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Beta lactam inhibitors (1) (1).pptx

This document discusses beta lactam inhibitors and other cell wall synthesis inhibitors. It describes several classes of antibiotics that work by inhibiting bacterial cell wall synthesis including penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors. These antibiotics share the beta-lactam ring structure and inhibit the final step of peptidoglycan synthesis in bacterial cell walls. Resistance can occur via beta-lactamase production or alterations in penicillin-binding proteins. The document provides details on the chemistry, mechanisms of action, clinical uses and adverse effects of various antibiotics in these classes.

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BETA LACTAM INHIBITORS AND OTHER CELL WALL SYNTHESIS INHIBITORS MUTUA MUTHEU
INTRODUCTION • Include • Penicillin • Cephalosporin • Carbapenems • Monobactams • β-lactamase inhibitors. • Share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics • All are so named because of their four membered lactam ring
• Share mechanism of action (i.e., inhibition of the synthesis of the bacterial peptidoglycan cell wall). • Peptidoglycan is a heteropolymeric component of the bacterial cell wall that provides rigid mechanical stability. • The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis • Bacterial resistance against the β-lactam antibiotics is widespread • Mechanism of resistance include • Production of β-Lactamase which inactivate the drug. inhibitors such as clavulanate and avibactam can extend the utility against β-lactamase–producing organisms. • alterations in the bacterial enzymes targeted by β-lactam antibiotics • decreased entry or active efflux of the antibiotic
Natural Penicillin – -Broken down by Amidase = (Removes Side Chain) •Penicillin – side chain = •6- Amino-Penicillanic acid (6-APA) •Active moiety •Has intact Betalactam ring (B) •With NH2 group at position 6 joined to thiazolidine ring.
Penicillin •First antibiotic to be used clinically in 1941 •One of the least toxic antibiotic even today •Obtained from Penicillium notatum (Early) Penicillium chrysogenum (Now, Better Yield) •Scientists- Fleming – Chain – Florey •Original Penicillin – •Penicillin G, Benzyl Penicillin ( R is Benzyl (CH2C6H5) )
Chemistry •Penicillin nucleus consists of •Thiazolidine ring (Ring A)- •Sulphur containing with COOH (Carboxyl group), •Beta lactam ring (Ring B) – (Broken by Betalactamase) •Side chain is attached at position – 6- (NHCOR) •Side chains attached through amide linkage. (Broken by Amidase)
•Beta Lactam ring is broken by – • Penicillinase (Beta Lactamase), and by gastric acid. • Resultant Product is Penicilloic acid with • No anti-bacterial activity but • Acts as antigenic determinant (Major determinant) • Penicillins are available as • Na+ or K+ salts . • Amine salts such as Procaine and Benzathine Penicillin.
PENICILLINS • All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta- lactam ring structure that is essential for antibacterial activity. • Penicillin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.these groups are 1. Penicillins (eg, penicillin G)—These have greatest activity against Gram- positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. little activity against Gram-negative rods, and they are susceptible to hydrolysis by β-lactamases
2. Antistaphylococcal penicillins (eg, nafcillin) • These penicillins are resistant to staphylococcal β-lactamases. • They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods. 3. Extended-spectrum penicillins (aminopenicillins and antipseudomonal • These drugs retain the antibacterial spectrum of penicillin and have improved activity against Gram-negative rods. • Like penicillin they are relatively susceptible to hydrolysis by β-lactamases
• Pharmacokinetics • oral bioavailability vary depending on resistance to gastric acid • Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available for injection. • Penicillins are polar compounds and are not metabolized extensively. • Excretion is unchanged via glomerular filtration and tubular secretion • Probenecid can inhibit tubular secretion and hence increase levels • 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 with long plasma half- lives as active drug is released very slowly into the bloodstream. • cross the bloodbrain barrier only when the meninges are inflamed.
MECHANISMS OF ACTION AND RESISTANCE • Beta-lactam antibiotics are bactericidal drugs. • They act to inhibit cell wall synthesis by the following steps • binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane • inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall • activation of autolytic enzymes that cause lesions in the bacterial cell wall.
MOA SUMMARY •Bacteria are unique •Don’t have osmotic regulating mechanism •Cell wall controls osmotic changes. •Cell wall is composed of •Peptidoglycans •Cross linked by peptide chains. •NAM – NAG ( N-acetyl muramic acid and N- acetyl glucosamine) •Cross linked by a Pentaglycine cross bridge (Extending from the L-lysine residue of one peptide chain to the D- alanine residue of another peptide chain).
• Cross bridging is transpeptidation reaction. • Transpeptidase and related proteins (Penicillin Binding Proteins) are used for making cross linkage. • Cross linking provides stability, strength.
•β-Lactams inhibit Transpeptidase leading to •Damage of cross linking •Weakening of cell wall •Swelling of cell due to Endosmosis •Bacterial membrane bursts •Bacterial lysis •Additional mechanism – •Activation of autolysing enzymes (Murein Hydrolase and Autolysins) •More lethal during active multiplication
• Mechanism of resistance include • The formation of beta-lactamases (penicillinases) by most staphylococci and many gram- negative organisms cause hydrolysis of the beta lactam ring with loss of antibacterial activity • Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) combination prevent their inactivation. • Structural change in target PBPs is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci • In some gram-negative rods (eg, Pseudomonas aeruginosa), changes in the porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs
CLINICAL USE • Narrow-spectrum penicillinase-susceptible agents e.g Penicillin G • limited spectrum of antibacterial activity • susceptible to beta-lactamases hence high resistance rate • It is acid labile and so must be given parenterally (inactivated in gastric acid) • It has a short half-life, so frequent injections are required. • Narrow spectrum,Clinical uses include therapy of infections caused by • common streptococci • Meningococci • gram-positive bacilli • and spirochetes-drug of choice for treatment of syphillis • Activity against enterococci is enhanced by aminoglycoside antibiotics.
• to overcome the problems of acid lability/frequent injection two formulations are in use • Procaine benzylpenicillin – this complex releases penicillin slowly from an intramuscular so a twice daily dosage only is required • Phenoxymethylpenicillin (‘penicillin V’) – this is acid stable and so is effective when orally (40–60% absorption). For mild infections only blood concentrations are variable, so it is not used in serious infections or with poorly sensitive bacteria. Tablets are given on an empty stomach to improve absorption
• Very-narrow-spectrum penicillinase-resistant drugs • methicillin (the prototype, but rarely used owing to its nephrotoxic potential),flucloxacillin nafcillin, and oxacillin • Their primary use is in the treatment of known or suspected staphylococcal infections. • Methicillin resistant S aureus(MRSA] and S epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs • Wider-spectrum penicillinase-susceptible drugs • A . Aminopenicillin like Ampicillin and amoxicillin • Wider spectrum of activity than penicillin G ,remains susceptible to penicillinases.
• Their clinical uses similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis • antibacterial activity is enhanced by beta-lactamase inhibitor e.g amoxicillin-clavulanic acid • In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides • B. Piperacillin and ticarcillin(antipseudomonal penicillins ) • Active against gram-negative rods, including Pseudomonas, Enterobacter, • synergistic actions when used with aminoglycosides • used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity • Effective against anerobic but poor and erratic against gram positive organism
ADVERSE EFFECTS OF PENICILLINS • Allergy-include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis.recur in About 5–10% of persons. complete cross allergenicity across different subgroups should be assumed • Gastrointestinal disturbances—Nausea and diarrhea may occur with oral penicillins, especially with ampicillin due to direct irritation or overgrowth of gram-positive organisms or yeasts. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, has followed oral and, less commonly, parenteral administration of penicillins • In renal failure, high-dose penicillin causes encephalopathy and seizures.
JARISCH HERXHEIMER REACTION
CEPHALOSPORIN AND CEPHAMYCINS • are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. • inhibit bacterial cell wall synthesis in a manner similar to that of penicillin • more stable to many bacterial β-lactamases hence broader spectrum of activity. strains of E coli and Klebsiella sp expressing extended-spectrum β-lactamases that can hydrolyze most cephalosporins are a growing clinical concern • They vary in their antibacterial activity and are designated first-, second-, third-, or fourth-generation drugs
FIRST-GENERATION CEPHALOSPORINS • Include • cefazolin • Cefadroxil • Cephalexin • Cephalothin • Cephapirin • Cephradine • cefazolin • Cephalexin • very active against Gram-positive cocci, such as streptococci and staphylococci but not MRSA. • Modest activity against most gram negative organism • Active against anerobes but B. fragilis is resistant
SECOND GENERATION CEPHALOSPORIN • Slightly less activity against gram-positive organisms than the first-generation drugs but have an extended gram negative coverage(less than 3rd generation ) • Marked differences in activity • Include • Cefuroxime • Cefuroxime axetil • Cefprozil • Cefoxitin • Cefotetan • Cefmetazole
3RD GENERATION CEPHALOSPORIN • Include • Cefotaxime • Ceftriaxone • Cefdinir • Cefditoren pivoxil • Ceftibuten • Cefpodoxime proxetil • Ceftizoxime • Ceftazidime and Ceftazidime/avibactam • Ceftolozane/tazobactam • less active than first-generation agents against gram-positive cocci, although ceftriaxone and cefotaxime in particular have excellent antistreptococcal activity.
4TH GENERATION CEPHALOSPORIN • Cefepime-Only available fourth-generation cephalosporin. • it is more resistant to hydrolysis by chromosomal β-lactamases (eg, those produced by Enterobacter). • like the third generation compounds, it is hydrolyzed by extended-spectrum β- lactamases. • Cefepime has good activity against P aeruginosa, Enterobacteriaceae, methicillin- susceptible S aureus, and S pneumoniae. • It is highly active against Haemophilus and Neisseria sp. • It penetrates well into cerebrospinal fluid
• Antipseudomonal cephalosporins • include ceftazidime ( classified as a third-generation cephalosporin) and cefepime. • These agents expand on the gram-negative activity of the third generation to provide useful activity against P. aeruginosa. • Ceftazidime and ceftolozane have weaker gram-positive activity than third-generation agents, while cefepime’s activity is similar to that of ceftriaxone. • Anti-MRSA cephalosporins have structural modifications allowing for binding to and inactivation of the altered PBPs expressed by MRSA, MRSE, and penicillin- resistant S. pneumoniae. Ceftaroline and ceftobiprole
• Cephalosporings have no activity against atypical bacterias like chlamydia,legionella,mycoplasma,clostridum difficile etc • Adverse effects • About 10% of patients who are allergic to penicillins are also allergic to cephalosporins. • Some first-generation cephalosporins are nephrotoxic, particularly if used with furosemide, aminoglycosides or other nephrotoxic agents. • Some of the third generation drugs are associated with bleeding due to increased prothrombin times, which is reversible with vitamin K.
• Cephalosporins Combined with a-lactamase Inhibitors • Novel cephalosporin-β-lactamase inhibitor combinations have been developed to combat resistant Gram-negative infections • Ceftolozane-tazobactam and ceftazidime-avibactam are approved for the treatment of complicated intra-abdominal and urinary tract infections. • potent in vitro activity against Gram-negative organisms, including P aeruginosa and A extended-spectrum β-lactamase producing Enterobacteriaceae. • limited activity against anaerobes, combined with metronidazole when treating complicated intra-abdominal infections. • Short half life of 2-3 hours and renally excreted hence dose adjusted in renal failure
BETA-LACTAMASE INHIBITORS • Include clavulinic acid, sulbactam, tazobactam, & avibactam • Resemble β-lactam molecules but they have very weak antibacterial action. • They are potent inhibitors of many but not all bacterial β-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. • They are available only in fixed combinations with specific penicillins and cephalosporins • extends the spectrum of its companion β-lactam provided that the inactivity against a particular organism is due to destruction by a β-lactamase
CARBAPENEM • Are structurally related to other β-lactam antibiotics • Include • Doripenem • ertapenem • imipenem • meropenem • Imipenem • Wide spectrum with good activity against most Gram-negative rods, including P aeruginosa, Gram-positive organisms, and anaerobes. • It is resistant to most β-lactamases • Susceptible to carbapenemases and metallo-β-lactamases. • Enterococcus faecium, MRSA C. difficile amongst others are resistant
• inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. • Co- administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. • Doripenem and meropenem • are similar to imipenem but have slightly greater activity against Gram-negative aerobes and slightly less activity against Gram-positives • not significantly degraded by renal dehydropeptidase and do not require an inhibitor. • ertapenem • does not have appreciable activity against P aeruginosa and Acinetobacter species. • It is not degraded by renal dehydropeptidase
• Pharmacokinetics • Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid for all but ertapenem. • All are cleared renally, and dose must be reduced in patients with renal insufficiency. • All except ertapenem have short half lives hence administered 8hourly • Clinical use • Together with aminoglycoside for treatment for febrile neutropenic patients • treatment of choice for serious infections caused by extended spectrum β-lactamase-producing Gram- negative bacteria • infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa • treatment of mixed aerobic and anaerobic infections
MONOBACTAMS • Are drugs with a monocyclic β-lactam ring • Their spectrum of activity is limited to aerobic Gram-negative organisms (including P aeruginosa). • Unlike other β-lactam antibiotics, they have no activity against Gram-positive bacteria or anaerobes. • Aztreonam • structural similarities to ceftazidime, and its Gram-negative spectrum is similar • It is stable to many β-lactamases but susceptible to extended spectrum β-lactamases. • It penetrates well into the cerebrospinal fluid • The half-life is 1–2 hours and is greatly prolonged in renal failure
ADVERSE EFFECTS • Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity is uncommon • Potential for cross reactivity possible with ceftazidime • In patients with a history of penicillin anaphylaxis, aztreonam may be used to treat serious infections such as pneumonia, meningitis, and sepsis caused by susceptible Gram-negative pathogens
GLYCOPEPTIDE ANTIBIOTICS • VANCOMYCIN • isolated from the bacterium now known as Amycolatopsis orientalis. • It is active primarily against Gram-positive bacteria due to its large molecular weight and lack of penetration through Gram-negative cell membranes. • mechanism of action • inhibits cell wall synthesis by binding firmly to the d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide . • This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross- linking. • The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. • The cell membrane is also damaged, which contributes to the antibacterial effect
• Resistance to vancomycin in enterococci is due to modification of peptidoglycan which facilitates high affinity binding of vancomycin to its target. • Antibacterial activity • bactericidal for Gram-positive bacteria. • Against most pathogenic staphylococci, including those producing β-lactamase and MRSA • is active against many Gram-positive anaerobes including C difficile • Synergistic activity against E.Faecalis,E.faecium with aminoglycoside
• Pharmacokinetics • poorly absorbed from the intestinal tract and is administered orally only for the treatment of colitis caused by C difficile. • Parenteral doses must be administered intravenously. • The drug is widely distributed in the body including adipose tissue. • Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. • Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur • Significant amount is removed during standard haemodialysis • Patients receiving a prolonged course of therapy should have serum trough concentrations monitored
• Clinical Uses • Important indications for parenteral vancomycin are bloodstream infections and endocarditis caused by methicillin-resistant staphylococci • in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. • in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a penicillin resistant strain of pneumococcus.
• Adverse effects • Common during infusion • Most reactions are relatively minor and reversible. • Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. • Chills and fever may occur. • Ototoxicity is rare • nephrotoxicity is still encountered regularly with current preparations, especially with high trough level co-administration with another nephrotoxic drug e.g aminoglycoside • “red man” syndrome an infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours (preferred) or pretreatment with an antihistamine such as diphenhydramine
TEICOPLANIN • Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. • Unlike vancomycin, it can be given intramuscularly as well as intravenously. • Has a long half-life (45–70 hours), permitting once-daily dosing.
OTHER CELL WALL- OR MEMBRANE-ACTIVE AGENTS • DAPTOMYCIN • Is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus • Its spectrum of activity is similar to that of vancomycin except that it may be active against vancomycin-resistant strains of enterococci and S aureus. • In-vitro has more rapid bactericidal activity than vancomycin • Mechanism of action not fully understood but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux and rapid cell death • Renal clearance • Used for severe skin and soft tissue infection,bacteremea and endocarditis
• Adverse effects • It can cause myopathy, and creatine phosphokinase levels should be monitored weekly. • Pulmonary surfactant antagonizes daptomycin, and it should not be used to treat pneumonia. • Daptomycin can also cause an allergic pneumonitis in patients receiving prolonged therapy (>2 weeks) • Its an effective alternative to vancomycin
FOSFOMYCIN • Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis. • it is structurally unrelated to any other antimicrobial agent. • It inhibits the cytoplasmic enzyme enolpyruvate transferase which is involved in the formation of N-acetylmuramic acid, which is found only in bacterial cell walls. • The drug is transported into the bacterial cell by glycerophosphate or glucose 6- phosphate transport systems. • Resistance is due to inadequate transport of drug into the cell.
• Fosfomycin trometamol is available in both oral and parenteral formulations • Oral bioavailability is approximately 40%. • The half-life is approximately 4 hours. • The active drug is excreted by the kidney, with urinary concentrations exceeding MICs for most urinary tract pathogens • approved for use as a single 3-g dose for treatment of uncomplicated lower urinary tract infections (UTI) in women. • Limited data in case reports have suggested efficacy in males with UTI and prostatitis • the drug appears to be safe for use in pregnancy.
BACITRACIN • . it is active against Gram-positive microorganisms. • inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. • There is no cross-resistance between bacitracin and other antimicrobial drugs • Nephrotoxic when administered systemically hence only used topically • Topical application results in only local antibacterial effects • used in combination with polymyxin or neomycin for infections of mixed bacterial flora on skin and mucous membranes. • commonly associated with hypersensitivity,shouldn’t be used for prevention
CYCLOSERINE • inhibits many Gram-positive and Gram-negative organisms, • almost exclusively to treat multi-drug resitstant TB • Cycloserine is a structural analog of d-alanine and inhibits the incorporation of d- alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, • The drug is widely distributed in tissues. • Most of the drug is excreted in active form into the urine. • Cycloserine causes serious, dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions.

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Beta lactam inhibitors (1) (1).pptx

  • 1.
    BETA LACTAM INHIBITORS ANDOTHER CELL WALL SYNTHESIS INHIBITORS MUTUA MUTHEU
  • 2.
    INTRODUCTION • Include • Penicillin •Cephalosporin • Carbapenems • Monobactams • β-lactamase inhibitors. • Share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics • All are so named because of their four membered lactam ring
  • 4.
    • Share mechanismof action (i.e., inhibition of the synthesis of the bacterial peptidoglycan cell wall). • Peptidoglycan is a heteropolymeric component of the bacterial cell wall that provides rigid mechanical stability. • The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis • Bacterial resistance against the β-lactam antibiotics is widespread • Mechanism of resistance include • Production of β-Lactamase which inactivate the drug. inhibitors such as clavulanate and avibactam can extend the utility against β-lactamase–producing organisms. • alterations in the bacterial enzymes targeted by β-lactam antibiotics • decreased entry or active efflux of the antibiotic
  • 5.
    Natural Penicillin – -Brokendown by Amidase = (Removes Side Chain) •Penicillin – side chain = •6- Amino-Penicillanic acid (6-APA) •Active moiety •Has intact Betalactam ring (B) •With NH2 group at position 6 joined to thiazolidine ring.
  • 6.
    Penicillin •First antibiotic tobe used clinically in 1941 •One of the least toxic antibiotic even today •Obtained from Penicillium notatum (Early) Penicillium chrysogenum (Now, Better Yield) •Scientists- Fleming – Chain – Florey •Original Penicillin – •Penicillin G, Benzyl Penicillin ( R is Benzyl (CH2C6H5) )
  • 7.
    Chemistry •Penicillin nucleus consistsof •Thiazolidine ring (Ring A)- •Sulphur containing with COOH (Carboxyl group), •Beta lactam ring (Ring B) – (Broken by Betalactamase) •Side chain is attached at position – 6- (NHCOR) •Side chains attached through amide linkage. (Broken by Amidase)
  • 8.
    •Beta Lactam ringis broken by – • Penicillinase (Beta Lactamase), and by gastric acid. • Resultant Product is Penicilloic acid with • No anti-bacterial activity but • Acts as antigenic determinant (Major determinant) • Penicillins are available as • Na+ or K+ salts . • Amine salts such as Procaine and Benzathine Penicillin.
  • 9.
    PENICILLINS • All penicillinsare derivatives of 6-aminopenicillanic acid and contain a beta- lactam ring structure that is essential for antibacterial activity. • Penicillin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.these groups are 1. Penicillins (eg, penicillin G)—These have greatest activity against Gram- positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. little activity against Gram-negative rods, and they are susceptible to hydrolysis by β-lactamases
  • 10.
    2. Antistaphylococcal penicillins(eg, nafcillin) • These penicillins are resistant to staphylococcal β-lactamases. • They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods. 3. Extended-spectrum penicillins (aminopenicillins and antipseudomonal • These drugs retain the antibacterial spectrum of penicillin and have improved activity against Gram-negative rods. • Like penicillin they are relatively susceptible to hydrolysis by β-lactamases
  • 11.
    • Pharmacokinetics • oralbioavailability vary depending on resistance to gastric acid • Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available for injection. • Penicillins are polar compounds and are not metabolized extensively. • Excretion is unchanged via glomerular filtration and tubular secretion • Probenecid can inhibit tubular secretion and hence increase levels • 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 with long plasma half- lives as active drug is released very slowly into the bloodstream. • cross the bloodbrain barrier only when the meninges are inflamed.
  • 12.
    MECHANISMS OF ACTIONAND RESISTANCE • Beta-lactam antibiotics are bactericidal drugs. • They act to inhibit cell wall synthesis by the following steps • binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial cytoplasmic membrane • inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall • activation of autolytic enzymes that cause lesions in the bacterial cell wall.
  • 14.
    MOA SUMMARY •Bacteria areunique •Don’t have osmotic regulating mechanism •Cell wall controls osmotic changes. •Cell wall is composed of •Peptidoglycans •Cross linked by peptide chains. •NAM – NAG ( N-acetyl muramic acid and N- acetyl glucosamine) •Cross linked by a Pentaglycine cross bridge (Extending from the L-lysine residue of one peptide chain to the D- alanine residue of another peptide chain).
  • 15.
    • Cross bridgingis transpeptidation reaction. • Transpeptidase and related proteins (Penicillin Binding Proteins) are used for making cross linkage. • Cross linking provides stability, strength.
  • 16.
    •β-Lactams inhibit Transpeptidaseleading to •Damage of cross linking •Weakening of cell wall •Swelling of cell due to Endosmosis •Bacterial membrane bursts •Bacterial lysis •Additional mechanism – •Activation of autolysing enzymes (Murein Hydrolase and Autolysins) •More lethal during active multiplication
  • 17.
    • Mechanism ofresistance include • The formation of beta-lactamases (penicillinases) by most staphylococci and many gram- negative organisms cause hydrolysis of the beta lactam ring with loss of antibacterial activity • Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) combination prevent their inactivation. • Structural change in target PBPs is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci • In some gram-negative rods (eg, Pseudomonas aeruginosa), changes in the porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs
  • 19.
    CLINICAL USE • Narrow-spectrumpenicillinase-susceptible agents e.g Penicillin G • limited spectrum of antibacterial activity • susceptible to beta-lactamases hence high resistance rate • It is acid labile and so must be given parenterally (inactivated in gastric acid) • It has a short half-life, so frequent injections are required. • Narrow spectrum,Clinical uses include therapy of infections caused by • common streptococci • Meningococci • gram-positive bacilli • and spirochetes-drug of choice for treatment of syphillis • Activity against enterococci is enhanced by aminoglycoside antibiotics.
  • 20.
    • to overcomethe problems of acid lability/frequent injection two formulations are in use • Procaine benzylpenicillin – this complex releases penicillin slowly from an intramuscular so a twice daily dosage only is required • Phenoxymethylpenicillin (‘penicillin V’) – this is acid stable and so is effective when orally (40–60% absorption). For mild infections only blood concentrations are variable, so it is not used in serious infections or with poorly sensitive bacteria. Tablets are given on an empty stomach to improve absorption
  • 21.
    • Very-narrow-spectrum penicillinase-resistantdrugs • methicillin (the prototype, but rarely used owing to its nephrotoxic potential),flucloxacillin nafcillin, and oxacillin • Their primary use is in the treatment of known or suspected staphylococcal infections. • Methicillin resistant S aureus(MRSA] and S epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs • Wider-spectrum penicillinase-susceptible drugs • A . Aminopenicillin like Ampicillin and amoxicillin • Wider spectrum of activity than penicillin G ,remains susceptible to penicillinases.
  • 22.
    • Their clinicaluses similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis • antibacterial activity is enhanced by beta-lactamase inhibitor e.g amoxicillin-clavulanic acid • In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides • B. Piperacillin and ticarcillin(antipseudomonal penicillins ) • Active against gram-negative rods, including Pseudomonas, Enterobacter, • synergistic actions when used with aminoglycosides • used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity • Effective against anerobic but poor and erratic against gram positive organism
  • 23.
    ADVERSE EFFECTS OFPENICILLINS • Allergy-include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis.recur in About 5–10% of persons. complete cross allergenicity across different subgroups should be assumed • Gastrointestinal disturbances—Nausea and diarrhea may occur with oral penicillins, especially with ampicillin due to direct irritation or overgrowth of gram-positive organisms or yeasts. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, has followed oral and, less commonly, parenteral administration of penicillins • In renal failure, high-dose penicillin causes encephalopathy and seizures.
  • 24.
  • 25.
    CEPHALOSPORIN AND CEPHAMYCINS •are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. • inhibit bacterial cell wall synthesis in a manner similar to that of penicillin • more stable to many bacterial β-lactamases hence broader spectrum of activity. strains of E coli and Klebsiella sp expressing extended-spectrum β-lactamases that can hydrolyze most cephalosporins are a growing clinical concern • They vary in their antibacterial activity and are designated first-, second-, third-, or fourth-generation drugs
  • 26.
    FIRST-GENERATION CEPHALOSPORINS • Include •cefazolin • Cefadroxil • Cephalexin • Cephalothin • Cephapirin • Cephradine • cefazolin • Cephalexin • very active against Gram-positive cocci, such as streptococci and staphylococci but not MRSA. • Modest activity against most gram negative organism • Active against anerobes but B. fragilis is resistant
  • 27.
    SECOND GENERATION CEPHALOSPORIN •Slightly less activity against gram-positive organisms than the first-generation drugs but have an extended gram negative coverage(less than 3rd generation ) • Marked differences in activity • Include • Cefuroxime • Cefuroxime axetil • Cefprozil • Cefoxitin • Cefotetan • Cefmetazole
  • 28.
    3RD GENERATION CEPHALOSPORIN •Include • Cefotaxime • Ceftriaxone • Cefdinir • Cefditoren pivoxil • Ceftibuten • Cefpodoxime proxetil • Ceftizoxime • Ceftazidime and Ceftazidime/avibactam • Ceftolozane/tazobactam • less active than first-generation agents against gram-positive cocci, although ceftriaxone and cefotaxime in particular have excellent antistreptococcal activity.
  • 29.
    4TH GENERATION CEPHALOSPORIN •Cefepime-Only available fourth-generation cephalosporin. • it is more resistant to hydrolysis by chromosomal β-lactamases (eg, those produced by Enterobacter). • like the third generation compounds, it is hydrolyzed by extended-spectrum β- lactamases. • Cefepime has good activity against P aeruginosa, Enterobacteriaceae, methicillin- susceptible S aureus, and S pneumoniae. • It is highly active against Haemophilus and Neisseria sp. • It penetrates well into cerebrospinal fluid
  • 30.
    • Antipseudomonal cephalosporins •include ceftazidime ( classified as a third-generation cephalosporin) and cefepime. • These agents expand on the gram-negative activity of the third generation to provide useful activity against P. aeruginosa. • Ceftazidime and ceftolozane have weaker gram-positive activity than third-generation agents, while cefepime’s activity is similar to that of ceftriaxone. • Anti-MRSA cephalosporins have structural modifications allowing for binding to and inactivation of the altered PBPs expressed by MRSA, MRSE, and penicillin- resistant S. pneumoniae. Ceftaroline and ceftobiprole
  • 31.
    • Cephalosporings haveno activity against atypical bacterias like chlamydia,legionella,mycoplasma,clostridum difficile etc • Adverse effects • About 10% of patients who are allergic to penicillins are also allergic to cephalosporins. • Some first-generation cephalosporins are nephrotoxic, particularly if used with furosemide, aminoglycosides or other nephrotoxic agents. • Some of the third generation drugs are associated with bleeding due to increased prothrombin times, which is reversible with vitamin K.
  • 32.
    • Cephalosporins Combinedwith a-lactamase Inhibitors • Novel cephalosporin-β-lactamase inhibitor combinations have been developed to combat resistant Gram-negative infections • Ceftolozane-tazobactam and ceftazidime-avibactam are approved for the treatment of complicated intra-abdominal and urinary tract infections. • potent in vitro activity against Gram-negative organisms, including P aeruginosa and A extended-spectrum β-lactamase producing Enterobacteriaceae. • limited activity against anaerobes, combined with metronidazole when treating complicated intra-abdominal infections. • Short half life of 2-3 hours and renally excreted hence dose adjusted in renal failure
  • 33.
    BETA-LACTAMASE INHIBITORS • Includeclavulinic acid, sulbactam, tazobactam, & avibactam • Resemble β-lactam molecules but they have very weak antibacterial action. • They are potent inhibitors of many but not all bacterial β-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. • They are available only in fixed combinations with specific penicillins and cephalosporins • extends the spectrum of its companion β-lactam provided that the inactivity against a particular organism is due to destruction by a β-lactamase
  • 34.
    CARBAPENEM • Are structurallyrelated to other β-lactam antibiotics • Include • Doripenem • ertapenem • imipenem • meropenem • Imipenem • Wide spectrum with good activity against most Gram-negative rods, including P aeruginosa, Gram-positive organisms, and anaerobes. • It is resistant to most β-lactamases • Susceptible to carbapenemases and metallo-β-lactamases. • Enterococcus faecium, MRSA C. difficile amongst others are resistant
  • 35.
    • inactivated bydehydropeptidases in renal tubules, resulting in low urinary concentrations. • Co- administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use. • Doripenem and meropenem • are similar to imipenem but have slightly greater activity against Gram-negative aerobes and slightly less activity against Gram-positives • not significantly degraded by renal dehydropeptidase and do not require an inhibitor. • ertapenem • does not have appreciable activity against P aeruginosa and Acinetobacter species. • It is not degraded by renal dehydropeptidase
  • 36.
    • Pharmacokinetics • Carbapenemspenetrate body tissues and fluids well, including the cerebrospinal fluid for all but ertapenem. • All are cleared renally, and dose must be reduced in patients with renal insufficiency. • All except ertapenem have short half lives hence administered 8hourly • Clinical use • Together with aminoglycoside for treatment for febrile neutropenic patients • treatment of choice for serious infections caused by extended spectrum β-lactamase-producing Gram- negative bacteria • infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa • treatment of mixed aerobic and anaerobic infections
  • 37.
    MONOBACTAMS • Are drugswith a monocyclic β-lactam ring • Their spectrum of activity is limited to aerobic Gram-negative organisms (including P aeruginosa). • Unlike other β-lactam antibiotics, they have no activity against Gram-positive bacteria or anaerobes. • Aztreonam • structural similarities to ceftazidime, and its Gram-negative spectrum is similar • It is stable to many β-lactamases but susceptible to extended spectrum β-lactamases. • It penetrates well into the cerebrospinal fluid • The half-life is 1–2 hours and is greatly prolonged in renal failure
  • 38.
    ADVERSE EFFECTS • Occasionalskin rashes and elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity is uncommon • Potential for cross reactivity possible with ceftazidime • In patients with a history of penicillin anaphylaxis, aztreonam may be used to treat serious infections such as pneumonia, meningitis, and sepsis caused by susceptible Gram-negative pathogens
  • 39.
    GLYCOPEPTIDE ANTIBIOTICS • VANCOMYCIN •isolated from the bacterium now known as Amycolatopsis orientalis. • It is active primarily against Gram-positive bacteria due to its large molecular weight and lack of penetration through Gram-negative cell membranes. • mechanism of action • inhibits cell wall synthesis by binding firmly to the d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide . • This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross- linking. • The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. • The cell membrane is also damaged, which contributes to the antibacterial effect
  • 40.
    • Resistance tovancomycin in enterococci is due to modification of peptidoglycan which facilitates high affinity binding of vancomycin to its target. • Antibacterial activity • bactericidal for Gram-positive bacteria. • Against most pathogenic staphylococci, including those producing β-lactamase and MRSA • is active against many Gram-positive anaerobes including C difficile • Synergistic activity against E.Faecalis,E.faecium with aminoglycoside
  • 41.
    • Pharmacokinetics • poorlyabsorbed from the intestinal tract and is administered orally only for the treatment of colitis caused by C difficile. • Parenteral doses must be administered intravenously. • The drug is widely distributed in the body including adipose tissue. • Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. • Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur • Significant amount is removed during standard haemodialysis • Patients receiving a prolonged course of therapy should have serum trough concentrations monitored
  • 42.
    • Clinical Uses •Important indications for parenteral vancomycin are bloodstream infections and endocarditis caused by methicillin-resistant staphylococci • in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. • in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a penicillin resistant strain of pneumococcus.
  • 43.
    • Adverse effects •Common during infusion • Most reactions are relatively minor and reversible. • Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. • Chills and fever may occur. • Ototoxicity is rare • nephrotoxicity is still encountered regularly with current preparations, especially with high trough level co-administration with another nephrotoxic drug e.g aminoglycoside • “red man” syndrome an infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours (preferred) or pretreatment with an antihistamine such as diphenhydramine
  • 44.
    TEICOPLANIN • Teicoplanin isa glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. • Unlike vancomycin, it can be given intramuscularly as well as intravenously. • Has a long half-life (45–70 hours), permitting once-daily dosing.
  • 45.
    OTHER CELL WALL-OR MEMBRANE-ACTIVE AGENTS • DAPTOMYCIN • Is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus • Its spectrum of activity is similar to that of vancomycin except that it may be active against vancomycin-resistant strains of enterococci and S aureus. • In-vitro has more rapid bactericidal activity than vancomycin • Mechanism of action not fully understood but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux and rapid cell death • Renal clearance • Used for severe skin and soft tissue infection,bacteremea and endocarditis
  • 46.
    • Adverse effects •It can cause myopathy, and creatine phosphokinase levels should be monitored weekly. • Pulmonary surfactant antagonizes daptomycin, and it should not be used to treat pneumonia. • Daptomycin can also cause an allergic pneumonitis in patients receiving prolonged therapy (>2 weeks) • Its an effective alternative to vancomycin
  • 47.
    FOSFOMYCIN • Fosfomycin trometamol,a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis. • it is structurally unrelated to any other antimicrobial agent. • It inhibits the cytoplasmic enzyme enolpyruvate transferase which is involved in the formation of N-acetylmuramic acid, which is found only in bacterial cell walls. • The drug is transported into the bacterial cell by glycerophosphate or glucose 6- phosphate transport systems. • Resistance is due to inadequate transport of drug into the cell.
  • 48.
    • Fosfomycin trometamolis available in both oral and parenteral formulations • Oral bioavailability is approximately 40%. • The half-life is approximately 4 hours. • The active drug is excreted by the kidney, with urinary concentrations exceeding MICs for most urinary tract pathogens • approved for use as a single 3-g dose for treatment of uncomplicated lower urinary tract infections (UTI) in women. • Limited data in case reports have suggested efficacy in males with UTI and prostatitis • the drug appears to be safe for use in pregnancy.
  • 49.
    BACITRACIN • . itis active against Gram-positive microorganisms. • inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. • There is no cross-resistance between bacitracin and other antimicrobial drugs • Nephrotoxic when administered systemically hence only used topically • Topical application results in only local antibacterial effects • used in combination with polymyxin or neomycin for infections of mixed bacterial flora on skin and mucous membranes. • commonly associated with hypersensitivity,shouldn’t be used for prevention
  • 50.
    CYCLOSERINE • inhibits manyGram-positive and Gram-negative organisms, • almost exclusively to treat multi-drug resitstant TB • Cycloserine is a structural analog of d-alanine and inhibits the incorporation of d- alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, • The drug is widely distributed in tissues. • Most of the drug is excreted in active form into the urine. • Cycloserine causes serious, dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions.