Beta Lactam antibiotics Other Cell Wall Synthesis Inhibitors

Beta Lactam antibiotics & Other Cell Wall Synthesis Inhibitors

Beta Lactam antibiotics • Clinically useful families of beta lactam compounds include the – Penicillins – Cephalosporins – Monobactams – Carbapenems

Introduction The penicillins constitute one of the most important groups of antibiotics – widely used – have unique advantages – choice for a large number of infectious diseases

Histor y • The penicillins were the first antibiotics discovered as natural products from the mold Penicillium • 1928 Alexander Fleming – Bread mold (Penicillin notatum) growing on petri dish • 1939 Florey, Chain, and Associates – Began work on isolating and synthesis large amounts of Penicillin • Late 1940 available for general use in US

Structure • Penicillins as well as cephalosporins are called beta lactam antibiotics and are characterized by three fundamental structural requirements: – Thiazolidine ring (A) – Β Lactam ring – Side chain (R)

Classification • Narrow spectrum penicillinase suseptible agents (penicillin G and Penicillin V) – – gram positive and gram negative cocci, non beta lactamase producing anaerobes • Very narrow spectrum penicillinase resistant – nafcillin, methicillin, cloxacilline, oxacillin – resistant to staphylococcal beta lactamases, active to staphylococci and streptococci

Classification • Extended spectrum penicillins (ampicillin, amoxicillin) – Gram negative organisms, but are destroyed by beta lactamases • Mezlocillin, azlocillin, piperacillin, carbenicillin, ticarcillin – Pseudomonas, kelebsiella and gram negative microorganism

Mechanisms of Drug Actions • All penicillin derivatives produce their bacteriocidal effects by: – Binding to specific enzymes (penicillin Binding Protein [PBP]) – Inhibition of the transpeptidation reaction and cell wall synthesis – Activation of autolytic enzyme in microorganism

Mechanisms of Drug Actions • 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 – two alternating amino sugars (N acetylglucosamine and N acetylmuramic acid) that are cross linked by peptide chains. (NAG NAM).

Mechanisms of Drug Actions • Binding to PBPs results in: – Inhibition of transpeptidase: transpeptidase catalyzes the cross linking of the pentaglycine bridge with the fourth residue (D Ala) of the pentapeptide. The fifth reside (also D Ala) is released during this reaction. Spheroblasts are formed – Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects

Transpeptididase

Comparison of the structure and composition of gram-positive and gram-negative cell walls

Pharmacokinet ics • Oral Administration of Penicillin G. – About one third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions • Food may interfere with enteric absorption of all penicillins, Gastric juice at p. H 2 rapidly destroys the antibiotic Ingestion – should be administered at least 30 minutes before a meal or 2 hours after

Pharmacokine tics • Oral Administration of Penicillin V. – It is more stable in an acidic medium, and therefore is better absorbed from the gastrointestinal tract • On an equivalent oral dose basis, penicillin V (K+ salt PEN VEE K, V CILLIN K, others) yields plasma concentrations two to five times greater than those provided by penicillin G.

Parenteral Administration of Penicillin G • After intramuscular injection, peak concentrations in plasma are reached within 15 to 30 minutes. This value declines rapidly, since the half life of penicillin G is 30 minutes. • Repository preparations of penicillin G are employed. – penicillin G procaine (maintained for as long as 4 to 5 days) – penicillin G benzathine. (duration of antimicrobial activity in the plasma is about 26 day) • Intrathecal administration is inadvisable particularly with benzylpenicillin as it can cause convulsions.

Distribution • Penicillin G is distributed widely throughout the body – Volume of distribution is about 0. 35 liters/kg – 60% of the penicillin G in plasma is reversibly bound to albumin • Penicillin does not readily enter the CSF when the meninges are normal

Excretion • Penicillin G is rapidly eliminated from the body, mainly by: – the kidney – in small part in the bile and by other routes • Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion. – Probenecid markedly decreases the tubular secretion of the penicillins • Clearance values are considerably lower in neonates and infants, because of incomplete development of renal function

Unitage of Penicillin • 1 unit = 0. 6 mcg; 1 million units of penicillin = 0. 6 g • 1. 0 milligram of pure penicillin G sodium thus equals 1667 units • 1. 0 mg of pure penicillin G potassium represents 1595 units • The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.

Mechanisms of Bacterial Resistance to Penicillins • Resistance to penicillins and other beta lactams is due to one of general mechanisms: – Inactivation of the antibiotic by beta lactamase – Modification of target PBPs – Imparied penetration of drug to target PBPs – The presence of an efflux pump – Production of biofilms • There are more than 300 different types of beta lactamase enzymes. The process is genetically controlled commonly with plasmids. • beta lactamase production is particularly important in Staphylococci, Neisseria gonorrhoeae, Hemophilus

Adverse effects • Hypersensitivity Reactions – rash, urticaria, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis and anaphylaxis • Penicillins and their breakdown products act as haptens after covalent reaction with proteins – The most abundant breakdown product is the penicilloyl (major) moiety • Very high doses of penicillin G can cause seizures in kidney failure • These are cross reactions between various types of

Management of the Patient Potentially Allergic to Penicillin Adverse effects • Evaluation of the patient‘s history • Desensitization occasionally is recommended for patients who are allergic to penicillin and who must receive the drug

Adverse effects cont • • • Convulsions and encephalopathy can occur, especially at higher doses and especially if administered intrathecally (NOT advised). Interstitial nephritis (Methicillin) Coomb's positive hemolytic anemia Neutropenia (especially the b lactamase resistant penicillins) Decreased platelet aggregation (carbenicillin and ticarcillin) Hypernatremia and hypokalemia (carbenicillin)

Drug drug Interactions • Penicillins bind to and inactivate aminoglycosides. This is a form of chemical antagonism. • When an aminoglycoside and a penicillin are administered, the infusions should be staggered by about 1 to 2 hours.

Cephalospori ns • Mechanism of Action: Cephalosporins are composed of a dihydrothiazine ring and a b lactam ring. The mechanism of action is identical to penicillins • Mechanism of Resistance: Same as penicillins • Cephalosporins are less susceptible to Staphylococcus beta lactamase; Methicillin resistant Staphylococcus is resistant to most cephalosporins. • Classification: The cephalosporins are classified as first, second, third generation or forth generation cephalosporins. This classification is dependent on the antimicrobial activity.

Cephalosporins First Generation Fourth Generation Second Generation Third Generation Cefadroxil * Cefaclor * Cefdinir Cefepime Cefazolin Cefamandole Cefoperazone Cefpirome Cephalexin * Cefonicid Cefotaxime Cefclidine Cephalothin Ceforanide Ceftazidime Cephaprin Cefotetan Ceftibuten Cephradine * Cefoxitin Ceftizoxime Ceftriaxone Cefuroxime * Oral Agent Cefixime Cefozopran

First generation cephalosporins • • • Cephalothin, cefazolin, cephalexin Gram positive cocci (Streptococcus, pneumococcus but not or methicillin resistant Staphylococcus) Gram negative organisms (Escherichia coli, Klebsiella pneumoniae, and the indole negative Proteus mirabilis) Anaerobic cocci (Peptococcus and Peptostreptococcus, but NOT Bacteroides fragilis). They are ineffective against Pseudomonas aeruginosa, Enterobacter, and indole positive Proteus species. These drugs do not cross the blood brain barrier.

Second generation cephalosporins • cefuroxime, cefamandole, cefoxitin, cefaclor, cefotetan – The spectrum is extended to more Gram negative bacteria Enterobacter species, Klebsiella species, and indole positive Proteus species. • Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor – Haemophilus influenza (meningitis) • cefoxitin, cefmetazole, and cefotetan – Bacteroid Fragilis • These drugs do not achieve adequate

Third generation cephalosporins • less active than first generation agents against gram positive cocci • more active against the Enterobacteriaceae, including b-lactamase-producing strains • cross the blood brain barrier • The spectrum is extended to include: Enterobacter, Pseudomonas (ceftazidime and cefoperazone only), Serratia, b lactamase producing Haemophillus influenza and Neisseria species. – Only ceftizoxime and moxalactam retain good activity against Bacteroides fragilis.

Fourth generation • cefepime, cefpirome, cefclidine, cefozopran • more resistant to some beta lactamases • active against P aeruginosa, Enterobacteriaceae , S aureus , and S pneumoniae , Haemophilus and Neisseria sp • Penetrate well into CSF • Good activity against gr+ and gr bacteria

Cephalosporins Active Against Methicillin Resistant Staphylococci • Ceftobiprole, ceftaroline – methicillin resistance in staphylococci – activity against enterococci and broad gram negative spectrum – powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance

Pharmacokineti cs • Some cephalosporins may be given orally but most are given parenterally (IM or IV). • They are widely distributed in the body like penicillins. • Some such as cefuroxime (2 nd genereation), cefoperazone, cefotaxime, , ceftriaxone, and ceftazidime (third generation) also cross the blood brain barrier and are drugs of choice for meningitis due to Gram negative intestinal bacteria.

Pharmacokinetic s • Almost all are primly eliminated via the kidneys and are actively secreted by the renal tubules. Cefoperazone and ceftriaxone are eliminated through the biliary tract.

Adverse effects • Hypersensitivity • Nephrotoxicity (cephaloridine) and intolerance to alcohol (disulfiram like reaction) – cefamandole, cefotetan, moxalactam, cefoperazone • Diarrhea may occur with oral forms (cefoperazone) • During treatment with such drugs, these resistant organisms as well as fungi, often proliferate and may induce superinfection. • Hypoprothrombinemia, Thrombocytopenia, Platelet dysfunction.

THERAPEUTIC USES • A cephalosporin with or without an aminoglycoside is first line treatment of Klebsiella. • First generation cephalosporins are used for surgical prophylaxis of wound infection. • Third generation cephalosporins are used to treat meningitis due to pneumococci, meningococci, and Haemophillus influenza. • Ceftriaxone is the drug of choice for treating beta lactamase producing Neisseria gonorrhea.

Carbapenems • Doripenem, ertapenem, imipenem, meropenem – structurally similar to the penicillins. These drugs were developed to deal with beta‑lactamase producing Gram negative organisms, which were resistant to broad spectrum and extended spectrum penicillins. – Carbapenems are derived from Streptomyces

Imipenem • Mechanism of action – • binds to PBP, disrupts cell wall synethesis and is bactericidal Antimicrobial spectrum – – – It is a broad spectrum antibiotic gram negative rods, including P aeruginosa, gram positive organisms, and anaerobes Enterococcus faecium, methicillin resistant strains of staphylococci, Clostridium difficile are resistant.

Imipene m • Metabolism: – hydrolyzed by dehydropeptidase, – it is always administered with cilastatin, an inhibitor of dipeptidase. • Side efects: Individuals who are allergic to the penicillins may demonstrate cross reactivity with imipenem. – Imipemem may produce nausea and vomiting. – Seizures have been reported with high doses, particularly in patients with renal failure.

Meropenem, Doripenem • It is similar to imipenem. • It is not degraded by dehydropeptidase, thus no cilastatin is needed. • Excessive levels in kidney failure can cause seizures with imipenem but not with meropenem. • They have slightly greater activity against gram negative aerobes and slightly less activity against gram positives

Ertapene m • longer serum t 1/2 that allows once daily dosing • inferior activity against P. aeruginosa • activity against gram positive organisms, Enterobacteriaceae and anaerobes • May use in intra abdominal and pelvic infections.

Monobactam • Aztreonam: This drug is a monocyclic beta lactam (a monobactam) • Mechanism of action: Aztreonam interacts with penicillin binding proteins and induces the formation of long filamentous bacteria. • Antimicrobial spectrum – resembles the spectrum of the aminoglycosides. • • • Gram positive and anaerobic bacteria are resistant. Susceptible organisms include: Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria. Aztreonam is resistant to the beta lactamase produced by gram negative organisms. Side effects: Generally, the drug is well tolerated. Patients who are allergic to penicillins do not exhibit

Beta Lactamase Inhibitors • Clavulanic Acid, Sulbactam and tazobactam • • Mechanism of action: They are potent inhibitors of many bacterial beta lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. They are included in combination with amoxacillin (Augmentum) or with ticaricillin. In particular, clavulanic acid is an irreversible, "suicide" inhibitor of beta lactamase. •

Beta Lactamase Inhibitors • They are available only in fixed combinations with specific penicillins: • Ampicillin + sulbactam • Amoxicillin + clavulanic acid • Ticarcillin + clavulanate potassium • Piperacillin + tazobactam sodium

Vancomyc in • Mechanism of Action: – inhibits cell wall synthesis by interfering with second stage of synthesis of peptidoglycan (inhibit transglycosilation by binding to the D Ala terminus) – no cross resistance with penicillin – may also have effect of inhibiting synthesis of RNA

Vancomyci n • Antimicrobial Activity – excellent activity against gram positive aerobes (especially staphylococci, streptococci, and enterococci) – Vancomycin+gentamicin • Enterococcus faecium , enterococcus fecalis • Pharmacokinetics – poorly absorbed from GI tract – penetrates well into most areas in body except CNS

Vancomyci n • Side Effects: – ototoxicity is most common serious side effect (is usually permanent) – nephrotoxicity rarely seen, higher incidence with concomitant use of aminoglycosides – "red man syndrome" (histamine release )

Vancomycin • Clinical Applications – Sepsis, endocarditis (+gentamicin) – Drug of choice for MRSA, coagulase negative staphylococci, and Corynebacterium jeikeium; – Alternate drug in staphylococcal, streptococcal, and enterococcal infections (penicillin allergic patients) – Clostridium difficile colitis (orally) and this regimen is much more expensive than metronidazole

Teicoplanin • Teicoplanin is a glycopeptide antibiotic • It is like vancomycin in mechanism of action, spectrum of activity, and renal elimination. • T 1/2 >vancomycin • i. m administration • MECHANISMS OF ACTION • Teicoplanin inhibits cell wall synthesis by binding to the D Ala terminus of cell

DALBAVANCI N • mechanism of action same as vancomycin • It has improved activity against many gram positive bacteria including methicillin resistant and vancomycin intermediate S aureus • It is not active against most strains of vancomycin resistant enterococci • Dalbavancin has an extremely long half life of 6– 11 days

TELAVANC IN • Like vancomycin, telavancin inhibits cell wall synthesis by binding to the D Ala terminus • disruption of membrane potential and increases membrane permeability • it is active versus gram positive bacteria, including strains with reduced susceptibility to vancomycin

Fosfomycin trometamol • Mechanism of Action: – Blocks very early step in bacterial cell wall synthesis – It inactivates enzyme enolpyruvyl transferase – Blocking the addition of phosphoenolpyruvate to UDP N acetylglucosamine – Reduces bacterial adherence to epithelial cells – bactericide

Fosfomycin • Antimicrobial Activity – E. coli (less effective than TMP SMX and fluoroquinolones) – Enterococcus faecalis – activity against other aerobic gram negative rods not clearly known – Safe for use in pregnancy

Fosfomycin • Pharmacokinetic: long half life • Side Effects: diarrhea (10%), headache (10%), and vaginitis (8%) • Clinical Applications – acute uncomplicated urinary tract infection in adults caused by either E. coli or Enterococcus faecalis

Daptomyci n • Mechanism of Action – Daptomycin (Cubicin) is in a novel antibiotic class known as a cyclic lipopeptides (bactericide) – bind to the cell membrane via calcium dependent insertion of its lipid tail – depolarize cell membrane with potassium efflux and rapid cell death • Antimicrobial Activity – extremely good activity against gram positive pathogens (anaerbic, aerobic), including MRSA – active against vancomycin-resistant strains of enterococci and S aureus

Daptomyci n • Pharmacokinetic: long half life allows for once daily dosing; available in IV form only • Side Effects: few adverse effects; elevation in CPK in about 3%, nephrotoxicity with aminoglycoside • Clinical Applications: complicated skin and soft tissue infections (MRSA); under investigation for endocarditis; VSEF*, not indicated for pneumonia (did not perform well in pneumonia trials)

BACITRACI N • The bacitracins are a mixed group of polypeptide antibiotics. The major constituent is bacitracin A. • inhibits cell wall formation – Interfer dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall

BACITRAC IN • gram positive & gram negative cocci and bacilli • Neisseria • H. influenzae, and Treponema pallidum • Dosage forms – ophthalmic and dermatologic ointments – the antibiotic also is available as a powder for the preparation of topical solutions

CYCLOSERI NE • Cycloserine is a structural analog of D alanine • inhibit alanine racemase • inhibits the incorporation of D alanine into peptidoglycan pentapeptide • inhibits many gram positive and gram negative organisms • treat tuberculosis caused by strains of Mycobacterium tuberculosis resistant to first line agents

CYCLOSERIN E • Adverse effects – headaches, tremors, acute psychosis, and convulsions