Beta-Lactams and Penicillins

Antimicrobials

Beta-Lactams

• Includes penicillins and cephalosporins
• Contains a beta-lactam ring
• Interferes with peptidoglycan synthesis
• Inhibits penicillin-binding proteins
• Interferes with murein hydrolase inhibitor
• Leads to cell wall destruction
• Bactericidal/bacteriolytic
• Bacterial resistance occurs through:
  • Inability to access the site
  • Production of beta-lactamases
  • Altered penicillin-binding proteins
  • Efflux pumps
  • Decreased porins in gram-negative bacteria

Penicillins

• Penicillin G originally
• Anti-staphylococcal penicillins: nafcillin, oxacillin
• Broad-spectrum penicillins: ampicillin, piperacillin
• Uses include prophylaxis for dental, oral, GI, GU, and vaginal surgeries
• Rapidly excreted renally
  • Ampicillin, piperacillin require dose adjustment in renal disease
• Beta-lactamase inhibitors: clavulanic acid
  • Combined with penicillins to protect from bacterial breakdown
• Penicillin allergy is the most common drug allergy
• Differentiate between severe reactions (anaphylaxis, Stevens-Johnson Syndrome) and mild intolerances
• Serious delayed reactions warrant avoidance of other beta-lactams
• Mild reactions may allow for later-generation cephalosporins or penicillin after test dose
• Family history of penicillin allergy is not a genetic trait
• Cross-sensitivity to other beta-lactams is possible

Cephalosporins

• Interferes with peptidoglycan synthesis by binding to penicillin-binding proteins (transpeptidases)
• Prevents cross-linking
• Surgical prophylaxis, meningitis
• Therapeutic levels in various body fluids
• Administered PO, IM, or IV
  • Dose adjustments needed in renal failure
• Resistance can occur due to the production of cephalosporinases
• Cefazolin (Ancef, Kefzol) is the drug of choice for surgical prophylaxis
  • Effective against gram-positive cocci (e.g., S. aureus) and penicillinase-producing staphylococci
  • Has relative resistance against gram-negative organisms
  • Higher blood levels than other first-generation cephalosporins
  • Crosses the placenta, poor penetration of the blood-brain barrier
  • Given with metronidazole for colorectal surgery
  • Surgical prophylaxis dosing:
    • 2 grams IV for patients under 120 kg
    • 3 grams IV for those 120 kg and above
    • Some facilities may still use 1 gram for patients under 70 kg
  • Administer within 60 minutes of incision
  • Reconstituted with 10-100 mL NS, D5W, or SW
  • Given over 3-5 minutes
  • Repeated every 4 hours until closure
  • Adjustments for renal failure based on creatinine clearance
  • Adverse effects:
    • N/V
    • Hypersensitivity
    • Phlebitis
    • Transient elevation of hepatic enzymes
    • Stevens-Johnson syndrome
    • Superinfection
    • Seizures (especially in seizure disorders)
    • Increased effects of anticoagulants
    • Increased risk of Lasix-induced nephrotoxicity
    • Pregnancy category B
• Other generations of cephalosporins (e.g., cefoxitin, ceftriaxone, cefepime)

Beta-Lactam Cross-Reactivity

• Penicillins and cephalosporins share a beta-lactam ring, cross-reactivity is rare (1-2% risk)
• Side chain structure determines cross-reactivity
• True allergy to penicillin does not automatically preclude use of all cephalosporins
• Assess for immediate reactions (laryngeal edema, bronchospasm, cardiovascular collapse) and delayed reactions (maculopapular rash, fever)
• Cefazolin is the most likely cephalosporin to cause anaphylaxis

Aminoglycosides

• Examples: gentamicin, tobramycin, and amikacin
• Binds to the 30s ribosomal subunit
• Interferes with protein synthesis during mRNA translation
• Bactericidal against aerobic gram-negative bacilli
• Effective with other agents for gram-positive infections
• Resistance occurs through:
  • Impaired cell penetration
  • Inactivation by microbial enzymes
  • Low affinity for bacterial ribosomes
• Poor lipid solubility and bioavailability w/ oral dosing
• Elimination is prolonged in renal failure, post-antibiotic effect
• Gentamicin used off-label for surgical prophylaxis, particularly in urology cases
  • Dose: 1.5-5 mg/kg IV within 60 minutes of procedure start
  • Infused over at least 30-120 minutes using an IV pump
  • Dose decreased in renal failure
  • Can increase the effects of neuromuscular blockers
  • Increased toxicity risk with loop diuretics
• Adverse effects:
  • Ototoxicity (vestibular and auditory dysfunction)
  • Nephrotoxicity (acute tubular necrosis)
  • Skeletal muscle weakness via inhibiting acetylcholine release and decreasing postsynaptic sensitivity
  • Hypersensitivity reactions are uncommon

Macrolides

• Examples: erythromycin, azithromycin, and clarithromycin
• Binds to the 50s ribosomal subunit
• Inhibits protein synthesis
• Broad-spectrum, usually bacteriostatic, bactericidal at high doses
• Effective against gram-positive and some gram-negative bacteria
• Used for respiratory tract and severe infections (IV)
  • IV administration carries risks of thrombophlebitis, nausea, and tinnitus
• Erythromycin is extensively metabolized by the liver, azithromycin has a long half-life
• Adverse effects:
  • Prolonged repolarization and QTc prolongation (cardiac)
  • Gastrointestinal issues
  • Increased effect of anticoagulants
  • CYP450 enzyme inhibition (especially erythromycin)

Clindamycin (Cleocin)

• A lincosamide antibiotic
• Binds to the 50s ribosomal subunit
• Inhibits peptide chain synthesis
• Used for surgical prophylaxis
• Effective against anaerobes, streptococci, and staphylococci
• Oral, pharyngeal, lung, respiratory, and intra-abdominal infections
• Good oral bioavailability
• Distributes well into bone and urine
• Crosses the placenta, minimal CSF levels
• Post-antibiotic effect for some bacteria
• Metabolized by the liver and excreted by the kidneys
• No typical dose adjustment needed for hepatic or renal disease
• Surgical prophylaxis dosing:
  • Adults: 900 mg IV infused over 10-60 minutes (ideally 30 minutes) within 60 minutes of incision
  • Redosed every 6 hours until closure
• Incompatible with barbiturates, calcium gluconate, and many other antibiotics
• Adverse effects:
  • Neuromuscular blockade (pre- and post-junctional effects)
  • Gastrointestinal issues (diarrhea, C. difficile colitis, abdominal pain, N/V)
  • Thrombophlebitis
  • Allergic reactions (rash, Stevens-Johnson syndrome, eosinophilia)
• Neuromuscular blockade due to direct effects at the neuromuscular junction, not CYP450 inhibition

Vancomycin (Vancocin)

• Binds tightly to the cell wall precursor
• Blocks glycopeptide formation and inhibits cell wall synthesis
• Bactericidal and highly effective against gram-positive bacteria
• Used for MRSA, C. difficile, penicillin-resistant endocarditis, and sepsis
• Used off-label for surgical prophylaxis in penicillin or cephalosporin allergy
• Distributes widely in tissues not CSF
• Serum trough levels, renal function, and CBC may be monitored with long-term use
• Primarily excreted unchanged by the kidneys
• Clearance reduced in the elderly
• Surgical prophylactic dose: 10-15 mg/kg IV, not exceeding 2 grams
• Started within 60-120 minutes of incision
• Infused over at least 60 minutes
• Redosing typically not done sooner than 12 hours later
• Adverse effects:
  • Red Man Syndrome (rate-related histamine release)
    • Redness, itching, hypotension, dyspnea
    • Treated by halting infusion
    • Giving histamine blockers (Benadryl and famotidine) before restarting at half the rate
  • True allergic reactions (requiring epinephrine and discontinuation)
  • Hypoxemia
  • Nephrotoxicity (increased risk with other nephrotoxic drugs)
  • Ototoxicity (rare, similar symptoms to aminoglycosides)
  • Prolonged use can lead to superinfection
• IV form generally not recommended in pregnancy due to potential risks of fetal malformation

Metronidazole (Flagyl)

• Diffuses into the bacterial cell
• Metabolized into cytotoxic particles that break down and destabilize the cell's DNA
• Bactericidal and highly effective against anaerobic bacteria, gram-negative bacteria, protozoa, Clostridium, and H. pylori
• Recommended for surgical prophylaxis in colorectal, urologic, and head/neck cases
• Given with Ancef to cover gram-positive skin flora
• Surgical prophylaxis dose: 500 to 1000 mg PO or IV within 60 minutes of incision
• Bacterial resistance is rare
• Adverse effects:
  • Headache, nausea, vomiting, dry mouth, metallic taste, infection, neurologic disturbances, and neuropathy
• Patients taking oral flagyl should avoid alcohol due to potential intolerance

Fluoroquinolones

• Examples: ciprofloxacin, moxifloxacin, and levofloxacin
• Inhibits DNA synthesis and promotes DNA breakage
• Bactericidal and broad-spectrum
• Effective against enteric organisms, gram-negative and gram-positive bacteria, anaerobes, mycobacteria, and respiratory/GI/GU pathogens
• Ciprofloxacin (Cipro) may be used off-label for surgical prophylaxis
  • Dose: 400 mg IV within 2 hours of incision
  • Administered slowly over 60+ minutes through a large bore IV
• Adverse effects:
  • Bacterial resistance
  • Gastrointestinal upset
  • CNS disturbances
  • Neuropathy
  • Hepatotoxicity (elevated liver enzymes)
  • Musculoskeletal issues (tendinopathy, tendon rupture, muscle weakness)
  • QTc prolongation

Pediatrics

• Antimicrobial selection for prophylaxis in pediatrics generally mirrors adult guidelines
• Cephalosporins are the agents of choice
• Vancomycin used for beta-lactam allergy
• Fluoroquinolones avoided due to toxicity risks
• Dosing is often weight-based for children less than 40 kg
• UCSF typical doses:
  • Cefazolin 25 mg/kg every 4 hours
  • Clindamycin 10 mg/kg
  • Flagyl 7.5 mg/kg
  • Vancomycin 10-15 mg/kg (same as adults)
• Adult doses should not be exceeded in pediatric patients based on weight

Topical Antiseptics

Chlorhexidine (ChloraPrep, Betasept)

• Common surgical wash or scrub, typically at a 2% concentration
• More effective at reducing skin flora than povidone-iodine
• Persistent effect and is poorly absorbed
• Application should be liberal for 2+ minutes and repeated
• Disrupts bacterial cell membranes, effective against gram-positive and gram-negative bacteria
• Risk of corneal toxicity (chemical burn)
• Potential neurotoxicity if it enters the neuraxial space (allow to dry thoroughly before needle insertion)
• For facial/head/neck surgery, eyes must be protected with occlusive dressings (e.g., Tegaderm) or eye shields with lubricant

Povidone-Iodine (Betadine, DuraPrep)

• Provides immediate bactericidal action
• A 10% solution can decrease skin flora by over 90% and lasts for 6-8 hours
• Application involves scrubbing for about 5 minutes
• Lower risk of corneal toxicity compared to chlorhexidine, but is still possible

Iodine

• Rapid-acting antiseptic that kills bacteria, viruses, and spores, often administered as a tincture
• Toxicity risk increases with concentration
• Carries a corneal toxicity risk and can rarely cause allergic skin reactions
• After prepping with any antiseptic, it is generally wiped off as much as possible at the end of the case