AntimicrobialsAntimicrobials

Reporter: I1, Lin YH.

Introduction

Patients in the ICU are often infected with multiresistant organisms.Frequently exposed to broad-spectrum antibiotics

and invasive proceduresJudicious used of empiric antimicrobial therapy

is needed to minimize emergence of resistant organisms.Choice of antibiotic: suspected source of

infection, severity of the illness, local (hospital or ICU) microbiologic flora

Chapter OutlineChapter Outline◇◇ Learning objectives◇◇ Antibacterial Antibiotics◇◇ Antifungal Drugs◇◇ Antiviral Drugs◇◇ Summary◇◇ Review Questions

Learning Objectives

Recognize the different classes of antimicrobials and their mechanisms of action.

Identify the spectrum of coverage for specific antimicrobials.

Describe possible adverse effects and drug interactions caused by antimicrobials.

Select appropriate antimicrobials for various pathogens.

Chapter OutlineChapter Outline◇◇ Learning objectives◇◇ Antibacterial Antibiotics • Mechanisms of action and resistance • Spectrum of coverage • Pharmacology and adverse effects

◇◇ Antifungal Drugs◇◇ Antiviral Drugs◇◇ Summary◇◇ Review Questions

Pharmacology

Basctericidal / bacteriostatic

Mode of action: concentration-dependent / time-dependent killing effect

Minimal inhibitory concentration (MIC)

Postantibiotic effect (PAE)

Syngery / Indifference / Antogonism

GRAM-POSITIVE COCCI

Micrococcaceae familyM. luteus, M. roseus, and M. varians.

Micrococcaceae familyaureus: S. aureus non-aureus: S. epidermis

α-hemolysis: S. pyogenesβ-hemolysis: S. agalactiaeγ-hemolysis: Enterococcus / non-EnterococcusS. pneumoniae

GRAM-POSITIVE RODS

Aerobic: Endospore-forming: Bacillus

Regular, non-endospore-forming: Listeria

Irregular, non-endospore-forming: Corynebacterium

Anaerobic:

Endospore-forming: clostridium

Non-endospore-forming: Actinomycetes

GRAM-NEGATIVE

Aerobic cocci: Neisseria-- N. gonorrhoeae, N. meningitidis; Moraxella

Anaerobic cocci: Vellionella

Rods: (1) Enterobacteriaceae: Escherichia coli, Shigella,

Salmonella, Klebsiella, Enterobacter, Proteus… (2) Pleomorphic: Haemophilus, Legionella, Pasteurella,

Brucella (3) Miscellaneous: Vibrio, Campylobacter, Helicobacter (4) Nonfermenters: Pseudomonas, Acinebacter,

Flavobacterium

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β-Lactams

Binding to penicillin-binding-protein (PBP)

inner cell membrane

endogeneous bacterial autolysis

Activity depend on:

(1) PBP type

(2) degree of affinity to a particular PBP

β-Lactams

Resistance:

(1)β-Lactamase enzyme: • nosocomial G (-) organisms: encoded on bacterial

chromosomes, plasmid mediated, or carried on transposons

•G(+): either inducible or constitutive and are ofter plasmid mediated

(2) Change permeability of outer membrane (3) Altering their PBP

β-Lactams

Penicillin groups: penicillin ring

Cephalosporin groups: cephalosporin ring

Monobactams: Aztreonam

Carbapenems:

(1) Imipenem-Cilastatin (Tienam)

(2) meropenem (Mepem)

β-Lactams : Penicillins

Penicillin G-like drugs: Penicillin G/ Penicillin V

Penicillinase-resistant penicillins: Dicloxacillin / Oxacillin / Methicillin / Nafcillin

Ampicillin-like drugs (Amino-PCNs) Ampicillin / Ampicillin + sulbactam (Unasyn)

Amoxicillin / Amoxicillin + clavulanic acid (Augmentin)

Broad-spectrum (antipseudomonal) penicillins: Ticarcillin/ Ticarcillin + Clavulanic Acid ( Timentin )

Piperacillin / Piperacillin + tazobactam (Tazocin )

β-Lactams : PCNs

Fallen out as 1st line empiric therapyDrug of choice for treatment of susceptible pathogensMost excreted rapidly by kidney (except: Nafcillin)Hypersensitivity most common side effectImmunogenicity

Penicillin: a. GPC: Streptococci, Treotococcus pneumoniae,

Enterococci b. Anaerobics: except Bacteroides fragilis c. Treptonema pallidum (syphilis)

Ampicillin / ampicillin-like drugs : GNB Hydrolyzed by many β-Lactamase Unasyn / Augmentin

a) Ampicillin: ‧ GPC: Liesteria monocytogenes & many Entecoccus spp. ‧ Community-acquired Enterobacteriaceae and Neiserria spp.

b) Amoxicillin: analog, superior oral bioavailability

New generation of penicillins: (1) β-lactam + β-lactamase inhibitor: a) Unasyn: Community acquired soft-tissue infection, intra-

abdomen or pelvic infection, polymicrobial RI. b) Augmentin: UTI, otitis media, sinusitis, bite wounds. (empiric coverage against β-lactamase-producing staphylococci, H.

influenzae, Neisseria gonorrhoeae, Moraxella catarrhalis, Bacteroides, and Klebsiella spp.)

(2) Antipseudomonal penicillins: GP + GN a) Timentin & Tazocin: polymicrobial soft-tissue infection

intra-abdomen or pelvic infection, LRI. b) Timentin Stenotrophomonas maltophilia; Tazocin p. aeruginosa.

First-generation Second-generation Third-generation Fourth-generation Cefadroxil Cefazolin (Veterin) Cephalexin (Ceflexin/ Keflex) Cephalothin Cephapirin Cephradine

Cefaclor (Keflor) Cefamandole Cefmetazole Cefonicid Cefotetan Cefoxitin Cefprozil Cefuroxime (Zinacef) Loracarbef

Cefixime (Cefspan) Cefoperazone (Cefobid) Cefotaxime Cefpodoxime Ceftazidime (Kefadin) Ceftibuten (Seftem) Ceftizoxime Ceftriaxone (Rocephin )

Latamoxcef (Shimarin)

Cefpirome(Cefrom ) Cefepime (Maxipime)

β-Lactams: Cephalosporins

2.5 generation- Cephamycinscefmetazole, ceftetan, cefoxitin

Similar mechanism to PCNsSide chain Coverage spectrum, pharmacokinetics, side

effectResistance: Enterobacter, Pseudomonas, Serratia,

Citrobacter spp. Not effect against enterococci or ORSAMost renally excreted Side effect:

a) Hypersensitivity

b) MTT side chain (N-methylthiotetrazole): ( 2nd- Cefamandole, Cefmetazole, Cefotetan)

caugulopathy (vit. K dependent CF) ; disulfiram-like reaction with ethanol flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia

β-Lactams: Cephalosporins

Against GPC

1st > 2nd > cephamycins > 3rd

Against GNB

1st < 2nd < cephamycins < 3rd

1st-generation cephalosporins

Activity: a) Against most GPC, including β-Lactamase

producine strains b) CAI-GNB, E. coli, Klebsiella spp. c) Typically resistance: B. fragilis, P. aeruginosa,

Enterobacter spp. d) No BBB penetration

Cefazolin (Veterin ): Longest T1/2 (1.7h) q8h; most effective to E. coli

2nd-generation cephalosporins

Expanded coverage to GNB

No BBB penetration

Cefuroxime (Zinacef):

a) very active against MSSA and Streptococcal species

b) β-Lactamase stable

3rd-generation cephalosporinsMore active in GNB but less active in GPC (especially S.

aureus)Drug of choice for GNB meningitisLead to superinfection with fungi. and enterococci (induce

production of β-Lactamase. Ex: p. aerugnosa, Citrobacter species…)

Anti-pseudomonal cephalosprins a) Ceftazidime (Kefadin) b) Cefoperazone (Cefobid)

Broad-spectrum cephalosporins: bac. Meningitis a) Ceftriaxone ( Rocephin= Sintrix) b) Cefotaxime

4th-generation cephalosporins

Anti-pseudomonas + Broad-spectrum 3rd

Less BBB peneration

Cefepime (Maxipime)

a) Enhanced stability against GNBβ-Lactamase ( Enterocobecter spp. Klebsiella…)

b) significant activity against GPC: S.aureus, pneumococci

c) Neutropenic fever: monotherapy

Penicillin groups: penicillin ring

Cephalosporin groups: cephalosporin ring

Monobactams: Aztreonam

Carbapenems:

(1) Imipenem-Cilastatin (Tienam)

(2) meropenem (Mepem)

β-Lactams : Monobactams

Aztreonam

a) only binds PBPs of aerobic G(-) bac.

(many strains of P.aeruginosa)

b) completely ineffective to all G(+) bac.

c) useful in allergic to PCNs

β-Lactams : Carbapenems

Tienam/ mepem Widest spectrum: 1) anaerobes, 2) most GPC (except Enterococcus faecium and ORSA)

3) most GNB (except: Stenotrophomonas maltophilia and Burkholderia cepacia )

Special stereochemical characteristics β-lactamase stable

Hypersensitivity similar with PCNsSeizure attack with predisposing factors (e.g., advanced age, renal insufficiency, Hx. of seizure)

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Amikacin (Amikin)/ Gentamicin/ Neomycin / Netromycin

Aminoglycosides

Amikacin (Amikin)/ Gentamicin/ Neomycin / NetromycinBactericidal for numerous G(+) & G(-) bacteriaNot active in

1) oxygen-poor environment 2) low PH ineffective to anaerobes and abscesses

Usually with β-Lactam antibiotics to GNBSynergy with PCNs to streptococcal, enterococcal

endocarditis

Interfering with protein synthesis during aerobic metabolism.

Good potensy: concentration-dependent killing effect and time-dependent PAE on G(+) and G(-) organismsPotency depend on

1) susceptibility to aminoglycoside-inactivating enzyme 2) permeability to cell wall

Aminoglycosides

Freeze initiation

Block peptide bond formation

Misreading of mRNA

AminoglycosidesExcreted rapidly by normally functioning kidney

TBW-dependent distribution: ↑dose in pregnancy, burns, ascites, septic shock ↓dose in renal insufficiency

Adverse effect: 1) Nephrotoxicity reversible but possible permanent renal failure monitor renal function during therapy

2) ototoxicity prolonged use (>14 days) , renal insufficiency,

concurrent use with other ototoxic agents.

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Fluoroquinolones:Ciprofloxacin (Ciproxin) Levofloxacin (Cravit ) / Nofloxacin ( Noxacin )

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Fluoroquinolones

Ciprofloxacin (Ciproxin) / Levofloxacin (Cravit ) / Nofloxacin ( Noxacin )快速且完全自腸胃道吸收Synergic effect with some β-lactam antibioticsActive against:

1) Most GNB : Enterobacteriaceae, H. influenza, P. aeruginosa… 2) Many GPC目前為一對 P. aeruginosa有效的口服抗生素Resistance: mutations in DNA gyrase

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Glycopeptides (Vancomycin )

Bactericidal against most G(+) bacteriaBacteriostatic to enterococci VRE↑Indication:

1) Serious infection with resistance to β-lactam-resistance G(+) bac.

2) Allergy with β-lactam antibiotics 3) Orally treatment of C. difficile colitis that lift-threatening 4) Endocarditis prophylaxis 5) prophylaxis in prosthetic implant 6) empiric use for suspected pneumococcal spp. meningitis

Histamine-related reaction: red men syndrome

Macrolides

Erythromycin/ Azithromycin / Clarithromycin (Klaricid) / Clindamycin

Bateriostatic

High tissue concentration but unreliable CSF penetration

Hepatic elimination

Resistance: alteration of ribosomal binding sites

Increase plasma level of theophylline, wafarin…

SulfonamideBuktar: Trimethoprim + SulfomethoxazolBacteriostatic antibiotics with a wide spectrum

against most G(+)& many G(-) organisms.Uncomplicated UTI, nocardiosis (土壤絲菌病） ,chancroid（軟下疳）

1) combine with pyrimethamine toxoplasmosis, 2) substitute for penicillin in prophylaxis of rheumatic fever 3) prophylaxis against susceptible meningococcal strains, in

ulcerative colitis (as sulfasalazine), in burns (as silver sulfadiazine or mafenide), in chloroquine-resistant Plasmodium falciparum infection, and in combination with trimethoprim

Nitromidazole (Metronidazole)

Active only against protozoa, such as Giardia lamblia（腸梨形蟲） , Entamoeba histolytica(痢疾阿米巴 ), and Trichomonas vaginalis（陰道滴蟲） , and strictly anaerobic bacteria (Bacteroides fragilis).

(Not active against aerobic or microaerophilic bacteria.)

Drug of choice in Clostridium difficile colitis.Drug of choice for bacterial vaginosis. It has also been

used successfully in Crohn's disease penetrates into the CSF in high concentrationsDisulfiram-like reaction may occur if alcohol is ingested

Others

Antituberculous antibiotics: Rifampin

Tetracyclin

Thanks For Your Attention !!!