chemotherapeutics of infectious diseases anton kohút
TRANSCRIPT
CHEMOTHERAPEUTICSOF INFECTIOUS DISEASES
Anton Kohút
Basic terminology
• antibacterial spectrum
• MIC
• resistance
• dysmicrobia
• superinfection
• bactericidal effect
• bacteriostatic effect
Basic criteria for ATB
• maximal microbial toxicity
• minimal organ toxicity
Mechanism of ATB action
1
2
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a b
a
b
Mechanisms of 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)
ResistanceIs antibiotic resistance inevitable?
Mechanisms of resistance
• 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 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;
• •
• 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
• decrease in SE
• prophylaxis of resistance
Bacteriostatic (with rapid onset)+
bactericidal
NEVER !
Principles of ATB therapy
Principles of ATB therapy
• 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 InfectionMouth Peptococcus Peptostreptococcus Actinomyces
Skin/Soft Tissue S. aureus S. pyogenes S. epidermidis Pasteurella
Bone and Joint S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods
Abdomen E. coli, Proteus Klebsiella Enterococcus Bacteroides sp.
Urinary Tract E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus
Upper Respiratory S. pneumoniae H. influenzae M. catarrhalis S. pyogenes
Lower Respiratory Community S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia
Lower Respiratory Hospital K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus
Meningitis 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
• procain-benzyl-PNC
• benzatine-PNC
• phenoxymethyl-PNC
• penamecilline
Natural Penicillins(penicillin G, penicillin VK)
Gram-positive Gram-negativepen-susc S. aureus Neisseria sp.pen-susc S. pneumoniae
Group streptococci Anaerobesviridans streptococci Above the diaphragmEnterococcus Clostridium sp.
OtherTreponema pallidum (syphilis)
Penicillin G
•
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
• Jarisch-Herxheimer
• sy Hoigné
• neurotoxicity
• allergy
• pregnancy breast feeding are not contraindicted
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 streptococciviridans 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)
Sensitivity:
• staphylococci(-lactamase-positive)
Resistance:
• enterococci• gram - bacteries
Aminopenicillins(ampicillin, amoxicillin)
Developed to increase activity against gram-negative aerobes
Gram-positive Gram-negative pen-
susc S. aureus Proteus mirabilisGroup streptococci Salmonella, Shigellaviridans streptococci some E. coliEnterococcus 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)
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
• clavulanic acid• sulbactam
• tazobactam
• irreversible inhibition• combination with -
lactame ATB• similar kinetics &
tissue penetration• with no antibacterial
activity
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 Gram-negative marginal
Proteus mirabilisSalmonella, Shigellasome E. coliL- H. influenzaeEnterobacter sp.Pseudomonas aeruginosa
Carboxy-PNC(antipseudomonas PNC)
• carbenicilline
• ticarcilline
• combination with clavulanic acid
• Pseudomonas• Proteus• anaerobs
• 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 Proteus mirabilisGroup strep Salmonella, Shigellasome Enterococcus E. coli
L- H. influenzae
Anaerobes Enterobacter sp.Fairly good activity Pseudomonas aeruginosa
Serratia marcescenssome 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
•
•
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• 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
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
• cefpirom• cefepim
• high effectiveness gram + & gram –
bacteries • Pseudomonas aer.
• 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
cephalosporinscephalosporins
ethanolethanol
QUESTIONS?QUESTIONS?
