Antibiotics are drugs that kill or inhibit the growth of bacteria. They are among the most important medical discoveries but are threatened by the emergence of antimicrobial resistance.
Mechanisms of Action
Antibiotics are classified by their mechanism of action against bacterial targets that differ from human cells.
Cell Wall Synthesis Inhibitors
These drugs inhibit the synthesis of peptidoglycan, the essential structural component of bacterial cell walls. Beta-lactams (penicillins, cephalosporins, carbapenems, monobactams) bind to penicillin-binding proteins (PBPs), inhibiting transpeptidation in peptidoglycan cross-linking. Vancomycin binds to the D-Ala-D-Ala terminus of the peptidoglycan precursor, preventing cross-linking. Both classes are bactericidal. Cell wall synthesis inhibitors are active against Gram-positive bacteria (thick peptidoglycan layer exposed) and Gram-negative bacteria (beta-lactams only, must penetrate the outer membrane).
Protein Synthesis Inhibitors
These drugs target the bacterial ribosome (70S), which differs from the human ribosome (80S). Aminoglycosides (gentamicin, tobramycin, amikacin) bind the 30S subunit, causing misreading of mRNA and are bactericidal. Tetracyclines (doxycycline, minocycline) bind the 30S subunit, blocking tRNA binding, and are bacteriostatic. Macrolides (azithromycin, erythromycin, clarithromycin) bind the 50S subunit, blocking peptide chain elongation, and are bacteriostatic or bactericidal depending on concentration and organism. Chloramphenicol, linezolid (oxazolidinone), clindamycin, and streptogramins also target the 50S subunit. Linezolid is uniquely effective against vancomycin-resistant enterococci (VRE) and MRSA.
DNA/RNA Synthesis Inhibitors
Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) inhibit DNA gyrase (topoisomerase II) and topoisomerase IV, preventing DNA supercoiling and replication. They are bactericidal and have broad spectrum. Rifampin inhibits RNA polymerase, blocking RNA transcription. It is bactericidal and used primarily in combination therapy for tuberculosis, staphylococcal infections, and as prophylaxis for Neisseria meningitidis. Metronidazole is a prodrug activated by bacterial nitroreductases, producing toxic metabolites that damage bacterial DNA — active against anaerobic bacteria and protozoa.
Folate Synthesis Inhibitors
Sulfonamides competitively inhibit dihydropteroate synthase (DHPS) in the bacterial folate synthesis pathway. Trimethoprim inhibits dihydrofolate reductase (DHFR). The combination (trimethoprim-sulfamethoxazole, TMP-SMX, co-trimoxazole) provides sequential blockade of the folate pathway and is bactericidal.
Major Antibiotic Classes
Penicillins include natural penicillins (penicillin G, penicillin V — narrow spectrum, Gram-positive, streptococci, oral anaerobes), antistaphylococcal penicillins (nafcillin, oxacillin, dicloxacillin — penicillinase-resistant), aminopenicillins (ampicillin, amoxicillin — extended spectrum to include some Gram-negative), and antipseudomonal penicillins (piperacillin-tazobactam). Penicillin allergy occurs in 5-10% of patients (true IgE-mediated in 1%).
Cephalosporins are classified by generation. First generation (cefazolin, cephalexin) — Gram-positive coverage. Second generation (cefuroxime, cefoxitin) — Gram-positive plus some Gram-negative. Third generation (ceftriaxone, cefpodoxime) — broad Gram-negative, less Gram-positive. Fourth generation (cefepime) — broad Gram-positive and Gram-negative including Pseudomonas. Fifth generation (ceftaroline) — broad plus MRSA. Ceftriaxone is a common first-line empiric choice for many community-acquired infections.
Carbapenems (imipenem, meropenem, ertapenem) have the broadest spectrum of any antibiotic class — Gram-positive, Gram-negative (including Pseudomonas — except ertapenem), and anaerobes. They are typically reserved for serious infections, multidrug-resistant organisms, and empiric therapy in critically ill patients.
Aminoglycosides (gentamicin, tobramycin, amikacin) are potent Gram-negative agents used in serious infections, often in combination with a beta-lactam for synergy. They require monitoring of peak and trough levels due to nephrotoxicity and ototoxicity (both vestibular and cochlear). Once-daily dosing is now standard.
Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) are broad-spectrum with excellent oral bioavailability. Ciprofloxacin is most active against Gram-negative bacteria (including Pseudomonas). Levofloxacin and moxifloxacin have better Gram-positive coverage. Fluoroquinolones carry FDA boxed warnings for tendinitis/tendon rupture, peripheral neuropathy, CNS effects, and exacerbation of myasthenia gravis. They are generally reserved for serious infections where alternatives are not available.
Antimicrobial Resistance
Antimicrobial resistance is a growing global crisis. Mechanisms of resistance include enzymatic inactivation (beta-lactamases — ESBLs, carbapenemases like KPC and NDM), target site modification (PBPs with reduced affinity — MRSA; altered ribosomes; altered DNA gyrase), reduced permeability (porin loss in Gram-negative bacteria — Pseudomonas, Acinetobacter), efflux pumps (active export of antibiotics from the bacterial cell — tetracyclines, fluoroquinolones), and bypass pathways (alternative metabolic pathways — vancomycin resistance in VRE through D-Ala-D-Lac substitution). Multidrug-resistant organisms of greatest concern include MRSA (methicillin-resistant Staphylococcus aureus), VRE (vancomycin-resistant Enterococcus), ESBL-producing Enterobacterales (especially E. coli, Klebsiella), carbapenem-resistant Enterobacterales (CRE — carbapenemase-producing), MDR Pseudomonas aeruginosa, MDR Acinetobacter baumannii, and drug-resistant Streptococcus pneumoniae.
Antibiotic Stewardship
Antibiotic stewardship aims to optimize antibiotic use to improve patient outcomes while minimizing resistance, adverse effects, and costs. Core strategies include: appropriate culture and sensitivity testing before antibiotics when possible; de-escalation (narrowing antibiotics based on culture results); appropriate duration (shorter courses are often equally effective — 3-5 days for uncomplicated UTI, 5-7 days for community-acquired pneumonia, 7 days for intra-abdominal infections); avoiding unnecessary antibiotics for viral infections (acute bronchitis, most sore throats, viral URI); minimizing unnecessary broad-spectrum coverage; and using therapeutic drug monitoring for vancomycin, aminoglycosides, and voriconazole.
Summary
Antibiotics target bacterial structures absent in human cells: cell wall (beta-lactams, vancomycin), protein synthesis (macrolides, tetracyclines, aminoglycosides), DNA/RNA synthesis (fluoroquinolones, rifampin), and folate synthesis (TMP-SMX). Resistance is driven by antibiotic overuse and spreads through genetic mechanisms (mutations, horizontal gene transfer). Antibiotic stewardship emphasizes appropriate prescribing, de-escalation, shortest effective duration, and avoiding antibiotics for viral infections. MDR organisms (MRSA, ESBL, CRE, MDR Pseudomonas) require specialized treatment.