Chapter 43: Beta-Lactam Antibiotics

Core structure of penicillins

They are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring structure essential for antibacterial activity.

General mechanism/effect of penicillins

Beta-lactam antibiotics are bactericidal.

Physicochemical properties of penicillins

They are polar compounds and are not extensively metabolized.

Primary route of penicillin excretion

Excreted unchanged in the urine via glomerular filtration and tubular secretion.

Penicillins excreted mainly in bile

Nafcillin and ampicillin.

Mechanism and clinical effect of Probenecid with Penicillins

Inhibits excretion of penicillin via renal glomerular filtration and tubular secretion. It is also used as a treatment for gout and hyperuricemia.

Long-acting formulations of Penicillin G

Procaine and benzathine forms, which are administered intramuscularly and have long plasma half-lives.

Route and indication for Penicillin V

Oral drug used mainly in oropharyngeal infections.

Drug of choice for Syphilis

Penicillin G.

Members of Antistaphylococcal Penicillins

Methicillin (prototype), nafcillin, and oxacillin.

Primary clinical use of Antistaphylococcal Penicillins

Treatment of known or suspected staphylococcal infections.

Toxicity note on Methicillin

Rarely used owing to its nephrotoxic potential (causes interstitial nephritis).

Resistance profile of Methicillin-resistant staphylococci (MRSA/MRSE)

Resistant to all penicillins and often resistant to multiple antimicrobial drugs.

Members of Aminopenicillins

Ampicillin and amoxicillin.

Spectrum of activity for Aminopenicillins

Enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis.

Penicillinase susceptibility of Aminopenicillins

Susceptible to penicillinases; antibacterial activity is often enhanced in combination with penicillinase inhibitors (e.g., clavulanic acid).

Members of Antipseudomonal Penicillins

Piperacillin and ticarcillin.

Spectrum of activity for Antipseudomonal Penicillins

Gram-negative rods, including Pseudomonas, Enterobacter, and some Klebsiella species.

Penicillinase susceptibility of Antipseudomonal Penicillins

Susceptible to penicillinases; often combined with penicillinase inhibitors (e.g., tazobactam, clavulanic acid) to enhance activity.

General allergic reactions to Penicillins

Urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis.

Specific adverse effect of Methicillin

Interstitial nephritis.

Specific adverse effect of Nafcillin

Neutropenia.

Dermatologic adverse effect of Ampicillin

Frequently causes a maculopapular skin rash.

Gastrointestinal adverse effects of oral penicillins

Nausea and diarrhea, especially with ampicillin.

Severe GI complication linked to Ampicillin

Pseudomembranous colitis.

Primary elimination mechanism of cephalosporins

Renal excretion via active tubular secretion (though side chains may undergo hepatic metabolism).

Cephalosporin excreted mainly in bile

Ceftriaxone.

Mechanism of action of cephalosporins

Bind to penicillin-binding proteins (PBPs) on bacterial cell membranes to inhibit bacterial cell wall synthesis.

Effect of cephalosporins on susceptible organisms

They are bactericidal.

Cephalosporin resistance in MRSA/MRSE

Methicillin-resistant staphylococci are also resistant to cephalosporins (with rare exceptions like ceftaroline).

Spectrum of First-generation cephalosporins

Active against gram-positive cocci, including staphylococci and common streptococci.

Second-generation cephalosporins active against Bacteroides fragilis

Cefotetan and cefoxitin.

Second-generation cephalosporins for sinus, ear, and respiratory infections

Cefuroxime and cefaclor (active against H. influenzae or M. catarrhalis).

Key features of Third-generation cephalosporins

Increased activity against gram-negative organisms resistant to other beta-lactams and ability to penetrate the blood-brain barrier.

Third-generation cephalosporin exception for blood-brain barrier penetration

Cefixime (does not penetrate BBB).

Most active cephalosporins against penicillin-resistant pneumococci (PRSP)

Ceftriaxone and cefotaxime.

Third-generation cephalosporin active against Pseudomonas

Ceftazidime.

Third-generation cephalosporin active against Bacteroides fragilis

Ceftizoxime.

Drugs of choice for Gonorrhea

Ceftriaxone (parenteral) and cefixime (oral).

Single-injection treatment alternative for acute otitis media

A single injection of ceftriaxone is usually as effective as a 10-day course of amoxicillin.

Key spectrum features of Cefepime (Fourth-generation)

More resistant to beta-lactamases produced by gram-negative organisms (Enterobacter, Haemophilus, Neisseria) and active against some PRSP strains.

Unique spectrum feature of Ceftaroline

Active against methicillin-resistant staphylococci (MRSA).

General allergic spectrum of cephalosporins

Range from mild skin rashes to life-threatening anaphylactic shock.

Administration site reactions of cephalosporins

Pain at intramuscular injection sites and phlebitis after intravenous administration.

Nephrotoxicity drug interaction with cephalosporins

Increases the nephrotoxicity of aminoglycosides when co-administered.

Adverse effects associated with methylthiotetrazole group (e.g., cefoperazone, cefotetan)

May cause hypoprothrombinemia and disulfiram-like reactions with ethanol.

Aztreonam drug class

Monobactam

Aztreonam spectrum of activity

Gram-negative rods only (e.g., Klebsiella, Pseudomonas, Serratia)

Aztreonam coverage gaps

No activity against Gram-positive bacteria or anaerobes

Aztreonam mechanism of action

Inhibits cell wall synthesis by preferentially binding to PBP3

Aztreonam drug synergy

Synergistic with aminoglycosides

Aztreonam half-life in renal failure

Prolonged

Aztreonam adverse effects

GI upset, superinfection, vertigo, headache, and rarely hepatotoxicity

Carbapenems examples

Imipenem, Meropenem, Ertapenem

Carbapenems structure & beta-lactamase susceptibility

Retain beta-lactam ring with low susceptibility to beta-lactamases

Carbapenems spectrum of activity

Broad activity: Gram-positive cocci, Gram-negative rods, and anaerobes

Carbapenems resistant organism

MRSA strains of staphylococci

Carbapenems drug of choice indications

Enterobacter, Citrobacter, and Serratia species

Carbapenems combination for pseudomonal infections

Often combined with an aminoglycoside

Imipenem inactivation mechanism

Rapidly inactivated by renal dehydropeptidase I

Reason Imipenem is co-administered with Cilastatin

Cilastatin inhibits renal dehydropeptidase I to prevent Imipenem degradation

Imipenem-Cilastatin adverse effects

GI distress, skin rash, and CNS toxicity (confusion, encephalopathy, seizures) at high levels

Advantage of Meropenem over Imipenem

Not metabolized by renal dehydropeptidases and less likely to cause seizures

Ertapenem activity limitations

Less active against enterococci and Pseudomonas

Ertapenem IM injection side effect

Pain and irritation at the injection site

Beta-lactamase inhibitors examples

Clavulanic acid, Sulbactam, Tazobactam

Beta-lactamase inhibitors administration

Given in fixed combinations with hydrolyzable penicillins

Beta-lactamase inhibitors primary target

Plasmid-encoded beta-lactamases (e.g., gonococci, streptococci, E. coli, H. influenzae)

Vancomycin drug class and target

Bactericidal glycoprotein that binds to D-Ala-D-Ala terminal of peptidoglycan pentapeptide

Vancomycin mechanism of action

Inhibits transglycosylation, preventing peptidoglycan chain elongation and cross-linking

Vancomycin resistance mechanism (Enterococci)

Replacement of terminal D-Ala with D-lactate, decreasing drug binding affinity

Vancomycin spectrum and key indication

Narrow spectrum for serious Gram-positive infections, including MRSA

Treatment for Penicillin-Resistant Pneumococci (PRSP)

Vancomycin in combination with a third-generation cephalosporin (e.g., Ceftriaxone)

Oral Vancomycin absorption and primary indication

Not absorbed from GI tract; used orally for Clostridioides difficile infection

Drug with better outcomes than Vancomycin for C. difficile

Fidaxomicin

Vancomycin toxicities

Chills, fever, phlebotomy/phlebitis, ototoxicity, and nephrotoxicity

Cause of diffuse flushing from rapid Vancomycin IV infusion

Histamine release ("Red Man Syndrome")

Other glycopeptide derivatives related to Vancomycin

Teicoplanin and Telavancin

Daptomycin drug class and spectrum

Cyclic lipopeptide active against Gram-positives, including VRE and MRSA

Daptomycin mechanism of action

Inserts into cytoplasmic membrane, causing potassium leakage and cell death

Daptomycin key toxicity and lab parameter to monitor

Causes myopathy; monitor Creatine Phosphokinase (CPK)

Fosfomycin mechanism of action

Antimetabolite inhibitor of cytosolic enolpyruvate transferase, preventing N-acetylmuramic acid formation

Fosfomycin mechanism of resistance

Decreased intracellular accumulation of the drug

Bacitracin mechanism of action

Peptide antibiotic that interferes with a late stage of cell wall synthesis in Gram-positives

Reason Bacitracin is limited to topical use

Marked nephrotoxicity

Cycloserine mechanism of action

Antimetabolite that blocks incorporation of D-Ala into the peptidoglycan pentapeptide side chain

Cycloserine major toxicities

Potential neurotoxicity (tremors, seizures, psychosis)

Primary clinical use of Cycloserine

Tuberculosis caused by organisms resistant to first-line antituberculosis drugs