scholarly journals Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance

2020 ◽  
Vol 7 ◽  
pp. 204993612095260
Author(s):  
Justin A. Clark ◽  
David S. Burgess
Keyword(s):  
Clinical Data ◽  
Vitro Activity ◽  
Original Research ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Carbapenem Resistant Enterobacteriaceae

Objective: To review the mechanism of action, mechanisms of resistance, in vitro activity, pharmacokinetics, pharmacodynamics, and clinical data for a novel aminoglycoside. Data sources: A PubMed search was performed from January 2006 to August 2019 using the following search terms: plazomicin and ACHN-490. Another search was conducted on clinicaltrials.gov for published clinical data. References from selected studies were also used to find additional literature. Study selection and data extraction: All English-language studies presenting original research ( in vitro, in vivo, pharmacokinetic, and clinical) were evaluated. Data synthesis: Plazomicin has in vitro activity against several multi-drug-resistant organisms, including carbapenem-resistant Enterobacteriaceae. It was Food and Drug Administration (FDA) approved to treat complicated urinary tract infections (cUTIs), including acute pyelonephritis, following phase II and III trials compared with levofloxacin and meropenem, respectively. Despite the FDA Black Box Warning for aminoglycoside class effects (nephrotoxicity, ototoxicity, neuromuscular blockade, and pregnancy risk), it exhibited a favorable safety profile with the most common adverse effects being decreased renal function (3.7%), diarrhea (2.3%), hypertension (2.3%), headache (1.3%), nausea (1.3%), vomiting (1.3%), and hypotension (1.0%) in the largest in-human trial. Relevance to patient care and clinical practice: Plazomicin will likely be used in the treatment of multi-drug-resistant cUTIs or in combination to treat serious carbapenem-resistant Enterobacteriaceae infections. Conclusions: Plazomicin appears poised to help fill the need for new agents to treat infections caused by multi-drug-resistant Enterobacteriaceae.

scholarly journals 1378. Evaluation of the In vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae, Including Isolates Resistant to Ceftazidime–Avibactam

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S422-S422
Author(s):  
William R Wilson ◽  
Ellen Kline ◽  
Chelsea Jones ◽  
Kristin Morder ◽  
Cornelius J Clancy ◽  
...  
Keyword(s):  
Premature Stop Codon ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Wild Type ◽  
In Vitro Susceptibility ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Meropenem-vaborbactam (M-V) is a novel antibiotic for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections. Our objective was to determine the in vitro activity of meropenem-vaborbactam against genetically-diverse CRE isolates, including those that have developed resistance to Ceftazidime–Avibactam (C-A). Methods Minimum inhibitory concentrations (MICs) were determined for meropenem (MER), M-V, and C-A by reference broth microdilution (BMD) methods in triplicate. Vaborbactam and avibactam were tested at fixed concentrations of 8 and 4 µg/mL, respectively. Quality control strains were used and within expected ranges. Polymerase chain reaction (PCR) with DNA sequencing was used to detect resistance determinants, including Klebsiella pneumoniae carbapenemase (KPC) subtypes and porin mutations. Results A total of 117 CRE isolates were tested, including K. pneumoniae (Kp; n = 83), E. cloacae (n = 17), E. coli (n = 10), and E. aerogenes (n = 7). Seventy-nine percent harbored blaKPC. KPC subtypes included KPC-2 (n = 32), KPC-3 (n = 41), KPC-3 variants (n = 16), and KPC [not typed] (n = 4, all E. coli). Among 74 K. pneumoniae, 95% had a premature stop codon in ompk35 and ompK36 genotypes included wild type (n = 48), IS5 insertion (n = 13), 135–136 DG duplication (n = 9), and other mutations (n = 4). The median (range) MICs for MER, C-A, and M-V were 8 (0.06 to ≥128), 1 (0.25 to ≥512), and 0.03 (0.015––16), respectively. Corresponding rates of susceptibility were 23, 84, and 98%, respectively. Fifty-three percent and 95% of C-A-resistant isolates were susceptible to MER and M-V, respectively. Among Kp, C-A MICs did not vary by KPC subtype or porin genotype. On the other hand, median M-V MICs were higher among KPC-2 than KPC-3 Kp (0.12 vs. 0.03; P = 0.002), and among Kp with ompK36 porin mutations compared with wild type (0.25 vs. 0.03; P < 0.001). Among Kp with KPC-3 variants (n = 16), the median M-V MIC was 0.03 (0.015––2); 100% were M-V susceptible. Median M-V MICs did not vary by CRE species. Only two isolates were M-V resistant, both were E. cloacae that did not harbor blaKPC. Conclusion M-V demonstrates high rates of in vitro susceptibility against diverse CRE isolates, including those that are resistant to C-A. As this agent is introduced into the clinic, it will be important to identify K. pneumoniae isolates harboring KPC-2 with ompK36 porin mutations that demonstrate higher MICs. Disclosures M. H. Nguyen, Merck: Grant Investigator, Research grant. Astellas: Grant Investigator, Research grant.

scholarly journals 1231. In Vitro Activity of Aztreonam-Avibactam and Comparator Agents Against Enterobacterales from Patients with Lower Respiratory Tract Infections Collected During the ATLAS Global Surveillance Program, 2017-2019

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S705-S705
Author(s):  
Sibylle Lob ◽  
Krystyna Kazmierczak ◽  
Francis Arhin ◽  
Daniel F Sahm
Keyword(s):  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Vitro Activity ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Lower Respiratory Tract Infections ◽  
Independent Contractor ◽  
Tract Infections

Abstract Background β-lactamase-producing Enterobacterales (Ebact) frequently co-carry resistance to antimicrobials from other classes, limiting treatment options. Avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases, while aztreonam (ATM) is refractory to hydrolysis by class B metallo-β-lactamases (MBLs). ATM-AVI is being developed for use against drug-resistant isolates of Ebact, especially those co-producing MBLs and serine β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Ebact collected in 2017-2019 from patients with lower respiratory tract infections (LRTI) as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Methods Non-duplicate clinical isolates were collected in 52 countries in Europe, Latin America, Asia/Pacific (excluding mainland China and India), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2021 and FDA (tigecycline) breakpoints. ATM-AVI was tested at a fixed concentration of 4 µg/mL AVI. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin, aztreonam, cefepime, colistin, levofloxacin, meropenem, and piperacillin-tazobactam. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC >1 µg/mL, and Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC >1 µg/mL. Results ATM-AVI was active in vitro against Ebact isolates from LRTI (MIC90, 0.25 µg/mL), with 99.97% of isolates inhibited by ≤8 µg/mL of ATM-AVI, including 100% of isolates that produced MBLs. ATM-AVI tested with MIC90 values of 0.5 µg/mL against subsets of cefepime-nonsusceptible (NS), meropenem-NS, amikacin-NS, colistin-resistant, and MBL-positive Ebact (Table). The tested β-lactam comparators showed susceptibility of < 78% against these subsets of resistant isolates. Results Table Conclusion Based on MIC90 values, ATM-AVI was the most potent agent tested against drug-resistant and MBL-positive subsets of Ebact collected from LRTI. The promising in vitro activity of ATM-AVI warrants further development of this combination for treatment of LRTI caused by drug-resistant Ebact. Disclosures Sibylle Lob, 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)

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