Activity of cefepime/zidebactam against MDR Escherichia coli isolates harbouring a novel mechanism of resistance based on four-amino-acid inserts in PBP3.

BACKGROUND: Recent reports reveal the emergence of Escherichia coli isolates harbouring a novel resistance mechanism based on four-amino-acid inserts in PBP3. These organisms concomitantly expressed ESBLs or/and serine-/metallo-carbapenemases and were phenotypically detected by elevated aztreonam/avibactam MICs. OBJECTIVES: The in vitro activities of the investigational antibiotic cefepime/zidebactam and approved antibiotics (ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and others) were determined against E. coli isolates harbouring four-amino-acid inserts in PBP3. METHODS: Whole-genome sequenced E. coli isolates (n = 89) collected from a large tertiary care hospital in Southern India (n = 64) and from 12 tertiary care hospitals located across India (n = 25) during 2016-18, showing aztreonam/avibactam MICs ≥1 mg/L (≥4 times the aztreonam epidemiological cut-off) were included in this study. The MICs of antibiotics were determined using the reference broth microdilution method. RESULTS: Four-amino-acid inserts [YRIK (n = 30) and YRIN (n = 53)] were found in 83/89 isolates. Among 83 isolates, 65 carried carbapenemase genes [blaNDM (n = 39), blaOXA-48-like (n = 11) and blaNDM + blaOXA-48-like (n = 15)] and 18 isolates produced ESBLs/class C ß-lactamases only. At least 16 unique STs were noted. Cefepime/zidebactam demonstrated potent activity, with all isolates inhibited at ≤1 mg/L. Comparator antibiotics including ceftazidime/avibactam and imipenem/relebactam showed limited activities. CONCLUSIONS: E. coli isolates concurrently harbouring four-amino-acid inserts in PBP3 and NDM are an emerging therapeutic challenge. Assisted by the PBP2-binding action of zidebactam, the cefepime/zidebactam combination overcomes both target modification (PBP3 insert)- and carbapenemase (NDM)-mediated resistance mechanisms in E. coli.

Novel hydroxamates potentiated in vitro activity of fluconazole against Candida albicans.

A set of 12 novel hydroxamate compounds (NHCs), structurally designed as inhibitors of histone deacetylase (HDAC) enzyme, were synthesized at our facility. These were adamantane derivatives with N-hydroxyacetamide as pharmacophore, and each of these compounds was tested for potentiating activity on fluconazole. The concentration of fluconazole which completely inhibited (concentration of complete inhibition [CCI]) the growth of Candida albicans ATCC 90028 and C. albicans ATCC 64550 was determined by micro-dilution method in the absence and presence of NHCs. The CCI of fluconazole without the NHC combination was 64 µg/ml and 1024 µg/ml against C. albicans ATCC 90028 and C. albicans ATCC 64550, respectively. The majority of the NHCs potentiated the fluconazole activity markedly as CCI of fluconazole against C. albicans ATCC 90028 reduced to 0.25 µg/ml. Similarly, CCI of fluconazole against C. albicans ATCC 64550 reduced to 4-8 µg/ml in combination with majority of NHCs while the best activity was displayed by the compound 1 with a reduction of CCI to 0.5 µg/ml. The study results revealed the potential usage of hydroxamate derivatives, structurally designed as HDAC inhibitors to enhance the activity of fluconazole against C. albicans.

Antibiotic susceptibility pattern of Enterobacteriaceae and non-fermenter Gram-negative clinical isolates of microbial resource orchid.

BACKGROUND: Microbial resource orchid is a collection of Gram-positive and Gram-negative clinical isolates sourced from different hospitals and diagnostic laboratories in India. We determined the antibiotic susceptibility of a set of Gram-negative Enterobacteriaceae and non-fermenter clinical isolates from microbial resource orchid, collected during the period of 2002-2012 against commonly used antibiotics. MATERIALS AND METHODS: A total of 247 Gram negative strains consisting of 142 Enterobacteriaceae and 105 non-fermenters from microbial resource orchid were selected for determining minimum inhibitory concentration against ß-lactams, aminoglycosides, quinolone, and tetracycline by agar dilution method as per clinical and laboratory standards institute guidelines. RESULTS: All the isolates had high resistance to ampicillin, piperacillin, ceftazidime, gentamicin, tetracycline, and ciprofloxacin. Pseudomonas aeruginosa showed moderate resistance to carbapenems. CONCLUSION: This study demonstrated the high level of antibiotic resistance among the strains collected under microbial resource orchid and further, such data and the strains can be used in new chemical entities profiling.