Antibiotics and Spectrum of Action PDF

Antibiotics / Antibacterials *Antibiotic are substances produced by microorganisms which are antagonistic (opposed) to the growth or life of other bacteria but is often used synonymously with antibacterial drug Considerations for Antibiotic Treatment Treatment Approach Ideal Begin therapy after ID a...

Antibiotics / Antibacterials *Antibiotic are substances produced by microorganisms which are antagonistic (opposed) to the growth or life of other bacteria but is often used synonymously with antibacterial drug Considerations for Antibiotic Treatment Treatment Approach Ideal Begin therapy after ID and sensitivity Formulate a clinical diagnosis Obtain specimens Formulate a microbiological diagnosis Empiric therapy Determine necessity Star Tx before ID and sensitivity is determined May be detrimental to life, if you don’t start Tx Pharmacological Sanctuaries Area of the body that is poorly penetrated by pharmacological agents Abscess Blood brain barrier Prostate gland Host status Immune system Renal function (aminoglycosides) Hepatic function (erythromycin) Pregnancy (all agents cross the placenta) Lactation Age (all functions diminish with age) Pregnancy/Fetal Risk Category Category Description Drug A No human or fetal risk or remote possibility of feta harm B No control studies show human risk; animal studies suggest toxic potential B lactams B lactams with inhibitors Cephalosporins Aztreonam Clindamycin Erythtromycin Azithromycin Metronidazole Nitrofurantoin Sulfonamides C Animal fetal toxicity demonstrated; human risk undefined Chloramphenicol Fluoroquinolones Clarithromycin Trimethropin Vancomycin Gentamycin Trimethropin - sulfamethoxazole D Human fetal risk present; benefits outweigh risks Tertacycline Aminoglycosides (except gentamycin) X Human fetal risk present but does not outweigh benefits; contraindicated in pregnancy Cost of Treatment Often several drugs have similar effectiveness but DIFFERENT CO$T 14 Day treatment Rx for peptic ulcer caused by Helicobacter pilory Drug Cost Tetracycline $ 5.00 Metronidazole $ 6.00 Bismuth Subsalicylate $ 1.00 Amoxicillin $ 17.00 Clarithromycin $120.00 General Characteristics and Factors Activity Bacteriostatic Arrest growth and replication of bacteria limiting spread infection while immune system works This agents DON’T kill the microorganism Bactericidal Eliminate (KILL) microorganism Subclassification Concentration dependent killing (aminoglycosides and quinolones) Time dependent killing (beta latam, vancomycin) MIC Minimum inhibitory concentrations (MICs) - defined as the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation - MICs are used by diagnostic laboratories mainly to confirm susceptibility / resistance AUC = antibiotic area under the curve AUC/MIC = the ratio of the antibiotic area under the curve to the time above MIC needed needed to inhibit microorganisms Cmax = the maximum serum concentration needed to inhibit microorganisms Cmax/MIC = ratio of maximum serum concentration (or peak) to the time above MIC to inhibit microorganisms MIC For antibiotics which confer timedependent antimicrobial activity, microbial killing is optimized when the concentration of antibiotic is above the MIC for as long of a time period as possible For antibiotics which confer concentration-dependent antimicrobial activity, microbial killing is optimized when a high peak concentration of antimicrobial is achieved Pulsed Dosing Interval drug dosing in escalating level past MIC early on in Tx followed by a prolonged dose-free period (e.g., two weeks of high interval dosing, then stop for 2 weeks; repeat cycle if need) Drug Treatment Spectrum Particular activity of the drug Narrow Single or limited group of organism e.g. Isoniazid (mycobacteria) Extended Effective against gram (+) and gram( -) organism e.g. Ampicillin, Amoxicillin Broad Wide variety of microbial species e.g Tetracycline Drug Resistance Drug failure to halt its grow by the maximal level of antibiotic tolerated by the host Genetic alteration Spontaneous mutation Transfer of drug resistance by R factors (plasmids) Modification of target site eg. Staph. aureus Decrease accumulation Decreased permeability for agent Enzymic inactivation В-lactamase resistant organism Drug Combinations The use of one agent with higher specificity for the organism is preferred – decreasing the risk of superinfection and emergence of resistant organism Advantages Synergism (combination is more efficient than either used separately (B- lactams & Aminoglycosides) Disadvantages some agents work only while organism is growing. If combined with bacteriostatic agent it becomes ineffective. Complications of Therapy Hypersensitivity Reaction to drug or metabolites is frequent (eg. Penicillin) Direct toxicity High levels in serum may be toxic to the host (eg. Aminoglycoside produce ototoxicity) Superinfections Therapy may alter the normal flora allowing overgrowth of opportunistic organisms Classification Distinguishing Characteristics 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 Mechanisms of Action Effects on cell wall integrity Inhibition of protein synthesis Interference with nucleic acid metabolism Inhibition of intermediary metabolism of folic acid - decreased synthesis of nucleotides and eventually inhibition of bacterial growth Inhibition of cell wall synthesis ß-lactams and glycopeptides 20 Beta Lactams Mechanism of Action of ß-lactams Penicillin and other ß-lactam antibiotics inactivate a set of transpeptidases (PBPs) that catalyze the final crosslinking reactions of peptidoglycan synthesis Penicillin inhibits these enzymes by inactivating them, forming a penicilloic-enzyme complex PBPs are responsible for the assembly, maintenance, and regulation of the peptidoglycan structures Classification of Penicillin and Cephalosporins Natural Penicillin Penicillin G potassium Penicillin V phenoxy methyl Semisynthetic Penicillin Penicillinase-resistant Cloxacillin Methicillin Aminopenicillin Ampicillin Amoxicillin Carboxypenicillin Carbenicillin and ticarcillin Ureidopenicillin Piperacillin Cephalosporins First generation Cefazolin Second generation Cefuroxime Cefoxitin Third generation Cefotaxime Ceftriaxone Ceftazidime Fourth generation Cefepime Cefpirome Other ß-lactam Antibiotics Carbapenems – subclass of B-lactams Broad spectrum, IV Used for Tx of severe infections of resistant bacteria Types Ertapenem (Invanz) Imipenem (Primaxin) -high affinity to high-molecularweight PBPs. Meropenem (Merem) Doripenem (Doribax) Monobactams IV Aztreonam ß-lacatmase inhibitors protects from the hydrolytic activity of ßlactamases by “suicide” inactivation (inhibitor is hydrolyzed): Amoxicillin-clavulanate Piperacillin-tazobactam Ampicillin/sulbactam Glycopeptides Mechanism of action Inhibit second stage of cell wall peptidoglycan synthesis by binding to the (D-alanyl-Dalanine 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 25 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 killing of the organism depends on whether this binding is reversible or irreversible Macrolides Lincosamide Erythromycin Clarithromycin Clindamycin Azithromycin Chemically unrelated but similar biologic properties inhibit protein synthesis at 50s ribosomal subunit Macrolides Mechanisms of action A single molecule of the antibiotic reversibly binds to the 50S ribosomal subunit, and lead to inhibition of protein synthesis Bacteriostatic, bactericidal action in alkaline environment mRNA 30 s 50 s ERYTHROMYCIN RIBOSOMAL COMPLEX “TRANSLATION” PP CHAIN ACCEPTOR SITE tRNA Macrolides Gastrointestinal absorption is variable Do not readily cross the blood brain barrier Resistance Alteration in cell membrane permeability Modification of 50 s subunit binding site Erythromycin Base, estolate, sterate, and ethylsuccinate Actvity Staphylococcus and streptococcus Mycobacterium Chlamydia Poor activity against Haemophilus Biliary excretion Macrolides Clarithromycin Biaxin (250/500 mg tablets; susp) Synthetic form of erythromycin by adding a methyl group to the chemical structure of erythromycin - provides gastrointestinal acid stability Same spectrum as erythromycin Hydroxyclarithromycin (active metabolite) Excretion is biliary and renal (dosage adjustment) Macrolides Azythromycin Zythromax (Z-pack.) Semi-synthetic form of erythromycin by adding a methylated nitrogen group Better spectrum (haemophilus) than the other macrolides and better activity ½ life (2-4 days) Not metabolize by cytochrome P450 Adverse effects of Macrolides Gastrointestinal disturbances Pseudomembranous colitis Cholestatic (canalicular) hepatitis (erythromycin estolate) Drug interaction with drugs metabolize by cytochrome P450 (e.g., anti-histamine) except azithromycin Clindamycin Lincosamide class of antibiotics 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. Aminoglycosides Bactericidal Binds to 30 s subunits leading to altered anticodon sequence of tRNA Main activity against gram(-) bacilli and staphylococcus species Systemic administration mainly via IM Not administered orally (except neomycin) due to poor gastrointestinal absorption Aminoglycosides Systemic administration may lead to ototoxicity, nephrotoxicity, and respiratory depression Reserved for severe systemic gram(-) infections Excreted in the urine (dosage adjustment) Effective in topical ophthalmic use , but only for short therapy (5-7 days) Resistance Alteration of 30 s subunit binding site Change cell membrane permeability Enzymatic inactivation Adverse effects Vestibular and auditory dysfunction Nephrotoxicity (tubular necrosis) Respiratory depression (neuromuscular paralysis) Tetracyclines Mechanism of action They penetrate the cell wall by passive diffusion and through the cytoplasmic membrane by ATP-dependent active transport system Once inside the cell they binds reversibly to the 30S ribosomal subunit Bacteriostatic Tetracyclines Tetracyclines Active against staphylococcus species and chlamydia Tetracycline, oxytetracycline, doxycycline, minocycline Tetracycline and oxytetracycline 60-70% absorbed Interfered by bivalent cations 40-80% protein bound Doxycycline and minocycline 95% absorption Less food interference, less protein bound Renal and biliary excretion Tetracyclines Resistance Impaired diffusion Bacteria protein synthesis interferes with binding of tetracyclines Enzymatic inactivation Adverse effects GI Pseudomembranous colitis Teratogenic defects Premature epiphysis closure (defective bone formation) and teeth discoloration in children under 12 years old Pseudo tumor cerebri Linezolid Oxazolidinone - used for gram-positive infections, can be bacteriostatic or bactericidal depending on bacteria being treated Inhibit of bacterial protein synthesis by blocking the formation of the 70s ribosomal initiation complex Linezolid (Zyvox) considered bacteriostatic against most organisms but has some bactericidal activity against streptococci Linezolid is bactericidal against pneumococci, GAS and anaerobes Antibiotics that Interfere with DNA Synthesis Quinolones Metronidazole Rifampicin Mechanism of Action of Fluoroquinolones Act on enzymes topoisomerases II (DNA gyrase) in gram-negative bacteria and topoisomerase IV in gram positive bacteria) Nicks and relaxes DNA supercoiled for DNA replication Believed to have activity on supercoiling after replication Classification of Fluoroquinolones Parent Drug Nalidixic acid (a quinolone) Broad spectrum Ciprofloxacin Ofloxacin Newer Generations Levofloxacin Moxifloxacin 41 Metronidazole Mechanism of action Enters bacteria via cell diffusion Activates via oxidation process by bacteria Generates metabolites that are toxic to bacteria DNA – DNA fragmentation Activity Protozoans - Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis Most Gram-negative and Grampositive anaerobic bacteria Antibiotics that Inhibit the Synthesis of Folic Acid 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) 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 Inhibition of bacterial growth by competitively incorporating of PABA into tetrahydropteroic acid. The combination TMP-SMX is synergistic against a wide spectrum of bacterial species. Intermediary Metabolic Pathway Inhibition Pathway for the synthesis of tetrahydrofolic Acid, a cofactor needed for the synthesis of DNA and RNA nucleotides