2 KS uc che tonghop vach 2018 đh dược Hà Nội

However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily par-enteral dose of 18–24 million unit

KHÁNG SINH Nguyễn Thùy Dương

BM Dược lý

Cấu tạo vách tế bào vi khuẩn

794 SECTION VIII Chemotherapeutic Drugs

Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentra-tions A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infection

After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough

to prevent β-hemolytic streptococcal infection A 600,000 unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/

mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection

Penicillin concentrations in most tissues are equal to those in serum Penicillin is also excreted into sputum and milk to levels 3–15% of those in the serum Penetration into the eye, the prostate, and the central nervous system is poor However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily par-enteral dose of 18–24 million units These concentrations

are sufficient to kill susceptible strains of pneumococci and meningococci

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours Ampicillin and the extended- spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min

or less ( Table 43–1 )

Nafcillin is primarily cleared by biliary excretion Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs

in renal failure Because clearance of penicillins is less efficient in

BP BP

BP BP

BP BP

5

Cytoplasmic membrane

Periplasmic space

UMP

PPi UDP

FIGURE 43–5 The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars; 1 = fosfomycin,

2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = β-lactam antibiotics) Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane; M, N -acetylmuramic acid; Glc, glucose; NAcGlc or G, N -acetylglucosamine

043-Katzung_Ch043_p789-808.indd 794 9/23/11 5:51:29 PM

794 SECTION VIII Chemotherapeutic Drugs

Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentra-tions A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infection

After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough

to prevent β-hemolytic streptococcal infection A 600,000 unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/

mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection

Penicillin concentrations in most tissues are equal to those in serum Penicillin is also excreted into sputum and milk to levels 3–15% of those in the serum Penetration into the eye, the prostate, and the central nervous system is poor However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily par-enteral dose of 18–24 million units These concentrations

are sufficient to kill susceptible strains of pneumococci and meningococci

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours Ampicillin and the extended- spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min

or less ( Table 43–1 )

Nafcillin is primarily cleared by biliary excretion Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs

in renal failure Because clearance of penicillins is less efficient in

BP

BP

BP BP

BP BP

5

Cytoplasmic membrane

Periplasmic space

UMP

PPi UDP

FIGURE 43–5 The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars; 1 = fosfomycin,

2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = β-lactam antibiotics) Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane; M, N -acetylmuramic acid; Glc, glucose; NAcGlc or G, N -acetylglucosamine

043-Katzung_Ch043_p789-808.indd 794 9/23/11 5:51:29 PM

794 SECTION VIII Chemotherapeutic Drugs

Benzathine and procaine penicillins are formulated to delay

absorption, resulting in prolonged blood and tissue

concentra-tions A single intramuscular injection of 1.2 million units of

benzathine penicillin maintains serum levels above 0.02 mcg/mL

for 10 days, sufficient to treat β-hemolytic streptococcal infection

After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough

to prevent β-hemolytic streptococcal infection A 600,000 unit

dose of procaine penicillin yields peak concentrations of 1–2 mcg/

mL and clinically useful concentrations for 12–24 hours after a

single intramuscular injection

Penicillin concentrations in most tissues are equal to those in

serum Penicillin is also excreted into sputum and milk to levels

3–15% of those in the serum Penetration into the eye, the prostate,

and the central nervous system is poor However, with active

inflammation of the meninges, as in bacterial meningitis, penicillin

concentrations of 1–5 mcg/mL can be achieved with a daily

par-enteral dose of 18–24 million units These concentrations

are sufficient to kill susceptible strains of pneumococci and meningococci

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours Ampicillin and the extended- spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min

or less ( Table 43–1 )

Nafcillin is primarily cleared by biliary excretion Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs

in renal failure Because clearance of penicillins is less efficient in

BP

BP

BP BP

BP BP

5

Cytoplasmic membrane

Periplasmic space

PPi UDP

FIGURE 43–5 The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars; 1 = fosfomycin,

2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = β-lactam antibiotics) Bactoprenol (BP) is the lipid membrane carrier that transports building

blocks across the cytoplasmic membrane; M, N -acetylmuramic acid; Glc, glucose; NAcGlc or G, N -acetylglucosamine

043-Katzung_Ch043_p789-808.indd 794 9/23/11 5:51:29 PM

794 SECTION VIII Chemotherapeutic Drugs

Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentra-tions A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infection

After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough

to prevent β-hemolytic streptococcal infection A 600,000 unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/

mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection

Penicillin concentrations in most tissues are equal to those in serum Penicillin is also excreted into sputum and milk to levels 3–15% of those in the serum Penetration into the eye, the prostate, and the central nervous system is poor However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily par-enteral dose of 18–24 million units These concentrations

are sufficient to kill susceptible strains of pneumococci and meningococci

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes About 10% of renal excretion is by glomerular filtration and 90% by tubular secretion The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours Ampicillin and the extended- spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min

or less ( Table 43–1 )

Nafcillin is primarily cleared by biliary excretion Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs

in renal failure Because clearance of penicillins is less efficient in

BP

BP

BP BP

BP BP

5

Cytoplasmic membrane

Periplasmic space

PPi UDP

FIGURE 43–5 The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars; 1 = fosfomycin,

2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = β-lactam antibiotics) Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane; M, N -acetylmuramic acid; Glc, glucose; NAcGlc or G, N -acetylglucosamine

043-Katzung_Ch043_p789-808.indd 794 9/23/11 5:51:29 PM

CÁC PENICILIN

Đặc điểm chung

Cơ chế tác dụng của penicilin/ b lactam

Liên kết ngang dotranspeptidase

Chuỗi amino acid Đường

Vi khuẩn

Vách tế bào Màng tế bào

Ức chế tổng hợp

Vách tế bào

D-ala Transpeptidase

Acid N- acetyl

muramic

glucosamin

N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly L-lys

N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly

glucosamin

N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly

L-lys D-ala

D-glu L-ala

Ï

Acid N- acetyl muramic

glucosamin

N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly N-acetyl-Gly L-lys

D-ala D-ala

D-glu L-ala

Gly

β-lactam ức chế transpeptidase, enzym cần thiết tổng hợp peptidoglycan

Các β-lactam tấn công transpeptidase (Penicillin binding protein – PBP)

Cấu hình không gian tương tự giữa penicillin và D-Ala-D-Ala (cơ chất của

các transpeptidase)

Nguồn: Talaro KP Foudation of Microbiology 4 th edition

β-lactam gây ly giải vi khuẩn (autolysis) Þ diệt khuẩn

Cơ chế tác dụng của penicilin/ b lactam

Cơ chế kháng penicilin/ b lactam

Cơ chế kháng penicilin/ b lactam

Thay đổi cấu dạng của PBP

Bơm tống thuốc

(Gr âm)

Ngăn cản KS tới vị trí đích

792 SECTION VIII Chemotherapeutic Drugs

1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin =

0.6 g) Semisynthetic penicillins are prescribed by weight rather

than units The minimum inhibitory concentration (MIC) of

any penicillin (or other antimicrobial) is usually given in mcg/mL

Most penicillins are formulated as the sodium or potassium salt of

the free acid Potassium penicillin G contains about 1.7 mEq of

K + per million units of penicillin (2.8 mEq/g) Nafcillin contains

Na + , 2.8 mEq/g Procaine salts and benzathine salts of penicillin

G provide repository forms for intramuscular injection In dry

crystalline form, penicillin salts are stable for years at 4°C

Solutions lose their activity rapidly (eg, 24 hours at 20°C) and

must be prepared fresh for administration

Mechanism of Action

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth

by interfering with the transpeptidation reaction of bacterial cell

wall synthesis The cell wall is a rigid outer layer unique to

bacte-rial species It completely surrounds the cytoplasmic membrane

( Figure 43–3 ), maintains cell shape and integrity, and prevents cell

lysis from high osmotic pressure The cell wall is composed of

a complex, cross-linked polymer of polysaccharides and

polypeptides, peptidoglycan (also known as murein or

mucopep-tide) The polysaccharide contains alternating amino sugars,

N -acetylglucosamine and N -acetylmuramic acid ( Figure 43–4 ) A five-amino-acid peptide is linked to the N -acetylmuramic acid

sugar This peptide terminates in D-alanyl-D-alanine binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide Cross-links give the cell wall its structural rigidity Beta-lactam antibiot-ics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs This inhibits the trans-peptidation reaction ( Figure 43–5 ), halting peptidoglycan synthe-sis, and the cell dies The exact mechanism of cell death is not completely understood, but autolysins and disruption of cell wall morphogenesis are involved Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall

Resistance

Resistance to penicillins and other β-lactams is due to one of four general mechanisms: (1) inactivation of antibiotic by β-lactamase, (2) modification of target PBPs, (3) impaired penetration of drug to target PBPs, and (4) efflux Beta-lactamase production is the most common mechanism of resistance Hundreds of different β-lactamases have been identified Some, such as those produced by

Staphylococcus aureus, Haemophilus influenzae , and Escherichia coli ,

β Lactamase

PBP

Cytoplasmic membrane

Periplasmic space

Cell wall

Peptidoglycan

Outer membrane

PBP

Porin

FIGURE 43–3 A highly simplified diagram of the cell envelope of a gram-negative bacterium The outer membrane, a lipid bilayer, is

present in gram-negative but not gram-positive organisms It is penetrated by porins, proteins that form channels providing hydrophilic access

to the cytoplasmic membrane The peptidoglycan layer is unique to bacteria and is much thicker in gram-positive organisms than in gram-

negative ones Together, the outer membrane and the peptidoglycan layer constitute the cell wall Penicillin-binding proteins (PBPs) are

membrane proteins that cross-link peptidoglycan Beta lactamases, if present, reside in the periplasmic space or on the outer surface of the

cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane

043-Katzung_Ch043_p789-808.indd 792 9/23/11 5:51:29 PM

Tạo β-lactamase

Penicilin tự nhiên

Penicilin tự nhiên

• Chỉ định

1 Nhiễm khuẩn do liên cầu:

Viêm phổi, viêm màng não do Streptococcus pneumoniae

Viêm họng do Streptococcus pyogenes: penicillin V

Viêm phổi, viêm khớp, viêm màng não, viêm nội tâm mạc do Streptococcus

pyogenes

Viêm nội tâm mạc do Streptococcus viridans

Dự phòng thấp tim do liên cầu, dự phòng phẫu thuật ở bệnh nhân có bệnh van

2 Nhiễm khuẩn do Enterococcus: viêm nội tâm mạc

3 Nhiễm khuẩn do vi khuẩn kỵ khí: viêm phổi, áp xe quanh răng, áp xe não

4 Nhiễm khuẩn do não mô cầu: viêm màng não

6 Khác: Hoại thư sinh hơi do Clostridium, bệnh bạch hầu do Dipthria, bệnh than do

Bacillus anthracis

Penicilin kháng penicillinase

• Phổ tác dụng

– Tác dụng tốt với vi khuẩn sinh penicillinase

– Kém pen.G trên các VK không sinh penicillinase

– Không có hoạt tính trên Enterococcus, Listeria

monocytogenes

• Chỉ định chung

– Trị tụ cầu tiết penicillinase

– Nhiễm khuẩn nặng do liên cầu Gr(+) (viêm màng trong tim, viêm tủy xương, NK da và mô mềm…)

à Penicilin chống tụ cầu

– à Kị khí, Enterococci, Listeria monocytogenes

– mất hoạt tính bởi penicillinase

– Nhiễm khuẩn hô hấp trên do Streptococcus

pyogenes/pneumoniae và H influenzae: viêm xoang,

viêm tai giữa, viêm phế quản: amox

– Nhiễm khuẩn tiết niệu không biến chứng do

Enterobacteriaceae, E coli: ampi

– Viêm màng não do S pneumoniae, N menigiditis, L

monocytogenes: amox/ampi

– Nhiễm Salmonella: ampi

phổi, NK tiết niệu

– Nhiễm Pseudomonas, phối

hợp AG

Penicilin phối hợp với chất ức chế betalactamase

– Hoạt tính kháng khuẩn rất yếu

– Gắn vào betalactamase à mất hoạt tính enzym

• Acid clavulanic (dx oxapenam)

– Kết hợp amoxicilin (tỷ lệ 1:4= Augmentin)

– Kết hợp ticarcilin (Tinmentin, Claventin)

• Sulbactam (dx penam sulfon)

– Kết hợp ampicilin (Unasyn)

• Tazobactam

– Kết hợp piperacilin (Zosyn)

Penicilin phối hợp với chất ức chế betalactamase

Sự phát triển của E.coli dưới tác dụng của amoxicilin phối hợp và không phối hợp với a clavulanic