Anti-infective Agents

• Anti-bacterials • Anti-virals • Anti-fungals• Anti-protozoals

강의 요점

• Classification of Infectious Organisms Bacteria, Virus, Fungi, Protozoa

• Terminology• Mechanism of Action (Sites of Action)• Drug of Choice• Side-effects• Drug Resistance

Basic Classification of Living Organisms

Kingdom Phylum( 門 )/Division( 類 ) Class( 綱 ) Order( 目 ) Family( 科 ) Genus( 屬 ) Species ( 種 ) *(Strain)Sub-species( 亞種 )

Hierarchy; by Carolus Linnaeus

* 세균들은 strain 으로 부르기도 함

Eubacteriales ( 眞正세균目 ): 13 개 科

Salmonellaceae, Salmonella; 간균 , Gram negative, 편모 , 보통은 혐기성 , Salmonella dysenteriae( 이질 ); S. enteritidis( 장염 )

E. coli : Escherichia( 속 ) coli ( 종 ) (Escherchieae)( 과 ): 대장균인체 장내 세균叢의 대부분을 구성하는 균종으로 • Gram negative, 桿균 ( 막대모양 )• Eubacteria 目 (Enterobacteriaceae 의 하나인 대장균과 )

Enterobacteriaceae ( 장내세균과 ) 에는 Escherichieae, Salmonelleae 외 3 종의 과가 있다 .

Examples:

Micrococcaceae( 科 )-staphylococcus ( 속 ); 포도상 구균Aerobic,

Staphylococcus aureus ( 황색 ~): 화농성

Streptococcaceae( 科 ) - 연쇄상 구균 , Gram +, 보통 혐기성 , -Streptococcocus pyrogenes: 화농성연쇄상 구균-S. pneumonia: 폐렴성 연쇄상 구균

Pseudomonaceae ( 과 ), Pseudomonas ( 속 )P. Aeruginosa ; 녹농균 , 병원성 , Gram-negative, 杆菌 , 편모에 의한 운동성 , Aerobic, ( 대부분 비병원성 )Bacillaceae 과 , Bacillus 속 ; 桿균 , Gram +, aerobicB. anthracis: 탄저균 ; B. coli ( 대장균 , E. coli)B. dysenteriae ( 이질균 ,), B. pyocyaneus( 녹농균 , P. aeruginosa), B. enteritidis( 장염균 ;)

Infectious organisms

Acellular* Viruses** 20 ~ 200 (nm)Unicellular Chlamydia 1,000 (Single cell) Mycoplasma 1,000

Rickettsia 1,000Bacteria 1,000Fungi/yeast 3,000~5,000Protozoa

Multicellular Fungi/mold 2,000~10,000Helminths

* Prion ( 병원성단백질 ): Creutzfeldt-Jacob Disease (Bovine Spongeform Encephalitis) 광우병

**needs host (eg. Bacteria) for replication; DNA- viruses and RNA-viruses (Retroviruses)

• Susceptibility: high sensitivity to a certain agent(s)• Spectrum: a range of activity against bacterial strains• Disc diffusion method; susceptibility test using bacterial culture• CFS: Colony Forming Unit• MIC and MBC: Minimal Inhibitory Concentration, ~Bactericidal~• Plasmid: a different genetic component derived from

bacterial chromosome• Bactericidal (killing) & Bacteriostatic (prevent bacterial growing)• Cell wall & peptidoglycan• Anatomical site of Infection• Central Dogma • Empirical therapy vs Drug of Choice• Resistance and Cross-resistance• Potentiation, Additive and Synergistic Effects• 1st, 2nd, 3rd generation of antibiotics• Endotoxin and Exotoxin

Terminology

Infection: • 미생물 ( 병원균 ; pathogenic micro-organisms) 이 인체에 침입 ( 공기 , 음식물 , 접촉 , 상처 등 ) 을 통하여 침입- 인체의 피부보호 , 점막세척작용 , 위장의 산성 등으로 1 차적 방어- Macrophage 등 백혈구의 제거 작용 ( 염증 발생 ) 으로 2 차적 방어 -면역작용의 작동으로 재침입 시 병원균 제거로 3 차적 방어- Non-pathogenic micro-organisms are not harmful.

Bacteria: • Single cell and Prokaryotic cell (different from Eukaryotic cells)

-- no nuclear membrane and cellular organelles, -- cell wall and plasmid available

• Gram staining: Positive and Negative ( 간단한 Identification)• Aerobic and Anaerobic• Morphological Classification: shapes of bacteria (bacillus: rod; coccus:spherical; spirillum-helical

Bacterial Infection;• Endotoxin: pieces of cell wall (pyrogen)• Exotoxin: internal toxins causes various reactions on

host cells (inflammation, blocking nerve, necrosisof tissue, and disturbs normal cell functions)

*toxoid: eliminated toxin action, and use for antiserum• Bacterial enzymes produces harmful activities• Tissue/Organ-dependant pathogenic activities

Anti-bacterial agents;• Bactericidal (killing/disintegration)• Bacteriostatics (no replication, but survived)(Immune)• Blocking bio-syntheses of unique bacterial components that are different from the host cell’s structure and physiology; cell wall, ribosomal structure, enzymes

Anti-bacterials; Antibiotics;• Synthetics • Isolated from living organisms (plants, fungi) - production from fermentation• Semi-syntheses; chemcal chages of moiety on the above• Spectrum of anti-bacterial activities: Sensitivity

- 특정균에만 유효 (Selective vs Poor selective)• Toxicity; side-effects mostly revealed • Bacterial resistance can occur (Plasmid R)

- Combination of two antibiotics overcome R- Cross-resistance can occur eventually

• Routes of administration; P.O. vs Parenteral, etc

Susceptibility (Sensitivity) Determination - Effective or Non-effective1. usually bacterial culture Antibiotics with differe

nt concentration on discCounting colonies ( takes several days)

2. Minimal Inhibitory Concentration (MIC); prevent growth of bacteria in culture (unknown of bactericidal? Or bacteristatic?

3. Minimal Bactericidal Concentration (MBC)- 99.9% killing bacteria

4. Serum Bactericidal Titer ; series of dilution of patient’s serum (containing antibiotics that have not been distributed to other sites) that is the concentration of killing pathogen.

Mechanism of Action

1. Cell wall (Inhibition of synthesis or Damage)• Penicillins, Cephalosporins, Monobactams, Carbapenems,

Bacitracin, Vancomycin, Cycloserine2. Cytoplasmic membrane (Inhibition & Damage)

• Polymixins, and Polyene antifungals3. Nucleic Acid (Inhibition of synthesis & metabolism)

• Quinolones, Rifampin, Nitrofurantoins, Nitroimidazoles4. Protein synthesis (Inhibition & Modification)

• Aminoglycosides, Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin,

5. Energy metabolism (Modification)• Sulfonamide, Isoniazid

Sites of Action of Anti-Bacterials

Anti-bacterial Effects on Cell Wall

1. Penicillins and Cephalosporins2. Vancomycin and Bacitracin3. Carbapenem 계열

• Imipenem, Meropenem4. Monobactam 계열

• Aztreonam

스스로 공부할 점 : 효과 ( 어느 strains 에 항생작용 ?), 부작용 , cell wall 억제 차이점 ? pp.102, Table 7.1

Gram’s staining method Crystal violet 염색

탈색

Resistance 의 일종

Beta-Lactam Agents 의 작용 및 저항

Penicillinase 라고도 함

Resistance derived from Chromosomal and Plasmid Mutation

Example of Resistance

Cepha 계 항생제

Side-effects of beta-Lactam antibiotics-11. Penicillin G

- allergic and anaphylaxis, neutropenia2. Ampicillin

- Delayed hypersensitivity, contact dermatitis, skin rash,- Diarrhea, enterocolitis

3. Oxacillin- Liver dysfunction, Neuropenia

4. Methicillin- intestinal nephritis

5. Nafcillin- Liver dysfunction

6. Carbenicillin- platelet dysfunction, liver dysfunction, Na+ overload

7. Imipenem- Seizures

Side-effects of beta-Lactam antibiotics-28. Amoxicillin

-Diarrhea9. Cephalosporins

- Idiopathic, Skin rash, fever, phlebitis10. Cefixime, cefpodoxime

-Dirrhea11. Cefoxitin

- Enterocolitis12. Cefoperazone

-Prothrombin abnormality13. Ceftriaxone

- Diarrhea, Precipitation in gallbladder

Aminoglycoside 항생제

Rifampin 의 작용

Effective to Mycobacteria (Tuberculosis & leprosy)• rod-shaped bacilli; weak gram+, •Form intracellular parasitic region after phagocytosis

Anti-tuberculosis action of Isoniazid

Sulfanilamide 및 analogs; Antimetabolite 작용Folic acid ( 엽산 ; vitamin) 생성을 억제 :DNA & RNA 합성에 필수

부작용 : 뇨로결석 생성

Factors to Consider for Selecting Anti-infectives1. Identification of Pathogens (Organisms)2. Susceptibility3. Bactericidal vs Bacteriostatic4. Host status

• Allergy history• Age• Pharmacokinetic factor (how many times?)• Renal & Hepatic function• Pregnancy??• Site of Infection• Genetic & metabolic abnormality (In-born error?)• Host defense function such as WBC counts?

Selection of Anti-bacterial Drugs1. Penicillins Gram+, cocci, some Gram-2. Cephalosporins 1st generation; Gram+, Gram –

2nd ; more Gram -, similar Gram+3rd; more Gram-, less Gram+, some Pseudomonas

4th; better Gram+, Pseudomonas, resistant tobeta-lactaminase

3. Imipenem Gram+, Gram-, anaerobes4. Aztreonam Aerobic Gram- only5. Vancomycin Gram+ only6. Aminoglycoside Aerobic, Gram- bacilli7. Tetracyclines Aerobic & anaerobic Gram+, -, Mycoplasma

Chlamydia8. Erythromycin Gram+, Mycoplasma, Chlamydia, Legionella9. Clindamycin Most Gram+ cocci, many anaerobic10. Sulfonamides Some Gram+, Gram-11. Quinolones Some Gram+, most Gram-12. Rifampin Gram+

Disc Diffusion Method

Susceptibility Test

Potentiation with two antibiotics,avoiding resistance also

Central Dogma: Flow of Information

DNA

RNA Protein

Transcription

Translation

Replication

Reverse-transcription X

X

RNA viruses contains reverse-transcriptase

Anti-viral agents for DNA and RNA viruses1. Acyclovir(Zovirax); Hepes simplex, Zoster2. Valacyclovir; Herpes zoster3. Ribavirin; respiratory virus infection

RNA Virus (Retroviruses)1. Zidovudine; inhibition of reverse-transcriptase; HIV2. Ritonavir; inhibition of protease; HIV combination therapy

Viral Infection

Anti-fungals1. Polyene 계

• Amphotericin B :fungal meningitis & uninary tract • Nystatin: intestinal and oral Candida

2. Imidazoles 계• Ketoconozole candida & dermatophtes

3. Griseofulvin: dermatophytes of hair, skin, and nailslong term (6 months, p.o.) caution of side-effects!!

Anti-fungals: 참조 :pp. 118

Anti-parasitic Drugs

1. Metrondazole: • protosoans; entamoeba• Trichomonas

2. Lindane: scabies, head and pubic louse

기생충 (antihelmenthic drugs)1. Mebendazole; roundworm2. Praziquantel; schistosome

Anti-malarial drugs1. Chloroquine, and quinine2. Artemisin

Anti-malaria Drugs

Artemisin derived from Artemisia annua is effective to the quinine resistant strain that are virulent in tropic areas.

Plasmodium falciform 말라리아원충