Carbapenem-resistant Gram-negative Pathogens Research Articles

Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii.

ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii (n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) (n = 252) or Klebsiella pneumoniae carbapenemase (KPC) (n = 180) carbapenemases, and Pseudomonas aeruginosa (n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii. This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations.

Emergence of carbapenem resistant gram-negative pathogens with high rate of colistin resistance in Egypt: A cross sectional study to assess resistance trends during the COVID-19 pandemic

The current study investigated the temporal phenotypic and genotypic antimicrobial resistance (AMR) trends among multi-drug resistant and carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa recovered from Egyptian clinical settings between 2020 and 2021. Bacterial identification and antimicrobial sensitivity of 111 clinical isolates against a panel of antibiotics were performed. Molecular screening for antibiotic resistance determinants along with integrons and associated gene cassettes was implemented. An alarming rate (98.2%) of these isolates were found to be phenotypically resistant to carbapenem. Although 23.9 % K. pneumoniae isolates were phenotypically resistant to colistin, no mobile colistin resistance (mcr) genes were detected. Among carbapenem-resistant isolates, blaNDM and blaOXA-48-like were the most prevalent genetic determinants and were significantly overrepresented among K. pneumoniae. Furthermore, 84.78% of K. pneumoniae isolates co-produced these two carbapenemase genes. The plasmid-mediated quinolone resistance genes (qnrS and qnrB) were detected among the bacterial species and were significantly more prevalent among K. pneumoniae. Moreover, Class 1 integron was detected in 82% of the bacterial isolates. This study alarmingly reveals elevated resistance to last-resort antibiotics such as carbapenems as well as colistin which impose a considerable burden in the health care settings in Egypt. Our future work will implement high throughput sequencing-based antimicrobial resistance surveillance analysis for characterization of novel AMR determinants. This information could be applied as a step forward to establish a robust antibiotic stewardship program in Egyptian clinical settings, thereby addressing the rising challenges of AMR.

Structural basis of metallo-β-lactamase resistance to taniborbactam.

The design of inhibitors against metallo-β-lactamases (MBLs), the largest family of carbapenemases, has been a strategic goal in designing novel antimicrobial therapies. In this regard, the development of bicyclic boronates, such as taniborbactam (TAN) and xeruborbactam, is a major achievement that may help in overcoming the threat of MBL-producing and carbapenem-resistant Gram-negative pathogens. Of concern, a recent report has shown that New Delhi MBL-9 (NDM-9) escapes the inhibitory action of TAN by a single amino acid substitution with respect to New Delhi MBL-1 (NDM-1), the most widely disseminated MBL. Here, we report a docking and computational analysis that identifies that "escape variants" against TAN can arise by disruption of the electrostatic interaction of negative charges in the active site loops of MBLs with the N-(2-aminoethyl)cyclohexylamine side chain of TAN. These changes result in non-productive binding modes of TAN that preclude reaction with the MBLs, a phenomenon that is not restricted to NDM-9. This analysis demonstrates that single amino acid substitutions in non-essential residues in MBL loops can unexpectedly elicit resistance to TAN.

2523. Outcomes by Resistance Phenotype and Genotype among Baseline Pathogen in Patients with Complicated Urinary Tract Infection (cUTI) in the Phase 3 CERTAIN-1 Study

Abstract Background Taniborbactam is an investigational β-lactamase inhibitor that restores cefepime (FEP) activity against FEP-, carbapenem-, and multidrug-resistant Enterobacterales and Pseudomonas aeruginosa producing serine- and metallo-β-lactamases. Cefepime-taniborbactam (FTB) was superior to meropenem (MEM) for the primary composite endpoint of microbiologic and clinical success at test of cure (TOC) in adults with cUTI in the CERTAIN-1 study (NCT03840148). We assessed outcomes in subsets defined by baseline pathogen resistance phenotype and genotype. Methods Composite, microbiologic and clinical responses at TOC were assessed in the extended microbiologic intent-to-treat (microITT) population (patients with Enterobacterales and/or P. aeruginosa at ≥105 CFU/mL in urine at study entry against which at least 1 study drug had activity [FTB MIC ≤16 µg/mL; MEM MIC ≤2 µg/mL (Enterobacterales) or ≤4 µg/mL (P. aeruginosa)]). Phenotypic subsets included FEP-, multidrug-, and/or carbapenem resistance. Genotypic subsets included carriage of ESBL, extended-spectrum AmpC, plasmidic AmpC, and/or carbapenemase genes. Results For patients in the FTB treatment group with Enterobacterales at baseline, composite, microbiologic, and clinical success rates in resistant subsets were similar to or higher than those overall (Table). FTB achieved composite success in 7/8 patients with carbapenem-resistant Enterobacterales and in 8/9 patients with Enterobacterales producing a carbapenemase (5 OXA-48-group; 2 KPC-3, 2 NDM-1). FTB achieved composite success in 8/16 patients (clinical success in 13/16 patients) with P. aeruginosa overall; from 1 to 5 patients in the FTB group had P. aeruginosa in defined resistance categories. Conclusion FTB demonstrated efficacy in cUTI patients infected with cefepime-, multidrug-, and carbapenem-resistant pathogens and pathogens carrying ESBL, AmpC, and carbapenemase genes. Rates of success at TOC in each resistance subset were similar to or higher than those overall. These results are consistent with the ability of taniborbactam to restore cefepime activity against cefepime-, multidrug-, and carbapenem-resistant gram-negative pathogens producing serine and metallo-β-lactamases in nonclinical studies. Disclosures Greg Moeck, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Leanne Gasink, MD, MSCE, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|CSL Behring: Advisor/Consultant|CSL Behring: Consulting fees|Everest Medicines: Grant/Research Support|Evopint Biosciences: Advisor/Consultant|Evopint Biosciences: Consulting fees|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|LBG Consulting, LLC: Principal|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees|Vera Therapeutics: Advisor/Consultant|Vera Therapeutics: Consulting fees Mary Beth Dorr, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Merck and Co.: Shareholder|Pfizer: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Hongzi Chen, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Florian Wagenlehner, MD, Achaogen: Advisory Board member, study participation|Astellas: Honoraria|AstraZeneca: Honoraria|AstraZeneca: Advisory Board member|Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Bionorica: Honoraria|Bionorica: Meeting/travel support, study participation|Deutsches Zentrum für Infektionsforschung (DZIF): Study participation|Enteris BioPharma: Study participation|Everest Medicines: Grant/Research Support|German S3 guideline Urinary tract infections: Board Member|Glaxo Smith Kline: Advisor/Consultant|Glaxo Smith Kline: Honoraria|Glaxo Smith Kline: Consulting fees, meeting/travel support, advisory board member, principal investigator in a GSK-sponsored study|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Guidelines European Association of Urology: Infections in Urology: Board Member|Helperby Therapeutics: Study participation|Janssen: Honoraria|Janssen: Advisory Board member|Klosterfrau: Honoraria|LeoPharma: Advisory Board member|MerLion: Advisory Board member|MIP Pharma: Honoraria|MSD: Advisory Board member|OM Pharma/Vifor Pharma: Advisory Board member, study participation|OM-Pharma: Honoraria|Pfizer: Honoraria|Pfizer: Advisory Board member|RosenPharma: Advisory Board member|Shionogi: Advisory Board member, study participation|Speaker research group German research foundation (DFG) Bacterial Renal Infections and Defense (FOR 5427): Study participation|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|University Hospital Giessen and Marburg GmbH, and Justus Liebig University, Germany: Employee|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees, Advisory Board member Tim Henkel, MD, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Employee, consulting fees, shareholder Paul McGovern, MD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Paratek Pharmaceuticals: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder

In vitro activity of cefiderocol and other newly approved antimicrobials against multi-drug resistant Gram-negative pathogens recovered in intensive care units in Spain and Portugal.

The antimicrobial resistance is a significant public health threat, particularly for healthcare-associated infections caused by carbapenem-resistant Gram-negative pathogens which are increasingly reported worldwide. The aim of this study was to provide data on the in vitro antimicrobial activity of cefiderocol and that of commercially available comparator antibiotics against a defined collection of recent clinical multi-drug resistant (MDR) microorganisms, including carbapenem resistant Gram-negative bacteria collected from different regions in Spain and Portugal. A total of 477 clinical isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia were prospectively (n=265) and retrospectively (n=212) included (2016-2019). Susceptibility testing was performed using standard broad microdilution and results were interpreted using CLSI-2021 and EUCAST-2021 criteria. Overall, cefiderocol showed a good activity against Enterobacterales isolates, being 99.5% susceptible by CLSI and 94.5% by EUCAST criteria. It also demonstrated excellent activity against P. aeruginosa and S. maltophilia isolates, all being susceptible to this compound considering CLSI breakpoints. Regarding A. baumannii (n=64), only one isolate was resistant to cefiderocol. Our results are in agreement with other studies performed outside Spain and Portugal highlighting its excellent activity against MDR gram-negative bacteria. Cefiderocol is a therapeutic alternative to those available for the treatment of infections caused by these MDR bacteria.

Cost-effectiveness of IMI/CIL/REL for the treatment of carbapenem non-susceptible Gram-negative bacterial infections

Objective: The objective of this analysis was to evaluate the cost-effectiveness of imipenem/cilastatin/relebactam compared to colistin-imipenem in the treatment of hospitalized patients with Gram-negative bacterial infections caused by imipenem-resistant pathogens. The perspective was both that of the National Health Service (NHS) and the social one. Methodology: A mixed model was developed to simulate a cohort of patients capable of highlighting the impacts of the disease on the quality of life and the absorption of economic resources of the patients in analysis. Modelled patients were those with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) or complicated urinal tract infection (cUTI) caused by carbapenem-resistant Gram-negative (GN) pathogens. The model begins with a short-term decision tree describing possible treatment routes and outcomes for patients during the hospitalization period. Patients who are healed in the decision tree enter the long-term Markov model, designed to capture the follow-up costs and health-related quality of life (HRQL) of patients healed over their lifetime. Results: The analysis, conducted on a hypothetical cohort of 1,000 patients, highlights how the use of imipenem/cilastatin/relebactam is advantageous both in terms of diagnosis and treatment in the short term and in terms of cost-effectiveness. In fact, it is dominant compared to colistin-imipenem both in the NHS and in the social perspective since, compared to an average saving of € 2,800.15 and € 3,174.63 respectively, it would generate an increase of 4.76 years of life and of 4.12 QALYs per patient.

Emergence of carbapenem-resistant Pseudomonas alcaligenes and Pseudomonas paralcaligenes clinical isolates with plasmids harbouring bla IMP-1 in Japan.

Introduction. The emergence of carbapenem-resistant Pseudomonas species producing metallo-β-lactamase (MBL) has become a serious medical problem worldwide. IMP-type MBL was firstly detected in 1991 in Japan. Since then, it has become one of the most prevalent types of MBLs.Hypothesis/Gap statement. Avirulent species of Pseudomonas, such as Pseudomonas alcaligenes, function as reservoirs of drug resistance-associated genes encoding carbapenemases in clinical settings.Methodology. Active surveillance for carbapenem-resistant Gram-negative pathogens was conducted in 2019 at a hospital in Tokyo, Japan. Of the 543 samples screened for carbapenem-resistant isolates, 2 were species of Pseudomonas. One was from a stool sample from a medical staff member, and the other was from a stool sample from a hospitalized patient.Results. Whole-genome sequencing showed that the former isolate was a strain of P. alcaligenes, and the latter was a strain of Pseudomonas paralcaligenes, a species close to P. alcaligenes. Both isolates were resistant to all carbapenems and harboured bla IMP-1 genes encoding IMP-1 MBL, which conferred resistance to carbapenems. The bla IMP-1 genes of P. alcaligenes and P. paralcaligenes were located on the plasmids, pMRCP2, 323125 bp in size, and pMRCP1333, 16592 bp in size, respectively. The sequence of 82 % of pMRCP2 was 92 % similar to the sequence of a plasmid of P. aeruginosa PA83, whereas the sequence of 79 % of pMRCP1333 was >95 % similar to the sequence of a plasmid of Achromobacter xylosoxidans FDAARGOS 162. The genomic environments surrounding the bla IMP-1 of pMRCP2 and pMRCP1333 differed completely from each other.Conclusions. These results indicate that the two isolates acquired bla IMP-1 from different sources and that P. alcaligenes and P. paralcaligenes function as vectors and reservoirs of carbapenem-resistant genes in hospitals.

Determination of polymyxin B in human plasma and epithelial lining fluid using LC-MS/MS and its clinical application in therapeutic drug monitoring

Polymyxin B (PB) is currently one of the last resort treatment options against carbapenem-resistant gram-negative bacterial pathogens. Pharmacokinetics/pharmacodynamics (PK/PD) guided therapeutic drug monitoring (TDM) of antibiotics is critical for optimizing dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. Currently, methods for determining PB in human plasma and epithelial lining fluid (ELF) are limited. In this study, we developed and validated a simple method for PB determination in human plasma and ELF using LC-MS/MS. Protein precipitation of the sample was conducted with 0.1% formic acid-acetonitrile. Polymyxin B1 and B2 were separated on a C18 column and detected within 4 min by the mass spectrometer in the positive mode coupled with multiple reaction monitoring. The calibration curve range was 0.156–10.0 and 0.0156–1.00 μg/mL in the plasma for polymyxin B1 and B2, respectively, and was 0.0625–2.00 and 0.00625–0.200 μg/mL for polymyxin B1 and B2, respectively in bronchoalveolar lavage fluid. The accuracy of the intra- and inter-assay studies ranged from 80.6% to 114.9%, and the coefficients of variation for intra- and inter-day assays were less than 14.8%. Among a considerable number of patients, the average steady-state plasma concentration of PB was suboptimal. Moreover, the exposure to PB in patients with acute kidney injury (AKI) was considerably higher than that in patients without AKI. Meanwhile, a higher concentration of PB in ELF could be achieved than that in plasma after PB nebulization treatment. The established method was proven to be rapid, simple, and suitable for TDM of PB and PK/PD studies in human plasma and ELF.

The menace of colistin resistance across globe: Obstacles and opportunities in curbing its spread

Colistin-resistance in bacteria is a big concern for public health, since it is a last resort antibiotic to treat infectious diseases of multidrug resistant and carbapenem resistant Gram-negative pathogens in clinical settings. The emergence of colistin resistance in aquaculture and poultry settings has escalated the risks associated with colistin resistance in environment as well. The staggering number of reports pertaining to the rise of colistin resistance in bacteria from clinical and non-clinical settings is disconcerting. The co-existence of colistin resistant genes with other antibiotic resistant genes introduces new challenges in combatting antimicrobial resistance. Some countries have banned the manufacture, sale and distribution of colistin and its formulations for food producing animals. However, to tackle the issue of antimicrobial resistance, a one health approach initiative, inclusive of human, animal, and environmental health needs to be developed. Herein, we review the recent reports in colistin resistance in bacteria of clinical and non-clinical settings, deliberating on the new findings obtained regarding the development of colistin resistance. This review also discusses the initiatives implemented globally in mitigating colistin resistance, their strength and weakness.

Global escalation in carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii infections: Serious threat to human health from the pink corner

Rise in carbapenem-resistant Gram-negative bacterial infections, especially among immunocompromised patients in healthcare settings is an imminent threat as they are difficult to treat and result in a prolonged length of hospital stay, frequent treatment failures, increased economic burden on the patient and the nation, and a high rate of morbidity and mortality. Major carbapenemase-producing Gram-negative bacteria are carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE) such as Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and others. These bacteria that contaminate health-care settings are the major causes of a wide range of hospital-associated infections including life-threatening septicemia, pneumonia, meningitis, bones and joint infections, and skin and soft-tissue infections. Carbapenems are regarded as last resort available antibiotics to treat multidrug-resistant Gram-negative bacterial infections that show resistance to most of the beta-lactam antibiotics in addition to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole. Emergence and spread of carbapenem-resistant Gram-negative pathogens such as CRE and CRAB is a matter of serious concern because of limited treatment options and grave consequences. The World Health Organization has given level one priority to these pathogens and the United States Centers of Disease Control and Prevention considers CRE and CRAB as one of the top five most priority pathogens of public health importance. Strict control measures by the government and public is critical to prevent emergence and dissemination of these dangerous pathogens. In this article, the authors have summarized the microbiological and epidemiological perspectives of CRE and CRAB with a special focus on diagnosis, prevention, and novel promising alternative treatment strategies.

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.

Current and Potential Therapeutic Options for Infections Caused by Difficult-to-Treat and Pandrug Resistant Gram-Negative Bacteria in Critically Ill Patients.

Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel β-lactam-β-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented.

Six-Year Time-Series Data on Multidrug-Resistant Bacteremia, Antibiotic Consumption, and Infection Control Interventions in a Hospital.

Background: Multidrug-resistant (MDR) bacteremia is a serious health care-associated infection with significant morbidity and excess hospitalization costs. Our aim is to study the association between incidences of MDR bacteremia, antibiotic consumption, and infection control measures in a hospital from 2013 to 2018. Methods: We analyzed the following indices: (1) incidence of bacteremia (carbapenem-resistant Acinetobacter baumanii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci); (2) use of antibiotics; (3) consumption of disinfectant solutions for hand hygiene; and (4) isolation rates of MDR carrier patients. Findings: The use of advanced antibiotics (p = 0.001) and carbapenems (p = 0.008) decreased significantly in all hospital departments but the incidence of total MDR bacteremia did not change significantly. Increased use of hand disinfectant solutions was statistically associated with decreased incidence of total MDR bacteremia (incidence rate ratio [IRR]: 0.94, confidence interval [95% CI]: 0.90-0.99, p: 0.020) in all hospital. Also, increased isolation rates of MDR carrier patients 2 months before correlated with decreased incidence of bacteremia due to carbapenem-resistant gram-negative pathogens (IRR: 0.35, 95% CI: 0.18-0.66, p: 0.001) in adults intensive care unit. Conclusion: In our hospital, hand hygiene and isolation of MDR carrier patients controlled MDR bacteremia.

Rapid, simple, and economical LC–MS/MS method for simultaneous determination of ceftazidime and avibactam in human plasma and its application in therapeutic drug monitoring

Carbapenem-resistant Gram-negative bacterial pathogens continue to threaten public health. Avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor, has been approved for use with ceftazidime (CAZ) mainly against carbapenem-resistant Enterobacteriaceae. Therapeutic drug monitoring (TDM) is urgently needed to optimize dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. This study aims to develop and validate a rapid, simple, and economical LC-MS/MS method for simultaneous determination of CAZ/AVI in human plasma. Samples were processed by simple protein precipitation, and gradient elution strategy was applied to separate CAZ and AVI on a reverse-phase C18 column; with subsequent detection by the mass spectrometer in a positive and negative ion switching mode. Plasma samples from patients were analysed. A 4-min run of LC-MS/MS was developed. The precision, trueness, matrix effect, extraction recovery, carry-over, dilution integrity, and stability were all acceptable for a bioanalytical method. The method was successfully applied to the determination of CAZ and AVI in patients, and a considerable PK variability of CAZ/AVI was observed among patients. A robust, rapid, simple, and economical LC-MS/MS method for the simultaneous determination of CAZ and AVI was developed. The considerable PK variability of CAZ/AVI among patients demonstrates the clinical significance of TDM.

Efficacy and In Vitro Activity of Novel Antibiotics for Infections With Carbapenem-Resistant Gram-Negative Pathogens.

Infections by Gram-negative multi-drug resistant (MDR) bacterial species are difficult to treat using available antibiotics. Overuse of carbapenems has contributed to widespread resistance to these antibiotics; as a result, carbapenem-resistant Enterobacterales (CRE), A. baumannii (CRAB), and P. aeruginosa (CRPA) have become common causes of healthcare-associated infections. Carbapenems, tigecycline, and colistin are the last resource antibiotics currently used; however, multiple reports of resistance to these antimicrobial agents have been documented worldwide. Recently, new antibiotics have been evaluated against Gram-negatives, including plazomicin (a new aminoglycoside) to treat CRE infection, eravacycline (a novel tetracycline) with in vitro activity against CRAB, and cefiderocol (a synthetic conjugate) for the treatment of nosocomial pneumonia by carbapenem-non-susceptible Gram-negative isolates. Furthermore, combinations of known β-lactams with recently developed β-lactam inhibitors, such as ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime-tazobactam, and meropenem-vaborbactam, has been suggested for the treatment of infections by extended-spectrum β-lactamases, carbapenemases, and AmpC producer bacteria. Nonetheless, they are not active against all carbapenemases, and there are reports of resistance to these combinations in clinical isolates.This review summarizes and discusses the in vitro and clinical evidence of the recently approved antibiotics, β-lactam inhibitors, and those in advanced phases of development for treating MDR infections caused by Gram-negative multi-drug resistant (MDR) bacterial species.

Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia

ObjectivesNew drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy. MethodsThree pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed. ResultsGood lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)ELF/AUCplasma = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (∼5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients. DiscussionApramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections.

In vitro activity of imipenem-relebactam alone and in combination with fosfomycin against carbapenem-resistant gram-negative pathogens

The aim of this study was to investigate in vitro activity of imipenem-relebactam alone and in combination with fosfomycin against carbapenem-resistant Gram-negative pathogens. A total of 100 Gram-negative bacteria resistant to carbapenem were collected. Among collected 25 carbapenem-resistant Klebsiella pneumoniae strains, 24 (96%) were KPC producers and none of them displayed NDM-1, NDM-5, and IMP carbapenemase. Among 25 carbapenem-resistant Escherichia coli strains, 3(12%), 1(4%), 17(68%), 25(100%) and 20(80%) harbored KPC, NDM-1, NDM-5, ESBLs, and membrane porin OmpC or OmpF mutations, respectively. Among all the carbapenem-resistant strains, 40% (40/100) were resistant to imipenem-relebactam. The FICI revealed the synergistic (60%, 6/10) and additive (40%, 4/10) effects of imipenem-relebactam in combination with fosfomycin, wherein synergistic activity was found against all tested Klebsiella pneumoniae and Acinetobacter baumannii. Imipenem-relebactam may be a new alternative for carbapenem-resistant Gram-negative pathogens infections and the combination of imipenem-relebactam and fosfomycin warrants further exploration.

Carbapenem-resistant Gram-negative pathogens associated with septic shock: a review of 120 cases

This study aimed to evaluate the influencing variables for outcomes in patients with septic shock having culture-proven carbapenem-resistant Gram-negative pathogens. It included 120 patients (mean age 64.29 ± 1.35 years and 58.3% female). The mean Sequential Organ Failure Assessment score during septic shock diagnosis was found to be 11.22 ± 0.43 and 9 ± 0.79 among the patients with mortality and among the survivors, respectively (P = 0.017). The logistic regression analysis showed that empirical treatment as mono Gram-negative bacteria–oriented antibiotic therapy (P = 0.016, odds ratio (OR) = 17.730, 95% confidence interval (CI): 1.728−182.691), Charlson Comorbidity Index >2 (P = 0.032, OR = 7.312, 95% CI: 5.7−18.3), and systemic inflammatory response syndrome score 3 or 4 during septic shock diagnosis (P = 0.014, OR = 5.675, 95% CI: 1.424−22.619) were found as independent risk factors for day 30 mortality. Despite early diagnosis and effective management of patients with septic shock, the mortality rates are quite high in CRGNP-infected patients.

Central-line-associated bloodstream infections, multi-drug-resistant bacteraemias and infection control interventions: a 6-year time-series analysis in a tertiary care hospital in Greece

Central-line-associated bloodstream infections (CLABSIs) are serious healthcare-associated infections with substantial morbidity and hospital costs. To investigate the association between the incidence of CLABSIs, the implementation of specific infection control measures, and the incidence of multi-drug-resistant (MDR) bacteraemias in a tertiary care hospital in Greece from 2013 to 2018. Analysis was applied for the following indices, calculated monthly: CLABSI rate; use of hand hygiene disinfectants; isolation rate of patients with MDR bacteria; and incidence of bacteraemias [total Gram-negative carbapenem-resistant Acinetobacter baumanii, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae; and/or Gram-positive meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci]. The total number of bacteraemias from carbapenem-resistant Gram-negative pathogens was significantly correlated with an increased CLABSI rate for all (total) hospital departments [incidence rate ratio (IRR) 1.17, 95% confidence interval (CI) 1.05-1.31, P=0.006] and the adult intensive care unit (ICU) (IRR 1.37, 95% CI 1.07-1.75, P=0.013). In the adult ICU, every increase in the incidence of each resistant Gram-negative pathogen was significantly correlated with a decreased CLABSI rate (carbapenem-resistant A.baumanii: IRR 0.59, 95% CI 0.39-0.90, P=0.015; carbapenem-resistant K.pneumoniae: IRR 0.48, 95% CI 0.25-0.94, P=0.031; carbapenem-resistant P.aeruginosa: IRR 0.54, 95% CI 0.33-0.89, P=0.015). The use of hand disinfectants was correlated with a decreased CLABSI rate 1-3 months before the application of this intervention for all (total) hospital departments (IRR 0.80, 95% CI 0.69-0.93, P=0.005), and for scrub disinfectants in the current month for the adult ICU (IRR 0.34, 95% CI 0.11-1.03, P=0.057). Isolation of patients with MDR pathogens was not associated with the incidence of CLABSIs. Hand hygiene was associated with a significant reduction in the incidence of CLABSIs at the study hospital. Time-series analysis is an important tool to evaluate infection control interventions.

POSC115 Cost Effectiveness Economic Evaluation of Cefiderocol for the Treatment of Suspected Carbapenem-Resistant Infections in Italy

The WHO has highlighted the threat of emerging carbapenem-resistant (CR) gram-negative pathogens which are resistant to multiple antibiotics. Cefiderocol, a new parental antibiotic is the first to address all three WHO priority pathogens. To determine the cost-effectiveness of cefiderocol compared to ceftazidime/avibactam, modelling results for the treatment of seriously ill patients with complicated Urinary Tract Infections (cUTI), Pneumonia and Bloodstream infection (BSI)/sepsis caused by suspected CR pathogens (Enterobacterales, Acinetobacter Spp., Stenotrophomonas Spp., Pseudomonas Spp) in Italy was analysed.