Transcript CHEMOTERAPEUTIKÁ INFEKČNÝCH OCHORENÍ L. Mirossay

CHEMOTHERAPEUTICS
OF INFECTIOUS DISEASES
Anton Kohút
Basic terminology
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antibacterial spectrum
MIC
resistance
dysmicrobia
superinfection
bactericidal effect
bacteriostatic effect
Basic criteria for ATB
• maximal microbial toxicity
• minimal organ toxicity
Mechanism of ATB action
a
3
4
b
1
2
a
b
Mechanisms of action
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interference with
cell wall synthesis
(-lactams, vancomycin, cycloserin)
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influence of
cell membrane
(polymyxines)
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interference with
protein synthesis
(CMP, TTC, AMG, macrolides)
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interference with
nucleic acid metabolism
(grizeofulvin, rifampicin, quinolones)
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interference with
intermediary metabolism
(sulfonamides)
Resistance
Is antibiotic resistance inevitable?
Mechanisms of resistance
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enzymes
change of cell wall permeability
↑ synthesis of antagonist (folic acid)
change of penicilin-binding protein (PBP)
Resistance to antibiotics occurs through four
general mechanisms: target modification; efflux;
immunity and bypass; and enzyme-catalyzed
destruction
In the past two decades we have witnessed:
• the rise of so-called extended spectrum βlactamases (ESBLs), which are mutants of
enzymes that previously could only
inactivate penicillins but now have gained
activity against many cephalosporins;
• carbapenemases such as KPC and NDM-1
that inactivate all β-lactam antibiotics;
• •
• plasmid-mediated (and thus horizontally disseminated) resistance to
fluoroquinolone antibiotics;
• the spread of virulent MRSA (methicillin-resistant Staphylococcus
aureus) in the community;
• the rise of multi-drug resistant Neisseria gonorrhoea;
• the emergence and global dissemination of multi-drug resistant
Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella
pneumoniae and Enterobacteriaceae;
• the spread of extensively drug resistant Mycobacterium tuberculosis;
• resistance to the two newest antibiotics to be approved for clinical
use - daptomycin and linezolid.
The discovery of antibiotic classes
Toxic effects of ATB
Toxic effects of ATB
myelosuppresion (CMP)
hematotoxicity (sulfonamides)
hepatotoxicity (macrolides)
nephrotoxicity (aminoglycosides)
ototoxicity (aminoglycosides)
neurotoxicity (anti-TBC)
Other side effects (SE)
allergy (-lactams)
dysmicrobia (large spectrum ATB)
superinfection (large spectrum ATB)
Jarisch-Herxheimer (PNC)
sy Hoigné (PNC-retard)
Jarisch-Herxheimer
Combinations of ATB
Combinations of ATB
Aims:
•
increase of therapeutic effect
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decrease in SE
prophylaxis of resistance
Bacteriostatic (with rapid onset)
+
bactericidal

NEVER !
Principles of ATB therapy
Principles of ATB therapy
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primary focus inf.
possible inf. agent
sensitivity
variability of
pacient´s response
• kinetics 
penetration
• hospitalisation
• ATB SE
• effectiveness of
elimination organs
• start therapy in right
time
• regular dosing
• optimal ther. period
• don´t repeat therapy
• price of ATB
Bacteria by Site of Infection
Mouth
Skin/Soft Tissue
Bone and Joint
Peptococcus
Peptostreptococcus
Actinomyces
S. aureus
S. pyogenes
S. epidermidis
Pasteurella
S. aureus
S. epidermidis
Streptococci
N. gonorrhoeae
Gram-negative rods
Abdomen
Urinary Tract
Upper Respiratory
E. coli, Proteus
Klebsiella
Enterococcus
Bacteroides sp.
E. coli, Proteus
Klebsiella
Enterococcus
Staph saprophyticus
S. pneumoniae
H. influenzae
M. catarrhalis
S. pyogenes
Lower Respiratory
Community
Lower Respiratory
Hospital
Meningitis
S. pneumoniae
H. influenzae
K. pneumoniae
Legionella pneumophila
Mycoplasma, Chlamydia
K. pneumoniae
P. aeruginosa
Enterobacter sp.
Serratia sp.
S. aureus
S. pneumoniae
N. meningitidis
H. influenza
Group B Strep
E. coli
Listeria
Inhibitors of cell wall synhesis
-lactams
Alexander Fleming, 1928
Penicillins
• basic PNC
• anti-staphyloccocal
• aminoPNC
• carboxyPNC
• acylureidoPNC
• carbapenems
• monobactams
• -lactamase inhib.
Penicillins
(bactericidal)
• Penicillium notatum
• 6-aminopenicillanic
acid
penem
Basic PNC
• benzylpenicilline –
PNC G
• phenoxymethyl-PNC
• procain-benzyl-PNC
• penamecilline
• benzatine-PNC
Natural Penicillins
(penicillin G, penicillin VK)
Gram-positive
Gram-negative
pen-susc S. aureus
pen-susc S. pneumoniae
Group streptococci
viridans streptococci
Enterococcus
Neisseria sp.
Other
Treponema pallidum (syphilis)
Anaerobes
Above the diaphragm
Clostridium sp.
Penicillin G
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Mechanism of action
• Gram +
peptidoglycane
 PBP
 lipidic bilayer
Mechanism of action
• Gram  LPS  lipids
 membrane 
porines
peptidoglycane
 PBP
 membrane
Pharmacokinetics
• i.v. benzylpenicilline – PNC G
• i.m. Pc-PNC, benzatine-PNC
• extracellular
distribution
• renal excretion of
active substance
(probenecide)
• acidostabile
• incomplete
absorption (60%)
• hydrolytic cleavage,
activation,
prolonged effect
(penamecilline)
PNC a poorly lipid soluble and do not
cross the blood brain brain barrier
Whey are actively excreted unchanged by
the kidney (the dose should be reduced in
severe renal failure)
 Tubular secretion can be blocked by
probenecid to potentiate PNC action
Antimicrobial spectrum
• gram + cocci
(St. pyogenes,
St.viridans, St.
pneumoniae)
• staphylococci
(-lactamase-negative)
• gram + bacilly
(B.anthracis, C. diphteriae,
L. monocytogenes, C.
perfringens  tetani)
• gram – bacilly
(Pasteurella)
• spirochetes
(Treponema)
• borelia, leptospira
(B.anthracis, C. diphteriae, L.
monocytogenes, C.
perfringens  tetani)
SE
• anaphylaxis
• allergy
• JarischHerxheimer
• pregnancy  breast
feeding are not
contraindicted
• sy Hoigné
• neurotoxicity
Penicillinase-Resistant
Penicillins
(nafcillin, oxacillin, methicillin)
Developed to overcome the penicillinase
enzyme of S. aureus which inactivated
natural penicillins
Gram-positive
methicillin-susceptible S. aureus
Group streptococci
viridans streptococci
Antistaphylococcal PNC
(penicillinase-resistant)
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meticilline (acidolabile)
oxacilline
cloxacilline
dicloxacilline
• acidostabile
• absorption subst.dependent
• strong alb. binding
• good diffusion in
parenchym. org.
• weak BB barrier
passage
Antistaphylococcal PNC
(penicillinase-resistant)
Sensitivity:
Resistance:
• staphylococci
• enterococci
• gram - bacteries
(-lactamase-positive)
Aminopenicillins
(ampicillin, amoxicillin)
Developed to increase activity against
gram-negative aerobes
Gram-positive
Gram-negative
pen-susc S. aureus
Group streptococci
viridans streptococci
Enterococcus sp.
Listeria monocytogenes
Proteus mirabilis
Salmonella, Shigella
some E. coli
L- H. influenzae
Amino-PNC
(penicillinase-non-resistant)
• ampicilline
• amoxicilline
• combination with
clavulanic acid
• acidostabile
• absorption variable
• low albumine
binding
• good inflammatory
tissue diffusion
• increased bile
concentration
• mild nephrotoxicity
Amino-PNC
(penicillinase-non-resistant)
Sensitivity:
• gram + cocci
• enterococci
• gram – cocci
(N.meningitis & gonorrhoeae)
• H. influenzae
• aerobic gram –
bacilly (E.coli,
Salmonella,Shigella)
Resistance:
• enterobacteriaceae
• staphylococci
(-lactamase-positive)
• Pseudomonas
• B. fragilis
-lactamase inhibitors
• irreversible inhibition
• combination with lactame ATB
• similar kinetics &
tissue penetration
• with no antibacterial
activity
• clavulanic acid
• sulbactam
• tazobactam
Penicillin Pearls
Amoxicillin - Largest selling antibiotic
Amoxicillin – High dose for otitis media
Augmentin now has several new products
Ampicillin/Sulbactam – Anaerobes!
Carboxypenicillins
(carbenicillin, ticarcillin)
Developed to further increase activity
against resistant gram-negative aerobes
Gram-positive
marginal
Gram-negative
Proteus mirabilis
Salmonella, Shigella
some E. coli
L- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa
Carboxy-PNC
(antipseudomonas PNC)
• Pseudomonas
• Proteus
• anaerobs
• carbenicilline
• ticarcilline
• combination with
clavulanic acid
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severe infections
septicemies
meningitis
endocarditis
urogenital &
respiratory infections
Ureidopenicillins
(piperacillin, azlocillin)
Developed to further increase activity
against resistant gram-negative aerobes
Gram-positive
Gram-negative
viridans strep
Group strep
some Enterococcus
Proteus mirabilis
Salmonella, Shigella
E. coli
L- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa
Serratia marcescens
some Klebsiella sp.
Anaerobes
Fairly good activity
Acylureido-PNC
(wider spectrum against gram – bacilly)
• gram + cocci
• gram - bacteries
• Pseudomonas
• piperacilline
• azlocilline
• combination with
tazobactam
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severe infections
septicemies
meningitis
endocarditis
abdominal cavity inf.
pneumonia
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Carbapenems
(-lactams with the widest spectrum)
• imipenem
• combination with
cilastatin
(renal dehydropeptidase
inhibitor)
• good tissue
penetration
• good BB barrier
difusion
• renal excretion-70%
of active substance
• rest as metabolites
Carbapenems
(-lactams with the widest spectrum)
• gram + cocci, staphylococci
(even producing penicillinase)
• Enterococcus faecalis, Listeria
monocytogenes
• gram – aerobs
• enterobacteries
• anaerobic bacteries
Monobactams
• aztreonam
• good tissue & body
fluid penetration
• good BB barrier
difusion
• good bone
penetration
• renal elimination
Monobactams
Sensitivity:
• exclusively gram –
aerobic bacteries
(N.meningitis a gonorrhoeae,
H. influenzae)
• aerobic gram –
bacilly (E.coli,
Salmonella,Shigella)
• Pseudomonas
aeruginosa
Resistance:
• gram + bacteries
• anaerobs
Cephalosporins
Cephalosporins
(bactericidal)
• Acremonium
chrysogenum
• 7- aminocephalosporanic
acid
cefem
Classification and Spectrum of
Activity of Cephalosporins
• Divided into 4 major groups called
“Generations”
• Are divided into Generations based on
 antimicrobial
activity
 resistance to beta-lactamase
Cephalosporins - I. generation
• cephazolin
• cephalotin
----------------------• cephalexin
• cephadroxil
• good GI
absorption
• higher levels &
activity (parent.)
• renal elimination of
active substance
• allergies, flebitis,
blood cell
formation
Cephalosporins - I. generation
Sensitivity:
• high effectiveness
gram + cocci
• resistance to
-lactamases of
staphylococci
Resistance:
• gram - bacteries
• weak resistance to
-lactamases of
gram - bacteries
Cephalosporins - II. generation
• cefuroxim
• cephamandol
--------------------------• cefuroxim-axetil
• cephaclor
• current gram – infections
with good sensitivity
• renal elimination 85-95%
(50% in cefuroxim-axetil)
• risk of bleeding
(cephamandol)
Cephalosporins - II. generation
Sensitivity:
• high effectiveness
gram + cocci
• good effectiveness
some gram bacteries
Resistance:
• Proteus vulgaris
• Providencia spp.
• Serratia spp.
Cephalosporins - III. generation
• cephotaxim
• cephtrizoxim
• cephtriaxom
• cephtazidine
---------------------• cephixim
• cephtibutem
• cephetametpivoxil
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rare gram – infections
mixed gram – & +
gram – meningitis
severe pseudomonas
infections
• severe Haemophilus inf.
infections
• renal elimination in
dependence on substance
• pseudomembranous
colitis, bleeding, allergy
Cephalosporins - III. generation
Sensitivity:
• lower effectiveness:
gram + cocci
• the highest
effectiveness gram –
bacteries
• majority of
pseudomonas
Resistance:
• Klebsiella
pneumoniae
(produces
cephotaximases)
• some E.coli, Proteus
mirabilis, Salmonella
spp. (chromosome
encoding -lactamases)
Cephalosporins - IV. generation
• high effectiveness
gram + & gram –
bacteries
• Pseudomonas aer.
• cefpirom
• cefepim
• enterobacter spp.
& citrobacter spp.
resist. to III. gen.
Pearls - Cephalosporins
 For gram positive coverage: Cefazolin
– When being used for osteomyelits, maximum dosing
(150 mg/kg/day) should be used to ensure adequate distribution to affected
areas.
 For meningitis in pediatrics patients:
Neonates-cefotaxime (plus ampicillin)
Infants and Children-ceftriaxone
Excreted via biliary and urinary tract.
May cause biliary sludging and cholecystitis.
 For Anaerobic coverage: cefoxitin
 For pseudomonas coverage: ceftazidime and cefepime

cephalosporins
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ethanol
QUESTIONS?