Compassionate use of a novel ß-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report.

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based ß-lactam/ ß-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo ß-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

Lack of Association of Helicobacter pylori in Laryngeal Pathologies.

To study the association of Helicobacter pylori (H. pylori) in patients with laryngeal pathologies. Study design: prospective observational study. Tertiary care teaching hospital. One hundred consecutive patients with laryngeal lesions scheduled for microlaryngoscopy were enrolled in the study. Laryngopharyngeal reflux was assessed using the reflux symptom index and reflux finding score. Tissue samples from the laryngeal lesions were taken under general anaesthesia and were screened for the presence of H. pylori using real time polymerase chain reaction (PCR) for ureA genes and histopathological examination. Of the 100 patients, 14 had a significant reflux symptom index score and 35 had significant reflux finding score. The lesions in the study subjects included both benign and malignant laryngeal pathologies. Vocal cord polyps formed more than half of the laryngeal pathology (57%) studied. Our study could not detect H. pylori in any laryngeal lesions by PCR analysis and histopathological examination. H. pylori may not be associated with laryngeal pathologies.

Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important clinical concern in patients, and is often associated with significant disease burden and metastatic infections. There is an increasing evidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) associated treatment failure. In this study, we aim to understand the molecular mechanism of teicoplanin resistant MRSA (TR-MRSA) and hVISA. A total of 482 MRSA isolates were investigated for these phenotypes. Of the tested isolates, 1% were identified as TR-MRSA, and 12% identified as hVISA. A highly diverse amino acid substitution was observed in tcaRAB, vraSR, and graSR genes in TR-MRSA and hVISA strains. Interestingly, 65% of hVISA strains had a D148Q mutation in the graR gene. However, none of the markers were reliable in differentiating hVISA from TR-MRSA. Significant pbp2 upregulation was noted in three TR-MRSA strains, which had teicoplanin MICs of 16 or 32 µg/ml, whilst significant pbp4 downregulation was not noted in these strains. In our study, multiple mutations were identified in the candidate genes, suggesting a complex evolutionary pathway involved in the development of TR-MRSA and hVISA strains.

Plasmid profiles among some ESKAPE pathogens in a tertiary care centre in south India.

Background & objectives: Plasmid has led to increase in resistant bacterial pathogens through the exchange of antimicrobial resistance (AMR) genetic determinants through horizontal gene transfer. Baseline data on the occurrence of plasmids carrying AMR genes are lacking in India. This study was aimed to identify the plasmids associated with AMR genetic determinants in ESKAPE pathogens. Methods: A total of 112 ESKAPE isolates including Escherichia coli (n=37), Klebsiella pneumoniae (n=48, including 7 pan-drug susceptible isolates), Acinetobacter baumannii (n=8), Pseudomonas aeruginosa (n=1) and Staphylococcus aureus (n=18) were analyzed in the study. Isolates were screened for antimicrobial susceptibility and whole genome sequencing of isolates was performed using Ion Torrent (PGM) sequencer. Downstream data analysis was done using PATRIC, ResFinder, PlasmidFinder and MLSTFinder databases. All 88 whole genome sequences (WGS) were deposited at GenBank. Results: Most of the study isolates showed resistant phenotypes. As analyzed from WGS, the isolates included both known and unknown sequence types. The plasmid analysis revealed the presence of single or multiple plasmids in the isolates. Plasmid types such as IncHI1B(pNDM-MAR), IncFII(pRSB107), IncFIB(Mar), IncFIB(pQil), IncFIA, IncFII(K), IncR, ColKP3 and ColpVC were present in K. pneumoniae. In E. coli, IncFIA, IncFII, IncFIB, Col(BS512), IncL1, IncX3 and IncH were present along with other types. S. aureus harboured seven different plasmid groups pMW2 (rep 5), pSAS1 (rep 7), pDLK1 (rep 10), pUB110 (rep US12), Saa6159 (rep 16), pKH12 (rep 21) and pSA1308 (rep 21). The overall incidence of IncF type plasmids was 56.5 per cent followed by Col type plasmids 18.3 per cent and IncX 5.3 per cent. Other plasmid types identified were <5 per cent. Interpretation & conclusions: Results from the study may serve as a baseline data for the occurrence of AMR genes and plasmids in India. Information on the association between phenotypic and genotypic expression of AMR was deciphered from the data. Further studies on the mechanism of antibiotic resistance dissemination are essential for enhancing clinical lifetime of antibiotics.

A comparative assessment of clinical, pharmacological and antimicrobial profile of novel anti-methicillin-resistant Staphylococcus aureus agent levonadifloxacin: Therapeutic role in nosocomial and community infections.

Staphylococcus aureus is of significant clinical concern in both community- and hospital-onset infections. The key to the success of S. aureus as a pathogen is its ability to swiftly develop antimicrobial resistance. Methicillin-resistant S. aureus (MRSA) is not only resistant to nearly all beta-lactams but also demonstrates resistance to several classes of antibiotics. A high prevalence of MRSA is seen across worldwide. For many decades, vancomycin remained as gold standard antibiotic for the treatment of MRSA infections. In the past decades, linezolid, daptomycin, ceftaroline and telavancin received regulatory approval for the treatment of infections caused by resistant Gram-positive pathogens. Although these drugs may offer some advantages over vancomycin, they also have significant limitations. These includes vancomycin's slow bactericidal activity, poor lung penetration and nephrotxicity;linezolid therapy induced myelosuppression and high cost of daptomycin greatly limits their clinical use. Moreover, daptomycin also gets inactivated by lung naturally occurring surfactants. Thus, currently available therapeutic options are unable to provide safe and efficacious treatment for those patients suffering from hospital-acquired pneumonia, bloodstream infections (BSIs), bone and joint infections and diabetic foot infections (DFI). An unmet need also exists for a safe and efficacious oral option for switch-over convenience and community treatment. Herein, the review is intended to describe the supporting role of anti-staphylococcal antibiotics used in the management of S. aureus infections with a special reference to levonadifloxacin. Levonadifloxacin and its prodrug alalevonadifloxacin are novel benzoquinolizine subclass of quinolone with broad-spectrum of anti-MRSA activity. It has been recently approved for the treatment of complicated skin and soft-tissue infection as well as concurrent bacteraemia and DFI in India.

Genomic insights of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) with reduced teicoplanin susceptibility: A case of fatal necrotizing fasciitis.

OBJECTIVES: Glycopeptides are increasingly being used to treat multiresistant methicillin-resistant Staphylococcus aureus (MRSA) infections. Here we report an MRSA isolate with low-level teicoplanin resistance (isolate VB26276) recovered from a patient treated with teicoplanin for fatal necrotizing fasciitis. METHODS: Minimum inhibitory concentrations (MICs) of MRSA isolates to vancomycin and teicoplanin were determined by Etest. Reduced glycopeptide susceptibility was screened by Etest GRD (glycopeptide resistance detection) and population analysis profile (PAP) method. Next-generation sequencing (NGS) was also performed to determine the molecular mechanism of antimicrobial resistance and virulence. RESULTS: The teicoplanin MIC of MRSA isolate VB26276 was 4µg/mL. NGS showed the presence of mutations in the tcaA and tcaB genes of the tcaRAB operon that determines the level of teicoplanin resistance. In addition, a mutation in the vraR gene was found to be associated with teicoplanin resistance, but not with vancomycin heteroresistance. CONCLUSION: Teicoplanin resistance may occur due to point mutations in the teicoplanin resistance operon tcaRAB. Further studies are warranted to determine the contribution of point mutations in tcaRAB to reduced teicoplanin susceptibility.

Polymyxin susceptibility testing, interpretative breakpoints and resistance mechanisms: An update.

Emerging multidrug-resistant (MDR) nosocomial pathogens are a great threat. Polymyxins, an old class of cationic polypeptide antibiotic, are considered as last-resort drugs in treating infections caused by MDR Gram-negative bacteria. Increased use of polymyxins in treating critically ill patients necessitates routine polymyxin susceptibility testing. However, susceptibility testing both of colistin and polymyxin B (PMB) is challenging. In this review, currently available susceptibility testing methods are briefly discussed. The multicomponent composition of colistin and PMB significantly influences susceptibility testing. In addition, poor diffusion in the agar medium, adsorption to microtitre plates and the synergistic effect of the surfactant polysorbate 80 with polymyxins have a great impact on the performance of susceptibility testing methods This review also describes recently identified chromosomal resistance mechanisms, including modification of lipopolysaccharide (LPS) with 4-amino-4-deoxy-l-arabinose (L-Ara4-N) and phosphoethanolamine (pEtN) resulting in alteration of the negative charge, as well as the plasmid-mediated colistin resistance determinants mcr-1, mcr-1.2, mcr-2 and mcr-3.

Strengths and limitations of various screening methods for carbapenem-resistant Enterobacteriaceae including new method recommended by clinical and laboratory standards institute, 2017: A tertiary care experience.

Carbapenemase-mediated carbapenem resistance is a major concern across the world. Rapid detection of carbapenemase-producing organisms is of great importance in clinical settings. However, it is essential to have a test with good sensitivity and specificity. The aim of the study was to compare the performance of RAPIDEC® CARBA NP and modified carbapenem inactivation method (mCIM) recommended by Clinical and Laboratory Standards Institute guideline 2017. A total of ninety carbapenem resistant Escherichia coli and Klebsiella pneumoniae have been tested. The presence of various carbapenemases was screened by conventional multiplex polymerase chain reaction. RAPIDEC® CARBA NP detected 90%, whereas mCIM detected 99% of the study isolates tested. Although RAPIDEC® CARBA NP is a rapid test, the sensitivity is reduced for blaOxa-48Likedetection; while mCIM could pick up blaOxa-48Likeenzymes with excellent sensitivity. Further, organisms producing low carbapenemase activity enzymes, thickness of the inoculum and the disc potency are likely to influence the test results of mCIM with an overnight delay.