Section 15

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

ContentsContents Part 7. Part 7. Antifungal agentsAntifungal agents Part 8. Part 8. Antiviral agentsAntiviral agentsPart 9. Antituberculous

Drugs and Anti-lepric Drugs Part 10. Clinical Rational

Uses of Antimicrobial Agents

Part 7.Part 7.

Antifungal agentsAntifungal agents(( 抗真菌药抗真菌药 ))

OverviewOverview

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.

ClassificationClassification

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(Amphotericin B(两性霉素 B ); Nystatin（制霉菌素）Griseofulvin(Griseofulvin(灰黄霉素灰黄霉素 ))

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 )

MMechanism echanism of actionof action

角鲨烯环氧化酶羊毛甾醇

葡聚糖合成酶氟胞嘧啶

特比萘芬

唑类

棘白菌素类

壳多糖

1 、 Antibiotic ( 抗生素类 ):

Amphotericin B( 两性霉素 B ); Nystatin （制霉菌素）Griseofulvin( 灰黄霉素 )

AntibiotiAntibioticc


amphotercin B

Amphotercin B( 两性霉素 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 .

AmphotercinAmphotercin BB

Mechanism of antifungal action

AmphotercinAmphotercin B 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 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.



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 ).

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.


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 ).

Amphotercin BAmphotercin B

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.


Griseofulvin(Griseofulvin( 灰黄霉素灰黄霉素 ))

(1) (1) Mechanism of action :: cellular level Binds to microtubules and prevents mitosis in fungi.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) (2) Clinical usesClinical uses::

Oral long-term therapy for dermatophyteOral long-term therapy for dermatophyte,, hair and hair and nail infectionsnail infections

（（ 33）） Adverse effectsAdverse effects An allergic syndrome much like serum sickness( 血清病 ), hepatitis, drug interactions with warfarin and phenobarbital.


2、 Azoles（唑类）

Imidazoles （咪唑类） : ketoconazole(酮康唑酮康唑 ), Miconazole(咪康唑咪康唑 ), clotrimazole (克霉唑克霉唑 )

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.

Azoles

Triazole CYP3A4 CYP2C9 CYP2C19

Fluconazole Moderate Strong Moderate

Itraconazole Strong - -

Voriconazole Moderate Moderate Weak

Posaconazole Moderate - -

- = no inhibition.

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 Clinical UsesUses: : 1. C1. Cutaneous candidiasis(utaneous candidiasis( 皮肤念珠菌病皮肤念珠菌病 )): :

vaginal vaginal 2. 2. Dermatophytosis(Dermatophytosis( 皮肤癣菌病皮肤癣菌病 ))3. 3. HHistoplasmosis(istoplasmosis( 组织胞浆菌病组织胞浆菌病 ))

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

fluconazole-resistant 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.

spectrumspectrum 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 ).

Azoles

Drug Uses Dose Adverse EffectsKetoconazole Multiple systemic

mycosesSevere recalcitrant dermatomycos

200 mg po once/dayor 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

Fluconazole

Mucosal and systemic candidiasisCryptococcal meningitis

3–12 mg/kg po or IV once/day

GI upset, dizziness, hepatitis, angioedema, anaphylaxis, seizures, exfoliative dermatitis, QT prolongation

ItraconazoleDermatomycosisMultiple systemic mycoses

100 mg po once/day to 200 mg po bidor 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 candidiasisOral candidiasis

200 mg po tid100 mg po bid on day 1, then 100 mg once/day for 13 days

Hepatitis, GI upset, rash, QT prolongation

Let’s take a rest !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.

Mechanism of ActionMechanism of Action Flucytosine is taken up by fungal Flucytosine is taken up by fungal

cells viacells via the enzymethe enzyme----cytosine cytosine permeasepermease((胞嘧啶渗透酶胞嘧啶渗透酶 )). It is converted . It is converted intracellularly first to 5-FU and then intracellularly first to 5-FU and then to 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate monophosphate

(FdUMP) and fluorouridine triphosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA (FUTP), which inhibit DNA and RNA synthesis, respectively.synthesis, respectively.

44 、、 FlucytosineFlucytosine ( ( 氟胞嘧氟胞嘧啶啶 ))

FlucytosiFlucytosinene

Mechanism of antifungal action:


胸腺嘧啶核苷合成酶

Flucytosine is a narrow-spectrum

anti-fungal 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.

FlucytosinFlucytosinee

Clinical uses:

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.


Adverse reactions:

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） .

Echinocandins

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.

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.

Echinocandins

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 therapy

肝炎病毒

艾滋病毒

疱疹病毒流感病毒 Influenza—RNA virus

herpesviruses (HSV)—DNA virus

human immunodeficiency virus (HIV)- RNA Reverse transcript virus

Antiviral drugs2

合成病毒核酸 \蛋白

质

病毒颗粒装配成熟(assembly)

合成核酸多聚酶

病毒脱壳(uncoating)

病毒吸附侵入(attachment & penetration)

从细胞内释放

(release)

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)

inhibitorsOseltamivir( 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） --DN

A &RNA viurs

Antiviral drugs1

MechanismMechanism of of Antiviral drug Antiviral drug actionaction

病毒吸附病毒侵入

病毒脱壳

合成病毒核酸 \ 蛋白质

病毒颗粒装配成熟

释放

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 useClinical use(1) Preventing influenza A infections during influenza season(1) Preventing influenza A infections during influenza season(2) Parkinson's disease(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.

Antiviral drugs1

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.

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.

Ribavirin （利巴韦林）

Antiviral drugs1

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

Acyclic guanosine derivative（无环鸟苷衍生物）

阿昔洛韦

伐更昔洛韦

更昔洛韦

伐阿昔洛韦

Antiviral drugs2

Acyclic guanosine derivative

胸苷激酶

Antiviral drugs2

Acyclovir(Acyclovir(阿昔洛韦阿昔洛韦 ,,无环鸟无环鸟苷苷 ))

1. 1. M Mechanism echanism of actionof action It inhibits viral DNA-polymerase, terminating the DNA-

chain. . 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 The bioavailability of oral acyclovir is low (15–20%) and is

unaffected by food. An intravenous formulation is unaffected by food. An intravenous formulation is available.available.

2. Clinical use:2. Clinical use:It is used to treat herps simplex viruses, varicella-zoster

viruses. First choice --Herpes simplex viruses infection.

ValganciclovirAntiviral drugs2

Ganciclovir(Ganciclovir( 更昔洛韦更昔洛韦 ))

Initial phosphorylation is catalyzed by the virus-specified 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.


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 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

kidney-pancreas transplant patients.


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,

hypo- or 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.

Foscarnet

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

Antiviral drugs2

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 ）

马拉韦罗（ maraviroc ）

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)

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)

Integrase Inhibitors （整合酶抑制药） : 雷特格韦（ raltegravir ）

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.

Zidovudine

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.

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. Short-term 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.

Zidovudine

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 inhibitorDrugs :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.


Part 9.

A. Antituberculous Drugs B. Antilepric Drugs

Main Antituberculous Drugs:

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.

0

20

40

60

80

100

120

一月二月三月四月

亚洲区欧洲区北美区

Isoniazid( 异烟肼 , Rimifon, 雷米封 ,INH, Isonicotinylhydrazide)

1. Antituberculous activity: Bacteriostatic for resting tubercle bacilli, a

nd 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.

Isonizid

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 NAD: nicotinamide-adenine dinucleotidedinucleotide

(( 烟酰胺腺嘌呤二核苷酸烟酰胺腺嘌呤二核苷酸 , , 辅酶Ⅰ辅酶Ⅰ ))

**

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.

Isonizid

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( 利福平利福平 ))

Antimicrobial activity: 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.

Mechanism of action: bactericidal inhibits DNA-dependent RNA polymerase

Adverse effects: hepatotoxicity.

Resistance : rapidly. no crossresistance to other classes of

antimicrobial drugs cross-resistance to other rifamycin

derivatives, eg, rifabutin and rifapentine.

Rifampin

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

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.

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, CY

P3A4, CYP2C). (4)Excretion: Excreted mainly through the liver into bile, then undergoes e

nterohe-patic recirculation.

Rifampicin

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.

Rifampin

Ethambutol(Ethambutol( 乙胺丁醇乙胺丁醇 ))

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

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

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

Ethambutol

pyrazinamide ( 吡嗪酰胺吡嗪酰胺 ,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.

Pyrazinamide

Antimycobacterial Activity & Resistance The drug is largely bacteriostatic, but can be bacterioci

dal 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 r

equired by the bacterium to synthesise fatty acids

Pyrazinamide

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.

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 ).

Pyrazinamide

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 emer-gence 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 admi-

nistration, 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 drugsRifapentine( 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 drugs1. 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).


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 (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-6-

phosphate 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 ).

Dapsone

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


(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 .


(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).


(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

(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 in-

fection); 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)(2) 在外科领域抗菌药的预防性用药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);

外科领域的预防用药外科领域的预防用药抗菌药物的预防性应用

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

(Appen-dectomy, 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 .




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 ).

(4) 抗菌药联合应用产生协同作用的机制 :

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 .


(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 .



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 .

可按正常可按正常适当减少适当减少显著减少显著减少禁止使用的药物禁止使用的药物剂量剂量剂量剂量给药剂量给药剂量给药剂量给药剂量

Penicillin G Penicillin G CefazolinCefazolinVancomycinVancomycinAminoglycosidesAminoglycosidesPolymixinsPolymixinsethambutolethambutol

ErythromycinErythromycinFlucytosineFlucytosine

PiperacillinPiperacillinMezocillinMezocillinCefalotinCefalotinCeftriaxoneCeftriaxoneLincomycinLincomycinClindamycinClindamycinFleroxacinFleroxacin

SulfonamidesSulfonamidesTetracyclinesTetracyclinesChloramphenicolChloramphenicolIsoniazidIsoniazidRifampicinRifampicinAmphotercin BAmphotercin BKetoconazoleKetoconazoleMiconazoleMiconazole

肝功能不良患者的抗菌药物应用肝功能不良患者的抗菌药物应用

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 :


肾功能不良患者的用药

可按正常可按正常适当减少适当减少显著减少显著减少禁止使用的药物禁止使用的药物剂量剂量剂量剂量给药剂量给药剂量给药剂量给药剂量

Macrolides Macrolides ChloramphenicolChloramphenicolIsoniazidIsoniazidRifampicinRifampicinDoxycyclineDoxycycline

Penicillin G Penicillin G CarbenicillinCarbenicillinCefazolinCefazolinCefamandoleCefamandoleCefuroximeCefuroximeOfloxacinOfloxacin

VancomycinVancomycinAminoglycosidesAminoglycosidesPolymixinsPolymixinsFlucytosineFlucytosine

Amphotercin BAmphotercin BCefaloridineCefaloridineSulfonamidesSulfonamidesTetracyclinesTetracyclinesnitrofurantoinnitrofurantoin


Today’s class is over !Today’s class is over !

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Section 15