Emergence of Imipenem-Resistant Gram-Negative Bacilli in Intestinal Flora of Intensive Care Patients

ABSTRACTIntestinal flora contains a reservoir of Gram-negative bacilli (GNB) resistant to cephalosporins, which are potentially pathogenic for intensive care unit (ICU) patients; this has led to increasing use of carbapenems. The emergence of carbapenem resistance is a major concern for ICUs. Therefore, in this study, we aimed to assess the intestinal carriage of imipenem-resistant GNB (IR-GNB) in intensive care patients. For 6 months, 523 consecutive ICU patients were screened for rectal IR-GNB colonization upon admission and weekly thereafter. The phenotypes and genotypes of all isolates were determined, and a case control study was performed to identify risk factors for colonization. The IR-GNB colonization rate increased regularly from 5.6% after 1 week to 58.6% after 6 weeks in the ICU. In all, 56 IR-GNB strains were collected from 50 patients: 36Pseudomonas aeruginosastrains, 12Stenotrophomonas maltophiliastrains, 6Enterobacteriaceaestrains, and 2Acinetobacter baumanniistrains. InP. aeruginosa, imipenem resistance was due to chromosomally encoded resistance (32 strains) or carbapenemase production (4 strains). In theEnterobacteriaceaestrains, resistance was due to AmpC cephalosporinase and/or extended-spectrum β-lactamase production with porin loss. Genomic comparison showed that the strains were highly diverse, with 8 exceptions (4 VIM-2 carbapenemase-producingP. aeruginosastrains, 2Klebsiella pneumoniaestrains, and 2S. maltophiliastrains). The main risk factor for IR-GNB colonization was prior imipenem exposure. The odds ratio for colonization was already as high as 5.9 (95% confidence interval [95% CI], 1.5 to 25.7) after 1 to 3 days of exposure and increased to 7.8 (95% CI, 2.4 to 29.8) thereafter. In conclusion, even brief exposure to imipenem is a major risk factor for IR-GNB carriage.

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ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02415-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 3

Author(s):

Ørjan Samuelsen ◽

Ove Alexander Høgmoen Åstrand ◽

Christopher Fröhlich ◽

Adam Heikal ◽

Susann Skagseth ◽

...

Keyword(s):

Active Site ◽

Therapeutic Potential ◽

Treatment Options ◽

Carbapenem Resistance ◽

Functional Space ◽

Bactericidal Effect ◽

Gram Negative ◽

Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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Reliability of three linguistically and culturally validated pain assessment tools for sedated ICU patients by ICU nurses in Finland

Scandinavian Journal of Pain ◽

10.1515/sjpain-2017-0139 ◽

2018 ◽

Vol 18 (2) ◽

pp. 165-173 ◽

Cited By ~ 1

Author(s):

Sanna-Mari Pudas-Tähkä ◽

Sanna Salanterä

Keyword(s):

Intensive Care ◽

Internal Consistency ◽

Pain Assessment ◽

Assessment Tools ◽

Endotracheal Suctioning ◽

Icu Patients ◽

Rater Reliability ◽

Intensive Care Patients ◽

Video Recordings ◽

Test Retest Reliability

Abstract Background and aims: Pain assessment in intensive care is challenging, especially when the patients are sedated. Sedated patients who cannot communicate verbally are at risk of suffering from pain that remains unnoticed without careful pain assessment. Some tools have been developed for use with sedated patients. The Behavioral Pain Scale (BPS), the Critical-Care Pain Observation Tool (CPOT) and the Nonverbal Adult Pain Assessment Scale (NVPS) have shown promising psychometric qualities. We translated and culturally adapted these three tools for the Finnish intensive care environment. The objective of this feasibility study was to test the reliability of the three pain assessment tools translated into Finnish for use with sedated intensive care patients. Methods: Six sedated intensive care patients were videorecorded while they underwent two procedures: an endotracheal suctioning was the nociceptive procedure, and the non-nociceptive treatment was creaming of the feet. Eight experts assessed the patients’ pain by observing video recordings. They assessed the pain using four instruments: the BPS, the CPOT and the NVPS, and the Numeric Rating Scale (NRS) served as a control instrument. Each expert assessed the patients’ pain at five measurement points: (1) right before the procedure, (2) during the endotracheal suctioning, (3) during rest (4) during the creaming of the feet, and (5) after 20 min of rest. Internal consistency and inter-rater reliability of the tools were evaluated. After 6 months, the video recordings were evaluated for testing the test-retest reliability. Results: Using the BPS, the CPOT, the NVPS and the NRS, 960 assessments were obtained. Internal consistency with Cronbach’s alpha coefficient varied greatly with all the instruments. The lowest values were seen at those measurement points where the pain scores were 0. The highest scores were achieved after the endotracheal suctioning at rest: for the BPS, the score was 0.86; for the CPOT, 0.96; and for the NVPS, 0.90. The inter-rater reliability using the Shrout-Fleiss intraclass correlation coefficient (ICC) tests showed the best results after the painful procedure and during the creaming. The scores were slightly lower for the BPS compared to the CPOT and the NVPS. The test-retest results using the Bland-Altman plots show that all instruments gave similar results. Conclusions: To our knowledge, this is the first time all three behavioral pain assessment tools have been evaluated in the same study in a language other than English or French. All three tools had good internal consistency, but it was better for the CPOT and the NVPS compared to the BPS. The inter-rater reliability was best for the NVPS. The test-retest reliability was strongest for the CPOT. The three tools proved to be reliable for further testing in clinical use. Implications: There is a need for feasible, valid and reliable pain assessment tools for pain assessment of sedated ICU patients in Finland. This was the first time the psychometric properties of these tools were tested in Finnish use. Based on the results, all three instruments could be tested further in clinical use for sedated ICU patients in Finland.

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Patterns of Antimicrobial Resistance Among Intensive Care Unit Patients of A Private Medical College Hospital in Dhaka

Bangladesh Journal of Medicine ◽

10.3329/bjmed.v25i2.25088 ◽

2015 ◽

Vol 25 (2) ◽

pp. 47-51 ◽

Cited By ~ 2

Author(s):

Quazi Tarikul Islam ◽

Md Mahmudur Rahman Siddiqui ◽

Farhana Raz ◽

Mohammad Asrafuzzaman ◽

Md Robed Amin

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Tracheal Aspirate ◽

College Hospital ◽

Icu Patients ◽

Gram Negative ◽

Pseudomonas Spp ◽

Medical College ◽

Acinetobacter Spp ◽

Klebsiella Spp

Because of importance of Hospital acquired infections (HAIs), it is critical to conduct surveillance studies to obtain the required data about the regional microorganisms and their susceptibility to antibiotics. This study to investigate antimicrobial resistance pattern among Intensive Care Unit (ICU) patients in a private medical college hospital setup. In a cross sectional study, 100 specimens from patients admitted in the ICU who had signs or symptoms of nosocomial infection were collected from 2012 - 2013. For each patient, samples of blood, urine, tracheal aspirate, sputum, wound swab, pus, and endotracheal tubes were obtained, cultured and analyzed with antibiogram. The most common primary diagnosis were aspiration pneumonia (49%) and UTI (20%) respectively. The most common locations for infection were tracheal aspirate (54%). The most frequent gram negative microorganisms derived from samples were Acinetobacter spp (29%), Klebsiella spp (26%) and Pseudomonas spp (18%). Klebsiella spp, Acinetobacter spp and Pseudomonas spp were most common resistant organisms among all. Klebsiella spp were resistant against Ceftriaxone (84.6%), Ceftazidime (82.6%), Amikacin (46.1%), Gentamicin (66.6%) and Quinolones (65-66.6%) respectively. Acinetobacter spp were resistant against Ceftriaxone (85%), Ceftazidime (88.8%), Cefotaxime (85.7%), Meropenem (79.3%),Amikacin (86.2%), Gentamicin (84.5%) and Quinolons (86.2-89.2%) respectively. Pseudomonas spp were resistant against Ceftriaxone (70.5%), Ceftazidime (66.6%), Amikacin (68.7%), Gentamicin (58.8%), Meropenem (52.9%) and Quinolones (81.2-86.6%) respectively. Meropenem was the most sensitive antibiotic against Klebsiella spp (84.6%) but Cotrimoxazole in case of Acinetobacter spp (60%) respectively. Escherichia coli were mostly isolated from urine, which was sensitive to Amikacin (73.3%) and Meropenem (86.6%) respectively. Gram-negative pathogens obtained from ICU patients in our settings show high resistance to antibiotics. Regular monitoring of the pattern of resistance of common pathogens in the ICUs is essential to up-to-date the use of rational antibiotics regiments.Bangladesh J Medicine Jul 2014; 25 (2) : 47-51

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Rapid Detection of Imipenem Resistance in Gram-Negative Bacteria Using Tabletop Scanning Electron Microscopy: A Preliminary Evaluation

Frontiers in Microbiology ◽

10.3389/fmicb.2021.658322 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriel Haddad ◽

Anthony Fontanini ◽

Sara Bellali ◽

Tatsuki Takakura ◽

Yusuke Ominami ◽

...

Keyword(s):

Bacterial Resistance ◽

Morphological Changes ◽

Carbapenem Resistance ◽

Preliminary Evaluation ◽

Gram Negative Bacteria ◽

Blind Test ◽

Gram Negative ◽

Length Width ◽

Imipenem Resistance ◽

Scanning Electron

Background: Enabling faster Antimicrobial Susceptibility Testing (AST) is critical, especially to detect antibiotic resistance, to provide rapid and appropriate therapy and to improve clinical outcomes. Although several standard and automated culture-based methods are available and widely used, these techniques take between 18 and 24 h to provide robust results. Faster techniques are needed to reduce the delay between test and results.Methods: Here we present a high throughput AST method using a new generation of tabletop scanning electron microscope, to evaluate bacterial ultra-structural modifications associated with susceptibilities to imipenem as a proof of concept. A total of 71 reference and clinical strains of Gram-negative bacteria were used to evaluate susceptibility toward imipenem after 30, 60, and 90 min of incubation. The length, width and electron density of bacteria were measured and compared between imipenem susceptible and resistant strains.Results: We correlated the presence of these morphological changes to the bacterial susceptibility and their absence to the bacterial resistance (e.g., Pseudomonas aeruginosa length without [2.24 ± 0.61 μm] and with [2.50 ± 0.68 μm] imipenem after 30 min [p = 3.032E-15]; Escherichia coli width without [0.92 ± 0.07 μm] and with [1.28 ± 0.19 μm] imipenem after 60 min [p = 1.242E-103]). We validated our method by a blind test on a series of 58 clinical isolates where all strains were correctly classified as susceptible or resistant toward imipenem.Conclusion: This method could be a potential tool for rapidly identifying carbapenem-resistance in Enterobacterales in clinical microbiology laboratories in <2 h, allowing the empirical treatment of patients to be rapidly adjusted.

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Colonization of central venous catheter in the intensive care units at the Institute of Cardiovascular Disease "Dedinje": One year study

Acta chirurgica iugoslavica ◽

10.2298/aci0503033c ◽

2005 ◽

Vol 52 (3) ◽

pp. 33-37

Author(s):

Ivana Cirkovic ◽

Vera Mijac ◽

Milena Svabic-Vlahovic ◽

S. Dukic ◽

I. Ilic ◽

...

Keyword(s):

Intensive Care ◽

Intensive Care Units ◽

Antimicrobial Agents ◽

Microbial Colonization ◽

Central Venous ◽

Candida Spp ◽

Icu Patients ◽

Gram Negative ◽

Microbiological Methods ◽

Increased Risk

Objectives: The application of Central Venous Catheters (CVC) is associated with increased risk of microbial colonization and infection. The aim of present study was to assess the frequency of pathogens colonizing CVC and to determine their susceptibility pattern to various antimicrobial agents. Materials and methods: A total of 253 samples of CVC from intensive care units (ICU) patients were received for culture during 2003. All microorganisms were identified by standard microbiological methods and the susceptibility to antimicrobial agents was determined according to NCCLS recommendations. Results: A total of 184 (72.7%) cultures were positive and 223 pathogens were isolated. Coagulase negative staphylococci (CNS) were the dominant isolates (24.7%), followed by Enterobacter spp. (12.1%), Pseudomonas spp. (11.7%), Enterococcus spp. (9.9%), Klebsiella spp. (8.6%), Candida spp. (7.6%), Acinetobacter spp. (7.6%), other Gram negative nonfermentative bacilli (5.8%), Serratia spp. (4.5%), Staphylococcus aureus (2.6%), Proteus mirabilis (2.2%), E. coli (1.8%) and Citrobacter spp. (0.9%). Meropenem (84.5%) and vancomycin (100%) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria, respectively. Conclusion: Gram negative bacilli and CNS are the commonest microorganisms colonizing CVC from ICU patients. The increasing resistance of the bacteria to antimicrobial agents is the major problem in spite of restricted policy of using antimicrobial agents in ICU.

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Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study

Critical Care ◽

10.1186/s13054-020-03397-1 ◽

2020 ◽

Vol 24 (1) ◽

Author(s):

Dennis Kühn ◽

Carlos Metz ◽

Frederik Seiler ◽

Holger Wehrfritz ◽

Sophie Roth ◽

...

Keyword(s):

Intensive Care ◽

Renal Replacement Therapy ◽

Therapeutic Drug Monitoring ◽

Extracorporeal Membrane Oxygenation ◽

Replacement Therapy ◽

Drug Monitoring ◽

Therapeutic Drug ◽

Serum Concentrations ◽

Icu Patients ◽

Intensive Care Patients

Abstract Background Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. Methods Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. Results The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. Conclusions ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

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High-Quality Complete Genome Sequences of Three Pseudomonas aeruginosa Isolates Retrieved from Patients Hospitalized in Intensive Care Units

Microbiology Resource Announcements ◽

10.1128/mra.01624-18 ◽

2019 ◽

Vol 8 (9) ◽

Cited By ~ 3

Author(s):

Bárbara Magalhães ◽

Laurence Senn ◽

Dominique S. Blanc

Keyword(s):

Pseudomonas Aeruginosa ◽

Intensive Care ◽

Intensive Care Units ◽

Genome Sequences ◽

High Quality ◽

Gram Negative ◽

Content Type ◽

Hospital Acquired Infections ◽

Hospital Acquired ◽

High Quality Genome

Pseudomonas aeruginosa is one of the major Gram-negative pathogens responsible for hospital-acquired infections. Here, we present high-quality genome sequences of isolates from three P. aeruginosa genotypes retrieved from patients hospitalized in intensive care units.

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Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2015.02.022 ◽

2015 ◽

Vol 46 (1) ◽

pp. 53-59 ◽

Cited By ~ 39

Author(s):

Helio S. Sader ◽

Mariana Castanheira ◽

Robert K. Flamm ◽

Rodrigo E. Mendes ◽

David J. Farrell ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Gram Negative Bacteria ◽

Ventilator Associated Pneumonia ◽

Icu Patients ◽

Gram Negative

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Metallo-β-lactamase-producing Clinical Isolates from Patients of a Tertiary Care Hospital

Journal of Laboratory Physicians ◽

10.4103/0974-2727.86841 ◽

2011 ◽

Vol 3 (02) ◽

pp. 093-097 ◽

Cited By ~ 6

Author(s):

Durgesh Gopalrao Deshmukh ◽

Ajit S Damle ◽

Jyoti K Bajaj ◽

Jayshree B Bhakre ◽

Neeta S Patwardhan

Keyword(s):

Intensive Care Unit ◽

Ethylenediaminetetraacetic Acid ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Carbapenem Resistance ◽

Resistance Mechanisms ◽

Care Hospital ◽

Gram Negative ◽

Serious Infections ◽

Imipenem Resistance

ABSTRACT Background: The growing increase in the rates of antibiotic resistance is a major cause for concern in both non-fermenting bacilli and isolates of the Enterobacteriaceae family. β-lactams have been the mainstay of treatment for serious infections, and the most active of these are the carbapenems. Acquired metallo-β-lactamases (MBL) have recently emerged as one of the most worrisome resistance mechanisms owing to their capacity to hydrolyze all β-lactams, including carbapenems. We have undertaken this investigation to ascertain the prevalence of MBL-producing non-fermenting bacilli and Enterobacteriaceae. Materials and Methods: The study was conducted over a period of 4 months in a 1200-bedded teaching hospital. Isolates included in the study were screened for imipenem resistance both by conventional methods and mini analytical profile index (miniAPI). The isolates that showed imipenem resistance were tested for MBL production by imipenem (IMP)-ethylenediaminetetraacetic acid combined disc test. Imipenem-resistant non-MBL isolates also tested for Modified Hodge test and AmpC β-lactamases production to detect other mechanisms of carbapenem resistance. Results: Of 638 gram negative bacilli isolates and 3.39% showed imipenem resistance, 2.9% showed MBL production, of which 1.7% were non-fermenters and 1.25% were Enterobacteriaceae, 0.3% showing non-MBL KPC carbapenemas. Most isolates were from the intensive care unit and from post-operative patients. Our findings show that there are significant numbers of isolates having MBL production along with multidrug resistance. There is a need for active surveillance to detect MBL producers.

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