Lecture 4,5

• Thienamycin (also known as thienpenem) was the first natural carbapenem antibiotics discovered in Streptomyces cattleya in 1976
• Carbapenems have the broadest antibacterial spectrum of any β-lactam antibiotic as they are active against many Gram +ve and Gram -ve, anaerobes, and P. aeruginosa
• Carbapenems Uses

  • Most effective for a wide variety of infections, including urinary tract and lower respiratory infections
  • Important in the empiric therapy of many mixed infections including polymicrobial pulmonary, intra-abdominal, gynecological, skin, soft-tissue, bone, and joint infections
  • Especially useful for the treatment of serious infections caused by the highly resistant nosocomial bacteria in hospitalized patients who have recently received other beta-lactam antibiotics - Extended spectrum β-lactamases (ESBLs) Enterobacteriaceae (Escherichia coli, Klebsiella, Enterobacter)
• Currently available carbapenems

  • imipenem
  • meropenem
  • doripenem
  • ertapenem
• Carbapenems: Pharmacokinetics

  1. Absorption: Carbapenem are given IV as they are not absorbed orally

  2. Distribution: Carbapenem are fairly distributed into body tissues and fluids

  3. However, their penetration into CSF is highly variable; a significant levels can reach CSF only with inflamed meninges (Not used for meningitis)

  4. Metabolism: no significant hepatic metabolism

  5. Excretion: mainly renal (glomerular filtration and active secretion) - Dosage should be reduced in patients with renal insufficiency
• Carbapenems are highly resistant to hydrolysis by β-lactamase enzymes
• Imipenem was the first a chemically stable analogue of thienamycin synthesized in 1985
• Carbapenems bind to PBPs

  Disrupting bacterial cell wall synthesis, resulting in death of susceptible microorganisms (bactericidal)
• Carbapenems Drugs - Imipenem

  1. Usual dose of 0.25–0.5 g IV every 6–8 hours

  2. Rapidly hydrolyzed by dehydropeptidase in the proximal renal tubule

  3. Primaxin® combined with 1:1 cilastatin (dehydropeptidase inhibitor) to protect active drug and prevent nephrotoxic metabolite
• Common adverse effects of carbapenems are nausea, vomiting, and diarrhea (up to 20%)
• Aztreonam is usually well tolerated; rarely causes allergic reactions in patients with a history of hypersensitivity to other β-lactam antibiotics
• Not used for meningitis
• Doses should be adjusted in patients with renal insufficiency or the elderly
• Meropenem and ertapenem are less likely to cause seizures
• Aztreonam may cause phlebitis, skin rash, and occasionally abnormal liver function tests
• Metabolism

  No significant hepatic metabolism
• Carbapenems Drugs - Meropenem

  1. 1 g IV every 8 hours

  2. Greater activity against Gram-negative aerobes and less activity against Gram-positive

  3. Not degraded by renal dehydropeptidase
• Hypersensitivity reactions include skin rashes and allergic reactions similar to penicillin and other β-lactams
• Levels of penetration into CSF are highly variable; significant levels can reach CSF only with inflamed meninges
• Monobactam - Aztreonam

  1. Not absorbed orally, given IV or IM (2 g every 6-8 hrs)

  2. Good distribution to most body tissues and fluids, including CSF in the presence of inflamed meninges

  3. No significant hepatic metabolism

  4. Excreted unchanged by glomerular filtration and renal secretion (dosage should be reduced in renal patients)
• Excretion

  Mainly renal (glomerular filtration and active secretion)
• High levels of imipenem may provoke seizures, especially in patients with CNS lesions or renal insufficiency
• Carbapenems Drugs - Ertapenem

  1. 1 g IV or IM once-daily dose

  2. Less active than imipenem

  3. Not degraded by renal dehydropeptidase
• Peptide antibiotics are chemically divergent
• Teicoplanin is currently not approved by FDA for use in the United States, but it is widely used in Europe, Asia, and South America
• Vancomycin Pharmacokinetics

  1. Absorption: Poorly absorbed orally, can be given orally for treatment of GI infection with Clostridium difficile, used parenterally IV for treatment of systemic infections

  2. Distribution: Good to most body tissues and fluids, can reach CSF only when meninges are inflamed

  3. Metabolism: None

  4. Excretion: by renal glomerular filtration, adjust dosage in renal dysfunction
• Teicoplanin is a new glycopeptide antibiotic derived from Actinomyces teichomyceticus
• Vancomycin has a narrow antibacterial spectrum, active only against Gram-positive bacteria, particularly staphylococci (MRSA)
• Vancomycin used to be the "magic bullet" for treating methicillin-resistant Staphylococcus aureus (MRSA), but now they are becoming resistant
• Resistance to Vancomycin caused by

  • Plasmid-mediated changes in the cell permeability to the drug
  • Decreased binding to peptidoglycan by changing the D-Ala-D-Ala unite to D-Ala-D-Lactate which cannot be bond by vancomycin
• Vancomycin Action

  1. Treating antibiotic-induced enterocolitis due to growth of opportunistic Clostridium difficile

  2. Inhibiting cell wall synthesis by binding to D-Ala-D-Ala terminal of peptidoglycan, thus preventing further elongation of peptidoglycan and cross-linking
• Vancomycin is used IV in sepsis or endocarditis caused by MRSA, especially in a patient with serious penicillin allergy, and in combination with cefotaxime or rifampin for treatment of meningitis
• Vancomycin is a complex polycyclic glycopeptide antibiotic produced by Streptomyces orientalis
• Bacitracin

  • Well tolerated topically and orally, not absorbed from GI and exerts local antibacterial activity without significant systemic toxicity
  • Used in combination with other antibiotics in creams, ointments, and aerosol preparations
• Indications for polymyxins are limited to topical use for treatment of skin lesions and external otitis caused by P. aeruginosa due to serious potential for systemic toxicity
• Bacitracin is a mixture of cyclic polypeptides produced by Bacillus subtilis, first isolated in 1943
• Teicoplanin

  • Similar to vancomycin in mechanism of action and antibacterial spectrum, but longer lasting
  • Has a long half-life (45–70 hours) permitting once-daily dosing
  • Can be given IM as well as IV
• Bacitracin Actions

  Inhibiting cell wall synthesis by preventing dephosphorylation step in the phospholipid carrier, interfering with transfer of peptidoglycan subunits to the growing cell wall
• Polymyxins

  • Have a narrow antibacterial spectrum, active against Gram -ve bacteria, particularly P. aeruginosa
  • Act as cationic, surface-active agents that disrupt the phospholipid structure of cell membrane and increase cellular permeability
  • Bind and inactivate lipopolysaccharides reducing the pathophysiologic effects of endotoxin in circulation
• Antibiotics

  • Bactam
  • Carbapenem
  • Peptide