Penicillins and Cephalosporins

Cell Wall Inhibitors

• Penicillins and cephalosporins are major antibiotics that inhibit bacterial cell wall synthesis.
• They are beta-lactams due to the 4-member ring common to all members.
• Beta-lactams are effective, widely used, and well-tolerated agents for microbial infections.

Penicillins

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

Pharmacokinetics

• Ampicillin with sulbactam, ticarcillin with clavulanic acid, piperacillin with tazobactam, nafcillin, and oxacillin are administered intravenously (IV) or intramuscularly (IM).
• Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations.
• Procaine penicillin G and benzathine penicillin G are administered IM as depot forms.
• Most penicillins are incompletely absorbed after oral administration, affecting intestinal flora.
• Food decreases absorption of penicillinase-resistant penicillins because of destruction by stomach acid, so they should be taken on an empty stomach.
• Penicillins distribute well and cross the placental barrier without teratogenic effects.
• Penetration into bone or CSF is insufficient for therapy unless these sites are inflamed.
• Excretion is primarily by glomerular filtration, requiring dosage adjustments for impaired renal function.
• Nafcillin and oxacillin are metabolized in the liver.
• Probenecid inhibits penicillin secretion, increasing blood levels.

Mechanisms of Action

• Beta-lactam antibiotics are bactericidal drugs.
• They inhibit cell wall synthesis:
  • Binding to penicillin-binding proteins (PBPs) in the bacterial cytoplasmic membrane.
  • Inhibition of transpeptidation, which cross-links peptidoglycan chains.
  • Activation of autolytic enzymes that cause lesions in the bacterial cell wall.

Mechanisms of Resistance

• Formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms.
  • Inhibitors of these bacterial enzymes: clavulanic acid, sulbactam, tazobactam used in combination with penicillins to prevent their inactivation.
• Structural change in target PBPs causes 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 of gram-negative rods may impede access of penicillins to PBPs.

Clinical Uses

• Narrow-spectrum penicillinase-susceptible agents (Penicillin G):
  • Therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes.
  • Effective against many strains of pneumococci (penicillin-resistant S. pneumoniae [PRSP] strains).
  • Staphylococcus aureus and Neisseria gonorrhoeae are often resistant via production of beta-lactamases.
  • Penicillin G remains the drug of choice for syphilis.
  • Activity against enterococci is enhanced by coadministration of aminoglycosides.
  • Penicillin V is an oral drug used mainly in oropharyngeal infections.
• Very-narrow-spectrum penicillinase-resistant drugs (methicillin, nafcillin, and oxacillin):
  • Primary use is in the treatment of known or suspected staphylococcal infections.
  • Methicillin-resistant (MR) staphylococci (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:
  • Ampicillin and amoxicillin:
    • Wider spectrum than penicillin G.
    • Clinical uses similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur.
    • Enhanced antibacterial activity when used with penicillinase inhibitors.
    • Synergistic with aminoglycosides in enterococcal and listerial infections.
  • Piperacillin and ticarcillin:
    • Activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species.
    • Synergistic actions with aminoglycosides against such organisms.
    • Susceptible to penicillinases and often used with penicillinase inhibitors (tazobactam and clavulanic acid).

Adverse Effects

• 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.
  • Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram-positive organisms or yeasts.

Cephalosporins

• Beta-lactam antibiotics closely related structurally and functionally to penicillins.
• Most cephalosporins are produced semisynthetically using 7-aminocephalosporanic acid.
• Same mode of action as penicillins and affected by the same resistance mechanisms, but more resistant to certain beta-lactamases.

Pharmacokinetics

• Several cephalosporins are available for oral use, but most are administered parenterally.
• Cephalosporins with side chains may undergo hepatic metabolism.
• 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

• Bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis similar to penicillins.
• Bactericidal against susceptible organisms.
• Cephalosporins less susceptible to penicillinases, but many bacteria are resistant through other beta-lactamases.
• Resistance also results from decreased membrane permeability and changes in PBPs.
• Methicillin-resistant staphylococci are also resistant to cephalosporins.

Clinical Uses

• First-generation:
  • Cefazolin (parenteral) and cephalexin (oral).
  • Active against gram-positive cocci, including staphylococci and common streptococci.
  • Many strains of E coli and K pneumoniae are also sensitive.
  • Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis.
• Second-generation:
  • Slightly less activity against gram-positive organisms but extended gram-negative coverage.
  • Marked differences in activity occur among the drugs in this subgroup.
  • Clinical uses include infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor).
• Third-generation:
  • Ceftazidime, cefoperazone, cefotaxime.
  • Increased activity against gram-negative organisms resistant to other beta-lactam drugs and ability to penetrate the blood-brain barrier (EXCEPT cefoperazone and cefixime).
  • Most are active against Providencia, Serratia marcescens, and beta-lactamase producing strains of H influenzae and Neisseria.
  • Ceftriaxone and cefotaxime are currently 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), currently drugs of choice in gonorrhea.
• Fourth-generation:
  • 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

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

Other Beta-Lactam Drugs

Aztreonam

• 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, and no cross allergenicity with penicillins.

Carbapenems (Imipenem, Doripenem, Meropenem, and Ertapenem)

• Parenterally administered beta-lactam drugs chemically different from penicillins.
• Wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), 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 are used in fixed combinations with certain hydrolyzable penicillins.
• Most active against plasmid-encoded beta-lactamases such as those 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

• Bactericidal glycoprotein that binds to the d-Ala-d-Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation.
• Action 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.
• Narrow spectrum and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA) and in combination with ceftriaxone for treatment of (PRSP).
• 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

• Antimetabolite inhibitor of cytosolic enolpyruvate transferase.
• Action 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).
• 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

• 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.
• Inactivated by pulmonary surfactants; thus, 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.
• Detergent-like effect disrupts cell membrane integrity, leading to leakage of cellular components and ultimately cell death.
• Concentration-dependent bactericidal agents with activity against P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter species, and Enterobacter species.
• Two forms: 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 increased risk of nephrotoxicity and neurotoxicity (slurred speech, muscle weakness) when used systemically.