RESUMEN

Carbapenem-resistant Enterobacterales (CRE) have become a major public health problem worldwide. The aim of this study was to investigate efficacy of ceftazidime/avibactam and plazomicin on carbapenem-resistant Klebsiella pneumoniae and Escherichia coli isolates. Susceptibility of imipenem, meropenem, ertapenem, ceftazidime/avibactam and plazomicin was investigated by broth-microdilution method. Major carbapenemases NDM, VIM, IMP, KPC, OXA-48 as well as other ß-lactamases namely, TEM, SHV, OXA-1-like, CTX-M, ACC, FOX, MOX, DHA, CIT, EBC, VEB, GES, PER were investigated by PCR. A total of 120 carbapenem-resistant isolates (60 E. coli and 60 K. pneumoniae) were included in this study and blaOXA-48-like was found in 78.33%, blaNDM in 26.66%, blaKPC in 7.5%, blaIMP in 5.83%, and blaVIM in 5%. Among 94 isolates with the blaOXA-48-like gene, 22.3% were resistant to ceftazidime/avibactam and 51.1% were resistant to plazomicin. Of 32 isolates with blaNDM, 31 (96.9%) were resistant to ceftazidime/avibactam and 30 (93.75%) were resistant to plazomicin, and both antibiotics had limited effects against blaNDM carriers (P < 0.001). Of the 12 isolates with blaNDM+OXA-48 combination, 11 (91.7%) were resistant to ceftazidime/avibactam and plazomicin. The effect of both antibiotics was significantly lower in strains with blaNDM+OXA-48 combination (P < 0.005).The most common carbapenemase genes in this study were blaOXA-48-like and blaNDM. Ceftazidime/avibactam demonstrated a good efficacy among OXA-48 producing K. pneumoniae and E. coli, however, plazomicin had a significantly lower antibacterial effect in our study. Both antimicrobial agents should be considered as an option by evaluating combined susceptibility results and gene patterns obtained by regional and global molecular data in the treatment of CRE infections.

Asunto(s)

Antibacterianos , Compuestos de Azabiciclo , Enterobacteriaceae Resistentes a los Carbapenémicos , Ceftazidima , Combinación de Medicamentos , Escherichia coli , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Sisomicina , beta-Lactamasas , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Ceftazidima/farmacología , Compuestos de Azabiciclo/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Antibacterianos/farmacología , Sisomicina/farmacología , Sisomicina/análogos & derivados , beta-Lactamasas/genética , Humanos , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Proteínas Bacterianas/genética , Carbapenémicos/farmacología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico

RESUMEN

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.

Asunto(s)

Aminoglicósidos , Antibacterianos , Humanos , Antibacterianos/farmacocinética , Pulmón , Amicacina

RESUMEN

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6' position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2'-N-acetyltransferase type Ia [AAC(2')-Ia], which reduces the antibiotic's potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib]. In particular, Ag+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6')-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2')-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2')-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.

RESUMEN

Limited treatment options exist for the treatment of carbapenem-resistant Enterobacterales (CRE) bacteria. Fortunately, there are several recently approved antibiotics indicated for CRE infections. Here, we examine the in vitro activity of various novel agents (eravacycline, plazomicin, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) and comparators (tigecycline, amikacin, levofloxacin, fosfomycin, polymyxin B) against 365 well-characterized CRE clinical isolates with various genotypes. Nonduplicate isolates collected from the largest public health hospital in Singapore between 2007 and 2020 were subjected to antimicrobial susceptibility testing (broth microdilution or antibiotic gradient test strips). Susceptibilities were defined using Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration (FDA) interpretative criteria. Sequence types and resistance mechanisms were characterized using short-read whole-genome sequencing. Overall, tigecycline and plazomicin exhibited the highest susceptibility rates (89.6% and 80.8%, respectively). However, the tigecycline susceptibility breakpoint utilized here may be outdated in view of prevailing pharmacokinetic-pharmacodynamic (PK/PD) data. Susceptibility varied by carbapenemase genotype; the ß-lactam/ß-lactamase inhibitor combinations were equally active (92.3 to 99.2% susceptible) against KPC producers, but only ceftazidime-avibactam retained high susceptibility (98.7%) against OXA-48-like producers. Against metallo-ß-lactamase producers, only plazomicin exhibited moderate activity (77.0% susceptible). Aminoglycoside activity was also influenced by carbapenemase genotypes. This work provides an insight into the comparative activity and presumptive utility of novel agents in this geographic region. IMPORTANCE This study determined the susceptibilities of carbapenem-resistant Enterobacterales isolates to various novel antimicrobial agents (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, eravacycline, and plazomicin). Whole-genome sequencing was performed for all strains. Our study findings provide insights into the comparative activities of novel agents in this geographic region. Plazomicin and ceftazidime-avibactam exhibited the lowest nonsusceptibility rates and may be considered promising agents in the management of carbapenem-resistant Enterobacterales infections. We note also that antibiotic activity is influenced by genotypes and that understanding the geographic region's molecular epidemiology could aid in the definition of the presumptive utility of novel agents and contribute to antibiotic decision-making.

Asunto(s)

Antibacterianos , Carbapenémicos , Meropenem , Carbapenémicos/farmacología , Tigeciclina/farmacología , Antibacterianos/farmacología , beta-Lactamasas/genética , Inhibidores de beta-Lactamasas/farmacología , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana

RESUMEN

OBJECTIVE: To assess the clinical efficacy and safety of novel antibiotics for complicated urinary tract infections (cUTIs). METHODS: Three electronic databases (Medline, Embase and the Cochrane Library) were searched from inception until 20 October 2022 to identify randomized controlled trials (RCTs) investigating the efficacy and safety of novel antibiotics (novel ß-lactam/ß-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones and cefiderocol) against cUTIs. The primary outcome was the clinical cure rate (CCR) at test of cure (TOC), while secondary outcomes included CCR at end of treatment (EOT), microbiological eradication rate, and the risk of adverse events (AEs). Trial sequential analysis (TSA) was used to examine the evidence. RESULTS: In total, 11 RCTs demonstrated a higher CCR [83.6% vs 80.3%, odds ratio (OR) 1.37, 95% confidence interval (CI) 1.08-1.74, P=0.01, I2=35%, 11 RCTs, 3514 participants] and microbiological eradication rate (77.7% vs 67.2%, OR 1.79, 95% CI 1.46-2.20, P<0.00001, 11 RCTs, 4347 participants) at TOC in the intervention group compared with the control group. At EOT, there was no significant difference in CCR (OR 0.96, P=0.81, I2=4%, nine RCTs, 3429 participants) or risk of treatment-emergent AEs (OR 0.95, P=0.57, I2=51%, 11 RCTs, 5790 participants) between the intervention and control groups. TSA showed robust evidence regarding microbiological eradication rate and treatment-emergent AEs, while the CCR at TOC and EOT remained inconclusive. CONCLUSIONS: While showing similar safety, the investigated novel antibiotics may be more effective than the conventional antibiotics for patients with cUTIs. However, as the pooled evidence relating to CCR remained inconclusive, further studies are required to address this issue.

Asunto(s)

Antibacterianos , Infecciones Urinarias , Humanos , Antibacterianos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Inhibidores de beta-Lactamasas/uso terapéutico , Resultado del Tratamiento

RESUMEN

Background: The Clinical and Laboratory Standards Institute (CLSI) lowered the Enterobacterales-susceptible/-resistant breakpoints for amikacin in 2023 from ≤16/≥64 mg/L to ≤4/≥16 mg/L and the breakpoints for gentamicin and tobramycin from ≤4/≥16 mg/L to ≤2/≥8 mg/L. Because aminoglycosides are frequently used to treat infections caused by multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE), we evaluated the impact of these changes on the susceptibility rates (%S) of Enterobacterales collected from US medical centers. Methods: A total of 9809 Enterobacterales isolates were consecutively collected (1/patient) from 37 US medical centers in 2017-2021 and susceptibility was tested by broth microdilution. Susceptibility rates were calculated using CLSI 2022, CLSI 2023, and US Food and Drug Administration 2022 criteria. Aminoglycoside-nonsusceptible isolates were screened for genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases (16RMT). Results: The CLSI breakpoint changes mostly affected amikacin, especially against MDR (94.0%S to 71.0%S), extended-spectrum ß-lactamase (ESBL)-producing (96.9%S to 79.7%S), and CRE (75.2%S to 59.0%S) isolates. Plazomicin was active against 96.4% of isolates and retained potent activity against CRE (94.0%S), ESBL-producing (98.9%S), and MDR (94.8%S) isolates. Gentamicin and tobramycin showed limited activity against resistant subsets of Enterobacterales. The AME-encoding genes and 16RMT were observed in 801 (8.2%) and 11 (0.1%) isolates, respectively. Plazomicin was active against 97.3% of the AME producers. Conclusions: The spectrum of activity of amikacin against resistant subsets of Enterobacterales was drastically reduced when interpretative criteria based on pharmacokinetic/pharmacodynamic parameters that are currently used to establish breakpoints for other antimicrobials were applied. Plazomicin was markedly more active than amikacin, gentamicin, or tobramycin against antimicrobial-resistant Enterobacterales.

RESUMEN

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKP) remain one of the greatest healthcare threats associated with significant morbidity and mortality. New antimicrobials were recently developed to address this threat. We assessed the epidemiology of carbapenemase-producing K. pneumoniae (CPKP) isolates recovered in a Greek university hospital during 2021, and their susceptibilities to old and newer antimicrobials. Minimum inhibitory concentrations (MICs) were determined by the MIC Test Strip method, except for cefiderocol (CFDC) and colistin that were evaluated by the broth microdilution method. A total of 110 CPKP strains were isolated, with KPC-producers being the most prevalent (64.6%). Among the agents tested, plazomicin (PL) displayed the highest activity against all the isolates (MIC50/MIC90, 0.5/1.5 µg/ml), followed by tigecycline (MIC50/MIC90, 1.5/4 µg/ml). All KPC-producing K. pneumoniae were susceptible to ceftazidime-avibactam (CAZ/AVI) and meropenem-vaborbactam (M/V) and 97.2% of them to imipenem-relebactam (I/R). Among the MBL-producing isolates, PL and CFDC exhibited the highest activity.

Asunto(s)

Klebsiella pneumoniae , Inhibidores de beta-Lactamasas , Humanos , Inhibidores de beta-Lactamasas/farmacología , Lactamas , Antibacterianos/farmacología , Cefalosporinas/farmacología , Ceftazidima/farmacología , beta-Lactamasas , Combinación de Medicamentos , Compuestos de Azabiciclo/farmacología , Pruebas de Sensibilidad Microbiana , Cefiderocol

RESUMEN

Diabetic foot infection is a frequent and potentially life-threatening complication of diabetes mellitus. Antibiotic treatment is the cornerstone of management of diabetic foot infection but the rising prevalence of antibiotic resistance has resulted in increasing rates of treatment failure. In this context, the development of several novel antibiotics might represent a useful tool in severe diabetic foot infections caused by multidrug-resistant bacteria. In the present review, we summarize the safety and efficacy of novel antibiotics in patients with diabetic foot infection. Relevant data are limited, and randomized controlled studies that evaluated the role of these agents in this field are lacking. Until more robust data are available, cefiderocol and dalbavancin, which have been studied more extensively in patients with bone infections, might be attractive options in carefully selected patients with severe diabetic foot infection.

RESUMEN

Anti-microbial resistance is an escalating worldwide threat. Thus, there is an utmost necessity for the introduction of novel anti-microbial agents. This research aimed to evaluate the in-vitro activity of plazomicin, meropenem-vaborbactam, and omadacycline against carbapenem-resistant Gram-negative isolates gathered from one Egyptian University group of Hospitals. 210 intensive care units (ICU) and 113 non-ICU samples were included. Resistance to carbapenems was reported in 37.5% and 21.05% of the isolated Gram-negative ICU and non-ICU organisms respectively (P < 0.001). Via disc diffusion, the sensitivity rates for carbapenem-resistant non-ICU and ICU strains were 68.8% & 64.4% for plazomicin, 68.8% & 48.9% for meropenem-vaborbactam, and 56.25% & 44.5% for omadacycline, respectively. Regarding MIC50/90, it was 1/16 µg/mL for plazomicin and 4/32 µg/mL for both meropenem-vaborbactam and omadacycline separately. In conclusion, plazomicin displayed potent activity against carbapenem-resistant strains. Moreover, meropenem-vaborbactam and omadacycline demonstrated satisfactory results.

Asunto(s)

Antibacterianos , Carbapenémicos , Humanos , Meropenem/farmacología , Carbapenémicos/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Egipto , Proteínas Bacterianas , Pruebas de Sensibilidad Microbiana , beta-Lactamasas

RESUMEN

Plazomicin is a next-generation semisynthetic aminoglycoside antibiotic that can be used to treat infections by multi-resistant bacteria. It is effective against many bacteria-producing carbapenemases or other specific hydrolases. This scoping review aims to define the role acquired by plazomicin from its approval by the FDA (US Food and Drug Administration) in 2018 to the present day. Furthermore, we aim to provide a base for a future meta-analysis. This project was conducted following the recommendations presented in the PRISMA extension for scoping reviews and the JBI Manual for Evidence Synthesis. Among 901 potentially engaging citations, 345 duplicates were removed, and only 81 articles were selected for the analysis. According to the data analysis, plazomicin has been used to treat urinary tract infections, bloodstream infections, and ventilation-associated pneumonia. The pathogens killed included multi-resistant E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, and S. aureus. Plazomicin can be a manageable, valid non-beta-lactam alternative for treating multi-resistant bacteria infections.

RESUMEN

Background: In the present study, we aimed to compare the efficacy and safety of plazomicin with comparators for the treatment of Enterobacterales infections. Methods: Randomized controlled trials (RCTs) assessing plazomicin for Enterobacterales infections were searched on the PubMed, Embase, and Cochrane Library databases. Meta-analyses were used to evaluate the efficacy and safety in RCTs. Results: A total of 3 RCTs consisting of 761 patients were included in the present analysis. The study population included complex urinary tract infections (cUTIs), bloodstream infections (BSIs), and hospital-acquired pneumonia (HAP). Plazomicin had a clinical remission rate in the modified intention-to-treat (MITT) population that was similar to that of comparators (odds ratio [OR], 1.02; 95% CI, 0.60-1.73; I2 = 45%) in the pooled analysis of the 3 studies. The overall microbiologic eradication rate in the microbiological MITT (mMITT) population was similar to that of the comparators group (OR, 1.46; 95% CI, 0.72-2.95; I2 = 0%). However, the microbiologic recurrence rate of plazomicin for Enterobacterales was lower than that in the comparators group (OR, 0.38; 95% CI, 0.17-0.86; P = .02; I2 = 0%). No significant differences were found between plazomicin and comparators for the risk of any adverse events (OR, 0.78; 95% CI, 0.55-1.11; I2 = 0%). Conclusions: Plazomicin is as good as comparators in terms of efficacy and tolerance in the treatment of Enterobacterales infections. Therefore, plazomicin is a suitable choice for antibiotic treatment in adult patients with cUTIs, BSIs, or HAP.

RESUMEN

P. aeruginosa is still one of the most threatening pathogens responsible for serious hospital-acquired infections. It is intrinsically resistant to many antimicrobial agents and additional acquired resistance further complicates the management of such infections. High rates of combined antimicrobial resistance persist in many countries, especially in the eastern and south-eastern parts of Europe. The aim of this narrative review is to provide a comprehensive assessment of the epidemiology, latest data, and clinical evidence on the current and new available drugs active against P. aeruginosa isolates with limited treatment options. The latest evidence and recommendations supporting the use of ceftolozane-tazobactam and ceftazidime-avibactam, characterized by targeted clinical activity against a significant proportion of P. aeruginosa strains with limited treatment options, are described based on a review of the latest microbiological and clinical studies. Cefiderocol, with excellent in vitro activity against P. aeruginosa isolates, good stability to all ß-lactamases and against porin and efflux pumps mutations, is also examined. New carbapenem combinations are explored, reviewing the latest experimental and initial clinical evidence. One section is devoted to a review of new anti-pseudomonal antibiotics in the pipeline, such as cefepime-taniborbactam and cefepime-zidebactam. Finally, other "old" antimicrobials, mainly fosfomycin, that can be used as combination strategies, are described.

RESUMEN

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.

Asunto(s)

Insuficiencia Renal , Infecciones Urinarias , Adulto , Antibacterianos/farmacocinética , Monitoreo de Drogas , Femenino , Humanos , Masculino , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/tratamiento farmacológico , Sisomicina/análogos & derivados , Sisomicina/farmacocinética , Infecciones Urinarias/tratamiento farmacológico

RESUMEN

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.

Asunto(s)

Infecciones Bacterianas , Tecnecio , Antibacterianos/química , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Humanos , Radiofármacos/química , Radiofármacos/farmacología , Sisomicina/análogos & derivados , Tecnecio/química , Distribución Tisular

RESUMEN

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.

Asunto(s)

Klebsiella pneumoniae , beta-Lactamasas , Antibacterianos/farmacología , Compuestos de Azabiciclo , Proteínas Bacterianas/genética , Ácidos Borónicos , Ceftazidima/farmacología , Combinación de Medicamentos , Humanos , Imipenem/farmacología , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Sisomicina/análogos & derivados , Tetraciclinas , beta-Lactamasas/genética

RESUMEN

INTRODUCTION: Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. AREAS COVERED: We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM). EXPERT OPINION: PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37-118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94-406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials.PLAIN LANGUAGE SUMMARYNew antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR Acinetobacter spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR Pseudomonas aeruginosa. More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.

Asunto(s)

Carbapenémicos , Infecciones por Bacterias Gramnegativas , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Estudios Prospectivos

RESUMEN

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.

Asunto(s)

Enterobacteriaceae , Pseudomonas aeruginosa , Antibacterianos/farmacología , Pruebas Antimicrobianas de Difusión por Disco/métodos , Humanos , Pruebas de Sensibilidad Microbiana , Sisomicina/análogos & derivados

RESUMEN

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.

Asunto(s)

Antibacterianos/farmacología , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , Enterobacteriaceae/efectos de los fármacos , Sisomicina/análogos & derivados , Infecciones Urinarias/tratamiento farmacológico , Antibacterianos/uso terapéutico , Estudios Transversales , Humanos , Pruebas de Sensibilidad Microbiana , Quinolonas/farmacología , Sisomicina/farmacología , Sisomicina/uso terapéutico

RESUMEN

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.

Asunto(s)

Antibacterianos/farmacología , Cefalosporinas/farmacología , Farmacorresistencia Bacteriana Múltiple , Infecciones por Escherichia coli/microbiología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Sisomicina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Escherichia coli/clasificación , Escherichia coli/enzimología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Femenino , Genotipo , Humanos , Imipenem/farmacología , Masculino , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Filogenia , Sisomicina/farmacología , Adulto Joven , beta-Lactamasas/genética , beta-Lactamasas/metabolismo

RESUMEN

OBJECTIVES: Carbapenem resistance in Klebsiella pneumoniae is a major clinical challenge. Aminoglycosides remain an important asset in the current therapeutic arsenal to treat these infections. We examined aminoglycoside resistance phenotypes and genomics in a collection of 100 invasive KPC-producing K. pneumoniae isolates sequentially collected in a Brazilian tertiary hospital between 2014 and 2016. METHODS: Aminoglycoside susceptibility testing was performed. We used a combined long-read (MinION) and short-read (Illumina) whole-genome sequencing strategy to provide a genomic picture of aminoglycoside resistance genes, with particular emphasis on 16S rRNA methyltransferases and related plasmids. RESULTS: 68% of the strains were resistant to gentamicin and 42% to amikacin, with 35% resistant to both of these commonly used aminoglycosides. We identified the 16S rRNA methyltransferase gene rmtB in 30% of these isolates: 97% (29/30) belonged to sequence type 258 (ST258) and a single isolate to the emergent ST16 clone. In ST258 and ST16 the rmtB gene was located on large IncC plasmids of 177 kb and 174 kb, respectively, highly similar to a plasmid previously identified in Proteus mirabilis in the same hospital. Moreover, 99% of the isolates remained susceptible to the veterinary-approved drug apramycin, currently under clinical development for human medicine. CONCLUSION: Such findings in geographically and temporally related isolates suggest a combination of vertical clonal spread as well as horizontal interspecies and intraspecies plasmid transfer. This broad rmtB dissemination in an endemic setting for KPC-producing clones is worrisome since it provides resistance to most clinically available aminoglycosides, including the novel aminoglycoside-modifying enzyme-resistant plazomicin.

Asunto(s)

Klebsiella pneumoniae , beta-Lactamasas , Proteínas Bacterianas/genética , Brasil , Humanos , Interleucinas , Klebsiella pneumoniae/genética , Metiltransferasas , Pruebas de Sensibilidad Microbiana , Plásmidos/genética , ARN Ribosómico 16S/genética , Sisomicina/análogos & derivados , beta-Lactamasas/genética