Introduction
Antibiotics are drugs that kill or inhibit the growth of bacteria. They are classified by mechanism of action, spectrum of activity, and chemical structure. Appropriate antibiotic use requires understanding of bacterial susceptibility, pharmacokinetics at infection sites, host factors, and local resistance patterns. Antimicrobial resistance (AMR) is a global health crisis driven by antibiotic misuse.
Antibiotic Classification by Mechanism
Cell Wall Synthesis Inhibitors
| Class | Mechanism | Site of Action | Bactericidal | Spectrum | Key Examples |
|---|---|---|---|---|---|
| Penicillins | Bind PBPs, inhibit transpeptidase (peptidoglycan crosslinking) | Cell wall | Yes | Narrow to broad | Amoxicillin, ampicillin, piperacillin, nafcillin |
| Cephalosporins | Same as penicillins (PBPs) | Cell wall | Yes | Broad (increasing with generations) | Cephalexin (1st), cefuroxime (2nd), ceftriaxone (3rd), cefepime (4th) |
| Carbapenems | Same as penicillins (PBPs, high PBP affinity) | Cell wall | Yes | Very broad | Meropenem, imipenem-cilastatin, ertapenem |
| Carbapenems (newer) | Same + PBP specificity for resistant organisms | Cell wall | Yes | ESBL, CRE | Ceftazidime-avibactam, meropenem-vaborbactam |
| Glycopeptides | Bind D-Ala-D-Ala, block transglycosylation/transpeptidation | Cell wall | Yes (slow) | Gram-positive only | Vancomycin, teicoplanin |
| Lipopeptides | Insert into cell membrane, depolarization | Cell membrane | Yes | Gram-positive | Daptomycin |
| Lipoglycopeptides | Dual mechanism (cell wall + membrane disruption) | Cell wall + membrane | Yes | Gram-positive (including VRE) | Telavancin, dalbavancin, oritavancin |
| Polymyxins | Bind LPS, disrupt outer membrane | Cell membrane (gram-negative) | Yes | Gram-negative | Polymyxin B, colistin (polymyxin E) |
Protein Synthesis Inhibitors
| Class | Subunit | Mechanism | Bacteriostatic/Cidal | Spectrum | Key Examples |
|---|---|---|---|---|---|
| Aminoglycosides | 30S | Bind 30S, impair proofreading, misreading of mRNA | Bactericidal | Gram-negative | Gentamicin, tobramycin, amikacin |
| Tetracyclines | 30S | Block tRNA binding to A site | Bacteriostatic | Broad | Doxycycline, minocycline, tigecycline |
| Oxazolidinones | 50S (23S) | Prevent 70S initiation complex formation | Bacteriostatic | Gram-positive (including VRE, MRSA) | Linezolid, tedizolid |
| Macrolides | 50S (23S) | Block peptide chain elongation (peptidyl transferase exit tunnel) | Bacteriostatic (cidal for some) | Broad (respiratory, atypicals) | Azithromycin, clarithromycin, erythromycin |
| Clindamycin | 50S | Blocks peptide bond formation (similar to macrolides) | Bacteriostatic | Gram-positive, anaerobes | Clindamycin |
| Chloramphenicol | 50S | Blocks peptidyl transferase | Bacteriostatic | Broad | Chloramphenicol |
| Mupirocin | Isoleucyl-tRNA synthetase | Inhibits isoleucine incorporation | Bacteriostatic | Gram-positive (skin) | Mupirocin (topical) |
| Fusidic acid | 50S (elongation factor G) | Blocks EF-G, prevents translocation | Bacteriostatic | Gram-positive (Staphylococcus) | Fusidic acid |
Nucleic Acid Synthesis Inhibitors
| Class | Mechanism | Bactericidal/Cidal | Spectrum | Key Examples |
|---|---|---|---|---|
| Fluoroquinolones | Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV | Bactericidal | Broad | Ciprofloxacin, levofloxacin, moxifloxacin |
| Metronidazole | Reductive activation forms toxic compounds that damage DNA | Bactericidal | Anaerobes, parasites | Metronidazole |
| Rifamycins | Inhibit DNA-dependent RNA polymerase | Bactericidal | Broad (mycobacteria, gram-positives) | Rifampin, rifabutin, rifaximin |
Folate Antagonists
| Class | Enzyme Target | Bacteriostatic/Cidal | Spectrum | Key Examples |
|---|---|---|---|---|
| Sulfonamides | Dihydropteroate synthase (PABA analog) | Bacteriostatic | Broad (UTIs, Nocardia) | Sulfamethoxazole, sulfadiazine |
| Trimethoprim | Dihydrofolate reductase | Bacteriostatic | Broad | Trimethoprim |
| Cotrimoxazole (SMX-TMP) | Sequential folate blockade (both enzymes) | Bactericidal | Broad | SMX-TMP |
Antibiotic Spectrum of Activity
Gram-Positive Coverage
| Antibiotic | MSSA | MRSA | Streptococcus | Enterococcus | VRE | Clostridioides difficile |
|---|---|---|---|---|---|---|
| Penicillin G | No | No | Yes | Yes (E. faecalis) | No | No |
| Nafcillin/oxacillin | Yes | No | Yes | No | No | No |
| Amoxicillin | Yes | No | Yes | Yes (E. faecalis) | No | No |
| Cephalexin (1st gen) | Yes | No | Yes | No | No | No |
| Ceftriaxone (3rd gen) | Yes | No | Yes | No | No | No |
| Vancomycin | Yes | Yes | Yes | Yes (E. faecium variable) | No | No (oral for C. diff) |
| Daptomycin | Yes | Yes | Yes | Yes (E. faecium variable) | Yes | No |
| Linezolid | Yes | Yes | Yes | Yes | Yes | No |
| Clindamycin | Yes | Some | Yes | No | No | No |
| Doxycycline | Yes | Some | Yes | Some | Some | No |
Gram-Negative Coverage
| Antibiotic | E. coli/Klebsiella | Pseudomonas | Anaerobes | ESBL-producing | Carbapenem-resistant |
|---|---|---|---|---|---|
| Ampicillin | Some | No | No | No | No |
| Amoxicillin-clavulanate | Some | No | Yes (some) | No | No |
| Cefazolin (1st gen) | Some | No | No | No | No |
| Ceftriaxone (3rd gen) | Yes | No | No | No | No |
| Cefepime (4th gen) | Yes | Yes | No | Some | No |
| Ceftazidime (3rd gen) | Yes | Yes | No | No | No |
| Ciprofloxacin | Yes | Yes | No | No | No |
| Gentamicin/tobramycin | Yes | Yes | No | Some | No |
| Piperacillin-tazobactam | Yes | Yes | Yes | Some | No |
| Meropenem | Yes | Yes | Yes | Yes | No |
| Ceftazidime-avibactam | Yes | Yes | No | Yes | Yes (KPC) |
| Colistin | Yes | Yes | No | Yes | Yes (last resort) |
Antibiotic Resistance Mechanisms
Biochemical Mechanisms
| Mechanism | Description | Examples |
|---|---|---|
| Beta-lactamase production | Enzymatic hydrolysis of beta-lactam ring | Penicillinase, TEM, SHV, CTX-M (ESBL), KPC, NDM, OXA-48 |
| Alteration of target site | Mutation or modification of antibiotic target | MRSA (mecA alters PBP2a), VRE (vanA/vanB alters D-Ala-D-Ala) |
| Decreased permeability | Reduced porin expression in gram-negative outer membrane | Pseudomonas (OprD loss decreases carbapenem entry) |
| Efflux pumps | Active extrusion of antibiotic from cell | Pseudomonas (MexAB-OprM), E. coli (AcrAB-TolC) |
| Ribosomal protection | Protein that displaces antibiotic from ribosome | Tetracycline resistance (tetM, tetO) |
| Target bypass | Alternative metabolic pathway | Trimethoprim resistance (alternative DHFR) |
| Drug modification/inactivation | Enzymatic modification of antibiotic | Aminoglycoside-modifying enzymes (acetyltransferase, phosphotransferase) |
Clinically Important Resistant Organisms
| Organism | Resistance Type | Resistance Mechanism | Treatment Options |
|---|---|---|---|
| MRSA (Methicillin-resistant S. aureus) | Beta-lactams (all) | mecA -> PBP2a (low affinity) | Vancomycin, daptomycin, linezolid, TMP-SMX, clindamycin |
| VRE (Vancomycin-resistant Enterococcus) | Vancomycin | vanA/vanB -> D-Ala-D-Lac | Linezolid, daptomycin, tigecycline, ampicillin (E. faecalis) |
| ESBL (Extended-spectrum beta-lactamase) | 3rd-gen cephalosporins (ceftriaxone, ceftazidime) | CTX-M, SHV, TEM variants | Carbapenems, ceftazidime-avibactam |
| KPC (Klebsiella pneumoniae carbapenemase) | Carbapenems | KPC (serine carbapenemase) | Ceftazidime-avibactam, meropenem-vaborbactam |
| NDM (New Delhi metallo-beta-lactamase) | Carbapenems (all beta-lactams except aztreonam) | NDM (metallo-beta-lactamase) | Tigecycline, colistin, aztreonam (if combined) |
| CRE (Carbapenem-resistant Enterobacteriaceae) | Carbapenems | Various (KPC, NDM, OXA-48) | Based on mechanism; often few options |
Antimicrobial Stewardship
| Strategy | Description | Examples |
|---|---|---|
| Prospective audit with feedback | Review antibiotic orders, recommend changes | ID pharmacist/microbiologist reviews after 48-72 hours |
| Formulary restriction | Limit use of broad-spectrum agents | Require ID approval for linezolid, carbapenems |
| De-escalation | Narrow spectrum based on culture results | Change piperacillin-tazobactam to cephalexin when culture shows MSSA |
| IV-to-oral conversion | Switch to oral when clinically appropriate | Sequential therapy: IV to oral fluoroquinolone or linezolid |
| Antibiotic timeout | Reassess at 48-72 hours: continue, change, or stop | Automatic stop orders |
| Dose optimization | PK/PD-based dosing for maximal efficacy | Extended-infusion beta-lactams, therapeutic drug monitoring of aminoglycosides |
| Duration optimization | Shortest effective duration | CAP: 5 days; UTI: 3-5 days; intra-abdominal: 4-7 days |
Empiric Antibiotic Selection
Common Infection Syndromes
| Infection | Common Pathogens | Empiric Regimen | Duration |
|---|---|---|---|
| Community-acquired pneumonia (CAP) | S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella | Amoxicillin (mild) or ceftriaxone + azithromycin (moderate-severe) | 5 days |
| Hospital-acquired pneumonia (HAP) | S. aureus (including MRSA), Pseudomonas, Enterobacteriaceae | Anti-pseudomonal beta-lactam (cefepime, piperacillin-tazobactam) +/- vancomycin or linezolid | 7 days |
| Urinary tract infection (uncomplicated) | E. coli (80%), S. saprophyticus, Klebsiella, Proteus | Nitrofurantoin, TMP-SMX, fosfomycin | 3-5 days |
| Urinary tract infection (complicated) | E. coli, Klebsiella, Proteus, Pseudomonas, Enterococcus | Ceftriaxone, ciprofloxacin, or piperacillin-tazobactam | 7-14 days |
| Intra-abdominal infection | E. coli, Bacteroides fragilis, other enterics, anaerobes | Ceftriaxone + metronidazole, piperacillin-tazobactam, or ertapenem | 4-7 days (if source controlled) |
| Skin and soft tissue (cellulitis) | S. aureus (MSSA), Streptococcus pyogenes | Cephalexin, clindamycin, or TMP-SMX (if MRSA concern) | 5-7 days |
| Skin and soft tissue (diabetic foot) | S. aureus, Streptococcus, gram-negatives, anaerobes | Variety based on severity; piperacillin-tazobactam, cefepime + metronidazole | 1-2 weeks after debridement |
| Meningitis (community-acquired) | S. pneumoniae, N. meningitidis, L. monocytogenes, S. agalactiae | Ceftriaxone + vancomycin + ampicillin (elderly/immunocompromised) | 7-21 days depending on pathogen |
| Bacteremia (primary) | Based on source | Broad spectrum until cultures | 7-14 days |
Prophylactic Antibiotics
| Indication | Timing | Agent | Duration |
|---|---|---|---|
| Surgical wound prophylaxis | Within 60 min before incision | Cefazolin (or vancomycin if MRSA concern) | Single dose (re-dose for prolonged surgery or major blood loss) |
| Dental procedures (endocarditis prophylaxis) | 30-60 min before procedure | Amoxicillin 2 g PO | Single dose |
| Recurrent UTI prophylaxis | Post-coital or daily | Nitrofurantoin, TMP-SMX | 6-12 months |
| Splenectomy | Lifelong | Penicillin VK or amoxicillin | Daily prophylaxis; also vaccinate |
| HIV with CD4 <200 | Primary prophylaxis for PCP | TMP-SMX | Until CD4 >200 |
Adverse Effects of Antibiotics
| Class | Common Adverse Effects | Serious Adverse Effects |
|---|---|---|
| Penicillins | Rash, diarrhea, nausea | Anaphylaxis, C. difficile colitis, drug fever |
| Cephalosporins | Diarrhea, rash, nausea | Anaphylaxis (cross-reactivity ~5-10% with penicillins), C. difficile, seizures (cefepime) |
| Carbapenems | Nausea, diarrhea, rash | Seizures (imipenem), C. difficile, anaphylaxis |
| Fluoroquinolones | GI upset, headache, dizziness | Tendonitis/tendon rupture, QT prolongation, dysglycemia, C. difficile, aortic dissection (rare), CNS effects |
| Macrolides | GI upset (especially erythromycin), prolonged QT | QT prolongation/TdP (erythromycin, clarithromycin), hearing loss |
| Aminoglycosides | Nephrotoxicity, ototoxicity (irreversible), vestibular toxicity | Acute kidney injury, hearing loss, vestibular dysfunction |
| Tetracyclines | GI upset, photosensitivity, esophageal ulceration | Hepatotoxicity (high dose), teeth discoloration (children), pancreatitis |
| Vancomycin | Red man syndrome (infusion reaction), phlebitis | Nephrotoxicity (especially with concurrent nephrotoxins), neutropenia |
| Metronidazole | Metallic taste, nausea | Peripheral neuropathy (prolonged use), disulfiram-like reaction with alcohol |
| TMP-SMX | Rash, GI upset, hyperkalemia | Stevens-Johnson syndrome, TEN, agranulocytosis, hepatitis, nephritis |
Conclusion
Antibiotics are essential therapeutic agents that require careful selection based on suspected or confirmed pathogens, local resistance patterns, infection site pharmacokinetics, and patient factors. Antimicrobial resistance is a critical threat requiring robust stewardship programs, appropriate diagnostic testing, antibiotic restriction policies, and development of novel agents. Optimal antibiotic use balances efficacy against individual patients with preservation of antibiotic effectiveness for future patients.