CHEMOTHERAPEUTICS OF INFECTIOUS DISEASES Anton Kohút

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?