scholarly journals 124. Microbiological Outcomes With Plazomicin (PLZ) Versus Meropenem (MEM) in Patients With Complicated Urinary Tract Infections (cUTI), Including Acute Pyelonephritis (AP) in the EPIC Study

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S7-S8
Author(s):  
Tiffany R Keepers ◽  
Deborah S Cebrik ◽  
Daniel J Cloutier ◽  
Allison Komirenko ◽  
Lynn Connolly ◽  
...  

Abstract Background PLZ is a next-generation aminoglycoside (AG) that is structurally protected from common AG-modifying enzymes (AMEs) in Enterobacteriaceae and with in vitro activity against multidrug-resistant Enterobacteriaceae, including ESBL-producing, AG-resistant, and carbapenem-resistant isolates. We report microbiological outcomes in the EPIC study, including outcomes for resistant pathogens and by the PLZ MIC. Methods EPIC was a multinational, randomized, double-blind study in hospitalized patients with cUTI or AP. Patients received IV PLZ (15 mg/kg q24h) or IV MEM (1 g q8h) for 4–7 days, followed by optional oral therapy, for a total of 7–10 days of therapy. The extended mMITT population included patients with ≥1 qualifying baseline pathogen (≥105 CFU/mL urine) who received study drug. Microbiological outcomes were assessed at TOC (day 15–19). Isolate identification and susceptibility testing were conducted by a central laboratory. Whole-genome sequencing was used to identify AME and β-lactamase genes. Results Of 609 patients enrolled, 407 (66.8%) were included in the extended mMITT population. The most common uropathogen was Escherichia coli (63.4%) followed by Klebsiella pneumoniae (19.7%). PLZ and MEM MIC50/90 for Enterobacteriaceae were 0.5/2 μg/mL (range: ≤0.06–>128 mg/mL) and 0.015/0.06 mg/mL (range: ≤0.004–128 mg/mL), respectively. ESBL and AG-NS phenotypes were found in 29% and 27% of isolates, respectively. Genotyping detected β-lactamase and AME genes in 32.5% and 36.8% of isolates, respectively, most commonly blaCTX-M-15 (n = 98), blaOXA-1/OXA-30 (n = 82), aac(6′)Ib-cr (n = 79), and aac(3)-IIa (n = 56). Rates of microbiological eradication are shown in Table 1. All Enterobacteriaceae in the PLZ group with a PLZ MIC of 4 µg/mL (6/6) were eradicated at TOC (Table 2). Across 49 patients with concurrent bacteremia, 100% (27/27) and 96% (24/25) of Enterobacteriaceae were cleared from the blood at TOC in the PLZ and MEM groups, respectively. Conclusion PLZ demonstrated comparable or higher microbiological eradication rates compared with MEM for common Gram-negative uropathogens, including resistant pathogens. The results support PLZ as a potential treatment option for cUTI, including AP, caused by Enterobacteriaceae with PLZ MICs of ≤4 mg/mL. Disclosures T. R. Keepers, Achaogen, Inc.: Employee, Salary. D. S. Cebrik, Achaogen, Inc.: Employee, Salary. D. J. Cloutier, Achaogen, Inc.: Employee and Shareholder, Salary. A. Komirenko, Achaogen, Inc.: Employee and Shareholder, Salary. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. Krause, Achaogen, Inc.: Employee, Salary.

1999 ◽  
Vol 10 (2) ◽  
pp. 122-127 ◽  
Author(s):  
Donald E Low ◽  
Joyce de Azavedo ◽  
Canadian Bacterial Surveillance Network ◽  
Ross Davidson

OBJECTIVE: To determine the in vitro activity of cefepime against multidrug-resistant Gram-negative bacilli and Gram-positive cocci obtained from an ongoing cross-Canada surveillance study.DESIGN: Clinical isolates of aerobic Gram-negative bacilli with inducible and constitutive chromosomally mediated cephalosporinases, viridans group streptococci andStreptococcus pneumoniaewere collected from laboratories serving hospitals, nursing homes and physician offices in the community from across Canada during 1996 and 1997. Laboratories were asked to submit only clinically relevant nonduplicate isolates for susceptibility testing. In vitro antimicrobial susceptibility testing was carried out on all isolates of Gram-negative and viridans group streptococci.S pneumoniaewere characterized as penicillin susceptible, intermediately resistant or highly resistant. Nonsusceptible isolates were defined as being intermediately or highly resistant (minimal inhibitory concentrations [MIC] greater than 0.06 mg/L). Only isolates ofS pneumoniaethat were nonsusceptible to penicillin were selected for further study. MICs were determined using a microbroth dilution technique according to the National Committee of Clinical Laboratory Standards.RESULTS: A total of 727 Gram-negative bacilli samples were collected. No resistance to cefepime was detected withCitrobacter freundii,Serratia marcescens,Morganella morganiiandEnterobacterspecies. Of these strains,Enterobacterspecies andC freundiiwere the most resistant to ceftazidime, cefotaxime and ceftriaxone with MIC90Sof 32 mg/L or greater and resistance rates of 6% or greater. Resistance rates ofPseudomonas aeruginosaandAcinetobacterspecies to cefepime were 4.8% and 3%, respectively. The two organisms had similar rates of resistance to ceftazidime. Less than 3% of the Gram-negative bacilli were resistant to imipenem and meropenem. There were 153 viridans group streptococci, of which 22 (14.4%) were resistant to penicillin. Of 1287S pneumoniaesamples, 193 (15%) were nonsusceptible to penicillin. Cefepime, ceftriaxone and cefotaxime had comparable activity against all isolates of viridans group streptococci andS pneumoniae.CONCLUSIONS: Cefepime demonstrated excellent in vitro activity against Gram-negative bacilli with inducible and constitutive chromosomally mediated cephalosporinases, and had equal or superior activity versus comparator beta-lactams against all isolates of viridans group streptococci andS pneumoniae.


2008 ◽  
Vol 52 (3) ◽  
pp. 1182-1183 ◽  
Author(s):  
W. T. M. Jansen ◽  
A. Verel ◽  
J. Verhoef ◽  
D. Milatovic

ABSTRACT We investigated the in vitro activity of AR-709, a novel diaminopyrimidine antibiotic currently in development for treatment of community-acquired upper and lower respiratory tract infections, against 151 Streptococcus pneumoniae strains from various European countries. AR-709 showed excellent activity against both drug-susceptible and multidrug-resistant pneumococci.


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S539-S539
Author(s):  
Yehuda Carmeli ◽  
Philipp Knechtle ◽  
Jeff Hardenberg ◽  
Mathias Knecht

Abstract Background Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae has been classified as critical priority pathogens. The novel extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (formerly AAI101; EMT) in combination with cefepime (FEP) is currently being developed as a carbapenem-sparing treatment of serious Gram-negative infections in settings with a high prevalence of 3GC-resistant Enterobacteriaceae. We report here the results from a phase 2 study that assessed safety, tolerability, and pharmacokinetics of FEP-EMT in patients with cUTI/AP. Methods Forty-five patients were enrolled in a randomized, multicenter, double-blind study of hospitalized adults with cUTI/AP. Patients received dosing regimens of FEP or FEP-EMT IV therapy q8h by 2 hours infusion (table) for 7 to 10 days with a 28-day follow-up. Efficacy was evaluated in the microbiological-modified ITT (µMITT) population. Safety was monitored in patients who received at least 1 dose of study drug. Clinical cure was designated as the resolution of cUTI symptoms present at study entry. Plasma and urine PK were determined from all patients. Results The study drugs were well tolerated in each cohort, with similar % adverse events and no new or unexpected safety concerns (table). Two discontinuations were due to allergic dermatitis. The microbiological- and clinical responses at test-of-cure for the combined FEP-EMT group were 83.3% (20/24) and 95.8% (23/24) compared with responses in the combined FEP group of 73.3% (11/15) and 93.3% (14/15), respectively (table). The most common baseline pathogens were Escherichia coli (66.7%) and Klebsiella pneumoniae (23.1%): 28.2% of isolates produced ESBLs with eradication rates for the combined FEP-EMT group of 85.7% (6/7) and for the combined FEP group of 75.0% (3/4). FEP and EMT PK were best described by a 2-compartment, linear PK model. Both agents exhibited half-lives of 2.3 hours. Creatinine clearance had a significant covariate effect on FEP and EMT, consistent with predominant renal excretion of both agents. Conclusion Results from this phase 2 study justify advancement to phase 3 studies to evaluate the safety and efficacy of FEP-EMT in patients with cUTI/AP. Disclosures All authors: No reported disclosures.


2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Nylev Vargas-Cruz ◽  
Joel Rosenblatt ◽  
Ruth A Reitzel ◽  
Anne-Marie Chaftari ◽  
Ray Hachem ◽  
...  

CAUTI remains a serious healthcare issue for incontinent patients whose urine drainage is managed by catheters. A novel double-balloon Foley catheter was developed which was capable of irrigating the extraluminal catheter surfaces within the periurethral space between the urethral-bladder junction and meatus. The catheter has a retention cuff that is inflated to secure the catheter in the bladder and a novel irrigation cuff proximal to the urethral-bladder junction capable of providing periurethral irrigation from the urethral-bladder junction to the meatus. Uniform periurethral irrigation was demonstrated in an ex vivo porcine model by adding a dye to the antimicrobial urethral irrigation solution. An in vitro biofilm colonization model was adapted to study the ability of periurethral irrigation with a newly developed antimicrobial combination consisting of polygalacturonic acid + caprylic acid (PG + CAP) to prevent axial colonization of the extraluminal urethral indwelling catheter shaft by common uropathogens. The extraluminal surface of control catheters that were not irrigated formed biofilms along the entire axial urethral tract after 24 hours. Significant (p<0.001) inhibition of colonization was seen against multidrug-resistant Pseudomonas aeruginosa (PA), carbapenem-resistant Escherichia coli (EC), and carbapenem-resistant Klebsiella pneumoniae (KB). For other common uropathogens including Candida albicans (CA), Proteus mirabilis (PR), and Enterococcus faecalis (EF), a first irrigation treatment completely inhibited colonization of half of the indwelling catheter closest to the bladder and a second treatment largely disinfected the remaining intraurethral portion of the catheter towards the meatus. The novel Foley catheter and PG + CAP antimicrobial irrigant prevented biofilm colonization in an in vitro CAUTI model and merits further testing in an in vivo CAUTI prevention model.


2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Hung-Jen Tang ◽  
Yee-Huang Ku ◽  
Mei-Feng Lee ◽  
Yin-Ching Chuang ◽  
Wen-Liang Yu

We investigated the synergism of colistin and imipenem against a multidrug-resistantK. pneumoniaeisolate which was recovered from a severe hip infection. PCR and DNA sequencing were used to characterize the outer membrane porin genes and the resistance genes mediating the commonβ-lactamases and carbapenemases. Synergism was evaluated by time-kill studies. TheblaSHV-31,blaCMY-2, andblaDHA-1were detected. Outer membrane porin genes analysis revealed loss ofompK36and frame-shift mutation ofompK35. The common carbapenemase genes were not found. Time-kill studies demonstrated that a combination of 1x MIC of colistin (2 mg/L) and 1x MIC of imipenem (8 mg/L) was synergistic and bactericidal but with inoculum effect. Bactericidal activity without inoculum effect was observed by concentration of 2x MIC of colistin alone or plus 2x MIC of imipenem. In conclusion, colistin plus imipenem could be an alternative option to treat carbapenem-resistantK. pneumoniaeinfections.


Author(s):  
Sharon Ong’uti ◽  
Mary Czech ◽  
Elizabeth Robilotti ◽  
Marisa Holubar

Abstract Cefiderocol is a novel injectable siderophore cephalosporin which hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug resistant (MDR) organisms like carbapenem resistant Enterobacterales (CRE), carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii. It was approved by the Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials demonstrating noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase III clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician’s armamentarium against MDR gram-negative infections.


2020 ◽  
Vol 75 (7) ◽  
pp. 1840-1849 ◽  
Author(s):  
Mercedes Delgado-Valverde ◽  
M del Carmen Conejo ◽  
Lara Serrano ◽  
Felipe Fernández-Cuenca ◽  
Álvaro Pascual

Abstract Background Cefiderocol is a novel siderophore cephalosporin, developed for activity against MDR Gram-negative bacilli (MDR-GNB). Objectives To assess the in vitro antibacterial activity of cefiderocol against a collection of MDR-GNB clinical isolates from hospitals in southern Spain. Methods Two hundred and thirty-one isolates of successful clones were tested: 125 Enterobacterales (121 ESBL- and/or carbapenemase-producing Klebsiella pneumoniae and 4 carbapenemase-producing Enterobacter cloacae), 80 Acinetobacter baumannii, 6 Pseudomonas aeruginosa and 20 Stenotrophomonas maltophilia. Ceftolozane/tazobactam, ceftazidime, ceftazidime/avibactam, cefepime, aztreonam, meropenem, amikacin, ciprofloxacin, colistin and tigecycline were used as comparators against Enterobacterales, P. aeruginosa and A. baumannii. Minocycline, levofloxacin and trimethoprim/sulfamethoxazole were studied against S. maltophilia instead of aztreonam, ciprofloxacin and cefepime. MICs were determined by broth microdilution according to CLSI guidelines. MIC determination was performed in CAMHB for all antimicrobials except cefiderocol, where iron-depleted CAMHB was used. Results Cefiderocol showed potent in vitro activity against the isolates analysed. MIC50 and MIC90 values were in the ranges 0.125–8 mg/L and 0.5–8 mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed cefiderocol MICs of &gt;4 mg/L: three ST2/OXA-24/40-producing A. baumannii, one ST114/VIM-1-producing E. cloacae and one ST114/VIM-1 + OXA-48-producing E. cloacae. All KPC-3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to ceftazidime/avibactam. P. aeruginosa isolates showed cefiderocol MICs of &lt;4 mg/L, including those resistant to ceftolozane/tazobactam. S. maltophilia isolates displayed cefiderocol MICs of &lt;4 mg/L, including those resistant to levofloxacin and/or trimethoprim/sulfamethoxazole. Conclusions Cefiderocol showed excellent activity against MDR-GNB, including carbapenem-resistant isolates, and was the most active antimicrobial tested against this collection.


2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S721-S721
Author(s):  
Mark Estabrook ◽  
Krystyna Kazmierczak ◽  
Francis Arhin ◽  
Daniel F Sahm

Abstract Background Hypervirulent Klebsiella pneumoniae (hvKp), unlike classical K. pneumoniae (cKp), are often responsible for community-acquired infections in otherwise healthy individuals. The acquisition of hypervirulence genes by sequence type 11 (ST11) carbapenem-resistant (CR) Kp endemic in Asia is a grave threat. Aztreonam-avibactam (ATM-AVI) is a monobactam combined with a β-lactamase inhibitor for the treatment of infections caused by Enterobacterales isolates that carry Class A, B, C and some Class D β-lactamases. Methods 487 K. pneumoniae isolates were collected from 17 sites in China in 2019 as a part of the ATLAS global surveillance study. 220 isolates with MICs &gt;1 µg/ml to meropenem (MEM), ceftazidime or ATM were selected for whole genome sequencing (Illumina Hiseq 2x150 bp reads). Analyses were carried out using the CLC Genomics Workbench (Qiagen). Presence of the aerobactin synthesis locus differentiated hvKp and cKp. Antimicrobial susceptibility was determined by CLSI broth microdilution. Results Of the 487 isolates, MIC90 values for ATM-AVI (0.5 µg/ml; Table) were lower than those for any comparator tested, with only two isolates testing with MIC &gt;4 µg/ml. Of the isolates sequenced, 82/220 (37.3%) were ST11. 53/82 (64.6%) of these ST11 isolates were hvKp (ATM-AVI, MIC90 1 µg/ml; range, 0.25-4 µg/ml) and showed percentages of susceptibility &lt; 90% to three last-line agents (0% MEM-susceptible (S); 18.9% amikacin (AMK)-S; 88.7% tigecycline (TGC)-S). Isolates of other STs (Non-ST11) were less frequently identified as hvKp (24/138, 17.4%) and more Non-ST-11 hvKp and cKp alike were S to MEM and AMK relative to isolates of ST11 (75.0-86.8% MEM-S; 83.3-96.5% AMK-S). Likewise, the ATM-AVI MIC90 value (0.25 µg/ml) was 4-fold lower for Non-ST11 isolates. Results Table Conclusion CR ST11 hvKp represented at least 10.9% of the collected Kp isolates. ATM-AVI retained potent in vitro activity against these isolates which displayed resistance to a range of last-line agents. CST and TGC also displayed some activity but are limited in utility due to nephrotoxicity and poor accumulation in blood, respectively. The spread of virulence factors leading to the complicated clinical presentation of hvKp infection into multidrug-resistant lineages warrants continued surveillance. Disclosures Mark Estabrook, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S581-S582
Author(s):  
Patrick James Nolan ◽  
Tiffeny Smith ◽  
James D Finklea ◽  
Leah Cohen ◽  
Raksha Jain

Abstract Background Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane–tazobactam (C/T) and ceftazidime–avibactam (CZA) exhibit promising activity against antimicrobial-resistant organisms, including P. aeruginosa. In this study, we compared in vitro activity of C/T and CZA against P. aeruginosa isolated from respiratory cultures obtained from adult patients with CF. Methods This is a retrospective study of respiratory cultures positive for P. aeruginosa collected from adult CF patients between January 1, 2015 to November 30, 2018. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin were included in the study. All isolates underwent in-house susceptibility testing for 9 anti-pseudomonal agents according to the methodology established by the Clinical Laboratory Standards Institute (CLSI). Susceptibility testing of C/T, CZA, and colistin were performed by a reference lab. Isolates were classified into 3 drug-resistant categories using the following definition: multidrug-resistant (MDR) non-susceptible (NS) to ≥1 agent in ≥3 different antimicrobial classes, extensive drug-resistant (XDR) NS to 4 or 5 different classes, and pan drug-resistant (PDR) NS to all 6 classes except colistin. Results Forty-two P. aeruginosa respiratory isolates from 32 patients with CF were included. The overall susceptibility to C/T and CZA was 59.5% and 42.9%, respectively. Thirty-eight (90%) isolates were considered MDR with susceptibility of 55.3% to C/T and 44.7% to CZA. Among the 11 XDR isolates, susceptibility to C/T was 81.8% vs. CZA 72.7%. Susceptibility to C/T vs. CZA was also higher (37.5% vs. 25%) among the 24 PDR isolates. Conclusion Among P. aeruginosa isolated from CF respiratory cultures, C/T appears to have better in vitro activity compared with CZA, and remained true among isolates considered XDR and PDR. These results suggest using C/T while awaiting susceptibilities when standard anti-pseudomonal agents cannot be used. Future studies evaluating clinical outcomes for the treatment of pulmonary CF exacerbations are needed to assess the applicability of in vitro susceptibility data. Disclosures All authors: No reported disclosures.


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