Lecture_20231211_Antibiotics_Part_II.pdf

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Treatment and Eradication of Pathogens Antibacterial Drugs – Part II Some of the Drugs that We will Cover Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Inhibitors of Bact...

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Treatment and Eradication of Pathogens Antibacterial Drugs – Part II Some of the Drugs that We will Cover Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Inhibitors of Bacterial Cell Wall Synthesis e.g. β-lactam antibiotics Have high degree of selective toxicity against bacteria because mammalian cells do not have cell walls What is selective toxicity? What is the mechanism of action of penicillins? Cell Wall Inhibitors - the Penicillins  Bacterial cell walls are composed of a lattice of peptidoglycan molecules  Transpeptidase – enzyme responsible for this cross-linking peptidoglycans  Penicillins - inhibiting transpeptidase ➔ inhibit peptidoglycan lattice formation ➔ inhibit cell wall synthesis Simmons Pharmacology: An Illustrated Review Cell Wall Inhibitors – the Penicillins Are penicillins bacteriocydal? Yes - Penicillins are bactericidal when bacteria are in their growth and replication phase Katzung’s Basic & Clinical Pharmacology, 14th Edition Therapeutic Actions of Penicillin G Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Disadvantages of Penicillin G Simmons Pharmacology: An Illustrated Review The Natural Penicillins – Penicillin V and G Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Disadvantages of Penicillin G Simmons Pharmacology: An Illustrated Review Are there penicillins that are resistant to penicillinase? Penicillinase-Resistant Penicillins e.g. Oxacillin, methicillin, cloxacillin, dicloxacillin, nafcillin  Very narrow Spectrum  Effective against gram-positive organisms and they remain useful if the bacteria produce penicillinase Uses  Infection due to Staphylococcus aureus (penicillinase-producing) Note: These agents should not be used for penicillin G–susceptible organisms Why? β-lactam Antibiotics – Summary of Penicillins Penicillins  Natural penicillins  G (unstable in gastric acid – perenteral)  and V (stable in gastric acid ➔ oral OK)  narrow spectrum  sensitive to β-lactamase  Extended-spectrum penicillins  Amoxicillin, ampicillin, ticarcillin  spectrum – some but not all gram +ve and –ve pathogens  sensitive to β-lactamase  do not penetrate CSF unless meningitis  Penicillinase-resistant penicillins  Oxacillin, methicillin, cloxacillin, dicloxacillin, nafcillin  very narrow spectrum – gram +ve β-lactam Antibiotics – Summary of Penicillins Penicillins Antipseudomonal penicillin - piperacillin Lippincott’s Illustrated Reviews: Pharmacology, 7th edition β-lactam Antibiotics - Summary Penicillins  Extended-spectrum penicillins  Penicillinase-resistant penicillins  Antipseudomonal penicillin - piperacillin When should we use the above classes of drugs? Restrict use to organisms that are NOT susceptible to penicillin G Can penicillins that are not resistant to penicillinase be given to combat βlactamase producing strains? β-Lactamase Inhibitors Many bacteria produce β-lactamase enzymes (e.g., penicillinase) that open the β-lactam ring and destroy the activity of the antibiotic Clavulanic acid is an irreversible inhibitor of many bacterial βlactamases Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Side Effects of Penicillin G Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Why is neurotoxicity a side effect here? Penicillin CNS Toxicity If penicillins in very high doses ➔ neurotoxic Why? High doses of penicillins can antagonize GABA Side Effects of Penicillin G Lippincott’s Illustrated Reviews: Pharmacology, 7th edition What is the mechanism of development of hypersensitivity against penicillins? Hypersensitivity to Penicillins Hypersensitivity - the most common adverse effect of penicillins  Human proteins – generally nonantigenic BUT  β-lactams can modify amino groups of proteins ➔ immunogenic human protein-β-lactam hapten is created ➔ antigen is recognized by antibodies as nonself ➔ hypersensitivity to penicillins If penicillins in very high doses ➔ neurotoxic Why? Simmons Pharmacology: An Illustrated Review Summary - Penicillins Cephalosporins The Cephalosporins are also β-lactam Antibiotics Cephalosporins i.e. cephalosporins (produced by Cephalosporium species) and cephamycins (produced by Streptomyces species)  Classified in 4 generations  cephamycins – greater resistance against β-lactamases  each consecutive generation shows:   activity against gram –ve bacteria  improved pharmacokinetics   t1/2 ➔ dosing frequency Simmons Pharmacology: An Illustrated Review 1st Generation Cephalosporins – Special Features  Parenteral agents: Cefazolin, cephalothin, cephapirin, and cephradine  Oral agents: Cephalexin, cefadroxil, and cephradine  all susceptible to β−lactamase  do NOT penetrate into the CSF  Cefazolin - longest t1/2 Uses  Surgical prophylaxis  Simple skin and soft tissue infections (parenteral cefazolin)  Skin and urinary tract infections (oral cefadroxil) 2nd Generation Cephalosporins – Special Features  Parenteral agents: Cefuroxime, cefamandole, cefonicid, cefoxitin, cefotetan  Oral agents: Cefaclor, cefuroxime axetil, cefpodoxime proxetil, cefprozil 1st-generation - preferred for most gram +ve pathogens 3rd-generation - usually more active against gram -ve pathogens  Cefoxitin – only one with activity against anaerobic bacteria  Cefuroxime is the ONLY 2nd-generation agent that penetrates CSF Uses  Upper and lower respiratory tract infections, sinusitis, and otitis media  Urinary tract infections caused by E. coli, Klebsiella, and Proteus  Surgical prophylaxis  Mild intra-abdominal infections, for example, cholecystitis (cefoxitin) 3rd Generation Cephalosporins – Special Features  Parenteral agents: Cefotaxime, ceftriaxone, ceftazidime, cefoperazone  Oral agent: Cefixime   activity against gram –ve BUT  potency against gram +ve microbes generally than 1st-generation agents  Resistant to β-lactamases  Ceftriaxone and cefotaxime - excellent activity against most strains of S. pneumoniae, including the vast majority of those resistant to penicillin Pharmacokinetics  Penetration into CSF (ceftazidime and cefotaxime)  Long t1/2 (ceftriaxone)  Eliminated via biliary excretion (cefoperazone and ceftriaxone) Uses  Bacterial meningitis (ceftriaxone and cefotaxime)  Pneumonia (ceftriaxone and cefotaxime) 4th Generation Cephalosporins – Special Features Cefepime  Extended spectrum - effective against the following:  Gram +ve organisms, including MRSA (BUT minimal)  Gram -ve organisms, including Pseudomonas aeruginosa  Multiresistant gram –ve bacilli  Significant activity against anaerobes   resistance to β-lactamases Uses  Infections caused by P. aeruginosa, including:  Urinary tract infections  Sepsis  Hospital-acquired pneumonia  Nosocomial meningitis – but IN COMBINATION WITH vancomycin The Advanced Generation Cephalosporins – Special Features Ceftaroline  Broad spectrum - effective against the following:  Gram +ve organisms, including MRSA (GOOD coverage)  Gram -ve organisms (NOT Pseudomonas aeruginosa)   resistance to β-lactamases Uses  Complicated skin and skin structure infections  Community-acquired pneumonia Cephalosporins - Summary Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Summary - Cephalosporins 4th Generation Cephalosporins – Special Features Cefepime  Extended spectrum - effective against the following:  Gram +ve organisms, including MRSA (BUT minimal)  Gram -ve organisms, including Pseudomonas aeruginosa  Multiresistant gram –ve bacilli  Significant activity against anaerobes   resistance to β-lactamases Uses  Infections caused by P. aeruginosa, including:  Urinary tract infections  Sepsis  Hospital-acquired pneumonia  Nosocomial meningitis – but IN COMBINATION WITH vancomycin What is vancomycin? A Glycopeptide Antibiotic - Vancomycin Mechanism of action  Terminal portion of peptidoglycan precursors is -D-alanine-D-alanine  Vancomycin binds there ➔ inhibits bacterial cell wall synthesis BUT different step from β-lactam antibiotics  Vancomycin binding causes bacterial autolysins to lyse the cell wall  Vancomycin is usually bactericidal  Spectrum – gram +ve bacteria Pharmacokinetics  Not absorbed via GI  Vancomycin SHOULD NOT be given intramuscularly, as it causes tissue necrosis  IV – but ONLY SLOWLY as a dilute solution to minimize thrombophlebitis + flushing reactions associated with histamine release  Can penetrate into CSF only if INFLAMMATION Uses - Skin and soft tissue infections; Susceptible pathogens in the e.g. treatment of antibiotic-associated pseudomembranous colitis Resistance – High prevalence ➔ prudent use advised Summary - Vancomycin The OTHER β-lactam Antibiotics Imipenem, Meropenem, Doripenem and Ertapenem Mechanism of action  Bind all penicillin binding proteins  Imipenem – Resistant to most β-lactamases ➔ the BROADEST spectrum of ALL β-lactam antibiotics Pharmacokinetics  Metabolized by renal peptidase  Can cause renal toxicity ➔ ONLY available formulation is in 1:1 ratio with cilastatin cilastatin – specific inhibitor of renal peptidase ➔ prolongs t1/2 of imipenem ➔ LIMITS renal toxicity that can be caused by imipenem alone  Penetration into CSF – variable; NOT used for meningitis Uses – SERIOUS infections caused by a mixture of gram +ve, gram –ve and anaerobic bacteria Resistance – possible ESPECIALLY Pseudomonas species The OTHER β-lactam Antibiotics Aztreonam – a monobactam Spectrum – against gram –ve Pharmacokinetics  Administered IV or IM  Can accumulate in patients with renal failure Side Effects – generally well-tolerated BUT:  Phlebitis  Skin Rush  Abnormal liver function tests Hypersensitivity  Low immunogenic potential + Limited cross-reactivity with Abs directed against other β-lactams ➔ May be used as alternative to other β-lactam antibiotics for allergic patients Summary – Carbapenems & Monobactams The Lipoglycopeptides Atwood & Laplante Am. Soc. Of Novel-System Pharmacists 2007 The Lipoglycopeptides Telavancin, Oritavancin and Dalbavancin Mechanism of action  Inhibit peptidoglycan polymerization (both transpeptidase and transglycosylase inhibited) ➔Spectrum – against gram +ve ALSO lead to  membrane permeability and depolymerization of the membranes of newly-divided bacteria Side Effects – special attention telavancin  Telavancin – may lead to:  Risk of fetal harm ➔ pregnancy test prior to treatment initiation  Nephrotoxicity ➔ kidney function assessment prior to treatment initiation  Telavancin – DDIs with drugs with risk of prolonging the QT interval (e.g. macrolides and fluoroquinolones) A Note on Daptomycin Step 1: Daptomycin binds membrane Step 2: Calcium-dependent complex formation of daptomycin Step 3: Daptomycin complexes putatively form a pore + depolarize membrane ➔Rapid loss of K+ ➔ DNA, RNA + Protein Synthesis Arrested BUT NO cell lysis Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Inhibitors of Protein Synthesis Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Protein Translation - Summary Inhibitors of Protein Synthesis Is selective toxicity for bacteria even possible? Yes These drugs are specific for BACTERIAL ribosomal subunits which are different from mammalian ones Macrolide Antibiotics – e.g. erythromycin Macrolides prevent the ribosome from moving along the mRNA to “read” it Bacteriostatic against mainly gram-positive pathogens Simmons Pharmacology: An Illustrated Review Macrolide Antibiotics – e.g. erythromycin 14- or 15-member lactone ring Macrolide = large ring  Erythromycin is the prototype  Newer macrolides  Improved pharmacokinetic properties BUT MODEST changes in the antibacterial spectrum Mechanism of action  Bind to the P site of the 50S bacterial ribosomal subunit ➔ Block protein synthesis when a large amino acid or a polypeptide is in the P site Katzung’s Basic & Clinical Pharmacology Macrolide Antibiotics – e.g. erythromycin  Spectrum - narrow-spectrum (active against gram-positive bacteria (similar in spectrum to penicillin G), Chlamydia, and Legionella organisms Pharmacokinetics  The best absorption is obtained with the estolate salt  Penetration into CSF - poor - even when the meninges are inflamed  Extensively metabolized in the liver ➔ NO need for dosage adjustments in renal failure Uses - Mild to moderately severe infections of the upper and lower respiratory tract Side effects - usually well tolerated  But patients complain of gastric effects  Reversible intrahepatic obstructive jaundice - possible, especially with the estolate salt  Parenteral forms - highly irritating Resistance - Develops rapidly Macrolide Antibiotics – e.g. erythromycin All 3 Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Macrolide Antibiotics – Summary Clarithromycin is much better absorbed after oral administration than erythromycin Side Effects The most unusual property of azithromycin is its uptake into several tissues (lung, tonsil, and cervix), where it maintains high concentrations for prolonged periods Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Macrolide Antibiotics – Inhibit P450 Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Summary – the Macrolides Fidaxomicin Chemically similar but pharmacologically different to erythromycin  Bind to the σ subunit of RNA polymerase ➔RNA polymerase enters a ‘closed clamp’ conformation ➔ DNA cannot bind ➔ transcription cannot occur ➔ NO translation ➔ protein synthesis Spectrum - very narrow (gram +ve bacteria aerobic + anaerobic) Pharmacokinetics  Absorption – minimal ➔ remains in the GI ➔ Main clinical use – C. difficile Lincomycin and Clindamycin Chemically unlike but pharmacologically similar to erythromycin  Bind to the 50S ribosomal subunit at or near the erythromycin site  Spectrum - narrow (gram +ve bacteria) BUT excellent activity against anaerobic bacteria Pharmacokinetics  Lincomycin - poor oral absorption  Clindamycin - excellent oral absorption not affected by food Lincomycin and Clindamycin Lippincott’s Illustrated Reviews: Pharmacology, 6th edition The Tetracyclines Tetracyclines inhibit the binding of amino acyl-tRNA complexes Bacteriostatic - broad spectrum Uses  Rickettsial infections, chlamydial infections, sexually transmitted diseases, acne, and brucellosis  Used as ALTERNATE THERAPY in penicillin-allergic patients Simmons Pharmacology: An Illustrated Review The Tetracyclines Tetracycline, Oxytetracycline, Doxycycline, Demeclocycline, Methacycline, and Minocycline Mechanism of action  preferentially bind to the 30S subunit of the microbial ribosome ➔ interfere with binding of amino acyl-tRNA ➔ inhibit chain elongation and termination  Broad-spectrum Pharmacokinetics  Most - incompletely absorbed after oral administration  Absorption - further delayed by food, calcium salts, and aluminum salts EXCEPTION – doxycycline - virtually unaffected by food.  Excretion - usually in the urine ➔ renal function considerations for dosage determinations EXCEPTION – doxycycline – excreted in bile  Tetracycline - rapidly eliminated BUT doxycycline and minocycline - long t1/2 Tetracyclines – Pharmacokinetic Summary Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Tetracyclines – Spectrum Summary Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Tetracyclines – Side Effects GI - cause irritation to mucous membranes Alter the natural flora of the gut ➔ allows pathogenic bacteria to proliferate ➔ propensity for superinfections Form insoluble complexes with cations, such as Ca2+ and Al3+ ➔ Limit absorption ➔ ALSO deposition in bones and teeth Damage to developing teeth and bones Liver damage (particularly in pregnant women after IV administration) Parenteral forms - irritating Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Summary – the Tetracyclines A Glycycline – a Tetracycline ‘Relative’ Tigecycline Mechanism of action  reversibly bins to the 30S subunit of the microbial ribosome ➔ inhibits chain elongation and termination  Broad-spectrum  Bacteriostatic Pharmacokinetics  Distribution – large Vd ➔ good tissue distribution BUT low plasma concentrations ➔ NOT suitable for bloodstream infections  Excretion – biliary/fecal - mostly ➔ dose adjustments in hepatic insufficiency patients Resistance – due to overexpression of efflux pumps Serious Side Effects Acute pancreatitis that may lead to death ➔BLACK BOX WARNING ➔ use only as a last resort when there is NO alternative therapy  May  clearance of warfarin  warfarin – already drug with narrow therapeutic index ➔AVOID – if must prescribe – international normalized ratio (INR) should be monitored The Aminoglycosides Aminoglycosides induce the binding of wrong amino acyl-tRNA complexes ➔ false proteins are synthesized Bactericidal - broad Simmons Pharmacology: An Illustrated Review The Aminoglycosides Streptomycin, Neomycin, Kanamycin, Gentamicin, and Amikacin (derivative of kanamycin) Mechanism of action  Antibacterial action - usually attributed to inhibition of protein synthesis BUT disruption of cell membrane function caused by transport of the antibiotics across the bacterial cell membranes may also be involved Transport into bacteria – depends on oxygen-dependent enzymes ➔ although broad spectrum only against aerobic bacteria Amikacin – resists INactivation by many bacterial enzymes Aminoglycosides - Pharmacokinetics Streptomycin, Neomycin, Kanamycin, Gentamicin, and Amikacin (derivative of kanamycin)  NOT absorbed from the GI tract BUT IM and subcutaneous – possible  Poor penetration in CSF, even if the meninges are inflamed  Excretion – glomerular filtration - unchanged Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Aminoglycosides – Uses and Adverse Effects Streptomycin, Neomycin, Kanamycin, Gentamicin, and Amikacin (derivative of kanamycin) Uses  Tuberculosis (TB), bacterial endocarditis, plague, and tularemia (streptomycin)  Gut sterilization (oral or topical neomycin) Gentamicin - systemic use in serious infections Amikacin resists inactivation by many bacterial enzymes ➔should be reserved for susceptible infections resistant to other aminoglycosides Side effects  Renal toxicity  May damage both vestibular and auditory functions of the vestibulocochlear nerve ➔ ototoxicity  Allergic reactions - occasionally Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Aminoglycosides – Summary Simmons Pharmacology: An Illustrated Review Aminoglycosides – Summary Chloramphenicol Peptide synthetase - enzyme links adjacent amino acids to form peptide Chloramphenicol inhibits peptide synthetase ➔ prevents growth of the peptide chain Bacteriostatic against a broad spectrum of pathogens Simmons Pharmacology: An Illustrated Review Chloramphenicol Pharmacokinetics  Absorption – good after oral administration  Distribution – good  high lipid solubility ➔excellent penetration into CSF, ocular fluids, and joint fluids  Excretion – urine – rapid (10% - unchanged + 90% - glucuronide conjugate) Uses Due to broad spectrum and penetration into CSF ➔ useful in meningitis, rickettsial infections, anaerobic, and Salmonella infections Side effects  Irreversible aplastic anemia - rare but serious  Reversible bone marrow depression  “Gray baby” syndrome in neonates due to deficient glucuronidation ➔ accumulation in the infant's body Chloramphenicol - Summary  Chloramphenicol is more effective than tetracyclines against typhoid fever and other Salmonella infections BUT Bone marrow toxicity severely limits use Simmons Pharmacology: An Illustrated Review Protein Synthesis Inhibitors - Summary Simmons Pharmacology: An Illustrated Review Protein Synthesis Inhibitors - Summary Simmons Pharmacology: An Illustrated Review Protein Synthesis Inhibitors - Summary Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Mechanism of Action of Antimicrobial Agents Simmons Pharmacology: An Illustrated Review Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Gyrase Inhibitors e.g. Fluoroquinolones (Quinolones) What is DNA Gyrase? What is DNA Gyrase? DNA is supercoiled  Replication initiation requires the separation of DNA strands BUT stand separation leads to the creation of excess ‘supercoils’ ➔ tension of DNA ➔ Further strand unwinding (necessary for replication) is PREVENTED ➔To avoid the termination of replication Topoisomerases are needed Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy What is DNA Gyrase? Bacterial chromosomes are circular PROBLEM – Complete replication leads to the formation of catenanes ➔ Segregation of progeny DNA cannot proceed To intertwine progeny DNA – Type II Topoisomerases are needed Image modified from the Asuaga & Vazquez Lab – Topological Molecular Biology Lab – UC Davis What is DNA Gyrase? Type II Topoisomerases in Bacteria  DNA gyrase – can introduce negative supercoils  Topoisomerase IV  Both cleave (2x-stranded break) and reseal DNA using ATP  DNA gyrase is critical for chromosomal segregation in some bacterial strains  Topoisomerase IV in other Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Gyrase Inhibitors e.g. Fluoroquinolones (Quinolones) = Inhibitors of either one or both Type II Topoisomerases in bacteria  Prevent the passage through of the T segment and the resealing of the G segment i.e. they stabilize the DNA-enzyme complex in a form where both DNA strands are broken ➔ Promote double stranded breaks and inhibit chromosomal segregation  Usually inhibit DNA Gyrase in gram –ve bacteria BUT Topoisomerase IV in gram +ve bacteria Selective Toxicity – accomplished because of structural difference in bacterial vs eukaryotic topoisomerases Gyrase Inhibitors e.g. Fluoroquinolones (Quinolones) Are they bacteriostatic or bacteriocydal? All are bacteriocydal Fluoroquinolones Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin All are chemically derived from nalidixic acid (urinary antiseptic that could not achieve systemic antibacterial levels)  All are fluorinated  Spectrum – broad  Wide variety of gram -ve bacteria  Gram +ve - usually less susceptible  Anaerobic bacteria respond poorly Pharmacokinetics  Absorption and Distribution – good  Highest concentrations accumulate in urine  Renal excretion - both glomerular filtration and active secretion  Metabolites - LESS antimicrobial activity than the parent drug  Relatively long t1/2 ➔ twice-daily dosing  Penetrate CSF BUT are NOT approved for use in meningitis Dietary Calcium Reduces Absorption of Ciprofloxacin Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Ciprofloxacin is an Inhibitor of CYP450 Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Fluoroquinolones – Uses and Side Effects Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin Clinical Uses  Complicated infections of the genitourinary tract  Abdominal, respiratory, skin, and soft tissue infections that are resistant to other agents  Gram-negative bone infections  Prophylaxis and treatment of anthrax Side effects – Generally well-tolerated BUT Animal studies – young animals - irreversible damage to developing cartilage ➔SHOULD NOT BE PRESCRIBED TO:  Patients <18 years old  Pregnant women Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Resistance to Fluoroquinolones High levels of resistance have emerged Mostly due to chromosomal mutations of: Altered target i.e. Topoisomerase IV or DNA Gyrase Decreased Intracellular Accumulation ➔ Drug cannot recognize target Mutations in Porin channels (=sites of fluoroquinolone entry) ➔ Drug cannot enter bacterial cytoplasm and nuclei  Expression of Efflux pumps ➔ Drug actively pumped out of bacteria ➔ Drug cannot find target Summary – Antibacterial Drugs Affecting the Interpretation of the Bacterial Genetic Code If DNA code cannot be read ➔ regulatory center of cell metabolism is damaged Metronidazole metabolites damage DNA by:  complex formation  or strand breakage Anaerobic bacteria are able to convert metronidazole to reactive metabolites ➔ Metronidazole – ONLY effective in ANAEROBIC bacteria Rifampin inhibits DNA-dependent RNA polymerase ➔ inhibits RNA transcription Simmons Pharmacology: An Illustrated Review Sites of Action of Antibacterial Agents Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Sites of Action of Antibacterial Agents Simmons Pharmacology: An Illustrated Review Inhibitors of Folate Metabolism (Antimetabolites) e.g. sulfonamides & trimethoprim Antimetabolites = drugs with structural similarity to substrates used in intermediary metabolism of the cell ➔Compete for binding to enzymes END RESULT = disruption of cellular functions (nucleic acids, proteins, and cell walls – can be effected) Inhibitors of Folate Metabolism (Antimetabolites) What is Folate Metabolism? Inhibitors of Folate Metabolism (Antimetabolites) Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Humans cannot synthesize dihydrofolic acid ➔ Sulfonamides – selective toxicity What is Folate Metabolism? Katzung’s Basic & Clinical Pharmacology Sulfonamides = Sulfas - Sulfacytine, Sulfadiazine, Sulfamethizole, Sulfisoxazole, and Sulfamethoxazole Mechanism of action  Structurally similar to p-aminobenzoic acid (PABA) ➔ compete with PABA and act as FALSE substrates ➔ Inhibit tetrahydrofolic acid synthesis ➔ Inhibit synthesis of purines and pyrimidines, amino acids, and thymidine ➔ protein, DNA, RNA ➔ significantly alter cellular metabolism  Bacteriostatic – at systemic concentrations (i.e. tissues and fluids)  Bactericidal – urine ➔ used for UTIs Spectrum – broad Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Sulfonamides = Sulfas - Sulfacytine, Sulfadiazine, Sulfamethizole, Sulfisoxazole, and Sulfamethoxazole Pharmacokinetics  Readily absorbed after oral administration  IV - Sodium salts BUT they are strongly alkaline and cause pain if extravasated  Distribution - 20 to 90% bound to albumin (range – due to type of sulfonamide and its concentration)  Excretion – kidney - glomerular filtration and tubular secretion  Lipophilic ➔ enter the CSF  Sulfamethoxazole – intermediate t1/2 ➔ dosing at 8- to 12-hour intervals - THE REST – short t1/2 ➔ usually 4x daily Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Sulfonamides – Uses and Side Effects = Sulfas - Sulfacytine, Sulfadiazine, Sulfamethizole, Sulfisoxazole, and Sulfamethoxazole Uses  Primarily – urinary tract infections BUT also other uses Side effects and Toxicities  If urine – acidic – PRECIPITATE ➔ can cause renal damage  Toxic to the hematopoietic system ➔Can lead to acute hemolytic anemia, thrombocytopenia, etc SHOULD BE NOT BE GIVEN – infants <2months + pregnant women in 3rd trimester Resistance – has developed in may bacterial strains Synergistic Effects of Sulfonamides and Trimethoprim Why? Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Synergistic Effects of Sulfonamides and Trimethoprim Lippincott’s Illustrated Reviews: Pharmacology, 6th edition & Katzung’s Basic & Clinical Pharmacology Trimethoprim – NOT a sulfonamide Trimethoprim – NOT a sulfonamide  Inhibits of bacterial dihydrofolate reductase Uses  UTIs – in combination with sulfonamides (esp. Sulfamethoxazole)  alone – only for uncomplicated UTIs caused by susceptible organisms  Spectrum – same as sulfononamides – broad BUT 50x more potent  Side effects:  due to folic acid deficiency  e.g. megaloblastic anemia, leukopenia Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Summary – Folate Antagonists Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Miscellaneous Antibacterial Drugs How about damaging the cell membrane? Polymyxin B and Colistin  damage the bacterial cytoplasmic membrane  bactericidal  spectrum – primarily gram –ve Pharmacokinetics Do NOT penetrate CSF BUT can be used topically or intravenously for meningitis (inflamed meninges allow penetration) Side effects - Renal damage and various neurologic changes ➔Uses  Topical  Life-threatening infections resistant to safer antibiotics Urinary Antiseptics = oral medications that provide significant antibacterial effect only in the urine e.g. Methenamine – decomposes in acidic urine to form formaldehyde ➔ toxic to bacteria e.g. Nitrofurantoin - bacterial metabolism of the drug ➔ formation of reactive metabolites that attack DNA External Antiseptics and Disinfectants = Germicides - TOO TOXIC FOR INTERNAL USE but that may be effective for removal of microbes from:  the skin – disinfectants or surgical instruments - antiseptics External Antiseptics and Disinfectants Simmons Pharmacology: An Illustrated Review Antibiotics and the Contraceptive Pill Antibiotics - thought to reduce the efficacy of the contraceptive pill BUT by how much – DEBATE Rifampin - known to induce hepatic enzymes ➔ speed up metabolism of the contraceptive pill Broad-spectrum antibiotics - eradicate the bacterial flora responsible for estrogen absorption ➔ Advice to patients – use barrier methods in addition while taking antibiotics and for 1 week after Antibiotics - Summary Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Inhibitors of Bacterial Cell Wall Synthesis Inhibitors of Protein Synthesis Miscellaneous Antibacterial Drugs Inhibitors of Folate Metabolism Inhibitors of Nucleic Acid Metabolism Summary - Mechanisms of Action of Antimicrobial Agents Simmons Pharmacology: An Illustrated Review Thank you