Carbapenem Non-susceptibility Research Articles

Shifting trends in bloodstream infection-causing microorganisms and their clinical impact in patients with haematologic malignancies in South Korea: A propensity score-matched study

BackgroundThis study aimed to identify recent trends in the epidemiology of bloodstream infection (BSI)-causing microorganisms among patients with haematologic malignancies (HMs) between 2011 and 2021, and to determine their impact on patient outcomes. MethodsThis retrospective study included 6792 patients with HMs, of whom 1308 (19.3%) developed BSI within 1 y of diagnosis. The incidence of BSI-causing microorganisms was determined, and a propensity score-matched study was performed to identify risk factors for 28-d all-cause mortality in patients with HM. ResultsA total of 6792 patients with HMs were enrolled. The cumulative incidence of BSI and neutropenia was significantly higher in the acute myeloid leukaemia and acute lymphoblastic leukaemia groups compared to other groups, and neutropenia and type of HMs were risk factors for the development of BSI. The annual incidence of coagulase-negative staphylococci (CoNS)-BSI decreased significantly (P < 0.001), whereas Klebsiella pneumoniae-BSI increased (P = 0.01). Carbapenem nonsusceptibility rates in K. pneumoniae isolates increased from 0.0% to 76.5% (P < 0.001). BSI caused by K. pneumoniae (adjusted odds ratio 2.17; 95% confidence interval 1.12–4.21) was associated with higher 28-d all-cause mortality compared to that caused by CoNS (adjusted odds ratio 0.86; 95% confidence interval 0.48–1.55). ConclusionThe pathogenic spectrum of BSI-causing bacteria in patients with HMs gradually shifted from Gram-positive to Gram-negative, especially from CoNS to K. pneumoniae. Considering that K. pneumoniae-BSI had a significantly higher 28-d mortality rate than CoNS-BSI, this evolving trend could adversely impact the clinical outcomes of patients with HMs.

Clinical isolates of Streptococcus mitis/oralis-related species with reduced carbapenem susceptibility, harboring amino acid substitutions in penicillin-binding proteins in Japan.

Streptococcus mitis/oralis group isolates with reduced carbapenem susceptibility have been reported, but its isolation rate in Japan is unknown. We collected 356 clinical α-hemolytic streptococcal isolates and identified 142 of them as S. mitis/oralis using partial sodA sequencing. The rate of meropenem non-susceptibility was 17.6% (25/142). All 25 carbapenem-non-susceptible isolates harbored amino acid substitutions in/near the conserved motifs in PBP1A, PBP2B, and PBP2X. Carbapenem non-susceptibility is common among S. mitis/oralis group isolates in Japan.

Carbapenem-resistant Enterobacterales susceptibility patterns to new antimicrobials: A single-center analysis

Background: Multidrug-resistant bacteria are of high concern, and empiric antimicrobial choice for infections caused by these pathogens, while awaiting susceptibilities, is increasingly encountered. We describe the susceptibility patterns of ceftazidime-avibactam (CZA), imipenem-rel-ebactam (I-R), meropenem-vaborbactam (MVB), cefiderocol (FDC), ceftolozone-tazobactam (C/T), minocycline (MIN), and tigecycline (TGC) for carbapenem-resistant Enterobacterales at an academic medical center. Methods: We performed a single-center analysis of Enterobacterales isolates from 110 hospitalized adult patients who had CZA, I-R, MVB, FDC, MIN, or TGC susceptibility testing performed between October 2020 and September 2022. The study included 1 isolate per patient per infection site per year. Isolates were divided into carbapenem susceptible and non susceptible categories. For carbapenem nonsusceptible isolates, phenotypic confirmatory testing of carbapenem nonsusceptibility was performed using disk diffusion, gradient diffusion, and/or broth microdilution. Interpretive categories were applied using CLSI- or FDA-approved break-points where applicable. Carbapenemase testing was also performed using the modified carbapenem inactivation method (mCIM) and, where applicable, this testing was confirmed at the Massachusetts State Public Health Laboratory using genotypic methods. Results: In total, 125 unique isolates were reviewed: 34 meropenem-susceptible and 91 meropenem-intermediate or resistant isolates. CZA, I-R, MVB, and FDC were active against all tested meropenem-susceptible isolates; however, 50% of tested isolates were susceptible to C/T. MIN and TGC, when tested, were active against 2 of 11 isolates (18%) and 14 of 16 isolates (86%), respectively. Of 91 meropenem-nonsusceptible isolates, most tested isolates were susceptible to MVB (59 of 72, 82%), followed by CZA (63 of 82, 77%), I-R (8 of 11, 73%), FDC (9 of 16, 56%), and C/T (1 of 12, 8%). TGC retained activity against 78 of 81 (96%) tested isolates. In contrast, MIN retained activity against 8 of 45 isolates (18%). Additionally, all (28 of 28, 100%) isolates that were nonsusceptible to at least 1 novel agent (CZA, I-R, MVB, FDC, or C/T) remained susceptible to TGC. State laboratory confirmatory testing was available for 75 isolates. Of 43 mCIM-positive isolates, all 28 KPC-producing isolates were susceptible to CZA, I-R, MVB, FDC and TGC. Conclusions: Among Enterobacterales, CZA, MVB, and I-R retained activity against most non-NDM CRE isolates in this local analysis, with comparable susceptibilities. TGC demonstrated excellent susceptibility for CRE and meropenem-susceptible isolates, offering an alternative for nonbloodstream infections. Choice of empiric agent with a newβ-lactam, β-lactam–β-lactamase inhibitors, or TGC appear to be reasonable empiric therapeutic options at our institution. CT and MIN warrant confirmatory testing prior to use due to low susceptibility rates among meropenem nonsusceptible isolates.Disclosures: None

Frequent Transmission of Streptococcus pneumoniae Serotype 35B and 35D, Clonal Complex 558 Lineage, across Continents and the Formation of Multiple Clades in Japan.

Streptococcus pneumoniae is a common bacterial pathogen that causes infections in children worldwide, even after administration of the pneumococcal conjugate vaccine. S. pneumoniae serotype 35B, especially the clonal complex 558 (CC558) lineage, has emerged globally following implementation of the 13-valent pneumococcal conjugate vaccine. Serotype 35B strains are also associated with multidrug resistance to both β-lactams and non-β-lactam drugs. In addition, a novel serotype, 35D, which is closely related to 35B and differs in polysaccharide structure, was recently reported. However, the genetic relationship among globally disseminating serotype 35B and D (35B/D) strains remains unknown. To investigate the molecular epidemiology of global serotype 35B/D strains, we conducted a genomic analysis of serotype 35B/D strains from various continents, including those from the Japanese national surveillance collection. A total of 87 isolates were identified as serotype 35B/D in the Japanese surveillance collection (n = 1,358). All the isolates were assigned to either CC558 or CC2755. Serotype 35D isolates were interspersed with serotype 35B isolates. Phylogenetic analysis revealed the formation of multiple clusters by the Japanese serotype 35B/D-CC558 isolates among the foreign isolates, which suggested multiple events of introduction of the clone into Japan. The global 35B/D-CC558 strains were found to share specific penicillin-binding protein profiles, pbp1a-4, pbp2b-7, and pbp2x-7, associated with penicillin, cephalosporin, and carbapenem nonsusceptibility. Moreover, 88.5% of the Japanese 35B/D-CC558 and 35B/D-CC2755 isolates were found to harbor the Tn916-like integrative and conjugative elements Tn2009, Tn2010, and Tn6002, associated with multidrug resistance to macrolides and tetracyclines. The results of this study imply that serotype 35B/D-CC558 strains could be frequently transmitted intercontinentally.

A Multicenter Comparison of Carbapenem-Nonsusceptible Enterobacterales and Pseudomonas aeruginosa Rates in the US (2016 to 2020): Facility-Reported Rates versus Rates Based on Updated Clinical Laboratory and Standards Institute Breakpoints.

ABSTRACTAdoption of revised antimicrobial susceptibility breakpoints is often slow, potentially leading to underreporting of antimicrobial resistance. We compared facility-reported rates of carbapenem nonsusceptibility (NS; intermediate or resistant) with NS rates based on current Clinical and Laboratory Standards Institute (CLSI) breakpoints for Enterobacterales or Pseudomonas aeruginosa isolates in ambulatory and inpatient adults in the BD Insights Research Database (US) from 2016 to 2020. Overall, 77.4% (937,926/1,211,845) and 90.6% (2,157,785/2,381,824) of nonduplicate Enterobacterales isolates with facility-reported susceptibility results had MIC data for ertapenem (ETP) and imipenem/meropenem/doripenem (IPM/MEM/DOR), respectively; 86.9% (255,844/294,426) of P. aeruginosa isolates had MIC data for IPM/MEM/DOR. Facility-reported susceptibility and susceptibility based on CLSI criteria resulted in comparable carbapenem susceptibility rates (99.3% versus 99.1% for ETP-susceptible Enterobacterales, 98.9% versus 98.4% for IPM/MEM/DOR-susceptible Enterobacterales, and 84.9% versus 83.3% for IPM/MEM/DOR-susceptible P. aeruginosa). However, compared with CLSI criteria, facilities underreported Enterobacterales- and IPM/MEM/DOR-NS isolates by 18.8% and 26.5%, respectively, and P. aeruginosa IPM/MEM/DOR-NS isolates by 9.8%. Underreporting was observed for both intermediate and resistant isolates. Our data suggest that delayed adoption of revised breakpoints has a small but potentially important impact on reported rates of antimicrobial resistance. Facilities should be aware of local epidemiology, evaluate potential underreporting of resistance, and assess the related clinical impact.IMPORTANCE Clinicians often base antimicrobial therapeutic decisions on laboratory determinations of pathogen susceptibility to an antibiotic based on MIC breakpoints. MIC breakpoints evolve over time based on new information; between 2010 and 2012 the CLSI lowered carbapenem breakpoints for Enterobacterales and Pseudomonas aeruginosa, and these were subsequently adopted by the US Food and Drug Administration. Carbapenems are important therapeutic options for these difficult-to-treat pathogens, so understanding resistance rates is critically important. However, laboratories can be slow to adopt updated breakpoints. We used MIC data to evaluate whether reports received by hospitals for carbapenem susceptibility were consistent with updated CLSI breakpoints. Although overall susceptibility rates were similar between hospital reports and susceptibility based on updated CLSI criteria, the percentages of carbapenem-resistant isolates were significantly underreported by hospital reports. Delayed adoption of MIC breakpoints may impact epidemiological understanding of resistance and contribute to the spread of resistant pathogens.

Cost-Effectiveness of Imipenem/Cilastatin/Relebactam Compared with Colistin in Treatment of Gram-Negative Infections Caused by Carbapenem-Non-Susceptible Organisms.

IntroductionImipenem/cilastatin/relebactam (IMI/REL), a combination β-lactam antibiotic (imipenem) with a novel β-lactamase inhibitor (relebactam), is an efficacious and well-tolerated option for the treatment of hospitalized patients with gram-negative (GN) bacterial infections caused by carbapenem-non-susceptible (CNS) pathogens. This study examines cost-effectiveness of IMI/REL vs. colistin plus imipenem (CMS + IMI) for the treatment of infection(s) caused by confirmed CNS pathogens.MethodsWe developed an economic model comprised of a decision-tree depicting initial hospitalization, and a Markov model projecting long-term health and economic impacts following discharge. The decision tree, informed by clinical data from RESTORE-IMI 1 trial, modeled clinical outcomes (mortality, cure rate, and adverse events including nephrotoxicity) in the two comparison scenarios of IMI/REL versus CMS + IMI for patients with CNS GN infection. Subsequently, a Markov model translated these hospitalization stage outcomes (i.e., death or uncured infection) to long-term consequences such as quality-adjusted life years (QALYs). Sensitivity analyses were conducted to test the model robustness.ResultsIMI/REL compared to CMS + IMI demonstrated a higher cure rate (79.0% vs. 52.0%), lower mortality (15.2% vs. 39.0%), and reduced nephrotoxicity (14.6% vs. 56.4%). On average a patient treated with IMI/REL vs. CMS + IMI gained additional 3.7 QALYs over a lifetime. Higher drug acquisition costs for IMI/REL were offset by shorter hospital length of stay and lower AE-related costs, which result in net savings of $11,015 per patient. Sensitivity analyses suggested that IMI/REL has a high likelihood (greater than 95%) of being cost-effective at a US willingness-to-pay threshold of $100,000–150,000 per QALY.ConclusionsFor patients with confirmed CNS GN infection, IMI/REL could yield favorable clinical outcomes and may be cost-saving—as the higher IMI/REL drug acquisition cost is offset by reduced nephrotoxicity-related cost—for the US payer compared to CMS + IMI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00607-x.

Risk factors and clinical impact of bacteremia due to carbapenem-nonsusceptible Enterobacteriaceae: A multicenter study in southern Taiwan.

The emergence of carbapenem-non-susceptible Enterobacteriaceae (CnSE) infections is a public health threat. This study investigated the risk factors and clinical impact of bacteremia due to CnSE. The study was conducted at three hospitals in southern Taiwan between January 1, 2017, and October 31, 2019. Only the first episode of CnSE bacteremia from each adult was included. For one episode of CnSE bacteremia, two subsequent bacteremic episodes due to carbapenem-susceptible Enterobacteriaceae isolates in each hospital were included as the controls. Among a total of 641 episodes of monomicrobial Enterobacteriaceae bacteremia were noted, 47 (7.3%) of which were of CnSE bacteremia. Ninety-four episodes of carbapenem-susceptible Enterobacteriaceae (CSE) bacteremia were selected as the controls for further analyses. In the multivariate analysis, hypertension (odds ratio [OR], 4.21; P=0.005), Pitt bacteremia score (OR, 1.61; P=0.002), and nosocomial bacteremia (OR, 3.30; P=0.01) were associated with carbapenem nonsusceptibility among Enterobacteriaceae bacteremia. The most abundant CnSE isolate was Klebsiella pneumoniae (91.5%), followed by Klebsiella oxytoca (6.4%) and Escherichia coli (2.1%). Patients with CnSE bacteremia had a higher overall in-hospital mortality rate than those with CSE bacteremia (53.2% vs. 23.4%, P=0.001). Moreover, in the multivariate analysis, the in-hospital mortality was significantly associated with higher Pitt bacteremia score (OR, 1.38; P=0.02) and marginally associated with CnSE infections (OR, 2.44; P=0.06). Among adults with Enterobacteriaceae bacteremia, carbapenem nonsusceptibility, male sex, and the presence of hypertension or chronic kidney disease indicate a poor prognosis during hospitalization.

Epidemiology study of carbapenam-resistant enterobacteriaceae (CRE): A 30-months experience at a tertiary centre in Northern Malaysia

Background: Carbapenam-resistant entrerobacteriaceae (CRE) is an emerging serious health threat worldwide however the treatment option is limited. Sultanah Bahiyah Hospital is a 900-bed tertiary hospital in Northern Malaysia. There has been a steady increase of CRE prevalence over the years. Objectives: To study the epidemiology of CRE, comparing the risk factors, antecedent exposure to antibiotics and related mortality. Methods and materials: Methods: A retrospective descriptive study was conducted on all clinical isolates of CRE from 2017 till July 2019 with molecular characterization of carbapenemase genes. Carbapenem non-susceptibility is confirmed by Etest based on CLSI breakpoints. Results: CRE samples reported before 2017 were scarce (less than 16 cases per-year). However, a total of 213 isolates were reported within the study period and the trend increased dramatically from 60 cases in 2017 to 95 cases in 2018;recorded a 56.7% increment and it continued to rise. Isolates were mainly from blood and urine, with similar distribution of 27.7% (59/213) followed by tissue 15% (32/213) and tracheal aspirate 10.3% (22/213). Majority of organisms were Klebsiella pneumoniae (71.8%) and Enterobacter sp (22.5%) followed by E. coli (5%). 59.3%(102/172) were NDM-producing CRE with only 4 isolates were IMP, 3 OXA-48 but no KPC was detected. The remaining 37.8% (65/172) were negative by PCR. Only 30% (64/213) of the patients with CRE required treatment, with mortality rate of 59.7%. This is inclusive of 26.6% (17/64) patients who succumbed before CRE was identified from clinical specimens. Analysis of risk factors showed that ICU (Intensive Care Unit) admission is associated with higher mortality (p= 0.008). All isolates were resistant to all generations of cephalosporins and carbapenems. About 80% of CRE-infected patients had prior exposure to either carbapenem (40%), Piperacillin-tazobactam (40%) or third-generation and fourth-generation cephalosporins (40%) before CRE detection. Conclusion: Majority of CRE isolates in our region are NDM-producers, treatment decision is hence challenging. ICU admission is an important risk factor for CRE acquisition. High suspicion for CRE infection should be considered in critically ill patients who have been exposed to broad spectrum antibiotics.

Carbapenem non-susceptibility associated with global transcriptional regulator MarA in Escherichia coli

Background: The AcrAB-TolC system of Escherichia coli is a multidrug efflux system pumping out a wide variety of substrates. Its expression is regulated by an intricate balance between local (AcrR and AcrS) and global regulators (MarA, SoxS and Rob). Global transcriptional regulators are known to be involved in stress response in bacteria. MarA along activating its own transcription; it activates the transcription of other genes including acrAB, tolC and micF. As carbapenem resistance is an increasing trend in hospital acquired infections. The present study was carried out to observe transcriptional response of marA, soxS and rob against concentration dependent carbapenem stress. Methods and materials: In the present study hospital isolates of Escherichia coli were tested for transcriptional expression of AcrAB-TolC and OmpF. Transcriptional expression of marA, soxS and rob with and without concentration gradient carbapenem stress were determined. Sequencing and cloning of marA, soxS and rob was also performed. Results: Twelve isolates with over-expressed AcrAB-TolC and downregulated OmpF were selected for further study. Among them, overexpression of marA against meropenem was observed in seven isolates. Antimicrobial susceptibility pattern of the clones showed that the zone of inhibition formed by the transformants (mar) was decreased as compared with that of parent strain (DH5α) as well as with the plasmid without gene of interest. Further, MIC range of the clones revealed two-fold or more increase in the inhibitory concentration against ertapenem and imipenem was noted for clone of mar while comparing with the parent strain (DH5α) Further, when the DNA sequences of marAwere compared with the reference strain of E. coli ATCC 25922, it displayed nucleotide alterations at many locations. Four-point mutation and 2 deletion mutations in marA sequence was observed. Conclusion: This study demonstrates the role of the global regulators marA in triggering the overexpression of AcrAB efflux pump system conferring resistance towards carbapenems. MarA plays a major role in efflux activity under carbapenem stress. Regulation of Rob under meropenem stress shows an antibiotic specific response and SoxS deviation in transcriptional expression amid particular concentration, needs further investigation.

Hidden carbapenem resistance in the community- and hospital-associated OXA-48 gene-carrying uropathogenic Escherichia coli

IntroductionEscherichia coli is the primary pathogen in complicated and uncomplicated urinary tract infections (UTIs). Today, the emergence of E. coli strains resistant to carbapenem antibiotics is a significant concern in UTIs treatment. The main carbapenemase enzymes in the E. coli are blaOXA-48,blaKPC,blaNDM, and to a less extent blaVIM and blaIMP. The aim of this study was the molecular screening of carbapenemase genes in Uropathogenic Escherichia coli (UPEC) isolated from the community- and hospital-associated UTIs. Material and methodsA total of 300 E. coli isolates were collected from outpatient and admitted patients in Tehran. The presence of blaOXA-48,blaKPC,blaNDM, blaVIM and blaIMP genes was detected by the PCR method. Antibiotic susceptibility test was performed by disk diffusion. Phylogrouping, serogrouping, and virulence typing (ompT, iha, pic, csgA, fyuA, iucD, papGII, kpsMII, cnf-1, hlyA, traT, and fimH) were performed for carbapenemase genes-carrying strains by PCR method. ResultsThe prevalence of blaOXA-48gene was 1% (three isolates), and blaKPC,blaNDM, blaVIM and blaIMP genes were not detected. All three blaOXA-48-carrying strains were susceptible to carbapenems such as imipenem, ertapenem, and meropenem in disk diffusion methods. The degree of resistance to ceftazidime, cefotaxime, amoxicillin, cefazolin, and augmentin was 100%. Two of the three strains were hospital-associated UPEC, and one strain was community-associated UPEC. Phylogroup and serogroup of isolates were B2-O16, B2-unknown, and B1-O25, respectively. All three blaOXA-48-carrying isolates were ESBL-producer and carried the blaCTX-M1 gene. iha, papП, FyuA, fimH, csgA, iucD, and traT virulence genes were detected in 100% of isolates. ConclusionThis study showed hidden carbapenem resistance due to the presence of the blaOXA-48 gene in carbapenem-susceptible, and ESBL-producer UPEC strains. Thus, routine susceptibility tests such as disk diffusion and E-test methods is unreliable for the detection of carbapenem non-susceptibility, so a rapid, easy and inexpensive method is still needed for testing carbapenem nonsusceptibility, especially in ESBL-producer isolates. Additionally, our results indicate the blaOXA-48 gene disseminates in the hospital- and community-associated E. coli isolates in Tehran city. Identification of strains with hidden carbapenem resistance would significantly help to restrict and prevent the spread of such strains in the community and hospital settings.

Escherichia coli Antibiotic Susceptibility Patterns for Infants Admitted to NICUs Across the United States from 2009 to 2017

Background:Escherichia coli (E. coli) is a leading cause of infections among term and preterm newborn infants. Continued surveillance of neonatal E. coli antibiotic susceptibility patterns is important to optimize empiric antibiotic prescription for infants at risk for infection, in light of evolving reports of multidrug-resistant gram-negative bacteria in all settings. Our objective was to determine E. coli epidemiology and antibiotic susceptibility patterns among a large sample of infants admitted to neonatal intensive care units (NICUs) across the United States from 2009 to 2017. Methods: Retrospective observational study using the Premier Database, including infants born from 2009 to 2017 and admitted to academic or community NICUs contributing microbiology data during the study period. We analyzed antibiotic susceptibilities for E. coli isolated from blood, cerebrospinal fluid, and urine. We focused on clinically relevant and priority susceptibility categories: (1) ampicillin nonsusceptible; (2) aminoglycoside nonsusceptible; (3) carbapenem nonsusceptible; and (4) extended-spectrum β-lactamase (ESBL; phenotypic definition). We determined the proportion of infants with nonsusceptible organisms in each category by year and tested for changes over time. Lastly, we assessed susceptibility patterns by specimen source, birthweight, and timing of infection. Results: Of the 117,484 included infants, 733 (0.6%) had at least 1 E. coli episode, of which 721 (98.4%) had available susceptibility results, from 69 centers. Patient and center characteristics of infants with E. coli are shown in Table 1. Most organisms were tested against ampicillin (99.9%), gentamicin (99.6%), and ceftriaxone (91.5%). Figure 1 shows nonsusceptibility rates for the categories of interest. Overall, ampicillin nonsusceptibility ranged from 63.3% to 68.6% per year (mean, 66.8%±1.5%); aminoglycoside nonsusceptibility ranged from 10.7% to 23.2% (mean, 16.8%±4.5%); carbapenem nonsusceptibility was 0% for all years; and ESBL ranged from 1.2% to 11.3% (mean, 5.1%±3.4%). We detected no statistically significant trends for any of the categories of interest over time (all P &gt; .05), and susceptibility trends were consistent when repeated by specimen source, birthweight, and timing of infection. Conclusions: We found stable, yet concerning, patterns of E. coli antibiotic nonsusceptibility among infants admitted to NICUs across the United States from 2009 to 2017. Rates of ampicillin nonsusceptibility and aminoglycoside nonsusceptibility were higher than previous reports. ESBL E. coli rates were low but present among neonatal patients. No carbapenem nonsusceptible E. coli was identified. These findings can inform empiric antibiotic prescription for infants admitted to NICUs across the United States.Funding: NoneDisclosures: None

The epidemiology of carbapenem-non-susceptible Acinetobacter species in Europe: analysis of EARS-Net data from 2013 to 2017

BackgroundDue to limited therapeutic options and their association with high mortality and morbidity, carbapenem-non-susceptible Acinetobacter spp. (CNA) are of significant public health importance. This study aimed to describe current epidemiological trends of CNA proportions in Europe and to identify factors that are associated with carbapenem non-susceptibility of isolates from patients with invasive Acinetobacter spp. infections.MethodsData from routine carbapenem susceptibility testing of 18,412 invasive clinical Acinetobacter spp. isolates from 30 European countries in 2013–2017 were analysed using descriptive statistical analyses and uni- and multivariable regression analyses. These data were obtained from the European Antimicrobial Resistance Surveillance Network (EARS-Net).ResultsThe population-weighted mean proportion of carbapenem-non-susceptible Acinetobacter spp. in Europe is 35.6% (95% confidence interval [CI] 29.7–42.0%). With CNA proportions of 75.5% (95% CI 71.2–79.4%) and 71.5% (95% CI 66.7–75.9%) the burden of CNA is particularly high in Southern and Eastern European regions. In contrast, Northern and Western European regions recorded CNA proportions of 2.8% (95% CI 1.2–6.0%) and 6.3% (95% CI 4.5–8.9%), respectively. Population-weighted mean CNA proportions are especially high in Acinetobacter spp. isolates from intensive care units (54.0% [95% CI 47.6–60.3%]). Male gender, age above 20 years and ICU admission were identified as independent factors associated with an increased likelihood of CNA.ConclusionThe burden of carbapenem-non-susceptible Acinetobacter spp. is particularly high in Southern and Eastern Europe. There is a risk that resistance could spread to other parts of Europe. Therefore, increased efforts in infection control and antibiotic stewardship, particularly in Intensive Care Units, are necessary to combat the spread of CNA in Europe.

Attributable burden in patients with carbapenem-nonsusceptible gram-negative respiratory infections.

ObjectiveWe aimed to describe the clinical and economic burden attributable to carbapenem-nonsusceptible (C-NS) respiratory infections.MethodsThis retrospective matched cohort study assessed clinical and economic outcomes of adult patients (aged ≥18 years) who were admitted to one of 78 acute care hospitals in the United States with nonduplicate C-NS and carbapenem-susceptible (C-S) isolates from a respiratory source. A subset analysis of patients with principal diagnosis codes denoting bacterial pneumonia or other diagnoses was also conducted. Isolates were classified as community- or hospital-onset based on collection time. A generalized linear mixed model method was used to estimate the attributable burden for mortality, 30-day readmission, length of stay (LOS), cost, and net gain/loss (payment minus cost) using propensity score-matched C-NS versus C-S cohorts.ResultsFor C-NS cases, mortality (25.7%), LOS (29.4 days), and costs ($81,574) were highest in the other principal diagnosis, hospital-onset subgroup; readmissions (19.4%) and net loss (-$9522) were greatest in the bacterial pneumonia, hospital-onset subgroup. Mortality and readmissions were not significantly higher for C-NS cases in any propensity score-matched subgroup. Significant C-NS–attributable burden was found for both other principal diagnosis subgroups for LOS (hospital-onset: 3.7 days, P = 0.006; community-onset: 1.5 days, P<0.001) and cost (hospital-onset: $12,777, P<0.01; community-onset: $2681, P<0.001).ConclusionsIncreased LOS and cost burden were observed in propensity score-matched patients with C-NS compared with C-S respiratory infections; the C-NS–attributable burden was significant only for patients with other principal diagnoses.

In Vitro Susceptibility to Ceftazidime/Avibactam and Comparators in Clinical Isolates of Enterobacterales from Five Latin American Countries.

Background: High rates of resistance to third-generation cephalosporins and carbapenems in Enterobacterales have been reported in Latin America. Ceftazidime/avibactam (CZA) is the combination of a third-generation cephalosporin and a non-β-lactam β-lactamase inhibitor, which has shown activity against isolates producing class A, C and D β-lactamases. Herein, we evaluated the activity of CZA and comparators against clinical isolates of Enterobacterales in Latin America. Methods: The activity of CZA and comparators was evaluated against clinical isolates of Enterobacterales from Argentina, Brazil, Chile, Colombia and Mexico that were collected between January 2016 and October 2017. One specific phenotypic subset was evaluated. A carbapenem non-susceptible (CNS) phenotype was defined as any isolate displaying a minimum inhibitory concentration (MIC) ≥1 mg/L for ertapenem. Results: CZA was active against 95.8% of all isolates and 77.5% of CNS isolates. Fosfomycin (FOS) and tigecycline (TGC) were the second most active antibiotics with 93.4% of Enterobacterales being susceptible. Conclusions: The results of this study underline the potential therapeutic role of CZA in Latin America.

517. Treatment Patterns of Hospitalized Adults with Infections Due to Carbapenem Non-Susceptible Gram-Negative Organisms in a Large Electronic Health Record Database in the United States

BackgroundInfections caused by carbapenem non-susceptible (C-NS) Gram-negative (GN) organisms pose a major threat, due in part to limited treatment options. The aim of this study was to assess treatment patterns for these infections in a large US electronic health record database.MethodsA retrospective cohort study of hospitalized adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), bacterial pneumonia (BP), or bacteremia (BAC) due to C-NS (resistant/intermediate susceptibility to carbapenem) GN organisms from January 2013 to March 2018. Patients with inherently C-NS organisms (e.g., Pseudomonas aeruginosa to ertapenem) were only included if resistance to another carbapenem was identified. The index date was the date of first C-NS culture in a qualifying hospitalization (±3 days from admission/discharge). Clinical characteristics and administered treatments were assessed from admission to discharge with variables summarized descriptively and stratified by infection type.Results7,702 patients met inclusion criteria: 31% cUTI ± BAC, 24% BP ± BAC, 21% cUTI + BP ± BAC, 17% cIAI ± BAC, cUTI, or BP, 7% BAC only. The median age was 66 years, ranging from 60 (BAC) to 69 (cUTI) years; male, 57%. The most common pathogens were Pseudomonas aeruginosa (64%) and Klebsiella pneumoniae (15%). Antibiotics were administered to the majority of patients (87%); of which, 79% received combination therapy (median classes: 3, maximum: 7), the remainder received monotherapy. For antibiotic-treated patients, 93% initiated an antibiotic before the non-susceptibility status of the underlying organism was known. The most common classes given during the index hospitalization were: penicillin (49%), fluoroquinolone (44%), carbapenem (40%), cephalosporin (39%), aminoglycoside (28%) (by infection type, Figure 1). Eleven percent of patients received colistin/polymyxin B.ConclusionVaried antibiotic use was observed in this cohort, with carbapenems frequently detected despite the C-NS nature of the underlying GN organisms. The use of antibiotics to which organisms are non-susceptible could lead to poor health outcomes, supporting the need for new targeted therapies to treat C-NS infections. Disclosures All authors: No reported disclosures.

AcrAB-TolC efflux pump system plays a role in carbapenem non-susceptibility in Escherichia coli

BackgroundEfflux pump mediated antibiotic resistance is an unnoticed and undetected mechanism in clinical microbiology laboratory. RND efflux systems are known for aminoglycoside and tetracycline resistance whereas their role in carbapenem non-susceptibility is not established. The study was undertaken to investigate the role of efflux pump in providing resistance against carbapenems and their response against concentration gradient carbapenem stress on the transcriptional level of the AcrAB gene in the clinical isolates of Escherichia coli from a tertiary referral hospital of Northeast India.ResultsOut of 298 non-susceptible Escherichia coli isolates 98 isolates were found to have efflux pump mediated carbapenem non-susceptibility. Among them thirty-five were non carbapenemase producers and their expressional levels were verified using qRT-PCR under concentration gradient carbapenem stress. In this study, a strong correlation between ertapenem resistance and AcrA overexpression was observed which has not been reported previously. Further, it was observed that imipenem stress increased AcrB expression in Escherichia coli which holds the novelty of this study. Additionally, the transcription of AcrR was insistently increased which is much higher than the transcriptional level of AcrA under concentration gradient carbapenem stress condition.ConclusionThe study established that AcrAB pump is a relevant antibiotic resistance determinant in bacterial pathogen, has an important role in developing resistance against carbapenem group of antibiotics.

Application of Molecular Methods for Carbapenemase Detection.

This study has evaluated the correlation between different carbapenemases detection methods on carbapenem non-susceptible Klebsiella pneumoniae strains from Northern and Eastern Europe; 31 institutions in 9 countries participated in the research project, namely Finland, Estonia, Latvia, Lithuania, Russia, St. Petersburg, Poland, Belarus, Ukraine, and Georgia. During the research program, a total of 5,001 clinical K. pneumoniae isolates were screened for any carbapenem non-susceptibility by the disk diffusion method, Vitek 2 or Phoenix system following the EUCAST guideline on detection of resistance mechanisms, version 1.0. Strains isolated from outpatients and hospitalized patients from April 2015 to June 2015 were included. All types of samples (blood, pus, urine, etc.) excluding fecal screening or fecal colonization samples have been represented. In total, 171 carbapenemase screening-positive K. pneumoniae isolates (3.42%) were found and characterized. Several methods were used for detection of carbapenemases production, including Luminex assay (PCR and hybridization), whole genome sequencing, MALDI-TOF based Imipenem degradation assay, and immunochromatography testing. Minimal inhibitory concentration determination for Meropenem by agar-based gradient method was also used. Finally, 83 K. pneumoniae strains were carbapenemase negative by all confirmation methods (49.4% of all screening-positive ones), 74 – positive by three methods (44.0%), 8 – positive by two methods (4.8%) and 3 – positive by only one method (1.8%). The sensitivity of the tests was 96.3% for Whole genome sequencing and MALDI-TOF assay (both three undetected cases), and 95.1% for Luminex-Carba (4 undetected cases). The most commonly detected carbapenemases were NDM (n = 54) and OXA-48 (n = 26), followed by KPC-2, VIM-5, and OXA-72 (one case of each). Our results showed that different types of carbapenemases can be detected in the countries involved in the project. The sensitivity of our methods for carbapenemase detection (including screening as a first step and further confirmation tests) was >95%, but we would recommend using different methods to increase the sensitivity of detection and make it more precise.

Nationwide surveillance of antimicrobial resistance among clinically important Gram-negative bacteria, with an emphasis on carbapenems and colistin: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) in 2018

Multicentre surveillance of antimicrobial susceptibility of clinically important Gram-negative bacteria (GNB) from 16 Taiwanese hospitals was performed. Escherichia coli (n = 398), Klebsiella pneumoniae (n = 346), Pseudomonas aeruginosa (n = 252) and Acinetobacter baumannii complex (ABC) (n = 188) bloodstream isolates, non-typhoidal Salmonella (n = 230) and Shigella flexneri (n = 18) from various sources were collected. Antimicrobial MICs were determined using broth microdilution. Genes encoding K. pneumoniae carbapenemases (KPCs), New Delhi metallo-β-lactamases (NDMs), Verona integron-encoded metallo-β-lactamase (VIM), OXA-48-like carbapenemase (OXA-48) as well as mcr-1-5 genes were detected by molecular methods. Rates of carbapenem non-susceptibility were 2.8%, 9.0%, 0.4%, 0%, 10.3% and 48.8% for E. coli, K. pneumoniae, Salmonella, Shigella, P. aeruginosa and ABC, respectively. For carbapenemases, one (0.3%) E. coli harboured blaNDM-1. Fifteen (4.3%), two (0.6%) and two (0.6%) K. pneumoniae contained blaKPC, blaOXA-48 and blaVIM, respectively. Two (0.5%) E. coli and fourteen (4.0%) K. pneumoniae were non-wild-type according to the colistin MIC. Among Enterobacteriaceae with a colistin MIC ≥ 2 mg/L, mcr-1 was detected in one E. coli, two K. pneumoniae and three Salmonella spp. All three mcr-1-positive Salmonella isolates were collected from community-acquired infections; none of the six mcr-1-positive Enterobacteriaceae were carbapenem-resistant. Carbapenem resistance has increased among clinically important GNB, especially among hospital-acquired infections. blaKPC, especially the blaKPC-2 variant, was detected in approximately one-half of the carbapenem-resistant K. pneumoniae isolates in this study. Although resistance rates to colistin remained low among Enterobacteriaceae, the finding of mcr-1 from different species raises concern of potential dissemination.

Risk Factors for Mortality in Children with Acinetobacter baumannii Bacteremia in South Korea: The Role of Carbapenem Resistance.

Aims: Acinetobacter baumannii has become an important nosocomial pathogen that causes invasive infections. We conducted a retrospective study to evaluate the risk factors for mortality due to A. baumannii bacteremia in children. Materials and Methods: We reviewed data from Seoul National University Children's Hospital from 2002 to 2013 for children with A. baumannii bacteremia, including age, gender, underlying disease, associated site of infection, duration of hospitalization, presence of neutropenia, and antibiotic susceptibility data. The outcome measures were the 7- and 30-day mortality rates. Results: Among 74 A. baumannii bacteremia cases, 35.1% were carbapenem nonsusceptible. Common comorbidities were malignancy or hematologic diseases (28.4%), followed by gastrointestinal/hepatobiliary diseases (21.6%). A total of 47.3% of patients had isolated bacteremia, and in 33.8% of patients, pneumonia accompanied bacteremia. The mortality rates were 18.9% at 7 days and 35.1% at 30 days. The significant associated factors for 30-day mortality were carbapenem nonsusceptibility (adjusted hazard ratio [aHR]: 1.28, 95% confidence interval [CI]: 1.10-11.82, p = 0.034), neutropenia (aHR: 1.68, 95% CI: 1.60-18.03, p = 0.007), and prior intensive care unit (ICU) admission (aHR: 1.15, 95% CI: 1.03-9.73, p = 0.045). The mortality rate among neutropenic patients with inappropriate empirical antibiotics was higher than that among patients with appropriate empirical antibiotics (90.1% vs. 33.3%, p = 0.031). Conclusions: We identified carbapenem nonsusceptibility, neutropenia, and prolonged ICU stay as independent risk factors for mortality due to A. baumannii bacteremia in children. An early administration of appropriate antibiotics should be enacted, especially in patients with neutropenia.

1174. Epidemiology of Carbapenem-Resistant Enterobacteriaceae, a 5-Year Experience at a Tertiary Care Hospital

BackgroundCarbapenem-resistant Enterobacteriaceae (CRE) has been increasing worldwide. Our objectives were to study the epidemiology of CRE and compare risk factors and mortality of carbapenem nonsusceptibility to ertapenem alone Enterobacteriaceae (NSEE) with nonsusceptibility to other carbapenems (imipenem, meropenem, or doripenem) Enterobacteriaceae (NSOCE) at a tertiary care hospital in Thailand.MethodsAll CRE isolated from clinical and surveillance cultures were identified from December 2011 to December 2016. Quarterly incidence rate per 100,000 patient-days was estimated. Hospital-wide carbapenem consumption were calculated as defined daily doses (DDD) per 1,000 patient-days. Relationships between hospital-wide carbapenem consumption and incidence of CRE were tested using Poisson regression. Comparative analysis of factors associated with NSEE and NSOCE, and risk factors associated with 14- and 30-day mortality in patients with CRE infection was conducted in adult patients.ResultsThe quarterly CRE incidence of unique patients increased significantly from 3.37 per 100,000 patient-days in the last quarter of 2011 to 32.49 per 100,000 patient-days in the last quarter of 2016. Quarterly CRE incidence increased 1.07 per 100,000 patient-days (95% confidence interval [CI], 0.49–1.06; P-value for trend <0.001). Quarterly hospital-wide carbapenem consumption increased 1.58 DDD per 1,000 patient-days (95% CI, 0.56–2.59; P-value for trend = 0.004). The expected increase of CRE incidence was 1.02 per 100,000 patient-days for a one DDD per 1,000 patient-days increase in carbapenem consumption (95% CI, 1.01–1.03; P < 0.001). There were 40 patients with NSEE and 134 patients with NSOCE. In the multivariate analysis, lower carbapenem exposure was significantly associated with the NSEE group (adjusted odds ratio: 0.25; 95% CI, 0.11–0.56). No difference in 14-day and 30-day all-cause mortality between NSEE group and NSOCE group was observed.ConclusionThe incidence of CRE has risen significantly over a 5-year period at our institution. The important risk factor for nonsusceptibility to other carbapenems compared with nonsusceptibility to ertapenem alone was previous carbapenem use. Our hospital-wide carbapenem use has significantly increased over time, and associated with the increasing incidence of CRE.Disclosures All authors: No reported disclosures.