Principles of Antimicrobial Therapy-Beta-Lactams I PDF 2024

Principles of Antimicrobial Therapy Beta-Lactams I Lecture Objectives 1. 2. 3. 4. 5. 6. Explain the concept of selective toxicity and specify the five main cellular targets of antibiotics. Explain how to select the most appropriate antimicrobial agent for a given infection. Define chemotherapeutic s...

Principles of Antimicrobial Therapy Beta-Lactams I Lecture Objectives 1. 2. 3. 4. 5. 6. Explain the concept of selective toxicity and specify the five main cellular targets of antibiotics. Explain how to select the most appropriate antimicrobial agent for a given infection. Define chemotherapeutic spectra of antimicrobial agents and explain the importance of using the most-narrow spectrum agent effective. Explain the difference between bacteriostatic and bactericidal agents and how this relates to mechanisms of action and combination antimicrobial therapy. Describe the advantages and disadvantages of combination antimicrobial therapy. Explain the concept and mechanisms of antimicrobial resistance. Principles of Antimicrobial Therapy Antimicrobial drugs Important advance of modern medicine Treat infections due to their selective toxicity Eradicate invading organism Do not harm host Principles of Antimicrobial Therapy Antimicrobial drugs Selective toxicity 1. 2. 3. 4. 5. Bacterial cell wall-synthesizing enzymes Bacterial ribosome DNA replication enzymes Nucleotide synthesis Bacterial cell membrane Five Basic Mechanisms of Antibiotic Action Selection of Antimicrobial Agents Factors Microorganism identification & antimicrobial sensitivity Site of infection Severity of infection Existing patient factors Safety of the antimicrobial agent Cost of antimicrobial therapy Effect of Infection Site on Therapy Natural barriers Limit penetration of antibiotic to site of infection Lipid solubility and pKa of antibiotic Blood-brain barrier Meningitis Inflammation may facilitate antibiotic penetration Status of the Patient Host factors Immune system Renal dysfunction Hepatic dysfunction Pregnancy Lactation Poor perfusion Age Chemotherapeutic Spectra Chemotherapeutic spectrum of an antibiotic Species of microorganisms affected by that drug Narrow spectrum Extended spectrum Broad spectrum Narrow Spectrum Narrow spectrum Agents acting on a single or limited group of microorganisms Isoniazid Effective only against mycobacteria Extended Spectrum Extended spectrum Agents effective against gram-positive and some gramnegative bacteria Amoxicillin Effective against gram-positive and some gram-negative organisms Broad Spectrum Broad spectrum Affect a wide variety of microbial species Tetracyclines and Chloramphenicol Superinfection Alter nature of the natural flora Antibiotic Selection Most appropriate antibiotic for a given infection Most narrow spectrum agent which is effective Antibiotic Selection Most appropriate antibiotic for a given infection Most narrow spectrum agent which is effective Reduces potential develop of resistance Streptococcus pyogenes is highly resistant to tetracyclines Bacteriostatic vs. Bactericidal Drugs Bacteriostatic agents Bactericidal agents Arrest growth & replication of bacterial at achievable serum levels Limits the spread of infection Kills bacteria Decreases the total number of viable microorganisms Bacteriostatic or bactericidal?? Antimicrobial Drug Combinations Treatment with a single agent Reduces the possibility of superinfections Decreases emergence of multi-drug resistant organisms Minimizes potential toxicity Advantages and disadvantages to combination therapy Advantages of Combination Therapy Certain antibiotic combinations exhibit synergism b-Lactams and aminoglycosides Sulfonamides and trimethoprim/pyrimethamine Mixed infections Serious infections Empiric therapy Treatment of tuberculosis and leprosy Reduce risk of microorganism developing resistance Disadvantages of Combination Therapy Bacteriostatic agents may interfere with the action of a bactericidal drug Certain antibiotics only work in the presence of actively proliferating microorganisms Antibiotic Resistance Bacteria are designated resistant If their growth is not inhibited by the maximum level of antibiotic tolerated by the host Some microorganisms are inherently resistant Resistance develops due to Imprudent and inappropriate use of antibiotics Antibiotic Resistance Mechanisms involved in development of resistance Genetic alterations Altered protein expression Genetic Alterations Leading to Resistance 1. Spontaneous mutations of DNA 2. DNA transfer of drug resistance Genetic Alterations Leading to Resistance Spontaneous mutations of DNA May persist, be corrected or be lethal If the cell survives Mutations may be passed to daughter cells Production of resistant strains Rifampin-resistant Mycobacterium tuberculosis Genetic Alterations Leading to Resistance DNA transfer of drug resistance Resistance properties are encoded into plasmids Plasmids are passed between cells Altered Protein Expression in Drug-Resistant Organisms 1. Modification of antibiotic target sites 2. Decreased accumulation of antibiotic 3. Enzymatic inactivation of antibiotic Modification of Target Sites Modification of target sites Alterations in target proteins Induce resistance to certain antibiotics Alteration of penicillin-binding proteins in methicillinresistant Staphylococcus aureus (MRSA) Modification of Target Sites Decreased Accumulation of Antibiotic Decreased accumulation Decreased penetration Antibiotic is unable to reach the site of action 1. Presence of a lipopolysaccharide layer 2. Efflux pump Decreased Accumulation of Antibiotic Decreased Accumulation of Antibiotic Enzymatic Inactivation of Antibiotic Enzymatic inactivation Ability to destroy or inactivate antibiotic Lead to development of resistance b-Lactamases Inactivate many penicillins & cephalosporins Enzymatic Inactivation of Antibiotic Complications of Antimicrobial Therapy Even though antibiotics exhibit selective toxicity Host may develop adverse effects 1. Hypersensitivity 2. Direct toxic effects 3. Development of superinfections Lecture Objectives 1. Review the indications, contraindications, and interactions for the use of b-lactam and other cell wall- and membrane-active antibiotics. 2. Discuss the mechanism of physiological action and most common unintended effects of b-lactam and other cell wall- and membraneactive antibiotics. 3. Relate the mechanisms of acquired drug resistance for b-lactam and other cell wall- and membrane-active antibiotics. Bacterial Cell Wall Inhibitors b-Lactams Peptides Penicillins Cephalosporins Carbapenems Monobactam Vancomycin Bacitracin Others Bacterial Cell Wall Inhibitors b-Lactams Target site PBPs → Transpeptidase → Inhibit transpeptidation reaction Bactericidal Time-dependent killing Synergistic with aminoglycosides Mechanism of Antibacterial Action Mechanism of Antibacterial Action Bacterial Cell Wall Inhibitors b-Lactams 1. Penicillins 2. Cephalosporins 3. Carbapenems 4. Monobactam b-Lactam Antibiotics Penicillins 1. Standard penicillins 2. Antistaphylococcal penicillins 3. Extended-spectrum penicillins 4. Antipseudomonal penicillin Penicillins Standard penicillins Penicillin G (Pfizerpen) i.v., i.m. Benzathine penicillin G suspension (Bicillin L-A) i.m. depot Penicillin V → Only p.o. for oropharyngeal infections (streptococci/pneumococci) Spectrum of activity (Pen G) Non-penicillinase producing gram-positive bacteria, spirochetes, meningococci Neisseria meningitidis, Treponema pallidum, Leptospira Syphilis, endocarditis, bacteremia, meningitis, anthrax, gas gangrene, actinomycosis Penicillins Antistaphylococcal penicillins Nafcillin Oxacillin Dicloxacillin Spectrum of activity Staphylococci & streptococci Bacteremia, endocarditis, meningitis, RTIs UTIs, RTIs, skin and soft tissue infections, bone infections Penicillins Extended-spectrum penicillins Amoxicillin (Moxatag) Amoxicillin/potassium clavulanate (Augmentin, Augmentin XR) Ampicillin Ampicillin/sulbactam sodium (Unasyn) Spectrum of Pen G (plus) Increased gram-negative activity Proteus mirabilis, E. coli, Haemophilus influenzae, Moraxella, Shigella, Salmonella & Helicobacter pylori UTIs, RTIs, endocarditis prophylaxis, meningitis, gastroenteritis, peptic ulcer Penicillins Antipseudomonal penicillin Piperacillin/tazobactam sodium (Zosyn) Broadest spectrum penicillin Spectrum of aminopenicillins Increased gram-negative activity Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter, Serratia & Bacteroides fragilis UTIs, RTIs, bacteremia, intra-abdominal infections Penicillins Adverse effects Hypersensitivity reactions Diarrhea Interstitial nephritis Neurotoxicity Platelet dysfunction Superinfections Pseudomembranous colitis Unasyn