Mechanisms of action of various antibiotics. (With permission from O’Leary JP, Tabuenca A, eds. Physiologic Basis of Surgery. 4th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007.)

Mechanism of Antibiotics

•Block bacterial cell wall synthesis by binding penicillin binding protein

•Penicillins, cephalosporins, aztreonam, imipenem

•Block peptidoglycan synthesis

•Vancomycin, bacitracin

•Block protein synthesis at the 50S ribosomal subunit

•Macrolides, chloramphenicol, lincosamides

•Block protein synthesis at the 30S ribosomal subunit

•Aminoglycosides, tetracyclines

•Block nucleotide synthesis

•Sulfonamides, trimethoprim

•Block DNA topoisomerases

•Fluoroquinolones

•Block mRNA synthesis

•Rifampin

•Disrupt cell membranes

•Polymixins

•Disrupt fungal cell membranes

•Amphotericin B, azoles

A 25-year-old male with no significant past medical history presents with a painless, ulcerated lesion on his penis. He has been sexually active with 10 partners in the past 2 months and denies using any protection. He otherwise feels well. What antibiotic should be used to treat his infection and what is its mechanism of action?

The patient has syphilis, which is susceptible to penicillin. It is imperative that his infection be treated or he could progress to secondary and tertiary syphilis, which are more resistant to treatment. Testing and treatment should also be offered to his partners.

•Penicillins

•Contain β-lactam ring

•Penicillin G, Penicillin V, ampicillin, amoxicillin, carbencillin, methicillin, nafcillin, oxacillin, ticarcillin

•Activity against Streptococci, pneumococci, gonococci, meningococci, spirochetes

•Mechanism of action: Bactericidal

•Inhibition of cell wall synthesis

•Bind drug-specific receptors in bacterial cytoplasmic membrane (penicillin-binding proteins)

•Inhibition of transpeptidases

•Activation of autocatalytic enzymes

•Resistance is via β-lactamases and is wide spread

•β-lactamase inhibitors in combination with β-lactam antibiotics are used to combat resistance: Clavulinic acid, sulbactam, tazobactam.

•Pharmacokinetics:

•Varying degrees of oral absorption

•Not metabolized

•Excreted renally, except ampicillin and nafcillin, which are excreted in bile

•Short half-lives (30 min to 1 hour)

•Toxicity:

•Allergic reactions

•Nausea and diarrhea

A 57-year-old female with a history of hypertension and hyperlipidemia presents for a routine laparoscopic cholecystectomy. What class of antibiotic should she receive 1 hour to 30 minutes before the incision is made?

This is considered to be a clean GI type of operation, thus a first-generation cephalosporin will suffice. The purpose of the antibiotic is to prevent a surgical site infection.

•Cephalosporins

•Also contain β-lactam rings

•1st generation: Cefazolin

•Treat gram-positive cocci, Proteus, E. coli, Klebsiella

•2nd generation: Cefotetan, cefoxitin, cefuroxime

•Treat gram-positive cocci, H. flu, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella, Serratia

•3rd generation: Cefotaxime, ceftazidime, ceftriaxone

•Treat serious gram-negative infections, meningitis

•Ceftazidime:Pseudomonas

•Ceftriaxone:N. gonorrhoeae

•4th generation: Cefepime, cefquinome

•Treat serious gram-negative and gram-positive infections

•Can cross the blood brain barrier

•Cefepime: Nosocomial Pseudomonas

•Mechanism of action: Bactericidal

•Inhibition of cell wall synthesis

•Bind drug-specific receptors in bacterial cytoplasmic membrane (penicillin-binding proteins)

•Resistance is via β-lactamases or mutation of penicillin-binding proteins

•Pharmacokinetics

•Variable oral absorption

•Not metabolized

•Excreted renally, except ceftriaxone, which is excreted in bile

•Short half-lives (30 min to 1 hour)

•Toxicity

•Allergic reactions—10% cross-reactivity with penicillin-allergic patients

•Other β-lactam Antibiotics

•Aztreonam

•Monobactam

•Resistant to β-lactamases

•Activity against Klebsiella, Pseudomonas, Serratia

•Inhibits cell wall synthesis

•Excreted renally

•Not cross-reactive with penicillins

•Imipenem

•Carbapenem

•Largely resistant to β-lactamases

•Activity against gram-positive cocci, gram-negative bacilli, anaerobes

•Administered with cilastatin to inhibit rapid renal inactivation

•Partially cross-reactive with penicillins

A 39-year-old nurse with no significant past medical history presents with a red, painful, swollen nodule on her arm. On further evaluation, the nodule is fluctuant. You perform an incision and drainage (I&D) of the area and infected fluid is evacuated, but the patient continues to be febrile and have significant cellulitis. A culture of the fluid demonstrates methicillin resistant staph aureus (MRSA). What antibiotic should be used for initial treatment in this patient?

Vancomycin should be used initially until the sensitivities on the antibiotic susceptibility are available and she is clinically improving. These patients can often be transitioned to Bactrim or another sensitivity-specific antibiotic.

•Vancomycin

•Activity against β-lactamase-producing Staph aureus and C. difficile

•Mechanism of action: Bactericidal

•Inhibition of cell wall mucopeptides

•Resistance is rare

•Pharmacokinetics:

•Not orally absorbed

•Can be used to treat bacterial enterocolitis

•Wide tissue penetration

•Not metabolized

•Excreted renally

•Dosing must achieve drug concentration within the therapeutic window

•Toxicity:

•Ototoxicity

•Nephrotoxicity

•“Red man” syndrome results from rapid infusion

•Bacitracin

•Activity against aerobic gram-positive bacteria

•Mechanism of action: Bactericidal

•Inhibition of cell wall synthesis

•Pharmacokinetics:

•Topical use only

•Toxicity:

•Nephrotoxic

A 57-year-old female who is POD 1 status post laparoscopic gastric bypass surgery has a persistent cough. She had no episodes of emesis and no witnessed aspiration events. A chest X-ray demonstrates diffuse patchy infiltrates. On further questioning, the patient does remember that she was starting to have a cough and feeling more tired for the 2 days prior to surgery. She is diagnosed with a community-acquired pneumonia. What antibiotic should be used?

The patient had no evidence of aspiration and was only intubated for a couple of hours for her procedure. Her chest X-ray and story are most compatible with a community-acquired pneumonia. She should be treated with a macrolide antibiotic.

•Macrolides

•Azithromycin, clarithromycin, erythromycin

•Activity against aerobic gram-positive cocci bacteria

•Mycoplasma pneumoniae, Corynebacterium, C. trachomatis, Legionella pneumophila, Bordetella pertussis

•Azithromycin also active against H. flu, M. catarrhalis, Neisseria

•Clarithromycin also active against M. avium-intracellulare, H. pylori

•Mechanism of action: Bactericidal or bacteriostatic

•Inhibition of protein synthesis

•Erythromycin binds the 23S rRNA component of the 50S ribosomal subunit, resulting in blocking of the initiation complex and ribosomal translocation

•Resistance is via multiple plasmid-mediated enzymes

•Pharmacokinetics:

•Azithromycin is cleared unmetabolized in urine

•Clarithromycin is metabolized in the liver

•Erythromycin is excreted in bile

•Toxicity:

•Hypersensitivity-based acute cholestatic hepatitis (rare)

•Inhibition of cytochrome P450 by erythromycin, resulting in increased plasma levels of other drugs (e.g., warfarin, digoxin)

•Chloramphenicol

•Broad-spectrum activity:

•Salmonella, H. meningitidis, H. flu (some strains only)

•Mechanism of action: Bacteriostatic

•Inhibition of peptidyl transferase

•Binds the 50S ribosomal subunit

•Resistance is via formation of inactivating acetyl transferases

•Pharmacokinetics:

•Metabolized in liver

•Toxicity:

•Irreversible aplastic anemia (~1:30,000 patients)

•Reversible bone marrow suppression

•Gray baby syndrome when used in neonates

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