Antibiotics: Classification and Mechanisms of - PowerPoint Presentation

1. Antibiotics: Classification and Mechanisms of ActionA/Prof Olga Perovic, Principal Pathologist, Center for Healthcare Associated Infections Antimicrobial Resistance and Mycoses, National Institute for Communicable Diseases at NHLS and Associate Professor at WITS Date: 2/4/2019WHO GLASS training workshop on AMR

2. ObjectivesTo explain general principles of antibiotics To classify antibiotics To describe and understand mechanisms of action of antibiotics.

3. What are antibiotics by definition?Antibiotics are substances produced by microorganisms which are antagonistic (opposed) to the growth or life of others bacteria. Difference between human (eukaryotic) and bacterial (prokaryotic) cell structure allow antibiotics to target bacterial structures but not host cell function-this phenomenon is called as selective toxicityBactericidal (killing) and bacteriostatic (growth inhibition)No harm to patient.3/1/20193

4. Evolution of antibiotics 3/1/20194

5. Climate and Culture Survey Embracing Diversity, Building UnityTitle Is antibiotics treatment indicated based on clinical findings? Evident bacterial infection Localized infections: pneumonia, pyelonephritis etc. Infections with characteristic clinical findings: cellulitis, bacterial arthritis. Inflammatory markers: leukocytosis, neutrophilia, lymphocytopenia, left shift, presence of bands, elevated C-reactive protein (CRP) and procalcitonin (PCT). 2. What is emergency of the patients condition Non-critical conditions: mild infection, which does not require treatment until the diagnosis is not established Critical conditions: the patient with suspected severe infection: Febrile neutropenia Bacterial meningitis Necrotizing cellulitis Severe sepsis and septic shockWhen to use them?3/1/20195

6. Role of the diagnostic stewardship Have appropriate clinical specimens been obtained, examined and cultured? MC&S Microscopy Gram stain; Culture - anaerobic and aerobic cultures; Latex agglutination Antibiotic Susceptibility Testing (AST)-Empirical antibiotic treatment must be modified when the AST becomes available. In consultation with microbiologist , additional tests such as antibiotic minimum inhibitory concentration (MIC), antibiotic assay, serum bactericidal activity and synergy tests of antibiotic combinations may be useful in serious infections (e.g. endocarditis and in immunocompromised patients). In vitro resistance generally predicts clinical ineffectiveness but not always. The pharmacokinetics and pharmacodynamics (e.g. penetration into relevant tissues) as well as the spectrum of activity of the antibiotic must be considered. Antibiotic pharmacokinetic principles should determine the dosage and frequency of antibiotic regimens.2. Which organisms are most likely to be causing the infection? Type of focal infection Age: bacterial meningitis of newborns – group B streptococci, Gram-negative bacteria Epidemiologic features: hospital vs. community acquired infections, prior antibiotic use, etc. 3. If multiple antibiotics are available to treat pathogen, which agent would be the best? Prior antibiotic allergies Antibiotic penetration - CNS infection, abscesses etc. pH - aminoglycosides are much more effective in an alkaline medium Potential side effects - linezolid – occurrence of pancytopenia after month of treatment Bactericidal (bc) vs. bacteriostatic agents - in life-threatening infections or in immunocompromised patients (bc) antibiotics are necessary3/1/20196

7. General principles, Right X 3All appropriate microbiological specimens, including blood cultures, should be obtained before commencing antibiotic therapy. An immediate Gram-stained report may indicate the appropriate antibiotic to use; Blood cultures should be taken from a venepuncture site, after adequate skin antisepsis, and not from an intravenous or arterial catheter. Antibiotics should be administered without delay.The decision for empiric therapy, i.e. cover for the most ‘likely’ organisms causing any specific infection, must include various factors such as the site of the infecting organism (respiratory tract pathogens differ from those of abdominal infections), community versus hospital-associated infection; recent previous antibiotic prescription; ward versus ICU-acquired infection and knowledge of the organisms commonly grown in patients in any specific area. Use a narrow-spectrum antibiotic whenever possible, appropriate empirical choice for nosocomial sepsis, requires initial broad-spectrum antibiotics, even a combination, until culture and AST results are back and de-escalation should be implemented. Inappropriate and/or delayed appropriate antibiotic use in the ICU has been shown to have an impact on morbidity and mortality.Evaluate the clinical response to treatment.3/1/20197

8. Classification of antibioticsAntibiotic activity Bactericidal (the agent kills the bacteria) vs. bacteriostatic (the agent inhibits growth of the organism)Chemical structureNatural are metabolic by-products of soil microorganisms including fungi. Semi-syntheticSynthetic Mechanisms of action. 3/1/20198

9. Antibiotics mechanisms of action Effects on cell wall integrityInhibition of protein synthesisInterference with nucleic acid metabolismInhibition of enzymes that synthesize folic acid, which automatically decreased synthesis of nucleotides and eventually inhibition of bacterial growth. 3/1/20199

10. Inhibition of cell wall synthesisß-lactams and glycopeptides3/1/201910

11. The structure of cell wall 3/1/201911

12. Mechanism of action of ß-lactamsPenicillin and other ß-lactam antibiotics inactivate a set of transpeptidases (PBPs) that catalyze the final cross-linking reactions of peptidoglycan synthesis. Penicillin inhibits these enzymes by inactivating them, forming an penicilloyl-enzyme complex. 3/1/201912PBPs are responsible for the assembly, maintenance, and regulation of the peptidoglycan structures

13. Classification of penicillins and cephalosporins Natural penicillinsPenicillin G potassiumPenicillin V phenoxymethylSemisynthetic PenicillinsPenicillinase-resistant penicillinsCloxacillinMethicillinAminopenicillinsAmpicillinAmoxicillinCarboxypenicillinsCarbenicillin and ticarcillinUreidopenicillinsPiperacillinCephalosporinsFirst generationCefazolin Second generationCefuroximCefoxitinThird generationCefotaximeCeftriaxoneCeftazidimeFourth generationCefepimecefpirome3/1/201913

14. Other ß-lactam antibioticsCarbapenemsErtapenemImipenem-high affinity to high-molecular-weight PBPs.Meropenem DoripenemMonobactamsAztreonamß-lacatmase inhibitors protects from the hydrolytic activity of ß-lactamases by “suicide” inactivation (inhibitor is hydrolyzed): Amoxicillin-clavulanatePiperacillin-tazobactamAmpicillin/sulbactamCeftolozane-tazobactam 3/1/201914

15. GlycopeptidesMechanism of actionInhibit second stage of cell wall peptidoglycan synthesis by binding to the (D-alanyl-D-alanine precursor) peptide side chain, which fits into a “pocket” in the vancomycin molecule and that prevents assemble of the murein monomer into peptidoglycan.These are representative antibiotics:Vancomycin Teicoplanin3/1/201915

16. Inhibition of transpeptidation3/1/201916

17. Macrolides, Lincosamide and Streptogramins-MLS (chemically unrelated but similar biologic properties) inhibit protein synthesis at 50s ribosomal subunit MacrolidesLincosamideStreptograminserythromycinclindamycinStreptogramins: quinupristin and dalfopristin for treatment of GRE and GISAazithromycinclarithromycin3/1/201917

18. Inhibition of protein synthesisBy interfering with protein synthesis at the ribosomal level. By binding of the agent to either the 50s or 30s ribosomal subunit. The final outcome which result in inhibition or killing of the organism depends on whether this binding is reversible or irreversible. 3/1/201918

19. MacrolidesMechanisms of actionA single molecule of the antibiotic reversibly binds to the 50S ribosomal subunit, and lead to inhibition of protein synthesis.Other activities Anti-inflammatory activities3/1/201919

20. Macrolide members Macrolides are divided into 14, 15, and 16 members:14-members are erythromycin, clarithromycin.Ketolides are semisynthetic 14-member-ring macrolides with a 3-keto instead of a 3-OH, and possess: Strong acid stabilityHigher in vitro activity against gram positive cocciRepresented with telithromycin 15-member is azithromycin16-members are carbomycin, josamycin and rokitomycin. 3/1/201920

21. Lincosamide - clindamycinClindamycin binds to 50S ribosomal binding site as other macrolides.At low concentrations, clindamycin inhibits production of toxic-shock and other toxins by GAS and S. aureus.Clindamycin is a bacteriostatic agent, but has a concentration-dependent bactericidal activity against staphylococci, streptococci, anaerobes, and H. pylori. 3/1/201921

22. AminoglycosidesNaturalNatural-MicromonosporaSemisyntheticstreptomycingentamicinamikacinneomycinsisomicinnetilmicinkanamycinparamomycintobramycin3/1/201922

23. Mechanism of action of aminoglycosidesInhibition of protein synthesis by irreversible binding to the 30 S bacterial ribosomal subunit.By displacing the cations (Ca and Mg), which makes outer membrane permeable and providing entry of the antibiotic. 3/1/201923Aminoglycosides interfere with the proofreading process that helps assure the accuracy of translation.

24. TetracyclinesMechanism of actionThey penetrate by a pH-dependent process (passive diffusion) trough hydrophilic pores. And trough cytoplasmic membrane by an energy dependent active transport systemOnce inside the cell they binds reversibly to the 30S ribosomal subunit. 3/1/201924

25. Antibiotics inhibition of protein synthesis Fusidic acidThe exact mechanisms by which fusidic acid inhibit protein synthesis have not been fully explained.Fusidic acid blocks elongation of polypeptide chain, by inhibiting ribosome-elongation factor.ChloramphenicolIntroduced in 1949, is one of many antibiotics derived from soil organisms of the genus Streptomyces.Mechanism of actionInterferes with protein synthesis by binding to the prokaryotic 50S ribosomal subunit. 3/1/201925

26. Linezolid- the first oxazolidinoneLinezolid acts as an inhibitor of bacterial protein synthesis by blocking the formation of the 70s ribosomal initiation complex.Against most susceptible bacterial species, linezolid is bacteriostatic.Linezolid is bactericidal against pneumococci, GAS and anaerobes. 3/1/201926

27. Linezolid mechanism of action 3/1/201927

28. Antibiotics that interfere with DNA synthesis QuinolonesMetronidazoleRifampicin3/1/201928

29. Mechanism of action of fluoroquinolones3/1/201929Quinolones acts on enzymes -topoisomerases II (DNA gyrase in gram-negative bacteria) and topoisomerase IV (in gram positive bacteria). DNA gyrase inserts negative supercoils into DNA.

30. Classification of quinolonesNarrow spectrum nalidixic acidBroad spectrum ciprofloxacinofloxacinnorfloxacinExpanded spectrumlevofloxacinmoxifloxacin3/1/201930

31. MetronidazoleMechanism of actionEnters bacteria via cell diffusionActivates via single reduction step by bacteria forms radicals reacts with nuclear acid cell death by decreased intracellular concentration of unchanged drug which generates intermediate products which are toxic to the cell. These toxic transitory products interact with DNA, causing standard breaks and unwinding, resulting in cell death.Spectrum of activity:Anaerobic bacteria, microaerophilic bacteria, protozoa 3/1/201931

32. RifampicinIn the 1960s derived from Streptomyces mediterranei. First line treatment of Mycobacterium tuberculosis. Bactericidal effect by inhibition of DNA synthesis.Adverse effectsHepatotoxicity Early phase hyperglycemiaImmune dysfunction (decreased albumin and T cell counts)3/1/201932

33. Antibiotics that inhibit folate synthesisSulfonamide is similar in structure to para-aminobenzoic acid (PABA), which is used for folic acid synthesis (necessary for synthesis of nucleotides in bacterial and mammalian cells).Inhibition of bacterial growth by competitively incorporating of PABA into tetrahydropteroic acid.Trimethoprim (TMP) is a structural analogue of dihydropteroic acid, the first step in the synthesis of dihydrofolic acid sequential inhibitor of folic acid as well.The combination TMP-SMX is synergistic against a wide spectrum of bacterial species.3/1/201933

34. Steps trough folate synthesisPathway for the synthesis of tetrahydrofolic Acid, a cofactor needed for the synthesis of DNA and RNA nucleotides3/1/201934

35. 3/1/201935Overview of antibiotics and their actions

36. TigecyclinesBroad spectrum glycylcyclineSemi-synthetic derivative of MinocyclineNo activity against Pseudomonas aeriginosa due to efflux by MexXY-OprM (Jian Li Lancet infect Dis 2006Activity against gram negative, gram positive, atypical, anaerobic and resistant bacteria.This includes activity against MRSA, VRE and penicillin resistant Streptococcus pneumoniae. Unlike existing tetracyclines, tigecycline is only available as an intravenous preparation, is administered twice daily. 3/1/201936New Antibiotics

37. Mechanism of action 3/1/201937Glycylcyclines overcome key mechanisms of resistanceGlycylcyclines bind to the ribosome with five times higher affinity than tetracyclineBinds to the 30S ribosomal and blocks the entry of amino-acyl tRNA to the acceptor siteInhibit protein synthesis and bacterial growthTigecyclines binds to additional sites of the ribosome in a manner not seen before, interfering with the mechanism of ribosomal protection proteinsTigecyclines is not interfered by macrolide or tetracycline efflux pumps.

38. Daptomycin3/1/201938

39. Ceftolozane and tazobactam 3/1/201939Ceftolozane exhibits greater affinity for all essential PBPs In clinical trials, some but not all isolates of E. coli and K. pneumoniae producing beta-lactamases were susceptible to ZERBAXA (MIC ≤2 mcg/mL)ZERBAXA is not active against bacteria that produce serine carbapenemases (K. pneumoniae carbapenemase [KPC]) and metallo-beta-lactamasesAs shown in separate, surveillance studies CTX-M is the most prevalent ESBL groupThe 3 most prevalent P. aeruginosa mechanisms of resistance are chromosomal AmpC, loss of outer membrane porin, and upregulation of efflux pumps.

40. Thank you for attention!