Transcript 幻灯片 1

antibacterial drugs
By
Dechang Zhang
Department of Pharmacology, School of
Basic Medicine, Peking Union Medical
College
History of antimicrobial therapy
Early
The first recorded successful use of antimicrobial
17th
therapy involving the use of an extract from cinchona
century bark for the treatment of malaria.
1909
Paul Ehrlich's quest for a "magic bullet" that would
bind specifically to particular sites on parasitic
organisms leads to an arsenic derivative, salvarsan,
with modest activity against syphilis. He also
suggested that antimicrobial drugs would be most
useful if the sites of action were not present in the
organs and tissues of the human host.
1929
Alexander Fleming discovers penicillin.
1935
Discovery of prontosil, a forerunner of sulfonamides.
1940
Florey and Chain first use penicillin clinically.
Principles of
antimicrobial use
12 Factors to consider when selecting
antimicrobial agents for therapy in
patients
1. Is an antimicrobial agent
necessary?
2. Identification of the pathogen
3. Empiric versus directed therapy
4. Susceptibility of infecting
microorganism
12 Factors to consider when selecting
antimicrobial agents for therapy in
patients
5. Need for bactericidal versus
bacteriostatic agent
6. Pharmacokinetic and
pharmacodynamic factors
7. Anatomical site of infection
8. Cost
9. Toxicity
12 Factors to consider when selecting
antimicrobial agents for therapy in
patients
10. Host factors
Allergy history
Age
Renal function
Hepatic function
Pregnancy status
Genetic or metabolic abnormalities
Host defenses function
12 Factors to consider when selecting
antimicrobial agents for therapy in
patients
11. Need for combination therapy
12. Antibiotic resistance concerns
1. Is an
antimicrobial
agent necessary?
• viral infections that do not
respond to antibiotics
• noninfectious processes
mimicking a bacterial infection
• culture isolation of an
organism that is colonizing
an anatomical site and not
causing an infection
In general, the clinician
should resist temptation to
begin antimicrobial therapy
unless there is a reasonable
probability that a bacterial
infection is present.
When the downside risk of
withholding therapy is great,
such as with bacterial meningitis
or in clinically unstable patients,
therapy should be started
without delay even when the
presence of a bacterial infection
is uncertain.
Another indication for
antimicrobials is prophylactic
therapy, which is intended to
prevent illness in someone at
risk of infection.
2. Identification
of the pathogen
Characterization of
the organism is
central to selection
of the proper drug.
Presence and
morphologic
features of
microoganisms
in body fluids
that are normally
sterile.
Culture the infective
organism to arrive
at a conclusive
diagnosis and to
determine the
susceptibility of
antimicrobial agents.
3.Empiric versus
directed therapy
The acutely ill patient with infections
of unknown origin
a neutropenic patient
a patient with severe headache, a
rigid neck, and sensitivity to bright
lights(meeningitis)
Therapy is initiated after
specimens for laboratory
analysis have been
obtained but before the
results of the culture are
available.
The choice of drug in the
absence of susceptibility
data
the site of infection
the patient's history
Broad-spectrum therapy
may be needed initially for
serious infections when
the identity of the organism
is unknown or the site
makes a polymicrobial
infection likely.
A gram-positive coccus in the spinal fluid
A newborn infant most likely to be Group B
Streptococcus.
sensitive to penicillin G.
A forty-year old patient most likely to be S.
pneumoniae.
frequently resistant to penicillin G, sensitive
to a third-generation cephalosporin or
vancomycin.
4.Need for bactericidal
versus
bacteriostatic agent
Bacteristatic drugs arrest the
growth and replication of
bacteria at serum levels
achievable in the patient, thus
limiting the spread of infection
while the body’s immune
system attachs, immoblilizes,
and eliminates the pathogens.
Bactericidal drugs kill
bacteria at drug serum
levels achievable in the
patient. They are more
aggressive compare
with bicteriostatic
antimicrobial drugs .
A given agent may show
bactericidal actions under
certain conditions but
bacteriostatic actions
under others, depending on
the concentration of drug
and the target bacteria.
A bacteriostatic agent often is
adequate in uncomplicated
infections because the host
defenses will help eradicate
the microorganism.
Bactericidal agents are
required for management of
infections in areas
"protected" from host immune
responses, such as
endocarditic vegetations and
cerebrospinal fluid (CSF).
5. Determination of
antimicrobial
susceptibility of
infective organisms
In the
laboratory,
susceptibility
is most often
measured
using a disk
diffusion
test
Stokes controlled sensitivity test
.
In the Stokes controlled
sensitivity test, a control
organism is inoculated on part
of a plate and the test organism
is plated on the remainder.
Disks are placed at the
interface and the zones of
inhibition are compared.
The use of a sensitive control
shows that the antibiotic is
active, so that if the test
organism grows up to the
disk it may safely be
assumed that the test
organism is resistant to that
drug.
An alternative measure of
susceptibility is to determine
the Minimum Inhibitory
Concentration (MIC) and
the Minimum Bactericidal
Concentration (MBC) of a
drug.
A series of broths are
mixed with serially
diluted antibiotic
solutions and a
standard inoculum is
applied. After
incubation, the MIC is
the first broth in which
growth of the organism
has been inhibited.
The more resistant
an organism is,
then the higher will
be the MIC.
The MBC is measured by
inoculating the broths used
for MIC determinations
onto drug-free medium.
The MBC is the first dilution
at which no growth is
observed.
Cidal drugs have MBC
values that are close to the
MIC value for particular
organisms. With static
agents, the MIC is much
lower than the MBC.
The MIC/MBC test of a moderately
resistant bacteriostatic drug.
Note that once the bacteria are removed
from the drug they can grow on drug free
medium at most concentrations.
The MIC/MBC test of a moderately
resistant bactericidal drug.
The bacteria removed from the drug cannot
grow on drug free medium.
One tube difference is allowed in this test.
6. Pharmacokinetic and
pharmacodynamic
factors
Oral
peak concentrations :
1 to 2 hours may be delayed
by food or delayed intestinal
transit vary widely in their oral
bioavailability
Most life-threatening
infections are treated, at
least initially, with IV agents.
Parenteral therapy ensures
adequate serum levels, and,
for many agents, higher
drug levels can be achieved
when administered IV.
The amount of drug that
reaches the extravascular
tissues and fluids depends
on :
● the
concentration gradient
between plasma and target
tissue,
degree of drug binding to
plasma and tissue proteins,
molecular size,
●
degree of ionization and
lipid solubility of the drug,
●
its rate of elimination or
metabolism.
●
concentration-dependent
killing
Fluoroquinolones and
aminoglycosides kill bacteria
faster at higher concentrations.
Post-antibiotic effect (PAE)
These agents also continue
to inhibit growth of bacteria
for several hours after the
concentrations of the drug
fall below the MIC in the
serum.
The Post-Antibiotic Effect
(PAE) shows the capacity of
an antimicrobial drug to inhibit
the growth of bacteria after
removal of the drug from the
culture.
To determine the PAE a liquid
culture with an initial count of
106 to 107 colony forming units
(CFU) per ml is exposed to a
certain concentration of the
drug for a certain time. A
control group is left untreated.
After the given time, drug of the
treated culture is removed, e.g., by
dilution 1:1000 in fresh, drug-free
medium. The same procedure is
applied to the untreated control. The
time it takes for both colonies to
increase their CFU by 1 log10 is
measured.
PAE is defined as the time
needed by a culture that was
treated with an antibiotic to
increase in number (CFU) by 1
log10 compared to untreated
controls, and is usually given in
hours.
The PAE provides additional
time for the immune system to
remove bacteria that might
have survived antibiotic
treatment before they can
eventually regrow after removal
of the drug from the animal's
organism.
A longer PAE can therefore
influence the clinical
outcome of antimicrobial
therapy.
Most β-lactam agents do
not exhibit concentrationdependent killing nor do
they have a prolonged
post-antibiotic effect.
7. Anatomical site
of infection
The site of infection often
influences not only the
agent used but also the
dose, route, and duration
of administration.
The desired peak
concentration of drug at the
site of infection should be at
least 4 times the MIC.
However, if host defenses are
adequate, peak oncentrations
may be much lower and even
be equal to the MIC and still
be effective.
When host defenses are
absent or inoperative, peak
concentrations 8- to 16-fold
greater than the MIC may be
required.
Blood-Brain
Barrier
1.Lipid solubility
(quinolones vs penicillin)
2.Molecular weight
(vancomycin)
3.Protein binding
Readily Enter CSF
Chloramphenicol
Sulfonamides
Trimethoprim 甲氧苄氨嘧啶
Rifampin
利福平
Metronidazole 甲硝唑
Enter CSF When Inflammation Present
Penicillin G
Ampicillin氨苄西林
Piperacillin哌拉西林
Oxacillin苯唑西林
Nafcillin萘夫西林
Cefuroxime头孢呋辛
Cefotaxime头孢噻肟
Ceftriaxone 头孢曲松
Ceftazidime头孢他定
Aztreonam氨曲南
Ciprofloxacin环丙沙星
Vancomycin万古霉素
Meropenem美罗培南
Cefepime头孢平
Do Not Enter CSF Adequately to
Treat Infection
Cefazolin 头孢唑啉
Cefoxitin头孢西丁
Erythromycin乙琥红霉素
Clindamycin克林霉素
Tetracycline 四环素
Gentamicin庆大霉素
Tobramycin 妥布霉素
Amikacin阿米卡星
Endocarditis Meningitis
Osteomyelitis
foreign body
abscesses
organisms that can survive
within phagocytic cells
(Mycobacterium, Salmonella)
8. Cost
9. Toxicity
Because of nephrotoxicity
and ototoxicity,
aminoglycoside use has
decreased with the
development of β-lactams
and fluoroquinolones with
broad gram-negative
activity.
10. Host factors
Allergy history
Significant allergy
appears to be more
common with β-lactams,
particularly penicillins, and
sulfonamides.
In anaphylactic reactions to
penicillins, the IgE antibody is
usually directed at the
penicillin nucleus, so the
potential for allergic reactions
to other penicillins is high.
Age
Renal function
Antimicrobial agents that require
dosage adjustment include
aminoglycosides, vancomycin,
certain penicillins, most
cephalosporins,
carbapenems(碳青霉烯类), and
quinolones.
Failure to adjust dosage can
lead to ototoxicity from
aminoglycosides and
neurotoxicity from penicillins,
imipenem, or quinolones.
Aminoglycosides can cause
renal toxicity and should be
used with caution in patients
with preexisting renal
insufficiency.
aminoglycosides
vancomycin
certain penicillins
most cephalosporins
carbapenems 碳青霉烯类
quinolones
Hepatic function
Antimicrobials metabolized in
the liver include
chloramphenicol, erythromycin,
clarithromycin, rifampin,
nitroimidazoles, and some of
the quinolones.
Pregnancy status
Agent
Potential Toxicity
Sulfonamides Hemolysis in newborn with
glucose-6-phosphate
dehydrogenase deficiency;
Tetracyclines
Trimethoprim
Limb abnormalities, dental
staining, inhibition of bone
growth
Altered folate metabolism
Quinolones
Abnormalities of cartilage
Vancomycin
Possible auditory toxicity
Agent
Aminoglycosides
Potential Toxicity
Eighth nerve damage
Chloramphenicol
Gray baby syndrome
Erythromycin
estolate
Cholestatic hepatitis (胆汁
淤积性肝炎) in mother
Metronidazole
Possible teratogenicity 致
畸性
Nitrofurantoin
Hemolytic anemia
Genetic or
metabolic
abnormalities
Genetic abnormalities of
enzyme function may alter
the toxicity of certain agents.
hemolysis in glucose-6phosphate dehydrogenasedeficient people can be
provoked by sulfonamides,
nitrofurantoin, pyrimethamine
(乙胺嘧啶), sulfones(砜), and
chloramphenicol.
Host defenses
function
An absence of white blood cells
predisposes a patient to serious
bacterial infection, and
bacteriostatic agents are often
ineffective in treating serious
infections in neutropenic hosts.
The critical white blood cell
count is between 500 and 1000
mature polymorphonuclear
3
cells/mm .
11. Antimicrobial
combinations
 To treat a life-threatening infection
 To treat a polymicrobial infection
 Empiric therapy when no one agent is
active against potential pathogens
 To achieve synergy (obtain enhanced
antibacterial activity)
 To prevent the emergence of resistant
bacteria
 To permit the use of a lower dose of one
of the antimicrobial agents
Box 44-3 Reasons for concurrent use of more than one antimicrobial agent in a patient
indifferent effects
The combined activity equals
the sum of the separate
activities.
Synergism ( 协同) is present if
the activity of the combined
antimicrobial agents is greater
than the sum of the independent
activities.
Combinations of antibiotics are
antagonistic when the activity
of the combination is less than
could be achieved by using the
agents separately.
The combination of an
inhibitor of cell-wall synthesis
with an aminoglycoside
antibiotic
The combination of agents
acting on sequential steps
in a metabolic pathway
The combination of agents
in which one (such as an
inhibitor of β-lactamases)
inhibits an enzyme that
inactivates the other
compound, such as
clavulanate with amoxicillin
Antibiotic decision
making after therapy
has started
Infection
Duration (days)
Streptococcal pharyngitis 10
Otitis media 中耳炎
5-10
Sinusitis 鼻窦炎
10
Uncomplicated urinary
tract infection
3
Pyelonephritis 肾盂肾炎
14
Cellulitis 蜂窝织炎
3 days after
inflammation
resolves
Infection
Pneumococcal
pneumonia
Other pneumonia
Duration (days)
3-5 days after fever
resolves
variable, often 14
Bacteremia
variable, often 10-14 days
without endocarditis
28-42
7-14
42
21
Endocarditis
Meningitis
Osteomyelitis
Septic arthritis
12. Antibiotic
resistance concerns
Prevalence of
antibiotic
resistant bacteria
Resistance in nosocomial
（医院） infections
• Nowadays, About 70 percent of
the bacteria that cause infections in
hospitals are resistant to at least
one of the drugs most commonly
used for treatment
Resistance in nosocomial
（医院）infections
• Some organisms are resistant to
all approved antibiotics and can
only be treated with experimental
and potentially toxic drugs (e.g.
MRSA耐甲氧金葡, Pseudomonas
假单胞)
Resistance in community
acquired infections
• Staphylococci - up to 60%
MRSA (Methicillin Resistant
Staph Aureus)
Resistance in community
acquired infections
• Pneumococci (Streptococcus
pneumoniae) - 25% resistant to
penicillin, while a further 25% are
resistant to more than one antibiotic
Resistance in community
acquired infections
• Mycobacterium tuberculosis 5% are multiple drug resistant
(MDR)
杨晓霞事件
1994年右手拇指局部感染抗生素治疗无效。
反复转院多次抗生素治疗，病情逐渐恶化直
至右手坏死3个月后截肢。创面继续感染。此
后，经首都13家医院的50 名中西医专家先后
两次会诊。几十次的细菌培养试验，伤口上
分离出12种细菌并且这些细菌已经对大多数
的抗生素产生了耐药性。其中有一种细菌对
59种药物和21种抗生素具有耐药性。
泰能
泰能含有两种成分：亚胺培南是新
型的β-内酰胺抗菌素-硫霉素，其特
性是杀菌谱较其它抗菌素广泛；西
司他丁钠盐为特异性酶抑制剂，它
可阻断亚胺培南在肾脏的代谢，继
而增加尿道中未经改变的亚胺培南
的浓度，本制剂之亚胺培南与西司
他丁钠盐的重量比率为1：1。
Antibiotic resistance can be
intrinsic or acquired.
Pseudomonas aeruginosa
outer membrane
Acquired resistance can be due
to mutation of existing genetic
information or acquisition of
new genes.
Spontaneous mutation
• mutation and selection of
antibiotic resistant mutants
in the presence of the antibiotic
• “vertical gene transfer” to progeny
results during normal cell division
Lateral or horizontal gene transfer
(HGT)
• genetic material contained in
small packets of DNA can
be transferred between individual
bacteria of the same species
or of different species
• Three mechanisms of HGT
Conjugation 接合
Transformation 转化
Transduction 转导
Conjugation:
occurs when
there is direct
cell-cell contact
between two
bacteria and
transfer of small
pieces of DNA
called plasmids
takes place
Transformation:
pieces of
DNA are taken
up from the
external
environment
Transduction:
bacteria-specific
viruses
(bacteriophages)
transfer DNA
between
two closely
related bacteria
Mechanisms of
bacterial resistance
to antibiotics
reduced uptake into cell
1. Reduced uptake into cell
2. Active efflux of antibiotic from the cell
3. Eliminate or reduce binding of antibiotic to
cell target
4. Enzymatic cleavage or chemical
modification inactivates antibiotic molecule
5. Metabolic bypass of inhibited reaction
6. Overproduction of antibiotic target
Reduced
uptake into cell
• Antibiotic must
be transported by
cell.A mutation in
the transport
system gene
could eliminate
uptake.
Decreased uptake has been
described for aminoglycosides,
some β-lactams, tetracyclines,
and others.
Active efflux of
antibiotic from
the cell
• Antibiotic is
pumped out of
the cell at a rate
equal to the rate
of entry
Efflux pumps are the main
mechanism of resistance for
tetracyclines and have also
been described for quinolones.
Eliminate or reduce
binding of antibiotic
to cell target
• Antibiotic must be
bound to cell surface
before transport.
Mutation in the
binding protein gene
reduces ability of
antibiotic
to bind to cell surface
Enzymatic cleavage
or chemical
modification
inactivates antibiotic
molecule
• Antibiotic is
degraded or
chemically modified
in some way losing
functionality
β-lactamases catalyze the
hydrolysis of penicillins,
cephalosporins, and other βlactams. When hydrolyzed, the βlactam is unable to bind to
bacterial transpeptidases and
other enzymes needed for cell
wall synthesis and repair.
Many enzymes have been
described that inactivate
aminoglycosides.
Metabolic bypass of inhibited
pathway
• Bacterium develops a new
pathway which bypasses the
inhibited reaction(s)
Some thymidine-requiring
streptococci are not inhibited by
trimethoprim and sulfonamides.
because the resistant bacteria
produce adequate concentrations
of thymidine nucleotides by an
alternative pathway and as a result
survive exposure to these drugs.
exposed to these agents.
Overproduction of antibiotic target
• Bacterium speeds up the inhibited
reaction or produces excessive
amount of the antibiotic’s target,
thereby “mopping up” the antibiotic
and allowing the uninhibited
reaction to proceed
Combating Antibiotic
Resistance
Defining the Problem
• Not enough new antibiotics to cope
with the development of resistance
to “old” antibiotics
Defining the Problem
• Widespread misuse of antibiotics in
agriculture and by patients and health
care workers in med/vet situations
e.g.use of antibiotics as feed additives
given to farm animals topromote
growth
unnecessary antibiotic prescriptions
Solving the problem
• Pharmaceutical companies
need new, less costly
strategies to develop
antimicrobials
Solving the problem
• Regulate use of antibiotics
as feed additives promote
growth
Solving the problem
• Stop administration and uses of
antibiotics for viral infections or nonmedical purposes
Antimicrobial prophylaxis in surgery. Medical
Lett 2001; 43:92.
Gold HS, Moellering RC Jr. Antimicrobialdrug resistance. N Engl J Med 1996;
335:1445-1453.
Steinberg JP, Blass MA. Non-surgical
antibiotic prophylaxis. In Schlossberg D:
Current therapy of infectious diseases,
Philadelphia, Mosby-Harcourt Health
Sciences, 2000.