CHEMOTHERAPEUTICS OF 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 ab 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)

Resistance Is 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

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

Aims: increase of therapeutic effect decrease in SE prophylaxis of resistance Bacteriostatic (with rapid onset) + bactericidal  NEVER !

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 Infection

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-negative pen-susc S. aureusNeisseria sp. pen-susc S. pneumoniae Group streptococci Anaerobes viridans streptococciAbove the diaphragm EnterococcusClostridium sp. Other Treponema 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 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) 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. aureusProteus mirabilis Group streptococciSalmonella, Shigella viridans streptococcisome 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) 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-positiveGram-negative marginalProteus 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

Ureidopenicillins (piperacillin, azlocillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negative viridans strepProteus mirabilis Group strepSalmonella, Shigella some EnterococcusE. coli  L- H. influenzae Anaerobes Enterobacter sp. Fairly good activityPseudomonas 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

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

cephalosporins cephalosporins ethanol ethanol

QUESTIONS?