Lecture #123: Pharmacology of Beta-lactam Antibiotics, Other Cell Wall Inhibitors, and Cell Membrane-Active Antibiotics, Part 2: Cephalosporins, Carbapenems, Monobactam, Vancomycin, and Daptomycin

What is the structural relationship between cephalosporins and penicillins?

Cephalosporins are beta-lactam antibiotics similar to penicillins but with a six-membered dihydrothiazine ring instead of a five-membered thiazolidine ring. This structural difference provides increased resistance to many beta-lactamases and broadens antimicrobial activity.

How are cephalosporins categorized?

They are divided into generations (1st, 2nd, 3rd, 4th, and advanced) based on antimicrobial spectrum and beta-lactamase stability, with each generation generally gaining gram-negative activity while sometimes losing gram-positive potency.

What is the general pharmacokinetic profile of cephalosporins?

Most are given parenterally, distribute widely into tissues and fluids, and are eliminated renally as unchanged drug. Some (e.g., ceftriaxone) have biliary excretion. CSF penetration is limited unless meninges are inflamed, except for certain agents with inherently better CNS penetration.

Which cephalosporins have good CSF penetration?

Cefuroxime, cefotaxime, ceftriaxone, ceftazidime, and cefepime achieve therapeutic CSF levels—especially when meninges are inflamed—making them useful in treatment of meningitis.

What organisms are first-generation cephalosporins most effective against?

They primarily target gram-positive cocci (MSSA, streptococci) and some gram-negative rods (Proteus, E. coli, Klebsiella—“PEcK”). They are useful for skin/soft tissue infections and surgical prophylaxis.

Which cephalosporin is preferred for MSSA?

Cefazolin is preferred due to strong activity against penicillinase-producing MSSA and favorable pharmacokinetics. It is widely used for surgical prophylaxis and soft tissue infections.

What organisms are second-generation cephalosporins active against?

They maintain gram-positive activity with improved gram-negative coverage, including H. influenzae and M. catarrhalis. Cephamycins (e.g., cefoxitin) uniquely cover anaerobic Bacteroides fragilis.

Why are second-generation cephalosporins less clinically favored?

They are associated with delayed clinical response and higher treatment failures; third-generation cephalosporins generally perform better for serious infections.

What distinguishes cephamycins from other second-generation agents?

Cefoxitin and cefotetan cover B. fragilis and other anaerobes. This makes them useful for abdominal/pelvic infections and surgical prophylaxis involving the GI tract.

What is the antimicrobial profile of third-generation cephalosporins?

They have broad gram-negative activity, good penetration into CSF, and effectiveness against β-lactamase–producing strains of H. influenzae and Neisseria. They retain gram-positive activity (except ceftazidime, which has weak G+ activity).

Which third-generation cephalosporin covers Pseudomonas aeruginosa?

Ceftazidime (and combination agents ceftazidime-avibactam and ceftolozane-tazobactam) provide strong activity against Pseudomonas and are used for serious gram-negative infections.

Why are ceftriaxone and cefotaxime important in meningitis treatment?

Both reach therapeutic CSF concentrations and have reliable activity against major meningitis pathogens. Ceftriaxone’s long half-life permits once-daily dosing.

What key differences exist between ceftriaxone and cefotaxime?

Ceftriaxone undergoes biliary excretion and may cause biliary sludge or kernicterus in neonates, whereas cefotaxime is renally eliminated and preferred for neonates due to its safety.

Which cephalosporins are used for gonorrhea?

Ceftriaxone is the single recommended agent for uncomplicated gonorrhea, given as a single IM injection due to high potency and excellent tissue penetration.

What characterizes fourth-generation cephalosporins like cefepime?

Cefepime has strong gram-negative activity—including Pseudomonas—and retains good gram-positive activity. It is also more stable against some chromosomal beta-lactamases from gram-negative bacteria.

What distinguishes advanced-generation cephalosporins?

Ceftaroline uniquely binds PBP2a and thus covers MRSA. Cefiderocol uses iron transport mechanisms (“siderophore”) to enter gram-negative bacteria and is potent against multidrug-resistant GNB, including carbapenem-resistant strains.

What mechanisms allow bacteria to resist cephalosporins?

Bacteria may produce ESBLs, AmpC, or KPC beta-lactamases; acquire altered PBPs; lose porins; increase efflux pumps; or exhibit intrinsic resistance, such as Enterococcus, Listeria, and atypicals.

Which pathogens are cephalosporins ineffective against?

MRSA (except ceftaroline), Enterococcus, Listeria, atypical organisms (Mycoplasma, Chlamydia, Legionella), C. difficile, and many MDR gram-negative species such as Stenotrophomonas.

What are common therapeutic uses of cephalosporins?

They treat skin/soft tissue infections, UTIs, respiratory infections, meningitis, intra-abdominal infections (with cephamycins), gonorrhea, and serious hospital-acquired infections depending on the agent’s generation.

What are major adverse effects of cephalosporins?

Hypersensitivity reactions, GI upset, C. difficile infection risk, nephrotoxicity (rare), disulfiram-like reaction with cefotetan, biliary stasis with ceftriaxone, and painful IM injections or IV thrombophlebitis.

What organisms do carbapenems cover?

They have the broadest beta-lactam spectrum, covering gram-positive, gram-negative, aerobic, anaerobic, and many resistant pathogens. Ertapenem does NOT cover Pseudomonas or Acinetobacter.

Why is cilastatin combined with imipenem?

Cilastatin inhibits renal dehydropeptidase I, preventing imipenem degradation in renal tubules and increasing its urinary concentration and therapeutic effectiveness.

What are therapeutic uses of carbapenems?

They treat severe hospital-acquired infections, ESBL-producing Enterobacterales, intra-abdominal infections, complicated UTIs, sepsis, and polymicrobial infections. They are often used in patients previously exposed to beta-lactams.

What are main adverse effects of carbapenems?

Hypersensitivity, seizures (especially imipenem), GI upset, C. difficile superinfection, and rare hematologic effects like leukopenia or bleeding.

How do carbapenem–beta-lactamase inhibitor combinations work?

Relebactam and vaborbactam inhibit Ambler class A and C beta-lactamases (including KPCs), restoring activity of imipenem and meropenem against resistant Enterobacterales.

What spectrum does aztreonam cover?

Aztreonam covers only gram-negative aerobic organisms, including Pseudomonas. It is ineffective against gram-positives and anaerobes.

Why is aztreonam useful in beta-lactam–allergic patients?

It has extremely low cross-reactivity with penicillins and cephalosporins, except ceftazidime due to a similar side-chain structure.

What is the mechanism of vancomycin?

Vancomycin binds D-Ala-D-Ala termini on peptidoglycan precursors, blocking transglycosylation and cell wall synthesis. This disrupts cell wall polymerization, leading to bactericidal activity against gram-positive organisms.

Which organisms are susceptible to vancomycin?

Gram-positive pathogens including MRSA, MRSE, penicillin-resistant Streptococcus pneumoniae, Enterococcus (bacteriostatic), and C. difficile (oral formulation).

How does resistance to vancomycin occur?

VanA and VanB gene clusters substitute D-Ala-D-Lac for D-Ala-D-Ala, reducing binding affinity by 1000-fold. Intermediate resistance in S. aureus results from thickened cell walls that trap the drug.

What are major adverse effects of vancomycin?

Nephrotoxicity, infusion-related “red man syndrome,” ototoxicity (rare), neutropenia, phlebitis, and hypersensitivity reactions. Red man syndrome is prevented by slow infusion and premedication.

Why is vancomycin ineffective against gram-negative organisms?

The large hydrophilic molecule cannot penetrate gram-negative outer membrane porins, preventing access to PBPs.

What is the mechanism of daptomycin?

Daptomycin inserts its lipid tail into bacterial membranes in a calcium-dependent manner, causing depolarization, potassium efflux, and inhibition of DNA/RNA/protein synthesis without cell lysis.

Which organisms are susceptible to daptomycin?

All clinically important gram-positive organisms, including MRSA, MRSE, VRE, VISA, and VRSA. It is used for bacteremia, endocarditis, osteomyelitis, and skin infections.

Why can’t daptomycin be used for pneumonia?

Pulmonary surfactant inactivates the drug, making it ineffective for lung infections.

What are key adverse effects of daptomycin?

Myopathy with elevated CK, eosinophilic pneumonia, peripheral neuropathy, and hypersensitivity reactions. CK levels must be monitored, especially in patients on statins due to additive muscle toxicity.