Quality Evaluation of Gentamicin Sulfate Reference Standards in Japanese Pharmacopoeia Using Hydrophilic Interaction Chromatography Combined With Tandem Mass Spectrometry.

BACKGROUND: Through the recent development of analytical technology, antibiotics quantification in the Japanese Pharmacopoeia (JP) has changed from traditional microbiological assays to physicochemical methods with high specificity and precision. However, for several multicomponent antibiotics without typical UV absorption, potency cannot be directly determined using instrumental methods such as high-performance liquid chromatography; therefore, traditional microbiological assays are still used. Gentamicin sulfate (GmS), which consists of three major components, C1, C1a, and C2, is such a typical antibiotic, and its antimicrobial potency continues to be assayed using microbiological methods in JP monographs. Introduction of a physicochemical assay for GmS is needed to help ensure its quality and quantity. OBJECTIVE: This study aimed to develop quality control measures for GmS that could be complementary to quantitative assays and purity tests specified in the JP. METHODS: For each gentamicin C component (C1, C2, and C1a), theoretical potencies were determined based on the quantitative relationship between purity and potency, as measured by quantitative 1H NMR and microbiological assays, respectively. Two lots of the JP reference standard (RS) were used as test samples, with the contents of each component and impurity (sisomicin and garamine) being determined using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). RESULTS: The ratios of theoretical potency for C1, C2, and C1a were 1.00, 1.21, and 1.80, respectively. The potencies of the GmS JP RSs, which were estimated based on the contents and theoretical potency of each C component, corresponded well with those determined through microbiological assays. Marked differences in impurities (%) between the two RS lots were highlighted by quantifying sisomicin and garamine. CONCLUSIONS: The developed analytical procedure enabled the characterization of two different JP RSs in terms of content ratio, potencies, and impurities. HIGHLIGHTS: Novel analytical procedures useful for routine quality control of GmS were developed using HILIC-MS/MS.

Use of pharmacokinetic/pharmacodynamic approaches for dose optimization: a case study of plazomicin.

With limited treatment options available for multidrug-resistant bacteria, dose optimization is critical for achieving effective drug concentrations at the site of infection. Yet, selecting an appropriate dose and appropriate time to administer the dose with dosing frequency requires extensive understanding of the interplay between drug pharmacokinetics/pharmacodynamics (PK/PD), the host immune system, and bacterial-resistant mechanisms. Model-informed dose optimization (MIDO) uses PK/PD models (e.g. population PK, mechanism-based models, etc.) that incorporate preclinical and clinical data to simulate/predict performance of treatment regimens in appropriate patient populations and/or infection types that may not be well-represented in clinical trials. Here, we highlight the stages of a MIDO approach for designing optimized regimens by reviewing current clinical, preclinical, and PK/PD modeling data available for plazomicin. Plazomicin is an aminoglycoside approved in 2018 for the treatment of complicated urinary tract infections in adults. Applying knowledge gained by PK/PD modeling can guide therapeutic drug monitoring to ensure that drug exposure is appropriate for clinical efficacy while limiting drug-related toxicity.

In Vitro Activity of Plazomicin Against Carbapenem Resistant Klebsiella pneumoniae Strains.

BACKGROUND: In our study, we evaluated the in vitro activities of plazomicin, amikacin, gentamicin, and tobramycin among fifty carbapenem resistant Klebsiella pneumoniae (CR-Kp) isolates. Aminoglycoside resistance genes in selected CR-Kp strains were also examined. METHODS: Minimum inhibitory concentration (MIC) of meropenem, plazomicin, tobramycin, gentamicin, and amikacin were determined by gradient test (G-test) method. In all strains carbapenemase activity was assessed by polymerase chain reaction (PCR). Aminoglycoside modifying enzyme (AME) genes in 14 CR-Kp strains that are resistant to at least one of tobramycin, gentamicin, and amikacin among fifty CR-Kp isolates, and 16S ribosomal methylase genes in 6 CR-Kp strains with plazomicin MIC ≥ 128 mg/L were investigated by PCR method. RESULTS: The most frequently detected carbapenemase enzyme in the strains in our study was OXA-48 (88%). Aminoglycoside susceptibilities of all isolates were determined; plazomicin 84%, amikacin 66%, gentamicin 50%, tobramycin 18%. The most common AME gene positivities were found, 93% (n = 13) ant(3')-I, 78% (n = 11) aac(6')-Ib, 57% (n = 8) aac(3')-IV, 42% (n = 6) aac(3')-IIa, and 29% (n = 4) aph(3')-VI. Most of the isolates examined for the presence of AME carry at least two or more AME genes. The most common 16S ribosomal methylase gene was rmtH. In our study, MIC values of ≥ 256 µg/mL were found in 6 (12%) of 50 isolates against amikacin, tobramycin, and gentamicin, including plazomicin. At least two 16S ribosomal methylase gene positivity has been shown in these 6 strains. CONCLUSIONS: In our study, increased in vitro efficacy of plazomicin was shown in CR-Kp isolates comparing to other aminoglycosides. Plazomicin is an effective treatment option against CR-Kp isolates and needs to be sup-ported by clinical studies.

Fluorescence-Based Binding Characterization of Small Molecule Ligands Targeting CUG RNA Repeats.

Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG)10 to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV Tm technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.

Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment. The exposure-response analysis was conducted to identify the relationship between plazomicin exposure and nephrotoxicity incidence in cUTI patients with renal impairment. Classification and regression tree (CART) analysis was utilized to assess the TDM strategy. The receiver operating characteristics curve was plotted to compare two TDM thresholds in cUTI patients with renal impairment. The analyses suggested that dose reduction is necessary for cUTI patients with moderate or severe renal impairment. TDM should be implemented for cUTI patients with mild, moderate, or severe renal impairment to reduce the risk of nephrotoxicity. The trough concentration of 3 µg/mL is a reasonable TDM threshold to reduce the nephrotoxicity incidence while maintaining efficacy in cUTI patients with renal impairment. The application of population PK modeling, exposure-response analysis, and CART analysis allowed for the evaluation of a dosage regimen and TDM strategy for plazomicin in cUTI patients with renal impairment. Our study demonstrates the utility of pharmacometrics and statistical approaches to inform a dosage regimen and TDM strategy for drugs with narrow therapeutic windows.

Radiolabeling, characterization, and preclinical evaluation of plazomicin: A potential tracer for bacterial infection.

In this study, 99m Tc-plazomicin, a new radio-antibiotic complex, was prepared specifically for bacterial infection localization and monitoring. Factors affecting the labeling reaction were studied and optimized to obtain a high yield (98.8 ± 0.2%). In silico, radiochemical and physicochemical characterization and biodistribution were performed to assess the complex aptness as a radiopharmaceutical. The complex was biologically evaluated in vitro using bacteria and in vivo using different inflammation models (sterile, bacterial, and fungal). Uptake in the bacterial model was highest (7.8 ± 0.3%). Results indicated that the technetium label did not alter the antibiotic biological behavior and backed the usefulness of 99m Tc-plazomicin as a potential tracer.

Multicenter Clinical Evaluation of ETEST Plazomicin (PLZ) for Susceptibility Testing of Enterobacterales.

Plazomicin (PLZ), brand name ZEMDRI (Cipla Therapeutics), is a novel aminoglycoside antibiotic approved by the U.S. Food and Drug Administration (FDA) for treatment of complicated urinary tract infections including pyelonephritis. ETEST® is a gradient diffusion method that represents an alternative to the more laborious broth micro-dilution (BMD) method for performing antimicrobial susceptibility testing (AST). A multi-center evaluation of the performance of the new ETEST PLZ (bioMérieux) was conducted in comparison with BMD following FDA and International Standards Organization (ISO) recommendations using FDA-defined breakpoints. Clinical isolates of Enterobacterales (n = 598) were included. Fifty-three isolates were resistant to PLZ according to BMD. Overall, the ETEST PLZ demonstrated 99.0% essential agreement (EA), 92.8% category agreement (CA), 1.9% very major errors (VME), 0% major errors (ME), and 7.0% minor errors (mE) with both clinical and challenge isolates of Enterobacterales. The VME was found for a single Serratia marcescens strain. Individual species demonstrated EA rates ≥ 90%. In conclusion, we report that ETEST PLZ represents an accurate tool for performing PLZ AST of Enterobacterales.

Epidemiology and in vitro activity of ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, eravacycline, plazomicin, and comparators against Greek carbapenemase-producing Klebsiella pneumoniae isolates.

BACKGROUND: The increase in carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is of great concern because of limited treatment options. New antimicrobials were recently approved for clinical therapy. This study evaluated the epidemiology of carbapenemase-producing K. pneumoniae isolates collected at a Greek university hospital during 2017-2020, and their susceptibilities to ceftazidime-avibactam (CAZ/AVI), meropenem-vaborbactam (M/V), imipenem-relebactam (I/R), eravacycline, plazomicin, and comparators. METHODS: Minimum inhibitory concentrations (MICs) were evaluated by Etest. Only colistin MICs were determined by the broth microdilution method. Carbapenemase genes were detected by PCR. Selected isolates were typed by multilocus sequence typing (MLST). RESULTS: A total of 266 carbapenemase-producing K. pneumoniae strains were isolated during the 4-year study period. Among them, KPC was the most prevalent (75.6%), followed by NDM (11.7%), VIM (5.6%), and OXA-48 (4.1%). KPC-producing isolates belonged mainly to ST258 and NDM producers belonged to ST11, whereas OXA-48- and VIM producers were polyclonal. Susceptibility to tigecycline, fosfomycin, and colistin was 80.5%, 83.8%, and 65.8%, respectively. Of the novel agents tested, plazomicin was the most active inhibiting 94% of the isolates at ≤ 1.5 µg/ml. CAZ/AVI and M/V inhibited all KPC producers and I/R 98.5% of them. All OXA-48 producers were susceptible to CAZ/AVI and plazomicin. The novel ß-lactam/ß-lactamase inhibitors (BLBLIs) tested were inactive against MBL-positive isolates, while eravacycline inhibited 61.3% and 66.7% of the NDM and VIM producers, respectively. CONCLUSIONS: KPC remains the predominant carbapenemase among K. pneumoniae, followed by NDM. Novel BLBLIs, eravacycline, and plazomicin are promising agents for combating infections by carbapenemase-producing K. pneumoniae. However, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship.

Repurposing Sitafloxacin, Prulifloxacin, Tosufloxacin, and Sisomicin as Antimicrobials Against Biofilm and Persister Cells of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a ubiquitous bacterium found in hospitals and the surrounding environment. The ability of P. aeruginosa to form biofilms confers high-level resistance to antibiotics, and the persister cells formed in the presence of high antibacterial drug concentrations make P. aeruginosa-related infections more refractory. Further, there rarely is an effective antimicrobial alternative when biofilm- and persister cell-targeting treatment fails. Using a high-throughput screening assay, we previously identified fluoroquinolones sitafloxacin, prulifloxacin, and tosufloxacin as well as aminoglycoside sisomicin among FDA-approved drugs with significant bactericidal activity against P. aeruginosa. In addition, in our current study, these antibiotics exhibited an effective time- and dose-dependent eradication effects against the preformed biofilms of P. aeruginosa at the concentrations of 2-4 µM. These agents also exhibited bactericidal efficacy against CCCP-induced P. aeruginosa persister cells with the viable cell count decreased from 9.14 log10 CFU/mL to 6.15 (sitafloxacin), 7.59 (prulifloxacin), 4.27 (tosufloxacin), and 6.17 (sisomicin) log10 CFU/mL, respectively, following 4 h of treatment. Furthermore, sisomicin was also effective against conventional antibiotics induced persister cells in a time-dependent manner within 24 h. In addition, we confirmed the in vivo anti-biofilm efficacy of the identified antibiotics in a subcutaneous implantation biofilm-related infection model. Tosufloxacin exhibited the greatest in vivo bactericidal activity against P. aeruginosa biofilms with a reduction of 4.54 ΔLog10 CFU/mL compared to the vehicle group, followed by prulifloxacin, sitafloxacin, and sisomicin. Taken together, our results indicate that sitafloxacin, prulifloxacin, tosufloxacin, and sisomicin have great potential as alternatives for the treatment of refractory infections caused by P. aeruginosa biofilms and persister cells.

Comparison of in vitro activities of plazomicin and other aminoglycosides against clinical isolates of Klebsiella pneumoniae and Escherichia coli.

OBJECTIVES: To compare the in vitro activity of plazomicin and two older aminoglycosides (gentamicin and amikacin) against 180 isolates of Escherichia coli and Klebsiella pneumoniae, including subsets of 60 non-ESBL-producing, 60 ESBL-producing and 60 carbapenem-resistant (46 carrying blaOXA-48, 11 carrying blaNDM and 3 carrying blaOXA-48 and blaNDM) strains. METHODS: MICs of plazomicin, gentamicin and amikacin were determined by a gradient diffusion method. Gentamicin and amikacin MICs were interpreted according to CLSI criteria and EUCAST breakpoint tables. Plazomicin MICs were interpreted using FDA-defined breakpoints. RESULTS: All non-ESBL-producing and ESBL-producing isolates were susceptible to plazomicin. The plazomicin susceptibility rate (71.7%) in carbapenem-resistant isolates was significantly higher than those observed for gentamicin (45%) and amikacin (56.7% and 51.7% according to CLSI and EUCAST breakpoints, respectively). Gentamicin, amikacin and plazomicin susceptibility rates (35.6% for gentamicin; 44.4% and 37.8% for amikacin according to CLSI and EUCAST breakpoints, respectively; 64.4% for plazomicin) in carbapenem-resistant K. pneumoniae were significantly lower than those observed for carbapenem-resistant E. coli isolates (73.3% for gentamicin; 93.3% for amikacin and plazomicin). Gentamicin, amikacin and plazomicin susceptibility rates for blaNDM-positive isolates were lower than those observed for blaOXA-48-positive isolates, but differences were not statistically significant. Among the isolates that were non-susceptible to both gentamicin and amikacin, the plazomicin susceptibility rate was less than 30%. CONCLUSIONS: Although plazomicin showed excellent in vitro activity against carbapenem-susceptible isolates, the plazomicin resistance rate increased to 35.6% among carbapenem-resistant K. pneumoniae and further increased to 45.5% among blaNDM-positive isolates.

Analysis of histamine and sisomicin in gentamicin: Search for the causative agents of adverse effects.

In 1998, the aminoglycoside antibiotic gentamicin sulfate caused several cases of deaths in the United States, after the switch from twice- to once-daily application. Endotoxins were discussed as the cause for the adverse effects and sisomicin was identified as the lead impurity; batches containing sisomicin were contaminated with more impurities and were responsible for the fatalities. In 2016, anaphylactic reactions in horses, and later in humans with one fatality, were observed after application of gentamicin sulfate contaminated with histamine. To determine whether histamine was responsible for the 1990s death cases as well, histamine was quantified by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 samples of gentamicin sulfate analyzed in previous studies. Furthermore, a relative quantification of sisomicin was performed to check for a correlation between histamine and the lead impurity. A maximum amount of 11.52 ppm histamine was detected, which is below the limit for anaphylactic reactions of 16 ppm, and no correlation of the two impurities was observed. However, the European Medicines Agency recommends a stricter limit with regard to the maximum single dose of gentamicin sulfate to reach a greater gap between the maximum histamine exposition of 4.3 µg and the quantity known to cause hypotension of 7 µg. The low amounts of histamine and the fact that there is no connection with the contamination with sisomicin showed that histamine was not the cause for the death cases in the United States in 1998, and endotoxins remain the most probable explanation.

Plazomicin for the treatment of multidrug-resistant Klebsiella bacteraemia in a patient with underlying chronic kidney disease and acute renal failure requiring renal replacement therapy.

A 75-year-old man presented with shortness of breath and somnolence and was found to have urosepsis. Blood and urine cultures subsequently grew multidrug-resistant (MDR) Klebsiella pneumoniae (Kp) with the New Delhi metallo-ß-lactamase gene. The patient was treated successfully with plazomicin and meropenem/vaborbactam combination therapy. The course was complicated by acute kidney injury temporarily requiring haemodialysis, gastrointestinal bleed requiring multiple transfusions and hospital readmission with blood cultures again positive with MDR Kp. Plazomicin drug levels were persistently high during treatment, suggesting that therapeutic drug monitoring may be needed to safely use this drug in patients with severe renal dysfunction. This case marks the first use of plazomicin for bacteraemia in the literature outside of a clinical trial and demonstrates its safe and effective use in a patient with advanced renal disease, and provides important insights about dosing and therapeutic drug monitoring considerations in this patient population.

Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2') enzymes.

Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2')-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2')-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2')-Ia-acetylated plazomicin complex, these structures outline AAC(2')-Ia's specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2')-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.

New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives.

The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one ß-lactam and one ß-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.

Structural basis for plazomicin antibiotic action and resistance.

The approval of plazomicin broadened the clinical library of aminoglycosides available for use against emerging bacterial pathogens. Contrarily to other aminoglycosides, resistance to plazomicin is limited; still, instances of resistance have been reported in clinical settings. Here, we present structural insights into the mechanism of plazomicin action and the mechanisms of clinical resistance. The structural data reveal that plazomicin exclusively binds to the 16S ribosomal A site, where it likely interferes with the fidelity of mRNA translation. The unique extensions to the core aminoglycoside scaffold incorporated into the structure of plazomicin do not interfere with ribosome binding, which is analogously seen in the binding of this antibiotic to the AAC(2')-Ia resistance enzyme. The data provides a structural rationale for resistance conferred by drug acetylation and ribosome methylation, i.e., the two mechanisms of resistance observed clinically. Finally, the crystal structures of plazomicin in complex with both its target and the clinically relevant resistance factor provide a roadmap for next-generation drug development that aims to ameliorate the impact of antibiotic resistance.

Activity of plazomicin against carbapenem-intermediate or -resistant Escherichia coli isolates from the United States and international sites in relation to clonal background, resistance genes, co-resistance, and region.

BACKGROUND: Emerging carbapenem resistance in Escherichia coli, including sequence type 131 (ST131), threatens therapeutic efficacy. Plazomicin (PLZ), a semisynthetic aminoglycoside approved by the FDA in 2018, overcomes the most common aminoglycoside resistance mechanisms and maintains activity against many carbapenem-intermediate or -resistant (CIR) E. coli strains. OBJECTIVES: To assess plazomicin susceptibility among CIR E. coli in relation to region and multiple bacterial characteristics. METHODS: We determined broth microdilution MICs for plazomicin and 11 comparators against 343 CIR clinical E. coli isolates, then compared susceptibility results by bacterial characteristics and region. The collection comprised 203 US isolates (2002-17) and 141 isolates from 17 countries in Europe, Latin America, and the Asia-West Pacific region (2003-17). Isolates were characterized for phylogenetic group, resistance-associated sequence types (STs) and subsets thereof, and relevant ß-lactamase-encoding genes. RESULTS: Plazomicin exhibited the highest percentage susceptible (89%) after tigecycline (99%). The percentage susceptible to plazomicin varied significantly by phylogroup (63%, group B1; versus >93%, others) and ST131 subclone (92%, H30Rx; versus 87%-89%, H30R1 and non-H30), but not ST. It also varied by resistance genotype [higher with Klebsiella pneumoniae carbapenemase (KPC), lower with metallo-ß-lactamases], global region [highest for Latin America (94%), lowest for Asia-West Pacific (69%)], and US region (80%, South, versus 96%-100%, others). Although reduced susceptibility to comparators often predicted reduced susceptibility to plazomicin, even among comparator-intermediate or -resistant isolates the plazomicin-susceptible fraction was ≥77%, except for amikacin (53%). CONCLUSIONS: The likely utility of plazomicin against CIR E. coli is high overall, but varies with region and multiple bacterial characteristics.

Advances in novel antibiotics to treat multidrug-resistant gram-negative bacterial infections.

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

Comparative activity of plazomicin against extended-spectrum cephalosporin-resistant Escherichia coli clinical isolates (2012-2017) in relation to phylogenetic background, sequence type 131 subclones, blaCTX-M genotype, and resistance to comparator agents.

Extended-spectrum cephalosporin-resistant Escherichia coli (ESCREC) are a growing threat. Leading ESCREC lineages include sequence type ST131, especially its (blaCTX-M-15-associated) H30Rx subclone and (blaCTX-M-27-associated) C1-M27 subset within the H30R1 subclone. The comparative activity against such strains of alternative antimicrobial agents, including the recently developed aminoglycoside plazomicin, is undefined, so was investigated here. We assessed plazomicin and 11 comparators for activity against 216 well-characterized ESCREC isolates (Minnesota, 2012-2017) and then compared broth microdilution MICs with phylogenetic and clonal background, beta-lactamase genotype (blaCTX-M; group 1 and 9 variants), and co-resistance. Percent susceptible was > 99% for plazomicin, meropenem, imipenem, and tigecycline; 96-98% for amikacin and ertapenem; and ≤ 75% for the remaining comparators. For most comparators, MICs varied significantly in relation to multiple bacterial characteristics, in agent-specific patterns. By contrast, for plazomicin, the only bacterial characteristic significantly associated with MICs was ST131 subclone: plazomicin MICs were lowest among O16 ST131 isolates and highest among ST131-H30R1 C1-M27 subclone isolates. Additionally, plazomicin MICs varied significantly in relation to resistance vs. susceptibility to comparator agents only for amikacin and levofloxacin. For most study agents, antimicrobial activity against ESCREC varied extensively in relation to multiple bacterial characteristics, including clonal background, whereas for plazomicin, it varied only by ST131 subclone (C1-M27 isolates least susceptible, O16 isolates most susceptible). These findings support plazomicin as a reliable alternative for treating ESCREC infections and urge continued attention to the C1-M27 ST131 subclone.

In vitro activity of plazomicin against quinolone-resistant gram-negative bacteria isolated from catheter-associated urinary tract infections.

Quinolone resistance among uropathogens is an increasing concern. Plazomicin is a new aminoglycoside that shows promising results against resistant bacteria. However, no study has yet tested its effect specifically on quinolone-resistant organisms. This study aimed to evaluate the in vitro activity of plazomicin and comparator drugs against quinolone-resistant Gram-negative isolates of catheter-associated urinary tract infections (CAUTI). Plazomicin demonstrated high inhibiting activity against Enterobacteriaceae isolates (95.9% at MIC≤ 2 mg/L), with MIC50/90 was 1/2 mg/L. High MICs values were detected against non-Enterobacteriaceae isolates (MIC50/90, 4/32 mg/L). Plazomicin had susceptibility rate of 97.2% against Enterobacteriaceae isolates carrying aminoglycosides modifying enzymes (AME) genes, while other aminoglycosides, amikacin and gentamicin showed reduced activity (32.4% and 25.4%, respectively). In conclusion, plazomicin showed potent in vitro activity against quinolone-resistant Enterobacteriaceae causing CAUTI, regardless of the AME pattern.