Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

In vitro activity of Ceftazidime-Avibactam and its comparators against Carbapenem resistant Enterobacterales collected across India: results from ATLAS surveillance 2018 to 2019.

ATLAS (Antimicrobial Testing Leadership and Surveillance) detects trends in multi-drug resistance longitudinally over time. In the present study, the in vitro activity of ceftazidime-avibactam and comparators was analyzed against Escherichia coli (n = 458) and Klebsiella pneumoniae (n = 455)  isolates obtained from 9 centers across India. The overall susceptibility to ceftazidime-avibactam was observed to be 72% among K. pneumoniae isolates and 87% among E. coli isolates. Among the tested carbapenem resistant isolates, 51% of CR-K. pneumoniae and 24% of CR-E. coli were susceptible to ceftazidime- avibactam. OXA-48 like was identified in 52% of the K. pneumoniae isolates followed by co-production of NDM with OXA-48 like in 27%. NDM was predominantly identified in 68% of the E. coli isolates followed by OXA-48 like in 24% isolates. The findings suggest that ceftazidime- avibactam is a reasonable alternative to standard therapy for management of carbapenem resistant Enterobacterales infections particularly with K. pneumoniae and E. coli with the OXA-48 like genotype.

Distinctive Mobile Genetic Elements Observed in the Clonal Expansion of Carbapenem-Resistant Klebsiella pneumoniae in India.

Background: Klebsiella pneumoniae (Kp), a common multidrug-resistant pathogen, causes a wide spectrum of nosocomial infections with high rates of morbidity and mortality. The emergence of pan drug-resistant international high-risk clones such as ST258, ST14, ST15, ST147, and ST101 is a global concern. This study was performed to investigate the carbapenemases, the plasmid profile, and the clonal relationship among Indian K. pneumoniae. Materials and Methods: A total of 290 K. pneumoniae isolates from seven centers in India were characterized to determine sequence types (STs) and carbapenemases. A subset of isolates was subjected to whole genome sequencing and hybrid genome assembly to obtain the complete genome. Plasmids carrying carbapenemases were characterized to determine the dissemination of carbapenem-resistant (CR) K. pneumoniae. Results: From this study, 75 different STs were observed with ST231 being predominant. About 79% of the analyzed isolates were CR with 59% (n = 136) producing OXA48-like carbapenemases. While ST231 was the predominant clone among the OXA48-like producers; NDM producers and NDM+OXA48-like producers were mostly associated with ST14. Interestingly, 61% (n = 138) of the total CR K. pneumoniae were colistin resistant, belonging to 22 different STs. Plasmid profiling shows that blaOXA48-like was exclusively carried by ColKP3, whereas blaNDM was associated with IncFII-like plasmids. Conclusion: The highly mosaic genome of K. pneumoniae coupled with the diverse ecological niches in India makes it a hotspot for antimicrobial resistance, leading to increased morbidity and mortality. Extensive molecular surveillance of the clonal spread of K. pneumoniae could help in understanding AMR dynamics and thus rework therapeutic management.