![Ceftolozane and tazobactam
8/25/2023 39
• Ceftolozane 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-lactamases
• As shown in separate, surveillance studies CTX-M is the most prevalent ESBL
group
• The 3 most prevalent P. aeruginosa mechanisms of resistance are chromosomal
AmpC, loss of outer membrane porin, and upregulation of efflux pumps.](https://image.slidesharecdn.com/antibiotics-and-spectrum-of-action-230825055327-a36dafad/85/Antibiotics-and-spectrum-of-action-pptx-39-320.jpg)
Antibiotics-and-spectrum-of-action.pptx
- 1. Antibiotics: Classification and Mechanisms of Action A/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: 2/4/2019 WHO GLASS training workshop on AMR
- 2. Objectives • To 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 toxicity • Bactericidal (killing) and bacteriostatic (growth inhibition) – No harm to patient. 8/25/2023 3
- 5. Climate and Culture Survey Embracing Diversity, Building Unity Title 1. 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 shock When to use them? 8/25/2023 5
- 6. Role of the diagnostic stewardship 1. 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 necessary 8/25/2023 6
- 7. General principles, Right X 3 1. All 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; 2. Blood cultures should be taken from a venepuncture site, after adequate skin antisepsis, and not from an intravenous or arterial catheter. 3. Antibiotics should be administered without delay. 4. 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. 5. Use a narrow-spectrum antibiotic whenever possible, 1. 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. 6. Evaluate the clinical response to treatment. 8/25/2023 7
- 8. Classification of antibiotics • Antibiotic activity – Bactericidal (the agent kills the bacteria) vs. bacteriostatic (the agent inhibits growth of the organism) • Chemical structure – Natural are metabolic by-products of soil microorganisms including fungi. – Semi-synthetic – Synthetic • Mechanisms of action. 8/25/2023 8
- 9. Antibiotics mechanisms of action Effects on cell wall integrity Inhibition of protein synthesis • Interference with nucleic acid metabolism Inhibition of enzymes that synthesize folic acid, which automatically decreased synthesis of nucleotides and eventually inhibition of bacterial growth. 8/25/2023 9
- 10. Inhibition of cell wall synthesis ß-lactams and glycopeptides 8/25/2023 10
- 12. Mechanism of action of ß-lactams • Penicillin 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. 8/25/2023 12 PBPs are responsible for the assembly, maintenance, and regulation of the peptidoglycan structures
- 13. Classification of penicillins and cephalosporins • Natural penicillins – Penicillin G potassium – Penicillin V phenoxymethyl • Semisynthetic Penicillins – Penicillinase-resistant penicillins • Cloxacillin • Methicillin – Aminopenicillins • Ampicillin • Amoxicillin – Carboxypenicillins • Carbenicillin and ticarcillin – Ureidopenicillins • Piperacillin • Cephalosporins – First generation • Cefazolin – Second generation • Cefuroxim • Cefoxitin – Third generation • Cefotaxime • Ceftriaxone • Ceftazidime – Fourth generation • Cefepime • cefpirome 8/25/2023 13
- 14. Other ß-lactam antibiotics • Carbapenems – Ertapenem – Imipenem-high affinity to high-molecular-weight PBPs. – Meropenem – Doripenem • Monobactams – Aztreonam • ß-lacatmase inhibitors protects from the hydrolytic activity of ß-lactamases by “suicide” inactivation (inhibitor is hydrolyzed): – Amoxicillin-clavulanate – Piperacillin-tazobactam – Ampicillin/sulbactam – Ceftolozane-tazobactam 8/25/2023 14
- 15. Glycopeptides • Mechanism of action – Inhibit 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 – Teicoplanin 8/25/2023 15
- 17. Macrolides, Lincosamide and Streptogramins-MLS (chemically unrelated but similar biologic properties) inhibit protein synthesis at 50s ribosomal subunit Macrolides Lincosamide Streptogramins erythromycin clindamycin Streptogramins: quinupristin and dalfopristin for treatment of GRE and GISA azithromycin clarithromycin 8/25/2023 17
- 18. Inhibition of protein synthesis • By 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. 8/25/2023 18
- 19. Macrolides • Mechanisms of action • A single molecule of the antibiotic reversibly binds to the 50S ribosomal subunit, and lead to inhibition of protein synthesis. • Other activities • Anti-inflammatory activities 8/25/2023 19
- 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 stability – Higher in vitro activity against gram positive cocci – Represented with telithromycin – 15-member is azithromycin – 16-members are carbomycin, josamycin and rokitomycin. 8/25/2023 20
- 21. Lincosamide - clindamycin • Clindamycin 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. 8/25/2023 21
- 22. Aminoglycosides Natural Natural- Micromonospora Semisynthetic streptomycin gentamicin amikacin neomycin sisomicin netilmicin kanamycin paramomycin tobramycin 8/25/2023 22
- 23. Mechanism of action of aminoglycosides • Inhibition 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. 8/25/2023 23 Aminoglycosides interfere with the proofreading process that helps assure the accuracy of translation.
- 24. Tetracyclines • Mechanism of action – They penetrate by a pH- dependent process (passive diffusion) trough hydrophilic pores. – And trough cytoplasmic membrane by an energy dependent active transport system – Once inside the cell they binds reversibly to the 30S ribosomal subunit. 8/25/2023 24
- 25. Antibiotics inhibition of protein synthesis Fusidic acid • The 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. Chloramphenicol • Introduced in 1949, is one of many antibiotics derived from soil organisms of the genus Streptomyces. • Mechanism of action – Interferes with protein synthesis by binding to the prokaryotic 50S ribosomal subunit. 8/25/2023 25
- 26. Linezolid- the first oxazolidinone • Linezolid 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. 8/25/2023 26
- 27. Linezolid mechanism of action 8/25/2023 27
- 28. Antibiotics that interfere with DNA synthesis • Quinolones • Metronidazole • Rifampicin 8/25/2023 28
- 29. Mechanism of action of fluoroquinolones 8/25/2023 29 Quinolones 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 quinolones • Narrow spectrum – nalidixic acid • Broad spectrum – ciprofloxacin – ofloxacin – norfloxacin • Expanded spectrum – levofloxacin – moxifloxacin 8/25/2023 30
- 31. Metronidazole Mechanism of action – Enters bacteria via cell diffusion – Activates 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 8/25/2023 31
- 32. Rifampicin • In the 1960s derived from Streptomyces mediterranei. • First line treatment of Mycobacterium tuberculosis. • Bactericidal effect by inhibition of DNA synthesis. • Adverse effects • Hepatotoxicity • Early phase hyperglycemia • Immune dysfunction (decreased albumin and T cell counts) 8/25/2023 32
- 33. Antibiotics that inhibit folate synthesis • Sulfonamide 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. 8/25/2023 33
- 34. Steps trough folate synthesis • Pathway for the synthesis of tetrahydrofolic Acid, a cofactor needed for the synthesis of DNA and RNA nucleotides 8/25/2023 34
- 35. 8/25/2023 35 Overview of antibiotics and their actions
- 36. Tigecyclines • Broad spectrum glycylcycline • Semi-synthetic derivative of Minocycline • No activity against Pseudomonas aeriginosa due to efflux by MexXY-OprM (Jian Li Lancet infect Dis 2006 • Activity 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. 8/25/2023 36 New Antibiotics
- 37. Mechanism of action 8/25/2023 37 Glycylcyclines overcome key mechanisms of resistance Glycylcyclines bind to the ribosome with five times higher affinity than tetracycline Binds to the 30S ribosomal and blocks the entry of amino-acyl tRNA to the acceptor site Inhibit protein synthesis and bacterial growth Tigecyclines binds to additional sites of the ribosome in a manner not seen before, interfering with the mechanism of ribosomal protection proteins Tigecyclines is not interfered by macrolide or tetracycline efflux pumps.
- 39. Ceftolozane and tazobactam 8/25/2023 39 • Ceftolozane 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-lactamases • As shown in separate, surveillance studies CTX-M is the most prevalent ESBL group • The 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!