Archive for month: May, 2024

Antibiotic Resistance – Global and Indian Brunt:

Antimicrobial resistance (AMR) is a significant global health concern in the twenty-first century. The spread of drug-resistant pathogens substantially threatens human health, and growing evidence shows that AMR is also a major health problem in India. (1) Bacterial AMR is estimated to have caused or contributed to 49.5 lakh deaths worldwide and is directly responsible for 12.7 lakh deaths, according to the World Health Organization (WHO) data. (2) In 2019, of the 10.7 lakh deaths linked to AMR in India, approximately 3 lakh deaths are directly caused by AMR. (3) The projections by the Organization for Economic Cooperation and Development (OECD) indicate an anticipated twofold surge in resistance to last-resort antibiotics by 2035, underscoring the urgent need for robust antimicrobial stewardship practices and enhanced surveillance coverage worldwide. (2) In India, Escherichia coli, Klebsiella pneumoniae, are common uropathogens responsible for complicated urinary tract infections (cUTIs) and pyelonephritis and are associated with a higher number of AMR deaths. (3)

Complicated urinary tract infections (cUTIs):

cUTIs are common bacterial infections in the community and healthcare settings (4). They are usually associated with a higher risk of recurrence, progression, or more unfavorable outcomes than uncomplicated UTIs. (5) The mean duration of hospital stay among cUTI is 9.1 ± 2.7 days among Indians, with frequent need for intensive care. Diabetes is one of the common risk factors for cUTI, which is highly pervasive in India (6) Most cUTI is caused by Enterobacteriaceae (commonly Escherichia coli, which accounted for 49.6%) (5,7), followed by Klebsiella pneumoniae and Enterococcus spp.). (8)

Current management of Urinary Tract Infections (UTIs)

The Indian Society of Critical Care Medicine (ISCCM) Guideline for Antibiotic Prescription in Intensive Care Unit recommended antibiotics that cover ESBL (extended-spectrum beta-lactamase) producing gram-negative organisms, include aminoglycosides, beta-lactam and beta-lactamase inhibitors or carbapenems (Level of Recommendation 2A), as the initial choice of antibiotics to treat UTIs in the ICU settings. (9)

The ICMR (Indian Council of Medical Research) Treatment Guidelines for Antimicrobials Use in Common Syndromes 2022 suggested Piperacillin–tazobactam, Ertapenem, Imipenem, Meropenem and Amikacin as an empirical treatment in treating infective urinary syndromes such as acute pyelonephritis. The guideline further noted that local antimicrobial resistance patterns should be the basis for empiric treatment. Antibiotics should be changed based on susceptibility results as soon as they are available. (10)

High Resistance to Current Anti-infectives Agents

Resistance to anti-infective drugs is an urgent public health problem threatening the treatment and control of infectious diseases. (11) The ICMR 2022 Annual Report for AMR Surveillance Network, emphasised that among hospital-acquired infections, Gram-negative bacteria (GNB) accounted for 74.4% of all Blood Stream Infection (BSI) cases. Among cUTIs, GNB accounted for 57.7% of cases, and Klebsiella spp. (30.4%) was the most common GNB involved. A high rate of resistance was seen against third-generation cephalosporins, carbapenems, fluoroquinolones, colistin, and aminoglycosides in Klebsiella pneumoniae, E. coli and Acinetobacter baumannii and Pseudomonas aeruginosa causing UTIs; nearly 60% isolates of Enterococcus faecium were vancomycin-resistant. (12) The mortality associated with Carbapenem-resistant Enterobacterales (CREs) infections, including bacteremia, may be as high as 20% to 54.3%, further underscoring the need for newer antimicrobial treatment options. (13)

Need for Novel Treatment Options for cUTIs

AMR among gram-negative pathogens, specifically MDR Enterobacterales, is a major public health concern. There is rising CRE prevalence, especially among Enterobacterales which limits antibiotic options available in India for treating cUTI. The higher prevalence of PBP3 insert amongst E. coli and rising colistin resistance further limit the treatment options. Thus, there is an urgent need for an antibiotic that has activity against MDR, carbapenem and colistin-resistant pathogens causing cUTI. (14)

Plazomicin a US-FDA approved (2018) molecule for treatment of cUTI and acute pyelonephritis in adult patients by susceptible microorganism(s): E. coli, K. pneumoniae, P. mirabilis, and E. cloacae. By virtue of its distinct structure, Plazomicin retains its activity against CRE [MBL, Oxa-48, KPC] (17), ESBL-producing, colistin-resistant (18), aminoglycoside-resistant Enterobacteriaceae and against most AME (aminoglycoside modifying enzymes) producing Enterobacteriaceae (19). Plazomicin will provide a new option for the treatment of cUTI and pyelonephritis in Indian patients and could meet an unmet demand in the era of AMR for managing cUTI patients in Indian clinical settings. (20)

References:

1. Vijay Pal Singh, Diksha Jha, Bilal Ur Rehman, Virendra S. Dhayal, Mahesh Shanker Dhar, Nitin Sharma. A mini-review on the burden of antimicrobial resistance and its regulation across one health sectors in India. Journal of Agriculture and Food Research. 2024. doi.org/10.1016/j.jafr.2024.100973.

2. World Health Organisation. Antimicrobial Resistance. Retrieved on 15 April 2024 from https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

3. IHME. University of Washington. The burden of antimicrobial resistance (AMR) in India. Retrieved on 13th April 2024 from https://www.healthdata.org/sites/default/files/files/Projects/GRAM/India_0.pdf

4. Lodise TP, Manjelievskaia J, Marchlewicz EH, Rodriguez M. Retrospective Cohort Study of the 12-Month Epidemiology, Treatment Patterns, Outcomes, and Health Care Costs Among Adult Patients With Complicated Urinary Tract Infections. Open Forum Infect Dis. 2022 Jun 20;9(7):ofac307. doi: 10.1093/ofid/ofac307. PMID: 35891695; PMCID: PMC9308450.

5. Hung KC, Tsai WW, Hsu CW, Lai CC, Tang HJ, Chen IW. Clinical efficacy and safety of novel antibiotics for complicated urinary tract infection: A systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents. 2023 Jul;62(1):106830. doi: 10.1016/j.ijantimicag.2023.106830. Epub 2023 Apr 24. PMID: 37100354.

​​6. Jindal J, Meelu A, Kaur S, Chahal HS, Makkar V, Garg V. Clinical Profile and Outcome in Patients of Complicated Urinary Tract Infections: A Single-Center Prospective Observational Study. Int J Appl Basic Med Res. 2022 Jul-Sep;12(3):167-170. doi: 10.4103/ijabmr.ijabmr_50_22. Epub 2022 Jul 26. PMID: 36131855; PMCID: PMC9484510.

7. M. A. A. Faraz, S. Mendem *, M. V. Swamy and P. Shubham. PREVALENCE OF URINARY TRACT INFECTIONS AND RELATED ANTI-MICROBIAL RESISTANCE IN INDIA: A SYSTEMATIC REVIEW AND META-ANALYSIS. 2021. IJPSR DOI: 10.13040/IJPSR.0975-8232.12(8).4314-21

8. NIKHAT, S. R., J. KAREEM, A. LATEEF, S. R. FATIMA, and R. SULTANA. “A PROSPECTIVE OBSERVATIONAL STUDY ON PREVALENCE AND TREATMENT OF URINARY TRACT INFECTIONS IN A TERTIARY CARE TEACHING HOSPITAL IN TELANGANA STATE”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 14, no. 12, Dec. 2022, pp. 1-5, doi:10.22159/ijpps.2022v14i12.46191.

9. Khilnani GC, Zirpe K, Hadda V, Mehta Y, Madan K, Kulkarni A, Mohan A, Dixit S, Guleria R, Bhattacharya P. Guidelines for Antibiotic Prescription in Intensive Care Unit. Indian Journal of Critical Care Medicine 2019;23(Suppl 1): S1-S63.

1‌0. Treatment Guidelines for Antimicrobial Use in Common Syndromes 2022 New Delhi, India. Retrieved on 13 April 2024 from https://main.icmr.nic.in/sites/default/files/upload_documents/treatment_amr_2022.pdf

11. Heymann DL. Resistance to anti-infective drugs and the threat to public health. Cell. 2006 Feb 24;124(4):671-5. doi: 10.1016/j.cell.2006.02.009. PMID: 16497576.

12. Indian Council of Medical Research. Annual Report. Antimicrobial Resistance Research and Surveillance Network. 2022. Retrieved on 25 April 2024 from https://main.icmr.nic.in/sites/default/files/guidelines/AMRSN_Annual_Report_2022.pdf

13. Portsmouth S, Bass A, Echols R, Tillotson G. Heterogeneity of Recent Phase 3 Complicated Urinary Tract Infection Clinical Trials. Open Forum Infect Dis. 2021 Feb 2;8(3):ofab045. doi: 10.1093/ofid/ofab045. PMID: 33738315; PMCID: PMC7953653.

14. Karishetti, Mallikarjun S.; Shaik, Hussain Basha. Clinicomicrobial assessment of urinary tract infections in a tertiary care hospital. Indian Journal of Health Sciences and Biomedical Research (KLEU) 12(1):p 69-74, Jan–Apr 2019. | DOI: 10.4103/kleuhsj.kleuhsj_296_17

15. Bilinskaya A, Linder KE, Kuti JL. Plazomicin: an intravenous aminoglycoside antibacterial for the treatment of complicated urinary tract infections. Expert Rev Anti Infect Ther. 2020 Aug;18(8):705-720. doi: 10.1080/14787210.2020.1759419

16. Zollner-Schwetz I, König E. Treatment options for multidrug-resistant Gram-negatives in urinary tract infections. Curr Opin Urol. 2023 May 1;33(3):173-179. doi: 10.1097/MOU.0000000000001084. Epub 2023 Mar 2. PMID: 36861769.

17. Serio AW, Keepers T, Krause KM. Plazomicin Is Active Against Metallo-β-Lactamase-Producing Enterobacteriaceae. Open Forum Infect Dis. 2019 Mar 12;6(4):ofz123. doi: 10.1093/ofid/ofz123. PMID: 30968059; PMCID: PMC6446133.

18. Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017 Oct 1;72(10):2787-2791. doi: 10.1093/jac/dkx239. PMID: 29091226.

19. Karishetti, Mallikarjun S.; Shaik, Hussain Basha. Clinicomicrobial assessment of urinary tract infections in a tertiary care hospital. Indian Journal of Health Sciences and Biomedical Research (KLEU) 12(1):p 69-74, Jan–Apr 2019. | DOI: 10.4103/kleuhsj.kleuhsj_296_17

20. Clark JA, Burgess DS. Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance. Ther Adv Infect Dis. 2020 Sep 4;7:2049936120952604. doi: 10.1177/2049936120952604. PMID: 32953108; PMCID: PMC7475792.

“The Petitioner admits that there exist legislative safeguards with respect to the apprising the patient about the possible side effects of the prescribed drugs. Schedule D(II) of the Act of 1945 obliges the manufacturer or his agent importing the drug to provide a package insert which shall duly disclose the side effects of the drugs to the consumer. In addition, Regulation 9.11 of Chapter 4 of the Regulations 2015 imposes a duty on the registered pharmacist to apprise the patient/carer about the possible side effects, etc.” noted the Court.

Therefore, the Court opined,

“The Petitioner does not dispute with respect to the sufficiency of the information supplied by the manufacturer through the insert provided with the drug at the time of sale by the registered pharmacist. The Petitioner however, contends that if the same insert is provided by the doctor along with the prescription, it can be presumed that the patient/carer would be able to make an informed choice with valid consent.”

“Since the legislature in its wisdom has elected to impose this duty on the manufacturer and the pharmacist, we do not find any ground for issuing a direction as prayed for in this PIL as it would amount to judicial legislation,” it further observed.

The analysis of the ORBITA-2 trial showed that symptom severity and nature were poorly associated with disease severity, however, the nature of symptoms powerfully predicted the placebo-controlled efficacy of PCI.

“Two groups more likely to benefit from PCI for angina relief in stable CAD: those with Rose pattern angina (OR 1.9) and those with guideline-based typical angina (OR 1.8),” the researchers reported.

“Typical angina and rose angina are excellent predictors of the placebo-controlled efficacy of PCI,” Florentina Simader, MD, of Imperial College London, said at the annual EuroPCR meeting, while presenting the results.

Stable CAD, characterized by the narrowing of coronary arteries, poses a significant health risk worldwide. PCI, a commonly employed intervention, involves the insertion of a stent to alleviate arterial blockages. However, the efficacy of PCI in improving patient outcomes has remained a subject of debate.

Placebo-controlled evidence from ORBITA-2 showed that PCI in stable coronary artery disease with little or no antianginal medication relieved angina, but residual symptoms persisted in many. There was no clarity on the reason. Considering this, the research team investigated the relationship between presenting symptoms and disease severity (non-invasive, anatomic, and invasive ischemia) and the ability of symptoms to predict the placebo-controlled PCI efficacy in an ORBITA-2 secondary analysis.

For this purpose, the researchers used the ORBITA smartphone application and symptom and quality of life questionnaires including the Rose angina questionnaire to assess the pre-randomization symptom severity and nature. Disease severity was assessed using stress echocardiography, quantitative coronary angiography (QCA), instantaneous wave-free ratio (iFR), and fractional flow reserve (FFR).

The study led to the following findings:

• At pre-randomization, the median number of daily angina episodes was 0.8, 64% had Rose angina, QCA diameter stenosis 61, stress echocardiography score 1.0, FFR 0.63, and iFR 0.78.
• There was little relationship between symptom severity and nature and disease severity: angina symptom score with QCA ordinal correlation coefficient 0.06; stress echocardiography 0.09; FFR 0.04; and iFR 0.04.
• Rose angina and guideline-based typical angina were strong predictors of placebo-controlled PCI efficacy (angina symptom score: OR 1.9 and OR 1.8, respectively).

“Whether a person had chest pains resolved by angioplasty hinged on the nature, not the severity, of their presenting symptoms,” the researchers concluded.

Reference:

Simader, F. A., Rajkumar, C. A., Foley, M. J., Ahmed-Jushuf, F., Chotai, S., Bual, N., Khokhar, A., Gohar, A., Lampadakis, I., Ganesananthan, S., Pathimagaraj, R. H., Nowbar, A., Davies, J. R., Keeble, T. R., O’Kane, P. D., Haworth, P., Routledge, H., Kotecha, T., Spratt, J. C., . . . Al-Lamee, R. K. (2024). Symptoms as a Predictor of the Placebo-Controlled Efficacy of PCI in Stable Coronary Artery Disease. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2024.04.016

A systematic review and meta-analysis of published randomized controlled trials was conducted to collate evidence from studies implementing ancient grains and investigate the impact of ancient grain consumption on health outcomes of patients with Diabetes Mellitus (DM). Twenty-nine randomized controlled trials were included, and 13 were meta-analyzed. Interventions ranged from 1 day to 24 weeks; most samples were affected by DM type 2 (n = 28 studies) and the ancient grains used were oats (n = 10 studies), brown rice (n = 6 studies), buckwheat (n = 4 studies), chia (n = 3 studies), Job’s Tears (n = 2 studies), and barley, Khorasan and millet (n = 1 study). Thirteen studies that used oats, brown rice, and chia provided data for a quantitative synthesis.

Four studies using oats showed a small to moderate beneficial effect on health outcomes including LDL-c (n = 717, MD: 0.30 mmol/l, 95% CI: 0.42 to −0.17, Z = 4.61, p < 0.05, I2 = 0%), and TC (n = 717, MD: 0.44 mmol/l, 95% CI: 0.63 to −0.24, Z = 4.40, p < 0.05, I2 = 0%). Pooled analyses of studies using chia and millet did not show significant effects on selected outcomes. For adults affected by DM type 2, the use of oats may improve lipidic profile. Further experimental designs are needed in interventional research to better understand the effects of ancient grains on diabetes health outcomes.

Reference:

Camilla Elena Magi, Laura Rasero, Edoardo Mannucci, Guglielmo Bonaccorsi, Francesco Ranaldi, Luigia Pazzagli, Paola Faraoni, Nadia Mulinacci, Stefano Bambi, Yari Longobucco, Ilaria Dicembrini, Paolo Iovino. Use of ancient grains for the management of diabetes mellitus: A systematic review and meta-analysis, Nutrition, Metabolism and Cardiovascular Diseases, Volume 34, Issue 5, 2024, Pages 1110-1128, ISSN 0939-4753, https://doi.org/10.1016/j.numecd.2024.03.005. (https://www.sciencedirect.com/science/article/pii/S0939475324000929)

While the epidemiological risk factors of metabolic diseases linked to hyperuricemia are well-documented, there is limited evidence regarding the nonlinear relationship between the TyG index and hyperuricemia. Hyperuricemia, characterized by high levels of uric acid in the blood, is a known risk factor for various metabolic and cardiovascular diseases. The TyG index, a reliable surrogate marker for insulin resistance, is computed as Ln [triglycerides (mg/dL) × fasting glucose (mg/dL)/2].

This cross-sectional study analyzed data from NHANES collected between 2011 and 2018, including 8572 participants. The primary outcome was the presence of hyperuricemia. Researchers employed weighted multiple logistic regression, subgroup analysis, generalized additive models, smooth fitting curves, and two-piecewise linear regression models to explore the association between the TyG index and hyperuricemia.

• The study revealed a nonlinear and reverse U-shaped association between the TyG index and hyperuricemia, with an inflection point at a TyG index of 9.69.

• In the regression model adjusting for all confounding variables, the odds ratio (OR) for the association between TyG and hyperuricemia was 2.34 (95% confidence interval [CI], 1.70-3.21).

• The OR (95% CI) before the inflection point was 2.64 (2.12-3.28), indicating a strong positive association.

• However, beyond the inflection point, the OR significantly decreased to 0.32 (0.11-0.98).

• Additionally, significant interactions were observed in analyses stratified by gender, BMI, hypertension, and diabetes.

The findings highlight a complex relationship between the TyG index and hyperuricemia. Initially, higher TyG index values are strongly associated with an increased risk of hyperuricemia. However, after reaching an inflection point, further increases in the TyG index correlate with a reduced risk. This reverse U-shaped relationship underscores the importance of considering nonlinear dynamics in metabolic risk assessments.

This study concludes that there is a strong positive connection between the TyG index and hyperuricemia up to a certain threshold, beyond which the relationship reverses. These findings necessitate further prospective studies to validate and understand the underlying mechanisms. Understanding this nonlinear relationship can aid in better risk stratification and management of hyperuricemia in clinical practice.

Reference: