Penicillins and Cell Wall Inhibitors

Cell Wall Inhibitors

• Penicillins and cephalosporins are major antibiotics that inhibit bacterial cell wall synthesis.
• Beta-lactams have a 4-member ring common to all members.
• Beta-lactams are effective, widely used, and well-tolerated.

Penicillins

• All penicillins are derivatives of 6-aminopenicillanic acid.
• Penicillins contain a beta-lactam ring that is essential for antibacterial activity.
• Penicillin subclasses have chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.

Pharmacokinetics of Penicillins

• Ampicillin with sulbactam, ticarcillin with clavulanic acid, piperacillin with tazobactam, nafcillin, and oxacillin administered intravenously (IV) or intramuscularly (IM).
• Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations.
• Other penicillins are effective by the oral, IV, or IM routes.
• Procaine penicillin G and benzathine penicillin G are administered IM as depot forms.
• Depot forms are slowly absorbed into the circulation and persist at low levels over a long period.
• Most penicillins are incompletely absorbed after oral administration.
• Food decreases the absorption of penicillinase-resistant penicillins due to destruction by stomach acid and should be taken on an empty stomach.
• All penicillins distribute well and cross the placental barrier, but none have shown teratogenic effects.
• Penetration into bone or CSF is insufficient for therapy unless these sites are inflamed.
• Excretion is primarily by glomerular filtration, so dosage regimens must be adjusted for impaired renal function.
• Nafcillin and oxacillin are metabolized in the liver.
• Probenecid inhibits the secretion of penicillins by competing for active tubular secretion, increasing blood levels.

Mechanisms of Action and Resistance of Penicillins

• Beta-lactam antibiotics are bactericidal drugs.
• They inhibit cell wall synthesis by:
  • Binding to penicillin-binding proteins (PBPs) in the bacterial cytoplasmic membrane.
  • Inhibiting the transpeptidation reaction that cross-links peptidoglycan chains.
  • Activating autolytic enzymes that cause lesions in the bacterial cell wall.
• Bacterial resistance mechanisms include:
  • Formation of beta-lactamases (penicillinases) by staphylococci and gram-negative organisms.
  • Inhibitors of beta-lactamases (e.g., clavulanic acid, sulbactam, tazobactam) are used in combination with penicillins.
  • Structural change in target PBPs is responsible for methicillin resistance in staphylococci (MRSA) and resistance to penicillin G in pneumococci (PRSP) and enterococci.
  • Changes in porin structures in the outer cell wall membrane can impede access of penicillins to PBPs in gram-negative rods (e.g., Pseudomonas aeruginosa).

Clinical Uses of Penicillins

• Narrow-spectrum penicillinase-susceptible agents (Penicillin G):
  • Used for infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes.
  • Many strains of pneumococci (penicillin-resistant S. pneumoniae [PRSP] strains), Staphylococcus aureus, and Neisseria gonorrhoeae are resistant via beta-lactamases.
  • Penicillin G remains the drug of choice for syphilis, with activity against enterococci enhanced by coadministration of aminoglycosides.
  • Penicillin V is an oral drug used mainly in oropharyngeal infections.
• Very-narrow-spectrum penicillinase-resistant drugs (methicillin, nafcillin, oxacillin):
  • Primarily used for treatment of known or suspected staphylococcal infections.
  • Methicillin-resistant (MR) staphylococci (S. aureus [MRSA] and S. epidermidis [MRSE]) are resistant to all penicillins and often to multiple antimicrobial drugs.
• Wider-spectrum penicillinase-susceptible drugs:
  • Ampicillin and amoxicillin have a wider spectrum than penicillin G, including enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis.
  • Activity is enhanced when used with penicillinase inhibitors (e.g., clavulanic acid).
  • Ampicillin is synergistic with aminoglycosides in enterococcal and listerial infections.
• Piperacillin and ticarcillin:
  • Active against gram-negative rods, including Pseudomonas, Enterobacter, and some Klebsiella species.
  • Synergistic with aminoglycosides against such organisms.
  • Susceptible to penicillinases and are often used with penicillinase inhibitors (e.g., tazobactam and clavulanic acid) to enhance activity.

Adverse Effects of Penicillins

• Allergy:
  • Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis.
  • Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia.
  • Complete cross-allergenicity between different penicillins 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.

Cephalosporins

• Cephalosporins are β-lactam antibiotics structurally and functionally related to penicillins.
• Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
• Cephalosporins have the same mode of action as penicillins but are more resistant to certain β-lactamases.

Pharmacokinetics of Cephalosporins

• Several cephalosporins are available for oral use, but most are administered parenterally.
• Cephalosporins with side chains may undergo hepatic metabolism.
• The major elimination mechanism is renal excretion via active tubular secretion.
• Cefoperazone and ceftriaxone are excreted mainly in the bile.
• Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.

Mechanisms of Action and Resistance of Cephalosporins

• Cephalosporins bind to PBPs to inhibit bacterial cell wall synthesis, similar to penicillins.
• Cephalosporins are bactericidal against susceptible organisms.
• Cephalosporins are less susceptible to penicillinases produced by staphylococci.
• Many bacteria are resistant through the production of other beta-lactamases that can inactivate cephalosporins.
• Resistance can also result from decreases in membrane permeability to cephalosporins and from changes in PBPs.
• Methicillin-resistant staphylococci are also resistant to cephalosporins.

Clinical Uses of Cephalosporins

• First-generation drugs (e.g., cefazolin, cephalexin):
  • Active against gram-positive cocci, including staphylococci and common streptococci.
  • Many strains of E coli and K pneumoniae are also sensitive.
  • Used for treatment of infections caused by these organisms and surgical prophylaxis in selected conditions.
• Second-generation drugs:
  • Slightly less activity against gram-positive organisms than first-generation drugs but have extended gram-negative coverage.
  • Marked differences in activity occur among the drugs.
  • Used for infections caused by Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor).
• Third-generation drugs (e.g., ceftazidime, cefoperazone, cefotaxime):
  • Increased activity against gram-negative organisms resistant to other beta-lactam drugs.
  • Able to penetrate the blood-brain barrier (EXCEPT cefoperazone and cefixime).
  • Active against Providencia, Serratia marcescens, and beta-lactamase producing strains of H influenzae and Neisseria.
  • Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains).
  • Also have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime).
  • Ceftriaxone (parenteral) and cefixime (oral) are currently drugs of choice in gonorrhea.
• Fourth-generation drugs:
  • Cefepime is more resistant to beta-lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin resistant pneumococci.
  • Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins.
  • Ceftaroline has activity in infections caused by methicillin-resistant staphylococci.

Adverse Effects of Cephalosporins

• Allergy:
  • Cause a range of allergic reactions from skin rashes to anaphylactic shock, but less frequently than with penicillins.
  • Complete cross-hypersensitivity between different cephalosporins should be assumed.
  • Cross-reactivity between penicillins and cephalosporins is incomplete (5–10%).
• Cephalosporins may cause pain at intramuscular injection sites and phlebitis after I.V administration.
• They may increase the nephrotoxicity of aminoglycosides when the two are administered together.

Other Beta-Lactam Drugs

• Aztreonam:
  • A monobactam resistant to beta-lactamases produced by certain gram-negative rods, including Klebsiella, Pseudomonas, and Serratia.
  • Has no activity against gram-positive bacteria or anaerobes.
  • Administered intravenously and is eliminated via renal tubular secretion.
  • Half-life is prolonged in renal failure.
  • Adverse effects include gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity, skin rash, with NO cross allergenicity with penicillins.
• Imipenem, Doripenem, Meropenem, and Ertapenem:
  • Carbapenems with wide activity against gram-positive cocci, gram-negative rods, and anaerobes.
  • Often used with an aminoglycoside for pseudomonal infections.
  • MRSA strains of staphylococci are resistant.
  • Imipenem is rapidly inactivated by renal dehydropeptidase-I and is administered with cilastatin, an inhibitor of this enzyme.
  • Cilastatin increases the plasma half life of imipenem and inhibits the formation of potentially nephrotoxic metabolite.
  • Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures).
  • There is partial cross allergenicity with the penicillins.
• Beta-Lactamase Inhibitors (Clavulanic acid, sulbactam, and tazobactam):
  • Used in fixed combinations with certain hydrolyzable penicillins.
  • Most active against plasmid-encoded beta-lactamases produced by gonococci, streptococci, E coli, and H influenzae.
  • NOT good inhibitors of inducible chromosomal beta-lactamases formed by Enterobacter, Pseudomonas, and Serratia.

Other Cell Wall or Membrane-Active Agents

• Vancomycin:
  • A bactericidal glycoprotein that binds to the d-Ala-d-Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation
  • Prevents elongation of the peptidoglycan chain and interferes with crosslinking.
  • Resistance in strains of enterococci (vancomycin-resistant enterococci [VRE]) and staphylococci (vancomycin-resistant S aureus [VRSA]) involves a decreased affinity of vancomycin for the binding site.
  • Has a narrow spectrum and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA).
  • Is combined with ceftriaxone for treatment of (PRSP).
  • Vancomycin is a backup drug for treatment of infections caused by Clostridium difficile.
  • Toxic effects include chills, fever, phlebitis, ototoxicity, and nephrotoxicity.
  • Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”) from histamine release.
• Fosfomycin:
  • An antimetabolite inhibitor of cytosolic enolpyruvate transferase.
  • Prevents the formation of N-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation.
  • Excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs), so It is indicated for urinary tract infections caused by E. coli or E. faecalis.
  • Maintains high concentrations in the urine over several days, allowing for a one-time dose
  • Adverse effects include diarrhea, vaginitis, nausea, and headache.
• Daptomycin:
  • A bactericidal, novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci.
  • Indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus.
  • Is inactivated by pulmonary surfactants, so it should never be used in the treatment of pneumonia.
  • Creatine phosphokinase should be monitored since daptomycin may cause myopathy.
• Polymyxins:
  • Cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria.
  • Have a detergent-like effect that disrupts cell membrane integrity, leading to leakage of cellular components and cell death.
  • Concentration-dependent bactericidal agents with activity against P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter species, and Enterobacter species.
  • Only two forms of polymyxin are in clinical use today, polymyxin B and colistin (polymyxin E).
  • Polymyxin B is available in parenteral, ophthalmic, otic, and topical preparations.
  • Colistin is only available as a prodrug, colistimethate sodium, which is administered IV or inhaled via a nebulizer.
  • Use has been limited due to the increased risk of nephrotoxicity and neurotoxicity (slurred speech, muscle weakness) when used systemically.