2010/1/20

1

INTRODUCTION OF ANTIBACTERIAL AGENTS

1

Factors Affecting the Kinetics1. Release from the dosage form2. Absorption from the site of administration

into the bloodstream3. Distribution to various parts of the body4. Rate of elimination from the body via

metabolism or excretion of unchanged drug

2

★ Time-Dependent Killing

★ Concentration-Dependent Killing

3

Time dependentvs.Concentration dependent

Time Dependent1. Beta-lactams2. Glycopeptide3. Clindamycin4. Marcolide

Concentration dependent1. Aminoglycoside2. Quinolone3. Metronidazole

4

Class of Antibacterial Agents

β-Lactams1. Penicillins2. Cephalosporins3. Aztreonam4. Carbapenem

Aminoglycoside Glycopeptide

Fluoroquinolones Marcolide Trimethoprim-

sulfamethoxazole Tetracyclines Metronidazole

5

Penicillins (需penicillin test)

Natural penicillin: penicillin G Penicillinase-resistent penicillin:

oxacillin(iv), methicillin(iv)dicloxacillin (po)

Broad-spectrum penicillin: amoxicillin (po), ampicillin (po,iv)

Extend-spectrum penicillinticarcillin(iv), piperacillin(iv)

6

2010/1/20

2

β-Lactam and β-lactamase inhibitor

Ampicillin + Sulbactam = Unasyn (q6h)

Amoxicillin + Clavulanic acid = Augementin(q8h)

Ticarcillin + Clavulanic acid = Timentin

Piperacillin + Tazobactam = Tazocin

7

1st generation Cephalosporins

1. Cefazolin (1–2 g IV/IM q8h)2. Cephalothin, cephapirin, and cephradine (1–2 g IV/IM

q4–6h)3. Ulex, po, 250mg/tab, 2#q6h

Indication: (SSEKP)staphylococcistreptococciEscherichia coli,Klebsiella Proteus species. Community-acquired

8

2nd generation Cephalosporins

Cefuroxime (Zinacef, zinnat po) (1.5 g IV/IM q8h)

above the diaphragm: Staphylococcus, Streptococcus, E.coli, Klebsiella, Proteus

GNB: H. influenzae, M.catarrhis, Nessiera gonorrhoeae, N. menigitidis, Salmonella, Shigella

Indication:

1. Community acquired pneumonia (CAP),2. Tonsillitis, otitis media, bronchitis, sinusitis

3. Soft tissue infection,

4. Complicated UTI

9

Cephamycin

Cefoxitin (Mefoxin) (1–2 g IV q4–8h), Cefmetazole (CMZ) (2 g IV q6–12h):

Below-the-diaphragm(x) Staphylococcus, Streptococcus(o) GNB as cefuroxime(o) Anaerobic: B. fragilis

Indication: Intraabdominal, gynecologic surgical prophylaxis

and infections, dirviticulitis, PID

10

3rd generation Cephalosporins

Ceftriaxone (Rocephine) (1–2 g IV/IM q12–24h),

Cefotaxime ( Claforan) (1–2 g IV/IM q4–12h),

Cefoperazone (CPZ) (2–4 g IV q12h)

Ceftazidime ( Fortum) (1–2 g IV/IM q8h)

Flomoxef (Flumarin) Moxalactam (Shiomarin)

Oral: cefixime(Cefspan), cefpodoxime (Banan)

Anti- P. aeruginosa– ceftazidime, CPZ

11

3rd generation Cephalosporins

Good CNS penetrationSpectrum: GNB: Enterobacteriacae(emergent resistance in E. cloacae), H.

influenze, M catarrhalis, Nessieria spp.

P. aeruginosa: ceftazidime, cefoperazone

Anaerobic(x)

Indication: meningitis, serious infection, multidrug resistance GNB

SE: cholecystits-like syndrome in ceftriaxone

12

2010/1/20

3

4th generation Cephalosporins

Cefepime (Maxipime) (500 mg–2 g IV/IM q8–12h)

Cefpirome (Cefrom) (1-2 g IV)

In vitro activity:G(+): S. aureus, Streptococci

G(-): * Enterobacteriaceae

* H. influenzae, M.catarrhis

* P.aeruginosa (Cefepime)

13

Aztreonam

Aztreonam (azactam) (1–2 g IV/IM q6–12h)

Aerobic GNB only, including P. aeruginosa

No gram-positive or anaerobic activity.

Useful in patients with known PCN or cephalosporin allergies, as no apparent cross reactivity is present.

14

Carbapenem

Imipenem (500 mg–1 g IV/IM q6–8h)

Meropenem (1 g IV q8h): less seizure activity

The widest spectrum ß-lactam antibiotic Active against most GP, GN bacteria, anaerobic Carbapenem resistance bacteria: 1. Ampicillin resistant enterococci2. Oxacillin-resistance S. aureus (ORSA)3. Stenotrophomonas maltophilia4. Burkholderia cepacia5. Corynebacterium Jeikeium

15

Aminoglycosides

Gentamicin Tobramycin Amikacin Streptomycin

16

Spectrum of aminoglycosides

Gram negative aerobes Community acquired G(-) organism Hospital acquires G(-) organism

Gram positive aerobes Against GPC in combination with ß-lactam or

glycopeptide (synergic effect) 3~5 days for severe S. aureus infection

Combination for severe Enterococus infection

Anaerobe (x)

17

Glycopeptide

Vancomycin 15 mg/kg IV q12h; 30 mg/kg IV q12h for meningitis

Peak level: (25-40), 給藥後0.5-1 hr Trough level(8-12,5-10): 給藥前

Teicoplanin Loading: 400 mg(6mg/kg) q12h x 3

Maintain: 400 mg(6mg/kg) qd Trend of less renal toxicity

18

2010/1/20

4

Indication of Glycopeptide

Serious infections caused by ORSA

Serious infections caused by ampicillin-resistant enterococci

Serious infections caused by gram-positive bacteria in patient allergic to other therapies

Oral treatment of Clostridium difficile colitis not responded to oral metronidazole

Immunocompromised status with high suspicion of G(+) infections

19

Fluoroquinolones

Ofloxacin Lomefloxacin Cirpofloxacin Levofloxacin Moxifloxacin

20

Andriole’s classification of Quinolones

G(+) G(-) Anaerobe

1st G(non-fluo)

× O ×

2nd G IIA(fluo-)

Ciprofloxacin,Lomefloxacin,

Ofloxacin,Levofloxacin

× O × Lack activity against streptococcus, enterococcus,

except levofloxacin2nd G IIB

(fluo-)sparfloxacin O O O esp streptococcus

3rd G(fluo-)

TravofloxacinGatifloxacin

Moxifloxacingemifloxacin

O O O esp streptococcus

21

Ciprofloxacin

The most active quinolone against P. aeruginosa Poor activity against gram-positive cocci and

anaerobes Second-line agents for TB therapy Oral and IV therapy give similar maximum serum

levels.

22

Adverse effects of Fluoroquinolones

Not be used in

* p’ts < 18 y/o

* pregnant or lactating women.

Age-related arthropathy

Discontinued in pts with joint pain or tendonitis (Achilles tendon)

23

Macrolide antibiotics

Erythromycin (250–500 mg PO qid or 0.5–1.0 g IV q6h;

poorly tolerated through peripheral veins)

Clarithromycin (250–500 mg PO bid)

Azithromycin (500 mg PO × 1 day, then 250 mg PO qd × 4

days (Zpack); 250–500 mg PO qd; 500 mg IV qd)

24

2010/1/20

5

Major Indications for Erythromycin

Chlamydia pneumoniae Chlamydia trachomatis Legionella pneumophila Mycoplasma pneumoniae Bordetella pertussis Corynebacterium diphtheriae Campylobacter jejuni gastroenteritis Bartonella henselae(cat scratch disease), Bartonella

quintana(Bacillary angiomatosis) Prevention of infection after colorectal surgery

25

Macrolide

Erythromycin: gram positive cocci except enterococcus. Atypical respiratory tract infection Resistance in H. influenzae, M catarrhalis

Clarithromycin: enhanced activity against upper respiratory pathogen (H. influenzae, M catarrhalis).

Sinusitis, bronchitis, otitis media, pharyngitis, CAP Soft tissue infection MAC infection in HIV H. pylori infection

Azithromycin: less drug interaction as erythromycin and clarithromycin

26

Trimethoprim-sulfamethoxazole Trimethoprim to sulfamethoxazole: 1: 5 1amp or 1 tab:

80mg trimethoprim/400mg sulfamethoxazole

The IV preparation: 5 mg/kg IV q8h (based on the trimethoprim) for serious infections

The oral preparations: almost completely bioavailable

27

Trimethoprim-sulfamethoxazole

Excellent tissue penetration, including bone, prostate, and CNS.

A broad spectrum of activity (not inhibit P. aeruginosa or anaerobes).

Use in * PCP pneumonia and PCP prophylaxis in AIDS p’t* Stenotrophomonas maltophilia* Trophermyma whippleii* Nocardia infections * Sinusitis, otitis media, bronchitis, prostatis,

UTI (2#bid)

28

Adverse effect of TMP-SMA

Bone marrow suppression

Interstitial nephritis Cholestatic jaundice

Severe hypersensitivity reactions

(Stevens-Johnson / erythema multiforme)

29

Tetracyclines

Tetracycline (250–500 mg PO q6h)

Doxycycline (100 PO/IV q12h) Minocycline (200 mg IV/PO, then 100 mg IV/PO q12h)

In vitro activity:

-- 1. Chlamydiae2. Mycoplasma

3. Rickettsiae

4. Vibrio spp and Aeromonas spp

30

2010/1/20

6

Metronidazole

Metronidazole (250–750 mg PO/IV q8h)

It has excellent tissue penetration, including abscess cavities, bone, and CNS.

greater activity against gram-negative than gram-positive anaerobes but is active against Clostridium perfringens and difficile.

Protozoan infections that are routinely treated with metronidazole include Giardia, Entamoeba histolytica, and Trichomonas vaginalis

31

Anaerobic infections

Empyema

Lung abscess Peritonitis

Intra-abdominal abscess

Pelvic, tubular, ovarian abscess, or Endometritis

B.fragilis: 33% resistance

Caution !

32

Indication for Combination Therapy

Prevention of the emergence of resistant mutants.

Synergistic or additive activity Therapy directed against multiple potential

pathogens Febrile, leukopenic patient

33

Synergistic Effect

Enterococci, Streptococci: ß-lactam + aminoglycoside

Pseudomonas: Anti-pseudomonas penicillin/cephasporin + aminoglycoside

K. pneumoniae: cephasporin + aminoglycoside

Vibrio spp, Aromonas spp: 3rd generation cephasporin + doxycyclin/minocyclin:

34

High Oral Bioavailability Amoxicillin Doxycycline TMP-SMX Chloramphenicol Fluoroquinolone

Cephalexin Minocyclin Metronidazole Clindamycin Fluconazole

35

Penetration Of BBB Penicillin Ampicillin Oxacillin 3rd generation

cephasporin Carbapenems

Chloramphenicol Vancomycin Rifampin Metronidazole TMP-SMX

36

2010/1/20

7

Avoid commitant drugs with potential to prolong QTc: torasdes de pointes, Vf

Antiarrythmic antiinfective AntiHTN CNS drug Misc

AmiodaroneResperidoneDisopyramideFlecainideSotalolQuinidineProcanamideIbutilideDofetilide

ClarithroErythroFoscarnetMefloquinePetamidine

NicardipineMoexiprilIsradipineBepridil

FluxetineSertralineTricyclicsVenlafaxineHaloperidolPhenothiazine

SalmeterolSumatriptan

37

Thanks for your attention !

38

39 40

Tigecycline

daptomycin

41