This document discusses antimicrobial chemotherapy and antibiotic resistance. It provides definitions and principles related to antimicrobial agents, including their spectrum of activity, mechanisms of action against bacteria, and factors that influence antibiotic choice. The document addresses various classes of antibiotics like beta-lactams, glycopeptides, macrolides and their mechanisms. It also discusses concepts like minimum inhibitory concentration, combination therapy, and factors that can accelerate the development of antibiotic resistance.
Microbiology is the study of microorganisms.
The overall theme of the Microbiology course is to study the relationship between microbes and our lives.
Microorganisms (microbes) are organisms that are too small to be seen with the unaided eye, and usually require a microscope to be seen.
This relationship involves harmful effects such as diseases and food spoilage as well as many beneficial effects.
Microbiology is the study of microorganisms.
The overall theme of the Microbiology course is to study the relationship between microbes and our lives.
Microorganisms (microbes) are organisms that are too small to be seen with the unaided eye, and usually require a microscope to be seen.
This relationship involves harmful effects such as diseases and food spoilage as well as many beneficial effects.
Antibiotics and their Classification, Beta LactamsZunaira Gillani
Description about some major Classes of antibiotics, beta lactams, antiobiotics acting on cell wall, antibiotics acting on cell membrane, antibiotics acting on protein synthesis, inhibitors of metabollites
Mechanism of action of major antibiotic classes including betal lactam agents, aminoglycosides, macrolides, tetracyclines, quinolons, vancomycin, oxazolidionons. Detailed review and illustrations
Antibiotics and their Classification, Beta LactamsZunaira Gillani
Description about some major Classes of antibiotics, beta lactams, antiobiotics acting on cell wall, antibiotics acting on cell membrane, antibiotics acting on protein synthesis, inhibitors of metabollites
Mechanism of action of major antibiotic classes including betal lactam agents, aminoglycosides, macrolides, tetracyclines, quinolons, vancomycin, oxazolidionons. Detailed review and illustrations
Antimicrobial Chemotherapy
• Use of drugs to combat infectious agents
• Antibacterial
• Antiviral
• Antifungal
• Antiparasitic
Antimicrobial Chemotherapy
• Differential(selective) toxicity: based on the concept that
the drug is more toxic to the infecting organism than to the
host
• Majority of antibiotics are based on naturally occurring
compounds
• or may be semi-synthetic or synthetic
What is the ideal antibiotic
• Have the appropriate spectrum of activity for the clinical
setting.
• Have no toxicity to the host, be well tolerated.
• Low propensity for development of resistance.
• Not induce hypersensitivies in the host.
What is the ideal antibiotic
• Have rapid and extensive tissue distribution
• Have a relatively long half-life.
• Be free of interactions with other drugs.
• Be convenient for administration.
• Be relatively inexpensive
Principles / Definitions
• Spectrum of Activity:
Narrow spectrum - drug is effective against a limited
number of species
Broad spectrum - drug is effective against a wide variety of
species
• Gram negative agent
Gram positive agent
Anti-anaerobic activity
Minimum Inhibitory Concentration (MIC)
- minimum concentration of antibiotic required to inhibit the growth of
the test organism.
• Minimum Bactericidal Concentration (MBC)
- minimum concentration of antibiotic required to kill the test
organism.
• Bacteriostatic
• Bactericidal
• Time dependent killing
• Concentration dependent killing
Principles / Definitions
• Treatment & prophylaxis
• Prophylaxis - antimicrobial agents are administered to
prevent infection
• Treatment - antimicrobial agents are administered to cure
existing or suspected infection
1. chemotherapy principles and problems JagirPatel3
The objective of chemotherapy is to study and to apply the drugs that have highly selective toxicity to the pathogenic microorganisms in the host body and have no or less toxicity to the host, so as to prevent and cure infective diseases caused by pathogens
2021 laboratory diagnosis of infectious diseases dr.ihsan alsaimarydr.Ihsan alsaimary
2021 laboratory diagnosis of infectious diseases
dr. ihsan alsaimary
university of basrah - college of medicine- DEPARTMENT OF MICROBIOLOGY
POBOX 696 ASHAR
BASRAH 42001
IRAQ
Src jbbr-21-125 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Src jbbr-20-120 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Doi10.18535ijmsciv7i11.06 Dr. ihsan edan abdulkareem alsaimary PROFESSOR I...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Assessment of immunomolecular_expression_and_prognostic_role_of_tlr7_among_pa...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Estimation of Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL MICR...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Tolerance & autoimmunity and organ specific autoimmune diseasesdr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Pathogenesis of microbial infections dr. ihsan alsaimarydr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
3. Antimicrobial Chemotherapy
Differential toxicity: based on the concept that the
drug is more toxic to the infecting organism than to
the host
Majority of antibiotics are based on naturally
occurring compounds
or may be semi-synthetic or synthetic
4. What is the ideal antibiotic
Have the appropriate spectrum of activity for the clinical
setting.
Have no toxicity to the host, be well tolerated.
Low propensity for development of resistance.
Not induce hypersensitivies in the host.
Have rapid and extensive tissue distribution
Have a relatively long half-life.
Be free of interactions with other drugs.
Be convenient for administration.
Be relatively inexpensive
5. Principles / Definitions
Spectrum of Activity:
Narrow spectrum - drug is effective against a limited
number of species
Broad spectrum - drug is effective against a wide
variety of species
Gram negative agent
Gram positive agent
Anti-anaerobic activity
6. Principles / Definitions
Minimum Inhibitory Concentration (MIC)
- minimum concentration of antibiotic required to inhibit the
growth of the test organism.
Minimum Bactericidal Concentration (MBC)
- minimum concentration of antibiotic required to kill the test
organism.
Bacteriostatic
Bactericidal
Time dependent killing
Concentration dependent killing
7. Principles / Definitions
Treatment vs prophylaxis
Prophylaxis - antimicrobial agents are
administered to prevent infection
Treatment - antimicrobial agents are administered
to cure existing or suspected infection
8. Combination Therapy
To prevent the emergence of resistance
- M.tuberculosis
To treat polymicrobial infections
Initial empiric therapy
Synergy
Why not use 2 antibiotics all the time?
Antagonism
Cost
Increased risk of side effects
May actually enhance development of resistance
inducible resistance
Interactions between drugs of different classes
Often unnecessary for maximal efficacy
9. What influences the choice of antibiotic?
Activity of agent against proven or suspected organism
Site of infection
Mode of administration
Metabolism and excretion
renal and hepatic function
Duration of treatment / frequency of dose
Toxicity / cost
Local rates of resistance
10. How do antimicrobial agents work?
must bind or interfere with an essential
target
may inhibit or interfere with essential
metabolic process
may cause irreparable damage to cell
12. Antimicrobial resistance
Resistance: the inability to kill or inhibit
the organism with clinically achievable
drug concentrations
Resistance may be innate
(naturally resistant)
Resistance may be acquired
- mutation
- acquisition of foreign DNA
13. Antimicrobial resistance
Factors which may accelerate the
development of resistance
1- inadequate levels of antibiotics at the
site of infection
2- duration of treatment too short
3- overwhelming numbers of organisms
4- overuse / misuse of antibiotics
14. Antimicrobial resistance
General mechanisms of resistance
1-Altered permeability
2-Inactivation / destruction of antibiotic
3-Altered binding site
4-Novel (new) binding sites
5-Efflux (pumps) mechanisms
6-Bypass of metabolic pathways
18. Cell Wall Active Agents
B-lactams bind to “penicillin binding proteins”
(PBP)
-PBP are essential enzymes involved in cell wall
synthesis
-weakened / distorted cell wall leading to cell lysis
and death
Glycopeptides bind to the terminal D-ala of
nascent cell wall peptides and prevents cross-
linking of these peptide to form mature
peptidoglycan ( ex ; vancomycin)
19. Vancomycin: Mechanism of Action
Inhibit peptidoglycan synthesis in bacterial cell wall by
complexing with the D-alanyl-D-alanyl portion of the cell
wall precurser
2L-ala
2D-ala
D-ala-D-ala
UDP-L-ala-D-glu-L-lys
UDP-L-ala-D-glu-L-lys-D-ala-D-ala
pentapeptide--
racemase
ligase (ddl)
adding enzyme
--L-ala-D-glu-L-lys-
-D-ala-D-ala
vancomycin
-L-ala-D-glu-L-lys-D-ala-D-ala
transglycosidase
-L-ala-D-glu-L-lys-D-ala-D-ala
-L-ala-D-glu-L-lys-D-ala-D-ala
transpeptidase
-L-ala-D-glu-L-lys-D-ala-D-ala
carboxypeptidase
20. Cell Wall Active Agents
B-lactam resistance
1. Production of a B-lactamase (most common)
2. Altered PBP (S.pneumoniae)
3. Novel PBP (MRSA)
4. Altered permeability
Glycopeptide resistance
1- primary concern is Enterococcus / S.aureus
2- altered target
3- bacteria substitutes D-lac for D-ala
4- vancomycin can no longer bind
21. Cephalosporins
History
Discovered in sewage in Sardinia in
the mid 1940s.
Cephalosporium sp was recovered
and proved a source of
cephalosporin.
Subsequently, four generations of
cephalosporins have emerged.
23. First-Generation Cephalosporins: What
do they cover?
Cefazolin (Kefzol) and cephalexin (Keflex)
Activity includes:
○ Methicillin susceptible staphylococci
○ Streptococci excluding enterococci
○ E. coli, Klebsiella sp., and P. mirabilis
○ Many anaerobes excluding B. fragilis
24. Where do you think they should be used?
Simple mixed aerobic infections.
In penicillin allergic (not immediate) patients.
Surgical prophylaxis.
Convenience drug for S. aureus and
streptococci?
25. What about second generation
cephalosporins?
Cefuroxime
Think Haemophilus in
addition to 1st
generation specturm
A respiratory drug
Cefoxitin/cefotetan
1st generation plus-
anaerobes
A mixed, non-serious
infection surgeon drug
Think cefazolin/metro
which is what we
would use
26. Third-Generation Cephalosporins
Cefotaxime, ceftriaxone (IV)
Enhanced activity against Enterobacteriaceae
Enhanced activity against streptococci, including
penicillin resistant S. pneumoniae.
Long half life favors ceftriaxone
Less diarrhea favors cefotaxime
Ceftazidime (IV)
Active against P. aeruginosa.
Decreased activity against gram positive cocci.
28. Carbapenems:
What don’t they get?
Everything except:
MRSA and MRSE
Enterococcus faecium
Stenotrophomonas maltophilia
Burkholderia cepacia
29. When to use carbapenems?
Life threatening polymicrobial infections
Intra abdominal sepsis in ICU esp nosocomial
in origin
Gram negative/ nosocomial pneumonia in
intubated patient
Monotherapy of febrile neutropenia (high
risk patients)
30. What are the beta-lactamase inhibitors?
Clavulanate (with amoxicillin or ticarcillin)
Tazobactam (with piperacillin)
31. What additional bugs do they cover?
S. aureus
H. influenzae
Neisseria sp.
Bacteroides fragilis
E. coli and Klebsiella
Not better for Pseudomonas or
Enterobacter
32. Inhibitors of protein
synthesis
Ribosomes are the site of protein synthesis
many classes of antibiotics inhibit protein
synthesis by binding to the ribosome
binding may be reversible or irreversible
Macrolides, ketolides, lincosamides,
streptogramins
Tetracyclines
Aminoglycosides
33. Inhibitors of protein synthesis
Macrolides (erythromycin, clarithromycin, azithromycin)
- primarily gram positive, mycoplasma, chlamydia
- bacteriostatic, time dependent killing
Lincosamides (clindamycin)
- gram positive, anaerobic activity
Resistance (acquisition of a gene)
- M phenotype: macrolides only
efflux
- MLSB phenotype:
macrolides, lincosamides, streptogramins
target site modification
constitutive, inducible
34. Inhibitors of protein synthesis
Aminoglycosides: gentamicin, tobramycin,
amikacin
- excellent gram negative, moderate gram positive
- bactericidal, concentration dependent
Resistance
Primarily due to aminoglycoside modifying
enzymes
35. Inhibitors of nucleic acid synthesis
Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)
- bactericidal, concentration dependent
- bind to 2 essential enzymes required for DNA replication
- DNA gyrase and topoisomerase IV
- gram pos and gram neg
- atypical bacteria, some have anaerobic activity
Resistance
- altered permeability (porin channels)
- altered target site
- efflux
36. Inhibitors of metabolic pathways
Trimethoprim/sulfamethoxazole (Septra,
TMP/SMX)
- good gram negative, some gram positive
-block folic acid synthesis at two different
points
TMP and SMX act synergistically
Resistance may arise if the organism can
“bypass” the pathway making it redundant
38. 38
Antibiotic resistance
Major health challenge
Due to largely to inappropriate use of antibiotics
in hospitals and the community
Treating patients with viral infections with antibiotics
(common cold, flu, viral pneumonia, viral
gastroenteritis)
Using broad spectrum rather than narrow spectrum
antibiotics
Using new, special antibiotics to treat infections when
an older antibiotic would be effective
Use of antibiotics to improve growth &
production in animals
39. 39
We are running out of new
classes of antimicrobials
Antimicrobial class Year of launch
Sulphonamides 1936
Penicillins 1940
Tetracyclines 1949
Chloramphenicol 1949
Aminoglycosides 1950
Macrolides 1952
Glycopeptides 1958
Streptogramins 1962
Quinolones 1962
Oxazolidinones 2001
Cyclic lipopeptides 2003
Ketolides 2004
Glycylcyclines 2005
1969 – US Surgeon General said “It is time to close the book on
infectious diseases.”
40. 40
The resistance
“crisis”
No new classes of antibiotics in the pipeline
Some have been retrieved from animal use:
Streptogramins – SynercidR – to treat multi-drug
resistant Gram-positive infections
○ Concern that resistance already present because of animal use
Already resistance emerging to newly released
antimicrobials
Community acquired MRSA an emerging
problem
Now facing untreatable Gram-positive & Gram-
negative infections
41. 41
MMWR Morb Mortal Wkly Rep 2002;51:565–567
Evolution of drug resistance in
S. aureus
S. aureus Penicillin-resistant
S. aureus
Penicillin Methicillin
1950s 1970s
Methicillin-resistant
S. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
Vancomycin-
intermediate
S. aureus (VISA)
Vancomycin
-resistant
S. aureus (VRSA)
1990s
1997
2002
42. 42
Emergence of resistance in Gram-
negative bacteria
1960s - E coli and its relatives started to emerge
as problems
These rapidly developed resistance to ampicillin,
early cephalosporins, aminoglycosides
Multi-drug resistant (MDR) G-ves major problem in
hospitals in 1970s and 1980s
More antibiotics (aminoglycosides, extended
spectrum -lactamases, -lactam/ -lactamase-
inhibitor combinations, fluoroquinolones) –
situation improved
2000 - extended spectrum -lactamase producing
Gram-negatives (ESBLs) – untreatable infections
43. 43
What enables a bacterium to
become resistant to an
antibiotic?
Some organisms are naturally resistant to some classes of
antibiotics (natural or intrinsic resistance)
Mutation continually occurring in bacterial genomes (all
genomes!)
Mutation of key genes important to the action of an antimicrobial
can result in resistance in that organism to that antimicrobial
This resistance may evolve before the organism has been
exposed to that antimicrobial
So, resistance determinants that have always been present in
bacteria
Antibiotic producing strains of bacteria (note that resistance
genes have been found in antibiotic preparations …)
Soil and gut organisms
Bacterial housekeeping proteins eg efflux pumps
44. 44
How does antibiotic resistance come
about?
Use of antibiotics selects out the
(low) number of resistant strains –
they multiply – the sensitive strains
die out – the population of bacteria is
resistant …….
So antibiotic resistant strains of
bacteria emerge under the selection
pressure from use of antibiotics
46. 46
Types of antibiotic resistance
Natural resistance - particular microbes are inherently resistant to particular
agents – eg multi-drug efflux pumps in Pseudomonas aeruginosa, aminoglycoside
resistance in strict anaerobes; inability of penicillin G to penetrate Gram-negative
cell wall
Acquired resistance involves bacteria becoming resistant to a drug that was
previously effective. eg multi-drug resistance in Mycobacterium tuberculosis,
fluoroquinolone resistance in Neisseria gonorrhoeae, methicillin resistance in
Staphylococcus aureus and penicillin resistance in Streptococcus pneumoniae
Multiple resistance of particular concern
Acquired resistance occurs in response to exposure of bacteria to antibiotics
Mutational change and resistance passed to progeny
Horizontal transfer of resistance genes
47. 47
Antibiotic resistance
Examples of natural or intrinsic resistance
1-Inaccessibility of the target (i.e.
impermeability resistance due to the absence
of an adequate transporter: aminoglycoside
resistance in strict anaerobes)
2-Multidrug efflux systems: i.e. AcrE in E. coli,
MexB in P. aeruginosa
3-Drug inactivation: i.e. AmpC
cephalosporinase in Klebsiella
48. 48
Antibiotic resistance
Examples of acquired resistance
1-Target site modification (i.e. Streptomycin
resistance: mutations in rRNA genes (rpsL), ß-
lactam resistance: change in PBPs (penicillin
binding proteins))
2-Reduced permeability or uptake
3-Metabolic by-pass (i.e trimethoprim resistance:
overproduction of DHF (dihydrofolate) reductase
or thi- mutants in S. aureus)
4-Derepression of multidrug efflux systems
49. 49
Antibiotic resistance
Examples of horizontal transfer of resistance genes
1-Mobile genetic elements – transposons & plasmids)
2-Drug inactivation (i.e. aminoglycoside-modifying
enzymes, ß-lactamases, chloramphenicol
acetyltransferase)
3-Efflux system (i.e. tetracycline efflux)
4-Target site modification (i.e. methylation in the 23S
component of the 50S ribosomal subunit: Erm
methylases)
5-Metabolic by-pass (i.e trimethoprim resistance:
resistant DHF reductase)
50. 50
Five strategies of antimicrobial
resistance
1. Antibiotic modification - the bacteria avoids the
antibiotic's deleterious affects by inactivating the antibiotic.
eg : production of B lactamases
2. Prevention of antibiotic entry into the cell - Gram –ve
bacteria - porins are transmembrane proteins that allow
for the diffusion of antibiotics through their highly
impermeable outer membrane. Modification of the porins
can bring about antibiotic resistance,
eg : Pseudomonas aeruginosa resistance to imipenem.
3. Active efflux of antibiotic - Bacteria can actively pump
out the antibiotic from the cell.
eg : energy dependent efflux of tetracyclines widely seen
in Enterobacteriaceae.
51. 51
Five strategies of antimicrobial
resistance
4. Alteration of drug target - Bacteria can also evade
antibiotic action through the alteration of the compound's
target.
eg : Streptococcus pneumoniae modified penicillin-
binding protein (PBP) which renders them resistant to
penicillins.
5. Bypassing drug's action - bacteria can bypass the
deleterious effect of the drug while not stopping the
production of the original sensitive target.
eg : alternative PBP produced by MRSA in addition to the
normal PBP;
sulfonamide-resistant bacteria that have become able to
use environmental folic acid like mammalian cells, and in
this way bypass the sulfonamide inhibition of folic acid
synthesis.
52. 52
Resistant mechanisms against the
major classes of antibiotics
antibiotics Mechanism of action Major resistance
mechanisms
-lactams Inactivate PBPs
(peptidoglycan
synthesis)
•-lactamases
•Low affinity PBPs
•Decreased transport
Glycopeptides Bind to precursor of
peptidoglycan
•Modification of
precursor
Aminoglycosides Inhibit protein synthesis
(bind to 30S subunit)
•Modifying enzymes
(add adenyl or PO4)
Macrolides Inhibit protein synthesis
(bind to 50S subunit)
•Methylation of rRNA
•Efflux pumps
Quinolones Inhibit topoisomerases
(DNA synthesis)
•Altered target enzyme
•Efflux pumps
53. 53
Mosaic PBP Genes in penicillin-resistant
Strep pneumoniae
Resistance is due to alterations in endogenous PBPs
Resistant PBP genes exhibit 20-30% divergence from sensitive
isolates (Science 1994;264:388-393)
DNA from related streptococci taken up and incorporated into S.
pneumoniae genes
Czechoslovakia (1987)
USA (1983)
South Africa (1978)
S SXN
= pen-sensitive S. pneumoniae = Streptococcus ?
PBP 2B
http://www.uhmc.sunysb.edu/microbiology/35
Target modification
54. 54
vanR vanY
vanS vanH vanA vanX vanZ
Vancomycin resistance gene sequence
Detects
glycopeptide;
switches on other genes
Cleaves
D-Ala-D-Ala
Produces D-Lac *Cleaves
D-Ala and
D-Lac from
Produces
D-Ala-D-Lac
Exact role?
Teicoplanin
resistance?
Resistance to vancomycin
Seven-step gene co-operation
Involves activity of resolvase, transposase and ligase
enzymes
Alters pentapeptide precursor end sequence from
D-alanyl-D-alanine to D-alanyl-D-x, where x is lactate, serine
or other amino acid
Or produces (vanY) tetrapeptide* that cannot bind
vancomycin
Target modification
56. 56
Examples of -lactamases
Group of
enzyme
Preferred substrate Inhibited
by
clavulanat
e
Representative
enzymes
1 cephalosporin - AmpC (G-ves)
2a penicillins + Penicillinases from
G+ves
2b Penicillins,
cephalosporins
+ TEM-1, TEM-2, SHV-
1 (G-ves)*
2be Penicillins,
cephalosporins,
monobactams
+ TEM-3 to TEM 26
2br penicillins +/- TEM-30 to TEM-36
2c Penicillins,
carbenicillin
+ PSE-1, PSE-3, PSE-
4
*Plasmid encoded (TEM, PSE, OXA, SHV)
57. 57
Enzyme modification of
antibiotics
Inactivation of aminoglycosides
Chemical inactivation
1- performed by enzymes produced by the
bacteria
2- three distinct classes based upon the
reactions that they catalyse:
(i) acetyltransferases which acetylate amino
groups on the aminoglycoside;
(ii) nucleotidyltransferases which transfer a
nucleotide moiety onto the drug, and
(iii) phosphotransferases which phosphorylate
one or more hydroxyl groups on the antibiotic.
58. 58
Multi-drug Efflux Pumps
Bacteria use ATP-powered membrane proteins to pump
foreign molecules out of the cell
- common in antibiotic-producing bacteria, to get substances out
of their cells without poisoning themselves
Powerful method of resistance, because many different drugs
will be equally affected by these efflux pumps
Examples: tetracyclines, macrolides, quinolones
60. 60
Transfer of antibiotic
resistance (horizontal
transfer of DNA)
Transformation
Conjugation
Transduction
Of these conjugation is the most
important
R plasmids
Transposons & integrons
65. 65
Examples of major antibiotic resistance
problems
Hospital
Methicillin resistant Staphylococcus aureus
(MRSA) – hospital and community acquired
Vancomycin resistant enterococci (VRE)
Multi-resistant Gram-negative bacteria (eg
Acinetobacter baumannii, many others
Community
Community acquired MRSA
Penicillin-resistant Streptococcus pneumoniae
Multi-drug resistant Mycobacterium tuberculosis
66. Antibiotic resistance in food-
borne organisms
Salmonella, Shigella,
Campylobacter,
Enterococcus spp, multi-
drug resistant E coli (and
salmonella)
67. 67
Strategies to reduce antibiotic
resistance
1. Hospitals
1-Improved infection control
2-Implement and enforce hospital policies
for prescribing antibiotics
Monitor antibiotic use
3-Use narrow spectrum antibiotics where
possible
4-Combined therapy where appropriate
5-Monitoring and surveillance of antibiotic
resistance patterns
6-Vaccines where available
68. 68
Strategies to reduce antibiotic
resistance
2. Community
1-Education of doctors and patients
eg : no antibiotics for simple viral infections
2-Vaccines where possible – Haemophilus
influenzae type b (Hib), Streptococcus
pneumoniae (pneumococcus)
3-Combined therapy for TB
4-Research - eg : to understand the
epidemiology of community acquired MRSA
69. Strategies to reduce antibiotic
resistance
3. Food borne infections
1-Reduce prevalence of salmonella, campylobacter on
farms
2-Reduce contamination of carcasses with faecal
material (salmonella, campylobacter, enterococci)
3-Reduce post-processing contamination (salmonella)
4-Reduce contamination of fresh produce (salmonella)
5-Improved hygiene in food handling and preparation in
home and in community (salmonella, shigella,
campylobacter)
6-Reduce antibiotic use on farms
70. 70
Common misuses of
antibiotics
1. the patient does not have an infection
2. the infection does not respond to antibiotics - eg viral
infections
3. the latest "wonder drug" is used when an older product
would be effective
protecting the new product for situations where it is really
needed
4. the patient "prescribes" for him/herself - using antibiotics
left over from a previous illness
5. in countries with poor health care services antibiotics
are sold without prescription
6. use of antibiotics for non-therapeutic purposes – eg
growth promotion or improved production in livestock
71. Alternatives to antibiotics
Probiotics, prebiotics & competitive exclusion
organisms
Reduce pathogenic microorganisms in animal GIT
Bacteriophages
Potential to use to control campylobacter, salmonella
Natural products – eg tea tree or eucalyptus oils
Bacteriocins
Vaccines
72. 72
Resistance to antiviral drugs
This is often a big problem – especially with RNA
viruses
Resistant mutants arise spontaneously (even in the
absence of drug) and are selected,
eg acyclovir-resistant mutants are unable to phosphorylate the
drug (TK mutants) or,
do not incorporate the phosphorylated drug into DNA (pol
mutants)
To overcome resistance it is crucial to use drugs at
sufficient concentration to completely block replication
The use of more than one drug, with more than one
target, reduces significantly the emergence of resistant
mutants
73. 73
Anti-protozoan resistance
Mechanisms
alteration in cell permeability
modifications of drug sensitive sites
increased quantities of the target enzyme
Means of development in protozoa
Physiological adaptations.
Differential selection of resistant individuals from a
mixed population of susceptible and resistant
individuals.
Spontaneous mutations followed by selection.
Changes in gene expression (gene amplification).
74. 74
Some useful and interesting web
sites
Communicable Disease Centre USA
http://www.cdc.gov/drugresistance/
World Health Organisation
http://www.who.int/drugresistance/en/
Australia
http://www.healthinsite.gov.au/topics/Ant
ibiotic_Resistance