Transcript 15-2-7to10抗真菌病毒抗结核2

Section 15.
Infection disease and
Anti-infective drugs
(感染性疾病与抗感染药)
Charpter 2.
Anti-infective drugs
(抗感染药物)-3
Contents
Part 7. Antifungal agents
Part 8. Antiviral agents
Part 9. Antituberculous Drugs
and Anti-lepric Drugs
 Part 10. Clinical Rational Uses
of Antimicrobial Agents
Part 7.
Antifungal agents
(抗真菌药)
Overview

Fungal infections traditionally have
been divided to two distinct classes:



Systemic infections(全身性感染)
Superficial infections(浅表真菌病)
So, the major antifungal agents
are described with “systemic” and
“topical”, although this distinction is
becoming arbitrary.
Classification
Ⅰ. Systemic antifungal agents:
Amphotercin B(两性霉素B);
Flucytosine(氟胞嘧啶).
Azoles antifungal agents:
Ketoconazole(酮康唑);
Fluconazol(氟康唑);
Itraconazole(伊曲康唑), etc.
Ⅱ. Topical antifungal agents:
Nystatin(制霉菌素);
Griseofulvin(灰黄霉素);
Terbinafine(特比萘芬);
Classification
1、Antibiotic (抗生素类):
Amphotericin B(两性霉素B ); Nystatin（制霉菌素）
Griseofulvin(灰黄霉素)
2、Azole (唑类) :
imidazoles （咪唑类）：ketoconazole(酮康唑),
Triazoles（三唑类）: Itraconazole(伊曲康唑),
3、Allylamine(丙烯胺类):
Terbinafine （特比萘芬）
4、Pyrimidine (嘧啶类) :
Flucytosine (氟胞嘧啶)
5、Echinocandins(棘白菌素类)
Caspofungin(卡泊芬净)
Mechanism of action
壳多糖
氟胞嘧啶
葡聚糖合成酶
特比萘芬
唑类
角鲨烯环氧化酶
羊毛甾醇
棘白菌素类
Antibiotic
1、Antibiotic (抗生素类):
 Amphotericin
B(两性霉素B );
 Nystatin（制霉菌素）
 Griseofulvin(灰黄霉素)
Antibiotic
Amphotercin B(两性霉素B)
amphotercin B
Amphotercin B
Mechanism of Action



Amphotericin B is selective in its fungicidal
effect because it exploits the difference in
lipid composition of fungal and mammalian cell
membranes.
Ergosterol(麦角固醇), a cell membrane sterol,
is found in the cell membrane of fungi, whereas
the predominant sterol of bacteria and human
cells is cholesterol(胆固醇).
Amphotericin B binds to ergosterol and alters
the permeability of the cell by forming
amphotericin B associated pores in the cell
membrane .
Amphotercin B

Mechanism of antifungal action
Amphotercin B
Antifungal Activity

Broadest spectrum.



Candida albicans and Cryptococcus neoformans(白
色念珠菌和新型隐球菌 );
Endemic mycoses(地方性真菌病 ): Histoplasma
capsulatum(组织胞浆菌), Blastomyces
dermatitidis(皮炎芽生菌), and Coccidioides
immitis（粗球孢子菌）;
Pathogenic molds（致病霉菌）, such as
Aspergillus fumigatus （ 曲霉）and mucor（毛霉
）.
Pharmacokinetics







Amphotercin B
Poorly absorbed from the gastrointestinal tract.
Oral amphotericin B cannot be used for treatment of
systemic disease.
>90% bound by serum proteins
Excreted slowly in the urine over a period of several
days.
The serum t1/2 is approximately 15 days.
Hepatic impairment, renal impairment, and dialysis
have little impact on drug concentrations, and
therefore no dose adjustment is required.
The drug is widely distributed in most tissues, but only
2–3% of the blood level is reached in cerebrospinal
fluid, thus occasionally necessitating intrathecal
therapy for certain types of fungal meningitis.
Amphotercin B
2. Clinical Uses:
Amphotericin B remains the drug of
first choice for all life-theatening
mycotic infections(真菌感染).
It is often as the initial regimen for
serious fungal infections:
eg. Cryptococcal meningitis(隐球菌脑膜
炎).
Amphotercin B
Adverse Effects
The toxicity of amphotericin B can be divided into two broad categories:

INFUSION-RELATED TOXICITY (输液相关性毒性)
 Fever, chills, muscle spasms, vomiting, headache, and hypotension.
 Prevention :
 (1)They can be ameliorated by slowing the infusion rate or decreasing the daily
dose.
 (2)Pretreatment with oral acetami-nophen(醋氨酚), or use of intrave-nous
hydrocortisone hemisuccinate (氢化可的松半琥酯) at the start of the infusion
decreases reaction;
 (3)Supplemental K+ is required;

CUMULATIVE TOXICITY(蓄积毒性)
 Renal damage is the most significant toxic reaction.
 Abnormalities of liver function tests are occasionally seen.
 After intrathecal therapy (鞘内注射 )with amphotericin, seizures and a chemical
arachnoiditis(蛛网膜炎) may develop, often with serious neurologic sequelae.
 hematological toxicity: hypochromic(低血红蛋白性) and normocytic anemia, etc.
Amphotercin B
5. New formulations of amphotercin B
(1)Liposomal Amphotercin B(L-AMPH B,
两性霉素B脂质体);
(2)Amphotercin B lipid complex(ABLC, 两
性霉素B脂质复合体);
(3)Amphotercin B collcodal dispersion
(ABCD, 两性霉素B胶质分散体).
Antibiotic
Nystatin（制霉菌素）





Nystatin is a polyene macrolide much like amphotericin B. It is too
toxic for parenteral administration（肠外给药 ） and is only used
topically.
Nystatin is currently available in creams, ointments, suppositories,
and other forms for application to skin and mucous membranes.
It is not absorbed to a significant degree from skin, mucous
membranes, or the gastrointestinal tract. As a result, nystatin has
little toxicity, although oral use is often limited by the unpleasant
taste.
Nystatin is active against most Candida sp and is most commonly
used for suppression of local candidal infections.
Common indications: oropharyngeal thrush（鹅口疮）, vaginal
candidiasis, and intertriginous candidal infections.
Antibiotic
Griseofulvin(灰黄霉素)
(1) Mechanism of action : cellular level



Binds to microtubules and prevents mitosis in fungi.
it is deposited in newly forming skin where it binds to keratin（角质 ）,
protecting the skin from new infection. Because its action is to prevent
infection of these new skin structures, griseofulvin must be
administered for 2–6 weeks for skin and hair infections to allow the
replacement of infected keratin by the resistant structures.
Nail infections may require therapy for months to allow regrowth of the
new protected nail and is often followed by relapse.
(2) Clinical uses:
Oral long-term therapy for dermatophyte, hair and nail
infections
（3）Adverse effects


An allergic syndrome much like serum sickness(血清病 ), hepatitis,
drug interactions with warfarin and phenobarbital.
Azoles
2、Azoles（唑类）

Imidazoles （咪唑类）:




ketoconazole(酮康唑),
Miconazole(咪康唑),
clotrimazole (克霉唑)
Triazoles（三唑类）:




Itraconazole(伊曲康唑),
Fluconazole(氟康唑),
Voriconazole(伏立康唑),
Posaconazole(泊沙康唑 ).
Azoles
Mechanism of Action





Reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450
enzymes.
The selective toxicity of azole drugs results from their
greater affinity for fungal than for human cytochrome
P450 enzymes.
Imidazoles exhibit a lesser degree of selectivity than the
triazoles, accounting for their higher incidence of drug
interactions and side effects.
Resistance to azoles occurs via multiple mechanisms.
The spectrum of action of azole medications is broad
Azoles
Pharmacokinetics
Azoles
Clinical Use


Many candida species(念珠菌 ), C neoformans(新
型隐球菌), the endemic mycoses (地方性真菌病 ),
blastomycosis(芽生菌 ), coccidioidomycosis(球孢
子菌病 ), histoplasmosis(组织胞浆菌病 ), the
dermatophytes(皮肤癣菌 ), and, in the case of
itraconazole and voriconazole, even aspergillus
infections(曲霉菌感染 ).
They are also useful in the treatment of
intrinsically amphotericin-resistant organisms
such as P boydii(波氏假霉样真菌).
Azoles
Adverse Effects



The most common adverse reaction is
relatively minor gastrointestinal upset.
All azoles have been reported to cause
abnormalities in liver enzymes and, very
rarely, clinical hepatitis.
All azole drugs affect the mammalian
cytochrome P450 system of enzymes to
some extent, and consequently they are
prone to drug interactions.
Triazole
CYP3A4
CYP2C9
CYP2C19
Fluconazole
Moderate
Strong
Moderate
Itraconazole
Strong
-
-
Voriconazole
Moderate
Moderate
Weak
Posaconazole
Moderate
-
-
- = no inhibition.
Azoles
Ketoconazole(酮康唑)



Ketoconazole was the first oral azole introduced
into clinical use.
Less selective for fungal P450 than newer azoles.
Greater propensity to inhibit mammalian
cytochrome P450 enzymes
Clinical Uses:
1. Cutaneous candidiasis(皮肤念珠菌病 ): vaginal
2. Dermatophytosis(皮肤癣菌病 )
3. Histoplasmosis(组织胞浆菌病 )
Azoles
Fluconazole(氟康唑)





Fluconazole displays a high degree of water solubility and good
cerebrospinal fluid penetration, its oral bioavailability is high.
The drug is available in oral and intravenous formulations.
Drug interactions are also less common because fluconazole has
the least effect of all the azoles on hepatic microsomal enzymes.
Because of fewer hepatic enzyme interactions and better
gastrointestinal tolerance, fluconazole has the widest therapeutic
index of the azoles, permitting more aggressive dosing in a variety
of fungal infections.
Fluconazole displays no activity against aspergillus(曲霉菌 ) or
other filamentous fungi(丝状真菌).
Clinical use



cryptococcal meningitis(隐球菌性脑膜炎).
Mucocutaneous candidiasis(皮肤粘膜念珠菌病).
Coccidioidal disease(球孢子菌病)
Azoles
Voriconazole(伏立康唑)
Voriconazole is available in intravenous and oral formulations. The drug
is well absorbed orally, with a bioavailability exceeding 90%, and it
exhibits less protein binding than itraconazole.
 Metabolism is predominantly hepatic. Voriconazole is a clinically
relevant inhibitor of mammalian CYP3A4.
Adverse Effects
 Observed toxicities include rash and elevated hepatic enzymes.
 Visual disturbances are common, occurring in up to 30% of patients
receiving intravenous voriconazole, and include blurring and changes in
color vision or brightness. These visual changes usually occur
immediately after a dose of voriconazole and resolve within 30 minutes.
 Photosensitivity dermatitis is commonly observed in patients receiving
chronic oral therapy.
spectrum of action
excellent activity against Candida sp（假丝菌）(including fluconazoleresistant species such as C krusei) and the dimorphic fungi（双相真菌）
。

Azoles
Itraconazole(伊曲康唑)


Oral and intravenous formulations. Drug
absorption is increased by food and by low
gastric pH.
Penetrates poorly into the cerebrospinal fluid.
 spectrum



Dermatophytoses(皮肤癣菌)and onychomycosis(甲癣).
Dimorphic fungi: histoplasma(组织胞浆菌),
Blastomyces(芽生菌 ), and sporothrix(孢子丝菌).
Aspergillosis(曲霉菌病): but it has been replaced by
voriconazole
Azoles
Posaconazole(泊沙康唑 )
Posaconazole is the newest triazole to be licensed in the
USA. It is available only in a liquid oral formulation.
 Posaconazole is rapidly distributed to the tissues, resulting
in high tissue levels but relatively low blood levels.
 Posaconazole is the broadest spectrum member of the azole
family, with activity against most species of candida (念珠
菌)and aspergillus(曲霉菌).
 It is the only azole with significant activity against the
agents of zygomycosis and mucormycosis(毛霉菌病).
Clinical use
 Prophylaxis of invasive aspergillosis(侵袭性曲霉病),
 Prophylaxis of fungal infections during induction
chemotherapy for leukemia, allogeneic bone marrow
transplant patients with graft-versus-host disease(异基因骨
髓移植患者的移植物抗宿主病).

Drug
Uses
Ketoconazole
Multiple systemic
mycoses
Severe recalcitrant
dermatomycos
Mucosal and
systemic candidiasis
Cryptococcal
meningitis
Dose
Adverse Effects
200 mg po once/day
or 3.3–6.6 mg/kg po
once/day (for patients
> 2 yr)
GI upset, hepatitis, depression, itching,
headache, dizziness, bone marrow
suppression, hemolysis, QT prolongation
3–12 mg/kg po or IV
once/day
GI upset, dizziness, hepatitis,
angioedema, anaphylaxis, seizures,
exfoliative dermatitis, QT prolongation
Itraconazole
Dermatomycosis
Multiple systemic
mycoses
100 mg po once/day to
200 mg po bid
or 200 mg IV bid
Hepatitis, GI upset, rash, headache,
dizziness, bone marrow suppression,
hemolysis, hypokalemia, hypertension,
edema, hepatitis, hallucinations, QT
prolongation
Voriconazole
Invasive
aspergillosis
200 mg po bid or 3 to
6 mg/kg IV q 12 h
GI upset, transient visual disturbances,
peripheral edema, rash, hepatitis, QT
prolongation
Posaconazole
Prophylaxis for
invasive aspergillosis
and candidiasis
Oral candidiasis
200 mg po tid
100 mg po bid on day 1,
then 100 mg once/day
for 13 days
Hepatitis, GI upset, rash, QT
prolongation
Fluconazole
Let’s take a rest !
3、Allylamine（丙胺类）
Terbinafine （特比萘芬）
 Terbinafine is a synthetic allylamine that is available in
an oral formulation.
 It is used in the treatment of dermatophytoses,
especially onychomycosis (灰指甲). it is fungicidal.
 It interferes with ergosterol biosynthesis, but rather
than interacting with the P450 system, terbinafine
inhibits the fungal enzyme squalene epoxidase (角鲨烯
环氧化酶). This leads to the accumulation of the sterol
squalene（甾醇角鲨烯）, which is toxic to the
organism.
Adverse effects ： rare
 Primarily of gastrointestinal upset and headache.
 Terbinafine does not seem to affect the P450 system
and has demonstrated no significant drug interactions
to date.
Flucytosine
4、Flucytosine (氟胞嘧啶)
Mechanism of Action
Flucytosine is taken up by fungal cells
via the enzyme--cytosine permease(胞嘧啶渗
透酶). It is converted intracellularly first to
5-FU and then to 5-fluorodeoxyuridine
monophosphate
(FdUMP) and fluorouridine triphosphate
(FUTP), which inhibit DNA and RNA
synthesis, respectively.
Flucytosine
Mechanism of antifungal action:
胸腺嘧啶核苷合成酶
Flucytosine
Clinical uses:
Flucytosine is a narrow-spectrum antifungal drug.
Drug resistance occurs rapidly when
flucytosine is used alone.
So, flucytosine is used predominantly
in combination with amphotericin B for
thearpy of crypotococcal meningitis in
AIDS patient, etc.
Flucytosine
Adverse reactions:
Depressing the function of bone
marrow(leading to leukopenia and
thrombo-cytopenia, etc.).
Plasma levels of hepatic transminase
are elevated(reversible).
Other reaction: including rash,
nausea, vomiting, diarrhea, etc.
Echinocandins
5、Echinocandins（棘白菌素类）



Caspofungin(卡泊芬净)
Micafungin(米卡芬净)
Anidulafungin（阿尼芬净）


Echinocandins are available only in
intravenous formulations.
Mechanism of Action

Act at the level of the fungal cell wall by
inhibiting the synthesis of (1–3)-glucan（葡聚
糖）.
 Spectrum


of action
Active effect against candida （念珠菌）and
aspergillus（曲霉菌）, but not C neoformans (隐
球菌) or the agents of zygomycosis and
mucormycosis(毛霉菌病).
Adverse Effects

Echinocandin agents are extremely well
tolerated, with minor gastrointestinal side
effects and flushing reported infrequently.
Echinocandins
Caspofungin（卡泊芬净）





water-soluble and highly protein-bound.
t1/2: 9–11 hours
metabolites are excreted by the kidneys and gastrointestinal
tract.
Dosage adjustments are required only in the presence of severe
hepatic insufficiency.
Clinical Use


Caspofungin is currently licensed for disseminated and
mucocutaneous candida infections（侵袭性和皮肤粘膜念珠菌病）
Note：caspofungin is licensed for use in invasive
aspergillosis（侵袭性曲霉病） only as salvage therapy（
抢救治疗）in patients who have failed to respond to
amphotericin B, and not as primary therapy.
Echinocandins
Micafungin （米卡芬净）

similar properties with Caspofungin

t1/2: 11–15 hours


Clinical use:
Micafungin is licensed for
mucocutaneous candidiasis, candidemia,
and prophylaxis of candida infections in
bone marrow transplant patients.
Anidulafungin （阿尼芬净）

t1/2: 24–48 hours.

Clinical use:



esophageal candidiasis and invasive
candidiasis, including candidemia.
For esophageal candidiasis, it is administered intravenously
at 100 mg on the first day and 50 mg/d thereafter for 14
days.
For candidemia, a loading dose of 200 mg is recommended with
100 mg/d thereafter for at least 14 days after the last positive
blood culture.
Part 2 Antiviral drugs
Anti-influenza virus agent
Antiherpes agents
 Anti-HIV agents
 Entry inhibitors(入胞抑制药)
 Reverse transcriptase inhibitor(逆转录酶抑制
剂)
 Nonnucleoside reverse transcriptase inhibitor(非
核苷逆转录酶抑制剂 , NNRTI);
 Nucleoside reverse transcriptase inhibitor(核苷
逆转录酶抑制剂 , NRTI);
 Protease inhibitor(蛋白酶抑制剂,PI)
 Integrase Inhibitors （整合酶抑制药）
Antiviral drugs2
Antiviral therapy



流感病毒
Influenza—RNA virus
herpesviruses (HSV)—DNA
virus
human immunodeficiency
virus (HIV)- RNA Reverse
transcript virus
疱疹病毒
艾滋病毒
肝炎病毒
病毒吸附侵入
(attachment &
penetration)
病毒脱壳
(uncoating)
合成
核酸多聚酶
合成病毒
核酸\蛋白质
病毒颗粒
装配成熟
(assembly
)
从细胞内
释放
(release)
Antiviral drugs1
1 Anti-influenza virus agents
 M2蛋白抑制剂：
Amantadine(金刚烷胺)--influenza A
 Neuraminidase(神经氨酸酶,NA) inhibitors
Oseltamivir(奥司他韦)；zanamivir（扎那米韦
）--influenza A &B
 广谱抗病毒药
Ribavirin(利巴韦林, virazole病毒唑）--DNA
&RNA viurs
Mechanism of Antiviral drug action
病毒侵入
病毒吸附
病毒脱壳
合成病毒
核酸\蛋白质
病毒颗粒
装配成熟
释放
Antiviral drugs1
Amantadine(金刚烷胺)


The mechanism of Amantadine's antiviral activity
involves interference with a viral protein, M2 (an
ion channel), which is required for the viral particle
to become "uncoated" once taken inside a cell by
endocytosis.
The mechanism of its antiparkinsonian effect is
poorly understood. The drug has many effects in
the brain, including release of dopamine and
norepinephrine from nerve endings. It appears to be
a weak NMDA receptor antagonist as well as an
anticholinergic.
Clinical use
(1) Preventing influenza A infections during influenza season
(2) Parkinson's disease

Antiviral drugs1
Side effects:



(1)CNS side effects include nervousness, anxiety,
agitation, insomnia, difficulty in concentrating, and
exacerbations of pre-existing seizure disorders and
psychiatric symptoms in patients with schizophrenia
or Parkinson's disease.
(2)Rare cases of severe skin rashes such as Stevens
Johnson Syndrome and suicidal ideation.
(3) Livedo reticularis (网状青斑) is a possible side
effect of amantadine use for Parkinson's disease.
Antiviral drugs1
Rimantadine(金刚乙胺)




Rimantadine is four to ten times more active than amantadine in
vitro.
Amantadine is well absorbed and 67% protein-bound. Its plasma
half-life is 12–18 hours and varies by creatinine clearance.
Rimantidine is about 40% protein-bound and has a half-life of 24–
36 hours. Nasal secretion and salivary levels approximate those in
the serum, and cerebrospinal fluid levels are 52–96% of those in
the serum; nasal mucus concentrations of rimantidine average
50% higher than those in plasma.
Amantadine is excreted unchanged in the urine, whereas
rimantadine undergoes extensive metabolism by hydroxylation,
conjugation, and glucuronidation before urinary excretion.
Neuraminidase(神经氨酸酶,NA) inhibitors
Oseltamivir(奥司他韦)；
zanamivir（扎那米韦）
 Both influenza A and influenza B viruses.
 analogs of sialic acid
 Mechanism:
 Interfere with release of progeny influenza virus from infected
to new host cells, thus halting the spread of infection within the
respiratory tract.
 Destroy the receptors recognized by viral hemagglutinin on cells,
newly released virions, and respiratory tract mucins.
 Early administration is crucial because replication of
influenza virus peaks at 24–72 hours after the onset
of illness.
Oseltamivir(奥司他韦)




Oseltamivir is FDA-approved for patients 1 year and
older,
Oseltamivir is an orally administered prodrug that is
activated by hepatic esterases and widely distributed
throughout the body.
Oral bioavailability is approximately 80%, plasma protein
binding is low, and concentrations in the middle ear and
sinus fluid are similar to those in plasma. The half-life of
oseltamivir is 6–10 hours, and excretion is by glomerular
filtration and tubular secretion in the urine.
Potential adverse effects include nausea, vomiting, and
abdominal pain, which occur in 5–10% of patients early in
therapy but tend to resolve spontaneously.
zanamivir（扎那米韦）




Zanamivir is delivered directly to the respiratory tract via inhalation.
Ten to twenty percent of the active compound reaches the lungs, and
the remainder is deposited in the oropharynx. The concentration of
the drug in the respiratory tract is estimated to be more than 1000
times the 50% inhibitory concentration for neuraminidase, and the
pulmonary half-life is 2.8 hours.
Five to fifteen percent of the total dose (10 mg twice daily for 5 days
for treatment and 10 mg once daily for prevention) is absorbed and
excreted in the urine with minimal metabolism.
Potential adverse effects include cough, bronchospasm (occasionally
severe), reversible decrease in pulmonary function, and transient nasal
and throat discomfort.
zanamivir is approved in patients 7 years or older.
Antiviral drugs1
Ribavirin（利巴韦林）
Mechanism of action

Ribavirin is a guanosine analog (鸟苷类似物) that is
phosphorylated intracellularly by host cell enzymes.



interfere with the synthesis of guanosine triphosphate,
inhibit capping of viral messenger RNA,
inhibit the viral RNA-dependent polymerase of certain viruses.
Action: It is effective against a broad spectrum of RNA and DNA
viruses.
 Influenza A and B,
 parainfluenza(副流感病毒)
 respiratory syncytial virus(呼吸道合胞体病毒)
 paramyxoviruses(副粘病毒)
 HCV
 HIV-1.




In addition to oral administration for hepatitis C
infection in combination with interferon alfa,
Aerosolized ribavirin is administered by nebulizer
(20 mg/mL for 12–18 hours per day) to children and
infants with severe respiratory syncytial virus
(RSV) bronchiolitis or pneumonia to reduce the
severity and duration of illness.
Aerosolized ribavirin has also been used to treat
influenza A and B infections but has not gained
widespread use.
Aerosolized ribavirin is generally well tolerated but
may cause conjunctival or bronchial irritation.
2、Antiherpes agents
 Herpessimplexvirus（疱疹病毒，HSV）
 Varicella-zoster virus (水痘/带状疱疹病毒，VZV)
 Cytomegalovirus(巨细胞病毒CMV)







idoxuridine(碘苷) -- HSV, VZV
Vidarabine(阿糖腺苷)—HSV,VZV,HBV,CMV
acyclovir（阿昔洛韦）; Valacyclovir(伐阿昔洛韦)--HSV、VZV
ganciclovir(更昔洛韦) ; valacyclovir(伐昔洛韦)--HSV、VZV、CMV
foscarnet (磷甲酸盐）--HSV, influenza ,CMV, HIV
cidofovir (西多福韦)—HSV,VZV,CMV
Trifluridine(屈氟尿苷)
Idoxuridine（IDU,碘苷）




Active against HSV and VZV(牛痘病毒）
Inhibit DNA synthesis by blocking thymidylic
acid synthetase
Topical use for treatment of HSV infections
of the eyelid, cornea and skin
High toxicity
Vidarabine （Ara-A,阿糖腺苷）



Convert to Ara-A triphosphate and inhibit DNA
polymerase
Active against HSV and vaccina virus
Treatment of HSV encephalitis and herpetic
keratitis
Antiviral drugs2
Acyclic guanosine derivative
（无环鸟苷衍生物）
阿昔洛韦
更昔洛韦
伐阿昔洛韦
伐更昔洛韦
Antiviral drugs2
Acyclic guanosine derivative
胸苷激酶
Antiviral
Valganciclovir
drugs2
Acyclovir(阿昔洛韦,无环鸟苷)
1. Mechanism of action
It inhibits viral DNA-polymerase, terminating the DNAchain.
 clinical activity --HSV-1, HSV-2, and VZV, but it is approximately 10
times more potent against HSV-1 and HSV-2 than against VZV.
 In vitro activity -- Epstein-Barr virus (EBV), cytomegalovirus (CMV),
and human herpesvirus-6 (HHV-6) is present but weaker.
The bioavailability of oral acyclovir is low (15–20%) and is
unaffected by food. An intravenous formulation is available.
2. Clinical use:
It is used to treat herps simplex viruses, varicella-zoster viruses.
First choice --Herpes simplex viruses infection.
Antiviral
Valganciclovir
drugs2
Ganciclovir(更昔洛韦)




Initial phosphorylation is catalyzed by the virusspecified protein kinase phosphotransferase UL97
in CMV-infected cells.
The activated compound competitively inhibits viral
DNA polymerase and causes termination of viral
DNA elongation.
Ganciclovir has in vitro activity against CMV, HSV,
VZV, EBV, HHV-6, and HHV-8.
Its activity against CMV is up to 100 times greater
than that of acyclovir.
Antiviral drugs2
Adverse effect






Myelosuppression.
nausea, diarrhea,
fever, rash,
headache, insomnia, and peripheral neuropathy.
Central nervous system toxicity (confusion, seizures,
psychiatric disturbance) and hepatotoxicity have
been rarely reported.
Ganciclovir is mutagenic in mammalian cells and
carcinogenic and embryotoxic at high doses in
animals and causes aspermatogenesis;
Antiviral
Valganciclovir
drugs2
Valganciclovir(伐昔洛韦)




After oral administration, both diastereomers are rapidly
hydrolyzed to ganciclovir by intestinal and hepatic esterases.
Valganciclovir is well absorbed and rapidly metabolized in the
intestinal wall and liver to ganciclovir;
The absolute bioavailability of oral valganciclovir is 60%. The
AUC0–24h resulting from valganciclovir (900 mg once daily) is
similar to that after 5 mg/kg once daily of intravenous ganciclovir
and approximately 1.65 times that of oral ganciclovir.
The major route of elimination is renal, through glomerular
filtration and active tubular secretion.
Clinical use


Cytomegalovirus(CMV) retinitis in patients with AIDS
Prevention of CMV disease in high-risk kidney, heart, and kidneypancreas transplant patients.
Foscarnet
Foscarnet(磷甲酸盐)

It has in vitro activity against
HSV, VZV, CMV, EBV, HHV-6(人类
疱疹病毒), HHV-8, and HIV-1.





inhibits viral DNA polymerase,
inhibits RNA polymerase,
inhibits HIV reverse transcriptase
Foscarnet blocks the
pyrophosphate（焦磷酸） binding
site of these enzymes and inhibits
cleavage of pyrophosphate from
deoxynucleotide triphosphates.
Foscarnet is available in an
intravenous formulation only;
Foscarnet
Adverse effects





Renal impairment, hypo- or hypercalcemia, hypoor hyperphosphatemia, hypokalemia, and
hypomagnesemia.
Nausea, vomiting, anemia, elevation of liver
enzymes, and fatigue
the risk of anemia may be additive in patients
receiving concurrent zidovudine.
Central nervous system toxicities include
headache, hallucinations, and seizures;
Foscarnet caused chromosomal damage in
preclinical studies.
Antiviral drugs2
Cidofovir（西多福韦）




Cidofovir is an acyclic cytosine nucleotide （无环胞
嘧 啶 核 苷 酸 ） analog with in vitro activity against
CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8,
adenovirus, poxviruses （ 痘 病 毒 ） , polyomaviruses,
and human papillomavirus（人乳头状瘤病毒）.
In contrast to ganciclovir, phosphorylation of
cidofovir to the active diphosphate is independent
of viral enzymes ; thus activity is maintained against
thymidine kinase-deficient or -altered strains of
CMV or HSV.
Cidofovir-resistant
isolates
tend
to
be
crossresistant
with ganciclovir but retain
susceptibility to foscarnet.
Adverse effects ： a dose-dependent proximal
tubular nephrotoxicity
Anti-HIV agents
1. Entry inhibitors(入胞抑制药)
2. Reverse transcriptase inhibitor(逆转录酶抑制剂)
 Nonnucleoside reverse transcriptase inhibitor(非
核苷逆转录酶抑制剂 , NNRTI);
 Nucleoside reverse transcriptase inhibitor(核苷逆
转录酶抑制剂 , NRTI);
3. Protease inhibitor(蛋白酶抑制剂,PI)
4. Integrase Inhibitors （整合酶抑制药）
Anti-HIV agents summary
Entry inhibitors(入胞
抑制药)
恩夫韦地（enfuvrtide）
西夫韦肽（sifuvirtide）
NNRTI:
地拉韦定(delavirdine)
奈韦拉平(nevirapine)
依法韦恩茨(efavirenz)
NRTI:
齐多夫定(zidovudine，
AZT)
扎西他宾(zalcitabine，
ddC)
司他夫定(stavudine，
d4T)
拉米夫定(lamivudine，
3TC)
去羟肌苷(didanosine，
ddI)
阿巴卡韦(abacavir，
ABC)
马拉韦罗（maraviroc）
Integrase Inhibitors （整合酶抑制药）:
雷特格韦（raltegravir）
Protease inhibitor(蛋白酶抑制剂
,PI)
利托那韦(ritonavir)
奈非那韦(nelfinavir)
沙奎那韦(saquinavir)
英地那韦(indinavir)
安谱那韦(amprenavir)
Zidovudine
Zidovudine(齐多夫定,zdv,azt)



Zidovudine (azidothymidine; AZT) is a
deoxythymidine（脱氧胸苷） analog
Zidovudine was the first antiretroviral agent to be approved
and has been well studied. The drug has been shown to
decrease the rate of clinical disease progression and prolong
survival in HIV-infected individuals.
Efficacy has also been demonstrated in the treatment of
HIV-associated dementia and thrombocytopenia.
Pharmakinetic




well absorbed (63%)
distributed to most body tissues and fluids,
including thecerebrospinal fluid, where drug levels
are 60–65% of those in serum.
The serum half-life averages 1.1 hours, the
intracellular half-life of the phosphorylated
compound is 3–4 hours, allowing twice-daily dosing.
eliminated primarily by renal excretion following
glucuronidation in the liver.
Zidovudine
Clinical use


Zidovudine is often co-administered with
lamivudine, and a combination formulation is
available.
In pregnancy, a regimen of oral zidovudine
beginning between 14 and 34 weeks of gestation,
intravenous zidovudine during labor, and
zidovudine syrup to the neonate from birth
through 6 weeks of age has been shown to reduce
the rate of vertical (mother-to-newborn)
transmission of HIV by up to 23%.
Zidovudine
Adverse effect








Myelosuppression, resulting in macrocytic anemia (1–4%) or
neutropenia (2–8%)，thrombocytopenia,
Gastrointestinal intolerance, headaches, and insomnia may occur
but tend to resolve during therapy.
Extremity fat loss
hyperpigmentation of the nails
myopathy.
High doses can cause anxiety, confusion, and tremulousness.
Zidovudine causes vaginal neoplasms in mice; however, no human
cases of genital neoplasms have been reported to date. Shortterm safety has been demonstrated for both mother and infant.
Hematologic toxicity may be increased during co-administration
of other myelosuppressive drugs such as ganciclovir, ribavirin,
and cytotoxic agents.
Non-nucleoside reverse
transcriptase inhibitors






Delavirdine(地拉韦定）
Nevirapine（奈韦拉平）
Efavirenz （依法韦恩茨）
Mechanism: different with NRTIs
Used in combination with NRTIs and PI
Toxicity: rash
Protease inhibitor





Drugs :saquinavir（沙奎那韦）, ritonavir(
利托那韦）,indinavir（英地那韦）, nelfinavir
（奈非地韦）
Mechanism: inhibit precursor molecules
convert to mature virions during HIV
replication
Clinical uses: in combination with other
agents to treat AIDS
Toxicity
Abnormality in metabolism include altered
body fat distribution, insulin resistance
and hyperlipidemia
Drug Toxicity and Side Effects



All available antiretroviral drugs are toxic.
Side effects of nucleoside analogs are
lactic acidosis and severe hepatomegaly
with steatosis (enlarged fatty liver).
Other side effects of anti-HIV drugs
include pancreatitis, myopathy, anemia,
peripheral neuropathy, nausea, and
diarrhea.
Reducing Drug Toxicity

The use of combination therapy:


Combining agents with favorable synergistic
properties allows a decrease in dose or dosing
frequency
Ritonavir alone cause gastrointestinal side
effects but when used in combination with
other PI’s it can be administered at a lower
dose.
Conclusions



An effective anti-HIV therapy is still
needed.
Several possible targets are being studied
and tested.
The area of anti-HIV drugs has more room
for growth and the future for the
discovery of new effective drugs is
promising.
Let’s take a rest !
Part 9.
A. Antituberculous Drugs
B. Antilepric Drugs
Antituberculous Drugs
Main Antituberculous Drugs:
First-line agents:
Isoniazid(异烟肼),
1945
Rifampin(利福平),
1965
Ethambutol(乙胺丁醇),
1959
Streptomycin(链霉素),
1944
Pyrazinamide(吡嗪酰胺),
1952
Second-line agents:
Para-aminosalicylic(对氨水杨酸),
Ethionamide(乙硫异烟胺)
Amikacin(阿米卡星)
Capreomycin(卷曲霉素)
Fluoroquinolones: Ciprofloxacin(环丙沙星),
Ofloxacin(氧氟沙星), etc.
120
100
80
亚洲区
欧洲区
北美区
60
40
20
0
一月
二月
三月
四月
Isoniazid(异烟肼, Rimifon, 雷米封,
INH, Isonicotinylhydrazide)
Isonizid
1. Antituberculous activity:
 Bacteriostatic for resting tubercle bacilli,
and bactericidal for actively growing
tubercle bacilli.
 Isoniazid penetrates into macrophages
and is active against both extracellular
and intracellular organisms.
 In vitro, isoniazid inhibits most tubercle
bacilli in a concentration of 0.025~0.05
μg/mL or less and is bactericidal for
actively growing tubercle bacilli.
 Resistance mutants occurs easily when
given as the sole drug.
 It is less effective against atypical
mycobacterial species.
Isoniazid
2. Mechanism of action:
 Inhibiting synthesis of mycolic
acids(分枝菌酸) of tubercle bacilli,
the mycolic acids are essential
components of mycobacterial cell
walls:

Isoniazid
*
* NAD: nicotinamide-adenine dinucleotide
(烟酰胺腺嘌呤二核苷酸, 辅酶Ⅰ)
Isonizid
3. Pharmacokinetics



Absorbtion: Isoniazid is readily absorbed from
the gastrointestinal tract. A 300-mg oral dose (5
mg/kg in children) achieves peak plasma
concentrations of 3–5 mcg/mL within 1–2 hours.
Distribution: Isoniazid diffuses readily into all
body fluids and tissues.
Metabolism: liver N-acetyltransferase(N乙酰转
移酶)



express acetylators(EM) --- hepatitis
poor acetylators(PM)-- Peripheral neuropathy
Excretion: The products of metabolism are
excreted mainly in the urine.
Isoniazid
Isoniazid
4. Clinical Uses:
Combination with rifampicin, or
second-line antituberculous agents,
isoniazid is used for severe
infections with tubercle bacilli.
 As a single agent, isoniazid is
indicated for prevent and
treatment of mild tuberculosis of
early stage.

Isoniazid
5. Adverse reactions:
(1)Allergic reactions: rash, fever, etc.
(2)Hepatotoxicity(rapid inactivator);
(3)Peripheral neuritis(slow inactiva-tor):
pyridoxine(吡哆醇, VitminB6 )
(4)CNS toxic effects(when overdose);
(5)GI effects.
Rifampin
rifampin(利福平 )

Antimicrobial activity:





Mechanism of action: bactericidal


inhibits DNA-dependent RNA polymerase
Adverse effects:


Rifampicin is a broad-spectrum antimicrobial
activity;
It is a bactericidal for tubercle bacilli;
It can readily penetrates most tissues and into
phagocytes;
Resistance mutants occurs easily if used as a
single drug.
hepatotoxicity.
Resistance : rapidly.


no crossresistance to other classes of
antimicrobial drugs
cross-resistance to other rifamycin
derivatives, eg, rifabutin and rifapentine.
Rifampicin



2. Mechanism of action:
Rifampicin can bind strongly to the b
subunit of bacterial DNA-dependent
RNA ploymerase, to inhibit bacterial
RNA synthesis selectively.
It is no effect to RNA ploymerase of
mammal cell(哺乳动物的细胞).
Rifampicin
Rifampicin
3. Mechanism of resistance:
 Resistance results from one of
several possible points mutation in
the gene for b subunit of RNA
polymerase.
 These mutation prevent binding of
rifampicin to RNA polymerase.

Rifampicin
4. ADME of rifampicin:









(1)Absorption:
Well absorbed after oral admini-stration. The absorption
is attenua-ted by food and para-aminosalicylic (PAS).
(2)Distribution:
Widely distributed, even in CSF when menings is
infectious.
(3)Metabolism:
Metabolized in liver by deacylation;
Rifampicin is a hepatic enzyme inducer(inducing CYP1A2,
CYP3A4, CYP2C).
(4)Excretion:
Excreted mainly through the liver into bile, then
undergoes enterohe-patic recirculation.
Rifampin
Clinical Uses

MYCOBACTERIAL INFECTIONS
 combination with isoniazid or other antituberculous drugs







Active tuberculosis to prevent emergence of drug-resistant mycobacteria.
Some atypical mycobacterial infections and in leprosy.--Rifampin 600
mg daily or twice weekly for 6 months
an alternative to isoniazid prophylaxis for patients with latent
tuberculosis only--Rifampin, 600 mg daily for 4 months as a single drug
OTHER INDICATIONS
prophylaxis meningococcal carriage— 600 mg twice daily for 2 days
prophylaxis in Haemophilus influenzae type b (流感嗜血杆菌)disease: 20
mg/kg/d for 4 days,
eradicate staphylococcal carriage: combination other agents


serious staphylococcal infections such as osteomyelitis (骨髓炎)
prosthetic valve endocarditis(人工瓣膜性心内膜炎)
Rifampin
Adverse Reactions




harmless orange color : urine, sweat, tear, and contact lenses
(soft lenses may bepermanently stained).
Occasional adverse effects :
 rashes, thrombocytopenia(血小板减少症), and nephritis(肾炎).
 cholestatic jaundice(胆汁淤积性黄疸) and occasionally
hepatitis.
flu-like syndrome : fever, chills(寒战), myalgias(肌痛), anemia(贫
血), and thrombocytopenia and sometimes is associated with
acute tubular necrosis(急性肾小管坏死).
Cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4)
inducer :
 increases the elimination of numerous other drugs including
methadone(美沙酮) , anticoagulants(抗凝剂), cyclosporine(环孢
素), some anticonvulsants, protease inhibitors, some
nonnucleoside reverse transcriptase inhibitors(非核苷逆转录
酶抑制剂), contraceptives, and a host of others.
 lower serum levels of these drugs.
Ethambutol
Ethambutol(乙胺丁醇 )


Mechanism of action: bacteriostatic
Mycobacterial arabinosyl transferases(阿拉伯糖基转
移酶). Arabinosyl transferases are involved in the
polymerization reaction of arabinogalactan , an
essential component of the mycobacterial cell wall.
Ethambutol(乙胺丁醇)





1. Antimycobacterial actvity:
Nearly all strain of tubercle bacilli are sensitive.
Be bactericidal to intercellular and
extrecellular tubercle bacilli.
Resistance to ethambutol developed very slowly
in vitro.
The mechanism of action is invol-ved in
inhibition of RNA synthesis.
Ethambutol
Ethambutol
Ethambutol
Clinical Use


Combination with isoniazid or rifampin.
Ethambutol hydrochloride, 15–25 mg/kg, a
single daily dose
tuberculous meningitis:
higher dose 50 mg/kg twice-weekly
Ethambutol
Adverse Reactions <2%





Retrobulbar neuritis(球后视神经炎 )
 loss of visual acuity (视敏度 )
 Red-green color blindness.
This dose-related adverse effect is more likely to
occur at dosages of 25 mg/kg/d continued for several
months.
At 15 mg/kg/d or less, visual disturbances are very
rare.
Periodic visual acuity testing is desirable if the 25
mg/kg/d dosage is used.
Hyperuricaemia
Pyrazinamide
pyrazinamide (吡嗪酰胺,PZA)


Pyrazinamide (PZA) is a relative of nicotinamide, stable, and slightly
soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits
tubercle bacilli and some other mycobacteria at concentrations of
approximately 20 mcg/mL.
The drug is taken up by macrophages and exerts its activity against
mycobacteria residing within the acidic environment of lysosomes.
Antimycobacterial Activity
& Resistance




Pyrazinamide
The drug is largely bacteriostatic, but can be
bacteriocidal on actively replicating tuberculosis
bacteria.
Pyrazinamide is converted to pyrazinoic acid(吡嗪酸)—
the active form of the drug—by mycobacterial
pyrazinamidase, which is encoded by pncA.
Mechanism of action:
inhibit the enzyme fatty acid synthase (FAS) I, which
is required by the bacterium to synthesise fatty acids
Resistance



impaired uptake of pyrazinamide
mutations in pncA that impair conversion
of pyrazinamide to its active form.
no cross-resistance with isoniazid or other
antimycobacterial drugs.
Pyrazinamide
Pharmacokinetics



Serum concentrations of 30–50 mcg/mL at 1–2
hours after oral administration are achieved
with dosages of 25 mg/kg/d.
Pyrazinamide is well absorbed from the
gastrointestinal tract and widely distributed in
body tissues, including inflamed meninges.
Pyrazinamide is an important front-line drug
used in conjunction with isoniazid and rifampin in
short-course (ie, 6-month) regimens as a
"sterilizing" agent active against residual
intracellular organisms that may cause relapse.
Pyrazinamide
Adverse Reactions

Major adverse effects :
 hepatotoxicity (in 1–5% of patients)
 nausea, vomiting, drug fever,
 Hyperuricemia(高尿酸血症 ) : may
provoke acute gouty arthritis(急性痛
风性关节炎 ).
Streptomycin(链霉素)




Streptomycin is the first effective
drug to treat tuberculosis.
It is bacteriostatic for the tuber-cle
bacillus.
Resistance to streptomycin deve-loped
easily when it is used alone.
Given simultaneously with other
antibacterial drugs to prevent emergence of toxic reaction & resistance
occurrence.
Para-aminosalicylic acid
(PAS, 对氨水杨酸)
 A folate synthesis antagonist, it is
structurally similar to PABA.
 Well absorbed after oral administration, and widely distributed in
tissues and body fluid except the CSF.
 PAS is used in combination with other
drugs. PAS alone is of little value in
the treatment of tubercu-losis.
Para-aminosalicylic acid
Resistance for PAS occurs much
more slowly than that for other
anti-tuberculous drugs.
 Adverse reactions:

GI symptom and
hematological abnormalities, etc.

Other antituberculous drugs

Rifapentine(利福喷汀) and Rifadin(
利福定)
Ethionamide(乙硫异烟胺)
 Amikacin(阿米卡星)
 Capreomycin(卷曲霉素)
 Fluoroquinolones(氟喹酮类)

The principle for using antituberculous
drugs
1. Treatment should be initiated
with antituberculous drugs early.
 2. Treatment should be initiated
with combination of antituberculous
drugs.
 3. Treatment should be continued
for a suitable time(at least 6-9
months).

Let’s take a rest !
B. Antilepric Drugs
Antileprotic drugs


Mycobacterium leprae has never been grown in vitro, but
animal models, such as growth in injected mouse footpads,
have permitted laboratory evaluation of drugs.
Only those drugs that have the widest clinical use are
presented here. Because of increasing reports of dapsone
resistance, treatment of leprosy with combinations of the
drugs listed below is recommended.
DAPSONE (氨苯砜)& OTHER
SULFONES（砜类）

Dapsone
dapsone (diaminodiphenylsulfone,DDS).



Inhibits folate synthesis.
Resistance can emerge in large populations of M leprae(麻风杆菌
), eg, in lepromatous leprosy（瘤型麻风 ）.
Skin heavily infected with M leprae may contain several times
more drug than normal skin.
Dapsone
Clinical use


Combination of dapsone, rifampin, and
clofazimine is recommended for initial
therapy.
Dapsone may also be used to prevent
and treat Pneumocystis jiroveci
pneumonia（耶氏肺孢子虫肺炎 ） in
AIDS patients.
Dapsone
Adverse Reactions






Hemolysis: particularly if they have glucose-6phosphate dehydrogenase deficiency.
Methemoglobinemia(高铁血红蛋白血症)
Gastrointestinal intolerance
Fever, pruritus
Various rashes occur.
Erythema nodosum leprosum(结节性红斑狼疮) :
It is sometimes difficult to distinguish reactions to
dapsone from manifestations of the underlying
illness.
Erythema nodosum leprosum may be suppressed by
corticosteroids or by thalidomide(沙利度胺).
RIFAMPIN


Rifampin in a dosage of 600 mg daily is
highly effective in lepromatous leprosy.
combination with dapsone or another
antileprosy drug. A single monthly dose
of 600 mg may be beneficial in
combination therapy.
Clofazimine(氯法齐明)






a phenazine dye an alternative to dapsone.
Its mechanism of action is unknown but may involve DNA
binding.
Absorption of clofazimine from the gut is variable, and a
major portion of the drug is excreted in feces.
Clofazimine is stored widely in reticuloendothelial tissues and
skin, and its crystals can be seen inside phagocytic
reticuloendothelial cells. It is slowly released from these
deposits, so that the serum half-life may be 2 months.
Clofazimine is given for sulfone-resistant leprosy or when
patients are intolerant to sulfones. A common dosage is 100
mg/d orally.
untoward effect :
 skin discoloration ranging from redbrown to nearly black.
 Gastrointestinal intolerance occurs occasionally.
Part 10.
Clinical Rational Uses of
Antimicrobial Agents
(抗菌药物的合理应用)
主要内容
一、临床应用抗菌药物的基本原则;
二、抗菌药物的预防性应用;
三、抗菌药物的治疗性应用;
四、抗菌药物的联合应用;
五、抗菌药在肝、肾功能减退患者的应用.
一、临床应用抗菌药物的基本原则:
有4个基本原则.

(1)尽早确立病原体诊断后选药
可以用以下方法:
 ①临床诊断(Clinical diagnosis);
 ②微生物学诊断(Microbiologic
diagno-sis);
 ③体外药敏试验(Testing results in
vitro.)

临床应用抗菌药物的基本原则
临床应用抗菌药物的基本原则





(2)根据抗菌药的作用特点合理用药
①根据药物吸收、分布和消除动力学选用
抗菌药;
②根据药物进入感染区域的能力选用抗菌
药物;
③根据药物潜在毒性(potential
toxicity)而选用适当的抗菌药物;
④根据抗菌药与其他药物在药效学和药动
学方面的相互作用选药.
临床应用抗菌药物的基本原则





(3)根据患者生理、病理、免疫状态选药:
①根据病人的年龄, 以及妊娠状态选药;
②根据病人的肝、肾功能选药;
③根据患者的防御功能状态选药;
④注意病人的个体差异(Individual
variation).
临床应用抗菌药物的基本原则






(4)下述情况时应严格控制抗菌药的应用:
①病毒感染(Viral infections);
②由不明原因引起的发热;
③局部应用(Topical applications);
④抗菌药的预防性应用(Antimicrobial
prophylaxis);
⑤抗菌药的联合应用(Antimicrobial
agents combinations).
二、抗菌药物的预防性应用:



目前在临床上, 抗菌药物的应用有较高的比例(大约为
30% ～50%)是用于预防感染而不是治疗感染. 这种用
于预防感染的方式大多数都可以归入抗菌药物的滥用
(abuse).
一般来说, 如果是由特定和单一的微生物感染, 用
特效的和无毒性的抗菌药预防感染, 或在感染早期应用
抗菌药以根除感染, 那么这种预防性用药是可行的, 通
常也会获得成功.
在另一方面, 如果预防用药的目的是防止多种细菌入
侵而引起的感染, 则往往很难奏效, 甚至会诱使耐药性
的产生和蔓延.
抗菌药物的预防性应用



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

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(1)在内科领域抗菌药的预防性应用:
①风湿热(Rheumatic fever);
②脑膜炎球菌感染(Meningococcal infection);
③结核病(Tuberculosis);
④新生儿眼炎(Newborn ophthalmia);
⑤尿路感染(Urinary tract infections);
⑥疟疾(Malaria).
抗菌药物的预防性应用
(2)在外科领域抗菌药的预防性用药:
①心血管手术(Cardiac operation);
 ②开胸手术(Thoracic operation);
 ③腹部或四肢手术(Operation of
abdominal and lower extremity);
 ④头、面部和颈部手术(Head, face,
and neck operation);
 ⑤胃肠道或胆囊手术(Gastroduodenal
or biliary operation);

抗菌药物的预防性应用
外科领域的预防用药




⑥植入金属器具的矫形手术(Orthopedic
operation with hardware insertion)
⑦贯穿性创伤(Penetrating trauma);
⑧严重烧伤(Severe burn wound);
⑨阑尾切除术, 结肠或直肠手术等(Appendectomy, and colorectal or rectal
operation, etc.)
三、抗菌药物的治疗性应用
在临床应用抗菌药之前, 首先应当确定
引起感染的病原体, 并做了病原体的药
敏试验.
 但在临床实际应用时, 常常是在没有完
全确定引起感染的病原体前, 就选用某
种对感染可能有效的抗菌药物开始治疗
. 我们通常把这种抗生素的用法称为“
经验疗法”(empirical therapy).

抗菌药物的治疗性应用

实施经验疗法的步骤:

①已确定病原体感染的临床诊断;

②已取得供实验室检查的样本;

③最好已确定了微生物学的诊断;

④决定经验疗法的必要性;

⑤实施治疗.
抗菌药物的治疗性应用
抗菌药物的治疗性应用
抗菌药物的治疗性应用
抗菌药物的治疗性应用


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合理的抗菌药治疗方案应包括以下考虑:
药物剂量,
给药途径,
治疗的疗程.
为了获得满意疗效, 治疗方案还应考
虑到病原体、宿主和药理学三方面的因素.
四、抗菌药物的联合应用:
(1)抗菌药物联合应用的可能结果有4种:
Ⅰ. 累加(Addition);
Ⅱ. 协同(Synergy);
Ⅲ. 拮抗(Antagonism);
Ⅳ. 无关(Indifference).


★抗菌药
物联合应
用的结果.
抗菌药物的联合应用
(2)抗菌药物根据其作用特点可分为4类:




①繁殖期杀菌药(bactericidal agents for
growing bacteria): 如-内酰胺类;
②静止期杀菌药(bactericidal agents for
resting bacteria): 如氨基糖苷类等;
③速效抑菌药(fast bacteriostatic
agents): 如大环内酯类、氯霉素类等;
④慢效抑菌药(slow bacteriostatic
agents): 如磺胺类.
抗菌药物的联合应用
(3)抗菌药物联合应用的临床结果:
① + ②  synergy(协同作用);
 ① + ③  antagonism(拮抗作用);
 ① + ④  addition(累加), 或
indifference(无关);
 ③ + ④  addition(累加).

抗菌药物的联合应用
(4)抗菌药联合应用产生协同作用的机制:





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①作用于相同机制的不同环节:
如SMZ + TMP;
②同时改变细菌细胞壁或细胞膜的通透性:
如青霉素类与链霉素合用;
③抑制抗菌药物的灭活酶:
如青霉素类与内酰胺酶抑制剂合用;
④抑制不同的耐药菌群:
如抗结核病药的联合应用.
抗菌药物的联合应用
(5)抗菌药物联合应用的适应证:
①病因未明的严重感染;
②单一抗菌药物不能有效控制的混合感染;
③单一抗菌药物不能有效控制的严重感染;
④治疗需要较长时间并且又容易产生耐药
性感染.
抗菌药物的联合应用
五、抗菌药在肝、肾功能减退患者的应用.
1. 肝功能不良患者的抗菌药物应用:

对于肝功能不良患者, 应适当减少主
要经肝脏代谢的药物剂量, 但没有十分严
格的指标. 因此, 在这类病人的抗菌药物
应用应注意以下3个问题:
 (1)药动学方面的改变;
 (2)使用的抗菌药物可能对肝功能的影响;
 (3)药效学方面的改变.

抗菌药在肝、肾功能减退患者的应用
肝功能不良患者的抗菌药物应用
可按正常
剂量剂量
适当减少
给药剂量
Penicillin G
Erythromycin
Cefazolin
Flucytosine
Vancomycin
Aminoglycosides
Polymixins
ethambutol
显著减少
给药剂量
禁止使用的药物
Piperacillin
Mezocillin
Cefalotin
Ceftriaxone
Lincomycin
Clindamycin
Fleroxacin
Sulfonamides
Tetracyclines
Chloramphenicol
Isoniazid
Rifampicin
Amphotercin B
Ketoconazole
Miconazole
抗菌药在肝、肾功能减退患者的应用

2. 肾功能不良患者的用药:

肾功能不良的病人有比较明确的肾功能减退
的指标, 见下表:
抗菌药在肝、肾功能减退患者的应用

肾功能不良患者的用药
可按正常
剂量剂量
适当减少
给药剂量
显著减少
给药剂量
禁止使用的药物
Macrolides
Chloramphenicol
Isoniazid
Rifampicin
Doxycycline
Penicillin G
Carbenicillin
Cefazolin
Cefamandole
Cefuroxime
Ofloxacin
Vancomycin
Aminoglycosides
Polymixins
Flucytosine
Amphotercin B
Cefaloridine
Sulfonamides
Tetracyclines
nitrofurantoin
Today’s class is over !