The Next Generation: Mentoring and Diversity in the Antibacterial Resistance Leadership Group.

The Antibacterial Resistance Leadership Group (ARLG) Mentoring Program was established to develop and prepare the next generation of clinician-scientists for a career in antibacterial resistance research. The ARLG Diversity, Equity, and Inclusion Working Group partners with the Mentoring Committee to help ensure diversity and excellence in the clinician-scientist workforce of the future. To advance the field of antibacterial research while fostering inclusion and diversity, the Mentoring Program has developed a number of fellowships, awards, and programs, which are described in detail in this article.

The Antibacterial Resistance Leadership Group: Scientific Advancements and Future Directions.

In this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.

Under the Hood: The Scientific Leadership, Clinical Operations, Statistical and Data Management, and Laboratory Centers of the Antibacterial Resistance Leadership Group.

Developing and implementing the scientific agenda of the Antibacterial Resistance Leadership Group (ARLG) by soliciting input and proposals, transforming concepts into clinical trials, conducting those trials, and translating trial data analyses into actionable information for infectious disease clinical practice is the collective role of the Scientific Leadership Center, Clinical Operations Center, Statistical and Data Management Center, and Laboratory Center of the ARLG. These activities include shepherding concept proposal applications through peer review; identifying, qualifying, training, and overseeing clinical trials sites; recommending, developing, performing, and evaluating laboratory assays in support of clinical trials; and designing and performing data collection and statistical analyses. This article describes key components involved in realizing the ARLG scientific agenda through the activities of the ARLG centers.

Black and White Patients With Staphylococcus aureus Bacteremia Have Similar Outcomes but Different Risk Factors.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) disproportionately affects Black patients. The reasons for this disparity are unclear. METHODS: We evaluated a prospectively ascertained cohort of patients with SAB from 1995 to 2020. Clinical characteristics, bacterial genotypes, and outcome were compared among Black and White patients with SAB. Multivariable logistic regression models were used to determine factors independently associated with the outcomes. RESULTS: Among 3068 patients with SAB, 1107 (36%) were Black. Black patients were younger (median, 56 years vs 63 years; P < .001) and had higher rates of diabetes (47.5% vs 34.5%, P < .001), hemodialysis dependence (40.0% vs 7.3%, P < .001), and human immunodeficiency virus (6.4% vs 0.6%, P < .001). Black patients had higher rates of methicillin-resistant S. aureus (49.3% vs 44.9%, P = .020), including the USA300 hypervirulent clone (11.5% vs 8.4%, P = .007). White patients had higher rates of corticosteroid use (22.4% vs 15.8%, P < .0001) and surgery in the preceding 30 days (28.1% vs 18.7%, P < .001). Although the median Acute Physiology Score (APS) at the time of initial SAB diagnosis was significantly higher in Black patients (median APS, 9; interquartile range [IQR], 5-14 vs median APS, 7; IQR, 4-12; P < .001), race was not associated with 90-day mortality (risk ratio, 1.02; 95% confidence interval, .93-1.12), and rates of metastatic infection were lower among Black patients (37.2% vs 41.3% White, P = .029). CONCLUSIONS: Despite differences in Black patients' higher APS on presentation and more risk factors, including a 5 times higher risk of hemodialysis dependence, 90-day mortality among Black and White patients with SAB was similar.

Priorities and Progress in Gram-negative Bacterial Infection Research by the Antibacterial Resistance Leadership Group.

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Interlaboratory comparison of Pseudomonas aeruginosa phage susceptibility testing.

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP8), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P. aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.

Staphylococcus aureus Bacteremia Among Patients Receiving Maintenance Hemodialysis: Trends in Clinical Characteristics and Outcomes.

RATIONALE & OBJECTIVE: Staphylococcus aureus (Saureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015. EXPOSURE: Clinical characteristics and bacterial genotype. OUTCOME: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications. ANALYTICAL APPROACH: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression. RESULTS: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent Saureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% [95% CI, -2.05 to-0.56%] per year) or arteriovenous graft (-1.08% [95% CI, -1.54 to-0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41]). LIMITATIONS: Single-center, inpatient cohort. CONCLUSIONS: The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.

Clustered DNA Damage Patterns after Proton Therapy Beam Irradiation Using Plasmid DNA.

Modeling ionizing radiation interaction with biological matter is a major scientific challenge, especially for protons that are nowadays widely used in cancer treatment. That presupposes a sound understanding of the mechanisms that take place from the early events of the induction of DNA damage. Herein, we present results of irradiation-induced complex DNA damage measurements using plasmid pBR322 along a typical Proton Treatment Plan at the MedAustron proton and carbon beam therapy facility (energy 137-198 MeV and Linear Energy Transfer (LET) range 1-9 keV/µm), by means of Agarose Gel Electrophoresis and DNA fragmentation using Atomic Force Microscopy (AFM). The induction rate Mbp-1 Gy-1 for each type of damage, single strand breaks (SSBs), double-strand breaks (DSBs), base lesions and non-DSB clusters was measured after irradiations in solutions with varying scavenging capacity containing 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris) and coumarin-3-carboxylic acid (C3CA) as scavengers. Our combined results reveal the determining role of LET and Reactive Oxygen Species (ROS) in DNA fragmentation. Furthermore, AFM used to measure apparent DNA lengths provided us with insights into the role of increasing LET in the induction of highly complex DNA damage.

Risk Factors for Recurrent Staphylococcus aureus Bacteremia.

BACKGROUND: To understand the clinical, bacterial, and host characteristics associated with recurrent Staphylococcus aureus bacteremia (R-SAB), patients with R-SAB were compared to contemporaneous patients with a single episode of SAB (S-SAB). METHODS: All SAB isolates underwent spa genotyping. All isolates from R-SAB patients underwent pulsed-field gel electrophoresis (PFGE). PFGE-indistinguishable pairs from 40 patients underwent whole genome sequencing (WGS). Acute phase plasma from R-SAB and S-SAB patients was matched 1:1 for age, race, sex, and bacterial genotype, and underwent cytokine quantification using 25-analyte multiplex bead array. RESULTS: R-SAB occurred in 69 (9.1%) of the 756 study patients. Of the 69 patients, 30 experienced relapse (43.5%) and 39 reinfection (56.5%). Age, race, hemodialysis dependence, presence of foreign body, methicillin-resistant Staphyloccus aureus, and persistent bacteremia were individually associated with likelihood of recurrence. Multivariate risk modeling revealed that black hemodialysis patients were nearly 2 times more likely (odds ratio [OR] = 9.652 [95% confidence interval [CI], 5.402-17.418]) than white hemodialysis patients (OR = 4.53 [95% CI, 1.696-10.879]) to experience R-SAB. WGS confirmed PFGE interpretations in all cases. Median RANTES (regulated on activation, normal T cell expressed and secreted) levels in acute phase plasma from the initial episode of SAB were higher in R-SAB than in matched S-SAB controls (P = .0053, false discovery rate < 0.10). CONCLUSION: This study identified several risk factors for R-SAB. The largest risk for R-SAB is among black hemodialysis patients. Higher RANTES levels in R-SAB compared to matched controls warrants further study.

Antibacterial Resistance Leadership Group 2.0: Back to Business.

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.

Emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in KPC-2-producing Klebsiella pneumoniae of sequence type 39 during treatment.

Three ceftazidime-avibactam-resistant KPC-2-producing Klebsiella pneumoniae strains of ST39 were isolated in Greece, from rectal swabs of three patients after 10-15 days of treatment. The patients were treated with ceftazidime-avibactam as monotherapy or in combination with colistin. Two of these strains harbored a D179Y or a D179V substitution in the Ω loop of KPC-2, corresponding to KPC-33, or to the novel KPC-57, respectively. The third strain had a 15 amino acid insertion after position 259 in the KPC-2, corresponding to KPC-44.

Characterization of 16S rRNA methylase genes in Enterobacterales and Pseudomonas aeruginosa in Athens Metropolitan area, 2015-2016.

The aim of this study was to characterize the 16S rRNA methylase (RMT) genes in aminoglycoside-resistant Enterobacterales and Pseudomonas aeruginosa isolates in 2015-2016 in hospitals in Athens, Greece. Single-patient, Gram-negative clinical isolates resistant to both amikacin and gentamicin (n = 292) were consecutively collected during a two-year period (2015-2016) in five tertiary care hospitals in Athens. RMT genes were detected by PCR. In all RMT-producing isolates, ESBL and carbapenemase production was confirmed by PCR, and the clonal relatedness and the plasmid contents were also characterized. None of the 138 P. aeruginosa isolates harbored any of the RMT genes surveyed although some were highly resistant to aminoglycosides (MICs > = 512 mg/L). Among 154 Enterobacterales, 31 Providencia stuartii (93.9%), 42 Klebsiella pneumoniae (37.8%), six Proteus mirabilis (75%), and two Escherichia coli (100%) isolates were confirmed as highly resistant to amikacin, gentamicin, and tobramycin with MICs ≥ 512 mg/L, harboring mainly the rmtB (98.8%). All were carbapenemase producers. P. stuartii, P. mirabilis, and E. coli produced VIM-type carbapenemases. K. pneumoniae produced KPC- (n = 34, 81.0%), OXA-48 (n = 4, 9.5%), KPC- and VIM- (n = 3, 7.1%), or only VIM-type (n = 1, 2.4%) enzymes. Two groups of similar IncC plasmids were detected one harboring rmtB1, blaVEB-1, blaOXA-10, and blaTEM-1, and the other additionally blaVIM-1 and blaSHV-5. Among RMT-producing Enterobacterales, rmtB1 predominated and was associated with carbapenemase-encoding gene(s). Similar IncC plasmids carrying a multiresistant region, including ESBL genes, and in the case of VIM-producing isolates, the blaVIM-1, were responsible for this dissemination. The co-dissemination of these genes poses a public health threat.

In vitro activity of ceftolozane/tazobactam alone and in combination with amikacin against MDR/XDR Pseudomonas aeruginosa isolates from Greece.

OBJECTIVES: We evaluated the in vitro activity of ceftolozane/tazobactam and comparator agents against MDR non-MBL Pseudomonas aeruginosa isolates collected from nine Greek hospitals and we assessed the potential synergistic interaction between ceftolozane/tazobactam and amikacin. METHODS: A total of 160 non-MBL P. aeruginosa isolates collected in 2016 were tested for susceptibility to ceftolozane/tazobactam and seven comparator agents including ceftazidime/avibactam. Time-kill assays were performed for synergy testing using ceftolozane/tazobactam 60 or 7.5 mg/L, corresponding to the peak and trough concentrations of a 1.5 g q8h dose, respectively, in combination with 69 mg/L amikacin, corresponding to the free peak plasma concentration. Synergy was defined as a ≥2 log10 cfu/mL reduction compared with the most active agent. RESULTS: Overall, ceftolozane/tazobactam inhibited 64.4% of the P. aeruginosa strains at ≤4 mg/L. Colistin was the most active agent (MIC50/90, 0.5/2 mg/L; 96.3% susceptible) followed by ceftazidime/avibactam (MIC50/90, 4/16 mg/L; 80.6% susceptible). GES-type enzymes were predominantly responsible for ceftolozane/tazobactam resistance; 81.6% of the non-producers were susceptible. MICs for the P. aeruginosa isolates selected for synergy testing were 2-32 mg/L ceftolozane/tazobactam and 2-128 mg/L amikacin. The combination of ceftolozane/tazobactam with amikacin was synergistic against 85.0% of all the isolates tested and against 75.0% of the GES producers. No antagonistic interactions were observed. CONCLUSIONS: Ceftolozane/tazobactam demonstrated good in vitro activity against MDR/XDR P. aeruginosa clinical isolates, including strains with co-resistance to other antipseudomonal drugs. In combination with amikacin, a synergistic interaction at 24 h was observed against 85.0% of P. aeruginosa strains tested, including isolates with ceftolozane/tazobactam MICs of 32 mg/L or GES producers.

Outbreak of KPC-2-producing Klebsiella pneumoniae endowed with ceftazidime-avibactam resistance mediated through a VEB-1-mutant (VEB-25), Greece, September to October 2019.

From September to October 2019, seven patients colonised or infected with a ceftazidime-avibactam (CZA)-resistant Klebsiella pneumoniae carbapenemase (KPC)-2-producing K. pneumoniae were detected in two intensive care units of a Greek general hospital. The outbreak strain was sequence type (ST)147 and co-produced KPC-2 and the novel plasmid-borne Vietnamese extended-spectrum ß-lactamase (VEB)-25 harbouring a K234R substitution associated with CZA resistance. Epidemiological investigations revealed that the resistance was probably acquired by horizontal transmission independently from previous CZA exposure.

Changing Characteristics of Staphylococcus aureus Bacteremia: Results From a 21-Year, Prospective, Longitudinal Study.

BACKGROUND: We conducted a longitudinal study to evaluate changes in the clinical presentation and epidemiology of Staphylococcus aureus bacteremia (SAB) in an academic, US medical center. METHODS: Consecutive patients with monomicrobial SAB were enrolled from January 1995 to December 2015. Each person's initial bloodstream S. aureus isolate was genotyped using spa typing. Clonal complexes (CCs) were assigned using Ridom StaphType software. Changes over time in both the patient and bacterial characteristics were estimated with linear regression. Associations between genotypes or clinical characteristics and complications were estimated using multivariable regression models. RESULTS: Among the 2348 eligible participants, 54.2% had an implantable, foreign body of some type. This proportion increased significantly during the 21-year study period, by 0.96% annually (P = .002), as did comorbid conditions and acquisition outside of the hospital. Rates of any metastatic complication also significantly increased, by 0.94% annually (P = .019). Among the corresponding bloodstream S. aureus isolates, spa-CC012 (multi-locus sequence type [MLST] CC30), -CC004 (MLST CC45), -CC189 (MLST CC1), and -CC084 (MLST CC15) all significantly declined during the study period, while spa-CC008 (MLST CC8) significantly increased. Patients with SAB due to spa-CC008 were significantly more likely to develop metastatic complications in general, and abscesses, septic emboli, and persistent bacteremia in particular. After adjusting for demographic, racial, and clinical variables, the USA300 variant of spa-CC008 was independently associated with metastatic complications (odds ratio 1.42; 95% confidence interval 1.02-1.99). CONCLUSIONS: Systematic approaches for monitoring complications of SAB and genotyping the corresponding bloodstream isolates will help identify the emergence of hypervirulent clones and likely improve clinical management of this syndrome.

Correction to: In vitro activity of imipenem-relebactam against non-MBL carbapenemase-producing Klebsiella pneumoniae isolated in Greek hospitals in 2015-2016.

The publisher regrets that the article has been published online on 01 March 2019 with errors in Table 1. In the originally published Table 1, the percentage of Imipenem-relebactam susceptibility was incorrectly written as 8 0, while correct data is 98.0. Also, in Meropenem row, column MIC50 (mg/L), the incorrect data 4 should be 64.

In vitro activity of imipenem-relebactam against non-MBL carbapenemase-producing Klebsiella pneumoniae isolated in Greek hospitals in 2015-2016.

Relebactam is a ß-lactamase inhibitor of class A and class C ß-lactamases, including carbapenemases. We evaluated the ability of relebactam to restore imipenem susceptibility against a collection of Klebsiella pneumoniae isolates from Greek hospitals. We tested 314 non-MBL carbapenemase-producing K. pneumoniae consecutive clinical strains isolated from unique patients at 18 hospitals in Greece, between November 2014 and December 2016. Susceptibility testing of imipenem, imipenem-relebactam, meropenem, doripenem, gentamicin, and colistin was performed using broth microdilution. Additionally, MICs of ceftazidime-avibactam, fosfomycin, and tigecycline were determined by MIC Test Strips. MICs were interpreted per EUCAST breakpoints. Imipenem-relebactam MICs were interpreted using the breakpoints proposed for imipenem. Carbapenemase genes were detected using PCR. Whole genome sequencing was performed for selected isolates. Imipenem-relebactam inhibited 98.0% of the KPC-producing isolates at ≤ 2 mg/L (MIC50/90, 0.25/1 mg/L) and was considerably more active than imipenem (MIC50/90, 32/> 64 mg/L). Reduced activity of imipenem-relebactam was rarely detected (2%) and was associated with chromosomal factors (ompK35 disruption and/or mutated ompK36). Only ceftazidime-avibactam showed in vitro activity comparable to imipenem-relebactam (99.6% susceptible). Relebactam provided only weak potentiation of imipenem activity against K. pneumoniae with class D OXA-48-like enzymes. Relebactam exhibited strong potential for restoring the in vitro activity of imipenem against KPC-producing K. pneumoniae, lowering the imipenem MIC50 and MIC90 from 32 to 0.25 mg/L, and from > 64 to 1 mg/L, respectively. Production of KPC carbapenemase represents the main cause of carbapenem resistance among K. pneumoniae in Greek hospitals (66.5%), and this carbapenemase appears to be very well inhibited by relebactam.

Correction to: Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance.

Following publication of the original article [1].

Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance.

BACKGROUND: To evaluate the in vitro activities of plazomicin and comparator aminoglycosides and elucidate the underlying aminoglycoside resistance mechanisms among carbapenemase-producing K. pneumoniae isolates collected during a nationwide surveillance study in Greek hospitals. METHODS: Three hundred single-patient carbapenemase-producing K. pneumoniae isolates were studied, including 200 KPC-, 50 NDM-, 21 VIM-, 14 KPC & VIM-, 12 OXA-48-, two NDM & OXA- and one KPC & OXA-producing isolates. Susceptibility testing was performed by broth microdilution, and minimum inhibitory concentrations (MICs) interpreted per EUCAST breakpoints. Carbapenemase-, aminoglycoside modifying enzyme- and 16S rRNA methylase- encoding genes were detected by PCR. RESULTS: Of 300 isolates tested, 5.7% were pandrug resistant and 29.3% extensively drug resistant. Plazomicin inhibited 87.0% of the isolates at ≤2 mg/L, with MIC50/MIC90 of 0.5/4 mg/L. Apramycin (a veterinary aminoglycoside) inhibited 86.7% of the isolates at ≤8 mg/L and was the second most active drug after plazomicin, followed by gentamicin (S, 43%; MIC50/MIC90, 4/> 256) and amikacin (S, 18.0%; MIC50/MIC90, 32/128). Twenty-three (7.7%) isolates (16 KPC-, 6 VIM- and one KPC & OXA-48-producers) exhibited MICs ≥64 mg/L for plazomicin, and harbored rmtB (n = 22) or armA (n = 1). AAC(6')-Іb was the most common aminoglycoside modifying enzyme (84.7%), followed by AAC(3΄)-IIa (25.3%), while those two enzymes were co-produced by 21.4% of the isolates. CONCLUSIONS: Plazomicin retains activity against most carbapenemase-producing K. pneumoniae isolated from Greek hospitals, with MICs consistently lower than those of the other aminoglycosides, even in the presence of aminoglycoside modifying enzymes. Dissemination of 16S- rRNA methylases in 8% of the isolates is an unwelcome event that needs strict infection control measures and rigorous stewardship interventions.

Empiric Therapy With Carbapenem-Sparing Regimens for Bloodstream Infections due to Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae: Results From the INCREMENT Cohort.

BACKGROUND: There is little information about the efficacy of active alternative drugs to carbapenems except ß-lactam/ß-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems. METHODS: A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed. Cox regression including a propensity score for receiving OADs was performed to analyze 30-day all-cause mortality as main outcome. Clinical failure and length of stay were also analyzed. RESULTS: Overall, 335 patients were included; 249 received empiric carbapenems and 86 OADs. The most frequent OADs were aminoglycosides (43 patients) and fluoroquinolones (20 patients). Empiric therapy with OADs was not associated with mortality (hazard ratio [HR], 0.75; 95% confidence interval [CI], .38-1.48) in the Cox regression analysis. Propensity score-matched pairs, subgroups, and sensitivity analyses did not show different trends; specifically, the adjusted HR for aminoglycosides was 1.05 (95% CI, .51-2.16). OADs were neither associated with 14-day clinical failure (adjusted odds ratio, 0.62; 95% CI, .29-1.36) nor length of hospital stay. CONCLUSIONS: We were unable to show that empiric treatment with OAD was associated with a worse outcome compared with carbapenems. This information allows more options to be considered for empiric therapy, at least for some patients, depending on local susceptibility patterns of ESBL-E.