Lecture: Beta-Lactams

Wednesday, November 02, 2011 10:42 AM

Lecture

Audio recording started: 10:42 AM Wednesday, November 02, 2011

Objectives Basic structure of the cell wall As a review The different beta lactam drugs We are going to classify them in a way you can follow Discuss the mechanism of action Pharmacokinetics and dynamics Interactions As we are giving 2 or more antibiotics usually We target many organisms For example your patient has an infection but is taking another medication for something else Adverse effects Bad effects are bad One common one is hypersensitivity leading to anaphylactic shock Thats why you have to get past history of drugs allergy in the history taking What is the resistance of the different drugs Such as resistance of penicillins Apply the drugs clinically Where and why do you use them Via a case study Case A 60 year old man brought to the ER, developed fever 3 days ago With cough 1 day ago had a change in sensorium Has hypertension treated with Has allergy to amoxicillin At the er Patient is febrile Hypotension Septicemia is present Tachypneic And tachycardia Chest x-ray has left lower lung consolidation So pneumonia The plan is to start empiric antibiotic to this patient and perform the lumbar puncture to combat bacterial meningitis What antibiotic regimen should be given? Does the history of amoxicillin affect what can be used The fever and the cough developed before the change in sensorium So it must be community acquired pneumonia What is the probable organism involved Probably gram positive Next to ask is if it is beta-lactamase producing or not This is produced by bacteria on the cell wall The bacterial cell wall Rigid outer layer that surrounds the cytoplasmic membrane
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Rigid outer layer that surrounds the cytoplasmic membrane It gives the shape and integrity It prevents the cell from lysis in high osmotic pressure There are different layers of the cell wall Gram positive and gram negative have differences The periplasmic layer Aka the cytoplasmic membrane Aka plasma membrane The outer layer has peptidoglycans In both But in gram negative the peptidoglycan layer is thinner The outer layer in gram negative has lipopolysaccharides (it is a hydrophilic cell wall) The water cannot penetrate the cell wall It has a porin channel Allowing water into the cell There is a thinner layer of peptidoglycans This is where the penicillin will try to penetrate There is also beta lactamases inside the cell (in gram positive they are outside the cell wall, in the cell membrane) The function is to protect the bacteria They hydrolyse the penicillin Lastly is the penicillin binding protein in the cell which is found in the plasma membrane Called the transpeptidase Enzymes that promote the elongation of the cell And integrity of the cell wall It is also the binding site of penicillin The cell wall has 3 components The polysaccharides Consists of amino sugars N acetylglucosamine N acetylmuramic acid The polypeptides The strand consists of a Pentapeptide, pentaglycine it also consist of a 5 amino-acid peptide that is linked to the N acetylmuramic acid of the polysaccharide And it ends with your two important amino acids D alanine D alanyl These two are the terminal amino acids in the dipeptide chain The peptidoglycan layer The penicillin binding protein Responsible for the transpeptidation reaction They remove the terminal d-alanyl-d-alanine This gets cleaved off via transpeptidation reactions Once that happens the pentaglycine attaches, elongating the chain Making the cell wall stronger In gram positive organisms they have a thicker cell wall 50-100 molecules thick than that of your gram negative organism which is only 1-2 molecules thick The peptidoglycan The 3rd component of the cell wall Very important for bacterial growth Composed of a heteropolymer component that provides the rigid mechanical stability Via highly cross-linking effects This is composed of glycan chains Which are linear strands of alternating amino sugars N acetylglucosamine N acetylmuramic acid Or called NAG and NAM So the alternating links form the peptidoglycan layer
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 So the alternating links form the peptidoglycan layer Biosynthesis needs 30 enzymes It undergoes 3 stages in the process Stage 1 The precursor formation The formation of the park nucleotide The product is the Uridine diphosphate acetylmuramyl Pentapeptide Formation of d-alanyl-d-alanine Added to finally complete the first stage of peptidoglycan synthesis Stage 2 Formation of the UDP acetylmuramyl Pentapeptide and UDP acetylglucosamine which are linked to form a larger polymer Stage 3 The completion of the cross link Completed via transpeptidation reaction The enzyme responsible for this is the transpeptidase enzyme Occurs outside the cell membrane There is joining of the pentaglycine with the d-alanine While the last peptide is being removed This is very crucial in the cell wall This is what the beta-lactam attempts to stop The drug must be able to do this to kill the bacteria Penicillin, cephalosporins It acts at the penicillin binding protein It mimics the DADA residues that would normally bind to the site Causing an irreversible inhibition of the enzyme So the third step is no longer possible Killing the cell Binding of PBP results in Inhibition of transpeptidase Causing the formation of spheroplasts in the cell wall Structural irregularities in the cell wall Abnormal shape Creation of the cell wall defect That is more prone to lyse in increased osmotic pressure The pressure will pop it like a ballon The beta-lactam drugs Penicillin Cephalosporins Beta-lactamase inhibitors Carbapenems Monobactam These drugs have different processes to destroy the cell wall Penicillins The very first antibiotic Discovered in 1928 by alexander Flemming Via culturing staph aureus in the petri dish Mold was found to stop staph aureus growth Found later that it inhibits the growth of gram positive bacteria In 1939 penicillin was used Used in ww2 which reduced death due to infection The structure Consists of 3 fundamental structures The fused beta lactam structure Amino acid side chains Cysteine and valine are fused to form the beta-lactam structure The 'square' is the beta lactam ring The other ring is the thiazolidine ring
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 The other ring is the thiazolidine ring The other component is the carboxyl group and amino acid side chain Beta lactamase is produced in the cell Once it attacks the ring it causes the formation of the penicillanic acid Its function is nothing That is the fate of penicillin when it is destroyed :( When you give penicillin to an organism with beta-lactamase it will hydrolyse the drugs, making it useless The amylase enzyme will bind to the carboxyl acid group and amino acid side chain forming the active penicillin Forming the active penicillin 6-aminopenicillinaic acid -the parent compound This happens when it becomes an active drug The side chain just extends the spectrum and prevents resistance and create other forms of penicillins Chemical properties The thiazolidine ring and the beta-lactam ring formed by the fusion of cysteine and valine Classifications Penicillin G Greatest activity against gram + or gram - cocci Not for beta-lactamase bacteria This is a broad classification Acid labile Easily destroyed in the mouth 60% protein bound Susceptible to beta lactamases Earlier activity against gram negative rods Nafcillin Anti staphylococcal penicillin Ethoxymaphethamidopenicillin Less strongly protein bound (90%) Not hydrolyzed by staph beta-lactamases Active to staph and strep Not active against enterococci, anaerobic bacteria and gram negative rods and cocci Extended spectrum Ampicillin and antipseudomonal penicillins Improved activity against the gram negative organisms Destroyed by beta lactamase Penicillin resistance Penicillinase resistant Choose anti staph penicillin Methicillin Nafcillin Isoxazolyl penicillin Not for gram negative Penicillinase susceptible Narrow spectrum and extended spectrum Narrow Benzylpenicillin Aka pen G High activity against gram + Low activity against gram Acid labile and destroyed by beta lactamase 60% protein bound Orally give pen V Only given orally It is stable in acidic pH
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 It is stable in acidic pH Extended Amino penicillin Ampicillin Amoxacillin Carboxy penicillin Antipseudomonal You have to remember that these drugs retain the antibacterial spectrum but extend into the gram negative organisms They are destroyed by Beta lactamase Unitage of penicillin Expressed in millions of units 1 unit is equivalent to .6 micrograms 1 million units is equal to .6 grams Dosage and the potency is expressed In terms weight in grams Remember that penicillin comes in two forms Procaine salts and benzathine salts -parenteral forms Procaine pen G and benzathine pen G The repository forms These are given via IM For gonorrhea for example give that IM every 3 weeks These are slowly released They have a longer half life It stays in the muscle and slowly releases over time Mechanism of action It inhibits the last step in peptidoglycan synthesis Inhibiting the transpeptidase enzyme Inactivation of the PBP Activation of autolysins Murein hydrolases Mechanisms of drug action by enzyme inhibition All pen. Derivatives produce their own bacteriocidal effects by inhibition of bacterial cell wall synthesis There is an influx of water causing the cell to burst Water can easily enter the gram positive, but hard for negative Via action of the drug the water goes into the porin channels causing it to burst Mechanisms of resistance Inactivation of antibiotics by beta lactamase Modification of PBP Impaired penetration of drug to target PBP's (gram - bacteria) Presence of an efflux pump Pharmacokinetics How is it absorbed It varies with the preparation of the drug Penicillin is impaired by other drugs and food Except amoxicillin Can be taken with or without food or even with an empty stomach Give 1-2 hours before or after meals Parenteral is completely absorbed and rapid Nafcillin is only via IV Cloxacillin can be given orally Gastric juice of pH 2 can cause inactivation Except for pen V Parenteral administration of pen G Repository forms are Pen G procaine (half life of 4-5 days) and benzathine pen G (HL of 26 days) Distribution Cannot penetrate the BBB
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 Cannot penetrate the BBB Only give penicillin in meningitis cases via the meningitic dose That is 18-24 million units per day Exam question We can do this because during the inflammation pores are larger Other organic acids can inhibit the transfer from the CSF to the blood stream Metabolism Metabolized in the liver Causing the formation of allergenic metabolites These are converted in the liver into Penicillic acid Penicillamine Penicilloid acid Other penicilloyl These are the allergenic metabolites This is why some people develop hypersensitivity to pen Excretion to the bile or kidney Adjust the dose In cases of renal impairment Renal excretion is inhibited by Probenecid A drug used for gout Causing toxicity Nafcillin is excreted to the bile Oxacillin dicloxacillin and cloxacillin are excreted to both Range of bacteria to kill Benzathine pen G Mean duration of action of 26 days Given IM 1-2 million units Given every 3-4 weeks Prophylaxis against reinfection with beta hemolytic strep For syphilis give 2.4 M for 1-3 weeks Procaine pen G Given for uncomplicated pneumococcal pneumonia or gonorrhea Rarely used because of penicillin resistant strains Amino penicillins Extended spectrum penicillin Use ampicillin for Shigella Amoxacillin has better absorption Most active of the oral beta lactams against pen resistant pneumococcal strains Amoxacillin Less active against gram positive For enterococcal and viridin group of streptococci Esters of ampicillins No inherent antimicrobial activity as esters but pharmacologically active following hydrolysis to ampicillin 50% higher blood concentration than amoxacillin and ampicillin Carboxy penicillins and ureidopenicillin Good against gram - anaerobes Used for pseudomonas infections Gotten from the hospital Also for bacteroides fragilis Carbenicillin First antipseudomonal carboxy penicillin Not used anymore Carbenicillin indanyl Na is a derivative used in UTI Ureidopenicillin Used for Klebsiella pneumonia Adverse effects
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 Adverse effects Hypersensitivity reactions Can be caused by penicilloyl polylysine (PPL) penicillic acid And products of alkaline hydrolysis Side effects include Skin rashes, Serum sickness Anaphylaxis GIT disturbances after oral administration Diarrhea usually develops Convulsions following rapid IV injection Accidental injection into the sciatic nerve will cause severe pain and nerve dysfunction Chronic use may lead to Hepatitis Overgrowth of atypical organisms Specific toxicities Procaine penicillin G after accidental IV injection Remember that this is not given thru IV, but IM instead Pulmonary embolism Acute psychotic reactions Oxacillin and nafcillin Can cause hepatitis, granulocytopenia Bone marrow depression Disodium carbenicillin and penicillin G in high doses can lead to hypernatremia Be careful if the patient is hypertensive Penicillin G potassium Hyperkalemia in higher doses Pen G sodium Jarisch Herxheimer reaction Carbenicillin and ticarcillin Bleeding diathesis Methicillin can lead to interstitial nephritis Ampicillin can develop pseudomembranous colitis with extended use Exam question Drug dose interactions Aminoglycosides one of your protein synthesis inhibitors, like gentamycin and amikacin Chemical antagonism when given together with this There will precipitation of penicillin salts Causing clogging of the IV line But you can combine them provided they are given 2 hours apart Quick review Pen G is given IV Pen V given Orally Hydrolyzed by penicillinase Ineffective against staph aureus Penicillin resistant one are used for this thing Ampicillin, amoxacillin and [audio unclear] Extend up to gram negative but hydrolyzed by beta lactamases Such as H. Influenza, E. Coli, and proteus mirabilis Cephalosporins They are classified as different generations There are 5 generations Why do we have so many generations Because we have improvement of the spectrum of the drug First gen only for gram positive
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First gen only for gram positive 2nd gen is equal better for gram + and 3rd gen is more gram negative and less gram positive 4th gen is for gram positive and gram negative and aerobic and anaerobic organisms Broad spectrum Very expensive The basic structure The same as penicillin But the active/parent compound is the 7-amino-cephalosparnic acid Exam question No difference in the structure Although they have 2 side chains Penicillin only has one side chain Altering the side chain can change the drug The skeleton is the same General properties of cephalosporins Antimicrobial spectrum Broader spectrum than penicillin Not susceptible to beta lactamase EXCEPT for Enterococci Methicillin resistant staph aureus Staph epidermidis 5th gen can kill these though Cefazolin is the only 1st gen available parenterally Exam question Gen 1 Better activity against gram positive but less effect on gram negative Inadequate penetration to the CSF Oral drugs used for the treatment of UTI Also for minor staph or polymicrobial infections Like cellulitis and tissue abcess We can use cephalexin The most commonly used first gen Not used for serious systemic infection Only for localized infection Cefazolin is the only IV form and the drug of choice for surgical prophylaxis If you undergo appendectomy cefazolin is given 2 hours before the operation Also given via IM The alternative for antistaphylococcic penicillin Gen 2 Equal activity against gram positive and negative Also good for anaerobes Cefamandole, cefuroxime, cefonicid, ceforanide and cefaclor Good against H. Influenza A gram negative organism Cefoxitin, cefmetazole and cefotetan For some Serratia strains and B. Fragilis Given via IV Oral 2nd gens used for sinusitis, otitis or lower respiratory tract infections: Cefaclor, cefuroxime, cefprozil, Loracarbef Also for beta lactamase producing H. influenza and Branhamella catarrhalis For peritonitis diverticulosis Cefoxitin, cefotetan, or cefmetazole Also for mixed anaerobic infections For community acquired pneumonia Use cefuroxime It normally doesnt cross the BBB If meningitis it can though (due to inflammation)
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 If meningitis it can though (due to inflammation) Gen 3 Less active against gram positive More effect against gram negative Cefoperazone and ceftazidime are good against pseudomonas Cefoperazone and cefotaxime are good against anaerobes For example patients with abdominal or bone infections or diverticulitis or peritonitis Ceftizoxime and moxalactam are good for B fragilis All 3rd gens can cross the BBB Except cefoperazone cefixime ceftibuten cefpodoxime proxetil Oral preparations Cefixime Cefdinir Ceftibuten Cefpodoxime The rest are given parenterally Cefoperazone and ceftriaxone are excreted in the bile The others are excreted in the kidney Ceftriaxone and cefotaxime Meningitis caused by pneumococci, meningococci, H. influenza, and susceptible gram - rods And penicillin resistant strains of pneumococci Note that cephalosporins are structurally similar to penicillin, so allergies to penicillin will also cause allergies with cephalosporins Used together with aminoglycosides when there is meningeal infection by P. aeruginosa 4th gen Broad spectrum More resistant to hydrolysis by beta lactamases Good against hemophilus and Neisseria Also good against pseudomonas aeruginosa Strep pneumoniae Staph aureus Enterobacteriaceae Good penetration to CSF In septicemia give this as last resort 5th gen Cephalosporins MRSA Currently under development Used in the US and Canada Ceftaroline fosamil Prodrug of Ceftaroline and ceftobiprole medocaril Enhanced binding to PBP2a which mediates MRSA, methicillin resistance in staph Adverse reactions Similar to penicillin Can cause renal toxicity Cephalosporins with a methyl thiotetrazole group like Cefamandole Moxalactam This causes severe bleeding as it interferes with platelet activity Cefmetazole Cefoteta Cefoperazone Can cause a disulfiram like reaction This is a reaction that happens when you take alcohol with antibiotics May also cause hyperprothrombinemia Also bleeding disorders, but give vitamin K 10mg twice a week to counter
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 Also bleeding disorders, but give vitamin K 10mg twice a week to counter Superinfection The growth of atypical organisms due to irrational use of the drug Monobactam Only has a monobactam ring No thiazolidine ring Resistant to beta lactamases Active against gram negative rods Like pseudomonas and Serratia No activity against gram positive bacteria or anaerobes Aztreonam The only monobactam Mechanism of action It alters the PBP, inducing the formation of a long filamentous structure that is no longer possible to promote the reaction Antimicrobial spectrum The antimicrobial spectrum of aztreonam differs from that of other beta lactams Closely resembles the spectrum covered by aminoglycosides Gram positive and anaerobic are resistant It is an unusual spectrum as it is only active against gram negative aerobic rods Specifically used against Enterobacteriaceae Pseudomonas Hemophilus and neisseria Good penetration to the CSF Will not cause allergies No cross reactions with penicillin either Used to treat gram negative pneumonia and sepsis along with meningitis No real side effects No allergies either Beta lactamase inhibitors Drugs that inhibit the enzyme beta lactamase It is a weak antibiotic You have to combine it with penicillin Clavulanic acid Combine with amoxicillin to make Augmentin Clavulanate K with ticarcillin to make Timentin Sulbactam pivoxil with ampicillin to make Unasyn Tazobactam with piperacillin to make tazocin Carbapenems A new class of cell wall inhibitors They were developed to deal with beta lactamase producing gram negative organisms Derived from the streptomyces family Imipenem The first to be developed A drug used together with another drug to produce cilastatin Because it is inactivated by kidney enzymes called dehydropeptidase You need to combine It with a inhibitor The only Carbapenem that needs to be given with this Covers gram negative and positive and anaerobes Mechanism of action Binds to the PBP Disrupting cell wall synthesis Considered as bactericidal MRSA is resistant to this Good against gram positive and negative, both aerobes and anaerobes Good against Streptococci
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 Streptococci Enterococci Staphylococci Lister Enterobacteriaceae Pseudomonas Bacteroides and clostridium Metabolism Hydrolyzed by the dehydropeptidase Found in the brush border of the proximal renal tubule More stable when adding cilastatin Side effects Allergic reactions Cross reaction as well Nausea and vomiting Seizures/convulsions can happen especially with patients with renal problems Meropenem Similar to imipenem Not degraded by dehydropeptidase Ertapenem Long acting Carbapenem Longest half life Only needed once a day IV Same mechanism of action and coverage Less active against Acinetobacter and pseudomonas Stable under dehydropeptidase enzyme Doripenem Similar to imipenem Also stable against dehydropeptidase Slightly greater activity against gram negative aerobes and less activity against gram positive Glycopeptide Vancomycin Specific for gram positive staph Produced by S. orientalis and A. orientalis Water soluble and stable It binds to the DADA terminus of nascent peptidoglycan Pentapeptide Altering the transpeptidation reaction Thus no separation or cleaving of the d alanine, So no elongation of the peptides Resistance can develop with modification of the binding of the DADA Poorly absorbed in the GIT So not given orally Except for local GIT infections caused by C. Difficile Usually given parenterally Good for sepsis and endocarditis caused by MRSA No cross reaction effect Can cause red neck syndrome Exam question Add cefotaxime, ceftriaxone, or rifampicin for treatment of meningitis caused by penicillin resistant pneumococcal infections Side effects include Phlebitis Chills and fever Ototoxicity and nephrotoxicity Red man syndrome A common reaction Teicoplanin Given orally or parenterally
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 Given orally or parenterally Similar to vancomycin Dalbavancin Similar to vancomycin as far as mode of action Good activity against gram positive bacteria and MRSA Not active against vancomycin resistant enterococci Telavancin Also similar to vancomycin Good for gram positive Inhibits by binding to DADA terminus Targets the bacterial cell membrane Other cell wall agents Fosfomycin Rarely used Inhibits the first step of cell wall synthesis The precursor formation It inhibits enol pyruvate transferase Transported in the cell by glycerophosphate or the glucose 6 phosphate transport system Resistance is due to inadequate transport Active against both grams Target organisms Gram positive and negative organisms This gives a synergistic effect For uncomplicated UTI and can be even during pregnancy Bacitracin Active against gram positive Nephrotoxic so it is only available topically It inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall Poorly absorbed as well Cylcoserine A second line drug for patients with TB If there is a resistance to the first line drugs It can cause CNS toxicity Headaches Psychosis Mechanism of action Inhibits incorporation of D-alanine into the peptidoglycan Daptomycin The new drug Novel cyclic Lipo peptide fermentation product of streptomyces roseosporus Binds via calcium dependent insertion of its lipid tail Results to depolarization of the cell membrane and rapid cell death Cleared by the kidney Causes myopathy and creatinine phosphokinase increase Antagonized by pulmonary surfactant

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