<i>Enterobacteriaceae</i>
            Bloodstream Infections: Presence of Integrons, Risk Factors, and Outcome

Daikos, George L.; Kosmidis, Chris; Tassios, Panayotis T.; Petrikkos, George; Vasilakopoulou, Alexandra; Psychogiou, Mina; Stefanou, Ioanna; Avlami, A.; Katsilambros, Nikolaos

doi:10.1128/aac.00044-07

Cited by 46 publications

(27 citation statements)

References 29 publications

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“…However, the effects of inappropriate empirical therapy on patient outcomes were often evaluated in cohorts combining ESBL and non-ESBL bacteremias. The results of these studies were similarly conflicting (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 49%

Appropriateness of Empirical Treatment and Outcome in Bacteremia Caused by Extended-Spectrum-β-Lactamase-Producing Bacteria

Frakking

Rottier

Dorigo-Zetsma

et al. 2013

Antimicrob Agents Chemother

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We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-␤-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of >3, an age of >75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received ␤-lactam-␤-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality. E xtended-spectrum ␤-lactamases (ESBLs) are enzymes that can hydrolyze penicillins, aztreonam, and cephalosporins. Therefore, ESBL-producing Enterobacteriaceae were considered to be resistant to all ␤-lactam antibiotics except carbapenems. Recently, it has been suggested that cephalosporins (1, 2) and ␤-lactam-␤-lactamase inhibitor combinations (BLBLICs) (3, 4) may still be used to treat infections with ESBL-positive isolates if MICs are below clinical breakpoints. Worldwide, numbers of infections caused by ESBL-producing Enterobacteriaceae are increasing in both the hospital and community settings. It is generally assumed that infections with ESBL-producing pathogens have a worse outcome than their non-ESBL-producing counterparts (5, 6).In the Netherlands, antibiotic resistance levels are low (7), presumably due to the restrictive use of antibiotics (8) and the national infection control policy, including active surveillance and isolation of admitted ESBL carriers (9). However, the proportion of Escherichia coli strains resistant or inter...

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Section: Discussionmentioning

confidence: 49%

Appropriateness of Empirical Treatment and Outcome in Bacteremia Caused by Extended-Spectrum-β-Lactamase-Producing Bacteria

Frakking

Rottier

Dorigo-Zetsma

et al. 2013

Antimicrob Agents Chemother

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“…Ribotyping was performed after HincII (New England Biolabs) digestion of genomic DNA, as described by Pignato et al (30). For PFGE, total P. mirabilis DNA in agarose plugs was prepared as described previously (8), digested with NotI and SfiI (New England Biolabs), and electrophoresed using a CHEF III Bio-Rad apparatus (Hercules, CA). All electrophoretic patterns were analyzed using GelCompar v4.1 (Applied Maths NV, Sint-Martens-Latem, Belgium), using the Dice coefficient and clustering by UPGMA (unweighted pairgroup method with arithmetic averages), with 1% tolerance in band position differences.…”

Section: Methodsmentioning

confidence: 99%

Evolution and Spread of a Multidrug-Resistant Proteus mirabilis Clone with Chromosomal AmpC-Type Cephalosporinases in Europe

D’Andrea

Literacka

Zioga

et al. 2011

Antimicrob Agents Chemother

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Proteus mirabilis isolates obtained in 1999 to 2008 from three European countries were analyzed; all carried chromosomal AmpC-type cephalosporinase bla CMY genes from a Citrobacter freundii origin (bla CMY-2 -like genes). Isolates from Poland harbored several bla CMY genes (bla CMY-4 , bla CMY-12 , bla CMY-14 , bla CMY-15 , and bla CMY-38 and the new gene bla CMY-45 ), while isolates from Italy and Greece harbored bla CMY-16 only. Earlier isolates with bla CMY-4 or bla CMY-12 , recovered in France from Greek and Algerian patients, were also studied. All isolates showed striking similarities. Their bla CMY genes resided within ISEcp1 transposition modules, named Tn6093, characterized by a 110-bp distance between ISEcp1 and bla CMY , and identical fragments of both C. freundii DNA and a ColE1-type plasmid backbone. Moreover, these modules were inserted into the same chromosomal site, within the pepQ gene. Since ColE1 plasmids carrying ISEcp1 with similar C. freundii DNA fragments (Tn6114) had been identified earlier, it is likely that a similar molecule had mediated at some stage this DNA transfer between C. freundii and P. mirabilis. In addition, isolates with bla CMY-12 , bla CMY-15 , and bla CMY-38 genes harbored a second bla CMY copy within a shorter ISEcp1 module (Tn6113), always inserted downstream of the ppiD gene. Sequence analysis of all mobile bla CMY-2 -like genes indicated that those integrated in the P. mirabilis chromosome form a distinct cluster that may have evolved by the stepwise accumulation of mutations. All of these observations, coupled to strain typing data, suggest that the bla CMY genes studied here may have originated from a single ISEcp1-mediated mobilization-transfer-integration process, followed by the spread and evolution of a P. mirabilis clone over time and a large geographic area.

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“…More than 130 gene cassettes, encoding resistance to nearly all antibiotic families, have been described (3). Several classes of integron have been described on the basis of the amino acid sequence of the IntI integrase (4), class 1 being the most frequently described for multidrug-resistant Gram-negative bacteria (5)(6)(7).…”

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confidence: 99%

Diversity of Class 1 Integron Gene Cassette Rearrangements Selected under Antibiotic Pressure

Barraud

Ploy

2015

J. Bacteriol.

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Integrons are bacterial genetic elements able to capture and express genes contained within mobile gene cassettes. Gene cassettes are expressed via a Pc promoter and can be excised from or integrated into the integron by integrase IntI. Although the mechanisms of gene cassette integration and excision are well known, the kinetics and modes of gene cassette shuffling leading to new gene cassette arrays remain puzzling. It has been proposed that under antibiotic selective pressure, IntI-mediated rearrangements can generate integron variants in which a weakly expressed gene cassette moves closer to Pc, thus leading to higher-level resistance. To test this hypothesis, we used an integron with four gene cassettes, intI1-aac(6=)-Ib-dfrA15-aadA1-catB9, and applied selective pressure with chloramphenicol, resistance to which is encoded by catB9. Experiments were performed with three different Pc variants corresponding to three IntI1 variants. All three integrases, even when not overexpressed, were able to bring catB9 closer to Pc via excision of the dfrA15 and aadA1 gene cassettes, allowing their host bacteria to adapt to antibiotic pressure and to grow at high chloramphenicol concentrations. Integrase IntI1 R32_H39 , reported to have the highest recombination activity, was able, when overexpressed, to trigger multiple gene cassette rearrangements. Although we observed a wide variety of rearrangements with catB9 moving closer to Pc and leading to higher chloramphenicol resistance, "cut-and-paste" relocalization of catB9 to the first position was not detected. Our results suggest that gene cassette rearrangements via excision are probably less cost-effective than excision and integration of a distal gene cassette closer to Pc. IMPORTANCEIntegrons are bacterial genetic elements able to capture and express gene cassettes. Gene cassettes are expressed via a Pc promoter; the closer they are to Pc, the more strongly they are expressed. Gene cassettes can be excised from or integrated into the integron by integrase IntI. The kinetics and modes of gene cassette shuffling, leading to new gene cassette arrays remain puzzling. We used an integron with 4 antibiotic resistance gene cassettes and applied selective pressure with the antibiotic for which resistance was encoded by cassette 4. All IntI variants were able to bring cassette 4 closer to Pc. Rearrangements occur via excision of the previous gene cassettes instead of cut-and-paste relocalization of the fourth gene cassette. Integrons are bacterial genetic elements able to capture and express genes contained within mobile gene cassettes (1). Integrons are composed of three key elements: (i) an intI gene encoding an integrase that mediates gene cassette integration and excision through site-specific RecA-independent recombination, (ii) recombination site attI, and (iii) a promoter, Pc (2). Integrons containing antibiotic resistance gene cassettes are located on transposons or plasmids and are widely involved in the spread of antibiotic resistance among Gram-negative bac...

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Enterobacteriaceae Bloodstream Infections: Presence of Integrons, Risk Factors, and Outcome

Cited by 46 publications

References 29 publications

Appropriateness of Empirical Treatment and Outcome in Bacteremia Caused by Extended-Spectrum-β-Lactamase-Producing Bacteria

Appropriateness of Empirical Treatment and Outcome in Bacteremia Caused by Extended-Spectrum-β-Lactamase-Producing Bacteria

Evolution and Spread of a Multidrug-Resistant Proteus mirabilis Clone with Chromosomal AmpC-Type Cephalosporinases in Europe

Diversity of Class 1 Integron Gene Cassette Rearrangements Selected under Antibiotic Pressure

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