Transcript Penicillins

Part 1.
General considerations
of antimicrobial agents
(抗微生物药物概论)
Contents
1. Overview
2. Term and definition
3. Classification and mechanism of
antibacterial action
4. Bacterial resistance
History of Antimicrobial Therapy
1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂）
“Magic bullet” for treatment of syphilis（梅毒）
1928 Fleming discovers penicillin(青霉素)
1932 Domagk discovers sulfonamides（磺胺类药物）
1940s Penicillin and streptomycin （链霉素）used widely,
cephalosporins （头孢菌素）discovered
1947 Chloramphenicol （氯霉素）discovered, first broad spectrum
agent
1950s Tetracycline （四环素）in use
1952 Erythromycin （红霉素）discovered (macrolides大环内酯类)
1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus
1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基苷类)
1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类)
1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum
cephalosporins
2000s Newer agents to combat resistant pathogens
抗
生
素
的
发
展
史
Antimicrobial drugs classification
According to bioactivity






Anti G+ antibiotic
Anti G- antibiotic
Broad-spectrum antibiotic
Anti mycobacterium（分支杆菌）
antibiotic
Anti anaerobe（厌氧菌） antibiotic
β- lactamase inhibitor
According to the chemical structure：
1、β-lactams: Penicillins; Cephalosporins;
2、Aminoglycosides;
3、Macrolides; Lincosamides ;Vancomycins
4、Tetracyclines; Chloramphenicol
5、Quinolones
6、Sulphonamides
7、Nitrofurans
8、Antimycobacterial agents
9、others: Oxazolidinones; Streptogramins
1. Overview:
Antimicrobial drugs:
Antibacterial drugs(抗菌药);
Antifungal drugs(抗真菌药);
Antiviral drugs(抗病毒药).
The relationship of the host, microorganisms,
antimicrobial drugs.
pathogenicity
Immunological
responses
Terminology
1. Antibacterial drugs(抗菌药)
2. Antibiotics(抗生素)
3. Bacteriostatic drugs(抑菌药)
4. Bactericidal drugs(杀菌药)
5. Antibacterial spectrum(抗菌谱)
6. Chemotherapetic index (化疗指数,CI)
7. Minimum inhibitory concentration (最小抑菌浓度, MIC)
8. Minimum bactericidal concentration (最小杀菌浓度, MBC)
9. Concentration Dependent killing
10. Post antibiotic effect (抗生素后效应,PAE)
11. Time-dependent killing
2. Terms and definition:
(1)Antibacterial drugs(抗菌药):
Substances that can kill bacteria
and/or inhibit its growth.
including:
①Antibiotics(抗生素);
②Synthetic antimicrobial agents,
such as sulfonamides(磺胺类) and
quinolones(喹诺酮类), etc.
Terms and definition
(2)Antibiotics(抗生素):
Substances produced by various
species of microorganisms(bacteria,
fungi, actinomyces, etc.), which
can kill other microorganisms or
inhibit their growth.
Terms and definition
(3)Chemotherapetic index:
LD50/ED50, or LD5/ED95
(4)Antibacterial spectrum(抗菌谱);
(5)Bacteriostatic drugs(抑菌药);
(6)Bactericidal drugs(杀菌药);
Terms and definition
agents
Antimicrobial Susceptibility Testing
7. Minimum inhibitory
concentration (MIC)
8. Minimum bactericidal
concentration (MBC):
99.9% decrease in growth
over 24 hours
Incubate 18 to
24 hr at 37℃
Measure
diameters of
nongrowth
zones
Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs
Terms and definition
9. Concentration Dependent killing: situation in which
the bactericidal activity of a drug depends by how
much the drug concentration exceeds the Minimum
inhibitory concentration of the organism in question.
e.g. aminoglycosides and quinolones
10. Time-dependent killing: situation in which the
bactericidal activity of a drug depends how long the
drug concentration exceeds the Minimum inhibitory
concentration of the organism in question. e.g. lactams and vancomycin
11. Post antibiotic affect (PAE) : Persistence of
suppression of bacterial growth after limited exposure
to an antimicrobial agent. e.g. aminoglycosides
Classification and mechanism of action
①
④
⑤
③
②
Classification and mechanism of action
(1)Inhibiting synthesis of bacterial cell walls:
UDP-乙酰胞壁酸-5肽
双糖十肽聚合物
Classification and mechanism of action
-Lactam antibiotics
vancomycin
transpeptidase
Classification and mechanism of action
(2)Affecting permeability of membrane:
①Ionic-adsorbed(streptomycin);
②binding to ergosterol(amphotercin B);
③Inhibiting the synthesis of ergosterol
(imidazoles);
④Surface-active agent, that interact
strongly with phospholipids(polymixins).
Classification and mechanism of action
(3)Inhibiting protein synthesis:
affecting the function of 30S：
Streptomycin, Tetracyclines(四环素类)
affecting the function of 50S：
Streptomycin, Macrolides (大环内酯类),
lincomycins, chloramphenicol etc.
Inhibiting protein synthesis
利奈唑胺
氨基苷类
氨基苷类
氨基苷类
大环内酯类
四环素类
氯霉素类
林可霉素类
Classification and mechanism of action
(4)Affecting bacterial nucleic acid metabolism:
quinolones, etc.
Classification and mechanism of action
(5)Blocking enzymes of folate metabolism:
Pteridine(蝶啶) + PABA(对氨苯甲酸)
Dihydropteroate
synthase
Blocked by sulfonamides
Dihydropteroic acid(二氢蝶酸)
Glutaminic acid
Dihydrofolic acid(二氢叶酸)
Dihydrofolate
reductasease
NADPH
Blocked by trimethoprim
NADP
Tetrahydrofolic acid(四氢叶酸)
Bacterial Resistance
4. Bacterial resistance:
(1)Category of resistance:
①Intrinsic resistance:
 Inherent features
 usually expressed by chromosomal genes
②Acquired resistance:
 emerge from previously sensitive
bacterial populations


Caused by mutations in chromosomal genes
Or by acquisition of plasmids or transposons
Bacterial Resistance
(2)Mechanism of bacterial resistance:
①Enzymatic inactivation and
modification;
②Inhance active efflux system:
③Decreased permeability;
④Target alteration;
Bacterial Resistance
Mechanism of bacterial resistance
①To produce inactivated enzyme:
Penicillin
Acetylation
OM
-lactam
Penicillinase
Phosphorylation
Inactive
IM
1A. Enzymatic inactivation
e.g. β-lactamase
Kanamycin
Adenylyation
1B. Enzymatic modification
e.g. Aminoglycoside
modification
Bacterial Resistance
Mechanism of bacterial resistance
② To enhance active efflux system(主动外排系统):
Bacterial Resistance
Mechanism of bacterial resistance
③ Decreased permeability :
Absence of, mutation in, or loss
of the appropriate porins(膜孔蛋白)
channel can slow the rate of drug
entry into the cell, or prevent entry
altogether, reducing the effective
drug concentration at the target site.
Bacterial Resistance
Mechanism of bacterial resistance
Porin channel(膜孔蛋白通道)
Bacterial Resistance
Mechanism of bacterial resistance
④ Target alteration :
Mutation of the natural target(such
as resistance to fluoroquinolone).
Target modification(ribosomal
protection type of resistance to
macrolides and tetracyclines).
Substitution with a resistant
alternative to the natural, susceptible
target (such as methicillin resistance in
staphylococci).
Bacterial Resistance
The transfer of resistance genes:
①Mutations(突变);
②Transduction(转导);
③Transformation(转化);
④Conjugation(接合).
Bacterial Resistance
The transfer of resistance genes
①Mutations(突变):
which may occur in the gene encoding.
1)The target protein;
2)The protein involved in drug transport;
3)Act on regulatory gene or promoter(启动
子) affecting expression of the target, a
transport protein, or an inactivating
enzyme.
such as aminoglycosides, quinolones, etc.
Bacterial Resistance
Bacterial Resistance
②Transduction(转导):
acquisition of bacterial DNA from
bacteriophage(噬菌体) that has
incorporated DNA from a previous host
bacterium within its outer protein coat.
Some phages can carry plasmids that
code for penicillinase, or genes encoding resistance to erythromycin, tetracycline, or chloramphenicol.
Bacterial Resistance
Transduction
Bacterial Resistance
③Transformation(转化):
Uptake and incorporation of DNA
that is free in the environment into
the host genome by homologous
recombination.
Bacterial Resistance
Bacterial Resistance
④Conjugation(接合):
The passage of genes from cell to
cell by direct contact through a sex
pilus(性菌毛) or bridge(桥接).
Bacterial Resistance
Transformation
Conjugation
Multi-drug resistance MDR
1.
2.
耐甲氧西林金葡菌MRSA
 社区获得性耐甲氧西林金葡菌（community-associated。
CA—MRSA）
 医院获得性耐甲氧西林金葡菌（ Hospital-associated ，
HA-MRSA
Methicillin-resistant coagulase negative staphylococci, MRCNS
PBP-2a
3.Penicillin-resistant streptococcus pneumoniae, PRSP
PBP-1a, PBP-2a, PBP-2x, PBP-2b
Active efflux system
4.Vancomycin-resistant Enterococcus, VRE
van-A, van-B, van C-1, van C-2, van C-3, van D, van E
Multi-drug resistance MDR
5. The 3rd generation-cephalosporins -resistant
• Extended spectrumβ-lactamases, ESBL
• Class I chromosone mediated β-lactamases
6.Carbapenem -resistant
• OprD porin
7.Quinolone-resistant escherichia coli, AREC
• Active efflux system
Let’s take a rest !
Part 2.
Beta-Lactam & Other Cell
Wall-& Membrane- Active
Antibiotics
Beta-Lactam & Other Cell Wall- &
Membrane- Active Antibiotics
Classification of
-Lactam Antibiotics








Ⅰ. Penicillins(青霉素类)
Ⅱ. Cepharosporins(头孢菌素类)
Ⅲ. Other -lactam antibiotics:
1.
2.
3.
4.
Cephamycins(头霉素类)
Carbapenems(碳青霉烯类)
Monobectams(单环类)
Oxacephalosporins(氧头孢烯类)
Ⅳ. -lactamase inhibitors(内酰胺
酶抑制剂)
(青霉素类)
Core structures
of beta-lactam
antibiotic
families
(头孢菌素类)
(单环类)
(碳青霉烯类)
(亚胺培南——碳青霉烯类)
Ⅰ. Penicillins(青霉素类)
A. Nature Penicillins:
(酰基侧链)
(噻唑烷环)
(青霉素类)
(-内酰胺环)

Chemical structure of penicillins
Penicillins
1. Classification of Penicillins:
(1)Nature penicillins:
Penicillin G(苄青霉素, 简称青霉素)
(2)Penicillinase-resistant penicillins:
Oxacillin(苯唑西林)
(3)Broad-spectrum penicillins:
Amoxicillin(阿莫西林)
(4)Anti-pseudomonas penicillins:
Ticarcillin(替卡西林)
(5)Anti-G- bacilli penicillins:
Mecillinam(美西林)
Penicillins
2. Antimicrobial activity:
The penicillin-susceptible bacteria:
(1)G+ bacilli(革兰阳性杆菌);
(2)Non-penicillinase-producing strains of
most G- cocci(大多数不产青霉素酶的球菌)
and Nisseria(奈瑟菌属), etc.
such as: Meningococcus(脑膜炎球菌),
Gonococcus(淋球菌), etc.
(3)Spirochetes(螺旋体), etc.
Penicillins
3. Mechanism of action:
(1)Inhibiting transpeptidase(转肽酶, PBP,
青霉素结合蛋白), and inhibiting the
synthesis of bacterial cell walls.
(2)Activation of cell-wall autolytic enzyme(自溶酶).
Penicillins

Comparison of the structure and composition
of G+/ G- cell walls.
Penicillins
Penicillins
Penicillins &
cephalosporins
can inhibit the
transpeptidase
reaction in sensitive organism
(敏感菌).
4. Mechanism of resistance:
Penicillins
(1)to produce penicillinase(-lactamase) by bacteria
(酰胺酶)
(青霉素酶)
(6-氨基青霉烷酸)
(青霉素裂解酸)
Penicillins
(2)to alter PBP, decreased affinity for
the antibiotic;
(3)to make deficiency of porins, or
enhance active efflux system,
let penicillins does not reach its
target, and inability to be effective.
(4) Lack of the autolysins
Penicillins
Antibiotic efflux pumps of G- bacteria.
Penicillins
5. Clinical Uses:
(1)Streptococcal(链球菌) infections:
such as:
Pharyngitis(咽炎), Scarlet fever(猩红
热);
Rheumatic fever(风湿热), Pneumonia(肺炎),
Endocarditis(心内膜炎), etc.
(2)Nisseria (奈瑟菌) infections:
Meningitis(脑膜炎);
Gonorrhea(淋病), etc.
Penicillins
(3)Leptospira(螺旋体) infection:
such as: Liptospirosis(钩端螺旋体病),
Syphilis(梅毒), Recurrent fever(回归热).
(4)G+ bacilli(G+ 杆菌) infection:
such as: Diphtheria(白喉),
Tetanus(破伤风), Anthrax(炭疽病), etc.
(5)Staphylococcal(葡萄球菌) infection
(generally resistant to penicillin G).
Penicillins
6. Adverse effects:
Penicillins are among the safest of
antibiotics, produce few direct toxic
reactions,
The most of the serious side
effects are hypersensitivity reactions.
Penicillins
(1)Hypersensitivity reactions:
Itching(痒), rashes, fever, serum
sick-ness, angioneurotic oedema(血管神经
性水肿).
Anaphylactic shock (5/10 000).
(2)Other adverse reactions:
Phlebitis(静脉炎), when i.v.;
Local inflammatory reactions, in
injection site when i.m.;
Jarisch-Herxheimer reaction(赫氏反
应) when treatment of syphilis,
liptospirosis.
Penicillins
7. ADME of Penicillin G:
Be destroyed easily by p.o.
Administration by i.m. or i.v. gtt.
Widely distributed (even in CSF,
when menings is infective);
Eliminated in the urine.
Penicillins
8. Preparation of long-acting
penicillin G:
Benzathine penicillin G(苄星青霉素)
Procain penicillin(普鲁卡因青霉素)
B. Semi-synthetic Penicillins:
1. Penicillins by oral administration
（耐酸青霉素）:
Phenoxymethylpenicillin
(苯氧甲基青霉素, Penicillin V)
It is resistant to gastric acid, and be well
absorbed(60%) when it is given on an empty stomach.
Its half-life(t½) is longer than that of penicillin G.
A satisfactory substitute for Penicillin G to treat
tonsilitis(扁桃体炎), or Pharyn-gitis(咽炎), etc.
Semisynthetic Penicillins
2. The penicillinase-resistant
penicillins(耐酶青霉素):
 Oxacillin(苯唑西林),
 Cloxacillin(氯唑西林),
 Dicloxacillin(双氯西林)
It is stable in an acidic medium, can be
administrated by po, or im, iv ; and it is resistant
to cleavage by penicillinase.

It is used for treatment of penicillin Gresistance staphylococcal infection.

Semisynthetic Penicillins
3. Broad spectrum penicillins（广谱
青霉素）:
Amipicillin(氨苄西林),
Carbenicillin(羧苄西林),
Piperacillin(哌拉西林), etc.
They have similar antibacterial activity
and a broader spectrum.
All can be destroyed by -lactamase.
Semisynthetic Penicillins
Broad spectrum penicillins
(1)Ampicillin(氨苄西林), Amoxicillin(阿莫西林)
Pseudomonas aeruginosa(铜绿假单孢菌
——绿脓杆菌)-resistance.
Clinical Uses:
Upper respiratory infections; Urinary
tract infections; Meningitis; Salmonella
infections.
(2)Carbenicillin(羧苄西林),Ticarcillin(替卡西林)
With activity against Pseudomonas
aeruginosa and some Proteus(变形杆菌).
Semisynthetic Penicillins
Broad spectrum Penicillins
(3)Piperacillin(哌拉西林),Mezlocillin(美洛西林)
They have the broadest antibacterial
spectrum, and the most activity of the
penicillins, with activity against Pseudo-monas
aeruginosa, etc.
Clinical Uses:
For the treatment of the patients with
severe infection caused by G- bacteria, usually in combination with aminoglycoside (氨基
苷类).
Semisynthetic Penicillins
4.
Anti-G




bacilli penicillins:
Mecillinam(美西林),
Temocillin(替莫西林)
Bacteriostatic drugs
Narrow antibacterial spectrum: have
activity against some G- bacilli.
Ⅱ. Cepharosporins
(头孢菌素类)
7-氨基头孢烷酸
Cepharosporins
B. Classification and Features:
1. First generation:
Cefazolin(头孢唑林), Cefradine(头孢拉定),
Cefalexin(头孢氨苄), etc.
(1)more active than second and third generation
against certain G+ microoganisms;
(2)more impervious than second and third generation
to attack by staphyloccal -lactamase;
(3)less active than second and third generation
against certain G- microoganisms;
(4)nonstable to G- bacilli -lactamase;
(5) Lack activity against certain Pseudomonas (铜绿假
单孢菌), anaerobes(厌氧菌), etc;
(6)certain kinds have kidney toxicity.
Cepharosporins
2. Second generation:
Cefuroxime(头孢呋辛), Cefamandole(头
孢孟多), Cefaclor(头孢克洛), etc.
(1)more active than first generation against
certain G- bacilli and more impervious than
first generation G- bacilli -lactamase;
(2)somewhat less active than first
generation against G+ cocci but more than third
generation;
(3)active against anaerobes(厌氧菌);
(4)lack activity against Pseudomonas;
(5)less toxic than first generation to kidney.
Cepharosporins
3. Third generation:
Ceftazidime(头孢他啶), Ceftriaxone(头孢曲松
), etc.
(1)far more active than first and second
gene-ration against G- bacilli;
(2)be highly resistant to -lactamase
produced by G- bacilli;
(3)with the extended spectrum against
anaerobes and Pseudomonas;
(4)well absorbed, penetration into tissue,
blood and body cavity as well in sufficient
concentration;
(5)less active than first and second
generation against G+ cocci;
(6)less toxic to kidney.
Cepharosporins
4. Fourth generation:
Cefepime(头孢匹肟), Cefpirome(头孢匹
罗), etc.
(1)resistant to type 1 -lactamase;
(2)more active than third generation against
Enterbacter(耐肠杆菌);
(3)less active than third generation against
Pseudomonas.
Therapeutic advantages of some
clinically useful cephalosporins.
1st
抗菌谱 G+
酶稳定性
肾毒性 大
半衰期
血脑屏障通透性
2st
3st
4st
强
好
长
好
G-
Ⅲ. Other -lactam antibiotics
1. Cephamycins(头霉素类):
Cefoxitin (头孢西丁)
It has the similar antibacterial
activity and spectrum to the second
generation cepharosporins,
also can be used for the treatment
of anaerobic infections.
Other -lactam antibiotics
2. Carbapenems(碳青霉烯类):
 Imipenem(亚胺培南)
 Meropenem(美罗培南)
 Panipenem (帕尼培南)
 Ertapenem（厄他培南）

Broad spectrum: wide activity
against gram-positive cocci
(including some penicillin-resistant
pneumococci), gram-negative rods,
and anaerobes.

With the exception of ertapenem, the
carbapenems are active against P
aeruginosa and Acinetobacter species.
抗
生
素
的
发
展
史


Imipenem+cilastatin(西司他丁)—Tienam(泰能),
a drug that inhibits the degradation of
imipenem by a renal tubular dipeptidase.
Panipenem+betamipron (倍他米隆)Carbenin(克倍宁)
Other -lactam antibiotics
3. Monobectams(单环类):
Aztreonam(氨曲南)
Carumonam(卡芦莫南)
For the treatment of aerobic Gbacilli infections.
Narrow-spectrum antibiotic.
Other -lactam antibiotics
4. Oxacephalosporins(氧头孢烯类)
Latamoxef(拉氧头孢)
Flomoxef(氟氧头孢)
Broad-spectrum antibiotic(anaerobic
infections).
Ⅳ. -lactamase inhibitors
(-内酰胺酶抑制剂)



Clavulanic acid(克拉维酸)
 Sulbactam(舒巴坦)
 Tazobactam(三唑巴坦)
Binding to -lactamases and inactivate them, thus
preventing the destruction of -lactam antibiotics
which are substrates for -lactamases.
They are most active against plasmid-encoded beta-lactamases such
as those produced by gonococci, streptococci, E coli, and H
influenzae. They are not good inhibitors of inducible chromosomal
betalactamases formed by Enterobacter, Pseudomonas, and
Serratia.
Penicillin -Mechanism of resistance
The in vitro growth of
Escherichia
coli in the presence of
amoxicillin,
with and without
clavulanic acid.
amoxicillin+ clavulanic acid = augmentin (奥格门汀)



阿莫西林+ 克拉维酸 = 奥格门汀augmentin
氨苄西林+舒巴坦 = 优立新unasyn
替卡西林+克拉维酸 =替门汀/特美汀
timentin
OTHER CELL WALL OR
MEMBRANE-ACTIVE AGENTS
I. glycopeptide antibiotic（糖肽类）
Vancomycin (万古霉素)
& Teicoplanin（替考拉宁）
Vancomycin
Vancomycin
Vancomycin (万古霉素)

Mechanism of action--Inhibit cell wall synthesis
-Lactam antibiotics
vancomycin
transpeptidase
Vancomycin
Vancomycin(万古霉素)

Antimicrobial spectrum:


Narrow spectrum, active
only against gram-positive
bacteria, paticularly
staphylococci
Pharmacokinetics


Poorly absorbed from
intestinal tract, iv
Excreted from glomerular
filtration 90%
Vancomycin
Vancomycin(万古霉素)

Clinical uses



Infection caused by MRSA, MRSE and
penicillin-resistant pneumococcus
Treatment of antibiotic-associated
enterocolitis caused by clostridium
difficile po
Adverse reaction


Ototoxicity & nephrotoxicity
Red-man syndrome
Vancomycin
Teicoplanin(替考拉宁)



Similar to vancomycin in mechanism and
antimicrobial spectrum
Can be given im as well as iv
Less adverse reactions
Daptomycin
II. lipopeptide antibiotic(环脂肽类)
Daptomycin(达托霉素)

Mechanism of action
Disruption of the bacterial membrane through the formation
of transmembrane channels, resulting in a loss of membrane
potential leading to inhibition of protein, DNA and RNA
synthesis, which results in bacterial cell death.
Daptomycin is a novel cyclic lipopeptide with spectrum similar to
vancomycin but active against vancomycin-resistant strains of
enterococci and staphylococci.
The drug is eliminated via the kidney. Creatine phosphokinase
should be monitored since daptomycin may cause myopathy.
daptomycin is inactivated by pulmonary surfactants; thus, it
should never be used in the treatment of pneumonia.
Gram-positive activity; used in endocarditis and sepsis
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Antimicrobial spectrum:
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Daptomycin is unable to permeate
the outer membrane of Gramnegative bacteria, thus its
spectrum is limited to Grampositive organisms only.
Daptomycin has activity against
Staphylococci (including MRSA,
VISA, and VRSA), Enterococci
(both E. faecalis and E.faecium,
including VRE), and Streptococci
(including DRSP), as well as most
other aerobic and anaerobic Grampositive bacteria.
Daptomycin
抗
生
素
的
发
展
史
III. lipoglycopeptide antibiotic
(脂糖肽类)
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 Telavancin (达巴万星)
It is an alternative to vancomycin, daptomycin,
linezolid, and quinupristin/dalfopristin in treating
complicated skin and skin structure infections,
caused by resistant gram-positive organisms,
including MRSA.
Mechanism of action：

Like vancomycin,inhibits bacterial cell wall synthesis.
Unlike vancomycin, telavancin exhibits an additional
mechanism of action similar to that of daptomycin, that
involves disruption of the bacterial cell membrane, due to
the presence of a lipophilic side chain moiety.
Adverse Effects
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The most common adverse reactions ：taste disturbances, nausea,
vomiting, insomnia, and foamy urine.
Telavancin is not recommended during pregnancy due to adverse
developmental outcomes observed with animal data.
Prolong the QTc interval, use should be avoided in patients with a
history of QTc prolongation, uncompensated heart failure, severe left
ventricular hypertrophy, or patients receiving other medications that
may prolong the QTc interval.
Telavancin may also interfere with tests used to monitor coagulation
(PT/INR, aPTT, ACT, coagulation based Xa tests). Thus, blood samples
monitoring coagulation should be collected as close to the next dose of
telavancin as possible.
END OF CLASS