the blaNDM-harboring Enterobacteriaceae spp. in Australia is increasing recently  [104,107,117,118] . Additionally, the United Arab Emirates (7% of in-hospital K. pneumoniae isolates having bla NDM-1) and Balkan countries have become the second reservoirs of bla NDM-1 unlinked to pandemics of the Indian subcontinent [87,97,119,120] . It is noteworthy that the patients infected or colonized with blaNDM-positive GNB without a definite link to the Indian epidemics have gradually increased in a few countries [121] . NDM-1-producing isolates of A. baumannii have also been identified worldwide, with the exception of countries in Central and South America  [111,122] . Thus, physicians should be also aware of a possible epidemic of infections caused by bla NDM-1-harboring A. baumannii. A scheme of important gene sequences that contain genetic traits encoding for important

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Review  Jean, Lee, Lam, Hsu, Chen & Hsueh carbapenemases (classes A, B and OXA-48) is illustrated in Figure 1.

horizontal gene transfer. Nevertheless, they were not reported elsewhere.

●●SPM, GIM & SIM

Molecular class D carbapenemases: the OXA β-lactamases Clinical isolates of carbapenem-resistant A. baumannii (CRAB; mostly with MDR phenotype) that harbor acquired genes encoding for various class D carbapenemases have resulted in numerous nosocomial outbreaks with high (>30%) mortality rates in hospitalized patients [129] and in septicemia in injured US military personnel who served in Iraq and Afghanistan from 2003 through 2005 [130] . The OXA β-lactamases, functionally defined as penicillinases capable of hydrolyzing cloxacillin and oxacillin [131] , were initially identified in the late 1970s. Despite considerable

SPM-1 was first identified from clinical P. aeruginosa isolates in Sao Paolo, Brazil in 2004 [123] . Genetic analysis of blaSPM-1 revealed that these genes were not part of the integron but were on transposons (comprising recombinase and promoter, among others). Therefore, blaSPM-1 also has the potential to cause nosocomial outbreaks [123,124] . In contrast, the GIM-1 enzyme was found on nontransferable plasmids of P. aeruginosa in Germany in 2002 [125] , and has more recently been found in Enterobacteriaceae spp. [126,127] . The blaSIM-1 genes were discovered on class 1 integrons of A. baumannii in Korea [128] , indicating the potential for

KPC (I)

IRL tnpR

tnpA

ISKpn7 blaKPC-2

ISKpn6

IRR

(Tn4401) orf5

VIM (II) IS26

int1 blaVIM-1 aacA7 dfrA1 aadA1 gacE sul1

IS5075

Tn1696

IS26

Tn1721

Tn2

(III)

IMP (IV)

IS26

int1

int1

blaIMP-8

blaVIM-1 aacA7 dfrA1aadA1

aacA4

smr

ISpa21

TniC

NDM (V) ISAba125 blaNDM-1

bleMBL

IS26

Tn3

(VI) OXA-48

ISEc33 ISAba125 blaVIM-1 bleMBL ISSen4 Tn1999

(VII) IS1999

blaOXA-48

IS1999

(VIII) IS4321

Tn3 blaOXA-163

IS4-like

Figure 1. Schematic illustration of sequences of important genetic components and their orientations from plasmids of various Enterobacteriaceae spp., which show the association of important carbapenemase (Ambler class A and B)-encoding genes with various mobile elements. (i) The blaKPC-2-containing Tn4401 transposon, from plasmid pNYC (GenBank accession no. EU176011). (ii & iii) Representative blaVIM-containing sequences from plasmid pNL194 (GenBank accession number: HQ651093) and pCC416 (GenBank accession number: AJ704863), respectively. (iv) The blaIMP-containing sequence from plasmid pFP10-2 (GenBank accession number: 651093). (v & vi) The blaNDM-1-containing sequences, carried by a plasmid from K. pneumoniae 05-506 (GenBank accession number: FN396876) and plasmid p271A (GenBank accession number: HQ162469). (vii & viii) The OXA-48-encoding transposon Tn1999 from plasmid pA-1 (GenBank accession number: 236073) and blaOXA-163-containing segment from plasmid p6299 (GenBank accession number: HQ700343), respectively. The two kinds of star symbol within sequences highlight locations of the genes that encode for carbapenemase enzymes. The underlined genetic components represent the ones with deletion of partial genes, and the black-filled rectangles denote genes of unknown function.  Adapted with permission from [122].

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Carbapenemase-producing Gram-negative bacteria  variability in amino-acid sequences [1] , they are characteristically not inhibited by clavulanate or EDTA. The first OXA β-lactamase that could hydrolyze carbapenem was identified on a large plasmid of MDR-A. baumannii in Scotland in 1985 [132] . It was categorized as OXA-23 enzyme of Ambler class D after gene sequencing [133] . Since then, OXA carbapenemases have been found in a number of clinical isolates of A. baumannii that display resistance to imipenem [134–137] . Of note, Héritier et al. found that after transformation of plasmids carrying blaOXA-23, blaOXA-40, or blaOXA-58 genes into imipenem-susceptible A. baumannii recipient strains, the OXA-23 and OXA-40 enzymes in A. baumannii would render originally susceptible isolates intermediate resistance to imipenem  [138] . Although efflux pumps [138] , porin deficiency  [139] and hyperproduction of AmpC cephalosporinase  [140] contribute to high-level resistance of A. baumannii to carbapenem agents, class D β-lactamases are still considered the most important cause of nonsusceptibility to carbapenems. It is also noteworthy that K. pneumoniae isolates harboring plasmidic blaOXA-48 genes have been detected [141] . The catalytic mechanism of some OX A enzymes shares similar features to class A serine carbapenemases, although the hydrolytic efficiency against carbapenems is weaker for the former [1] . Amino-acid sequence analysis of both class A and D enzymes has revealed that the catalytic serine residue lies in the S-T-F-K tetrad at positions 70 to 73, where serine and lysine residues are well conserved [142] . Although variability of sequences on the Y-G-N motif (positions 144 to 146) and the K-T-G triad motif (positions 216 to 218) was found between different variants of the OXA enzyme in class D β-lactamases [1,143] , variants of OXA-23, -24, -25, -26 and -27 shared the S-T-F-K tetrad and S-X-V triad motifs. Furthermore, based upon the analysis of crystal structure of OXA enzymes, β-lactam drugs are hydrolyzed through the process of formation of a covalent acyl intermediate (carbamate) between a β-lactam substrate and the OXA enzyme, with subsequent deacylation [144] . ●●OXA-23-like, OXA-24-like & OXA-58

According to amino-acid sequence analyses, the OXA-27 and OXA-49 enzyme variants share high amino-acid identities with that of OXA-23, thus all of them were classified as the blaOX Agenes. In contrast to the second group of 23-like

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acquired class D β-lactamases, in other words, OXA-58-like enzymes (comprising OXA-58 and OXA-96) [145] , a third group of acquired class D oxacillinases, consisting of OXA-24/40, OXA-25, OXA-26 and OXA-72 because of similar amino-acid arrangements, was identified in A. baumannii isolates with a carbapenemresistant phenotype. They were categorized as blaOXA-24-like genes after sequencing [143,146] . Compared with the blaOXA-51-like genes located on the chromosomal genome [147] , the blaOXA-23 genes are usually located on plasmids and have high transferable potential when combined with transposon Tn2006, Tn2007 or Tn2008  [5,6] . The blaOXA-23 genes are flanked by two copies of insertion sequences, in other words, ISAba1 (one member of the IS4 family) in opposite directions on transmissible transposon Tn2006 and Tn2008 [6,7] . By contrast, the transposon Tn2007 lacks the second copy of ISAba1, and instead its blaOXA-23 genes are associated with one copy of ISAba4 (belonging to the IS982 family) [6] . These transposons confer A. baumannii medium-tohigh resistance against antipseudomonal carbapenem agents (MIC ≥16 mg/l) and ceftazidime [12] . Acquisition of these composite and highly transmissible transposons by clinical A. baumannii isolates, which subsequently reside on their chromosomal or plasmidic genome, might theoretically result in a resistance epidemic if appropriate measures of infection control are not taken [5,7,12,14] . As seen in the blaOXA-23 genes, many acquired insertion sequences (ISAba1, ISAba2, ISAba3like element, IS1008 and IS18) have been shown to provide a promoter involved in the overexpression of plasmidic blaOXA-58 genes in A. baumannii and A. nosocomialis  [148,149] . However, Poirel et al. hypothesized that high-level carbapenem resistance happens after a series of step-bystep recombination events rather than simply the acquisition of an integron or transposon [148] . In addition, the results of an in vitro electrotransformation experiment of oxacillinase genes in A. baumannii isolates revealed that OXA-23 has higher imipenem hydrolytic capacity than OXA58  [138] . In contrast to blaOX A-23 and blaOX A-58 genes which can be on either plasmid or chromosome, blaOXA-24-like genes are mainly located on chromosomes and no mobile elements have been identified [150] . Polyclonal dissemination of CRAB isolates harboring the blaOXA-23 genes has been reported in Brazil [134] , China [13] , South Korea [151] , French Polynesia [5] , Bulgaria [152] , Algeria [153] ,

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Review  Jean, Lee, Lam, Hsu, Chen & Hsueh the Kingdom of Saudi Arabia [119] , central Taiwan  [154] and the United Kingdom [135] . During the last decade, the SENTRY program investigated the spread of oxacillinase genes among species of Acinetobacter collected from Asia-Pacific nations. That surveillance study revealed that the blaOXA-23 genes were common in Acinetobacter spp. (>90% of which were A. baumannii, and >40% of which were nonsusceptible to imipenem or meropenem) in China and in other countries [13] . In addition, 41% of blaOX A-23 -bearing Acinetobacter isolates coharbored the blaOXA-58 genes [13] . These findings were consistent with those reported by Mugnier et al., who found that a dynamic worldwide spread of the blaOX A-23 genes on plasmids of polyclonal A. baumannii strains occurred in 2010 [12] . In contrast, the blaOXA-58-like genes, which are far more prevalent than the blaOXA-23-like genes in A. baumannii isolates in many European countries [155] , has also been detected on Acinetobacter spp. in Argentina and Kuwait [156,157] . In addition, OXA-24 enzyme variants in A. baumannii have been identified in outbreaks in Spain, Portugal, Belgium and the USA [136,146,155,158] . ●●OXA-48

The OXA-48 enzyme, along with OXA-54, OXA-181, were identified in Shewanella oneidensis (a natural carrier of the progenitor blaOXA-48-like genes)  [159] , as well as K. pneumoniae  [141] and other enterobacteria [8,159] . In contrast to KPC, the hydrolysis of carbapenems for OXA-48 carbapenemase needs the rotation of carbapenem’s α-hydroxyethyl group within the active site [122] , which plausibly explains its weaker hydrolytic capacity against imipenem than that of KPC. It is noteworthy that the blaOXA-48-like traits are carried by transferable transposon Tn1999 (or Tn1999.2) on plasmids, which confers mediumto-high spread potential [1,8] . In fact, the in vitro hydrolytic efficiency of OXA-48 itself against imipenem is approximately tenfold higher than that of other oxacillinases in Acinetobacter spp.  [160] . In addition, enteric GNB with the blaOXA-48-like genes could coharbor genes encoding for ESBL (blaCTX-M, blaSHV, blaTEM) or AmpC enzymes, or both [8,161] , thereby conferring nonsusceptibility to aztreonam, extended-spectrum cephalosporins and carbapenem agents. Because of their specific location on plasmids, the worldwide spread of blaOX A-48-like genetic determinants is not surprising. Isolates of blaOXA-bearing K. pneumoniae were initially identified 48

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in Turkey [141] , subsequently in a number of countries of the Middle East [8] , North Africa [162] and Western Europe (UK, Belgium, France, Germany, Netherlands)  [48,85] . India [163] , Senegal [161] , Spain  [48,164] and Argentina [165] have also identified the OXA-48-producing Enterobacteriaceae species other than K. pneumoniae. Although the KPC-2, NDM-1 and VIM-2 carbapenemases dominated in Greece, an outbreak due to the blaOXA-48-harboring K. pneumoniae isolates of ST11 clone was also reported in 2012 [166] . Thus, a global dissemination of blaOXA-48-carrying GNB has emerged. The sites of worldwide distribution regarding high regional prevalences of GNB harboring various kinds of important carbapenemases are illustrated in Figure 2. Antimicrobial treatment of infections due to carbapenemase-producing organisms Experience using antimicrobial therapy against infections caused by carbapenemase-producing GNB is limited. ●●Enterobacteriaceae

Against the KPC-producing K. pneumoniae isolates with doripenem MIC ≤16 mg/l, Wiskirchen  et al.  [167] demonstrated that the dual-carbapenem regimen (standard-dose ertapenem as the high-affinity substrate of KPC [168] , followed by doripenem 2 g every 8 h with 4‐h infusion intravenously) would significantly reduce the bacterial density (but not to a bactericidal level, as compared with control or respective monotherapy groups) in the murine thigh in vivo model. However, its clinical efficacy on humans needs to be investigated. By contrast, colistin and tigecycline used to be considered the drugs of choice for treating infections due to carbapenemase-producing GNB, and especially for GNB of KPC and MβL producers [50,169] . Unfortunately, extensive usage and the spread of resistant clones have resulted in a considerable drop of the in vitro susceptibilities to these two antimicrobial agents [170,171] . Resistance to colistin is notably more frequent among carbapenem-resistant K. pneumoniae than in MDRP. aeruginosa and MDR-A. baumannii  [172] . To maximize the clinical effectiveness of colistin against impending resistant GNB (colistin MIC, 2 mg/l), studies have shown that the loading and maintenance doses should be increased [173] . In addition, tigecycline is merely a bacteriostatic agent with suboptimal concentrations in the bloodstream (23%) [122] . Finally, the other recent large-scale survey [185] retrospectively investigated the impact of different antimicrobial regimens on clinical outcome regarding the bloodstream infections caused by carbapenemase-producing K. pneumoniae isolates collected from 205 patients (79.5% due to KPC, or KPC plus VIM variants) in great details. In this survey, the MIC

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breakpoints recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2013 (of which the MIC judgment criteria categorized as resistant for imipenem, meropenem and doripenem being >8, >8, >4 mg/l, respectively) were applied for determining the nonsusceptibilities [186] . Independence of the declining stages of sepsis and underlying comorbidities, they also observed that combination therapy is significantly superior to monotherapy on 28‐day mortality rate (27.2 vs 44.4%, p = 0.018), particularly for the regimen consisting of a carbapenem with the MIC ≤8 mg/l and the other in vitro active agent (achieving the lowest case-fatality rate, 19.3%). This carbapenem MIC limit (8 mg/l) verified to confer benefits on survival is similar to the pharmacodynamic (PD) features of carbapenems [187,188] , and is exactly the same as the MIC breakpoints of EUCAST 2013 [186] . Of note, in the sub-analysis regarding the impact of in vitro activity of drug(s) employed in conjunction with carbapenem(s) on clinical outcome, the therapeutic benefit provided by carbapenem agent was prominently compromised once carbapenem was combined with inactive drug(s)  [185] . The advantage of carbapenemcontaining combination regimens on decreasing case-fatality rates (18.8%, as compared with 30.7% for carbapenem-sparing schemes) of sepsis caused by the carbapenemase (primarily KPC and VIM)-producing Enterobacteriaceae is also seen in one latest systematic review by Tzouvelekis et al.  [114] . In addition to receipt of inadequate antimicrobial therapy initially [184] , the independent predictors of mortality about the infections due to carbapenemase-producing enterobacteria also included: high clinical severity (including septic shock) [184,185] , and presence of any underlying comorbidity [185] . Studies have shown that avibactam, a bridged diazabicyclo octanone, exhibits good activity against GNB with serine β-lactamases (especially KPC producers) when combined with ceftazidime, but is inactive against class B β-lactamases [122,189,190] . Evidence derived from murine models also reveals that a ceftazidimeavibactam regimen is effective against infection due to KPC producers [191] . The other β-lactamase inhibitor, MK-7655, in vitro potentiates imipenem against Enterobacteriaceae spp. with KPC production plus membrane impermeability  [192] . Hence, it is also a future promising drug effective against enteric GNB which produce class A carbapenemases.

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Carbapenemase-producing Gram-negative bacteria 

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Table 1. Summary of transmission medium (regarding assistance by transposon, or integron or none) and dissemination mode (significant polyclonality versus limited diverse clones) of various kinds of important carbapenemases. Transmission medium, dissemination mode 

Mobile transposon assistance  

No proven mobile transposon association

Significant polyclonality   Possible limited diverse clones  

OXA-23-like (Tn2006, Tn2007, Tn2008) VIM OXA-48 (Tn1999, 1999.2)    KPC, limited in K. pneumoniae (Tn4401, or variants in other species) IMP

OXA-58-like   NDM traits

NDM-1 

OXA-24-like

With integron

 

Without identified integron

The spread of resistance genes assisted by transfer of plasmids is also seen in the blaKPC-harboring [24] Enterobacteriaceae species, and assisted by an identically clonal expansion for the blaNDM-carrying enteric GNB isolates [11]. IMP: Imipenemase; KPC: Klebsiella pneumoniae carbapenemase; NDM: New Delhi metallo-β-lactamase; VIM: Verone integron-encoded metallo-β-lactamase. ●●Acinetobacter spp.

Nosocomial A. baumannii isolates have many intrinsic resistance mechanisms [150] . Clinically, monotherapy used for treating a susceptible A. baumannii isolate has great potential to select the emergence of resistant strains during therapy. Only few clinical studies confirmed that combination therapy prominently improves survival of patients with CRAB bacteremia (treated by antipseudomonal carbapenem plus sulbactam or aminoglycoside), serious respiratory tract infections due to extensively drug-resistant (XDR) A. baumannii (treated mainly by doripenem plus colistin) [193,194] , while one recent survey revealed that patients with XDR A. baumannii infection only got the benefit of microbiological eradication when treated with rifampicin plus colistin as compared with colistin monotherapy  [195] . Additionally, high-dose sulbactam plus infusion of meropenem at maximal dosage (2 g every 8 h) for an extended duration (≥3 h) was reported as effective treatment for ventilator-associated pneumonia due to XDR- and CRAB by a PD assessment, if the meropenem MIC were ≤8 mg/l [187] . An in vitro combination of dual antibiotics (involving rifampicin, levofloxacin, azithromycin, doxycycline, amikacin, sulbactam, imipenem, meropenem, tigecycline and colistin) was investigated using a checkerboard titration method and the result showed that there was no evidence for antagonism [196] .

international transport of patients with infections due to GNB that harbor resistance determinants have fueled the unstoppable rise of antimicrobial resistance. The threat of pandrug resistance has considerably lowered the appropriateness of empirical antibiotic therapy recommended by infectious disease experts. In addition to reinforcement of infection control measures [52] , the development of new antibiotics is warranted to combat against these troublesome GNB in the future. Future perspective The spread routes of the resistance genetic traits encoding for carbapenemases, especially for KPC, VIM, NDM and some OXA variants, are complex and difficult to be completely prevented. Therefore, reinforcement of infection control tasks, along with in-time initiation of diagnostic works regarding early detection of the carbapenemase-producing GNB in healthcare settings, are of utmost importance. Once infections due to carbapenemase (KPC and VIM)-producing GNB isolates are encountered, we recommend combination schemes, particularly carbapenem (when the MIC ≤16 mg/l)containing regimens, as the most preferred therapeutic regimens. Although controversy exists, combination regimens are also favored to effectively treat the infections caused by XDR-A. baumannii isolates. Financial & competing interests disclosure

Conclusion The transmission media and dissemination modes of various kinds of important carbapenemases in GNB are summarized in Table 1. As the aging population and recipients of organ transplantation or chemotherapy increase gradually, these immunosuppressed hosts have made carbapenemase-producing GNB evolving into common communityacquired bacteria [48] . Moreover, interhospital and

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Review  Jean, Lee, Lam, Hsu, Chen & Hsueh EXECUTIVE SUMMARY Klebsiella pneumoniae carbapenemase ●●

Transmission via transposons, or plasmids that harbor the blaKPC traits.

●●

Primarily reported in worldwide Enterobacteriaceae spp., except Australia, and the countries in Africa and South America.

●●

Usually pandrug-resistant (PDR) phenotype. Carbapenem-containing regimens are preferred for treatment of the

Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae species if the carbapenem MIC value is ≤16 mg/l. Otherwise, other alternatives could also be considered. Verona integron-encoded metallo-β-lactamase ●●

Transmission via integrons between Enterobacteriaceae spp., but the transmission between Pseudomonas spp. remains unknown.

●●

Less frequently reported in Australia and China.

●●

Sometimes PDR phenotype. Therapeutic recommendation is similar to that of the Klebsiella pneumoniae

carbapenemase. The bloodstream infection due to blaVIM-1-carrying, imipenem MIC >4 mg/l K. pneumoniae isolates predicts a high case-fatality rate. New Delhi metallo-β-lactamase ●●

Transmission media and spread modes are more complex than above two.

●●

Reported in worldwide countries except those in Central and South America.

●●

Usually PDR phenotype. The treatment recommendation is lacking till now.

OXA-48-like carbapenemase ●●

Transmission primarily via transposons.

●●

Reported in Turkey, Argentina, a few countries in the Western Europe, and especially in the Middle East, South Europe and North Africa (surrounding the Mediterranean Sea).

●●

Sometimes PDR phenotype. The therapy recommendation still lacks now.

OXA-23 & OXA-58-like carbapenemases ●●

Transmission via transposons with specific insertion sequences.

●●

Reported primarily in the countries of Asia-Pacific region, Europe, South America (Brazil) and North Africa.

●●

Usually PDR phenotype. Combination regimens are favored, although they were only supported by in vitro synergy tests predominantly.

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Review

92 Livermore DM. Multiple mechanisms of

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94 Tsakris A, Pournaras S, Woodford N et al.

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95 Jones RN, Deshpande LM, Bell JM et al.

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103 Blyth CC, Pereira L, Goire N. New Delhi

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96 Toleman MA, Biedenbach D, Bennett D,

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104 Walsh TR, Weeks J, Livermore DM, Toleman

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Paterson DL. β-Lactamase production in key gram-negative pathogen isolates from the Arabian Peninsula. Clin. Microbiol. Rev. 26(3), 361–380 (2013). •

A review focusing on the prevalences of ESBL and carbapenemases among clinical GNB isolates in the Arabian countries.

99 Daikos GL, Karabinis A, Paramythiotou E

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A prospective survey revealing the clinical impact of blaVIM-1-harboring BSI K. pneumoniae isolates with carbapenem MICs >4 mg/l, on case fatality.

101 Yong D, Toleman MA, Giske CG et al.

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Discusses all cases infected with NDMcarrying Enterobacteriaceae spp. in Australia till now.



Briefly addresses the complex transmission routes of NDM genes carried on Enterobacteriaceae spp.

106 Ho PL, Lo WU, Yeung MK et al. Complete

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112 Jovcic B, Lepsanovic Z, Suljagic V et al.

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Carbapenemase-producing Gram-negative bacteria  •• Detailed review comprising a wealth of data about worldwide epidemiology, antimicrobial nonsusceptibilities, detection methods and comparison of outcome on various therapies against carbapenemase-producing Enterobacteriaceae spp.

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133 Donald HM, Scaife W, Amyes SG, Young

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124 Zavascki AP, Gaspareto PB, Martins AF,

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135 Turton JF, Kaufmann ME, Glover J et al.

126 Rieber H, Frontzek A, Pfeifer Y. Emergence of

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127 Hamprecht A, Poirel L, Göttig S, Seifert H,

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137 Ku WW, Kung CH, Lee CH et al. Evolution

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129 Huang ST, Chiang MC, Kuo SC et al. Risk

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Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center. Antimicrob. Agents Chemother. 50(12), 4114–4123 (2006).

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Proves that A. baumannii isolates harboring OXA-23, OXA-40 would exhibit greater carbapenem nonsusceptibility than those with OXA-58.

139 Bou G, Cerveró G, Domínguez MA, Quereda

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Review

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153 Mesli E, Berrazeg M, Drissi M, Bekkhoucha

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172 Samonis G, Matthaiou DK, Kofteridis D,

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162 Cuzon G, Naas T, Lesenne A, Benhamou M,

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173 Garonzik SM, Li J, Thamlikitkul V et al.

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163 Castanheira M, Deshpande LM, Mathai D,

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152 Stoeva T, Higgins PG, Bojkova K, Seifert H.

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161 Moquet O, Bouchiat C, Kinana A et al. Class

151 Jeon BC, Jeong SH, Bae IK et al.

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171 Spanu T, De Angelis G, Cipriani M et al.

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164 Oteo J, Saez D, Bautista V et al.

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165 Poirel L, Castanheira M, Carrër A et al.

OXA-163, an OXA-48-related class D β-lactamase with extended activity toward expanded-spectrum cephalosporins. Antimicrob. Agents Chemother. 55(6), 2546–2551 (2011). 166 Voulgari E, Zarkotou O, Ranellou K et al.

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•• Designs a formula to accurately calculate the appropriate colistin dose in accordance with population pharmacokinetics and creatinine clearance data. 174 Yahav D, Lador A, Paul M, Leibovici L.

Efficacy and safety of tigecycline: a systematic review and meta-analysis. J. Antimicrob. Chemother. 66(9), 1963–1971 (2011). •

A meta-analysis regarding the tigecycline’s clinical efficacy, and adverse effects documented in PubMed data.

175 Falagas ME, Lourida P, Poulikakos P,

Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenemresistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob. Agents Chemother. 58(2), 654–663 (2014). 176 Endimiani A, Patel G, Hujer KM et al.

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Carbapenemase-producing Gram-negative bacteria  polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection. J. Clin. Microbiol. 47(5), 1611–1612 (2009).

Klebsiella pneumoniae carbapenemase ± Verone integron-encoded metallo-β-lactamase infections in great details.

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•• An investigation issuing the impact of clinical characteristics, as well as therapeutic regimens on clinical outcomes of patients with the

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An important international reference about MIC breakpoints. antimicrobial treatment of nosocomial pneumonia caused by multidrug-resistant pathogens. Expert. Opin. Pharmacother. 12(14), 2145–2148 (2011).



192 Livermore DM, Warner M, Mushtaq S.

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Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J. Clin. Pharmacol. 43(10), 1116–1123 (2003). •

193 Lee NY, Lee JC, Li MC, Li CW, Ko WC.

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Review suggesting appropriate regimens against difficult pathogens, including extensively drug-resistant A. baumannii.

188 Kuti JL, Dandekar PK, Nightingale CH,

PD study recommending the upper threshold of meropenem MIC level which is predicted to exert synergistic effect with high-dose sulbactam on therapy against the resistant GNB.

194 Shields RK, Clancy CJ, Gillis LM et al.

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189 Bonnefoy A, Dupuis-Hamelin C, Steier V

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185 Daikos GL, Tsaousi S, Tzouvelekis LS et al.

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ME, Weiss WJ, Bonomo RA. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob. Agents Chemother. 55(1), 82–85 (2011).

187 Jean SS, Hsueh PR. Current review of

184 Tumbarello M, Viale P, Viscoli C et al.

Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin. Infect. Dis. 55(7), 943–950 (2012).

191 Endimiani A, Hujer KM, Hujer AM, Pulse

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183 Lee GC, Burgess DS. Treatment of Klebsiella

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in the treatment of Gram-negative bacterial infections. Core Evid. 9, 13–25 (2014).

186 European Committee on Antimicrobial

180 Qureshi ZA, Paterson DL, Potoski BA et al.



Issues the promising potential of avibactam against Ambler class A, and class C β-lactamase-producing enteric Gram-negative bacteria when it is combined with ceftazidime with a fixed ration of 1:4.

190 Lagacé-Wiens P, Walkty A, Karlowsky JA.

Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use

Review



Demonstrates that colistin plus rifampicin is not superior to colistin monotherapy on XDR-A. baumannii infections in terms of decreasing mortality rates.

196 Entenza JM, Moreillon P. Tigecycline in

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