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CHEMOTHERAPEUTICS OF INFE CTIOUS DISEASES. Anton Kohút. Basic terminol o g y. antiba c teri a l spe c trum MI C re s ist a nc e dysmi c r o bia superinfe ction ba c teric i d al e f fe c t ba c teriostatic e f fe c t. Basic criteria for ATB. maxim al mi c robia l toxicit y

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basic terminol o g y
Basic terminology
  • antibacterial spectrum
  • MIC
  • resistance
  • dysmicrobia
  • superinfection
  • bactericidal effect
  • bacteriostatic effect
basic criteria for atb
Basic criteria for ATB
  • maximal microbial toxicity
  • minimal organ toxicity
mechani s m s of action
Mechanismsof action
  • interference with

cell wall synthesis

(-lactams, vancomycin, cycloserin)

  • influence of

cell membrane

(polymyxines)

  • interference with

protein synthesis

(CMP, TTC, AMG, macrolides)

  • interference with

nucleic acid metabolism

(grizeofulvin, rifampicin, quinolones)

  • interference with

intermediary metabolism

(sulfonamides)

mechani sms of re s ist a nce
Mechanisms of resistance
  • enzymes
  • change ofcell wall permeability
  • ↑synthesis of antagonist(folic acid)
  • change ofpenicilin-binding protein(PBP)
  • Resistance to antibiotics occurs through four general mechanisms: target modification; efflux; immunity and bypass; and enzyme-catalyzed destruction
slide12
In the past two decades we have witnessed:

• the rise of so-called extended spectrum β-lactamases (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;

slide13
• 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.

toxic effects of atb1
Toxic effects of ATB

myelosuppresion(CMP)

hematotoxicity(sulfonamides)

hepatotoxicity(macrolides)

nephrotoxicity(aminoglycosides)

ototoxicity (aminoglycosides)

neurotoxicity(anti-TBC)

other side effects se
Other side effects (SE)

allergy(-lactams)

dysmicrobia(large spectrum ATB)

superinfection (large spectrum ATB)

Jarisch-Herxheimer (PNC)

sy Hoigné(PNC-retard)

combinations of atb1
Combinations of ATB

Aims:

  • increase of therapeutic effect
  • decrease in SE
  • prophylaxis of resistance

Bacteriostatic (with rapid onset)

+

bactericidal

NEVER !

principles of atb therapy1
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

Principles of ATB therapy
slide29
Penicillins

basic PNC

anti-staphyloccocal

aminoPNC

carboxyPNC

acylureidoPNC

carbapenems

monobactams

-lactamase inhib.

basic pnc
benzylpenicilline – PNC G

procain-benzyl-PNC

benzatine-PNC

phenoxymethyl-PNC

penamecilline

Basic PNC
natural penicillins penicillin g penicillin vk
Natural Penicillins(penicillin G, penicillin VK)

Gram-positiveGram-negative

pen-susc S. aureusNeisseria sp.

pen-susc S. pneumoniae

Group streptococciAnaerobes

viridans streptococci Above the diaphragm

EnterococcusClostridium sp.

Other

Treponema pallidum (syphilis)

mechanism of action
Mechanism of action
  • Gram +
  • peptidoglycane
  • PBP
  • lipidic bilayer
mechanism of action1
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)

Pharmacokinetics
slide38
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)

Antimicrobial spectrum
slide41
anaphylaxis

Jarisch-Herxheimer

sy Hoigné

neurotoxicity

allergy

pregnancy  breast feeding are not contraindicted

SE
penicillinase resistant penicillins nafcillin oxacillin methicillin
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
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)
antistaphylococcal pnc penicillinase resistant1
Sensitivity:

staphylococci

(-lactamase-positive)

Resistance:

enterococci

gram - bacteries

Antistaphylococcal PNC (penicillinase-resistant)
aminopenicillins ampicillin amoxicillin
Aminopenicillins(ampicillin, amoxicillin)

Developed to increase activity against gram-negative aerobes

Gram-positive Gram-negativepen-susc S. aureus Proteus mirabilis

Group streptococci Salmonella, Shigella

viridans streptococci some E. coli

Enterococcus sp. L- H. influenzae

Listeria monocytogenes

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)
amino pnc penicillinase non resistant1
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

Amino-PNC (penicillinase-non-resistant)
lactamase inhibitors
clavulanic acid

sulbactam

tazobactam

irreversible inhibition

combination with -lactame ATB

similar kinetics & tissue penetration

with no antibacterial activity

-lactamase inhibitors
penicillin pearls
Penicillin Pearls
  • Amoxicillin - Largest selling antibiotic Amoxicillin – High dose for otitis media
  • Augmentin now has several new products
  • Ampicillin/Sulbactam – Anaerobes!
carboxypenicillins carbenicillin ticarcillin
Carboxypenicillins(carbenicillin, ticarcillin)

Developed to further increase activity against resistant gram-negative aerobes

Gram-positiveGram-negativemarginalProteus mirabilis

Salmonella, Shigella

some E. coli

L- H. influenzae

Enterobacter sp.

Pseudomonas aeruginosa

carboxy pnc antipseudomonas pnc
carbenicilline

ticarcilline

combination with clavulanic acid

Pseudomonas

Proteus

anaerobs

severe infections

septicemies

meningitis

endocarditis

urogenital &respiratory infections

Carboxy-PNC(antipseudomonas PNC)
ureidopenicillins piperacillin azlocillin
Ureidopenicillins(piperacillin, azlocillin)

Developed to further increase activity against resistant gram-negative aerobes

Gram-positiveGram-negative

viridans strep Proteus mirabilis

Group strep Salmonella, Shigella

some Enterococcus E. coli

L- H. influenzae

AnaerobesEnterobacter sp.

Fairly good activity Pseudomonas aeruginosa

Serratia marcescens

some Klebsiella sp.

acylureido pnc wider spectrum against gram bacilly
piperacilline

azlocilline

combination with tazobactam

gram + cocci

gram - bacteries

Pseudomonas

severe infections

septicemies

meningitis

endocarditis

abdominal cavity inf.

pneumonia

Acylureido-PNC(wider spectrum against gram – bacilly)
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)
carbapenems lactams with the widest spectrum1
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
monobactams1
Sensitivity:

exclusively gram – aerobic bacteries

(N.meningitis a gonorrhoeae, H. influenzae)

aerobic gram – bacilly(E.coli, Salmonella,Shigella)

Pseudomonas aeruginosa

Resistance:

gram + bacteries

anaerobs

Monobactams
cephalosporins bactericidal
Acremonium chrysogenum

7- aminocephalosporanic acid

cefem

Cephalosporins(bactericidal)
classification and spectrum of activity of cephalosporins
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
cephalosporins i generation1
Sensitivity:

high effectiveness gram + cocci

resistance to

-lactamases of staphylococci

Resistance:

gram - bacteries

weak resistance to -lactamases of gram - bacteries

Cephalosporins - I. generation
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
cephalosporins ii generation1
Sensitivity:

high effectiveness gram + cocci

good effectiveness some gram - bacteries

Resistance:

Proteus vulgaris

Providencia spp.

Serratia spp.

Cephalosporins - II. generation
cephalosporins iii generation
cephotaxim

cephtrizoxim

cephtriaxom

cephtazidine

----------------------

cephixim

cephtibutem

cephetamet-pivoxil

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
cephalosporins iii generation1
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 - III. generation
cephalosporins iv generation
cefpirom

cefepim

high effectiveness gram + &gram –

bacteries

Pseudomonas aer.

enterobacter spp. & citrobacter spp.resist. to III. gen.

Cephalosporins - IV. generation
pearls cephalosporins
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