Beta-Lactam Antibiotics

Chemistry and Structure

• Penicillins: beta-lactam ring + thiazolidine ring (5-membered sulfur ring). Variable R-group on the amino group creates the many different penicillins (Figure 43-1, Katzung 16e).
• Cephalosporins: beta-lactam ring + dihydrothiazine ring (6-membered ring). Derived from 7-aminocephalosporanic acid.
• Carbapenems: similar bicyclic structure but with a different stereochemical configuration in the lactam ring - this confers resistance to most common beta-lactamases.
• Monobactams: monocyclic beta-lactam ring only (no fused ring). Only aztreonam is available in the USA.

Mechanism of Action

1. The bacterial cell wall is made of peptidoglycan - a cross-linked polymer of alternating N-acetylglucosamine and N-acetylmuramic acid sugars, with pentapeptide side chains.
2. Transpeptidase enzymes (also called penicillin-binding proteins, PBPs) normally remove the terminal d-alanine residue from the peptide side chain and form cross-links between adjacent chains - this cross-linking gives the wall its rigidity.
3. Beta-lactams are structural analogs of the natural d-Ala-d-Ala substrate. They covalently bind to the active site of PBPs, irreversibly inhibiting the transpeptidation reaction.
4. Peptidoglycan synthesis stops; bacterial autolysins continue degrading the wall and the cell dies.

Classes of Beta-Lactams

1. Penicillins

• Most are renally excreted (90% by tubular secretion); dose-adjust in renal failure.
• Normal half-life of penicillin G is ~30 minutes (up to 10 hours in renal failure).
• Food impairs absorption of most oral penicillins (amoxicillin is an exception).
• Penetration into CNS is poor normally, but adequate for meningitis treatment when inflamed meninges are present (with high IV doses).
• Nafcillin is cleared by bile, not kidneys - no dose adjustment needed in renal failure.

2. Cephalosporins (by generation)

• Good gram-positive (MSSA, streptococci), limited gram-negative.
• Used for: skin/soft tissue infections, UTI, surgical prophylaxis.
• Poor CNS penetration.

• Improved gram-negative (H. influenzae, M. catarrhalis).
• Cefoxitin/cefotetan have anaerobic coverage (B. fragilis) - used for abdominal/pelvic infections, PID.
• Cefuroxime crosses blood-brain barrier but inferior to 3rd gen for meningitis.

• Expanded gram-negative coverage including Citrobacter, Serratia, Providencia.
• Most penetrate CSF - used for meningitis.
• Ceftazidime is the only 3rd-gen agent with useful anti-Pseudomonas activity.
• Ceftriaxone: half-life 7-8 hours (once-daily dosing); used for pneumonia, meningitis, gonorrhea.
• Hydrolyzed by AmpC beta-lactamases; not reliably active against Enterobacter sp.

• Extended gram-negative activity including Pseudomonas.
• Stable to AmpC beta-lactamases (can treat Enterobacter).
• Good gram-positive activity.
• Penetrates CSF; used for nosocomial pneumonia, febrile neutropenia.

• Activity against MRSA (unique among cephalosporins).
• Used for community-acquired pneumonia, skin/soft tissue infections.

3. Carbapenems (imipenem, meropenem, ertapenem, doripenem)

• Broadest spectrum of all beta-lactams.
• Active against gram-positives, gram-negatives (including most Pseudomonas and Enterobacter), and anaerobes.
• Resistant to most beta-lactamases due to altered stereochemistry of the lactam ring.
• Imipenem is combined with cilastatin (a renal dehydropeptidase inhibitor) to prevent renal inactivation.
• Used for: severe hospital-acquired infections, polymicrobial infections, infections with ESBL-producing organisms.
• Carbapenemases (KPC, NDM, OXA-48 enzymes) represent the most serious resistance threat - can render organisms resistant to essentially all beta-lactams.

4. Monobactams (Aztreonam)

• Monocyclic beta-lactam; the only available agent.
• Spectrum limited to aerobic gram-negative bacteria only (including Pseudomonas) - no activity against gram-positives or anaerobes.
• Structurally similar to ceftazidime - potential cross-reactivity with ceftazidime allergy.
• Safe in penicillin-allergic patients (no cross-reactivity with penicillins).
• IV dosing: 1-2 g every 8 hours; penetrates CSF well.
• Half-life 1-2 hours; requires dose adjustment in renal failure.

5. Beta-Lactamase Inhibitors (BLIs)

Mechanisms of Resistance

1. Alteration of PBP target - reduced affinity for beta-lactams:
   • MRSA acquires an additional low-affinity PBP (PBP2a, encoded by mecA) via a transposon - conferring resistance to all beta-lactams.
   • Penicillin-resistant pneumococci have altered PBPs via interspecies homologous recombination.
2. Reduced concentration at the target site:
   • Porin loss in gram-negative bacteria - reduced outer membrane permeability.
   • Efflux pumps - actively remove the drug before it can act.
   • When porin loss + efflux combine with beta-lactamase production = high-level resistance.
3. Enzymatic degradation - beta-lactamases:
   • The most common and clinically important mechanism.
   • Gram-positive bacteria: secrete large amounts of narrow-spectrum penicillinase (encoded on plasmids; transferable by bacteriophage).
   • Gram-negative bacteria: beta-lactamases in the periplasmic space provide maximal protection.
   • ESBL (extended-spectrum beta-lactamases): hydrolize most penicillins AND cephalosporins.
   • Carbapenemases (KPC, NDM, OXA-48): hydrolize carbapenems too - organisms carrying these may resist virtually all beta-lactams in clinical use.

Adverse Effects

Hypersensitivity (most important)

• ~5-8% of patients report penicillin allergy, but only a small fraction have true type I hypersensitivity.
• Antigenic determinants: degradation products (penicilloic acid and alkaline hydrolysis products) bound to host proteins.
• Anaphylaxis: very rare (0.05% of recipients) but potentially fatal.
• Serum sickness: urticaria, fever, joint swelling, angioedema, occurs 7-12 days after exposure (now rare).
• Skin rashes, eosinophilia, interstitial nephritis, hemolytic anemia, vasculitis.
• Skin testing for type I hypersensitivity: negative result allows safe re-administration in most patients.
• Desensitization possible when penicillin is absolutely needed (e.g., enterococcal endocarditis, neurosyphilis).

Cephalosporin cross-reactivity

• Risk of cross-reactivity with penicillins is low (historically overestimated at ~10%; actual rate ~1-2%).
• Highest risk when the R1 side chain is identical (e.g., amoxicillin-cefadroxil, ampicillin-cefaclor).
• Aztreonam has NO cross-reactivity with penicillins but does cross-react with ceftazidime (shared R1 side chain).

Other toxicities

• Seizures: high-dose IV penicillin in renal failure.
• Nafcillin: neutropenia, interstitial nephritis.
• Oxacillin: hepatitis.
• Ampicillin/amoxicillin: maculopapular rash (especially with concurrent EBV infection).
• Piperacillin-tazobactam + vancomycin: increased risk of acute kidney injury vs. other beta-lactams combined with vancomycin.
• C. difficile colitis: all antibiotics including beta-lactams can predispose.
• Secondary candidiasis: oropharyngeal and vaginal thrush.

PK/PD Principle

Quick Clinical Reference