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This study determined the in vitro activity of finafloxacin against panels of bacterial strains, representative of those associated with infection in cystic fibrosis patients and predominately isolated from clinical cases of respiratory disease. Many of these isolates were resistant to various antimicrobials evaluated including the aminoglycosides, cephalosporins, carbapenems and fluoroquinolones. Broth microdilution assays were performed at neutral and acidic pH, to determine antimicrobial activity. Finafloxacin demonstrated superior activity at reduced pH for all of the bacterial species investigated, highlighting the requirement to determine the activity of antimicrobials in host-relevant conditions. [ABSTRACT FROM AUTHOR]

Antimicrobial susceptibility was determined for clinical gram-negative isolates from Czech Republic, Hungary, and Poland, where published data for ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL) is scarce. C/T was active against 94.3% of Enterobacterales, 10–18% higher than the tested cephalosporins and piperacillin/tazobactam. IMI/REL was the most active tested agent against non-Morganellaceae Enterobacterales (99.7% susceptible). C/T was the most active among all studied agents except colistin against Pseudomonas aeruginosa (96.0% susceptible); susceptibility to IMI/REL was 90.7%. C/T maintained activity against 73.7–85.3% of β-lactam-resistant or multidrug-resistant P. aeruginosa subsets. C/T and IMI/REL could represent important treatment options for patients from these countries. [ABSTRACT FROM AUTHOR]

The absence of novel antibiotics for drug-resistant and biofilm-associated infections is a global public health crisis. Antimicrobial peptides explored to address this need have encountered significant development challenges associated with size, toxicity, safety profile, and pharmacokinetics. We designed PLG0206, an engineered antimicrobial peptide, to address these limitations. PLG0206 has broad-spectrum activity against >1,200 multidrug-resistant (MDR) ESKAPEE clinical isolates, is rapidly bactericidal, and displays potent anti-biofilm activity against diverse MDR pathogens. PLG0206 displays activity in diverse animal infection models following both systemic (urinary tract infection) and local (prosthetic joint infection) administration. These findings support continuing clinical development of PLG0206 and validate use of rational design for peptide therapeutics to overcome limitations associated with difficult-to-drug pharmaceutical targets. [ABSTRACT FROM AUTHOR]

The rapid worldwide spread of antimicrobial resistance highlights the significant need for the development of innovative treatments to fight multidrug-resistant bacteria. This study describes the potent antimicrobial activity of the novel peptide OMN6 against a wide array of drug-resistant Acinetobacter baumannii clinical isolates. OMN6 prevented the growth of all tested isolates, regardless of any pre-existing resistance mechanisms. Moreover, in vitro serial-passaging studies demonstrated that no resistance developed against OMN6. Importantly, OMN6 was highly efficacious in treating animal models of lung and blood infections caused by multidrug-resistant A. baumannii. Taken together, these results point to OMN6 as a novel antimicrobial agent with the potential to treat life-threatening infections caused by multidrug-resistant A. baumannii avoiding resistance. [ABSTRACT FROM AUTHOR]

Objectives: Relebactam is a diazabicyclooctane non-β-lactam inhibitor of Ambler class A and C β-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries.Methods: MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam.Results: Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other β-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype.Conclusions: Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients. [ABSTRACT FROM AUTHOR]

Objectives: Relebactam is an inhibitor of class A β-lactamases, including KPC β-lactamases, and class C β-lactamases, and is currently under clinical development in combination with imipenem. The objective of the current study was to evaluate the in vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) submitted by clinical laboratories in 17 European countries to the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme in 2015.Methods: MICs were determined using the CLSI standard broth microdilution method and interpreted using EUCAST clinical breakpoints. Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using breakpoints for imipenem.Results: Rates of susceptibility to imipenem and imipenem/relebactam for isolates of P. aeruginosa (n = 1705), K. pneumoniae (n = 1591) and Enterobacter spp. (n = 772) were 72.0/94.7%, 88.7/94.8% and 95.6/96.8%, respectively. Relebactam restored imipenem susceptibility to 81.1%, 54.2% and 26.5% of imipenem-non-susceptible isolates of P. aeruginosa (n = 477), K. pneumoniae (n = 179) and Enterobacter spp. (n = 34). Most imipenem/relebactam-non-susceptible isolates carried MBLs, OXA-48 or GES carbapenemases. Relebactam did not increase the number of isolates of A. baumannii (n = 486) susceptible to imipenem.Conclusions: Relebactam restored susceptibility to imipenem for the majority of imipenem-non-susceptible isolates of P. aeruginosa and K. pneumoniae tested as well as some isolates of imipenem-non-susceptible Enterobacter spp. Based on our results, imipenem/relebactam appears to be a promising therapeutic option for treating patients with infections caused by antimicrobial-resistant Gram-negative bacilli. [ABSTRACT FROM AUTHOR]

Summary: Objectives: During 2011, a total of 1442 gram-negative pathogens from intra-abdominal infections were collected as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 19 hospital sites within the United States. Susceptibility to ertapenem and comparators and molecular analysis of ertapenem resistant isolates was performed. Methods: Extended-spectrum beta-lactamase ESBL (ESBL) isolates were determined using the Clinical and Laboratory Standards Institute's recommended phenotypic test. Isolates were identified to the species level, and tested for antimicrobial susceptibility using custom MicroScan dehydrated broth microdilution panels ESBLs and carbapenemases were characterized using the Check-Points microarray. Strain typing of Klebsiella pneumoniae was performed by rep-PCR on the DiversiLab System. Results: The majority of isolates were Escherichia coli (36%), K. pneumoniae (18.6%), Pseudomonas aeruginosa (12.1%) and Enterobacter cloacae (8.4%). Incidence of ESBL-positive isolates was 12.7%, 9.7%, 3.6% and 3.1% for K. pneumoniae, E. coli, Proteus mirabilis and Klebsiella oxytoca, respectively. Against the majority of isolates and species tested, the most active antibiotics were amikacin, ertapenem, and imipenem, with the carbapenems being the most active in vitro, including against ESBL-positive isolates of E. coli. All other antibiotics exhibited diminished activity. Against K. pneumoniae, the carbapenems were notably less active against ESBL-positive isolates though their activity against this sub-population was still the highest of all antibiotics tested; however, 41.1% (14 of 34) of the phenotypically ESBL-positive K. pneumoniae co-produced a carbapenemase (KPC2 or KPC3), and >90% of the isolates producing only an ESBL remained susceptible to ertapenem. Conclusions: Further monitoring of susceptibility of intra-abdominal isolates is warranted due to limited therapeutic options available to physicians. [Copyright &y& Elsevier]

Surveillance of antimicrobial agent resistance provides important information to guide microbiologists and infectious disease specialists understanding of the control and the spread of resistance mechanisms within the local environment. Continued monitoring of antimicrobial resistance patterns in the community and in local hospital environments is essential to guide effective empiric therapy. The Study for Monitoring Antimicrobial Resistance Trends (SMART) has monitored the in vitro susceptibility patterns of clinical Gram-negative bacilli to antimicrobial agents collected worldwide from intra-abdominal infections since 2002 and urinary tract infections since 2009. Resistance trends, with a particular focus on carbapenem resistance and the rate of extended-spectrum β-lactamases (ESBLs), were analyzed. Isolates from intra-abdominal infections (n = 92,086) and urinary-tract infections (n = 24,705) were collected and tested using Clinical and Laboratory Standards Institute methods. This review presents carbapenem susceptibility and ESBL rates over ten years of SMART study analysis, including key publications during this period. The SMART study has proved to be a valuable resource in determining pathogen prevalence and antibiotic susceptibility over the last ten years and continues to provide evidence for regulatory susceptibility breakpoints and clinical decision making. [ABSTRACT FROM AUTHOR]

Summary: Objectives: The Study for Monitoring Antimicrobial Resistance Trends (SMART) was intended to reveal the evolving profiles of antimicrobial resistance among Gram-negative pathogens causing intra-abdominal infections (IAIs) from Asia-Pacific region in 2009. Methods: A total of 3577 aerobic and facultative Gram-negative bacilli associated with IAIs were collected from 32 centers in 12 countries. The in vitro susceptibilities of these isolates to 12 antimicrobial agents were determined using the broth microdilution method. Susceptibility results for selected species of Enterobacteriaceae were also compared using different MIC interpretive criteria recommended by the Clinical and Laboratory Standards Institute in 2009 (M100-S19), in January 2010 (M100-S20), in June 2010 (M100-S20-U) and the European Committee on Antimicrobial Susceptibility Testing in 2010 (EUCAST-2010). Results: Enterobacteriaceae comprised 89.5% of the isolates of which Escherichia coli was the most common species (56.7%). Enterobacteriaceae showed poor susceptibility to ampicillin-sulbactam in China (25.3%) and India (19%), and to fluoroquinolones in India (23.4%) and China (37.7%). The rates of extended-spectrum β-lactamase (ESBL)-producing E. coli (36.8%) and Klebsiella pneumoniae (26.3%) remained high. The resistance of ESBL-producing K. pneumoniae to carbapenems also increased, especially to ertapenem (9.9%). Using M100-S20 criteria, 19% of ESBL-producing E. coli and 9% of ESBL-producing K. pneumoniae were susceptible to ceftazidime; 5% and 10% were susceptible to cefepime, respectively. Using M100-S20-U guidelines, the susceptibility rates of ESBL-producing K. pneumoniae (88%) and Enterobacter cloacae (69%) to ertapenem were substantially decreased from those determined using M100-S20. Conclusions: These up-to-date epidemiology and antimicrobial resistance surveillance data are crucial to select appropriate treatment of IAIs. [ABSTRACT FROM AUTHOR]

Abstract: SMART (Study for Monitoring Antimicrobial Resistance Trends) is an ongoing multiyear surveillance study to monitor worldwide antimicrobial resistance trends among aerobic and facultative anaerobic Gram-negative bacilli (GNB) isolated from intra-abdominal infections. During 2005–2007, a total of 255 laboratories from 37 countries in five global regions collected intra-abdominal GNB for antimicrobial susceptibility testing using broth microdilution according to Clinical and Laboratory Standards Institute guidelines. A total of 19703 GNB were isolated from intra-abdominal infections, comprising 5476, 6633 and 7594 GNB were isolated in the years 2005, 2006 and 2007 from 75, 84 and 96 medical centres, respectively. The most frequently isolated organisms were Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae, of which 18.0% of E. coli and 26.2% of K. pneumoniae were positive for extended-spectrum β-lactamase (ESBL). Overall, resistance among GNB increased during 2005–2007 and resistance rates in 2007 were generally higher than data from previous years. Ertapenem and imipenem were the only agents that maintained consistent activity against GNB, including most ESBL-producing isolates. [Copyright &y& Elsevier]

Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings. [ABSTRACT FROM AUTHOR]

Iclaprim, a new selective dihydrofolate inhibitor was synthesized based on rational drug design. Iclaprim''s interaction with a resistant Staphylococcus aureus dihydrofolate reductase (DHFR) is outlined in comparison to trimethoprim (TMP). This compound is active against methicillin, TMP and vancomycin resistant strains. Arpida Ltd. is developing Iclaprim for serious hospital infections from Gram-positive pathogens and respiratory tract infections. [Copyright &y& Elsevier]

The effects of antifungal agents, with different mechanisms of action, on the morphogenetic transformation by synchronised yeast-phase Candida albicans cells in vitro and their respective anti-Candida activities are described. MIC data demonstrated that the azoles, amphotericin B and echinocandin were the most active agents against four C. albicans strains. Morphogenetic transformation experiments demonstrated that amphotericin B was significantly better at preventing the transformation, under a variety of test conditions, than the azoles and flucytosine: amphotericin B abolished the transformation at low concentrations while the azoles only prevented the morphogenetic transformation at much higher concentrations (>100 × MIC). [ABSTRACT FROM PUBLISHER]

A spectrophotometric method for studying the morphogenetic transformation by Candida albicans is described. Synchronous yeast-phase C. albicans cells incubated at 35 degrees C formed germ-tubes and resulted in an absorbance increase at 340 nm but not at 595 nm. Furthermore, measurements of germ tube length increases correlated strongly (r2 > 0.95) with increases in absorbance at 340 nm during the morphogenetic transformation. Amphotericin B significantly affected the morphogenetic transformation, at the MIC and 1/10 MIC, whereby no increase in absorbance was observed at 340 nm. In contrast, identical measurements demonstrated that ketoconazole, at the MIC and 1/10 MIC, did not exhibit the same effects on the morphogenetic transformation by C. albicans cells. [ABSTRACT FROM AUTHOR]

Background The development of new anti-infectives has increased rapidly over the past ten years. The need to support these important, life-saving products has increased as well. The STAR program was developed in 2018 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. STAR reports the susceptibility patterns of the earliest STAR data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Candida albicans and non-albicans strains including C. auris from worldwide sources. Methods Clinical isolates of Candida spp. (n = 203, from 2017–2018) from culture KOL investigator sites in the United States, Asia and the EU, were tested. Of these, 203 were isolated from blood or body tissues, and the remaining 11 from miscellaneous sources. Species distribution included mainly C. albicans , C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis , and the emerging pathogen C. auris. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 methodology. Results Overall, MIC50, MIC90, MIC range and percent susceptibility for each drug are listed in Table 1. Our data showed that for ANID, ISA and POS ≥ 93% of isolates were susceptible. While 84 and 88% were susceptible to FLU and VOR, respectively. Moreover, only 78% of isolates were susceptible to AMB. Interestingly, our data show that C. auris isolates were resistant to at least 1 antifungal with 15% of the C. auris strains (n = 40) showing multidrug resistance. Conclusion Ongoing antifungal resistance surveillance like STAR is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing STAR study will provide a resource to better support the biopharmaceutical industry's goals to develop new and more potent antifungal agents. STAR will continue to monitor yeasts and will also include more unusual fungi including Mucor , Rhizopus amongst others. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background The incidence and outcomes of patients with S. aureus isolates with an iclaprim MIC >8 µg/mL, a concentration that is not systemically achievable, were determined among patients from two Phase 3 studies for the treatment of ABSSSI, REVIVE-1 and -2. Methods REVIVE-1 and REVIVE-2 studies were 600-patient, double-blinded, randomized (1:1), active-controlled trials among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg (adjusted for renal function), both administered intravenously over 2 hours every 12 hours for 5–14 days. Patients had a bacterial skin infection suspected or confirmed to be due to a Gram-positive pathogen with a lesion size ≥75 cm2. An early clinical response (ECR) was defined as a ≥20% reduction in lesion size compared with baseline at the early time point (ETP) 48–72 hours after the start of administration of the study drug in the intent-to-treat (ITT) population. A clinical cure, defined as complete resolution of all signs and symptoms of ABSSSI was measured at the end of therapy (EOT) and test of cure (TOC) visit, 7–14 days after the last dose of study drug. At baseline, EOT and TOC visits, ABSSSIs were sampled for microbiological culture and broth microdilution susceptibility testing conducted in accordance with CLSI M7. Results The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC >8 µg/mL was 2.0% (16/790). Six were MSSA and 10 were MRSA. The clinical outcomes of these infections included ECR of 63% (10/16), EOT response of 81.3% (13/16) and the TOC response of 75% (12/16). For microbiological outcomes of these infections, the end of therapy response was 92.9% (13/14) and the test of cure response was 92.3% (12/13). In comparison, there was less variation in vancomycin MICs among the S. aureus isolates. For patients who were randomized to vancomycin and had a pathogen identified from their ABSSSI, the pooled ECR was 82.6% (242 of 293) at a vancomycin MIC of 0.5–1 µg/mL and one isolate from a patient with ECR had a MIC of 2 µg/mL. Conclusion Patients receiving iclaprim had good clinical and microbiological responses against S. aureus isolates with an iclaprim MIC >8 µg/mL, which are uncommon (2.0%). Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Abstract: Escherichia coli is the most important uropathogen. The Study for Monitoring Antimicrobial Resistance Trends program collected 1643 E. coli isolates in 2009–2010 from urinary tract infection (UTI) specimens of hospitalized patients in countries worldwide. Ertapenem and imipenem were the most active agents tested, inhibiting >98% of all E. coli phenotypes. Overall, 17.9% of isolates were extended-spectrum beta-lactamase (ESBL) producers. The highest ESBL rate was from the Asia/Pacific region (27.7%). Amikacin and piperacillin–tazobactam achieved 90% inhibition levels only for ESBL-negative isolates. Ciprofloxacin and levofloxacin were not effective for ESBL-positive isolates, with only 14.6% and 15.9% susceptible, respectively. These observations highlight the need for continued monitoring of susceptibility of E. coli isolated from hospitalized patients with UTIs. [Copyright &y& Elsevier]

Abstract: The management of patients with complicated intra-abdominal infections has increased in complexity because of the evolution of antibiotic resistance and the development of multidrug-resistant (MDR) Enterobacteriaceae implicated in this clinical infectious process. The Study for Monitoring Antimicrobial Resistance Trends study 2002 to 2007 monitored the susceptibility of Enterobacteriaceae from intra-abdominal infections to a panel of appropriate antimicrobials. During 2002 to 2007, 6644 MDR (resistant to 2 or more antimicrobial classes) Enterobacteriaceae species were isolated and tested against selected antimicrobials from varying classes. The carbapenems were the most consistently active agents. Escherichia coli was the most commonly isolated MDR pathogen. The susceptibility of E. coli to the quinolone (8–21.6%), cephalosporin (30.2–70.7%), aminoglycoside (81.0–92.1%), and carbapenem (91.9–99.3%) agents varied by year. Susceptibilities of other Enterobacteriaceae were similar to those of E. coli. Surveillance of pathogens responsible for intra-abdominal infections is useful in the monitoring of changing susceptibility patterns and in the formulation of more effective treatment modalities. [Copyright &y& Elsevier]

• 93.3% of Pseudomonas aeruginosa from Western Europe were ceftolozane/tazobactam-susceptible • 23.1% of P. aeruginosa from Western Europe were multidrug-resistant (MDR) • 72% of MDR P. aeruginosa in Western Europe were ceftolozane/tazobactam-susceptible • ∼30% of MDR P. aeruginosa in Western Europe were meropenem- or imipenem-susceptible • 16.6% of MDR P. aeruginosa carried a carbapenemase (8.8% MBL, 7.6% GES, 0.2% GPC) Multidrug-resistant (MDR) Pseudomonas aeruginosa infections compromise both empirical and definitive antimicrobial therapies. The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program identified 943 MDR P. aeruginosa (from a total of 4086 P. aeruginosa isolates [23.1%]) collected at 32 clinical laboratories in six countries in Western Europe from 2017 to 2020. Minimum inhibitory concentrations (MICs) for ceftolozane/tazobactam and 10 comparator agents were determined by broth microdilution and interpreted using 2021 EUCAST breakpoints. β-lactamase genes were identified in selected isolate subsets. Most isolates of P. aeruginosa in Western Europe (93.3%) were ceftolozane/tazobactam-susceptible. A total of 23.1% of P. aeruginosa isolates were MDR. Of these, 72.0% were ceftolozane/tazobactam-susceptible, which is similar to that for ceftazidime/avibactam (73.6%) but >40% higher than for carbapenems, piperacillin/tazobactam, third- and fourth-generation cephalosporins, and levofloxacin. Metallo-β-lactamases (MBLs) were carried by 8.8% of molecularly characterized MDR P. aeruginosa , and 7.6% of molecularly characterized MDR isolates carried Guiana Extended Spectrum (GES) carbapenemases. MBLs were identified in isolates from all six countries, ranging from 3.2% of all P. aeruginosa isolates from Italy to 0.4% of all isolates from the United Kingdom. Acquired β-lactamases were not identified in 80.0% of molecularly characterized MDR P. aeruginosa isolates. Percentages of MDR isolates without detected β-lactamases were higher in the United Kingdom (97.7%), Spain (88.2%), France (88.1%), and Germany (84.7%) than in Portugal (63.0%) and Italy (61.3%), where carbapenemases were more prevalent. Ceftolozane/tazobactam is an important treatment option for patients infected with MDR P. aeruginosa that are not susceptible to first-line antipseudomonal agents. [ABSTRACT FROM AUTHOR]