[항생제 각론] 항생제 분류와 각각의 기능 (2)

 

 

30S ribosome binding

  : Aminoglycoside*, Tetracycline

50S ribosome binding

  : Macrolide, Lincosamide,  

    Chlororamphenicol,  streptogramine

Block of 70S initial complex

  : Oxazolidinone

 

* Bactericidal activity

 

 

DNA 합성 억제

 : Quinolone, Metronidazole

RNA polymerase 억제

 : Rifamycin

Folate 합성 억제

 : Sulfonamide, Trimethoprim

 

2. 리보솜(Ribosome)에 작용하는 항생제 (단백합성억제)

1) Tetracyclines(30s) : Tetracycline, Doxycycline

Tetracycline

•Tetracycline, doxycycline; minocycline; Tigecycline

•Good GI absorption; Good CSF penetration

•Broad antibiotic spectrum: G(+), G(-)

•Clinical use

 1. Rickettsial infections; Mycoplasma, Chalmydia 감염

 2. V. vulnificus, V. cholerae infections

 3. Inflammatory acne vulgaris

•Contraindication

  : pregnanant & lactating women, children younger than 8 years due to mottling of permanent teeth

 

Ix: Gram(+)/(-). leptospirosis⋅rickettsia⋅chlamycia⋅vibrio cholera

 

2) Macrolides(50s) : erythromycin, clarithromycin, azithromycin

Mechanism of action

 : inhibition of protein synthesis

   by binding to 50S ribosome

 

Classifications

•14-membered : erythromycin, roxithromycin,

                          clarithromycin, teithromycin

•15-membered : azithromycin

•16-membered : josamycin, midecamycin, spiramycin

 

Macrolide의 약리학적 특성

•Good oral bioavailability

  :  TTM (60%), CRM (50%), AZM (40%)

•Drug to drug interaction  (cytochrome P-450)

  :  terfenadine, anticoagulant, dogoxin, cabamazepine

•Longer half-life

  :  TTM (10h)  > CRM (4.7h) > AZM (2.4h) > EM (1.7h)

•Good tissue penetration

  : AZM (10~100배),  EM (10-20배),  TTM (2-10배)

 

Macrolides의 항균범위

 

항생제	MSSA	Strepto	PSSP	PRSA	Enterococci	GNC	Intracellular	MAC
EM	2+	3+	3+	1+	1+	2+	2-3+	0
CLM	2+	3+	3+	1+	1+	1+	3+	0
AZM	0	2+	3+	1+	0	3+	3+	2+
TTM	3+	3+	3+	3+	2+	3+	3+	0

0: 효과 없음,  1+: 미약,   2+: 보통,   3+: 우수

No or little activity against MRSA, anaerobes, GNB

 

Macrolide의 임상적응증

호흡기 감염증

 : S. pneumoniae, M. catarrhalis, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella pneumophila

   - CAP, mild to moderate

   - acute sinusitis, otitis media, pharynigitis :

   - Bodertella pertussis,  Corynebacterium diphteria

위장관 감염증 : Campylobacter jejunii, H. pylori

피부 및 연조직 감염 : S. pyogenes, MSSA

비뇨기계 감염 : C. trachomatis, H. ducreyi

Mycobacterium avium complex 감염 : Clarithromycin

Ix: Gram(+). mycoplasma⋅legionella에 의한 community aquired pneumonia

 

3) Amonoglycoside(30s) : gentamicin, amikacin, tobramicin, neomicin, streptomycin

Aminoglycoside의 임상적응증

 

Spectrum of activity

–Gram-negative bacilli

–Staphylococcus

–Mycobacterium : SM, KM, Amikacin

Indication

   1. Usually combination with b-lactams

–Gram-negative bacterial infection

    : Severe sepsis,  Severe pneumonia

–Severe staphylococcal infection

–Enterococcal infectionc

   2. Anti-TB medication

 

Gentamicin

  Amingolycoside of choice

    - in hospitals with low levels of resistance

      among Enterobacteriacae and P aeruginosa

  Low cost (319/80mg)

  Combination with b-lactam antibiotics

  - enterococci, streptococci, staphylocicci

  Monotherapy for UTI or tularemia

 

Gentamicin Ix: gram(-) infection에 광범위하게 사용 (※신독성, 이독성 주의)

 

 

   

Streptomycin

    Monotherapy : tularemia, plaque

    Combination

        - with tetracycline for Tx of brucellosis
        - Tx of tuberculosis, esp, MOR-tuberculosis

        - with penicillin, ampillin, or vancomycin for Tx of endocarditis d/t enterococci (high-level R to GM, S to SM)

 

  Streptomycin Ix: Tb 치료. 임산부에서 금기

 

Tobramvcin

  • Less nephrotoxic than GM
  • Higher cost (2,567180mg)
  • Less activity against S. marcescens
  • Cross resistance with GM

  • Greater activity against P. aeruginosa, Acinetobacter

  • Aerosolized tobramycin : PFT t, hospitalization 
  • Not synergic against Enterococcus faecium

 

Amikacin

 

  More expensive (2,665/500mg)

  Useful against organisms resistant to other AG

  - affected by relatively few AG-modifying enzymes

  AG of choice for the Tx of GM-resistant GNB

  Tx of susceptible Norcardia and NTM

  Not synergistic against E. facium

 

Arbekacin

 

  Derivative of dibekacin

  Activity against MRSA

  Less activity against P aeruginosa
  Cost : 20,843/100mg 

 

Adverse Reactions

  Major

      Nephrotoxicity- reversible      Ototoxicity- irreversible (Cochlear Vestibular)

      Neuromuscular blockade

 

  Minor 

      Drug fever           Rash 

  

 

4) Chloramphenicol(50s)

•Good bioavailablity; Good CSF penetration

• Broad spectrum: G (+), G(-), anaerobes

• Alternative therapy for Infections that cannot be treated by other drugs

– Typhoid fever, invasive salmonellosis, V. vulnificus 감염

– Meningitis d/t H. influenzae, S. pneumoniae, N. meningitidis

– Brain abscess (B. fragilis)

– Rickettsial infections

–C. perfringens infection

• BM suppression : reversible, dose-dependent

    Gray baby syndrome in neonate

 

Ix: gram(+)/(-), aerobe/anaerobe 모두사용. Typhoid fever(내성으로사용), CNS infection

 

5) 기타: clindamycin(50s), lincomycin(50s)

Lincosamide

Lincomycin : first isolated from Streptomyces lincolnesis

Clindamycin : a derivative of lincomycin

Inhibition of protein synthesis by binding to 50S ribosome

Clindamycin replaced lincomycin

•Better absorption

•Greater antibacterial activity

Less adverse reactions

 

Clindamycin

 

•Active against most anaerobes, streptococci, staphylococci

•No activity against facultative enteric GNB

•Clinical use

–Anaerobic pleuropulmonary infections :  superior to PCN

–Intra-abdominal or gynecologic infections, DM foot infections

–Malaria

•Adverse reactions

–GI distress: most common

–Antibiotic-associated colitis (AAC)

 

 

 

 

3. DNA 합성을 억제하는 항생제 및 기타 항생제

 

1) Sulfonamide(folate 합성 억제) : sulfamethoxazole

TMP/SMX

 

•Spectrum of activity

 1. Wide spectrum of activity for G(+) & G(-) bacteria

  - GPC : MSSA, PSSP, viridans streptococci

  - GNB : Enterobacteriacea, Salmonella, Shigella

               B. cepacia, S. maltophilia

 2. Active against Nocardia spp., rapid-growing Mycobacteria and

    Protozoa (Pneumocystis carinii, Toxoplasma gondii, Plasmodium falciparum)

 4. No activity against MRSA, E. faecium, P. aeruginosa, B. fragilis, etc

 

Clinical uses

 1. UTI     

 2. Genital infection : gonococcus, chlamydia

 3. Enteric infection : typhoid fever, shigellosis,   

                                  Travelers` diarrhea

 4. Nocardiosis, PCP : prophylaxis and therapy

Adverse effects

 1. GI disorders : N/V, diarrhea

 2. Pancytopenia : most serious S/E,

                             related to folate deficiency

 

Ix: pneumocystis carinii 감염 치료에 trimethoprim과 함께 사용

(bactrim : trimethoprim-sulfamethoxazole. TMP-SMX)

 

 

 

2) Fluoroquinolone(topoisomerase 억제) : ciprofloxacine, norfloxacin, ofloxacin

FQ의 분류와 항균 범위

분류		항균범위
1st	Nalidixic acid	Modest G(-) activity
2nd	Ciprofloxacin Norfloxacin Ofloxacin	- Powerful against G (-) bacteria, including P. aeruginosa - Good activity against intracellular bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila) - Some activity against GPC (MSSA) - Active against Mycobacteria

분류		항균범위
3rd*	Levofloxacin	1) Slightly ↓ activity against GNB & P. aeruginosa, 2) Much ↑ activity against GPC (e.g. PRSP)  & 3) ↑ activity against Mycobacteria  than 2nd. FQ
4th*	Moxifloxacin Gemifloxacin Gatifloxacin	↑ activity against anaerobes than 3rd. FQ

FQ에 내성인 세균

•MRSA/MRSE

•Enterococcus faecium

•Stenotrophomonas maltophila (cf: gemifloxacin)

•B. cepacia

•Clostridium difficile

•Anaerobic G (- ) bacilli : Bacteroides spp.

 

FQ의 약리학적 특성

•Good oral bioavailability

  : CPFX (70~85%), LVFX (~100%), MOFX(>90%)

  ※ Reduced oral absorption with Al, Mg, Ca, Fe, Zn

•Drug to drug interaction

  : theophylline, NSAID, anticoagulants

•Long half-life

•Good tissue penetration

 

Clinical Uses of FQ

 

2nd. FQ

•GU tract infection (UTI, prostatitis): CPFX, NOFX

•STD (Gonorrhea, chancroid) : CPFX, OFX

•GI tract infection(enteric fever, shigellosis, traveler’s diarrhea): CPFX, NOFX, OFX

•Prevention of infection in neutropenic pt. : CPFX

•Bone & joint infection : CPFX, OFX

•Skin & Soft tissue infection in DM : CPFX, LVFX

 

3rd.  4th. FQ

• Respiratory infection : LVFX, MOFX, GMFX

• Tuberculosis : LVFX, MOFX

 

Adverse effects of FQ

 

Drug	GI	CNS	Dermatolo-gical reactions	Cardio-vascular reactions	Idiosyncra-tic reactions
Norfloxacin	±	+	+	ND	ND
Ciprofloxacin	+	+	+	±	±
Levofloxacin	±	±	+	±	±
Gatifloxacin	++	+	±	±	±
Moxifloxacin	++	+	±	+	+
Gemifloxacin	±	±	++	±	ND

 

(new quinolones: levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin)

Ix: salmonellosis, shigellosis, chlamydia

Ciprofloxacine Ix: adult의 acute diarrhea.

New quinolones Ix: atypical pneumonia(chlamycia, mycoplasma, legionella)

 

3) Metronidazole (항원충약. 혐기성균에 항균작용有)

Nitroimidazole

 

•Metronidazole, tinidazole, ornidazole

•Active only against organisms that can anaerobic metabolism

 

Mechanism of Action

: Entry of MTZ into bacterial cells

 → its activation by reductive process

      (ferredoxin oxidoreductase system)

 → interaction of the reduced metabolite

     with bacterial DNA

→ inhibition of DNA replication

→ bacterial cell death

 

•Spectrum of activity

 1. extremely active against anaerobic bacteria

 2. Amoeba, Trichomonas vaginalis, Giardia lamblia

•Clinical uses

 1. most anaerobic infections

 2. C. difficile-associated colitis

 3. eradication of H. pylori

 4. bacterial vaginosis (Lactobacillus, Gardnerella, Bacteroides, & Mycoplasma)

 5. protozoal infections : amebiasis, giardiasis, trichomoniasis

 

•Adverse effects

 1. GI Sx. : abd. discomfort, anorexia, nausea, metallic taste

 2. CNS Sx. : seizure, encephalopathy, tremor, ataxia

 3. carcinogenic effects (+) in animals

 4. teratogenic effects (+) → Not used in 1st. trimester

 5. drug interaction with warfarin, alcohol, phenytoin, lithium, pheniobarbital, PD, rifampin, cimetidine, antacids

Oxazolidinone

  -Linezolid

Linezolid 항균 범위

•그람양성균, 혐기성균, Mycobacteria에 효과적

1. G (+) cocci : staphylococci, streptococci, enterococci

2. G (+) bacilli

  - Bacillus, Corynebacterium, Listeria

  - Glycopeptide-resistant Leuconostoc, Pediococcus,

     Erysipelothrix rhusipathiae

 3. Anaerobes : Bacteroides fragilis, C. perfringens,

           C. difficile, Fusobacterium, Peptostreptococcus

 4. M. tuberculosis, MAC

Linezolid 임상적응증

•VRE  infection

•HAP or CAP d/t S. aureus or S. pneumoniae

•SSTI d/t S. aureus or streptococci

•MRSA infections

   - Vancomycin treatment  failure

   - d/t strain with reduced vancomycin susceptibility

 

Linezolid PK/PD, 용량

•Rapidly absorbed, Oral bioavailability ≈ 100%

•Half-life:  4.5~5.5 h

•BBB penetration: 66~100%

•Lung tissue/serum ratio: 2~8

•Clearance: renal 30%, non-renal 65~70%

•Dosing

  - severe : 600 mg q 12 h, IV or PO

  - mild or SSTI: 400 mg q 12 h, IV or PO

 

Linezolid  부작용

 

•설사(8.3%), 오심(6.2%), 구토(3.7%);

    두통(6.5%), 발진

•가역적인 골수기능 억제: 혈소판감소증(2.2%)

•serotonin syndrome

  - selective serotonin reuptake inhibitor (SSRI)와 함께 또는 중단 직후에 사용시

  - 발열, tremor, agitation, 의식변화, myoclonus 등

•Pregnancy category C

 

 

 

4) Rifampicin (DNA dependant RNA polymerase inhibitor)

 

•Rifampin, Rifabutin, Rifaximin

•Active against GPC (cf: enterococci), GNC; mycobacteria

•Clinical use

  1. Tuberculosis : therapy and prophylaxis

  2. Combination therapy with other drugs

    - PVE, PJI d/t MRSA, MRSE : Vanc + RFP  + GM

    - PRSP meningitis : Vanc + CTRX + RFP

    - MDR-Pseudomonas or Acinetobacter : Colistin + RFP

      ( ※ No monotherapy of Rifampin)

  3. PEP : N. meningitidis, H. influenzae

 

 

 

 

※살균(Bacteriocidal) : penicillines, cephalosporins, aminoglycosides, vancomycin, aztreonam, imipenem, quinolones, metronidazole, bacitracin, pyrazinamide, rifampin, isoniazide

 

※정균(Bactriostatic) : erythromycin, clindamycin, tetracycline, sulfonamides, chloramphenicol, ethambutol