This document discusses strategies for managing infections caused by carbapenem-resistant bacteria. It begins by outlining the objectives of understanding the epidemiology of carbapenemase resistant infections in animals and identifying management strategies. It then provides background on the increasing issue of antimicrobial drug resistance globally and in India. The document discusses common resistance mechanisms like reduced permeability, target alteration, and enzymatic inactivation. It also summarizes different classes of beta-lactam antibiotics and carbapenemases, and the genetics of beta-lactamase resistance. Finally, it presents the author's observations on increasing drug resistance in veterinary clinical isolates in India.
Best Practice for Colistin Susceptibility Testing: Methods and Evidence (Mini...Abdullatif Al-Rashed
Mini-Review presentation
Best Practice for Colistin Susceptibility Testing: Methods and Evidence
Clinical Microbiology Residency Program, King Fahd Hospital of the University
Al Khobar, Saudi Arabia
Best Practice for Colistin Susceptibility Testing: Methods and Evidence (Mini...Abdullatif Al-Rashed
Mini-Review presentation
Best Practice for Colistin Susceptibility Testing: Methods and Evidence
Clinical Microbiology Residency Program, King Fahd Hospital of the University
Al Khobar, Saudi Arabia
Issues in Veterinary Disease Diagnosis.pptxBhoj Raj Singh
Diagnosis of a disease or a problem is the first step towards solution/ treatment/ control/ prevention.
Diagnosis is successfully. important to determine Prevalence (True prevalence, apparent prevalence) and Incidence of the disease to estimate the disease burden so that prevention and control measures can be planned and implemented.
However, in few years with the invasion of pharmaco-politics in disease control the term got vitiated.
Epidemiological Approaches for Evaluation of diagnostic tests.pptxBhoj Raj Singh
Diagnosis of a disease or a problem is the first step towards solution/ treatment. Clinical Diagnosis or Provisional Diagnosis is the first step in diagnosis and is done after a physical examination of the patient by a clinician. Clinical diagnosis may or may not be true and to reach Final diagnosis Laboratory Investigations using gross and microscopic pathological observations and determining the disease indicators are required. The diagnostic tests may be Non-dichotomous Diagnostic Tests (when continuous values are given by the test in a range starting from sub-normal to above-normal range) and Dichotomous Diagnostic Tests (when results are given either plus or minus, disease or no-disease). To make non- Dichotomous diagnostic test a Dichotomous one you need to establish the cut-off values based on reference values or Gold Standard test readings or with the use of Receiver operator characteristic (ROC) curves, Precision-Recall Curves, Likelihood Ratios, etc., and finally establishing statistical agreement (using Kappa values, Level of Agreement, χ2 Statistics) between the true diagnosis and laboratory diagnosis. Thereafter, the Accuracy, Precision, Bias, Sensitivity, Specificity, Positive Predictive value, and Negative Predictive value, of a diagnostic test are established for use in clinical practice. Diagnostic tests are also used to determine Prevalence (True prevalence, apparent prevalence) and Incidence of the disease to estimate the disease burden so that control measures can be implemented. There are several Phases in the development and use of a diagnostic assay starting from conceptualization of the diagnostic test, development and evaluation to determine flaws in diagnostic test use and Interpretation influencers. This presentation mainly deals with the epidemiological evaluation procedures for diagnostic tests.
Types of Trials in Medicine, vaccine efficacy or effectiveness trials and rel...Bhoj Raj Singh
The importance of learning about medicines’ and vaccines’ efficacy or effectiveness trials is not only necessary to those who are developing, producing or marketing these pharmaceutical products but to the users also because: The Emergency approval of Covid-19 vaccines and many other medicines in last few years has created so much fuss to understand the reality. The lesson learnt from Covid-19 vaccine(s) by vaccine production, marketing, vaccination and finally the revenue earned by vaccine developers and producers, and political gain by politicians, is proving deleterious to the society as several vaccine(s), useless or scarcely proven safe and useful, are going to infest and some have already infested the market (the health industry). So reading this presentation may be useful to you so that you may question the authorities if any is engaged in bluffing you. The presentation talks briefly about Prevention trials, Screening trials, Treatment trials, Feasibility studies, Pilot studies, Phases in clinical trial, Multi-arm multi-stage (MAMS) trials, Global Clinical Trials, Vaccine efficacy, Vaccine safety, Emergency Use Authorization (EUA), Serious Adverse Events (SAE), SEA rules, The Vaccine Adverse Event Reporting System (VAERS), Vaccine Safety Datalink (VSD), The Advisory Committee on Immunization Practices (ACIP), Clinical Immunization Safety Assessment (CISA), CDSCO Rules Governing Clinical Trials, Schedule Y, The Ethics Committee, Empowered Committee on Animal Health, Tracking Vaccine Quality, Pre-clinical and Clinical data, Proof of Concept, Biological License Application (BLA) and Clinical hold.
Detection and Characterization of Pathotypes, Serotypes, Biotypes, Phenotypes...Bhoj Raj Singh
This presentation of my lecture, to Epidemiology students, briefs about different methods for differentiating or finding similarities among isolates of pathogens required establishing causal associations in epidemiological disease diagnosis.
Epidemiology of antigenic, genetic and biological diversity amongst pathogens...Bhoj Raj Singh
This presentation briefly describes the Antigenic, genetic and biological diversity amongst pathogens, and their origin and emergence. It also discusses with their association with different forms associated with a disease/ outbreak. The presentation also enlists diversity in strains causing some common diseases of livestock in India.
Differentiation of field isolates (wild) from vaccine strains (Marker, DIVA &...Bhoj Raj Singh
Nowadays vaccination is often reported as the cause of disease outbreaks. To ward off this misconception (vaccines are made to save the masses not to risk their lives)or to understand vaccination failures, it is necessary to understand the difference between a field strain causing the disease and a vaccine strain having attenuated virulence. This presentation talks about DIVA and DISA vaccines too.
Lumpy skin disease (LSD) Globally and in India.pptxBhoj Raj Singh
LSD has emerged as a dairy industry devastating disease in India in the last four years. First noticed in Orrisa and is now present all over India. Recurring outbreaks are now noticed in Rajasthan, Uttarakhand and other states indicating that the disease is becoming endemic in India.
Molecular determinants of pathogenicity and virulence among pathogens.pptxBhoj Raj Singh
The presentation discusses the pathogenicity and virulence of pathogens, their determinants and their interaction with the host. It talks briefly about pathogenicity, virulence, adhesions, invasions, toxins, disease, pathogenesis, pathogenicity islands (PAIs), intracellular, extracellular, bacteria, virus, fungi, prion, metazoan worms, protozoa, tuberculosis, E. coli, Salmonella, Yersinia, Mycobacterium, cytotoxins, enterotoxins, exotoxins, neurotoxins, endotoxins, in-silico, in-Vitro, in-vivo, immunohistology, haemagglutinins, spike proteins, integrins, and phagolysosomes.
Molecular epidemiology and Disease causation.pptxBhoj Raj Singh
This short presentation describes molecular epidemiology, differentiate it from genetic epidemiology, and also deals with ascertaining the cause of disease.
My research proposals, to porotect holy cow, rejected by the ICAR-IVRI in the...Bhoj Raj Singh
The presentation relates to my three research proposals, aimed at Protection of Holy cow, rejected at ICAR-ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, India, in last five years
Clinical evaluation of newly advocated therapies for brucellosis in cattle and buffaloes. Duration: September 2019 to August 2021
A cross-sectional survey of Holy Cow Infectious Problems in Gaushalas (Gaushalas are protective shelters for stray cows in India). Duration: September 2022-August 2024
Explorative study on Epidemiological determinants associated with a drastic reduction in Milk Production of Dairy Animals with reference to communicable diseases. Duration: September 2022-August 2024
Animal Disease Control and Antimicrobial Resistance-A Message to Veterinary S...Bhoj Raj Singh
This presentation is for
• Introspection by all authorities before criticizing Veterinarians for an increase in AMR & to Doyens of Veterinary Science sitting mum when Vets are criticized!
• To realize that DAHD and State Animal/ Livestock Departments are:
– Fake data masters!
A realization to Doyens of Veterinary Science that they are:
– Spineless when their voice is the most needed!
– Don’t understand epidemiology to the least and make minimal attempts to improve Epidemiological understanding in veterinarians!
– The real negative thinkers!
– Suffering from an inferiority complex!
– Real killers of the holy cow!
– Interested to develop the best vet doctors but creating butchers!
– Real anti-nationals!
They talk of one health without understanding it!
– Much more!!!
Causes of Disease and Preserving Health in Different systems of Medicine.pptxBhoj Raj Singh
This presentation deals with concepts of disease causation and methods used for the alleviation of those causes to ensure health. It has briefed the causes of diseases according to Ayurvedic medicine, Unani medicine, Siddham medicine, Naturopathy, Homeopathy, Chinese medicine, Touch therapy- Reiki, Mantra therapy, and Allopathy. It also summarizes the treatments and practices in different systems of medicine. DOI: 10.13140/RG.2.2.30883.22569
AMR challenges in human from animal foods- Facts and Myths.pptxBhoj Raj Singh
This presentation talks about ÄMR: A public health threat, a “silent pandemic”.
Infections caused by Antimicrobial-drug-resistant (AMR) pathogens caused >1.27 million deaths worldwide in 2019 (low level or no surveillance) and increasing year after year which may be > million in coming decades. Covid-19 caused ~6.8 million deaths in >3 years but now the pandemic is ending but the AMR pandemic has no timeline for its ending. Many deaths are also attributed to AMR pathogens.
More antibiotic use (irrespective of the sector) = More AMR.
This presentation also talks about ways and means to mitigate the AMR pandemic. 1. Stopping the blame game. All are equally responsible for the emergence of AMR, the share of developed and educated communities is much more than poor and un-educated communities.
2. Working together: On-Line Real-Time AST Data Sharing Platform for different diagnostic and research laboratories doing AST routinely.
3. Implementing not only antibiotic veterinary and medical stewardship but antimicrobial production and distribution stewardship too.
4. Educating for Environmental health not only human, plant, and animal health.
5. AMR's solution is not in searching for alternatives to antibiotics but in establishing environmental harmony.
6. More emphasis on AMR epidemiology than on AMR microbiology and pharmacology.
7. Development of understanding that bacteria and other microbes are more essential for life on earth than the human race. Microbes can live without humans, but humans can’t without microbes.
Global-Health is of prime importance than economic growth/ greediness.
Herbal antimicrobials are considered as an important alternative to antibiotic and probable tools to mitigate emerging antimicrobial-drug-resistance (AMR). However, it is difficult to accept that microbes may not adapt to herbal antimicrobials as rapidly as to antibiotics. This is now well documented that herbal antimicrobial resistance is also common among common pathogenic microbes and genes are now known to encode herbal drug-resistance too. This lecture gives description how resistance to conventional antimicrobials impacts susceptibility of microbes for herbal antimicrobials. Lecture Scheduled on 21st February 2023, In: Antimicrobial Resistance (AMR) in Foodborne pathogens” sponsored under the ICAR-NAHEP-CAAST project by the MAFSU, Mumbai Veterinary College, at the Division of Veterinary Public Health, ICAR-IVRI from 20th February to 25th February, 2023.
Epidemiological characterisation of Burkholderia cepacia complex (Bcc) from c...Bhoj Raj Singh
The presentation is extracted from the thesis talking about
1. The presence of Bcc organisms in the clinical infections of animals.
2. Ultrasound gels as a potential source of pathogens, especially Bcc.
3. Multidrug resistance in BCCs.
4. Lack of regulatory guidelines in Indian Pharmacopeia as existing in USP.
There are hundreds of diseases of livestock and pet animals that can be printed through properly used quality vaccines. This presentation summarises different types of vaccines used by veterinarians to control/ prevent diseases. The presentation enlists the vaccine-preventable diseases of pets and livestock, and also the different vaccines used.
Major flaws in Animal Disease Control Leading to Partial Success or Failure.pptxBhoj Raj Singh
This presentation summarises major problems of Animal Disease Control Programs ongoing in India. India is a hyperendemic country for many animal diseases and zoonotic diseases. Every year billions of rupees are spent on disease control, surveillance, monitoring, and vaccination against vaccine-preventable diseases. However, due to the failure of most animal disease control programs for one or other reasons India directly losses about 20 and 25 thousand crores annually due to endemicity of FMD & brucellosis, respectively. The presentation identifies problems at different levels of different ongoing disease control programs in India. The non-availability of authentic disease data and flaws in vaccine quality control are the biggest problems.
Animal Disease Control Programs in India.pptBhoj Raj Singh
India is a hyperendemic country for many animal diseases and zoonotic diseases. Every year billions of rupees are spent on disease control, surveillance, monitoring, and vaccination against vaccine-preventable diseases. However, due to the failure of most animal disease control programs for one or other reasons India directly losses about 20 and 25 thousand crores annually due to endemicity of FMD & brucellosis, respectively. The presentation describes the pros and cons of different ongoing disease control programs going on in India.
Control and Eradication of Animal diseases.pptxBhoj Raj Singh
The presentation details different methods and terminologies used in disease management. It briefs about different types of disease control programs run at global, regional, and national levels. It also tells about the success and failure of different disease control programs. The presentation also briefed about methods of disease control.
The presentation summarises important methods and protocols of Clinical Microbiology. It may be useful to learners of Clinical microbiology at the undergraduate label. The presentation describes the procedures for collecting clinical samples, transport, and testing. It also describes the different methods of antimicrobial susceptibility testing and standards.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Development of strategies for management of infections with carbapenem resistant bacteria myths and facts
1. Development of strategies for
management of infections with
carbapenem resistant bacteria
Myths and Facts
Dr. Bhoj R Singh
Act. Head of Division of Epidemiology
Indian Veterinary Research Institute, Izatnagar-243122,
India
Ph. No. +91-8449033222; Email: brs1762@ivri.res.in;
brs1762@gmail.com
2. Objectives
• To understand epidemiology and emergence
of carbapenemase resistant infections in
animals.
• To look for strategies for management of
infections with carbapenemase resistant
bacteria.
3. Present scenario
• Antimicrobial drug resistance in common and
consistently emerging problem all over the globe
including Indian sub-continent.
• Antimicrobial drug resistance is either flow
vertically or horizontally.
• Genes for drug resistance may be either on
chromosome or on mobile genetic elements (R
factors, plasmids, transposons, Insertion
elements, integrons, bacteriophages).
• Emergence of antimicrobial drug resistance is
natural.
5. Target site of Antibiotics
Inhibition of cell wall synthesis
Penicillins, Cephalosporins, Carbapenems, Monobactams,
Daptomycin, Glycopeptides
Inhibition of protein synthesis
Tetracyclines, Chloramphenicol, Macrolides, Aminoglycosides,
Lincosamides, Oxazolidinones, Streptogramins
Interference of nucleic acid synthesis
Quinolones, Nitroimidazoles, Rifampicin
Disruption of bacterial membrane
Polymixins, Colistin
Inhibition of folic acid pathway
Sulphonamides, Trimethoprim
6. Antimicrobial drug resistance
mechanisms
• Reduced permeability and active efflux: Gram-negative pathogens like
Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter
baumannii show resistance to β-lactams by altering the porins or by loss of
porins. Another strategy is expelling the antibiotics out of the bacterial cell by
active efflux through membrane bound efflux pumps to counter action of
variety of antimicrobials, P. aeruginosa harbour several efflux pumps like
MexAB-OprM, MexCDOprJ, and MexXY-OprM.
• Target alteration: Modification of penicillin binding proteins (PBPs, main
targets for β-lactams). MRSA is achieved by the acquisition of an altered PBP
(PBP2a or PBP2’) by the mecA gene. Also in Gram-negative bacteria such as A.
baumannii and P. aeruginosa altered PBPs have been implicated in resistance
towards β-lactams.
• Enzymatic inactivation or modification: Most of the antibiotics are
characterized by ester or amide bonds, which are hydrolytically susceptible,
targeted by certain bacterial enzymes, and render them inactive. β-
lactamases are the major resistance mechanisms both in Gram positive and
Gram negative bacteria. Modification of the antibiotic molecule is a major
resistance mechanism in Gram-negatives to aminoglycosides conferred by
aminoglycoside modifying enzymes
7. β-lactam antibiotics
•The β-lactam antibiotics comprise six different structural
subtypes, including penams, cephems, monobactams, cla-
vams, penems, and carbapenems.
•Penams: benzylpenicillin and ampicillin.
•Cephems: These Cephaloridine, nitrocefm, cefotaxime,
cephamycins (7-α-methoxy-cephalosporins) the classical
cephalosporins,
•Monobactams are monocyclic β-lactams, aztreonam.
•Penems have a 2, 3-double bond in the fused thiazolidine
ring (dihydrothiazole) and Carbapenems (Imipenem,
biapenem)
10. β-Lactamases
More than 400 β-lactamases have been reported and new β-lactamases continue to
emerge worldwide (Jacoby, 2009). http://www.laced.uni-stuttgart.de/;
http://www.lahey.org/Studies/
Now as on December 2014 about 800 β-lactamases
~190 SHV ESBLs; ~239 OXA BLS of which >37 are carbapenemases; ~193 TEM ESBLs
~100 MBLs (VIM-48 variants; IMP-44 variants; NDM-12 variants)
12. Molecular classification of B-lactamases
Molecular class (Ambler
classes) and common
names
Bush Jacoby groups Inhibited by
Clavulanic
acid,
subactam
Inhibited
by
EDTA
Mechanism of
Action
A (>500) ESBLs
TEM ~193; SHV ~190;
CTX-M ~90; GES~15;
PER~5; VEB~7;
KPC~9, SME~3)
2a, 2b, 2be, 2br, 2ber, 2c, 2e
2f (carbapenems and B-
lactams are ineffective)
Yes No Serine B-
lactamase
B (>100) MBLs
B1: IMP(1-44), VIM (1-
40), NDM (1-12), IND
(1-8), GIM-1, BcII,
CcrA
B2: CphA, Sfh-1
B3-FEZ; L1
3a (IMPs, VIMs, NDMs,
GIM-1, BcII, CcrA, L1,
AIM-1, FEZ-1).
3b (CphA, Sfh-1)
Carbapenems are
ineffective but aztreonam
may be effective.
No Yes Zinc metallo-
B-lactamase
C (CMY1-CMY50) ~50 1, 1e (most of the B-lactams
and Aztreonam ineffective)
No No Serine B-
lactamase
D (OXA-1 to OXA-
58)~239
2d, 2de, 2df (carbapenems
are also ineffective)
Partially
inhibited
No Serine B-
lactamase
Up to 2007: GIM- German imipenemase; GES - Guiana extended spectrum β-lactamase; BES- Brazil extended spectrum β-
lactamase; SPM-1-Sao Paulo metallo-β-lactamases; SIM-1 -Seoul imipenemase; CTX-M- cefotaxime Munich; MIR-1, Miriam
Hospital in Providence extended spectrum β-lactamase; DHA- the Dhahran Hospital in Saudi Arabia extended spectrum β-
lactamase.; VEB -Vietnam extended-spectrum β-lactamase ; TLA- Tlahuicas Indians ESBL; TEM-1- Temoneira ESBL
(1965); BIL1 was named after the patient Bilal in 2002.
In 2008: NDM-New Delhi Metallo-β-lactamase.
13. Genetics of β-lactamses
• Chromosomal: AmpC ESBLs of many Gram-negative bacteria, including
Citrobacter, Serratia and Enterobacter. blaSHV of K. pneumoniae, blaCTX-M of
Kluyvera,
• Mobile genetic elements (MGEs), such as insertion sequences (ISs),
integrons, transposons, plasmids and phage-related elements.
– Plasmids: AmpC of E. coli and Klebsiella and many other ESBLs viz., DHA-1, MIR-
1, 2, BIL-1, CMY, FOX, LAT; blaCMY-13 on an IncN plasmid from Escherichia coli,
blaCTX-M genes on IncI1 and IncFII and other plasmids.
– Transposons- Most of the blaTEM variants are associated with Tn1, Tn2 and Tn3
transposition, blaCTX-M-15
– Integrons and IS Elements: IBC (integron-borne cephalosporinase), IS-5
mediated bleomycin resistance; blaSHV of K. pneumoniae on IS26; ISEcp1 and
ISCR1 responsible for transposition of blaCTX-M ; blaGES-1 and blaVEB-1 gene
cassettes are on class 1 integrons, blaGES-1 gene cassette on class 3 integron,
insertion sequence ISEcp1 has been identified in association with many blaCMY
genes, Citrobacter blaCMY-13 gene is bound to IS26 elements; blaCTX-M-15
associated with ISEcp1 in Enterobacteriaceae.
– Phage related/ mediated: blaCTX-M , blaTEM , and mecA , genes
(qnrA, qnrB and qnrS) conferring reduced susceptibility to fluoroquinolones,
14. Carbapenemases
• Class A (serine based)
– KPC, GES, SME, NMC, IMI
• Class B (metallo-enzymes)
– NDM (NDM-1 in 2008 at New Delhi K. pneumoniae and
E. coli), IMP (IMP-1 in 1988 in Japan P. aeruginosa), VIM
(VIM-1, in 1999 in Italy P. aeruginosa, VIM-2 in France
1996 isolate), GIM, SIM, SMP, L1, BCII, Ccra
• Class D (serine)
– OXA (37 of 239) Mostly from A. baumannii isolate. First from
Scotland in 1985. OXA-48 was isolated from a clinical isolate of K.
pneumoniae from Turkey.
15. Genetic regulation of carbapenemases
• Chromosomal
– Class A
• SME (1982), NMC (1984), IMI (1990)
– Class B
CphA & SPM-1-Aeromonas spp., BCI,
BCII- Bacillus cereus, L1-
Stenotrophomonas maltophilia,
CcrA-Bacteroides fragilis; GOB1,
FEZ1, Mbl1b, CAU1, BJP1
– Class D
• OXA
• Plasmid
– Class A
• KPC (1996), GES (2000)
– Class B
Bla-IMP, bla-VIM, bla-GIM,
bla-SIM, blaKMH, NDM
(2008), IMP, L1, AIM1, SMB1
– Class D
• OXA
Integrons- on Class I integrons IPM and VIM (Verona integron-encoded MBL )
IS elements
In A. baumannii, the insertion sequences of ISAba1 type carrying strong promoters are present
upstream of chromosomal OXA genes.
16. Mettalo-B-lactamases
Susceptible to inhibition by aztreonam and metal ion chelators (EDTA)
B1 B3 B2
Broad spectrum-hydrolyse penicillins,
cephalosporins and carbapenems
Narrow spectrum- Hydrolyse
carbapenems only
Require two Zn ions bound to active site Requires only one Zn ions bound to
active site
Clinically more
important (NDM,
VIM, IMP)
Clinically less
important
Clinically less important
Zn 1 site present Zn 1 site present Zn 1 site absent
Zn 2 ligand in Cys22 Zn 2 ligand in His121 Only Zn 2 site is active
17. Carbapenems
Imipenem is susceptible to hydrolysis by dehydropeptidase found in renal brush
border. Hence, they have to be co-administered with the inhibitors such as
cilastatin (or betamipron). Subsequently, meropenem, biapenem, doripenem
and ertapenem were developed by addition of methyl group to 1-β position to be
protected from dehydropeptidase hydrolysis.
18. How Carbapenems act?
• Carbapenems enter Gram-negative bacteria through OMPs
(porins) and reach periplasmic space.
• Carbapenems have ability to bind to multiple different PBPs.
• Permanently acylate the PBPs.
• Inhibit peptide cross linking and other peptidase reactions.
• Weakening of cell wall leading to autolysis and death of the
bacterium.
• Carbapenems have broader antimicrobial spectrum than
penicillins, cephalosporins or β-lactam/β-lactamase inhibitor
combinations.
• Imipenem, panipenem, and doripenem are potent
antibiotics against gram-positive bacteria whereas
• Meropenem, biapenem, ertapenem (and doripenem) are
slightly more effective against Gram-negative bacteria.
19. Our observations on Veterinary
Clinical isolates of bacteria
5.5
11.9
4.6
68
18.3
38.3
8.4
20
20.7
25.4
20.6
16.5
18.9
49.6
10.7
79.5
61.3
34.5
26.2
10
7.6
2.5
57.5
33.9
19.4
14.2
13
38.1
49.6
24.9
16.5
14.3
64.9
6.5
40.6
30.8
59.6
24.6
0
10
20
30
40
50
60
70
80
G-ve Bacteria (901) G +ve Bacteria (416)
In Vitro Drug Resistance in Veterinary Clinical Isolates of Bacteria (2011-14) at IVRI,
Izatnagar Bareilly (Figures are shown as % of total isolates resistant to the drug).
Do herbal drugs may be an option for antibiotic resistant bacterial infection?
20. Changing Resistance pattern of Drug resistance in last
three years period (2012-2014) Figures are shown as % of total isolates
20.9
27.9
63.7
13.9 12.3
47
5.4
30.5
0
10
20
30
40
50
60
70
2012 2013 2014
ESBL+
Carbapenemase+
ESBL+ Carbapenemase+
All clinical isolates of Bacteria (1317)
25.5
32.8
73.2
13.8 13.7
41.7
6.9
31.3
0
10
20
30
40
50
60
70
80
2012 2013 2014
ESBL+
Carbapenemase+
Gram Negative isolates of Bacteria (901)
10.4
13.6
52.4
14.3
8
54.1
1
29.4
0
10
20
30
40
50
60
2012 2013 2014
ESBL+
Carbapenemase+
ESBL+ Carbapenemase+
Gram Positive isolates of Bacteria (416)
Resistance is increasing in
bacteria due to ESBL and
Carbapenemase production
ability at alarming rate in
veterinary clinical isolates.
Drug resistance is emerging
faster in Gram Negative
bacteria than Gram positive
bacteria.
21. Probability of Drug resistance and its type changes
with types of bacteria (Based on clinical isolates of bacteria (1317)
identified in Epidemiology Laboratory of IVRI, Izatnagar 2011-2014).
29.9
26.9
18.1
19.5
50.0 50.0
20.0
32.3
21.7
12.6
19.4
13.8
21.1
19.4
37.5
5.0
15.4
8.7
6.7
9.0
5.6
3.3
8.1
12.5
2.5
7.7
6.5
0.0
10.0
20.0
30.0
40.0
50.0
60.0 % ESBL +ve % Carbapenemase +ve % ESBL & Carbapenemase +ve
22. Successful therapy of
Infections needs
• Knowledge of local epidemiology
• Local situation: Antimicrobial drug resistance
trends i.e.
• clonal spread (all isolates have the same
antibiogram) or
• polyclonal, transmission of plasmid
– sensitivities vary depending on the background of the
strain carrying the plasmid
– MIC
– Preparedness to think laterally
23. MIC
MIC ≤8 mcg mL-1 Mortality 29%, MIC>8 mcg mL-175%
Mortality Carmeli et al. CMI 2010; Daikos et al, AAC 2009
S I R
Erta ≤0.5 1 >1
0.5->64
Imi ≤2 4-8 >8
0.5->64
Mero ≤2 4-8 >8
1-64
24. Options
• Exhausted: B-lactam antibiotics (~80% or more bacteria are resistant)
• Still possible (Need Antibiogram studies to execute)
– Quinolones(~75% isolates with ESBL and Carbapenemase production were sensitive)
– Aminoglycosides (~77% isolates with ESBL and Carbapenemase production were sensitive)
– Tigecycline (Only 65% isolates with ESBL and Carbapenemase production were sensitive)
– Colistin (Only 40-60% isolates with ESBL and Carbapenemase production were sensitive)
– Trimethoprim(Only 50% isolates were sensitive)
– Chloramphenicol (>85% isolates with ESBL and Carbapenemase production were sensitive)
– Fosfomycin
– Temocillin
– Combinations (which ones?)
– Herbal drugs? Which? How? What do they do?
25. Herbal drugs
MIC for the best effective Herbal oils as
antimicrobials
Lemon Grass oil 5 mcg to >5000 mcg mL-1
Holy Basil oil 20 mcg to >2560 mcg mL-1
Cinnamon oil 10 mcg to > 1280 mcg mL-1
Carvacrol from Oregano oil 5mcg to >5000mcg mL-1
The Questions are:
•How we can administer these effective herbal oil safely to
achieve the required systemic concentrations?
•What are the toxicities and safety limits for Herbal oils
while treating infection?
•How they interact with other drugs used simultaneously?
26. In Vitro Sensitivity of Veterinary Clinical Isolates of
Bacteria Having Different Types of Drug-Resistance
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
ESBL+ve Carbpenemase +ve ESBL & Carbapenemase +ve
27. What should we do?
• Review of 298 published cases (244 BSI)
Tzouvelekis et al, CMR 2011
Treatment Failure rate
2 drugs, inc carbapenem (MIC<8) 8%
2 drugs, no carbapenem 29%
Aminoglycoside alone 24%
Carbapenem alone (MIC<8) 25%
Tigecycline alone 36%
Colistin alone 47%
Inappropriate Rx 54%
On the basis of our data on in vitro antimicrobial sensitivity of the isolates at
Indian Veterinary Research Institute, Izatnagar, similar predictions could be
made.
28. What should we do? Studies!
• Understanding of Resistance mechanism: Chromosome or MGEs.
• Individual patient approach.
• Treatment: Usually based on sensitivities of previous screening or the
current clinical isolates.
• Combination therapy: Aztreonam, ceftazidime and aminoglycoside
(amikacin/ genatmicin)
• Some broad principles: 2 or more agents
• Aztreonam: Aztreonam is stable to metallo-carbapenemases IMP, VIM and NDM
but ineffective in isolates that also co-produce AmpC or ESBL. It seems to be not
useful in Indian context with high percentage of Am,p C and ESBL producers.
• B-lactams (co production of AmpC or an ESBL make them useless) In Indian
context more important.
• Aminoglycoside if possible (Strains with KPC, VIM, IMP and OXA-48
enzyme are variably resistant to aminoglycosides). Our data indicates their
potential as one of the best option.
• Fosfomycin and Colistin: never alone, the last resort antibiotics for
multidrug-resistant P. aeruginosa, and A. baumanni. Colistin resistance is
quite common in Indian isolates from aniamls.
• Tigecycline: effective for in Enterobacteriaceae and Acinetobacter spp.
Seems to be one of the best option for veterinary cases in India.
29. Herbal drugs can modulated action of some of the
potential drugs which can be used for treatment of
infections with ESBL, MBL and MDR strains
Colistin antibacterial activity enhanced by Cinnamon oil
E. coli 26
Bacillus 7
Enterobacter 3
Pasteurella 3
Staphylococcus 5
Streptococcus 1
Colistin antibacterial activity enhanced by Carvacrol
E. coli 1
Bacillus 5
Micrococcus 1
Flavobacter 1
Staphylococcus 3
Streptococcus 1
Imipenem antibacterial activity on Carbapenemase positive strains enhanced by Carvacrol
E. coli 5
Imipenem antibacterial activity on Carbapenemase positive strains enhanced by Cinnamon oil
E. coli 10
30. Newer areas of Resaerch
• Search for clinically usable modulators of carbapenem
drugs: Till date no clinically usable inhibitor of MBLs is
known. ESBLs can be managed due to availability of
clinically usable inhibitors- Sulbactam, Tazobactam,
Clavulanic acid).
• Expoloitation of herbal drugs for their role as
antimicrobial drug modulators. There are indications that
some herbs can modulate the effect of antimicrobials
including carbapenems and drugs of last resort as colistin
and polymyxin B. If we can reduce the effective dose of
these potentially toxic drugs it can be miracle.
• Finding the ways for clinical use of herbal oils to treat
infections: Herbal oils can inhibit growth of ESBL/
carbapenemase/ MBL producer strains in vitro.
31. Your Ideas!
• Welcome
• Anticipated
• Valued
• May be ice-breaking
• May change the life- Visionary
• May help to sustain the life
• May open new era of science and scientific
thinking.