抗生素的将来？(英文PPT)What future for antibiotics？
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抗生素的将来(英文)What future for antibiotics
“Natural selection makes antibiotic resistance inevitable, rendering any antibiotic less profitable over time; the situation is exacerbated by the overuse and misuse of currently available antibiotics.” Stephen J. Projan, 43rd ICAAC, Chicago 2003
– Central role in microbial physiology – High conservation among various pathogens – Enzyme assays suitable for high through-put
screening – Numerous targets must exist?
Emergence of antibiotic resistance by selective pressure
• EDG Murray (1917 – 1954) strain collection
– ‘pre-antibiotic era’ isolates of enteric bacteria practically fully sensitive to a range of antibiotics
Hospital-acquired infections to drugresistant bacteria (USA 2002)
Pathogen
Antibiotic
Estimated cases
Staphylococcus aureus Coag –ve staphylococci
– Central role in microbial physiology – High conservation among various pathogens – Enzyme assays suitable for high through-put
screening – Numerous targets must exist?
Emergence of antibiotic resistance by selective pressure
• EDG Murray (1917 – 1954) strain collection
– ‘pre-antibiotic era’ isolates of enteric bacteria practically fully sensitive to a range of antibiotics
Hospital-acquired infections to drugresistant bacteria (USA 2002)
Pathogen
Antibiotic
Estimated cases
Staphylococcus aureus Coag –ve staphylococci
抗生素的将来？(英文PPT)What future for antibiotics？
Mechanism of resistance
b-lactams Glycopeptides Aminoglycosides Tetracyclines Chloramphenicol Macrolides Fusidic acid Oxazolidinones Quinolones Rifampicin
b-Lactams - mode of action
OH
RN H
O
D-Ala-D-Ala
O
R
HN H
NH O
COOH
HO
Amoxicillin
O H N
NH2 O
S CH3
N
CH3
COOH
•
Is the emergence of antibiotic resistance inevitable?
1950
1960
MRSA
methicillin resistance
1970
Epidemic 1980 strains 1990 1996 2000 2002
gentamicinresistant MRSA
GISA VRSA
MRSA in Europe (2002 data)
• Greece • UK • Germany
inhibit peptidoglycan synthesis
NAG
NAM
Glycopeptides
Bind terminal D-Ala-D-Ala Prevent subunit incorporation
NAG
NAM
NAG
NAM
NAG
NAM
Beta-Lactams
Bind ‘PBPs’ Prevent trans and carboxypeptidation
抗生素PPT课件(英文精品) ANTIBIOTIC PROPHYLAXIS in Premature Rupture of Membranes
Current evidence
• Recommend routine prescription of macrolide antibiotics in this clinical situation.
• The routine prescription of macrolide antibiotic (erythromycin) is recommended as beta lactum antibiotics (augmentin) is associated with a statistically significant increase in neonatal necrotising enterocolitis.
Current evidence
• 7 days of antibiotics, as proposed by the NICHD-MFMU study of PROM, should be the antibiotic regimen used in patients with PPROM who are being managed expectantly.
• The following markers of neonatal morbidity were reduced: neonatal infection,
• use of surfactant • oxygen therapy • and abnormal cerebral ultrasound scan prior to discharge
• When another antibiotic is being used for other indications, such as a urinary tract infection, attempts should be made to avoid duplicated therapy.
抗生素PPT课件(英文精品) Chemotherapeutic Agents Antibiotics
is n o t s u p p o rte d
M acintosh P IC T im age form at
is not supported
Chemotherapeutic Agents / Antibiotics, chapter 34-39
•Antibacterial compounds (procaryotes)
is not supported
M acintosh P IC T im age form at
is not supported
M acintosh P IC T im age form at
is not supported
M acintosh PICT im age form at
is not supported
Vorikonazol Flukonazol (Racemate)
M a c iIntratkoonaszol:h P I C T im a g e fo rm a t
is n o t s u p p o rte d
SAR: -Weakly basic azole ring, imidazol / 1,2,4-triazol (less tox. humans), pKa 6.5-6.8 -2 or 3 other aromatic rings -Cl (or F) on at least one aromatic ring (F i flukonazol) -Lipophilic structures (as lanosterol)
is n o t su p p o rted
Proad spectrum. Some effect on certain protozoa.
Isolated, Streptomyces sp.
M acintosh P IC T im age form at
is not supported
Chemotherapeutic Agents / Antibiotics, chapter 34-39
•Antibacterial compounds (procaryotes)
is not supported
M acintosh P IC T im age form at
is not supported
M acintosh P IC T im age form at
is not supported
M acintosh PICT im age form at
is not supported
Vorikonazol Flukonazol (Racemate)
M a c iIntratkoonaszol:h P I C T im a g e fo rm a t
is n o t s u p p o rte d
SAR: -Weakly basic azole ring, imidazol / 1,2,4-triazol (less tox. humans), pKa 6.5-6.8 -2 or 3 other aromatic rings -Cl (or F) on at least one aromatic ring (F i flukonazol) -Lipophilic structures (as lanosterol)
is n o t su p p o rted
Proad spectrum. Some effect on certain protozoa.
Isolated, Streptomyces sp.
抗生素的历史沿革及演变(英文PPT)UHCW NHS Trust Clostridium difficile rates 2002 - 2005
Antimicrobial resistance
• Multiple resistance genes
• Plasmids • Spread
• Factors leading to resistance:
– Inappropriate clinical use of ABx – Poor infection control – Excessive ABx use in non clinical settings:
A bit of background A potted history of Antibiotics
• The use of antimicrobials in the treatment of infection is one of the triumphs of modern medicine.
Coventry and Warwickshire Pathology
History of Antibiotics
Decade 1940s & 1950s
1960s 2000s
Antibiotics Streptomycin Synthetic penicillins Cephalosporins Chloramphenicol
Jul-10 Aug-10 Sep-10 Oct-10 Nov-10 Dec-10 Jan-11 Feb-11 Mar-11
£3,000 £2,500 £2,000 £1,500 £1,000
£500 £0
Expenditure
Diagnostics and Service Division Medicine and Emergency Division Rugby St Cross Specialised Networks Division Surgery Division Women and Childrens TRUST TOTAL
抗生素 (英文PPT)ANTIBIOTICS
*Treatment of chronic adult periodontitis almost totally amenable to mechanical therapy.
*Administration instead of mechanical therapy for periodontitis.
✓ Unwanted effects ✓ Precautions ✓ Contraindications ✓ Patient’s point if view ✓ Patient
PATTERNS OF MISUSE
➢ They are used as “drugs of fear” to cover for potential errors of omission or commission & thereby prevent a claim of negligence.
PERIOD OF EMPIRICAL USE • Use of mouldy curd by chinese on boils •Chaulmoogra oil by hindus in leprosy •Chenopodium by aztecs for intestinal worms •Mercury by paracelsus for syphilis •Cinchona bark for fevers
•NON-EFFECTIVE CONDITIONS IN DENTISTRY
•NEWER ANTI-MICROBIAL APPROACHES
•MACROLIDES
•ANTIBIOMA
•MISCELLANEOUS ANTIBIOTICS
•ANTI FUNGALS &ANTI VIRAL DRUGS
*Administration instead of mechanical therapy for periodontitis.
✓ Unwanted effects ✓ Precautions ✓ Contraindications ✓ Patient’s point if view ✓ Patient
PATTERNS OF MISUSE
➢ They are used as “drugs of fear” to cover for potential errors of omission or commission & thereby prevent a claim of negligence.
PERIOD OF EMPIRICAL USE • Use of mouldy curd by chinese on boils •Chaulmoogra oil by hindus in leprosy •Chenopodium by aztecs for intestinal worms •Mercury by paracelsus for syphilis •Cinchona bark for fevers
•NON-EFFECTIVE CONDITIONS IN DENTISTRY
•NEWER ANTI-MICROBIAL APPROACHES
•MACROLIDES
•ANTIBIOMA
•MISCELLANEOUS ANTIBIOTICS
•ANTI FUNGALS &ANTI VIRAL DRUGS
抗生素PPT课件(英文精品) Miscellaneous Antibiotics
Diarrhea , nausea, Skicolitis Impaired liver function Neutropenia ( not common )
Vancomycin
Bactericidal
Inhibits bacterial cell wall synthesis
Bacitracin
Bactericidal Inhibits cell wall synthesis Active against gram +ve organisms
associated enterocolitis
Adverse effects
Phlebitis at the site of infusion Fever Ototoxicity & nephrotoxicity ( not common). Red man or red neck syndrome. Hypotension
tissues except brain &CSF. Penetrates well into abscess & is taken up
by phagocytic cells.
Metabolized by the liver.
Both active drug & active metabolites are excreted in bile & urine
infections. Widely distributed Cerebrospinal fluid levels are achieved in
meningeal inflammation Excreted mainly through renal route
Vancomycin
Bactericidal
Inhibits bacterial cell wall synthesis
Bacitracin
Bactericidal Inhibits cell wall synthesis Active against gram +ve organisms
associated enterocolitis
Adverse effects
Phlebitis at the site of infusion Fever Ototoxicity & nephrotoxicity ( not common). Red man or red neck syndrome. Hypotension
tissues except brain &CSF. Penetrates well into abscess & is taken up
by phagocytic cells.
Metabolized by the liver.
Both active drug & active metabolites are excreted in bile & urine
infections. Widely distributed Cerebrospinal fluid levels are achieved in
meningeal inflammation Excreted mainly through renal route
抗生素的过去、现在与将来(英文PPT)Antibiotics Past, Present and Future
Landmarks continued…..
• 1940: Oxford University pathologist Howard Florey isolates pure penicillin and demonstrates how it can cure a wide range of pathogens, including strep infections, gonorrhea and syphilis.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1976: Several weeks after attending an American Legion convention in Philadelphia, 34 people die from a mysterious form of pneumonia that thwarts available treatments and comes to be known as Legionnaires’ disease.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1988-95: Studies in Finland, the Netherlands and other European Countries find increasing drug resistance in farm animals. Many of the livestock are fed antibiotics as growthpromoters.
抗生素PPT课件(英文精品) Antibiotics and Pain Control
– Fullen, et al.
• Both the timing and the choice are important.
– Thadepalli, et al.
What Bugs?
• Yom Kippur War
– Pseudomonas – 25.6% isolates – Gm Neg bacilli – 70% isolates overall
General Preventive Measures
• Adequate and Timely Resuscitation
• Early Wound Care • Antibiotics • Tetanus Immune Prophylaxis
Adequate and Timely Resuscitation
Why not?!
• Antibiotics not routinely given in the field by civilian pre-hospital personnel (EMT/paramedic model for
medic training).
• Combat medics don’t typically see wound infections during the time they care for them – may not appreciate their devastating effect.
• Debridement
– excise devitalized tissue
• Irrigation
– high pressure, solution
• Eliminate Dead Space
– fluid, blood
• Both the timing and the choice are important.
– Thadepalli, et al.
What Bugs?
• Yom Kippur War
– Pseudomonas – 25.6% isolates – Gm Neg bacilli – 70% isolates overall
General Preventive Measures
• Adequate and Timely Resuscitation
• Early Wound Care • Antibiotics • Tetanus Immune Prophylaxis
Adequate and Timely Resuscitation
Why not?!
• Antibiotics not routinely given in the field by civilian pre-hospital personnel (EMT/paramedic model for
medic training).
• Combat medics don’t typically see wound infections during the time they care for them – may not appreciate their devastating effect.
• Debridement
– excise devitalized tissue
• Irrigation
– high pressure, solution
• Eliminate Dead Space
– fluid, blood
抗生素PPT课件(英文精品) TOWARDS THE RATIONAL USE OF ANTIBIOTICS
A r g e n tin a Egypt
B r a s il
• Antibiotics are
Rw anda
prescribed in 79% of the
encounters with general
Ethiopia
pria
0% 10% 20% 30% 40% 50% 60%
may not be the clue. Soc Sci Med. 1996. 42(8): p1141-53
Determinants of irrational use (II)
Prescribers Lack of appropriate knowledge
Lack / delayed lab results, fear of clinical failures Inappropriate peer norms, local medical cultures Economic incentives
Avorn, J. and D.H. Solomon, Cultural and economic factors that (mis)shape antibiotic use: the nonpharmacologic basis of therapeutics. Ann Intern Med, 2000. 133(2): p. 128-35.
• An understanding of the determinants of antibiotic consumption is critical to explain current patterns of use and to devise programmes to improve their rational use.
B r a s il
• Antibiotics are
Rw anda
prescribed in 79% of the
encounters with general
Ethiopia
pria
0% 10% 20% 30% 40% 50% 60%
may not be the clue. Soc Sci Med. 1996. 42(8): p1141-53
Determinants of irrational use (II)
Prescribers Lack of appropriate knowledge
Lack / delayed lab results, fear of clinical failures Inappropriate peer norms, local medical cultures Economic incentives
Avorn, J. and D.H. Solomon, Cultural and economic factors that (mis)shape antibiotic use: the nonpharmacologic basis of therapeutics. Ann Intern Med, 2000. 133(2): p. 128-35.
• An understanding of the determinants of antibiotic consumption is critical to explain current patterns of use and to devise programmes to improve their rational use.
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Mechanism of resistance
b-lactams Glycopeptides Aminoglycosides Tetracyclines Chloramphenicol Macrolides Fusidic acid Oxazolidinones Quinolones Rifampicin
b-Lactams - mode of action
OH
RN H
H
O H
N
O
O
D-Ala-D-Ala
O
R
HN H
NH O
COOH
HO
Amoxicillin
O H N
3
COOH
•
Is the emergence of antibiotic resistance inevitable?
Pseudomonas aeruginosa
Escherichia coli
Pseudomonas aeruginosa
methicilli n
methicilli n
vancomyc in
ceftazidim e
ampicillin
imipenem
102,000 130,000 26,000 12,000 65,000 16,000
1950
1960
MRSA
methicillin resistance
1970
Epidemic 1980 strains 1990 1996 2000 2002
gentamicinresistant MRSA
GISA VRSA
MRSA in Europe (2002 data)
• Greece • UK • Germany
Evolution of antibiotic resistance in Staphylococcus aureus
penicillin
oxacillin, flucloxacillin methicillin
vancomycin teicoplanin
1940
Penicillin resistance
What future for antibiotics?
Anthony W. Smith, BPharm, PhD, MRPharmS Dean
The School of Pharmacy University of London
World Health
Antibiotic targets
• Peptidoglycan synthesis • Beta-lactams, glycopeptides
• RNA polymerase • Protein synthesis
• Aminoglycosides, tetracyclines, macrolides, oxazolidinones,
• Nucleic acid synthesis
• Fluoroquinolones
Beta-lactams and glycopeptides
Emergence of antibiotic resistance by selective pressure
• EDG Murray (1917 – 1954) strain collection
– ‘pre-antibiotic era’ isolates of enteric bacteria practically fully sensitive to a range of antibiotics
“Natural selection makes antibiotic resistance inevitable, rendering any antibiotic less profitable over time; the situation is exacerbated by the overuse and misuse of currently available antibiotics.” Stephen J. Projan, 43rd ICAAC, Chicago 2003
inhibit peptidoglycan synthesis
NAG
NAM
Glycopeptides
Bind terminal D-Ala-D-Ala Prevent subunit incorporation
NAG
NAM
NAG
NAM
NAG
NAM
Beta-Lactams
Bind ‘PBPs’ Prevent trans and carboxypeptidation
Antibiotics – mechanisms of resistance
• Alteration in target site • Alteration in access to the target site • Production of inactivating enzymes
Resistance to antibacterial agents
– 2/433 penicillin resistant – 9/433 tetracycline resistant
• Rapid emergence of resistance of the past 60 years
– Mutation – Genetic re-arrangement – Genetic resistance determinants – Resistance genes can be spread by horizontal transfer
Hospital-acquired infections to drugresistant bacteria (USA 2002)
Pathogen
Antibiotic Estimated cases
Staphylococcus aureus
Coag –ve staphylococci Enterococci
48.6% 44.5% 27.2%
• Spain
23.5%
• Belgium
19.2%
• Czech Republic 6.2%
• Netherlands 1.0%
• Sweden
0.7%
Source: European Antimicrobial Resistance Surveillance System