scholarly journals Clonally Related Neisseria gonorrhoeae Isolates with Decreased Susceptibility to the Extended-Spectrum Cephalosporin Cefotaxime in Amsterdam, the Netherlands

2012 ◽  
Vol 56 (3) ◽  
pp. 1516-1522 ◽  
Author(s):  
Raymond Heymans ◽  
Sylvia M. Bruisten ◽  
Daniel Golparian ◽  
Magnus Unemo ◽  
Henry J. C. de Vries ◽  
...  
Keyword(s):  
The Netherlands ◽  
Neisseria Gonorrhoeae ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
New Drugs ◽  
Control Group ◽  
Content Type ◽  
High Risk Sexual Behavior ◽  
Extended Spectrum ◽  
Group A

ABSTRACTFrom 2006 to 2008,Neisseria gonorrhoeaeisolates were identified with decreased susceptibility to the extended-spectrum cephalosporin (ESC) cefotaxime among visitors of the Amsterdam sexually transmitted infections (STI) clinic, the Netherlands. Spread, clonality, and characteristics of 202 isolates were examined using antibiograms, conventionalpenAmosaic gene PCR, andN. gonorrhoeaemultiple-locus variable-number tandem repeat analysis (NG-MLVA). A strictly defined subset was further characterized byN. gonorrhoeaemultiantigen sequence typing (NG-MAST) and sequencing of ESC resistance determinants (penA,mtrR, andporB1b). Seventy-fourN. gonorrhoeaeisolates with a cefotaxime MIC of >0.125 μg/ml (group A), 54 with a cefotaxime MIC of 0.125 μg/ml (group B), and a control group of 74 with a cefotaxime MIC of <0.125 μg/ml (group C) were included. Fifty-three clonally relatedpenAmosaic-positive isolates (penicillin-binding protein 2 type XXXIV) were identified in group A (n= 47 isolates; 64%) and B (n= 6 isolates; 11%). The 53penAmosaic-positive isolates were predominantly NG-MAST ST1407 (87%) and contained anmtrRpromoter A deletion (98%) andporB1balterations G101K/A102N. All were assigned to the same NG-MLVA cluster that comprised in total 56 isolates. A correlation was found between decreased cefotaxime susceptibility and ST1407 that was highly prevalent among visitors of the Amsterdam STI clinic. The rapid spread of this strain, which also has been identified in many other countries, might be facilitated by high-risk sexual behavior and should be monitored closely to identify potential treatment failure. Quality-assured surveillance of ESC susceptibility on the national and international levels and exploration of new drugs and/or strategies for treatment of gonorrhea are crucial.

scholarly journals Prevalence and Characterization of Heterogeneous Variable-Number Tandem-Repeat Clusters Comprising Drug-Susceptible and/or Variable ResistantMycobacterium tuberculosisComplex Isolates in the Netherlands from 2004 to 2016

2018 ◽  
Vol 56 (11) ◽  
Author(s):  
Inge Roof ◽  
Rana Jajou ◽  
Miranda Kamst ◽  
Arnout Mulder ◽  
Albert de Neeling ◽  
...  
Keyword(s):  
The Netherlands ◽  
Tandem Repeat ◽  
Variable Number Tandem Repeat ◽  
Multivariate Logistic Regression Analysis ◽  
Variable Number ◽  
Linkage Data ◽  
Nucleotide Polymorphisms ◽  
Typing Method ◽  
Content Type ◽  
Heterogeneous Clustering

ABSTRACTThe variable-number tandem-repeat (VNTR) typing method is used to study tuberculosis (TB) transmission. Clustering ofMycobacterium tuberculosisisolates with identical VNTR patterns is assumed to reflect recent transmission. Hence, clusters are thought to be homogeneous regarding antibiotic resistance. In practice, however, heterogeneous clusters are also identified. This study investigates the prevalence and characteristics of heterogeneous VNTR clusters and assesses whether isolates in these clusters remain clustered when subjected to whole-genome sequencing (WGS). In the period from 2004 to 2016, 9,072 isolates were included. Demographic and epidemiological linkage data were obtained from the Netherlands Tuberculosis Register. VNTR clusters were defined as homogeneous when isolates shared identical resistance profiles or as heterogeneous if both susceptible and (variable) resistant isolates were found. Multivariate logistic regression analysis was performed to identify factors associated with heterogeneous clustering. Isolates from 2016 were subjected to WGS, and a genetic distance of 12 single nucleotide polymorphisms (SNPs) was used as the cutoff for WGS clustering. In total, 4,661/9,072 (51%) isolates were clustered into 985 different VNTR clusters, of which 217 (22%) were heterogeneous. Patient characteristics associated with heterogeneous clustering were non-Dutch ethnicity (odds ratio [OR], 1.46 [95% confidence interval {CI}, 1.22 to 1.75]), asylum seeker (OR, 1.51 [95% CI, 1.24 to 1.85]), extrapulmonary TB (OR, 1.26 [95% CI, 1.09 to 1.46]), previous TB diagnosis (OR, 1.38 [95% CI, 1.04 to 1.82]), and not being a contact of a TB patient (OR, 1.35 [95% CI, 1.08 to 1.69]). With WGS, 34% of heterogeneous and 78% of homogeneous isolates from 2016 remained clustered. Heterogeneous VNTR clusters are common but seem to be explained by a substantial degree of false clustering by VNTR typing compared to WGS.

scholarly journals A Predominant Variable-Number Tandem-Repeat Cluster of Mycobacterium tuberculosis Isolates among Asylum Seekers in the Netherlands and Denmark, Deciphered by Whole-Genome Sequencing

2017 ◽  
Vol 56 (2) ◽  
Author(s):  
Rana Jajou ◽  
Albert de Neeling ◽  
Erik Michael Rasmussen ◽  
Anders Norman ◽  
Arnout Mulder ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
The Netherlands ◽  
Genetic Distance ◽  
Genome Sequencing ◽  
Tandem Repeat ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Whole Genome ◽  
Average Genetic Distance ◽  
Content Type

ABSTRACT In many countries, Mycobacterium tuberculosis isolates are routinely subjected to variable-number tandem-repeat (VNTR) typing to investigate M. tuberculosis transmission. Unexpectedly, cross-border clusters were identified among African refugees in the Netherlands and Denmark, although transmission in those countries was unlikely. Whole-genome sequencing (WGS) was applied to analyze transmission in depth and to assess the precision of VNTR typing. WGS was applied to 40 M. tuberculosis isolates from refugees in the Netherlands and Denmark (most of whom were from the Horn of Africa) that shared the exact same VNTR profile. Cluster investigations were undertaken to identify in-country epidemiological links. Combining WGS results for the isolates (all members of the central Asian strain [CAS]/Delhi genotype), from both European countries, an average genetic distance of 80 single-nucleotide polymorphisms (SNPs) (maximum, 153 SNPs) was observed. The few pairs of isolates with confirmed epidemiological links, except for one pair, had a maximum distance of 12 SNPs. WGS divided this refugee cluster into several subclusters of patients from the same country of origin. Although the M. tuberculosis cases, mainly originating from African countries, shared the exact same VNTR profile, most were clearly distinguished by WGS. The average genetic distance in this specific VNTR cluster was 2 times greater than that in other VNTR clusters. Thus, identical VNTR profiles did not represent recent direct M. tuberculosis transmission for this group of patients. It appears that either these strains from Africa are extremely conserved genetically or there is ongoing transmission of this genotype among refugees on their long migration routes from Africa to Europe.

scholarly journals Occurrence and Nature of Double Alleles in Variable-Number Tandem-Repeat Patterns of More than 8,000 Mycobacterium tuberculosis Complex Isolates in The Netherlands

2017 ◽  
Vol 56 (2) ◽  
Author(s):  
Rana Jajou ◽  
Miranda Kamst ◽  
Rianne van Hunen ◽  
Carolina Catherina de Zwaan ◽  
Arnout Mulder ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
The Netherlands ◽  
Tandem Repeat ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Structural Basis ◽  
Nucleotide Polymorphisms ◽  
Bacterial Populations ◽  
Content Type ◽  
Source Case

ABSTRACTSince 2004, variable-number tandem-repeat (VNTR) typing ofMycobacterium tuberculosiscomplex isolates has been applied on a structural basis in The Netherlands to study the epidemiology of tuberculosis (TB). Although this technique is faster and technically less demanding than the previously used restriction fragment length polymorphism (RFLP) typing, reproducibility remains a concern. In the period from 2004 to 2015, 8,532 isolates were subjected to VNTR typing in The Netherlands, with 186 (2.2%) of these exhibiting double alleles at one locus. Double alleles were most common in loci 4052 and 2163b. The variables significantly associated with double alleles were urban living (odds ratio [OR], 1.503; 95% confidence interval [CI], 1.084 to 2.084;P= 0.014) and pulmonary TB (OR, 1.703; 95% CI, 1.216 to 2.386;P= 0.002). Single-colony cultures of double-allele strains were produced and revealed single-allele profiles; a maximum of five single nucleotide polymorphisms (SNPs) was observed between the single- and double-allele isolates from the same patient when whole-genome sequencing (WGS) was applied. This indicates the presence of two bacterial populations with slightly different VNTR profiles in the parental population, related to genetic drift. This observation is confirmed by the fact that secondary cases from TB source cases with double-allele isolates sometimes display only one of the two alleles present in the source case. Double alleles occur at a frequency of 2.2% in VNTR patterns in The Netherlands. They are caused by biological variation rather than by technical aberrations and can be transmitted either as single- or double-allele variants.

scholarly journals A Case-Control Study of Molecular Epidemiology in Relation to Azithromycin Resistance in Neisseria gonorrhoeae Isolates Collected in Amsterdam, the Netherlands, between 2008 and 2015

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Carolien M. Wind ◽  
Sylvia M. Bruisten ◽  
Maarten F. Schim van der Loeff ◽  
Mirjam Dierdorp ◽  
Henry J. C. de Vries ◽  
...  
Keyword(s):  
The Netherlands ◽  
Neisseria Gonorrhoeae ◽  
Molecular Epidemiology ◽  
Variable Number Tandem Repeat ◽  
Hierarchical Cluster ◽  
Dual Therapy ◽  
23S Rrna ◽  
Content Type ◽  
Epidemiological Characteristics ◽  
Azithromycin Resistance

ABSTRACT Neisseria gonorrhoeae resistance to ceftriaxone and azithromycin is increasing, which threatens the recommended dual therapy. We used molecular epidemiology to identify N. gonorrhoeae clusters and associations with azithromycin resistance in Amsterdam, the Netherlands. N. gonorrhoeae isolates (n = 143) were selected from patients visiting the Amsterdam STI Outpatient Clinic from January 2008 through September 2015. We included all 69 azithromycin-resistant isolates (MIC ≥ 2.0 mg/liter) and 74 frequency-matched susceptible controls (MIC ≤ 0.25 mg/liter). The methods used were 23S rRNA and mtrR sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), N. gonorrhoeae multilocus variable-number tandem-repeat analysis (NG-MLVA), and a specific PCR to detect mosaic penA genes. A hierarchical cluster analysis of NG-MLVA related to resistance and epidemiological characteristics was performed. Azithromycin-resistant isolates had C2611T mutations in 23S rRNA (n = 62, 89.9%, P < 0.001) and were NG-MAST genogroup G2992 (P < 0.001), G5108 (P < 0.001), or G359 (P = 0.02) significantly more often than susceptible isolates and were more often part of NG-MLVA clusters (P < 0.001). Two resistant isolates (2.9%) had A2059G mutations, and five (7.3%) had wild-type 23S rRNA. No association between mtrR mutations and azithromycin resistance was found. Twenty-four isolates, including 10 azithromycin-resistant isolates, showed reduced susceptibility to extended-spectrum cephalosporins. Of these, five contained a penA mosaic gene. Four of the five NG-MLVA clusters contained resistant and susceptible isolates. Two clusters consisting mainly of resistant isolates included strains from men who have sex with men and from heterosexual males and females. The co-occurrence of resistant and susceptible strains in NG-MLVA clusters and the frequent occurrence of resistant strains outside of clusters suggest that azithromycin resistance develops independently from the background genome.

scholarly journals Potentially Human-Pathogenic Escherichia coli O26 in Norwegian Sheep Flocks

2011 ◽  
Vol 77 (14) ◽  
pp. 4949-4958 ◽  
Author(s):  
C. Sekse ◽  
M. Sunde ◽  
B.-A. Lindstedt ◽  
P. Hopp ◽  
T. Bruheim ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Human Pathogens ◽  
Content Type ◽  
Representative Sampling ◽  
E Coli ◽  
Pathogenic Escherichia Coli ◽  
Close Relationship ◽  
Large Survey

ABSTRACTA national survey ofEscherichia coliO26 in Norwegian sheep flocks was conducted, using fecal samples to determine the prevalence. In total, 491 flocks were tested, andE. coliO26 was detected in 17.9% of the flocks. One hundred forty-twoE. coliO26 isolates were examined for flagellar antigens (H typing) and four virulence genes, includingstxandeae, to identify possible Shiga toxin-producingE. coli(STEC) and enteropathogenicE. coli(EPEC). Most isolates (129 out of 142) were identified asE. coliO26:H11. They possessedeaeand may have potential as human pathogens, although only a small fraction were identified as STEC O26:H11, giving a prevalence in sheep flocks of only 0.8%. Correspondingly, the sheep flock prevalence of atypical EPEC (aEPEC) O26:H11 was surprisingly high (15.9%). The genetic relationship between theE. coliO26:H11 isolates was investigated by pulsed-field gel electrophoresis (PFGE) and multilocus variable number tandem repeat analysis (MLVA), identifying 63 distinct PFGE profiles and 22 MLVA profiles. Although the MLVA protocol was less discriminatory than PFGE and a few cases of disagreement were observed, comparison by partition mapping showed an overall good accordance between the two methods. A close relationship between a few isolates of aEPEC O26:H11 and STEC O26:H11 was identified, but all theE. coliO26:H11 isolates should be considered potentially pathogenic to humans. The present study consisted of a representative sampling of sheep flocks from all parts of Norway. This is the first large survey of sheep flocks focusing onE. coliO26 in general, including results of STEC, aEPEC, and nonpathogenic isolates.

scholarly journals Multiple-Locus Variable-Number Tandem Repeat Analysis of Dutch Bordetella pertussis Strains Reveals Rapid Genetic Changes with Clonal Expansion during the Late 1990s

2004 ◽  
Vol 186 (16) ◽  
pp. 5496-5505 ◽  
Author(s):  
Leo M. Schouls ◽  
Han G. J. van der Heide ◽  
Luc Vauterin ◽  
Paul Vauterin ◽  
Frits R. Mooi
Keyword(s):  
The Netherlands ◽  
Tandem Repeat ◽  
Bordetella Pertussis ◽  
Minimum Spanning Tree ◽  
Whooping Cough ◽  
Variable Number Tandem Repeat ◽  
Clonal Expansion ◽  
Variable Number ◽  
Multiple Locus ◽  
Repeat Analysis

ABSTRACT Bordetella pertussis, the causative agent of whooping cough, has remained endemic in The Netherlands despite extensive nationwide vaccination since 1953. In the 1990s, several epidemic periods have resulted in many cases of pertussis. We have proposed that strain variation has played a major role in the upsurges of this disease in The Netherlands. Therefore, molecular characterization of strains is important in identifying the causes of pertussis epidemiology. For this reason, we have developed a multiple-locus variable-number tandem repeat analysis (MLVA) typing system for B. pertussis. By combining the MLVA profile with the allelic profile based on multiple-antigen sequence typing, we were able to further differentiate strains. The relationships between the various genotypes were visualized by constructing a minimum spanning tree. MLVA of Dutch strains of B. pertussis revealed that the genotypes of the strains isolated in the prevaccination period were diverse and clearly distinct from the strains isolated in the 1990s. Furthermore, there was a decrease in diversity in the strains from the late 1990s, with a remarkable clonal expansion that coincided with the epidemic periods. Using this genotyping, we have been able to show that B. pertussis is much more dynamic than expected.

scholarly journals Prediction of Local Transmission of Mycobacterium tuberculosis Isolates of a Predominantly Beijing Lineage by Use of a Variable-Number Tandem-Repeat Typing Method Incorporating a Consensus Set of Hypervariable Loci

2017 ◽  
Vol 56 (1) ◽  
Author(s):  
Yoshiro Murase ◽  
Kiyohiko Izumi ◽  
Akihiro Ohkado ◽  
Akio Aono ◽  
Kinuyo Chikamatsu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tandem Repeat ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Trend Test ◽  
Typing Method ◽  
Content Type ◽  
Tuberculosis Transmission ◽  
High Prevalence ◽  
Hypervariable Loci

ABSTRACT Strain genotyping based on the variable-number tandem repeat (VNTR) is widely applied for identifying the transmission of Mycobacterium tuberculosis. A consensus set of four hypervariable loci (1982, 3232, 3820, and 4120) has been proposed to improve the discrimination of Beijing lineage strains. Herein, we evaluated the utility of these four hypervariable loci for tracing local tuberculosis transmission in 981 cases over a 14-month period in Japan (2010 to 2011). We used six different VNTR systems, with or without the four hypervariable loci. Patient ages and weighted standard distances (a measure of the dispersion of genotype-clustered cases) were used as proxies for estimating local tuberculosis transmission. The highest levels of isolate discrimination were achieved with VNTR systems that incorporated the four hypervariable loci (i.e., the Japan Anti-Tuberculosis Association [JATA]18-VNTR, mycobacterial interspersed repetitive unit [MIRU]28-VNTR, and 24Beijing-VNTR). The clustering rates by JATA12-VNTR, MIRU15-VNTR, JATA15-VNTR, JATA18-VNTR, MIRU28-VNTR, and 24Beijing-VNTR systems were 52.2%, 51.0%, 39.0%, 24.1%, 23.1%, and 22.0%, respectively. As the discriminative power increased, the median weighted standard distances of the clusters tended to decrease (from 311 to 80 km, P < 0.001, Jonckheere-Terpstra trend test). Concurrently, the median ages of patients in the clusters tended to decrease (from 68 to 60 years, P < 0.001, Jonckheere-Terpstra trend test). These findings suggest that strain typing using the four hypervariable loci improves the prediction of active local tuberculosis transmission. The four-locus set can therefore contribute to the targeted control of tuberculosis in settings with high prevalence of Beijing lineage strains.

scholarly journals Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

2011 ◽  
Vol 56 (2) ◽  
pp. 916-920 ◽  
Author(s):  
Shu-ichi Nakayama ◽  
Chanwit Tribuddharat ◽  
Sasiprapa Prombhul ◽  
Ken Shimuta ◽  
Somporn Srifuengfung ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Sexual Network ◽  
Genetic Event ◽  
Content Type ◽  
Extended Spectrum ◽  
Resistance To Penicillin ◽  
High Level ◽  
International Awareness

ABSTRACTNeisseria gonorrhoeaeis a major public health problem globally, especially because the bacterium has developed resistance to most antimicrobials introduced for first-line treatment of gonorrhea. In the present study, 96N. gonorrhoeaeisolates with high-level resistance to penicillin from 121 clinical isolates in Thailand were examined to investigate changes related to their plasmid-mediated penicillin resistance and their molecular epidemiological relationships. A β-lactamase (TEM) gene variant,blaTEM-135, that may be a precursor in the transitional stage of a traditionalblaTEM-1gene into an extended-spectrum β-lactamase (ESBL), possibly causing high resistance to all extended-spectrum cephalosporins inN. gonorrhoeae, was identified. Clonal analysis using multilocus sequence typing (MLST) andN. gonorrhoeaemultiantigen sequence typing (NG-MAST) revealed the existence of a sexual network among patients from Japan and Thailand. Molecular analysis of theblaTEM-135gene showed that the emergence of this allele might not be a rare genetic event and that the allele has evolved in different plasmid backgrounds, which results possibly indicate that it is selected due to antimicrobial pressure. The presence of theblaTEM-135allele in the penicillinase-producingN. gonorrhoeaepopulation may call for monitoring for the possible emergence of ESBL-producingN. gonorrhoeaein the future. This study identified ablaTEMvariant (blaTEM-135) that is a possible intermediate precursor for an ESBL, which warrants international awareness.

scholarly journals Examination of Taxonomic Uncertainties Surrounding Brucella abortus bv. 7 by Phenotypic and Molecular Approaches

2013 ◽  
Vol 80 (5) ◽  
pp. 1570-1579 ◽  
Author(s):  
Bruno Garin-Bastuji ◽  
Virginie Mick ◽  
Gilles Le Carrou ◽  
Sebastien Allix ◽  
Lorraine L. Perrett ◽  
...  
Keyword(s):  
Brucella Abortus ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Epidemiological Methods ◽  
Content Type ◽  
Phenotypic Profile ◽  
Molecular Approaches ◽  
Content Classification ◽  
Species Specific ◽  
Kenyan Strain

ABSTRACTBrucellataxonomy is perpetually being reshuffled, at both the species and intraspecies levels. Biovar 7 ofBrucella abortuswas suspended from theApproved Lists of Bacterial NamesBrucellaclassification in 1988, because of unpublished evidence that the reference strain 63/75 was a mixture ofB. abortusbiovars 3 and 5. To formally clarify the situation, all isolates previously identified asB. abortusbv. 7 in the AHVLA and ANSES strain collections were characterized by classical microbiological and multiple molecular approaches. Among the 14 investigated strains, including strain 63/75, only four strains, isolated in Kenya, Turkey, and Mongolia, were pure and showed a phenotypic profile in agreement with the former biovar 7, particularly agglutination with both anti-A/anti-M monospecific sera. These results were strengthened by molecular strategies. Indeed, genus- and species-specific methods allowed confirmation that the four pure strains belonged to theB. abortusspecies. The combination of most approaches excluded their affiliation with the recognized biovars (biovars 1 to 6 and 9), while some suggested that they were close to biovar 3.These assays were complemented by phylogenetic and/or epidemiological methods, such as multilocus sequence analysis (MLSA) and variable-number tandem repeat (VNTR) analysis. The results of this polyphasic investigation allow us to propose the reintroduction of biovar 7 into theBrucellaclassification, with at least three representative strains. Interestingly, the Kenyan strain, sharing the same biovar 7 phenotype, was genetically divergent from other three isolates. These discrepancies illustrate the complexity ofBrucellataxonomy. This study suggests that worldwide collections could include strains misidentified asB. abortusbv. 7, and it highlights the need to verify their real taxonomic position.

scholarly journals Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-ProducingEnterobacteriaceae

2018 ◽  
Vol 31 (2) ◽  
Author(s):  
Jesús Rodríguez-Baño ◽  
Belén Gutiérrez-Gutiérrez ◽  
Isabel Machuca ◽  
Alvaro Pascual
Keyword(s):  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Beta Lactamase ◽  
Content Type ◽  
Extended Spectrum Beta Lactamase ◽  
Development Of Resistance ◽  
Extended Spectrum ◽  
Invasive Infections ◽  
Risk Patients

SUMMARYTherapy of invasive infections due to multidrug-resistantEnterobacteriaceae(MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam–β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producingEnterobacteriaceae(CPE), only some “second-line” drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.

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