Meropenem-resistant Isolates Research Articles

Predicting early appropriate therapy for patients infected by carbapenem-resistant Gram-negative pathogens in intensive care units in Italy

BackgroundAntibiotic resistance among Gram-negative bacteria in intensive care units (ICUs) is linked with high morbidity and mortality in patients. In this study, we estimated the therapeutic coverage of various antibiotics, focusing on cefiderocol and comparators, administered empirically against an infection of unknown origin in the ICU.MethodsIn the ARTEMIS surveillance study, susceptibilities of 624 Italian Gram-negative isolates to amikacin, aztreonam-avibactam, cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, colistin, imipenem-relebactam, meropenem, and meropenem-vaborbactam were tested by broth microdilution, and results were interpreted by European Committee on Antimicrobial Susceptibility Testing breakpoints. The susceptibility rates from the ARTEMIS study were extrapolated to Gram-negative isolates obtained from 5,774 patients in Italian ICUs in 2021. The sum of the predicted susceptibilities of individual pathogens represented the overall likelihood of in vitro activity of each antibiotic as early targeted therapy for ICU patients.ResultsA total of 624 Italian Gram-negative isolates included 206 Pseudomonas aeruginosa, 138 Acinetobacter baumannii, 187 Klebsiella pneumoniae, and 93 Escherichia coli. Against A. baumannii, K. pneumoniae, P. aeruginosa, and E. coli, the overall susceptibility rates for cefiderocol were 87.7%, 96.8%, 99%, and 100%, respectively; and for comparator agents, 8.7–96.4%, 25.7–100%, 73.3–100%, and 89.2–100%, respectively. Among the subset of meropenem-resistant isolates, susceptibility rates of A. baumannii, K. pneumoniae, and P. aeruginosa to cefiderocol were 86.4%, 96.2% and 100%, respectively. Corresponding susceptibility rates to comparator agents were 0–96.8%, 0–100%, and 6.4–100%, respectively. There were no meropenem-resistant isolates of E. coli. The extrapolation of data to isolates from Italian ICUs showed that the highest likelihood of therapeutic coverage, both overall and among meropenem-resistant isolates, was reported for colistin (96.8% and 72.2%, respectively) and cefiderocol (95.7% and 71.4%, respectively). All other antibiotics were associated with a likelihood below 73% overall and between 0% and 41.4% for meropenem-resistant isolates.ConclusionsBased on confirmed susceptibility rates and reported ICU prevalence of multiple Gram-negative species, cefiderocol showed a higher predicted therapeutic coverage and utility in ICUs compared with comparator beta-lactam–beta-lactamase inhibitor antibiotics. Cefiderocol may be a promising early treatment option for patients at high risk of carbapenem-resistant Gram-negative bacterial infections in the ICU.

The Association Between Antibiotic Resistance and Biofilm Production in Klebsiella pneumoniae Isolated from Urinary Tract Infections.

Background and aims This research investigates the link between biofilm formation and antibiotic resistance among Klebsiella pneumoniae bacteria in Sana'a city, Yemen, a common cause of hospital-acquired infections and community-acquired infections. Methods: A 6-month study investigated 300 urinary tract infections samples, with 241 culture-positive. Standard methods were used for isolation and identification, including biofilm production and antibiogram susceptibility patterns of Klebsiella pneumoniae. Results: The study reveals that penicillin resistance is linked to Klebsiella pneumoniae's ability to form biofilms. Ampicillin-resistant isolates formed biofilms 97.5% of the time, while non-biofilm-producing isolates had a lower rate of resistance. Carbapenem group resistance was also significant, with Meropenem-resistant isolates forming biofilms 42.5% of the time. Cephalosporin resistance ranged from 80-95% for Biofilm-Forming Isolates, while Quinolones resistance ranged from 65-82%. Aminoglycoside resistance was also significant, with gentamicin and amikacin resistance rates being 42.5% and 42.5%, respectively. These findings highlight the importance of understanding the phenotypes of Klebsiella pneumoniae in forming biofilms. Conclusion: The study found a strong correlation between the biofilm production of Klebsiella pneumoniae and antibiotic resistance, with quinolones and cephalosporins being the least active, while carbapenems and aminoglycosides showed slight sensitivity.

Detection of Metallo β-Lactamase in Acinetobacter Species Using Phenotypic Methods with their Antibiotic Resistance Profile in Tertiary Care Hospital

Background: Acinetobacter species are commonly found in nature, in water, and in soil, and also, and they have been isolated from humans and animals. In the hospital setting, Acinetobacter species has emerged as a major opportunistic pathogen, being able to colonize and develop infections in patients. In Acinetobacter species, β-lactamases and outer membrane alterations are likely to function together to impart resistance. Understanding the epidemiology, and resistance mechanism, and for infection management and preventing a potential global health crisis, techniques for identifying Carbapenem-Resistant-Acinetobacter species are essential. Aim: To detect Metallo β-Lactamase (MBL) in Acinetobacter species with their antimicrobial susceptibility pattern. Material and Methods: 100 Acinetobacter species isolates from various clinical samples such as blood, cerebrospinal fluid, sputum, bronchoalveolar lavage, pus, urine, wound swab, and body fluids were included in the study. Phenotypic tests such as, Disc Potentiation test & Modified Hodge test were used to detect the presence of Metallo β-lactamase in imipenem & meropenem-resistant isolates. Results: The highest prevalence of Acinetobacter was found in blood (37%), followed by sputum (31%) and others [pus, urine, ascitic fluid, cerebrospinal fluid (CSF), bronchoalveolar Lavage (BAL), and pleural fluid]. A maximum number of Acinetobacter were isolated from MICU followed by medicine and surgery. The Modified Hodge test yielded the largest percentage of MBL-positive Acinetobacter isolates (67.26%) when compared to the Disc Potentiation test method (50.45%). Conclusion: Early detection of Metallo β-lactamase production is essential for planning appropriate treatment according to the resistance mechanisms of the multi-drug resistant strains, as well as for efficient infection control procedures to prevent the spread of infection.

Phenotypic and Molecular Detection of Carbapenemase-Producing Klebsiella pneumoniae Isolated from Patients Admitted to Teaching Hospitals in Shiraz, Iran

Background: Carbapenem-resistant Klebsiella pneumoniae (Cr-KPN) poses a significant global public health challenge. Objectives: This study aimed to investigate the prevalence and expression levels of carbapenemase-encoding genes in Cr-KPN isolated from patients admitted to teaching hospitals in Shiraz, Iran. Methods: A total of 671 distinct clinical samples were collected from two teaching hospitals in Shiraz. Initial identification and final confirmation of K. pneumoniae isolates were carried out using conventional biochemical tests and PCR assays, respectively. The detection of carbapenemase-producing K. pneumoniae, both phenotypically and genotypically, was performed through modified carbapenem inactivation methods (mCIM) and multiplex PCR assays. Real-time PCR was utilized to assess the expression levels of carbapenemase-encoding genes. Results: The overall frequency of K. pneumoniae strains was 14.9% (n = 100/671). mCIM indicated that 26% of K. pneumoniae isolates exhibited carbapenemase production. Furthermore, 24% and 17% of K. pneumoniae isolates demonstrated resistance to imipenem and meropenem, respectively. The blaIMI/IMP gene was detected in 91% of the isolates. Among imipenem-resistant isolates, 62.5% tested positive for the blaOXA-48 gene. Additionally, 29.4%, 76.5%, and 11.8% of meropenem-resistant isolates were positive for the blaKPC, blaOXA-48, and blaNDM genes, respectively. Real-time PCR analysis revealed increased expression levels of blaKPC (1.66-fold), blaOXA-48 (7.30-fold), blaNDM (4.22-fold), and blaIMI/NMC (2.39-fold) genes in resistant isolates when exposed to imipenem. Conclusions: These findings underscore the significance of establishing active surveillance networks to monitor and track the dissemination of carbapenemase-producing K. pneumoniae, which presents a global public health threat.

Activity of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected in central and northern Europe (Belgium, Norway, Sweden, Switzerland)-SMART 2017-21.

To evaluate the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in four central and northern European countries (Belgium, Norway, Sweden, Switzerland) during 2017-21. Participating clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intraabdominal, lower respiratory tract or urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted using 2022 EUCAST breakpoints. β-Lactamase genes were identified in select β-lactam-non-susceptible isolate subsets. Ninety-five percent of all Enterobacterales (n = 4158), 95% of ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype Escherichia coli and 85% of ESBL-positive non-CRE phenotype Klebsiella pneumoniae were ceftolozane/tazobactam susceptible. By country, 88% (Belgium), 91% (Sweden, Switzerland) and 96% (Norway) of ESBL-positive non-CRE phenotype Enterobacterales were ceftolozane/tazobactam susceptible. Greater than ninety-nine percent of non-Morganellaceae Enterobacterales and all ESBL-positive non-CRE phenotype Enterobacterales were imipenem/relebactam susceptible. Ceftolozane/tazobactam (96%) and imipenem/relebactam (95%) inhibited most Pseudomonas aeruginosa (n = 823). Both agents retained activity against ≥75% of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam susceptible and imipenem/relebactam susceptible, respectively. By country, 94% (Belgium), 95% (Sweden) and 100% (Norway, Switzerland) of P. aeruginosa were ceftolozane/tazobactam susceptible and 93% (Sweden) to 98% (Norway, Switzerland) were imipenem/relebactam susceptible. Carbapenemase gene carriage among Enterobacterales and P. aeruginosa isolates was generally low (<1%) or completely absent with one exception: an estimated 2.7% of P. aeruginosa isolates from Belgium carried an MBL. Recent clinical isolates of Enterobacterales and P. aeruginosa collected in four central and northern European countries were highly susceptible (≥95%) to ceftolozane/tazobactam and imipenem/relebactam.

In vitro activities of ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam and other comparators against Pseudomonas aeruginosa isolates with discrepant resistance to carbapenems: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012–2021

In this study, we aimed to investigate the in vitro susceptibility and β-lactamase-encoding genes of Pseudomonas aeruginosa isolates with discrepant resistance to various carbapenems. We obtained data on P. aeruginosa isolates from the Antimicrobial Testing Leadership and Surveillance program from 2012 to 2021. Minimum inhibitory concentrations of P. aeruginosa isolates were determined using the broth microdilution method. β-lactamase-encoding genes were identified using multiplex polymerase chain reaction assays. Among the P. aeruginosa isolates tested, the percentages of isolates resistant to imipenem, meropenem, and doripenem were 26.9% (14,447/53,617), 20.5 (14,098/68,897), and 17.5% (3,660/20,946), respectively. Imipenem-resistant P. aeruginosa isolates were more susceptible to all tested antimicrobial agents (except colistin) than the meropenem- or doripenem-resistant P. aeruginosa isolates. Carbapenemase genes were detected in 14.3% (2,020/14,098) of meropenem-resistant P. aeruginosa isolates. Imipenem-resistant meropenem-susceptible P. aeruginosa isolates had higher susceptibility profiles, fewer carbapenemase genes (0.3% [5/1,858] vs. 4.1% [10/242]; p < 0.05), and a lower risk of being classified as multidrug-resistant than the imipenem-susceptible meropenem-resistant isolates (16.1% [299/1,858] vs. .73.6% [178/242]; p < 0.05). Among all β-lactam combination agents, ceftazidime-avibactam and ceftolozane-tazobactam had higher susceptibility rates than meropenem-vaborbactam for meropenem-resistant P. aeruginosa (61.8% and 55.5% vs. 30.2%; p<0.05). In conclusion, discrepancy in the resistance of different P. aeruginosa isolates to various carbapenems suggests their different underlying resistance mechanisms. These findings can be useful for effective resistance trend monitoring and accurate antimicrobial treatment in the future.

Phenotypic and Genotypic Correlation of Antimicrobial Susceptibility of Bacteroides fragilis: Lessons Learnt.

Background Bacteroides fragilis is an opportunistic pathogen causing severe infections, including bacteremia. There have been increased reports of antimicrobial resistance in B. fragilis. However, phenotypic testing of susceptibility is time consuming and not cost effective for anaerobes. The present study investigates the correlation of phenotypic susceptibility with genotypic markers; to determine if these could be considered for deciding empirical therapy for B. fragilis. Material and methods Bacteroides fragilis isolates from various clinical samples including exudates, tissue, and body fluids were collected between November 2018 and January 2020 in the Department of Clinical Microbiology, Christian Medical College (CMC) Vellore. Species identification was done by MatrixAssistedLaserDesorptionIonization time of flight mass spectrometry (MALDI TOF) according to the manufacturer's instructions. A total number of 51 B. fragilis isolates were tested against metronidazole, clindamycin, piperacillin/tazobactam, and meropenem phenotypically by agar dilution method using Clinical & Laboratory Standards Institute (CLSI) 2019 guidelines and minimum inhibitory concentrations (MIC) were interpretated. The genotypic markers for antimicrobial resistance genes (nim, emrF, and cfiA) were studied by polymerase chain reaction (PCR) assay as per the standard protocol on all isolates to detect resistance genes. Results B. fragilis isolates in this study expressed 45%, 41%, and 16% phenotypic resistance to clindamycin, metronidazole, and meropenem, respectively, with least resistance topiperacillin/tazobactam (6%). Among the metronidazole resistant isolates, 52% harbored nim gene. Nim gene was also present in 76% (23/30) of the metronidazole susceptible isolates. Similarly, cfiA was present in all eight meropenem resistant isolates in addition to 22% (9/41) of the susceptible isolates. All cfiA negative isolates were phenotypically susceptible. Interestingly, 74% (17/23) of the clindamycin resistant isolates were positive for ermF. Conclusions Detection of a limited set of genes does not always correlate with phenotypic resistance to metronidazole and clindamycindue to the reported influence of insertion sequence (IS) elements, efflux, and other genetic determinants. Certainly, the absence of the cfiA gene can be employed to rule out meropenem resistance. However, redundant use of antibiotics such as meropenem along with metronidazole could be avoided for B. fragilis, which might otherwise elevate meropenem resistance. Recommendation of metronidazole requires prior phenotypic testing due to the reported 41% resistance.

High incidence of carbapenemase-producing Pseudomonas aeruginosa clinical isolates from Lagos, Nigeria.

Carbapenem-resistant Pseudomonas aeruginosa strains are on the rise worldwide. This study characterized clinical isolates of P. aeruginosa from three Nigerian hospitals for carbapenem resistance. Strains isolated from wounds (n = 88), urine/catheter tips (n = 25), sputum/tracheotomy aspirates (n = 5), ear swabs (n = 4) and vaginal swabs (n = 1) were identified by MALDI-TOF and antibiotic susceptibility testing was performed using the VITEK 2 system. The genomic DNA of each isolate was subject to sequencing using Illumina and Oxford nanopore technology. Bioinformatics analyses were performed to detect antimicrobial resistance genes, clonal affiliations and phylogenetic relations of 123 non-duplicate P. aeruginosa isolates, whereas assembly of the nanopore reads using the plasmIDent pipeline enabled the identification of plasmids. Forty-three percent of the isolates were resistant to all antibiotic categories tested. More than 40% of the isolates were resistant to the carbapenems imipenem and/or meropenem (39% and 44%, respectively). Among the meropenem-resistant isolates, 48 (89%) carried at least one carbapenemase gene. The predominant one was bla NDM-1 (n = 34), which conferred resistance to all five antibiotic categories and highly increased the MICs of both meropenem and imipenem. The other recurrent carbapenemase genes were bla VIM-2 (n = 4), and bla VIM-5-like (n = 11), which co-existed with bla NDM-1 in two isolates. The study revealed a high rate of carbapenem resistance and conjugative, broad host range plasmids carrying carbapenemase-encoding genes, especially the NDM-1 type, among isolates of P. aeruginosa. This may forebode the emergency of ubiquitous carbapenem resistance urging the implementation of infection control and antimicrobial stewardship strategies in Nigerian hospitals.

In vitro activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa collected from patients with bloodstream, intra-abdominal and urinary tract infections in Western Europe: SMART 2018-2020.

Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa; new agents with improved activity are needed.Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use.Aim. To describe the in vitro activity of IMR against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates.Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P. aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020).Results. IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant (n=1601) and 73.7 % of meropenem-resistant (n=152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against P. aeruginosa; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant P. aeruginosa. In total, 1.6 % of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD-deficient.Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.

In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.

Taniborbactam is a novel cyclic boronate β-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales (n = 13,731) and Pseudomonas aeruginosa (n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 μg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 μg/mL underwent whole-genome sequencing. β-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales, taniborbactam reduced the cefepime MIC90 value by >64-fold (from >16 to 0.25 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum β-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 μg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-β-lactamases (MBLs).

Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii

New antimicrobials are needed for the treatment of extensively drug-resistant Acinetobacter baumannii. The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that A.baumannii DHODH (AbDHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on AbDHODH. The most potent (DSM186, DHODH IC50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse A.baumannii strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of AbDHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of AbDHODH as a drug target for the development of antimicrobials for the treatment of A.baumannii and potentially other high-risk bacterial infections.

Facial microbial flora in bearded versus nonbearded men in the operating room setting: A single-center cross-sectional STROBE-compliant observational study.

Beards are controversial in the operating room setting because of the possible retention and shedding of pathogens. Surgical site infection poses a significant burden on healthcare systems. All male healthcare workers who entered the operating room were approached to participate in the study. Four facial swab samples were anonymously collected and a hygiene practice questionnaire was administered. Sample A was taken from the upper and lower lips, sample B from cheeks, and samples C and D were collected by 20 and 40 cm shedding below the face. Colony-forming units (CFUs) and minimum inhibitory concentrations (MICs) of meropenem resistance were determined for samples A and B. Random samples from A, B, C, and D, in addition to meropenem-resistant isolates were cultured with chlorohexidine. Sixty-one bearded and 19 nonbearded healthcare workers participated in the study. 98% were positive for bacterial growth with CFU ranging between 30 × 104 and 200 × 106 CFU/mL. Bacterial growth was significantly higher in bearded participants (P < .05). Eighteen (27.1%) isolates were resistant to meropenem; of these which 14 (77.8%) were from bearded participants, this was not statistically significant. Chlorohexidine was effective in inhibiting the growth of all strains including the meropenem-resistant isolates. Bearded men in the operating room had a significantly higher facial bacterial load. Larger-scale resistance studies are needed to address facial bacterial resistance among healthcare workers in the operating room.This study aimed to estimate the facial microbial load and identify strains and antimicrobial resistance profiles in bearded versus nonbearded male healthcare workers in the operating room of a tertiary hospital in the Middle East.

In vitro Activity of Cefiderocol and Comparators against Carbapenem-Resistant Gram-Negative Pathogens from France and Belgium.

Infections with carbapenem-resistant (CR) Gram-negative (GN) pathogens have increased in many countries worldwide, leaving only few therapeutic options. Cefiderocol (CFDC) is approved in Europe for the treatment of aerobic GN infections in adults with limited treatment options. This study evaluated the in vitro activity of cefiderocol and comparators against multidrug-resistant (MDR) bacteria including meropenem-resistant (MR) or pandrug-resistant (PR) GN clinical isolates from France and Belgium. The minimum inhibitory concentrations (MICs) of CFDC were determined by broth microdilution, using iron-depleted cation-adjusted Mueller–Hinton broth, and were compared to those of 10 last-line antibiotics. The MICs were interpreted according to EUCAST and CLSI breakpoints, and in the absence of species-specific breakpoints, non-species-related pharmacokinetic/pharmacodynamic breakpoints were used. Among the 476 isolates tested, 322 were carbapenemase producers (CP), 58 non-CP-CRs, 52 intrinsically CR, 41 expanded-spectrum cephalosporin resistant and 5 were multi-susceptible. Susceptibility to CFDC was high using EUCAST breakpoints 81%, 99% and 84%, and was even higher using CLSI breakpoints to 93%, 100% and 88% for Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii, respectively. Susceptibility to cefiderocol using non-species-related breakpoints for Stenotrophomonas maltophilia, Achromobacter xylosoxydans and Burkholderia cepacia, was 100%, 100% and 92.3%, respectively. The susceptibility rates were lower with the NDM producers, with values of 48% and 30% using EUCAST breakpoints and 81% and 50% using CLSI breakpoints for Enterobacterales and Acinetobacter spp, respectively. CFDC demonstrated high in vitro susceptibility rates against a wide range of MDR GN pathogens, including MR and PR isolates.

Identification of a potential inhibitor for New Delhi metallo-β-lactamase 1 (NDM-1) from FDA approved chemical library- a drug repurposing approach to combat carbapenem resistance

Superbugs producing New Delhi metallo-β-lactamase 1 (NDM-1) enzyme is a growing crisis, that is adversely affecting the global health care system. NDM-1 empowers the bacteria to inactivate entire arsenal of β-lactam antibiotics including carbapenem (the last resort antibiotic) and remains ineffective to all the available β lactamase inhibitors used in the clinics. Limited therapeutic option available for rapidly disseminating NDM-1 producing bacteria makes it imperative to identify a potential inhibitor for NDM-1 enzyme. With drug repurposing approach, in this study, we used virtual screening of available Food and Drug Administration (FDA) approved chemical library (ZINC12 database) and captured ‘adapalene’ (FDA drug) as a potent inhibitor candidate for NDM-1 enzyme. Active site docking with NDM-1, showed adapalene with binding energy −9.21 kcal/mol and interacting with key amino acid residues (Asp124, His122, His189, His250, Cys208) in the active site of NDM-1. Further, molecular dynamic simulation of NDM-1 docked with the adapalene at 100 ns displayed a stable conformation dynamic, with relative RMSD and RMSF in the acceptable range. Subsequently, in vitro enzyme assays using recombinant NDM-1 protein demonstrated inhibition of NDM-1 by adapalene. Further, the combination of adapalene plus meropenem (carbapenem antibiotic) showed synergistic effect against the NDM-1 producing carbapenem (meropenem) resistant clinical isolates (Escherichia coli and Klebsiella pneumoniae). Overall, our data indicated that adapalene can be a potential inhibitor candidate for NDM-1 enzyme that can contribute to the development of a suitable adjuvant to save the activity of carbapenem antibiotic against infections caused by NDM-1 positive gram-negative bacteria. Communicated by Ramaswamy H. Sarma

Global update on the in vitro activity of tigecycline and comparators against isolates of Acinetobacter baumannii and rates of resistant phenotypes (2016–2018)

ObjectivesThis study presents 2016–2018 in vitro antimicrobial activity data and rates of resistant phenotypes for clinical isolates of Acinetobacter baumannii from Africa/Middle East, Asia/South Pacific, Europe, Latin America, and North America. MethodsA total of 4320 A. baumannii isolates were collected across all regions between 2016 and 2018. The in vitro antimicrobial activities of amikacin, colistin, levofloxacin, meropenem, and tigecycline were determined using the broth microdilution methodology of the Clinical and Laboratory Standards Institute. MICs were interpreted using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (version 11.0). Rates of subsets that were resistant to amikacin, colistin, levofloxacin, and meropenem, according to EUCAST breakpoints, are also presented. ResultsIn each region, tigecycline and colistin were active against isolates of A. baumannii (MIC90 values, 1 or 2 mg/L) and the lowest rate of resistance was to colistin (1.2%–7.3%). The rates of resistance to the panel of agents were generally lower among A. baumannii from North America (1.3%–42.7%), compared with the other regions. Fewer than 11% of meropenem-resistant A. baumannii were also resistant to colistin. The rates of amikacin-, levofloxacin- and meropenem-resistant A. baumannii were lowest in North America and mostly higher in Africa/Middle East and Latin America. ConclusionIn each geographical region, tigecycline and colistin maintained good in vitro antimicrobial activity against isolates of A. baumannii, including antimicrobial-resistant subsets. The higher rates of meropenem-resistant isolates, particularly in Africa/Middle East and Latin America, require continued monitoring because of the scarcity of effective treatment options.

German Multicenter Study Analyzing Antimicrobial Activity of Ceftazidime-Avibactam of Clinical Meropenem-Resistant Pseudomonas aeruginosa Isolates Using a Commercially Available Broth Microdilution Assay.

Multidrug resistance is an emerging healthcare issue, especially concerning Pseudomonas aeruginosa. In this multicenter study, P. aeruginosa isolates with resistance against meropenem detected by routine methods were collected and tested for carbapenemase production and susceptibility against ceftazidime-avibactam. Meropenem-resistant isolates of P. aeruginosa from various clinical materials were collected at 11 tertiary care hospitals in Germany from 2017–2019. Minimum inhibitory concentrations (MICs) were determined via microdilution plates (MICRONAUT-S) of ceftazidime-avibactam and meropenem at each center. Detection of the presence of carbapenemases was performed by PCR or immunochromatography. For meropenem-resistant isolates (n = 448), the MIC range of ceftazidime-avibactam was 0.25–128 mg/L, MIC90 was 128 mg/L and MIC50 was 16 mg/L. According to EUCAST clinical breakpoints, 213 of all meropenem-resistant P. aeruginosa isolates were categorized as susceptible (47.5%) to ceftazidime-avibactam. Metallo-β-lactamases (MBL) could be detected in 122 isolates (27.3%). The MIC range of ceftazidime-avibactam in MBL-positive isolates was 4–128 mg/L, MIC90 was >128 mg/L and MIC50 was 32 mg/L. There was strong variation in the prevalence of MBL-positive isolates among centers. Our in vitro results support ceftazidime-avibactam as a treatment option against infections caused by meropenem-resistant, MBL-negative P. aeruginosa.

Expression of Mex AB-Opr M efflux pump system and meropenem resistance in Pseudomonas aeruginosa isolated from surgical intensive care unit

Background: Meropenem resistance of Pseudomonas aeruginosa (P. aeruginosa) is considered an increasing problem. Efflux pump is one of multiple mechanisms that are responsible for this resistance. This study aimed to phenotypically and genotypically detect prevalence of efflux pump mediated meropenem resistance among P. aeruginosa isolates. Methods: Pseudomonas aeruginosa was isolated from different clinical specimens and identified by conventional methods and confirmed by Vietek MS Malditof Mass Spectroscopy. Antibiotic susceptibility test was done by disc diffusion method then minimum inhibitory concentrations (MIC) for meropenem was detected twice by agar dilution method without and after addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP). Efflux pump genes were detected by polymerase chain reaction ( PCR). Results: Out of 265 specimens, 78 P. aeruginosa were isolated with an isolation rate (29.4%). By disc diffusion method and MIC by agar dilution methods, 35 (44.8%) isolates were meropenem resistant. There was a significant difference regarding distribution of efflux pump genes in meropenem resistant isolates as 23 isolates (65.7%) were positive for efflux pump genes and 12 (34.3%) were negative (p value= 0.13). The MICs of meropenem for P. aeruginosa isolates were significantly decreased after addition of CCCP where MIC of 21 (60%) meropenem resistant isolates had an efflux pump-overexpressing phenotype (p value =0.001). Conclusion: High prevalence of meropenem resistance in P. aeruginosa is mediated by efflux pump genes including, mex A, mex B and opr M.

In vitro activity of cefiderocol and comparators against isolates of Gram-negative bacterial pathogens from a range of infection sources: SIDERO‑WT‑2014−2018 studies in Spain

The incidence of antimicrobial resistance in Europe is rising. Cefiderocol is approved in Europe for treatment of aerobic Gram-negative bacterial (GNB) infections in adults with limited treatment options. We report the in vitro activity of cefiderocol versus comparators against GNB clinical isolates from Spain. MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol was tested using iron-depleted cation-adjusted Mueller-Hinton broth. Susceptibility rates were based on EUCAST breakpoints; if a species-specific breakpoint was unavailable, pharmacokinetic/pharmacodynamic breakpoints were used. Of 2303 isolates [1502 (65.2%) Enterobacterales and 801 (34.8%) non-fermenters], 2260 (98.1%) were susceptible to cefiderocol compared with 80.8-86.9% for comparators. By infection source, susceptibility to cefiderocol ranged from 97.3% (721/741) in isolates from patients with nosocomial pneumonia to 98.9% (349/353) in bloodstream infection isolates and was greater than susceptibility to comparators (70.7-93.6% across infection sources). Overall, 368/2303 isolates (16.0%) were meropenem-resistant. A high proportion of meropenem-resistant Acinetobacter baumannii [169/175 (96.6%)] and Pseudomonas aeruginosa [48/50 (96.0%)] were cefiderocol-susceptible, similar to colistin [169/175 (96.6%) and 47/50 (94.0%), respectively] but higher than ceftazidime/avibactam [26/175 (14.9%) and 20/50 (40.0%), respectively] and ceftolozane/tazobactam [17/175 (9.7%) and 25/50 (50.0%), respectively]. All meropenem-resistant Stenotrophomonas maltophilia isolates [120/120 (100%)] were cefiderocol-susceptible, including one trimethoprim/sulfamethoxazole-resistant isolate, with fewer susceptible to colistin [86/120 (71.7%)], ceftazidime/avibactam [42/120 (35.0%)] and ceftolozane/tazobactam [35/120 (29.2%)]. A high proportion of clinical isolates from Spain, representing a wide range of pathogens across multiple infection sources, were susceptible to cefiderocol. Cefiderocol retained activity against meropenem-resistant isolates.

PIN27 Cost-utility Analysis Focused on Nosocomial Pneumonia Antimicrobial Therapy - Is Ceftolozane/Tazobactam an Option to Fight Antimicrobial Resistance Sustaining Public Health System Affordability in Brazil?

Gram-negative bacterial (GNB) infections have become increasingly difficult to treat due to raising antimicrobial resistance rates in certain geographic regions such as Latin America. Ceftolozane-tazobactam (C/T) is a beta-lactam-beta-lactamase inhibitor agent that can be considered a clinical option for nosocomial pneumonia in critically ill patients caused by suspected meropenem and piperacillin-tazobactam resistant isolates in public Brazilian hospitals. We applied a model previously described by Naik et al. for patients that could be at risk of nosocomial pneumonia (NP) caused by Enterobacterales or Pseudomonas aeruginosa and should receive empiric antimicrobial therapy. The pathogens’ distribution was adapted from a 2018-2019 Brazil subsample in a global pathogen surveillance database. Clinical outcomes were extracted from a phase 3 trial of NP patients comparing C/T against meropenem. Piperacillin-tazobactam and meropenem were selected as comparators, being the most used antimicrobials in NP. Costs considered in this model were obtained through publications and publicly available databases such as SIGTAP and SIH that represent the Brazilian public healthcare system perspective on costs and care. A 5% discount rate was applied to costs and outcomes. When compared to meropenem the use of C/T can reduce mortality from 32.7% to 29.0%. The use of C/T resulted in 0.28 additional LYs and 0.22 incremental QALYs with R$8,592.87 incremental costs resulting in an ICER of R$39,723.33/QALY. Considering piperacillin-tazobactam as comparator, C/T could reduce mortality from 36.3% to 29.0%, generating 1.12 incremental LYs and 0.93 additional QALYs with R$3,987.06 additional costs. Resulting in an ICER of R$4,286.93/QALY. Antimicrobials accounts for 29.1% of total costs when considering treatment, hospital resource use, adverse events and patient monitoring. Against both comparators the C/T arm patients presented shorter ventilator and ICU length of stay. C/T could be a cost-effective option for NP in the Brazilian public healthcare system according to the World Health Organization's threshold.

PIN10 Cost-Utility Analysis Focused on Nosocomial Pneumonia Antimicrobial Therapy - Ceftolozane/Tazobactam Role in New Technologies Incorporation within Private Hospitals and HMOs in Brazil

Gram-negative bacterial (GNB) infections have become increasingly difficult to treat due to raising antimicrobial resistance rates in Latin America. The development of new antimicrobial agents is urgent to address resistance mechanisms that current molecules do not tackle. Ceftolozane-tazobactam (C/T) is a beta-lactam-beta-lactamase inhibitor agent that can be considered a clinical option for nosocomial pneumonia in critically ill patients at a high risk of meropenem and piperacillin-tazobactam resistant isolates.