Download penicillins

Antimicrobials
Reporter: I1, Lin YH.
Introduction
Patients in the ICU are often infected with
multiresistant organisms.
Frequently exposed to broad-spectrum antibiotics
and invasive procedures
Judicious 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 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 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 family
M. luteus, M. roseus,
and M. varians.
α-hemolysis: S. pyogenes
β-hemolysis: S. agalactiae
γ-hemolysis: Enterococcus / non-Enterococcus
S. pneumoniae
Micrococcaceae family
aureus: S. aureus
non-aureus: S. epidermis
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
★
★
★
★
★
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 therapy
Drug of choice for treatment of susceptible
pathogens
Most excreted rapidly by kidney (except:
Nafcillin)
Hypersensitivity most common side
effect
Immunogenicity
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, intraabdomen 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.
β-Lactams: Cephalosporins
First-generation
Cefadroxil
Cefazolin (Veterin)
Cephalexin
(Ceflexin/ Keflex)
Cephalothin
Cephapirin
Cephradine
Second-generation
Cefaclor (Keflor)
Cefamandole
Cefmetazole
Cefonicid
Cefotetan
Cefoxitin
Cefprozil
Cefuroxime (Zinacef)
Loracarbef
Third-generation
Cefixime (Cefspan)
Cefoperazone (Cefobid)
Cefotaxime
Cefpodoxime
Ceftazidime (Kefadin)
Ceftibuten (Seftem)
Ceftizoxime
Ceftriaxone (Rocephin )
Latamoxcef (Shimarin)
Fourth-generation
Cefpirome(Cefrom )
Cefepime (Maxipime)
2.5 generation- Cephamycins
cefmetazole,
ceftetan,
cefoxitin
Similar mechanism to PCNs
Side chain Coverage spectrum, pharmacokinetics, side
effect
Resistance: Enterobacter, Pseudomonas, Serratia, Citrobacter
spp.
Not effect against enterococci or ORSA
Most 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
st
1 -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
nd
2 -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 cephalosporins
More active in GNB but less active in GPC
(especially S. aureus)
Drug of choice for GNB meningitis
Lead 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
th
4 -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 PCNs
Seizure attack with predisposing factors (e.g.,
advanced age, renal insufficiency, Hx. of seizure)
★
★
★
★
★
Amikacin (Amikin)/
Gentamicin/
Neomycin /
Netromycin
Aminoglycosides
Amikacin (Amikin)/ Gentamicin/ Neomycin /
Netromycin
Bactericidal for numerous G(+) & G(-) bacteria
Not active in
1) oxygen-poor environment
2) low PH
 ineffective to anaerobes and abscesses
Usually with β-Lactam antibiotics to GNB
Synergy with PCNs to streptococcal, enterococcal
endocarditis
Aminoglycosides
Interfering with protein synthesis during
aerobic metabolism.
Good potensy: concentration-dependent
killing effect and time-dependent PAE on
G(+) and G(-) organisms
Potency depend on
1) susceptibility to aminoglycoside-inactivating enzyme
2) permeability to cell wall
Freeze initiation
Block peptide
bond formation
Misreading of mRNA
Aminoglycosides
Excreted 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.
★ Fluoroquinolones:
Ciprofloxacin (Ciproxin)
Levofloxacin (Cravit ) /
Nofloxacin ( Noxacin )
★
★
★
★
★
Fluoroquinolones
Ciprofloxacin (Ciproxin) / Levofloxacin (Cravit )
/ Nofloxacin ( Noxacin )
快速且完全自腸胃道吸收
Synergic effect with some β-lactam antibiotics
Active 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
★
★
★
★
★
Glycopeptides (Vancomycin )
Bactericidal against most G(+) bacteria
Bacteriostatic 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…
Sulfonamide
Buktar: Trimethoprim + Sulfomethoxazol
Bacteriostatic 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 concentrations
Disulfiram-like reaction may occur if alcohol is
ingested
Others
Antituberculous antibiotics: Rifampin
Tetracyclin
Thanks For Your Attention !!!