CARBAPANEMS AND CEPHALOSPHORINS

• Carbapenems

  • Parenteral bactericidal beta-lactam antibiotics
  • Have an extremely broad spectrum

  
• Carbapenems are active against

  • Haemophilus influenzae
  • Anaerobes
  • Most Enterobacteriaceae (including those that produce AmpC beta-lactamase and extended-spectrum beta-lactamase [ESBL], although Proteus mirabilis tends to have a higher imipenem minimum inhibitory concentration [MIC])
  • Methicillin-sensitive staphylococci and streptococci, including Streptococcus pneumoniae (except possibly strains with reduced penicillin sensitivity)
• Carbapenems


  • No thiazolidine ring or dihydrothiazine ring
  • Have two strained rings which decrease the chemical stability as well as acid stability
  • The inverse stereochemistry at C6 and the presence of hydroxyl group increase stability toward beta-lactamase enzymes

  
• Carbapenems have broad spectrum of activity
• Thienamycin


  Beta-lactam antibiotics that differ from penicillins in having the thiazolidine sulfur atom replaced by carbon, the sulfur then becoming the first atom in the side chain

  
• Thienamycin


  • They are unstable chemically, but have a very broad antibacterial spectrum
  • Thienamycin and its more stable derivatives are proposed for use in combinations with enzyme inhibitors

  
• Thienamycin is a novel Beta lactam antibiotic first isolated and identified by researchers at Merck from fermentation of cultures of Streptomyces cattleya

  
• Thienamycin displays outstanding broad-spectrum antibacterial properties in vitro

  
• Thienamycin is highly active against most aerobic and anaerobic gram-positive and gram-negative bacteria

  
• Thienamycin


  • Disadvantage: chemical instability in solution
  • More susceptible to hydrolysis to both acidic and alkaline solutions than most beta lactam antibiotics because of the strained nature of its fused ring system containing endocyclic double bond

  
• Cilastin


  An inhibitor of DHP-1
• The combination of imipenem and cilastin (Primaxin) provides a chemically and enzymatically stable form of thienamycin that has clinically useful pharmacokinetic properties

  
• Imipenem


  • It has a wide spectrum of antibacterial activity against gram (-) and gram (+) aerobic and anaerobic bacteria, including many multi-resistant strains
  • It is not used in meningitis because it may cause seizure
  • It is stable to many beta-lactamases
• Meropenem


  • Have greater activity against Gram (-) bacteria
• Ertapenem


  • Exhibits a longer half-life due to increased binding to plasma proteins
  • Commonly used in combination with cilastatin and is now available in a triple-drug product with cilastatin and relebactam which was recently approved by the FDA
• Ertapenem was first approved by the FDA in November 1985 as the combination product Primaxin marketed by Merck & Co
• Cilastin


  Inhibitor of renal dehydropeptidase, an enzyme responsible for both the metabolism of thienamycin beta-lactam antibiotics as well as conversion of leukotriene D4 to leukotriene E4
• The solution of the combination of imipenem and cilastin is stable for 4 hours at 25 degrees celsius and up to 24 hours when refrigerated
• Meropenem


  • A second generation, broad-spectrum carbapenem antibiotic
  • It is active against Gram-positive and Gram-negative bacteria
  • It penetrates bacterial cells readily and interferes with the synthesis of vital cell wall components, which leads to cell death
  • It is used to treat skin and abdominal (stomach area) infections caused by bacteria and meningitis (infection of the membranes that surround the brain and spinal cord) in adults and children 3 months of age and older
  • It is not active orally
• Biapenem


  • Newer second generation carbapenem with chemical and microbiological properties similar to those of meropenem
  • It has a broad spectrum of in vitro antibacterial activity encompassing many Gram (-) and Gram (+) aerobic and anaerobic bacteria, including species producing beta-lactamases
  • It is more stable than imipenem, meropenem and panipenem to hydrolysis by human renal dihydropeptidase-I (DHP-I), and therefore does not require the co-administration of a DHP-I inhibitor
  • After intravenous administration, biapenem is widely distributed and penetrates well into various tissues (e.g. lung tissue) and body fluids (e.g. sputum, pleural effusion, abdominal cavity fluid)
• Doripenem


  • Has a black box warning stating that when used to treat patients with ventilator-associated bacterial pneumonia, it has an increased risk of death compared with imipenem
  • Clinical response rates were lower with doripenem
• Mechanisms of resistance to carbapenems

  • Carbapenemase production
  • Loss or alteration of porin channels, the expression of efflux pumps, or penicillin-binding protein (PBP) modification
• The novel beta-lactamase inhibitors, avibactam, relebactam, and vaborbactam, can inhibit most carbapenemases but are ineffective against metallo-beta-lactamases (a type of carbapenemase that uses reactive zinc to destroy the carbapenem)
• Coformulation of avibactam with ceftazidime, vaborbactam with meropenem, or relebactam with imipenem increases activity against certain carbapenemase-producing pathogens
• Cephalosporins


  • Beta lactam antibiotics isolated from Cepholosporium spp. or prepared synthetically
  • They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell synthesis
  • Nucleus contains a beta lactam ring and a dihyrothiazine ring

  
• Limitations of cephalosporins


  • Lack of activity against enterococci
  • Lack of activity against methicillin-resistant staphylococci (except for ceftaroline and ceftobiprole)
  • Lack of activity against anaerobic gram-negative bacilli (except for cefotetan and cefoxitin)

  
• Structure-activity relationship of cephalosporins

  • Molecular changes can improve in vitro stability, antibacterial activity and stability towards beta lactamase
  • Addition of amino or hydrogen to the alpha position results in a basic compound that is protonated under the acidic conditions of the stomach
  • The acetoxy substituent is important to the mechanism

  
• Possible modifications to cephalosporins

  • 7-acylamino side chain
  • 3-acetoxymethyl side chain
  • Substitution at C-7

  
• Cephalosporin structure


  • Chemically it is composed of a cephem nucleus that is attached to a six membered ring of dihydrothiazine
  • At position 3, cephem nucleus has a vinyl group for the absorption of intact molecule through intestine and at 7-position acetic acid oxy-imine group and aminothiazole ring are attached for antibacterial activity

  
• Ammonium ion improves the stability of the beta lactam of cephalosporin leading to orally active drugs

  
• The 7-beta amino group is essential for antimicrobial activity of cephalosporins

  
• Classification of cephalosporins


  • Classified into four generations depending upon antibacterial spectrum
  • 1st generation —— more effective against gram positive bacteria
  • 2nd generation—— more effective against gram negative and less against gram positive bacteria
  • 3rd generation——- no activity against gram positive bacteria
  • 4th generation——- no activity against gram positive, effective against gram negative only

  
• First-generation cephalosporins


  • They have excellent activity against Gram-positive cocci
  • Oral 1st-generation cephalosporins are commonly used for uncomplicated skin and soft-tissue infections, which are usually due to staphylococci and streptococci
  • Parenteral cefazolin is frequently used for endocarditis due to methicillin-sensitive S. aureus and for prophylaxis before cardiothoracic, orthopedic, abdominal, and pelvic surgery

  
• First-generation cephalosporin products


  • Cephalexin
  • Cephalothin
  • Cefapirin
  • Cefazolin
  • Cefadroxil
  • Cefadrine

  
• Cephalexin


  • 7 alpha-(D-amino-a-phenylacetamido)-3-methyl-cephemcarboxylic acid
  • It is used to treat certain infections caused by bacteria such as pneumonia and other respiratory tract infections; and infections of the bone, skin, ears, , genital, and urinary tract
  • It comes as a capsule, tablet, and suspension (liquid) to take by mouth
  • It is taken with or without food every 6 or 12 hours for 7 to 14 days, depending on the condition being treated
  • It occurs as a white crystalline monohydrate
  • It is freely soluble in water, resistant to acid, and absorbed well orally
  • Food does not interfere with its absorption
• Cephalothin


  • It occurs as white to off white, crystalline powder that is practically odorless
  • It is poorly absorbed in the GIT and must be administered parenterally for systemic infections
  • It is a broad-spectrum used for the treatment of serious bacterial infections in various locations, such as the urinary tract, skin, bone, and lower respiratory tract
  • Its mechanism of action is to bind to and inactivate penicillin-binding proteins (PBP) located on the inner membrane of the bacterial cell wall
• Cephapirin


  • It is a semi-synthetic 7 ACA derivative
  • It closely resembles cephalothin in chemical and pharmacokinetic properties
  • It is unstable in acid and must be administered parenterally in the form of aqueous solution of the sodium salt

  
• Cefazolin


  • It provides higher serum levels, slower renal clearance, and a longer half-life than other first generation cephalosporins
  • The injection is used to treat certain infections caused
• line monohydrate


  Freely soluble in water, resistant to acid, and absorbed well orally
• Food does not interfere with its absorption