In Vitro and In Vivo Activity of Amoxicillin-Clavulanate Combined with Ceftibuten or Cefpodoxime Against Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae.

Infections due to extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales are an increasingly common problem. For many of these infections, no oral treatment options are available. The activity of amoxicillin-clavulanate combined with ceftibuten or cefpodoxime was evaluated against a group of Escherichia coli and Klebsiella pneumoniae clinical isolates possessing a variety of CTX-M- and SHV-type ESBLs; some possessed blaTEM1 as well. In time-kill studies, the combination of subinhibitory concentrations of amoxicillin-clavulanate with ceftibuten was bactericidal and synergistic for all strains with an amoxicillin-clavulanate MIC ≤32 µg/mL, regardless of the type of ESBL and the cephalosporin minimal inhibitory concentration (MIC). The combination with cefpodoxime was also bactericidal and synergistic against all but one of these strains. These combinations were further tested against two strains of K. pneumoniae and one E. coli in a sepsis model using Galleria mellonella larvae. The combination of amoxicillin-clavulanate with ceftibuten demonstrated a synergistic survival benefit against all three strains. The combination with cefpodoxime also improved survival against the two K. pneumoniae strains, but not the E. coli strain. These findings support combining amoxicillin-clavulanate with ceftibuten, and possibly cefpodoxime, for the treatment of infections due to ESBL producers and suggest that having an amoxicillin-clavulanate MIC of 32 µg/mL or less may predict activity at clinically achievable concentrations. Clinical studies are warranted to further evaluate this therapeutic approach.

Trends in Healthcare Facility-Onset Clostridioides difficile Infection and the Impact of Testing Schemes in an Acute Care Hospital System in New York City, 2016-2019.

BACKGROUND: Healthcare facility-onset Clostridioides difficile infection is associated with adverse clinical outcomes and hospital reimbursement. A four-year review involving eleven hospitals of the NYC Health + Hospital system was undertaken. METHODS: From 2016-2019, infection rates and standardized infection ratios (SIRs) were gathered from National Healthcare Safety Network. The C. difficile testing scheme at each facility was recorded. RESULTS: For the eleven hospitals, declines in rates of C. difficile infection and SIRs were documented. However, this decline was driven by two hospitals that had high rates of infection in 2016; for the remaining nine hospitals, rates of infection and SIRs were at a plateau. Most hospitals used a testing scheme that fell into the nucleic acid amplification test (NAAT) category for SIR risk adjustment. Hospitals that used the algorithm glutamate dehydrogenase (GDH) and toxin A/B immunoassay (EIA) followed by NAAT for discrepant results had significantly lower rates of C. difficile infection but similar SIRs. CONCLUSIONS: For most hospitals in this system, rates of C. difficile remained level. Within the NAAT test categories, SIRs may not correlate with infection rates. Given the controversies regarding testing and calculation of SIRs, alternatives to C. difficile infection should be sought as a hospital quality measurement.

Trends in central-line-associated bloodstream infections and catheter-associated urinary tract infections in a large acute-care hospital system in New York City, 2016-2019.

BACKGROUND: Central-line bloodstream infections (CLABSIs) and catheter-associated urinary tract infections (CAUTIs) negatively impact clinical outcomes and hospital reimbursement. In this report, 4 year trends involving 11 hospitals in New York City were examined. METHODS: Data from the National Healthcare Safety Network (NHSN) were extracted for 11 acute-care hospitals belonging to the NYC Health + Hospital system from 2016 through 2019. Trends in device infections per 1,000 patient days, device utilization ratios, and standardized infection ratios (SIRs) were examined for the 11 hospitals and for the entire system. RESULTS: Over the 4-year period, there were progressive declines in central-line days, infections per 1,000 central-line days, and device utilization ratios for the system. The average annual SIRs for the system also declined: 1.40 in 2016, 1.09 in 2017, 1.04 in 2018, and 0.82 in 2019. Case-mix indices correlated with SIRs for CLABSIs. Level 1 trauma centers had higher SIRs and a disproportionately greater number of CLABSIs in patients located in NHSN-defined surgical intensive care units. Similar trends with CAUTIs were noted, with progressive declines in catheter days, infections per 1,000 patient days, device utilization ratios, and SIRs (1.42 in 2016, 0.93 in 2017, 1.18 in 2018, and 0.78 in 2019) over the 4-year period. CONCLUSIONS: Across an 11-hospital system, continuing efforts to reduce device utilization and infection rates resulted in declining SIRs for CLABSIs and CAUTIs. Hospitals with higher case-mix indices, and particularly level 1 trauma centers, had significantly higher central-line infection rates and SIRs.

Cefiderocol Resistance in Acinetobacter baumannii: Roles of ß-Lactamases, Siderophore Receptors, and Penicillin Binding Protein 3.

Cefiderocol is a siderophore cephalosporin active against many multidrug-resistant (MDR) Gram-negative pathogens. We examined the resistance mechanisms in 12 Acinetobacter baumannii strains with cefiderocol MICs ranging from ≤0.03 to >32 µg/ml. Cefiderocol resistance could not be explained by ß-lactamase activity. Cefiderocol resistance was associated with reduced expression of the siderophore receptor gene pirA Mutations involving PBP3 may have contributed to resistance in one strain. Additional studies are needed to assess the role of other siderophore receptors.

Emergence of Delafloxacin-Resistant Staphylococcus aureus in Brooklyn, New York.

Delafloxacin is an option for infections due to methicillin-resistant Staphylococcus aureus. In 2017, 22% of isolates from 7 hospitals in Brooklyn, New York, were nonsusceptible to delafloxacin. Isolates belonging to ST105, a strain associated with healthcare-related infections, predominated. Resistance was also found in ST8, a strain (USA300) associated with community-associated infections.

Combination of 12-O-tetradecanoylphorbol-13-acetate with diethyldithiocarbamate markedly inhibits pancreatic cancer cell growth in 3D culture and in immunodeficient mice.

The aim of the present study was to determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and diethyldithiocarbamate (DDTC) alone or in combination on human pancreatic cancer cells cultured in vitro and grown as xenograft tumors in nude mice. Pancreatic cancer cells were treated with either DDTC or TPA alone, or in combination and the number of viable cells was then determined by trypan blue ecxlusion assay and the number of apoptotic cells was determined by morphological assessment by staining the cells with propidium idiode and examining them under a fluorescence microscope. Treatment with DDTC or TPA alone inhibited the growth and promoted the apoptosis of pancreatic cancer cells in a concentration-dependent manner. These effects were more prominent following treatment with TPA in combination with DDTC than following treatment with either agent alone in PANC-1 cells in monolayer cultures and in 3 dimensional (3D) cultures. The potent effects of the combination treatment on PANC-1 cells were associated with the inhibition of nuclear factor-κB (NF-κB) activation and the decreased expression of Bcl-2 induced by DDTC, as shown by NF-κB-dependent reporter gene expression assay and western blot analysis. Furthermore, treatment of nude mice with DDTC + TPA strongly inhibited the growth of PANC-1 xenograft tumors. The results of the present study indicate that the administration of TPA and DDTC in combination may be an effective strategy for inhibiting the growth of pancreatic cancer.