An integrated FoodNet in North East India: fostering one health approach to fortify public health.

BACKGROUND: Food safety is a critical factor in promoting public health and nutrition, especially in developing countries like India, which experience several foodborne disease outbreaks, often with multidrug-resistant pathogens. Therefore, implementing regular surveillance of enteric pathogens in the human-animal-environment interface is necessary to reduce the disease burden in the country. OBJECTIVE: To establish a network of laboratories for the identification of major food and waterborne pathogens prevailing in the northeast region of India through integrated surveillance of animal, food, human, and environment and investigate the antimicrobial susceptibility pattern of the pathogens of public health significance. METHODS: The Indian Council of Medical Research (ICMR) has identified FoodNet laboratories; based on their geographical location, inclination to undertake the study, preparedness, proficiency, and adherence to quality assurance procedures, through an 8-step process to systematically expand to cover the Northeastern Region (NER) with comprehensive diagnostic capacities for foodborne pathogens and diarrhea outbreak investigations. Network initiated in the NER given the unique food habits of the ethnic population. FINDINGS: This surveillance network for foodborne enteric pathogens was established in Assam, Arunachal Pradesh, Tripura, and Sikkim, and expanded to other four states, i.e., Manipur, Mizoram, Meghalaya, and Nagaland, thereby covering the entire NER by including nine medical and three veterinary centers. All these centers are strengthened with periodic training, technical support, funding, capacity building, quality assurance, monitoring, centralized digital data management, and website development. RESULTS: The ICMR-FoodNet will generate NER-specific data with close to real-time reporting of foodborne disease and outbreaks, and facilitate the updating of food safety management protocols, policy reforms, and public health outbreak response. During 2020-2023, 13,981 food samples were tested and the detection of enteric pathogens ranged from 3 to 4%. In clinical samples, the detection rate of the pathogens was high in the diarrheal stools (8.9%) when 3,107 samples were tested. Thirteen outbreaks were investigated during the study period. CONCLUSION: Foodborne diseases and outbreaks are a neglected subject. Given the frequent outbreaks leading to the deaths of children, it is crucial to generate robust data through well-established surveillance networks so that a strong food safety policy can be developed for better public health.

Pan-India influenza-like illness (ILI) and Severe acute respiratory infection (SARI) surveillance: epidemiological, clinical and genomic analysis.

Background: Over time, COVID-19 testing has significantly declined across the world. However, it is critical to monitor the virus through surveillance. In late 2020, WHO released interim guidance advising the use of the existing Global Influenza Surveillance and Response System (GISRS) for the integrated surveillance of influenza and SARS-CoV-2. Methods: In July 2021, we initiated a pan-India integrated surveillance for influenza and SARS-CoV-2 through the geographically representative network of Virus Research and Diagnostic Laboratories (VRDLs) across 26 hospital and laboratory sites and 70 community sites. A total of 34,260 cases of influenza-like illness (ILI) and Severe acute respiratory infection (SARI) were enrolled from 4 July 2021 to 31 October 2022. Findings: Influenza A(H3) and B/Victoria dominated during 2021 monsoon season while A(H1N1)pdm09 dominated during 2022 monsoon season. The SARS-CoV-2 "variants of concern" (VoC) Delta and Omicron predominated in 2021 and 2022, respectively. Increased proportion of SARI was seen in extremes of age: 90% cases in < 1 year; 68% in 1 to 5 years and 61% in ≥ 8 years age group. Approximately 40.7% of enrolled cases only partially fulfilled WHO ILI and SARI case definitions. Influenza- and SARS-CoV-2-infected comorbid patients had higher risks of hospitalization, ICU admission, and oxygen requirement. Interpretation: The results depicted the varying strains and transmission dynamics of influenza and SARS-CoV-2 viruses over time, thus emphasizing the need to continue and expand surveillance across countries for improved decision making. The study also describes important information related to clinical outcomes of ILI and SARI patients and highlights the need to review existing WHO ILI and SARI case definitions.

Molecular analysis of rpoB gene mutation in MTB detected isolates in a tertiary care centre (AGMC) of North-East, India.

BACKGROUND: Rifampicin (RIF), one of the first line drug in treatment of tuberculosis. It acts on rpoB gene which encodes RNA polymerase ß subunit. In 95% of RIF resistant cases, mutations are present in rpoB gene. Most of them are within 81bp RIF-resistance determining region (RRDR).Xpert MTB/RIF assay has been tremendously revolutionalised the diagnosis of tuberculosis (TB).Also sequencially detect bacteria and resistance to rifampicin (rif).Approximately 96% of rif-resistant Mycobacterium tuberculosis (MTB) strains worldwide, showed mutations in a region at the 507-533rd amino acid residuals (81 bp) in the MTB rpoB gene. Here evaluation is made about frequent regions of amplification and mutation in various codons of 81bp of rpoB gene in rif sensitive and rif resistant cases. METHODS: A total of 4116 samples were received at Mycobacteriology laboratory, AGMC and processed in CBNAAT.Data of MTB detected samples were collected & statistically analysed to detect frequency of amplification & no amplification in various regions of 81bp of rpoB genes. RESULTS: Out of 4116 samples, MTB was detected in 1323 samples. Among them 1291 (97.58%) cases were Rif sensitive (RS) and 32 (2.41%) cases were rif resistance (RR).Most of the MTBC detected samples showed amplification in probe A then in probe C.78.12% rif resistant cases showed mutation in either of the probe, commonest is probe E. Study also showed low bacillary loads in most of the RR cases. CONCLUSION: Study highlighted variations in amplification of different regions of 81bp of rpoB gene in MTBC detected cases. North-east India, like other part of world, also showed highest frequency of mutation in probe E in rif resistant cases.

Comparison of SARS-CoV-2 diagnosis by rapid antigen detection kit with RT-qPCR in a tertiary care setup in North Eastern India.

PURPOSE: Real time reverse transcriptase polymerase chain reaction (RT-qPCR) is still considered a gold standard for the diagnosis of COVID-19. However, due to several limitations, use of RT-qPCR is limited in a resource poor setting like North East India. Rapid antigen detection testing kit has revolutionized the diagnosis and management of COVID-19 in India. However, conflicting reports exist regarding the efficacy of the kits for diagnosis of COVID-19. This study aims to highlight the performance of Standard Q COVID-19® Antigen detection kit (SD Biosensor) compared with RT-qPCR in the setup of North East India. METHODS: Nasopharyngeal and oropharyngeal swab samples were collected from consenting patients attending the flu clinic in the period from 1st July to December 31, 2020. Samples were transferred to Viral Research and Diagnostic Laboratory (VRDL) for RT-qPCR test. Antigen detection from the patient samples were undertaken using Standard Q ® COVID-19 antigen detection kit (SD Biosensor, Republic of Korea). Data were then analyzed for comparison between RT-qPCR and antigen kit results. RESULTS: During the study period, 189 samples were collected, out of which 119 were positive by RT-qPCR. Out of 119 positive samples, calculated sensitivity and specificity of the rapid antigen kit was 63% and 100% respectively. Sensitivity and diagnostic accuracy increases in symptomatic patients as compared to asymptomatic patients. Cohen's Kappa coefficient showed a moderate association (0.6) between the kit and RT-qPCR test. The kit performed optimally at a CT value of ≤32.5 for N gene with a predicted sensitivity of 77.3% and specificity of 93.3%. CONCLUSION: The study shows an overall acceptable sensitivity and specificity of the testing kit, with a better performance in symptomatic patients. The association of the kit result is moderate with the results obtained in RT-qPCR. In this study, the rapid antigen test kit performed optimally at N gene qRT PCR cut off value of ≤32.5.

Role of Innate Immune Regulatory Genes, FOXP3 and FOS in Chronic Hepatitis B Infection.

Persistence of hepatitis B virus (HBV) infection leading to chronic infection and its sequalae is responsible for over half a million deaths worldwide. The reason for persistence of chronic hepatitis B (CHB) infection is still not clearly understood. An attempt was made to understand the role of immune regulatory genes in CHB in comparison to spontaneously cleared HBV infection. Relative gene expression of 26 genes involved in innate immunity were studied using Real-Time Polymerase Chain Reaction Array. A total of 679 subjects from three different geographical regions of Northeast India (Assam, Arunachal Pradesh, and Tripura) were included in this case-control study. The cases were subdivided into CHB cases with HBeAg(+)(72), CHB with HBeAg(-)(278), spontaneously cleared controls (88), and healthy controls (228). Overall, 28.3% of the subjects had previous exposure with HBV, while 28.6% had protective antibodies IgG/IgM against HBV. There was a statistically higher number of CHB in men (66.4%) compared to women (33.6%) (p = 0.0001). Proto-oncogene FOS has been found to be moderately upregulated in CHB with HBeAg +ve (2.3-fold) and significantly upregulated (4.1-fold upregulation) in hepatocellular carcinoma. Further, FOXP3 was found to be significantly upregulated (3.0-fold, p = 0.01) in CHB with HBeAg (+) compared to spontaneously cleared HBV infection. In conclusion, CHB with HBeAg positivity was found to have disrupted immune response with upregulation of FOS and FOXP3. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogs along with FOS inhibitors can have important clinical implications in the management of CHB and preventing cirrhosis and HCC.

Self-reported survey on infection prevention and control structures in healthcare facilities part of a national level healthcare associated infection surveillance network in India, 2019.

BACKGROUND: Healthcare associated infections (HAIs) are prevalent and difficult to treat worldwide. Most HAIs can be prevented by effective implementation of Infection Prevention and Control (IPC) measures. A survey was conducted to assess the existing IPC practices across a network of Indian Hospitals using the World Health Organization designed self-assessment IPC Assessment Framework (IPCAF) tool. METHODS: This was a cross sectional observation study. Thirty-two tertiary care public and private facilities, part of the existing Indian HAI surveillance network was included. Data collected was analyzed by a central team at All India Institute of Medical Sciences, New Delhi, a tertiary care hospital of India. The WHO questionnaire tool was used to understand the capacity and efforts to implement IPC practices across the network. RESULTS: The overall median score of IPCAF across the network was 620. Based on the final IPCAF score of the facilities; 13% hospitals had basic IPC practices, 28% hospitals had intermediate and 59% hospitals had advanced IPC practices. The component multimodal strategies had the broadest range of score while the component IPC guidelines had the narrowest one. CONCLUSIONS: Quality improvement training for IPC nurses and healthcare professionals are needed to be provided to health facilities.

Blood Stream Infection Caused by Carbapenem-resistant Chryseobacterium indologenes Harboring blaNDM-1 Gene Isolated from a Tertiary Care Hospital in Tripura: An Emerging Threat.

OBJECTIVES: Chryseobacterium indologenes has recently been identified as an inherently drug-resistant organism, responsible for a wide spectrum of infections, mainly device-associated infections in hospital settings. The presence of carbapenem resistance due to blaNDM-1 metallo-ß-lactamase (MBL) gene further complicates the matter, leading to widespread dissemination of carbapenem resistance. This study aims to find out the presence of blaNDM-1 gene among C. indologenes strains causing bloodstream infections in a tertiary care hospital. MATERIALS AND METHODS: During 1 year of the study period, blood culture samples were collected from patients with features of bacteremia, and C. indologenes strains were isolated and identified as per protocol. Antibiotic sensitivity test was performed by using VITEK 2 Compact Automated AST machine (Biomerieux, France). Carbapenem-resistant strains were subjected to a combined disk diffusion test for detecting the presence of MBL enzyme. Strains positive for MBL production were subjected to a polymerase chain reaction (PCR) for detection of blaNDM-1 gene. RESULTS: Out of 21 strains isolated during the study period, 12 strains (57.1%) were carbapenem-resistant. Among them, seven strains (58.3%) were MBL producers. After PCR, 3 strains (42.9%) were found to be harboring blaNDM-1 gene Discussion: As per our knowledge, this is the first report of blaNDM-1 gene harboring C. indologenes strain from Northeast India. This shows the emerging therapeutic dilemma due to the narrowing of treatment options against bloodstream infections due to C. indologenes strains. Strict antimicrobial stewardship has to be implemented to prevent the further compounding of the problem.

An Epidemiological Analysis of SARS-CoV-2 Genomic Sequences from Different Regions of India.

The number of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) cases is increasing in India. This study looks upon the geographic distribution of the virus clades and variants circulating in different parts of India between January and August 2020. The NPS/OPS from representative positive cases from different states and union territories in India were collected every month through the VRDLs in the country and analyzed using next-generation sequencing. Epidemiological analysis of the 689 SARS-CoV-2 clinical samples revealed GH and GR to be the predominant clades circulating in different states in India. The northern part of India largely reported the 'GH' clade, whereas the southern part reported the 'GR', with a few exceptions. These sequences also revealed the presence of single independent mutations-E484Q and N440K-from Maharashtra (first observed in March 2020) and Southern Indian States (first observed in May 2020), respectively. Furthermore, this study indicates that the SARS-CoV-2 variant (VOC, VUI, variant of high consequence and double mutant) was not observed during the early phase of virus transmission (January-August). This increased number of variations observed within a short timeframe across the globe suggests virus evolution, which can be a step towards enhanced host adaptation.

Geographical distribution of primary & secondary dengue cases in India - 2017: A cross-sectional multicentric study.

Background & objectives: Dengue virus infection is endemic in India with all the four serotypes of dengue virus in circulation. This study was aimed to determine the geographic distribution of the primary and secondary dengue cases in India. Methods: A multicentre cross-sectional study was conducted at Department of Health Research / Indian Council of Medical Research (DHR)/(ICMR) viral research and diagnostic laboratories (VRDLs) and selected ICMR institutes located in India. Only laboratory-confirmed dengue cases with date of onset of illness less than or equal to seven days were included between September and October 2017. Dengue NS1 antigen ELISA and anti-dengue IgM capture ELISA were used to diagnose dengue cases while anti-dengue IgG capture ELISA was used for identifying the secondary dengue cases. Results: Of the 1372 dengue cases, 897 (65%) were classified as primary dengue and 475 (35%) as secondary dengue cases. However, the proportion varied widely geographically, with Theni, Tamil Nadu; Tirupati, Andhra Pradesh and Udupi-Manipal, Karnataka reporting more than 65 per cent secondary dengue cases while Srinagar, Jammu and Kashmir reporting as low as 10 per cent of the same. The median age of primary dengue cases was 25 yr [interquartile range (IQR 17-35] while that of secondary dengue cases was 23 yr (IQR 13.5-34). Secondary dengue was around 50 per cent among the children belonging to the age group 6-10 yr while it ranged between 20-43 per cent among other age groups. Interpretation & conclusions: Our findings showed a wide geographical variation in the distribution of primary and secondary dengue cases in India. It would prove beneficial to include primary and secondary dengue differentiation protocol in the national dengue surveillance programme.

Molecular characterization of NDM-1-producing Klebsiella pneumoniae ST29, ST347, ST1224, and ST2558 causing sepsis in neonates in a tertiary care hospital of North-East India.

Geographical differences can manifest in different spectra of microorganisms and patterns of antibiotic resistance. Considering this, Enterobacteriacae isolated from septicemic neonates from a tertiary care centre in Agartala, India were studied with focus on carbapenem resistance. Two hundred non-duplicate Enterobacteriaceae, of which 12 NDM-1-producing Klebsiella pneumoniae were recovered. Antibiotic susceptibility tests and detection of ESBLs and carbapenemases were performed for all Enterobacteriaceae. For NDM-1-producing isolates, plasmid-mediated quinolone resistance genes, addiction systems, genetic environment of blaNDM-1 and virulence genes was investigated by PCR. Bacterial clonal relatedness was established using REP-PCR, PFGE, and multi-locus sequence typing (MLST). Transferability of blaNDM-1 was tested by conjugation and transconjugants were characterized. K. pneumoniae was the primary organism causing sepsis in neonates. Resistance to different antimicrobials was high except for aminoglycosides and carbapenems. blaCTX-M was present in all isolates. All carbapenem-resistant isolates harboured blaNDM-1 as the only carbapenemase. blaCTX-M-15 and qnrS1 were detected in all NDM-1-producing isolates. Plasmid analysis of transconjugants revealed that blaNDM-1 along with blaCTX-M-15, qnrS1, qnrB1, aac(6')-Ib, aac(6')-Ib-cr and ccdAB or vagCD addiction systems were carried on large IncFIIK conjugative plasmids of varied sizes. blaNDM-1 was associated with ISAba125 or ISEc33 element at its 5'-end. In addition, isolates also harboured wabG, uge, fimH, mrkD, and entB virulence genes. The NDM-1-producing K. pneumoniae belonged to four distinct clones and were distributed in 4 STs (ST347, ST29, ST2558, and ST1224), of which ST347 was predominant. The association of blaNDM-1 with diverse STs in K. pneumoniae from neonates indicates the promiscuity of the gene and its widespread dissemination.

Pradigastat disposition in humans: in vivo and in vitro investigations.

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans.

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline-adjusted and placebo-corrected QTc intervals. During the 60-minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin significantly increased the QTc interval at multiple points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects.

PURPOSE: QMF149 is a fixed-dose combination of the long-acting ß2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 µg/mometasone furoate 320 µg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid.

Evaluation of Multidrug Resistant Staphylococcus aureus and their Association with Biofilm Production in a Tertiary Care Hospital, Tripura, Northeast India.

BACKGROUND: High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureus (MRSA) because of development of multidrug resistance. Staphylococcus aureus (S. aureus) has the ability to colonize and form biofilms on biomaterials which is causing resistance towards antimicrobials and thus making them difficult to eradicate from the infected hosts. MATERIALS AND METHODS: Culture isolation, identification was done following standard protocol and antibiogram of the isolates were done. The detection of MRSA, Macrolide-Lincosamide-Streptogramin B resistance (MLSB), vancomycin resistance phenotypes were done by using cefoxitin disc diffusion test, D zone test and vancomycin E test. Biofilm was detected by Congo red agar method. RESULTS: A total of 100 (31.7%) S. aureus strains were isolated from 315 clinical specimens. The prevalence of MRSA was 47% (47/100) with 85.1% were homogeneous MRSA and 14.9% were heterogeneous. Out of 47 MRSA strains, 63.8% were Hospital acquired-MRSA (HA-MRSA) infections whereas rests 36.2% were caused by Community acquired-MRSA (CA-MRSA) strains. Maximum number of MRSA isolates belonged to group A biotype (34%). A 14.9% isolates were of nontypeable group. Out of 100 S. aureus isolates, the prevalence of Vancomycin resistant S. aureus (VRSA) was found to be 3%. The MLSB phenotypes showed that the rates of inducible MLSB (iMLSB), constitutive MLSB (cMLSB) and Macrolide-Streptogramin B (MSB) in case of MRSA to be 19.1%, 31.9% and 12.8%. Prevalence of low-level (MUP(L)) and high-level mupirocin resistance (MUP(H)) among MRSA was 19.1% and 6.4%. Biofilm production was found in 55% strains of S. aureus. Out of 47 MRSA strains 76.6%were producing biofilm in comparison to 38.8% in methicillin-sensitive S. aureus (MSSA). Higher degree of antibiotic resistance in biofilm producers was seen especially in case of ciprofloxacin, co-trimoxazole, rifampicin, kanamycin, erythromycin and clindamycin whereas gentamycin, tetracycline and penicillin resistance was more in non-biofilm producers. CONCLUSION: This study shows high rate of circulating MRSA with a majority of these isolates are multi-drug resistant of which mostly are biofilm producers in our hospital setup. Development of antimicrobial stewardship program based on the local epidemiological data and national guidelines is the need of the hour.

Evaluation of food effect on the oral bioavailability of pradigastat, a diacylglycerol acyltransferase 1 inhibitor.

Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open-label, parallel group designs in healthy subjects (n=24/treatment/study) are presented. In study 1, a single dose of 20 mg pradigastat was administered under the fasted condition or with a high-fat meal. In study 2, a single dose of 40 mg pradigastat was administered under the fasted condition or with a low- or high-fat meal. At the 20 mg dose, the pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high-fat meal. When 40 mg pradigastat was administered with a low-fat meal, the Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high-fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with the pooled data from 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both the Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects.

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase 1, an enzyme highly expressed in the small intestine that plays a key role in postprandial triglyceride synthesis. This first-in-human study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat administered at single and multiple doses in overweight or obese healthy subjects. In single-dose cohorts (n = 72), subjects were randomized sequentially to receive single doses of pradigastat (1, 3, 10, 30, 100, or 300 mg) or placebo under fasted condition and prior to breakfast. In multiple-dose cohorts (n = 106), subjects were randomized to receive pradigastat (1, 5, 10, or 25 mg) or placebo prior to breakfast for 14 days. Following a single oral dosing, pradigastat was absorbed slowly, with a median tmax of ∼10 hours and eliminated slowly with a long half-life. With multiple oral doses, a 10- to 17-fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to dose-dependent suppression of postprandial triglyceride excursions over 9 hours following a high-fat meal test. In addition, pradigastat suppressed postprandial glucose and insulin and increased plasma glucagon-like peptide-1 levels. Overall, pradigastat was safe and tolerated at single and multiple doses in healthy subjects.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects.

PURPOSE: The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. METHODS: Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. RESULTS: The geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. CONCLUSION: In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.