Imipenem-resistant A. Baumannii Research Articles

581. The Epidemiology of Imipenem-Resistant Acinetobacter baumannii Bacteremia in a Pediatric Intensive Care Unit and Carbapenem Use

Background Acinetobacter baumannii (AB) infections cause high mortality and morbidity in intensive care unit patients. There are limited data on the epidemiology of imipenem-resistant A. baumannii (IRAB) amongst pediatric ICU patients.MethodsA retrospective chart review was performed in patients with AB bacteremia in a pediatric intensive care unit at a tertiary teaching hospital from January 2000 to December 2016. Antimicrobial susceptibility tests, multilocus sequence typing (MLST) and PCR for antimicrobial resistance genes were performed for stored isolates. In addition, antibiotic prescription days of therapy (DOT per 1,000 patient-days) of the pediatric department from January 2001 to December 2016 was analyzed.ResultsBacteremia episodes occurred in 27 patients. Male patients were 11 (41%) and the median age at the onset of bacteremia was 5.2 years (range, 0–18.6 years). There was a clear shift in antibiogram of AB during the study period. From 2000 to 2003, all isolates were imipenem-sensitive (ISAB, N = 6). From 2005 to 2008, both IRAB (N = 5) and ISAB (N = 4) were isolated. However, since 2009, all the AB isolates were IRAB (N = 12). In 33% (9/27) of patients, first AB was isolated from tracheal aspirate and patients developed bacteremia later (median duration from AB positive tracheal culture to AB positive blood culture, 8 days [range 5–124]). The overall mortality of patients with AB bacteremia was 59.3% (16/27) within 28 days. There was no statistical difference in mortality between ISAB and IRAB groups (50% vs. 71%; P = 0.42). From MLST analysis of 10 available isolates, sequence type 138 was predominant (N = 7). All 10 isolates were positive for OXA-23-like and OXA-51-like carbapenemase. In 2001, carbapenem DOT per 1,000 patient-days was 15.3 and later strikingly raised to 82.5 in 2009 when all the isolates were imipenem resistant. After this IRAB outbreak in PICU, proactive infection control and antimicrobial stewardship were reinforced among multidisciplinary teams in PICU. IRAB outbreak was terminated and carbapenem DOT per 1,000 patient-days was decreased to 51.7 in 2016.ConclusionIRAB bacteremia causes serious threat in high-risk pediatric patients in PICU. Proactive infection control measures and antimicrobial stewardship are crucial to manage serious IRAB infection in PICU.Disclosures All authors: No reported disclosures.

Mutation of CarO participates in drug resistance in imipenem-resistant Acinetobacter baumannii.

Objective Acinetobacter baumannii has become an important problem because of the high drug resistance rate. The aim of this study was to assess the antimicrobial resistance profile and explore the role of membrane porin in imipenem resistance of A baumannii.MethodsA total of 63 isolates of imipenem‐resistant A baumannii (IRAB) and 21 of imipenem‐sensitive A baumannii (ISAB) were collected. Susceptibility testing to 16 kinds of antimicrobial agents was conducted by K‐B method. PCR technique was used to detect carO and oprD genes, and sequencing was performed to compare the sequence between IRAB and ISAB. Three‐dimensional structure model of CarO protein was established.ResultsWhile ISAB isolates presented sensitive to most classes of antibiotics, isolates of IRAB displayed much higher resistance rate except tigecycline (3.2%), cefoperazone/sulbactam (28.6%), and minocycline (30.2%). All 84 isolates were observed carrying both carO and oprD genes. Further sequencing revealed important mutations of carO gene existed in IRAB in comparison with ISAB. Meanwhile, significant differences in three‐dimensional structure of carO protein molecule were also found between IRAB and ISAB.ConclusionsThe drug resistance profile of IRAB is increasingly severe in clinical settings. Mutation of CarO was identified as one of the molecular mechanisms involved in imipenem resistance in A baumannii.

Risk factors and molecular epidemiology of Acinetobacter baumannii bacteremia in neonates.

Acinetobacter baumannii infections in neonates are not uncommon but rarely studied. Clinical and molecular epidemiology of 40 patients with A. baumannii bacteremia in the neonatal intensive care units (NICUs) of a medical center from 2004 to 2014 was analyzed. Multi-drug resistance was found in only 3 isolates (7.5%). Sequence types (STs) of A. baumannii defined by multilocus sequencing typing were diverse, and 72.4% identified isolates belonged to novel STs. Majority of the isolates were susceptible to antibiotics tested. Among the 3 imipenem-resistant A. baumannii (IRAB) isolates, 2 (66.7%) belonged to ST684, a novel ST. All of the 3 isolates were susceptible to tigecycline and colistin. The predominant mechanism of imipenem resistance in these neonatal isolates is ISAba1-blaOXA-80, which has never been reported in Asia before. Most infected newborns were premature (95%), with very low birth weight (70%<1500g), prolonged intubation, usage of percutaneous central venous catheter (65%) and long-term usage of total parenteral nutrition or intravenous lipid (95%). IRAB infection, inappropriate initial therapy, 1-minute Apgar score and early onset infection within the first 10 days of life were found to correlate with mortality by log-rank test. Prior use of imipenem for at least 5 days and use of high frequency oscillation ventilation (HFOV) were statistically significant risk factors for acquiring IRAB infections. To reduce mortality of IRAB infection, it is crucial to consider giving effective agents, such as colistin, in 2 days for high risk neonates who has been given imipenem or used HFOV.

Trends in Drug Resistance of Acinetobacter baumannii over a 10-year Period: Nationwide Data from the China Surveillance of Antimicrobial Resistance Program.

Background:Acinetobacter baumannii has emerged as an important pathogen causing a variety of infections. Using data from the China Surveillance of Antimicrobial Resistance Program conducted biennially, we investigated the secular changes in the resistance of 2917 isolates of A. baumannii from 2004 to 2014 to differ antimicrobial agents.Methods:Pathogen samples were collected from 17 to 20 hospitals located in the eastern, central, and western regions of China. Minimum inhibitory concentrations (MICs) were determined by a 2-fold agar dilution method, and antimicrobial susceptibility was established using the 2014 Clinical Laboratory Standards Institute-approved breakpoints. Isolates not susceptible to all the tested aminoglycosides, fluoroquinolones, β-lactams, β-lactam/β-lactam inhibitors and carbapenems were defined as extensively drug resistant.Results:The rates of nonsusceptibility to common antimicrobial agents remained high (>65%) over the years with some fluctuations to certain agents. The prevalence of imipenem-resistant A. baumannii (IRAB) increased from 13.3% in 2004 to 70.5% in 2014 and that of extensively drug-resistant A. baumannii (XDRAB) increased from 11.1% in 2004 to 60.4% in 2014. The activity of tigecycline was stable with MIC90 ≤4 mg/L against A. baumannii from 2009 to 2014. Susceptibility to colistin remained high (97.0%) from 2009 to 2014. The prevalence of XDRAB increased in all the three surveillance regions over the years and was significantly higher in Intensive Care Unit (ICU) wards than non-ICU wards.Conclusions:This longitudinal multicenter surveillance program revealed the nationwide emergence of A. baumannii in China and showed a significant increase in prevalence from 2004 to 2014. High levels of bacterial resistance were detected among samples collected from clinical settings in China, with IRAB and XDRAB being especially prevalent. This study will help to guide empirical therapy and identify at-risk groups requiring more intense interventional infection control measures, while also helping to focus surveillance efforts.

Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients.

Acinetobacter baumannii is one of the most important noscomial pathogens worldwide. The study aimed to use multilocus sequence typing (MLST) for epidemiological surveillance of A. baumannii isolates in Taiwan and analyze the clinical presentations and patients' outcomes. MLST according to both Bartual's PubMLST and Pasteur's MLST schemes was applied to characterize bloodstream imipenem-resistant A. baumannii (IRAB) infection in intensive care units in a medical center. A total of 39 clinical IRAB bloodstream isolates in 2010 were enrolled. We also collected 13 imipenem-susceptible A. baumannii bloodstream isolates and 30 clinical sputum isolates (24 IRAB and 6 imipenem-susceptible A. baumannii) for comparison. Clinical presentations and outcome of the patients were analyzed. We found that infection by ST455B/ST2P and inappropriate initial therapy were statistically significant risk factors for mortality. More than one third of the IRAB isolates belonged to ST455B/ST2P. Most ST455B/ST2P (80%) carried ISAba1-blaOXA-23, including 10 (66.7%) with Tn2006 (ISAba1-blaOXA-23-ISAba1) in an AbaR4-type resistance island. ST455B/ST2P appears to evolve from ST208B/ST2P of clonal complex (CC) 92B/CC2P. In this hospital-based study, A. baumannii ST455 accounted for 38.5% of IRAB bacteremia, with a high mortality of 86.7%. Approximately 85% of ST455B/ST2P bacteremia had a primary source of ventilation-associated pneumonia. We report the emergence in Taiwan of IRAB ST455B/ST2P, which is the current predominant clone of IRAB in our hospital and has been causing bacteremia with high mortality in critical patients.

Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients.

Acinetobacter baumannii is one of the most important nosocomial pathogens worldwide. This study aimed to use multilocus sequence typing (MLST) for the epidemiological surveillance of A. baumannii isolates in Taiwan and analyze the clinical presentations and patients' outcome. MLST according to both Bartual's PubMLST and Pasteur's MLST schemes was applied to characterize bloodstream imipenem-resistant A. baumannii (IRAB) infection in intensive care units in a medical center. A total of 39 clinical IRAB bloodstream isolates in 2010 were enrolled. We also collected 13 imipenem-susceptible A. baumannii (ISAB) bloodstream isolates and 30 clinical sputum isolates (24 IRAB and 6 ISAB) for comparison. Clinical presentations and outcome of the patients were analyzed. We found that infection by ST455(B)/ST2(P) and inappropriate initial therapy were statistically significant risk factors for mortality. More than one-third of the IRAB isolates belonged to ST455(B)/ST2(P). Most ST455(B)/ST2(P) (80%) carried ISAba1-blaOXA-23, including 10 (66.7%) with Tn2006 (ISAba1-blaOXA-23-ISAba1) in an AbaR4-type resistance island. ST455(B)/ST2(P) appears to evolve from ST208(B)/ST2(P) of clonal complex (CC) 92(B)/CC2(P). In this hospital-based study, A. baumannii ST455 accounted for 38.5% of IRAB bacteremia, with a high mortality of 86.7%. Approximately 85% of ST455(B)/ST2(P)bacteremia had a primary source of ventilation-associated pneumonia. We report the emergence in Taiwan of IRAB ST455(B)/ST2(P), which is the current predominant clone of IRAB in our hospital and has been causing bacteremia with high mortality in critical patients.

Wide spread of Tn2006 in an AbaR4-type resistance island among carbapenem-resistant Acinetobacter baumannii clinical isolates in Taiwan

Carbapenem resistance in Acinetobacter baumannii is a global problem. The purpose of this study was to elucidate current resistance mechanisms of imipenem-resistant A. baumannii (IRAB) in Taiwan and their correlation with patient outcomes. Acinetobacter baumannii clinical isolates from two teaching hospitals in Taiwan were collected in 2009 and were examined by Etest for determination of the minimum inhibitory concentrations (MICs) of imipenem, ceftazidime and ceftriaxone. Primers specific for carbapenemase genes and upstream regions were designed for PCR amplification. Bacterial isolates were genotyped by pulsed-field gel electrophoresis (PFGE). Clinical presentations of patients were analysed retrospectively. Upstream insertion sequence ISAba1 was found in 34 isolates that carried blaOXA-23, including 28 with transposon Tn2006 (ISAba1–blaOXA-23–ISAba1) in an AbaR4-type resistance island and 6 with Tn2008 (ISAba1–blaOXA-23), as well as in 8 isolates carrying ISAba1–blaOXA-51-like. All of these isolates expressed full resistance to imipenem (MIC>32mg/L). Forty-one different PFGE genotypes were found among 62 isolates. Tn2006 was found in 19 genotypes (46.3%), which is more common than ISAba1–blaOXA-51-like (12.2%) (P=0.001). Prior use of carbapenems or extended-spectrum cephalosporins for ≥5 days was the only independent risk factor significantly associated with IRAB infection (odds ratio=361.175). Higher mortality was significantly associated with infection caused by IRAB and ISAba1–blaOXA-23-carrying strains compared with infection caused by imipenem-susceptible A. baumannii and ISAba1–blaOXA-51-like-carrying strains (P=0.009 and 0.027, respectively). Tn2006 is currently the most common imipenem resistance determinant, which showed a higher ability to spread among A. baumannii and was associated with a higher mortality in IRAB-infected patients.

Study of the Correlation of Imipenem Resistance with Efflux Pumps AdeABC, AdeIJK, AdeDE and AbeM in Clinical Isolates of Acinetobacter baumannii

Background: To investigate the role of efflux pumps AdeABC, AdeIJK, AdeDE and AbeM in reduced susceptibility to imipenem in clinical isolates of Acinetobacter baumannii. Methods: Susceptibility testing was conducted by the agar dilution method. The presence and expression of pump genes were analyzed by conventional PCR and real-time RT-PCR, respectively. Results: Most antibiotics, including carbapenem, aminoglycosides, fluoroquinolones and cephalosporins showed high minimum inhibitory concentration (MIC) values in imipenem-resistant A. baumannii (IRAB). After exposure to the efflux pump inhibitor Phe-Arg-β-naphthylamide, a 4- to 32-fold reduction of imipenem MICs was observed in 33 (66%) isolates of IRAB, while no significant decrease occurred in imipenem-susceptible A. baumannii (ISAB). The majority of IRAB isolates (>80%) were found to be positive for adeB, adeR, adeS, adeJ and abeM. Positive adeE was discovered in 6 isolates of IRAB and coexisted with adeB. Approximate 4-, 3- and 11-fold increases in adeB, adeJ and abeM expression were observed, respectively, in IRAB compared to those in ISAB. Conclusions: A variety of efflux pump systems, including AdeABC, AdeIJK and AbeM, seem to play important roles in the resistance to imipenem of A. baumannii. Moreover, this is the first time that adeE has been found to coexist with adeB in a small number of isolates of A. baumannii.

Detection of OXA‐type carbapenemases and integrons among carbapenem‐resistant Acinetobactor baumannii in a Teaching Hospital in China

The increasing trend of carbapenem-resistance (CR) and multi-drug resistance (MDR) in A. baumannii worldwide has limited the therapeutic effectiveness of antibiotic therapy. The study was conducted to determine the prevalence of carbapenemases and integrons among the isolates of imipenem-resistant A. baumannii (IRAB). A total of 71 non-repetitive imipenem- resistant A. baumannii isolates were collected and tested for susceptibility to 17 antimicrobials. The modified Hodge test and EDTA-disc synergy test were performed for the screening of carbapenemases and metallo-β -lactamases (MBLs) production, respectively. Isolates were then subjected to multiplex-PCR targeting genes encoding for OXA-type carbapenemase, MBLs and integrases. Random amplified polymorphic DNA (RAPD) genotyping was performed to assess genetic relatedness. All isolates exhibited multi-drug resistant phenotype. Colistin was the most active antimicrobial agent tested. Seventy-one isolates (100%) demonstrated positive in the modified Hodge test. Thirty-nine isolates showed positive in the EDTA-disc synergy test, however, no MBL genes were detected. All strains possessed a bla(OXA-51) -like gene. The co-exis-tence of bla(OXA-51) -like/bla(OXA-23) -like/intI1, bla(OXA-51) -like/bla(OXA-23) -like, bla(OXA-51) -like/bla(OXA-24) -like was detected in 91.6% (n = 65), 5.6% (n = 4), 2.8% (n = 2), respectively. Analysis of the genetic con-text of bla(OXA-23) showed the presence of ISAba1 upstream of bla(OXA-23) . No ISAba1 was detected upstream of bla(OXA-51) . Two different gene cassettes were found in these strains, and a high prevalence of aacA4, aadA1 and catB8 genes was observed. RAPD of 71 isolates showed 7 genotypes. The strains were mainly recovered from patients in intensive care unit, neurosurgery and department of respiratory disease. These findings show that multi-drug resistance in A. baumannii is a common problem. This study also shows a high distribution of bla(OXA-23) -like and intI1 genes in imipenem-resistant A. baumannii isolates. The clonal spread played an important role in the increase of OXA-23 producing IRABs in the hospital environment.

Nosocomial imipenem-resistant Acinetobacter baumannii infections: Epidemiology and risk factors

The incidence, clinical characteristics, risk factors, antimicrobial susceptibility, and outcomes of nosocomial imipenem-resistant A. baumannii (IRAB) infections during a 5-y period (2003-2007) were retrospectively analyzed. A total of 720 patients with 925 episodes of A. baumannii infection were included in the study. A. baumannii infections were seen mostly in intensive care units. The incidence was 6.2 per 1000 admissions. The most common infections were pneumonias and bloodstream infections. Imipenem resistance among Acinetobacter strains increased significantly each y of the study (from 43.3% to 72.9%). Mortality was related to the presence of imipenem resistance, stay in intensive care unit, female gender, old age, and pneumonia. Haemodialysis, malignancy, and mechanical ventilation were significant risk factors for IRAB infections. Imipenem resistance was higher in strains isolated from patients with pneumonia. IRAB strains showed higher resistance rates to other antibiotics than imipenem-susceptible strains. The most active antimicrobial agents against A. baumannii were cefoperazone-sulbactam and netilmicin. The incidence of A. baumannii infections and imipenem resistance increased during the study period. IRAB infections should be considered in patients on mechanical ventilation and haemodialysis and in patients with malignancies.

Epidemiology and Impact of Imipenem Resistance in Acinetobacter baumannii

Acinetobacter baumannii is an emerging gram-negative pathogen that can cause healthcare-acquired infections among patients. Treatment is complicated for cases of healthcare-acquired infection with A. baumannii resistant to imipenem. To elucidate the risk factors for imipenem-resistant A. baumannii (IRAB) infection or colonization and to identify the effect of resistance on clinical and economic outcomes. We analyzed data from 2 medical centers of the University of Pennsylvania. Longitudinal trends in the prevalence of IRAB clinical isolates were characterized during the period from 1989 through 2004. For A. baumannii isolates obtained from 2001 through 2006, a case-control study was conducted to investigate the association between prior carbapenem use and IRAB infection or colonization, and a cohort study was performed to identify the effect of IRAB infection or colonization on mortality, length of stay after culture, and hospital cost after culture. From 1989 through 2004, the annual prevalence of IRAB isolates ranged from 0% to 21%. During the period from 2001 through 2006, there were 386 unique patients with A. baumannii isolates, and 89 (23.1%) had IRAB isolates. Prior carbapenem use was independently associated with IRAB infection or colonization (adjusted odds ratio, 3.04 [95% confidence interval, 1.07-8.65]). There was a borderline significant association between IRAB infection or colonization and mortality, although this association was limited to isolates recovered from blood samples (adjusted odds ratio, 5.30 [95% confidence interval, 0.81-34.59]). Compared with patients with imipenem-susceptible A. baumannii infection or colonization, patients with IRAB infection or colonization had a longer hospital stay after culture (median, 21 vs 16 days; P = .07) and greater hospital charges after culture (mean, $334,516 vs $276,059; P = .03). After controlling for patient location in an intensive care unit, transfer from another facility, and length of hospital stay before culture, there was no longer an independent association between IRAB infection or colonization and higher cost after culture and length of stay after positive culture result. Many A. baumannii isolates exhibit imipenem resistance, which is strongly associated with prior use of carbapenems. Given the high mortality rate associated with A. baumannii infection or colonization, interventions to curb further emergence of cases of IRAB infection and strategies to optimize therapy are needed.