Antibacterial DrugsAntibacterial Drugs

— — General considerations —General considerations —

Part 1.Part 1. OverviewOverview• Chemotherapy (Chemotherapy ( 化学治疗化学治疗 ))

• Chemotherapeutic agents (Chemotherapeutic agents ( 化学治疗药，化疗药化学治疗药，化疗药 )) Antimicrobial drugsAntimicrobial drugs Antibacterial drugs Antibacterial drugs Antifungal drugsAntifungal drugs Antiviral drugsAntiviral drugs Antiparasitic durgsAntiparasitic durgs Antineoplastic (anticancer) drugsAntineoplastic (anticancer) drugs

Pharmacokineti

Pharmacokineti

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Adverse

Adverse

effectseffects

pathogenicitypathogenicityImmunologicalImmunological

responsesresponses

Ther

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Ther

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Effec

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Effec

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Resis

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Resis

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HostHost

patient’s age, patient’s age, gender, gender, constitution, constitution, hepatic/renal hepatic/renal function function MicrobialsMicrobials

Antimicrobial drugsAntimicrobial drugs Interactions betweeInteractions between microbials, host, an microbials, host, and antimicrobial drund antimicrobial drugsgs

1.1. Antibacterial drugsAntibacterial drugs （（抗菌药抗菌药））• killing bacteria or arresting their growthkilling bacteria or arresting their growth

• antibioticsantibiotics (( 抗生素）抗生素）• synthetic antimicrobial drugssynthetic antimicrobial drugs （合成抗菌药），（合成抗菌药），

such as sulfonamidessuch as sulfonamides(( 磺胺类磺胺类 )); quinolones; quinolones (( 喹诺酮类喹诺酮类 )); ; metronidmetronid

azoleazole (( 甲硝唑甲硝唑 )); fluconazol; fluconazol （氟康唑）（氟康唑）

A. TerminologyA. Terminology

2. Antibiotics2. Antibiotics （抗生素）（抗生素） • produced by various species of mproduced by various species of m

icroorganisms (bacteria, fungi, acicroorganisms (bacteria, fungi, actinomycetes) tinomycetes)

• suppress the growth of other micsuppress the growth of other microorganisms.roorganisms.

• Natural and semi-syntheticNatural and semi-synthetic

A. TerminologyA. Terminology

3. 3. Antibacterial spectrumAntibacterial spectrum （抗菌谱）（抗菌谱）• NarrowNarrow• BroadBroad

4. Chemotherapetic index (CI, 4. Chemotherapetic index (CI, 化疗指数化疗指数 ))• CI = LDCI = LD5050/ED/ED50 50

• Safety margin = LDSafety margin = LD55/ED/ED9595

A. TerminologyA. Terminology

EDED9595 LDLD55

5. Bacteriostatic drugs5. Bacteriostatic drugs （抑菌药）（抑菌药）• inhibiting the growth of microorganismsinhibiting the growth of microorganisms e.g. tetracycline, sulfonamidese.g. tetracycline, sulfonamides

6. Bactericidal drugs 6. Bactericidal drugs （杀菌药）（杀菌药） • killing microorganismskilling microorganisms e.g. penicillin, aminoglycosidese.g. penicillin, aminoglycosides

A. TerminologyA. Terminology

Bactericidal Bactericidal vsvs Bacterostatic Bacterostatic

7. Minimum inhibitory 7. Minimum inhibitory concentration concentration (MIC)(MIC)

8. Minimum bactericidal 8. Minimum bactericidal concentration concentration (MBC)(MBC)

9. Post antibiotic effect 9. Post antibiotic effect (PAE)(PAE)

A. TerminologyA. Terminology

1. Inhibiting synthesis of bacterial cell walls1. Inhibiting synthesis of bacterial cell walls （抑制细菌细胞壁合成（抑制细菌细胞壁合成））2. Affecting permeability of cell membrane and leading to le2. Affecting permeability of cell membrane and leading to le

akage of intracellular contentsakage of intracellular contents （影响胞浆膜通透性，导致胞浆外漏）（影响胞浆膜通透性，导致胞浆外漏）3. Inhibiting protein synthesis3. Inhibiting protein synthesis （抑制蛋白质合成）（抑制蛋白质合成）4. Affecting nucleic acid metabolism4. Affecting nucleic acid metabolism （影响核酸代谢）（影响核酸代谢）5. Blocking essential enzymes of folate metabolism5. Blocking essential enzymes of folate metabolism （抑制叶酸（抑制叶酸

代谢的关键酶）代谢的关键酶）

B. Mechanism of ActionB. Mechanism of Action

1.1. Inhibiting synthesis of bacterial cell wallsInhibiting synthesis of bacterial cell walls

肽聚糖肽聚糖肽聚糖肽聚糖

IntracellularIntracellular

membranemembrane

ExtracellularExtracellular

2. Affecting permeability of membrane 2. Affecting permeability of membrane

• Ionic- sorbent Ionic- sorbent （离子吸附）（离子吸附） e.g. aminoglycosidese.g. aminoglycosides

• Interfering ergosterol Interfering ergosterol （干扰麦角固醇）（干扰麦角固醇） e.g. amphotericin B, nystatin, imidazolese.g. amphotericin B, nystatin, imidazoles

• Cationic detergent Cationic detergent （阳离子去污剂样作用）（阳离子去污剂样作用） e.g. polymyxinse.g. polymyxins

Lipopoly-saccharide

Outermembrane

Peptidoglycan

Cytoplasmicmembrane

polymyxinspolymyxins

Ribosomal structureRibosomal structure• Bacteria 30S + 50S 70SBacteria 30S + 50S 70S

30S subunit30S subunit • binds mRNA in initiation complexbinds mRNA in initiation complex• holds growing peptide chain holds growing peptide chain

50S subunit50S subunitaccepts / translocates charged tRNAs accepts / translocates charged tRNAs

• "A" site"A" site :: Aminoacyl-tRNA (acceptor) site Aminoacyl-tRNA (acceptor) site • "P" site"P" site :: Peptidyl-tRNA (donor) site Peptidyl-tRNA (donor) site

• Mammals 40S + 60S 80SMammals 40S + 60S 80S

3. Inhibiting protein synthesis3. Inhibiting protein synthesis

AP

aminoglycosidesaminoglycosides

aminoglycosidesaminoglycosides

(1)(1)(2)(2)(3)(3)

chloramphenicol, chloramphenicol, clindamycinclindamycin

tetracyclinestetracyclines

macrolidesmacrolides

4. Affecting nucleic acid metabolism4. Affecting nucleic acid metabolism

quinolones

(-)(-)

Break back Break back segmentsegment

(+)(+)

(-)(-)

5. Blocking essen5. Blocking essential enzymes of foltial enzymes of folate metabolismate metabolism

TMPTMP ，甲氧苄啶，甲氧苄啶

二氢蝶酸合成酶二氢蝶酸合成酶

二氢叶酸还原酶二氢叶酸还原酶

1. Types of resistance1. Types of resistance• Intrinsic resistanceIntrinsic resistance （固有耐药）（固有耐药）– – Inherent features, usually expressed by chromosomal Inherent features, usually expressed by chromosomal genesgenes

• Acquired resistance Acquired resistance （获得耐药） （获得耐药） – – emerge from previously sensitive bacterial populatioemerge from previously sensitive bacterial populationsns– – caused by mutations in chromosomal genescaused by mutations in chromosomal genes– – or by acquisition of plasmids or transposonsor by acquisition of plasmids or transposons

C. Bacterial resistanceC. Bacterial resistance

• Enzymatic inactivationEnzymatic inactivation• Modification of target sitesModification of target sites• Reduced permeabilityReduced permeability• Active efflux system Active efflux system

2. Resistance mechanisms2. Resistance mechanisms

• Examples: Examples: -lactamase;-lactamase; aminoglycoside-modifying enzymesaminoglycoside-modifying enzymes

(1) Enzymatic inactivation(1) Enzymatic inactivation

(2) Modification of target sites(2) Modification of target sites

•Mutation of the natural target Mutation of the natural target (quinolone resistan(quinolone resistance)ce)

•Substitution with a resistant alternative to the Substitution with a resistant alternative to the native, susceptible target native, susceptible target (methicillin resistance)(methicillin resistance)

•Target modificationTarget modification (ribosomal protection type of (ribosomal protection type of resistance to macrolides and tetracyclines)resistance to macrolides and tetracyclines)

•Increase of the targetsIncrease of the targets

•Absence, mutation or loss of the appropriAbsence, mutation or loss of the appropriate ate transportertransporter or or porinsporins (( 膜孔蛋白）膜孔蛋白）

(3) Reduced permeability(3) Reduced permeability

(4) Active efflux system(4) Active efflux system (( 主动外排系统主动外排系统 ) )

Tripartite efflux system Tripartite efflux system (( 三联外排系统三联外排系统 )):: efflux transporteefflux transporter; accessory protein; outer membrane channelr; accessory protein; outer membrane channel — Gram-neg— Gram-negativeative

• Mutations Mutations 突变突变• Transduction Transduction 转导转导• Transformation Transformation 转化转化• Conjugation Conjugation 接合接合

3. The transfer of resistance genes 3. The transfer of resistance genes

Rational uses of Rational uses of antimicrobial drugsantimicrobial drugs

1. Formulating a 1. Formulating a pathogenic diagnosispathogenic diagnosis early early, , which depends on clinical diagnosis, microbiologic which depends on clinical diagnosis, microbiologic diagnosis and testing results diagnosis and testing results in vitroin vitro..

2. Choiceness of antimicrobial agents depends 2. Choiceness of antimicrobial agents depends on on the properties of the drugsthe properties of the drugs..

3. Choiceness of antimicrobial agents depends 3. Choiceness of antimicrobial agents depends on on patient factorspatient factors..

4. The uses of antimicrobial agents is 4. The uses of antimicrobial agents is strictly strictly controlledcontrolled in some situations. in some situations.

Basic principlesBasic principles

1. Formulating a pathogenic diagnosis early1. Formulating a pathogenic diagnosis early

• Empiric TherapyEmpiric Therapy• Vast majority of all antimicrobial therapyVast majority of all antimicrobial therapy• Should be approached rationallyShould be approached rationally

– SyndromeSyndrome– Likely pathogensLikely pathogens– Known resistance patternsKnown resistance patterns– Host factorsHost factors

Identification of Identification of iinfecting nfecting oorganismrganismss• Staining of clinical specimensStaining of clinical specimens

– Gram stain, acid-fast stain, silver stains…• Antigen detection (e.g. ELISA, latex Antigen detection (e.g. ELISA, latex

agglutination)agglutination)• Nucleic acid detection (e.g. PCR)Nucleic acid detection (e.g. PCR)• Culture methodsCulture methods

– Obtain culture material prior to antimicrobial therapy, if possible

in brothin broth

A. Kinetics of absorption, distribution, and eliminationA. Kinetics of absorption, distribution, and eliminationB. Bacteriostatic B. Bacteriostatic vsvs bactericidal activity: bactericidal activity: concentration-depconcentration-dep

endent killingendent killing (eg. aminoglycosides and quinolones) and (eg. aminoglycosides and quinolones) and time-dependent killing time-dependent killing (eg. (eg. -lactams and vancomycin)-lactams and vancomycin)

C. The potential toxicity of an agentC. The potential toxicity of an agent

D. Pharmacodynamic, pharmacokinetic or D. Pharmacodynamic, pharmacokinetic or pharmaceuticpharmaceuticalal interaction with other drugs. interaction with other drugs.

2. Choiceness of antimicrobial agents 2. Choiceness of antimicrobial agents depends on the properties of the drugsdepends on the properties of the drugs

A. Site of infectionB. The age and pregnancy statusC. Hepatic or renal functionD. The functional state of host defense

mechanismE. Individual variation

3. Choiceness of antimicrobial agents 3. Choiceness of antimicrobial agents depends on patient factorsdepends on patient factors

PatientPatient ffactorsactors

• Site of infectionSite of infection– Adequate concentrations of antimicrobials must be

delivered to the site of infection– Local concentrations greater than MIC– Subinhibitory concentrations may still alter

bacterial adherence, morphology, aid in phagocytosis and killing

– Serum concentration easy to determine, tissue concentrations more difficult to assess

– Protein binding of drugs

• ExcretionExcretion– Urine

• Aminoglycosides, fluoroquinolones

– Bile• Ceftriaxone

• Penetration into various sitesPenetration into various sites– Central nervous system– Lung– Bone– Foreign bodies

• AgeAge– Gastric acidity low in young children and elderly– Renal & hepatic function vary with age

• Dose adjustment for creatinine clearance and hepatic dysfunction is critical to avoid toxicities

– Developing bone and teeth• Tetracyclines stain teeth• Quinolones may impair bone and cartilage growth

– Sensitive to ototoxicity

• Genetic and metabolic abnormalities– Isoniazid acetylation varies greatly– G-6-PD deficiency and risk of hemolysis

• Sulfonamides, nitrofurantoin, primaquine

• Pregnancy– Teratogenicity and other toxicity to the fetus– Other toxic reactions (lactic acidosis, pancreatitis)

• Excretion in breast milk• Immunocompromise

4. The uses of antimicrobial agents is str4. The uses of antimicrobial agents is strictly controlled in some situationsictly controlled in some situations

The uses of antimicrobial agents is The uses of antimicrobial agents is strictly controlled in: strictly controlled in:

A.A. Viral infectionsViral infectionsB.B. Fever caused by unidentified reasonsFever caused by unidentified reasonsC.C. Topical applicationsTopical applicationsD.D. Antimicrobial prophylaxisAntimicrobial prophylaxisE.E. Combined uses of antimicrobial drugsCombined uses of antimicrobial drugs

• Non-surgical prophylaxisNon-surgical prophylaxis

(1) Rheumatic fever (1) Rheumatic fever (( 风湿热风湿热 ))(2) Meningococcal infection(2) Meningococcal infection(3) Tuberculosis(3) Tuberculosis(4) Newborn ophthalmia (4) Newborn ophthalmia (( 新生儿眼炎新生儿眼炎 ) ) (5) Urinary tract infections(5) Urinary tract infections

Prophylaxis use of antimicrobialsProphylaxis use of antimicrobials

• Surgical prophylaxis National research council Expected infection wound classification criteria rateClean ≤2%Clean contaminated ≤10%Contaminated about 20%Dirty about 40%

• Surgical prophylaxis (1) Cardiac operation(2) Oral, head, neck, thoracic operation(3) Vascular (abdominal and lower extremity) operation(4) Arthritic or bone fracture operation(5) Gastroduodenal or biliary operation(6) Colorectal operation, appendectomy （阑尾切除术）（阑尾切除术）(7) Penetrating trauma, complex trauma(8) Uterectomy (( 子宫切除术子宫切除术 )), uterine-incision delivery (( 剖宫产剖宫产 ))(9) Severe burn wound(10) Orthopedic (( 整形整形 )) operation (with hardware insertion)

(1) Diagnosis for choice of effective drugs(1) Diagnosis for choice of effective drugs(2) Severity of infections(2) Severity of infections(3) Optimal doses, routes and duration(3) Optimal doses, routes and duration(4) Sensitivity of bacteria to drugs(4) Sensitivity of bacteria to drugs (5) Consideration of host situations(5) Consideration of host situations

Therapeutic use of antimicrobialsTherapeutic use of antimicrobials

According to their actions, According to their actions, antimicrobial agentsantimicrobial agents can be classified:can be classified:

(1) (1) bactericidalbactericidal agents for growing bacteria agents for growing bacteria (eg. (eg. –lactams)–lactams)(2) (2) bactericidalbactericidal agents for resting bacteria agents for resting bacteria (eg. aminoglycos(eg. aminoglycos

ides, quinolones)ides, quinolones)(3) fast b(3) fast bacteriostatic acteriostatic agents agents (eg. macrolides, tetracycline, chl(eg. macrolides, tetracycline, chl

oramphenicol)oramphenicol)(4) slow b(4) slow bacteriostatic acteriostatic agents agents (eg. sulfonamides)(eg. sulfonamides) (1) + (2): synergism(1) + (2): synergism (1) + (3): antagonism(1) + (3): antagonism (1) + (4): addition or indifference(1) + (4): addition or indifference (3) + (4): addition(3) + (4): addition

Combined use of antimicrobialsCombined use of antimicrobials

Mechanism of synergistic action Mechanism of synergistic action

(1) Blockade of sequential steps in a metabolic (1) Blockade of sequential steps in a metabolic sequencesequence

(2) Inhibition of enzymatic inactivation(2) Inhibition of enzymatic inactivation(3) Enhancement of antimicrobial agent uptake(3) Enhancement of antimicrobial agent uptake(4) Inhibition of different resistant strain (4) Inhibition of different resistant strain

respectivelyrespectively

• Indications – Indications – when ineffective with single drugwhen ineffective with single drug(1) Pathogens unknown(1) Pathogens unknown(2) Mixed polymicrobial(2) Mixed polymicrobial infection infectionss(3) Severe infections(3) Severe infections(4) (4) Prevent emergence of resistancePrevent emergence of resistance (long-term)(long-term)

Combination therapyCombination therapy Mycobacterium tuberculosisMycobacterium tuberculosis HIVHIV Pseudomonas aeruginosaPseudomonas aeruginosa Invasive aspergillosisInvasive aspergillosis (( 曲霉病曲霉病 ))

Combined use of antimicrobialsCombined use of antimicrobials

Use of antimicrobial drugs in patients Use of antimicrobial drugs in patients with hepatic impairmentwith hepatic impairment

No suitable markers are available for hepatic functionNo suitable markers are available for hepatic function. So, drug use in patients with liver disease must take . So, drug use in patients with liver disease must take into account 3 general principles:into account 3 general principles:

(1) Pharmacokinetics are modified.(1) Pharmacokinetics are modified.(2) Drugs may modify the functional status of th(2) Drugs may modify the functional status of th

e liver.e liver.(3) Pharmacodynamics may be modified.(3) Pharmacodynamics may be modified.

normal dosage decreasing dose decreasing dose using prohibited at necessary time

Penicillin G Penicillin G CefazolinCefazolinCefazidimeCefazidimeVancomycinVancomycinAminoglycosidesAminoglycosidesPolymixinsPolymixinsEthambutolEthambutol

ErythromycinFlucytosine

PiperacillinMezocillinCefalotinCeftriaxoneLincomycinClindamycinFleroxacin

SulfonamidesSulfonamidesTetracyclinesTetracyclinesChloramphenicolChloramphenicolIsoniazidIsoniazidRifampicinRifampicinAmphotercin BAmphotercin BKetoconazoleKetoconazoleMiconazoleMiconazole

Use of antimicrobial drugs in hepatic insufficiencyUse of antimicrobial drugs in hepatic insufficiency

Use of antimicrobial drugs in renal insufficiencyUse of antimicrobial drugs in renal insufficiency

normal dosage decreasing dose decreasing dose using prohibited at necessary time

Macrolides Macrolides ChloramphenicolChloramphenicolIsoniazidIsoniazidRifampicinRifampicinDoxycyclineDoxycycline

Penicillin G CarbenicillinCefalotinCefazolinCefamandolecefuroximeCefazidimeofloxacin

VancomycinAminoglycosidesPolymixinsFlucytosine

SulfonamidesSulfonamidesTetracyclinesTetracyclinesNitrofurantoinNitrofurantoin