Beta-lactam Antibiotics PDF

Okay, here is the converted text from the images into a structured markdown format. ### INTRODUCTION $\beta$-lactam antibiotics are named after the chemical component of the drugs (the 4-membered $\beta$-lactam ring). They contain a $\beta$-lactam ring in their molecular structure. ### CLASSES OF...

Okay, here is the converted text from the images into a structured markdown format. ### INTRODUCTION $\beta$-lactam antibiotics are named after the chemical component of the drugs (the 4-membered $\beta$-lactam ring). They contain a $\beta$-lactam ring in their molecular structure. ### CLASSES OF $\beta$-LACTAM ANTIBIOTICS 1. Penicillin derivatives 2. Cephalosporins 3. Carbapenems 4. Monobactams ### PENICILLINS In 1928, while studying staphylococcus variants in the laboratory at St. Mary's Hospital in London, Alexander Fleming observed that a mould contaminating one of his cultures caused the bacteria in its variant to undergo lysis. Broth in which the fungus was grown was markedly inhibitory for many microorganisms. Because the mould belonged to the genus penicillium, Fleming named the antibacterial substance penicillin. The penicillin nucleus consists of fused thiazolidine and $\beta$-lactam rings to which side chains are attached during amide linkage. Here is a description of the image of "Substituted 6-aminopenicillinic acid (Penicillin)": The image is a chemical structure. It has two rings shown as Beta-lactam Ring and Thiazolidine Ring connected and labelled appropriately. Delineation of various chemical agents such as $R-C-N-C$, $CH_3$, $COOH$. ### CLASSIFICATION OF PENICILLINS 1. Naturally-occurring penicillins (original penicillins) * Eg - Penicillin-G (Benzyl penicillin). The only naturally-occurring penicillin in clinical use. It is usually not administered orally b/c it is acid labile. The parenteral route is used (IV or IM). 2. Semi-synthetic penicillins * This is classified as follows: * Acid-resistant alternative to penicillin-G * Eg - Phenoxymethyl penicillin (penicillin-V) * Penicillinase-resistant penicillins * Eg - cloxacillin * Oxacillin * Nafcilin * Dicloxacillin * Methicillin * These congeners have side chains that protect the $\beta$ lactam ring from attack by staphylococcus penicillinase. However, they are not resistant to $\beta$-lactamases produced by gram-ve bacteria. * Extended-spectrum penicillins * Amino penicillins * Ampicillins * Bacampicillins * Amoxicillin * Carboxypenicillins * Carbenicillin * Ticarcillin * Ureidopenicillins * Mezocillin * Azlocillin * Piperacillin * Ureidopenicillins are active against *P. aeruginosa*. Extended spectrum antibiotics are sensitive to $\beta$ lactamase and are administered in combination with $\beta$ lactamase inhibitors such as clavulinic acid, sulbactam, tazobactam. Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability. Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available for injection. Penicillins are polar compounds and are not metabolized extensively. They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion; the latter process is inhibited by probenecid. Nafcillin is excreted mainly in the bile and ampicillin undergoes enterohepatic cycling. The plasma half-lives of most penicillins vary from 30 min to 1 h. Procaine and benzathine forms of penicillin G are administered intramuscularly and have long plasma half-lives because the active drug is released very slowly into the bloodstream. Most penicillins cross the blood-brain barrier only when the meninges are inflamed. ### MECHANISM OF ACTION OF $\beta$-LACTAM ANTIBIOTICS $\beta$-lactam antibiotics inhibit the synthesis of bacterial cell wall by interfering with the transpeptidase enzyme responsible for the formation of the cross-link btw peptidoglycan cell wall. These enzymes are associated with a group of proteins in both gram +ve and gram -ve bacteria called Penicillin-binding proteins (PBPs). There are different PBPs that comprise bacteria cell wall and different $\beta$-lactam antibiotics may target PBPs accounting for difference in the spectrum of activity and resistance. The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure. In gram +ve microorganisms, the cell wall is 50-100 molecules thick, but in gram -ve it is 1-2 molecules thick. The peptidoglycan is composed of glycan chains which are linear strands of two alternating amino sugars (N-acetylglucosamine & N-acetylmuramic acid) that are cross-linked by peptide chains. Inhibition of the transpeptidases causes spheroplast formation and rapid lysis of the bacteria. $\beta$-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps: 1. binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane. 2. inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall. 3. activation of autolytic enzymes that cause lesions in the bacterial cell wall. ### Penicillin G **Pharmacokinetics** * It is acid labile, so it is destroyed by gastric acid. * Absorption is rapid if given IM * Distributes widely but penetration of cavities & CNS is poor * Plasma half life - 30 minutes * Elimination is via kidney by tubular secretions * Aged people and those with Kidney failure excrete penicillins slowly. Tubular secretion can be blocked by probenecid so that higher and longer lasting plasma concentrations are achieved. Probenecid also decreases the volume of distribution of penicillin. **Adverse Effects** 1. Pain at injection site 2. Thrombophlebitis if given IV 3. Bleeding in higher doses b/c of interference with platelet function. 4. Hypersensitivity reactions (rash, itching, urticaria, fever) 5. Wheezing 6. Angioedema 7. Serum sickness 8. Exfoliative dermatitis **Clinical uses** include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes. The allergy is worse with parenteral than oral administration. ### Ampicillin This is active against all organisms sensitive to penicillin G and in addition, many gram -ve bacilli such as, * H. influenza * E. coli * Proteus * Saemonella * H. pylori * Enterocolli * L. monocytogenes * Shigella ### Amoxicillin **Pharmacokinetics** * Not degraded by gastric acid * Incomplete oral absorption but adequate * Food interference with absorption. * Mainly excreted via - kidneys & a little in bile * Plasma half life - 1 hour This is a dose congener of ampicillin - Similar to ampicillin in all respects. Used in the triple combination regimen for the treatment of PUD for *H. pylori* eradication. |Amoxicillin|Triple combination regimen| |:---:|:---:| |Protein-pump inhibitor|| |Clarithromycin|| ### CLINICAL USES OF PENICILLINS 1. Urinary tract infections (UTI) 2. Respiratory tract infections (Bronchitis, sinusitis, otitis media) 3. Meningitis 4. Gonorrhea 5. Typhoid fever 6. Bacillary dysentery 7. Cholera 8. Septicemia ### CEPHALOSPORINS They are a group of semisynthetic antibiotics derived from cephalosporium-c obtained from a fungus called *Cephalosporium.* It is chemically related to penicillin. The nucleus consists of a $\beta$-lactam ring fused to a dihydrothiazine ring (7-aminocephalosporanic acid). Cephalosporins are similar to penicillins but more stable to many bacterial $\beta$-lactamase & therefore have a broader spectrum of activity. **Image Description:** The image shows the chemical structure of Substituted 7-aminocephalosporanic acid, also known as (cephalosporin). It shows the Beta-lactam Ring and Dihydrothiazine Ring are connected. It shows various chemical moieties with labels such as $RL-C-N-C$ (Acyl side chain), $R_2$ delineations as well. ### GENERATIONS OF CEPHALOSPORINS There are 5 generations of cephalosporins according to their chronological sequence of development and the overall spectrum & potency. |The gram +ve activity will decrease from 1st to 5th generation while| gram-ve| |:---:|:---:| |the gram -ve activity will increase -| $\implies$| 1. ### 1st Generation * Examples - Cefazolin: this is the prototype 1st generation cephalosporins. It is given parenterally. The t1/2 is 2hrs. * Cephalexin: most commonly used orally effective 1st gen t1/2 is 1hr. It is excreted unchanged in the urine. * Cefadroxil * Cefalotin * Cephradine * Cephaptrin * Cefaloridine 2. ### 2nd Generation * This has increased gram -ve coverage. It is not active against P. aeruginosa. * Examples * Cefuroxime -- Parenteral * Cefoxitin * Cefaclor * Cefprozil -- Oral * Cefuroxine axentil * Cepotetan * Cefamandole Cefuroxine and cefaclor are active against anaerobes but not *B. fragilis* Cefuroxine is resistant to gram -ve beta lactamases. It is active against gram +ve cocci & certain anaerobes except *B. fragilis.* It can be applied for single dose IM therapy for gonorrhea due to PPNG (Penicillase-producing Neisseria gonorrhea)! 3. ### 3rd Generation * Examples * Cefotaxime -- Parenteral * Cefoperazone * Ceftriaxone * Ceftazidime * Cefixime -- Oral * Cefdinir * Ceftibuten * Cefpodoxine * Ceptamet pivoxil * Ceftizoxine * Cefditoren pivoxil * Moxalactam. All the 3rd generation are highly resistant to beta lactamases produced by gram-ve bacteria. They are active against gram +ve cocci and anaerobes. Few ca inhibit pseudomonas. #### Cefotaxime * This is the prototype of 3rd generation. It is not active against anaerobes esp. *B. fragitis, S. aureus* & *P. aernginosa*. It penetrates the CSF very well (b/c it is lipid soluble). * t1/2 - 1 hour * Excretion - Kidneys * Uses - Meningitis, pneumonia, gonorrhea, pyelonephritis UTI, septicemia, typhoid fever **Ceftriaxone** * It is very lipid soluble, therefore penetrates the CSF very well (crosses the blood brain barrier) * t1/2 - Has a longer half life (8hrs) which distinguishes it from other cephalosporins. * Elimination - Urine and bile salt * Uses - bacterial meningitis, multi-resistant typhoid fever, complicated UTI, abdominal sepsis, septicemia - * Side effects - Hypoprothrombinemia * Bleeding * Hemolysis Ceftriaxone can be combined with sulbactam or tazobactam to overcome resistance. #### Ceftazidime * This is highly active against Pseudomonas, but less active against *S. aureus*, cocci and anaerobes like *B. fragilis* * t1/2 - 1.5-1.8hrs * Uses - Neutropenic fever with harmatological malignancies * Burns * Side effects * Neutropenia * Thrombocytopenia * Increased ALT * ↑ AST * ↑ Blood urea. 4. ### 4th Generation * Examples * Cefepime -- Parenteral * Cefpirome They have similar activity to that of 3rd generation. They are highly resistant to $\beta$-lactamases. They are active against *S. aereus,* *pseudomonas* but not MRSA. * t1/2 - 2 hours * Excretion - Kidneys 5. ### 5th Generation * Examples * Ceftolozane * Ceftaroline * Ceftobirpole * Ceftolozane is combined with tazobactam * They are active against most mutations in PBPS & MRSA and also active against pseudomonas and anaerobes. * It crosses the blood brain barrier. ### Uses of Cephalosporins 1. ENT, RTI, skin infections 2. UTI, soft tissue infections (cefuroxine, cefotaxime, ceftriaxone) 3. Penicillinase-producing staphylococcal infections 4. Septicemia 5. Surgical prophylaxis (cefazolin) 6. Meningitis 7. Gonorrhea ### General Adverse Effects of Cephalosporins 1. Pain at IM injection site 2. Phlebitis - inflammation of vein 3. Diarrhea 4. Neutropenia 5. Nephrotoxicity 6. Hypersensitivity. A tre coomb's test out hemolysis is rare. Rashes are common. 7. Bleeding due to hypoprothrombinemia caused by the same mechanism as Warfarin. Common in cancer, intraabdominal infections & renal failure). 8. Disulfiram-interactions with alcohol (esp. cefoperazone & cefobitan). They inhibit the enzyme , acetaldehyde dehydrogenase Cephalosporins are sensitizing & this elicit hypersensitivity b/c * it originates from fungh * it contains sulfur ### BETA-LACTAMASE INHIBITORS $\beta$-lactamases are a family of enzymes produced by many gram positive and gram negative bacteria that inactivate $\beta$-lactam antibionas by opening the $\beta$-lactam ring. They include, 1. Clavulinic acid * clavulinic acid / Amoxicillin $\implies$ Augmentin * clavulinic acid/Ticarcillin $\implies$ Timentin 2. Sulbactam * Sulbactam / Ampicillin $\implies$ Sullsacin * Sulbactam/Ceftriazone * Sulbactam/Ceftoperazone 3. Tazobactam * Tazobactam/Piperacillin $\implies$ Tazobid * (similar to sulbactam) * Tazobactam/Ceftriaxone 4. Avibactam ### MECHANISMS OF RESISTANCE TO PENICILLIN & CEPHALOSPORINS 1. Alteration or acquisition of novel PBPS * The microorganisms may be intrinsically resistant b/c of structural differences in the PBPs that are the target for the drugs. * A sensitive strain may acquire resistance of this type by development of high molecular weight PBPS that have decreased affinity for the antibiotic. * Altered PBPs with decreased affinity for $\beta$-lactam antibiotics are acquired by homologous recombination btw PBPs genes of different bacteria spectes. 2. Decreased entry into the bacteria * Bacterial resistance to the $\beta$-lactam antibiotics are caused by the inability of the agent to penetrate to its site of action. In gram positive bacteria, the peptidoglycan polymer is very near the cell surface. * Some gram +ve bacteria have polysaccharide capsules - Inspite of these, small $\beta$-lactam antibiotic molecules penetrate the bacteria vastly ty to onter layer of the cytoplasmic membrane, where the final stages of peptidoglycan synthesis take place. * The surface structure of gram -ve is more complex - The inner membranes (cytoplasmic membranes) of gram -ve bacteria 4 mycobacteria are covered by the onter membrane Hpopolysaccharides & capsule. The onter membrane functions as an impenetrable barrier to some antibiotics. * However , some small hydrophilic antibiotics diffuse through aqueous channels in the outer membrane formed by proteins called Porins. * Broader spectrum penicillins such as the ampicillin and amoxicillin and most of the cephalosporins diffuse through these pores in E-coli onter membrane. The number and size of pores in the onter membrane vary among different gram -ve bacteria. 3. Efflux Pumps * Active effluk pumps serve as another mechanism of resistance, removing the antibiotics from the site of action before it can act. This is an important mechanism of $\beta$-lactam resistance in E-coli, P. aeruginosa , N. conorrhoea. 4. Production of $\beta$-lactamases * Bacteria can destroy $\beta$ lactam antibiotics enzymatically. The $\beta$-lactamases destroy the $\beta$ lactam ring (open the ring) of the antibiotik and render it incapable of binding to the PBPs and thus the bacteria becomes resistant to that drno. * In gram +ve bacteria, the $\beta$-lactamases are generally tmchictible resulting inn large amount of the enzymes being prochiced inn the presence of the dino. * In gram-ve bacteria, the $\beta$-lactamase enzymes are produced constitutively (ire even when the antibiotic is not present). The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms is a major mechanism of bacterial resistance. Structural change in target PBPs is another mecha- nism of resistance and is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumo- cocci. In some gram-negative rods (eg, Pseudomonas aeruginos changes in the porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs. ### CARBAPENEMS They are the broadest antibacterial spectrum of any antibiotic. They are used in the treatment of multi-ding resistant infections. * Administration - IM or IV * Excretion - Kidneys, hence dosage adjustment is required in Kidney failure. * Examples * Doripenem * Imipenem * Meropenem * Ertapenem Imipenem is inactivated by dihydropeptidases in renal tubule, consequently it is given together with an inhibitor of renal dihydropeptidases called alastatin. ### MONOBACTAM (Monocyclic $\beta$-lactam ring) * They have monocyctic $\beta$-lactam ring * They are active against only gram - ve bacteria (aerobic gram-ve rods including *P-aeruginosa*) * They have no activity against gram +ve bacteria * Excretion - kidneys * Examples * Azactam * Aztreonam ### Other Cell Wall Inhibitor Antibiotics 1. Vancomycin 2. Bacitracin 3. Fosfomycin 4. Cycloserine They inhibit different steps in the process of the synthesis of peptidoglycan in the bacteria cell wall.