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Explain every drug in anti microbial in detail along with reasons , explanations and clinical correlation

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I now have rich content from Goodman & Gilman's across all major antimicrobial classes. Let me now write the comprehensive answer.

Complete Guide to Antimicrobial Drugs

Based on Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14e, and Katzung's Basic & Clinical Pharmacology, 16e.

Overview: Classification of Antimicrobial Agents

Antimicrobials work by exploiting structural and metabolic differences between microbes and human cells. The main targets are:
  1. Cell wall synthesis - unique to bacteria (no equivalent in humans)
  2. Protein synthesis - bacterial ribosomes (70S) differ from human (80S)
  3. DNA/RNA synthesis - selective inhibition of bacterial enzymes
  4. Cell membrane integrity - targeting bacterial membrane composition
  5. Metabolic pathways - blocking folate synthesis (sulfonamides)

CLASS 1: BETA-LACTAMS

1A. PENICILLINS

Mechanism of Action
Beta-lactams bind covalently to penicillin-binding proteins (PBPs) - transpeptidase enzymes that cross-link peptidoglycan strands during cell wall synthesis. Inhibition causes accumulation of unlinked peptidoglycan precursors, activates autolytic enzymes, and leads to cell lysis and death. This mechanism is bactericidal.
Why it works on bacteria but not humans: Human cells have no cell wall or PBPs. This makes beta-lactams among the safest antibiotic classes.
Penicillin G (Benzylpenicillin) and Penicillin V
Spectrum:
  • Most streptococci (Group A, B, viridans, S. pneumoniae - though resistance is rising)
  • Neisseria meningitidis (remains very susceptible)
  • Anaerobic gram-positive bacteria (Clostridium spp.)
  • Spirochetes: Treponema pallidum (syphilis), Borrelia burgdorferi (Lyme disease), Leptospira spp.
  • Actinomyces israelii
  • NOT effective against amebae, plasmodia, rickettsiae, fungi, or viruses
Resistance: >90% of S. aureus and most S. epidermidis are now resistant via beta-lactamase production (breaks the beta-lactam ring).
ADME:
  • Penicillin V is acid-stable - preferred for oral use; better GI absorption
  • Penicillin G is acid-labile - used parenterally
  • Peak levels in 30-60 min orally; 15-30 min after IM injection
  • ~60% albumin-bound; distributed widely including bile, kidney, joint fluid
  • Poor CSF penetration normally, but penetrates with inflamed meninges
  • t½ ~30 min; eliminated by renal tubular secretion
  • Repository forms: Benzathine penicillin G - very long duration (~26 days of detectable antimicrobial activity); Procaine penicillin G - intermediate duration
Clinical Correlation:
  • Syphilis: Benzathine penicillin G 2.4 million units IM single dose (primary/secondary); 3 weekly doses for latent/tertiary
  • Streptococcal pharyngitis: Penicillin V orally 10 days
  • Meningococcal meningitis: High-dose IV penicillin G (when sensitive)
  • Rheumatic fever prophylaxis: Monthly benzathine penicillin G injections
  • Probenecid blocks renal tubular secretion of penicillin, increasing and prolonging plasma levels - used clinically when higher levels are desired

Anti-Staphylococcal Penicillins: NAFCILLIN, OXACILLIN, DICLOXACILLIN

Mechanism: Penicillinase-resistant penicillins - modified side chains resist beta-lactamase hydrolysis. Same PBP-binding mechanism.
Spectrum: Narrow - primarily S. aureus (MSSA) and streptococci. NOT effective against MRSA (resistance here is due to altered PBP2a encoded by mecA gene, not beta-lactamase).
Clinical Correlation:
  • Drug of choice for MSSA bacteremia, osteomyelitis, septic arthritis, and endocarditis
  • If patient is MRSA - switch to vancomycin or daptomycin

Extended-Spectrum Penicillins: AMPICILLIN, AMOXICILLIN

Spectrum adds: Gram-negative coverage - Haemophilus influenzae, E. coli, Proteus mirabilis, Salmonella, Shigella, Listeria monocytogenes, Enterococcus
ADME: Amoxicillin has better oral absorption than ampicillin (food does not interfere)
Clinical Correlation:
  • Amoxicillin: community sinusitis/otitis media/pneumonia (H. influenzae), UTIs, H. pylori regimens
  • Ampicillin IV: Listeria meningitis (important - cephalosporins do NOT cover Listeria)
  • Amoxicillin-clavulanate (Augmentin): adds clavulanate (beta-lactamase inhibitor) for resistant strains, animal bite wounds, diabetic foot infections

Anti-Pseudomonal Penicillins: PIPERACILLIN-TAZOBACTAM, TICARCILLIN

Spectrum adds: Pseudomonas aeruginosa, expanded gram-negative coverage
Clinical Correlation:
  • Pip-tazo is a first-line empiric agent for hospital-acquired pneumonia, febrile neutropenia, intra-abdominal infections, complicated UTIs
  • "Pip-tazo syndrome" - electrolyte wasting (hypokalemia) with high-dose therapy

Beta-Lactamase Inhibitors: CLAVULANATE, SULBACTAM, TAZOBACTAM, AVIBACTAM

These have weak intrinsic antibacterial activity but irreversibly bind and inactivate beta-lactamases, restoring efficacy of partner beta-lactam. Used only in combination.

1B. CEPHALOSPORINS

Same mechanism as penicillins (PBP binding), but the beta-lactam ring is fused to a 6-membered dihydrothiazine ring (vs. 5-membered thiazolidine in penicillins), making them more resistant to many beta-lactamases.
Generational Classification:
GenerationKey DrugsSpectrum
1stCefazolin (IV), Cephalexin (PO), CefadroxilGram-positives (strep, MSSA), some E. coli, Klebsiella, Proteus
2ndCefuroxime, Cefprozil, Cefoxitin, CefotetanLess gram-positive, more gram-negative (H. influenzae, Moraxella); Cefoxitin/cefotetan add Bacteroides fragilis
3rdCeftriaxone, Cefotaxime, Cefdinir, CefpodoximeBroad gram-negative (Citrobacter, Enterobacter, Serratia, Neisseria), CSF penetration
Anti-PseudomonalCeftazidime, CefepimeAdd Pseudomonas aeruginosa
5thCeftarolineExtends to MRSA (binds PBP2a)
NovelCeftazidime/avibactam, CefiderocolCarbapenem-resistant Enterobacterales (CRE), KPC, NDM
Key Rules to Remember:
  • No cephalosporin covers Enterococcus or Listeria - critical clinical pitfall
  • No cephalosporin covers MRSA (except ceftaroline)
  • 3rd gen cephalosporins penetrate CSF well - useful for bacterial meningitis
  • Cefazolin is the standard surgical prophylaxis agent
Clinical Correlations:
  • Bacterial meningitis: Ceftriaxone 2g IV q12h (covers S. pneumoniae, N. meningitidis, H. influenzae)
  • Community pneumonia (hospitalized): Ceftriaxone + azithromycin
  • Gonorrhea: Ceftriaxone 500mg IM single dose (resistance to older options has driven this)
  • Surgical prophylaxis: Cefazolin (1st gen - gram-positive skin flora)
  • Septic arthritis/osteomyelitis: Ceftriaxone for gram-negatives
  • Cross-reactivity with penicillin allergy: low risk (~1-2%); safe to use in patients with minor penicillin reactions

1C. CARBAPENEMS: IMIPENEM, MEROPENEM, ERTAPENEM, DORIPENEM

Mechanism: Same as penicillins, but broadest spectrum of any beta-lactam class. Resistant to most beta-lactamases including extended-spectrum beta-lactamases (ESBLs).
Spectrum: Covers virtually everything:
  • Gram-positives including streptococci, S. aureus (MSSA)
  • Gram-negatives including Pseudomonas (not ertapenem), Enterobacterales, H. influenzae
  • Anaerobes including Bacteroides fragilis
  • ESBL-producing organisms
Does NOT cover: MRSA, Enterococcus faecium, Stenotrophomonas maltophilia (intrinsically resistant), C. difficile
Imipenem is combined with cilastatin - an inhibitor of renal dehydropeptidase-I, which would otherwise hydrolyze imipenem in renal tubules.
Notable ADR: Imipenem lowers seizure threshold - use meropenem for CNS infections.
Clinical Correlation:
  • Reserved for serious infections with resistant organisms (ESBL producers, complicated intra-abdominal sepsis)
  • Carbapenem-resistant organisms (CRE with KPC, NDM) are now a major global threat - treated with ceftazidime/avibactam or colistin

1D. MONOBACTAMS: AZTREONAM

Spectrum: Only gram-negative aerobes (including Pseudomonas). No gram-positive or anaerobic activity.
Key advantage: Safe in penicillin-allergic patients (no cross-reactivity with penicillin except caution with ceftazidime due to shared side chain).
Clinical Correlation:
  • Used when aminoglycosides would be too toxic for serious gram-negative infections in penicillin-allergic patients

CLASS 2: GLYCOPEPTIDES

VANCOMYCIN

Mechanism: Vancomycin is a large glycopeptide that binds to the D-Ala-D-Ala terminus of peptidoglycan precursors (lipid II). This physically blocks transglycosylation and transpeptidation - it does not bind PBPs directly. Because of its size, it cannot penetrate gram-negative outer membranes, explaining its gram-positive only spectrum.
Spectrum: Gram-positive organisms only:
  • MRSA (primary use)
  • Coagulase-negative staphylococci
  • Enterococcus (except VRE)
  • S. pneumoniae (including penicillin-resistant)
  • C. difficile (oral vancomycin, not absorbed)
Resistance: Vancomycin-resistant Enterococcus (VRE) - caused by altered terminal D-Ala-D-Lac instead of D-Ala-D-Ala, drastically reducing binding affinity. The VanA and VanB operons encode this modification.
ADME:
  • Poorly absorbed orally - IV required for systemic infections; oral used specifically for C. difficile colitis (acts locally)
  • Eliminated renally - dose adjustment required for renal impairment
  • TDM (therapeutic drug monitoring) required - target AUC/MIC ≥400 for serious MRSA infections
Adverse Effects:
  • Nephrotoxicity - dose-dependent; monitor creatinine; combination with aminoglycosides increases risk
  • "Red Man Syndrome" - not a true allergy; histamine release due to rapid infusion; causes flushing, erythema of face/neck/trunk, hypotension. Prevented by slowing infusion rate and pre-treating with antihistamines
  • Ototoxicity (less common with modern dosing)
Clinical Correlations:
  • Drug of choice for MRSA bacteremia, endocarditis, osteomyelitis, meningitis
  • Oral vancomycin for severe/fulminant C. difficile colitis
  • Surgical prophylaxis in beta-lactam-allergic patients or when MRSA risk is high

TEICOPLANIN, TELAVANCIN, DALBAVANCIN, ORITAVANCIN

These are newer glycopeptides or lipoglycopeptides with longer half-lives. Dalbavancin and oritavancin offer once-weekly dosing - major advantage for outpatient treatment of bone and joint infections.

CLASS 3: PROTEIN SYNTHESIS INHIBITORS

3A. AMINOGLYCOSIDES

Drugs: Gentamicin, Tobramycin, Amikacin, Streptomycin, Neomycin, Paromomycin, Plazomicin
Mechanism: Aminoglycosides are polycationic compounds that:
  1. Bind to the 30S ribosomal subunit (specifically the 16S rRNA of the 30S subunit, at the A-site decoding region)
  2. Cause misreading of mRNA - wrong amino acids are incorporated
  3. Produce abnormal proteins that insert into the bacterial cell membrane, causing permeability changes
  4. These permeability changes allow more aminoglycoside to enter - this "self-potentiation" is why aminoglycosides are concentration-dependent bactericidal agents
Why they require oxygen for uptake: Aminoglycosides rely on the bacterial electron transport chain (proton-motive force) for active transport into the cell. This is why they are inactive against anaerobes - anaerobes have no electron transport chain.
Spectrum: Aerobic gram-negative bacteria (E. coli, Klebsiella, Pseudomonas, Enterobacter, Serratia); also used in combination for Enterococcus endocarditis and mycobacterial infections
ADME:
  • Not absorbed orally (<1% oral bioavailability) - must be given parenterally for systemic infections
  • Poor CSF penetration even with inflamed meninges
  • Eliminated by kidney; accumulate in renal cortex and inner ear
  • Concentration-dependent killing - once-daily dosing now preferred for most indications (maximizes peak/MIC ratio while reducing toxicity)
Adverse Effects:
  • Nephrotoxicity: Accumulates in proximal tubular cells, causing tubular necrosis. Risk increased by dehydration, concurrent NSAIDs, amphotericin, vancomycin, cisplatin. Usually reversible if caught early.
  • Ototoxicity: Damages outer hair cells of cochlea (cochleotoxicity - high-frequency hearing loss first) and vestibular apparatus. Streptomycin causes more vestibular than cochlear toxicity. Ototoxicity may be irreversible.
  • Neuromuscular blockade: Can cause respiratory paralysis, especially with concurrent neuromuscular blocking agents, myasthenia gravis, or hypocalcemia. Reversed by calcium gluconate.
Resistance mechanisms:
  1. Aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases) - most common
  2. Efflux pumps
  3. Decreased permeability
Clinical Correlations:
  • Enterococcal endocarditis: Gentamicin + penicillin/ampicillin (synergistic killing; cell wall agent allows aminoglycoside entry)
  • Hospital-acquired pneumonia: Empiric combination with beta-lactam to cover P. aeruginosa
  • Serious gram-negative sepsis: IV gentamicin/tobramycin/amikacin
  • TB: Streptomycin or amikacin in MDR-TB regimens
  • Neomycin oral: Bowel decontamination pre-surgery; NOT used systemically due to extreme nephrotoxicity
  • Paromomycin: Intestinal amebiasis, cryptosporidiosis, visceral leishmaniasis
  • Plazomicin: Complicated UTI including pyelonephritis when limited options exist (FDA-approved)
  • Tobramycin inhaled: chronic Pseudomonas suppression in cystic fibrosis

3B. TETRACYCLINES

Drugs: Tetracycline, Doxycycline, Minocycline, Tigecycline (glycylcycline), Eravacycline, Omadacycline
Mechanism: Bind reversibly to the 30S ribosomal subunit, blocking binding of aminoacyl-tRNA to the A-site. This prevents elongation of the peptide chain. Bacteriostatic.
Spectrum: Broad - gram-positives, gram-negatives, but most importantly:
  • Intracellular pathogens: Chlamydia, Mycoplasma, Rickettsia, Coxiella (Q fever), Brucella, Ehrlichia
  • Spirochetes: Borrelia (Lyme disease), Treponema pallidum
  • Unusual organisms: Vibrio cholerae, Yersinia pestis (plague), Francisella tularensis (tularemia), Bartonella
  • Also active vs. MRSA (doxycycline, minocycline)
ADME:
  • Oral absorption ranges ~33% (omadacycline) to ~90% (doxycycline, minocycline)
  • Chelation: Divalent/trivalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺/³⁺, Zn²⁺) chelate tetracyclines and impair absorption. Avoid dairy products, antacids, iron supplements within 2-4 hours. Doxycycline and minocycline are less affected.
  • Distributed widely including urine, prostate, reticuloendothelial cells, bone, teeth
  • Cross placenta and enter breast milk - contraindicated in pregnancy and children <8 years
  • Doxycycline and minocycline excreted hepatically - safe in renal failure (unlike tetracycline)
  • t½: 6-12 h for most agents
Adverse Effects:
  • GI disturbances: Nausea, vomiting, diarrhea, esophageal ulceration (take with plenty of water, remain upright)
  • Photosensitivity: Especially doxycycline
  • Teeth and bone: Permanent yellow-grey discoloration and enamel hypoplasia in developing teeth; bone growth inhibition. Contraindicated in children <8 years and pregnancy (2nd/3rd trimester)
  • Pseudotumor cerebri: Benign intracranial hypertension (rare; particularly minocycline)
  • Vestibular toxicity: Dizziness, vertigo with minocycline
  • Hepatotoxicity: Fatty liver, especially with IV use in pregnancy
  • Tigecycline-specific: FDA black-box warning - pooled clinical trials showed small but statistically significant increased mortality vs. comparators; avoid as monotherapy for serious infections
Resistance:
  • Efflux pumps (TetA-TetE) exporting drug from bacteria
  • Ribosomal protection proteins (TetM, TetO)
  • Enzymatic inactivation (tigecycline largely overcomes TetA-TetE)
Clinical Correlations:
  • Chlamydia trachomatis (non-LGV): Doxycycline 100mg PO BID × 7 days (first-line)
  • Lyme disease: Doxycycline 100mg BID × 14-21 days (early Lyme, not in pregnancy)
  • Rocky Mountain Spotted Fever (RMSF)/Rickettsia: Doxycycline - drug of choice in all ages including children (benefit outweighs teeth risk in life-threatening RMSF)
  • Community-acquired pneumonia (Mycoplasma, Chlamydophila pneumoniae): Doxycycline alternative
  • MRSA skin infections: Doxycycline or trimethoprim-sulfamethoxazole
  • Brucellosis: Doxycycline + rifampicin (6 weeks)
  • Cholera: Single-dose doxycycline reduces severity
  • Malaria prophylaxis: Doxycycline 100mg daily

3C. MACROLIDES AND RELATED AGENTS

Drugs: Erythromycin, Azithromycin, Clarithromycin; Clindamycin (lincosamide); Streptogramins (quinupristin-dalfopristin)
Mechanism: Bind to the 50S ribosomal subunit (23S rRNA, domain V), blocking translocation of the ribosome along the mRNA. Bacteriostatic for most organisms.
Azithromycin vs. Clarithromycin vs. Erythromycin:
  • Erythromycin: prototype; significant drug interactions (CYP3A4 inhibitor); GI adverse effects prominent (prokinetic via motilin receptor activation)
  • Azithromycin: better tolerated; concentrates in tissues (t½ ~68 h); once-daily dosing; long post-antibiotic effect
  • Clarithromycin: best CNS/intracellular penetration; active vs. H. pylori and MAC; strongest CYP3A4 inhibitor of the three
Spectrum:
  • Gram-positive cocci (streptococci, S. aureus - though resistance common)
  • Atypical pneumonia organisms: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila
  • H. pylori (clarithromycin triple therapy)
  • Non-tuberculous mycobacteria (MAC)
  • Bordetella pertussis (whooping cough - azithromycin preferred)
  • Campylobacter (azithromycin)
Drug Interactions (Erythromycin/Clarithromycin):
  • Strong CYP3A4 inhibitors - increase levels of statins (rhabdomyolysis risk), warfarin (bleeding), cyclosporine (nephrotoxicity), QT-prolonging drugs
  • QT prolongation itself - especially erythromycin IV
Resistance:
  • Methylation of 23S rRNA (MLSB resistance - confers cross-resistance to macrolides, lincosamides, streptogramins B)
  • Efflux pumps (mefA gene - M phenotype; affects only macrolides)
Clinical Correlations:
  • Community-acquired pneumonia: Azithromycin (outpatient, low severity)
  • Legionella pneumonia: Azithromycin (first-line) or fluoroquinolone
  • H. pylori eradication: PPI + clarithromycin + amoxicillin (triple therapy)
  • MAC prophylaxis in HIV/AIDS (CD4 <50): Azithromycin 1200mg weekly
  • Pertussis (whooping cough): Azithromycin - reduces infectivity, shortens illness if given early
  • Chlamydia (urethritis/cervicitis): Azithromycin 1g single dose (alternative to doxycycline)

CLINDAMYCIN

Mechanism: Lincosamide - binds 50S ribosomal subunit at same site as macrolides. Bacteriostatic; bactericidal against some anaerobes.
Spectrum: Gram-positive cocci (streptococci, MSSA, some MRSA); excellent anaerobic coverage especially above the diaphragm (Bacteroides fragilis often resistant)
Adverse Effects:
  • C. difficile-associated diarrhea/pseudomembranous colitis - historically the antibiotic most commonly linked to C. difficile (though any antibiotic can cause it). Due to disruption of colonic flora.
  • Skin rashes (~10%)
  • Elevated liver enzymes
Clinical Correlations:
  • Aspiration pneumonia/lung abscess: Clindamycin (excellent anaerobic coverage above diaphragm)
  • Toxin suppression in necrotizing fasciitis/streptococcal toxic shock: Clindamycin added to beta-lactam (inhibits ribosomal protein synthesis, reducing toxin/exotoxin production even if bacteriostatic)
  • MRSA skin/soft-tissue infections: Clindamycin (check D-zone test for inducible resistance)
  • Bacterial vaginosis: Clindamycin cream topically
  • Malaria: Combination with quinine for severe P. falciparum (especially in pregnancy)
  • Toxoplasma encephalitis (sulfa-allergic patients): Clindamycin + pyrimethamine

3D. OXAZOLIDINONES

Drugs: Linezolid, Tedizolid
Mechanism: Unique and distinct from other protein synthesis inhibitors. Bind to the P-site of the 50S ribosomal subunit and prevent formation of the 70S initiation complex (the 50S + 30S + fMet-tRNA complex that starts translation). This prevents initiation of protein synthesis entirely, not elongation or translocation. Because the mechanism is unique, there is no cross-resistance with other antibiotics.
Spectrum: Primarily gram-positive:
  • MRSA, VISA, VRSA
  • VRE (vancomycin-resistant Enterococcus) - one of few options
  • Penicillin-resistant S. pneumoniae
  • Gram-positive anaerobes, Nocardia, Listeria
  • Moderate activity vs. Mycobacterium tuberculosis (used in XDR-TB)
Bacteriostatic against staphylococci and enterococci; bactericidal against streptococci.
ADME:
  • 100% oral bioavailability - same dose IV and PO (rare for antibiotics)
  • t½ ~4-6 h; 30% protein-bound
  • Good CNS penetration
  • Nonenzymatic oxidation - no significant CYP interactions for linezolid itself, but...
Drug Interactions - Important:
  • MAO inhibition: Linezolid is a reversible, non-selective MAO inhibitor. Concurrent use with SSRIs, SNRIs, TCAs, or sympathomimetics risks serotonin syndrome (hyperthermia, agitation, clonus, autonomic instability) or hypertensive crisis (with tyramine-rich foods, pressor agents). Contraindicated with serotonergic drugs.
Adverse Effects:
  • Myelosuppression: Thrombocytopenia, anemia, neutropenia - especially with >2 weeks therapy; monitor CBC weekly
  • Peripheral/optic neuropathy: With prolonged use (>28 days); optic neuropathy may lead to irreversible vision loss
  • Lactic acidosis (rare; mitochondrial ribosome inhibition)
Clinical Correlations:
  • Drug of choice for VRE infections (vancomycin-resistant Enterococcus)
  • Alternative for MRSA when vancomycin cannot be used
  • XDR-TB regimens (BPaL regimen)
  • Advantages in CNS infections due to excellent penetration

CLASS 4: FLUOROQUINOLONES

Drugs: Ciprofloxacin, Levofloxacin, Moxifloxacin, Delafloxacin; (older: norfloxacin, ofloxacin)
Mechanism: Inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV:
  • DNA gyrase (target A subunit/GyrA) - removes positive supercoils ahead of the replication fork
  • Topoisomerase IV (target ParC subunit) - involved in decatenation of daughter chromosomes after replication
Fluoroquinolones stabilize the enzyme-DNA cleavage complex, preventing religation, causing double-strand DNA breaks. Bactericidal and concentration-dependent.
Why selective: Human topoisomerase II has ~100-fold lower affinity for fluoroquinolones.
Spectrum:
  • Ciprofloxacin: excellent gram-negative (E. coli, Pseudomonas aeruginosa - the only oral anti-pseudomonal), Enterobacterales, Neisseria, atypicals; relatively weak gram-positive
  • Levofloxacin: broad including gram-positives (S. pneumoniae), atypicals, legionella, some Pseudomonas
  • Moxifloxacin: excellent gram-positive and anaerobic coverage but NO anti-pseudomonal activity; no urinary excretion (not for UTI)
ADME:
  • Excellent oral bioavailability (~70-100%) - oral and IV doses equivalent
  • Widely distributed including CSF, prostate, bone, lung
  • Renal excretion (except moxifloxacin which is hepatically metabolized)
  • Chelation with divalent cations - do not co-administer with antacids, sucralfate, iron, dairy (2h separation)
Adverse Effects:
  • Tendinopathy and tendon rupture: Especially Achilles tendon. Risk increased in elderly, concurrent corticosteroids, renal failure. Mechanism: fluoroquinolones inhibit tenocyte metabolism. Black-box warning. Discontinue at first sign of tendon pain.
  • QT prolongation: Risk of torsades de pointes - avoid with other QT-prolonging drugs
  • CNS effects: Seizures, confusion, insomnia, headache; lower threshold in elderly/renal impairment; contraindicated with NSAIDs (synergistic seizure risk via GABA-A receptor antagonism)
  • Peripheral neuropathy: May be permanent; black-box warning
  • Cartilage damage in animal models: Hence avoided in children and pregnancy (though evidence in humans is limited)
  • Phototoxicity: Especially sparfloxacin (withdrawn)
  • Glucose dysregulation: Hypoglycemia with concurrent sulfonylureas
Resistance:
  • Point mutations in gyrA/parC genes (most common)
  • Efflux pumps
  • Plasmid-mediated quinolone resistance (PMQR - qnr genes, aac(6')-Ib-cr)
Clinical Correlations:
  • Complicated UTI/pyelonephritis: Ciprofloxacin - drug of choice if susceptible (but check local resistance rates for E. coli)
  • Pseudomonas infections: Ciprofloxacin is the ONLY oral anti-pseudomonal
  • Traveler's diarrhea: Ciprofloxacin (though azithromycin now preferred in areas with quinolone-resistant Campylobacter)
  • Community-acquired pneumonia: Levofloxacin or moxifloxacin ("respiratory quinolones") - cover S. pneumoniae, atypicals, legionella
  • Anthrax (Bacillus anthracis): Ciprofloxacin - drug of choice for inhalational anthrax
  • Tuberculosis: Levofloxacin or moxifloxacin in MDR-TB regimens (Group A drugs in WHO 2022 guidelines)
  • Neisseria gonorrhoeae: No longer first-line due to widespread fluoroquinolone resistance

CLASS 5: SULFONAMIDES AND TRIMETHOPRIM

Drugs: Sulfamethoxazole (SMX), Sulfadiazine, Sulfadoxine; Trimethoprim (TMP); TMP-SMX (co-trimoxazole, Bactrim)
Mechanism - Sequential Folate Blockade:
Bacteria must synthesize their own folic acid (they cannot import folate from the environment, unlike human cells which obtain folate exogenously from diet).
  • Sulfonamides: Structural analogs of para-aminobenzoic acid (PABA). Competitively inhibit dihydropteroate synthase (DHPS) - the enzyme that incorporates PABA into dihydropteroic acid (step toward tetrahydrofolate).
  • Trimethoprim: Selectively inhibits bacterial dihydrofolate reductase (DHFR), which reduces dihydrofolate (DHF) to tetrahydrofolate (THF). TMP has ~50,000-fold greater affinity for bacterial DHFR vs. human DHFR.
  • Combined (TMP-SMX): Sequential blockade at two steps in the folate pathway produces synergistic bactericidal action.
Tetrahydrofolate is required for synthesis of purines and thymidine - without it, DNA synthesis stops.
Spectrum of TMP-SMX:
  • E. coli, Klebsiella, Proteus, H. influenzae (if susceptible)
  • S. aureus including MRSA
  • S. pneumoniae, Listeria monocytogenes
  • Stenotrophomonas maltophilia (TMP-SMX is drug of choice)
  • Pneumocystis jirovecii - PCP pneumonia
  • Nocardia
  • Toxoplasma (prophylaxis and treatment)
ADME:
  • Good oral absorption; widely distributed including CSF
  • SMX t½ ~10-12 h; TMP t½ ~10-12 h (matched to maintain optimal ratio)
  • Renal elimination; dose reduction in renal impairment
Adverse Effects:
  • Hypersensitivity reactions: Rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis - especially sulfonamide component; risk markedly higher in HIV patients
  • Hematologic: Megaloblastic anemia (folate deficiency effect), agranulocytosis, thrombocytopenia - worse in folate-deficient patients
  • Kernicterus: Displacement of bilirubin from albumin - avoid in neonates and late pregnancy
  • Nephrotoxicity: Crystalluria with older sulfonamides; trimethoprim competitively inhibits creatinine secretion (falsely elevated serum creatinine without true renal impairment)
  • Hyperkalemia: Trimethoprim blocks renal potassium excretion (amiloride-like effect); monitor K⁺
  • Drug interactions: TMP increases warfarin effect (inhibits its metabolism), increases methotrexate toxicity
Clinical Correlations:
  • PCP (Pneumocystis jirovecii) pneumonia: TMP-SMX is drug of choice (treatment and prophylaxis); give with corticosteroids if PaO₂ <70 mmHg
  • MRSA skin/soft-tissue infections (community-acquired): TMP-SMX - effective and inexpensive
  • Nocardiosis: TMP-SMX (or sulfonamide alone)
  • Toxoplasma prophylaxis in HIV (CD4 <200): TMP-SMX DS daily (also covers PCP)
  • Stenotrophomonas maltophilia: TMP-SMX is drug of choice (intrinsically resistant to carbapenems)
  • Urinary tract infections: TMP-SMX (but check local E. coli resistance rates; >20% resistance in many regions)
  • Traveler's diarrhea: No longer preferred (Shigella and E. coli resistance common)

CLASS 6: CELL MEMBRANE-DISRUPTING AGENTS

POLYMYXINS: COLISTIN (POLYMYXIN E), POLYMYXIN B

Mechanism: Polymyxins are cyclic polypeptides with both hydrophilic and hydrophobic regions. They act like detergents on the bacterial outer membrane:
  1. Displace calcium and magnesium from negatively charged lipopolysaccharide (LPS) phosphate groups
  2. Insert hydrophobic tails into the outer membrane
  3. Disrupt membrane integrity, causing leakage of intracellular contents and cell death
Bactericidal, concentration-dependent.
Spectrum: Gram-negative only:
  • Pseudomonas aeruginosa (including multidrug-resistant strains)
  • Acinetobacter baumannii (including carbapenem-resistant)
  • E. coli, Klebsiella
  • NOT Proteus, Serratia, Burkholderia (intrinsically resistant)
ADME:
  • Colistin (polymyxin E) is administered as a prodrug, colistimethate sodium (CMS), which is hydrolyzed to active colistin
  • Complex pharmacokinetics; both renal and non-renal elimination
  • Poor CNS penetration (intrathecal use sometimes needed)
  • Polymyxin B: renally eliminated, does NOT achieve high urinary levels - not suitable for UTI
Adverse Effects:
  • Nephrotoxicity: Major dose-limiting toxicity; acute tubular necrosis; occurs in ~30-50% of patients. Monitor closely.
  • Neurotoxicity: Paresthesias, dizziness, neuromuscular blockade; respiratory failure possible
  • Nephrotoxicity limits their use to last-resort scenarios
Clinical Correlations:
  • Last-resort agents for carbapenem-resistant Acinetobacter baumannii (CRAB) and CRE
  • Inhaled colistin: prevention of Pseudomonas exacerbations in cystic fibrosis
  • Often combined with other agents (rifampicin, meropenem) for synergy against pandrug-resistant organisms
  • Polymyxin B is preferred when patient is not dependent on urinary levels

DAPTOMYCIN

Mechanism: Cyclic lipopeptide antibiotic. Inserts its lipophilic tail into the gram-positive bacterial cell membrane in a calcium-dependent manner, causing rapid membrane depolarization and loss of membrane potential. This leads to inhibition of DNA, RNA, and protein synthesis and cell death. Bactericidal, concentration-dependent.
Spectrum: Gram-positive only - MRSA, VRSA, VRE, streptococci, enterococci (including resistant strains)
ADME:
  • Only IV; t½ ~8-9 h; once-daily dosing
  • ~80% renal elimination; dose every 48h if CrCl <30 mL/min
  • Inactivated by pulmonary surfactant - cannot be used for pneumonia
Adverse Effects:
  • Myopathy/CPK elevation: Monitor CPK weekly; discontinue if >10× ULN or symptomatic myopathy
  • Rhabdomyolysis (rare)
  • Eosinophilic pneumonia (rare)
  • Caution with statins (increased myopathy risk) and aminoglycosides (increased nephrotoxicity)
Clinical Correlations:
  • MRSA bacteremia and right-sided endocarditis: Daptomycin as effective as vancomycin (non-inferior in trials); often used when vancomycin MIC is elevated ("MIC creep") or patient intolerant of vancomycin
  • VRE infections: Daptomycin + ampicillin (synergistic combination)
  • Complicated skin and soft-tissue infections (gram-positive): FDA-approved indication
  • Do NOT use for pneumonia (inactivated by surfactant)

CLASS 7: ANTI-TUBERCULOSIS DRUGS

First-Line: ISONIAZID (INH), RIFAMPICIN (RIF), PYRAZINAMIDE (PZA), ETHAMBUTOL (EMB)

Isoniazid (INH):
  • Mechanism: Prodrug activated by mycobacterial catalase-peroxidase (KatG). Active form inhibits InhA (enoyl-ACP reductase) in the type II fatty acid synthesis pathway, blocking synthesis of mycolic acids - essential components of the mycobacterial cell wall.
  • Bactericidal for rapidly dividing mycobacteria; bacteriostatic for slowly dividing
  • Resistance: most commonly by katG mutations (preventing activation) or inhA promoter mutations
  • Adverse effects: Peripheral neuropathy (prevented by pyridoxine/Vitamin B6 supplementation - especially in diabetics, alcoholics, pregnant, malnourished); hepatotoxicity; drug-induced lupus; CNS effects
  • Interactions: Potent inhibitor of CYP2C9, 2C19 - increases levels of phenytoin, warfarin, carbamazepine
  • Clinical: Part of all standard TB regimens; also used for latent TB (LTBI) 9-month course
Rifampicin (RIF) / Rifampin:
  • Mechanism: Inhibits bacterial DNA-dependent RNA polymerase (specifically binds the beta subunit, encoded by rpoB), blocking transcription. Does NOT inhibit human RNA polymerase.
  • Potent bactericidal - sterilizing activity against all metabolic states of mycobacteria
  • Resistance: Mutations in rpoB gene (>95% of rifampicin-resistant TB); rapid single-step resistance if used as monotherapy
  • Adverse effects: Hepatotoxicity; flu-like syndrome (with intermittent dosing); red-orange discoloration of body fluids (urine, tears, sweat, saliva) - warn patients; thrombocytopenia
  • Interactions: Most potent inducer of CYP450 enzymes (CYP3A4, 2C9, 2C19, 1A2, 2B6) - dramatically reduces levels of oral contraceptives (contraception failure), antiretrovirals, methadone, warfarin, steroids, many others. This is one of the most clinically significant drug interactions in medicine.
  • Clinical: Core component of all TB regimens; also used for meningococcal prophylaxis, leprosy (MDT), Staphylococcal prosthetic valve endocarditis (always combine - never monotherapy)
Pyrazinamide (PZA):
  • Mechanism: Prodrug converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase/nicotinamidase (pncA). Pyrazinoic acid disrupts membrane energy metabolism and mycobacterial membrane transport
  • Active specifically against slowly dividing or dormant bacilli in acidic environments (within macrophage phagolysosomes)
  • Allows 6-month vs. 9-month course - shortens therapy from 9 to 6 months
  • Adverse effects: Hepatotoxicity (most common dose-limiting toxicity); hyperuricemia (inhibits renal uric acid excretion) - can precipitate gout; arthralgia; GI disturbance
  • Resistance: pncA mutations
Ethambutol (EMB):
  • Mechanism: Inhibits arabinosyl transferases (encoded by embB) which synthesize arabinogalactan - a component of the mycobacterial cell wall
  • Bacteriostatic; used mainly to prevent emergence of resistance to other agents
  • Adverse effects: Optic neuritis (dose-dependent) - visual acuity testing and color vision testing monthly; contraindicated in young children who cannot report visual changes; usually reversible if discontinued early
  • Resistance: embB gene mutations
Standard Regimens:
  • Active TB: 2HRZE/4HR (2 months of INH + RIF + PZA + EMB, then 4 months of INH + RIF)
  • Latent TB (LTBI): 9H (isoniazid daily × 9 months) or 3HP (isoniazid + rifapentine weekly × 12 doses)

CLASS 8: ANTIFUNGALS

AZOLES: FLUCONAZOLE, ITRACONAZOLE, VORICONAZOLE, POSACONAZOLE, ISAVUCONAZOLE

Mechanism: Inhibit fungal 14-alpha-demethylase (CYP51/Erg11) - a cytochrome P450 enzyme that converts lanosterol to ergosterol (the key component of fungal cell membranes, analogous to cholesterol in humans). Depletion of ergosterol and accumulation of toxic methylated sterols disrupts membrane integrity. Fungistatic for most fungi (fungicidal against some Candida with fluconazole).
Spectrum:
  • Fluconazole: Candida (not C. krusei, C. glabrata often resistant), Cryptococcus; NO mold activity
  • Itraconazole: Candida, Cryptococcus, Aspergillus, endemic fungi (Histoplasma, Blastomyces, Coccidioides, Sporothrix)
  • Voriconazole: Broader - Aspergillus (drug of choice), Candida including fluconazole-resistant species, Fusarium, Scedosporium
  • Posaconazole: Even broader including Mucormycetes (Mucor, Rhizopus) - prophylaxis in high-risk hematology patients
Drug Interactions: Azoles (especially voriconazole, itraconazole) are potent CYP3A4 inhibitors - major interactions with cyclosporine, tacrolimus, statins, warfarin, benzodiazepines
Adverse Effects:
  • GI intolerance, hepatotoxicity (monitor LFTs)
  • Voriconazole: visual disturbances (transient blurred vision, photopsia), photosensitivity, skin squamous cell carcinoma with prolonged use, neurotoxicity, periostitis
  • Fluconazole: QT prolongation
  • Azoles contraindicated in pregnancy (teratogenic)
Clinical Correlations:
  • Fluconazole: Candida UTI, esophageal candidiasis, maintenance therapy of cryptococcal meningitis, vaginal candidiasis
  • Voriconazole: Invasive aspergillosis (drug of choice)
  • Posaconazole: Mucormycosis prophylaxis and treatment (with liposomal amphotericin B as primary option)

ECHINOCANDINS: CASPOFUNGIN, MICAFUNGIN, ANIDULAFUNGIN

Mechanism: Inhibit beta-1,3-D-glucan synthase (encoded by FKS genes) - an enzyme that polymerizes glucan into the fungal cell wall. Disruption of cell wall integrity leads to osmotic lysis. Fungicidal against Candida, fungistatic against Aspergillus. No mammalian equivalent of this enzyme - excellent safety profile.
Spectrum: Candida (including azole-resistant C. glabrata, C. krusei), Aspergillus; NOT active against Cryptococcus, Mucor, or Fusarium
Clinical Correlations:
  • First-line for invasive Candida infections (candidemia) - especially in critically ill or azole-resistant settings
  • Aspergillus salvage therapy
  • Safer than amphotericin B; can be used in renal failure

POLYENES: AMPHOTERICIN B (Conventional and Lipid Formulations)

Mechanism: Binds to ergosterol in the fungal cell membrane, forming pores (ion channels) that cause leakage of intracellular cations and cell death. Also activates oxidative killing. Fungicidal, broad-spectrum.
Why selective: Binds ergosterol with greater affinity than cholesterol (human membrane sterol), but some cholesterol binding explains human toxicity.
Spectrum: Broadest antifungal agent:
  • Candida (all species), Aspergillus, Cryptococcus, Mucormycetes, Histoplasma, Coccidioides, Blastomyces, Sporothrix
Formulations:
  • Conventional amphotericin B deoxycholate: cheapest, most nephrotoxic
  • Liposomal amphotericin B (L-AmB): delivers drug preferentially to fungi (ergosterol-rich), spares human kidney; much less nephrotoxic; preferred in patients with renal impairment or who require prolonged treatment
Adverse Effects:
  • Nephrotoxicity: Vasoconstriction of afferent arterioles and direct tubular toxicity; renal tubular acidosis type 1, hypokalemia, hypomagnesemia. Most feared and common toxicity.
  • Infusion reactions: Rigors, fever, headache, nausea during infusion ("shaking chills" or "amphotericin shakes") - premedicate with paracetamol, diphenhydramine, hydrocortisone
  • Anemia (reduced erythropoietin)
Clinical Correlations:
  • Cryptococcal meningitis (induction): Liposomal amphotericin B + flucytosine × 2 weeks, then fluconazole consolidation
  • Severe invasive aspergillosis: When voriconazole fails or contraindicated
  • Mucormycosis: Liposomal amphotericin B + surgical debridement (urgent)
  • Disseminated histoplasmosis (severe): Liposomal amphotericin B induction
  • Lipid formulations preferred in most clinical scenarios when cost allows

CLASS 9: ANTIVIRALS

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs): TENOFOVIR, EMTRICITABINE, ABACAVIR, LAMIVUDINE, ZIDOVUDINE

Mechanism: Structural analogs of natural nucleosides/nucleotides. After intracellular phosphorylation to their triphosphate form, they:
  1. Compete with natural nucleotides for incorporation into viral DNA by reverse transcriptase (RT)
  2. Act as chain terminators - once incorporated, they lack a 3'-OH group, preventing further DNA strand extension
Clinical Correlations:
  • TDF/FTC (tenofovir/emtricitabine = Truvada): Backbone of most HIV regimens; also used for hepatitis B
  • Abacavir: Requires HLA-B*5701 testing before use - positive result predicts fatal hypersensitivity reaction (fever, rash, GI symptoms); do not rechallenge
  • Zidovudine: First antiretroviral ever used; now mainly for prevention of mother-to-child transmission (PMTCT)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): EFAVIRENZ, NEVIRAPINE, RILPIVIRINE, DORAVIRINE

Mechanism: Bind directly to a hydrophobic pocket on HIV RT (different site from NRTIs), causing conformational change that reduces polymerase activity. Do NOT require phosphorylation.
Important: Active only against HIV-1 (not HIV-2); single point mutations in RT can cause high-level resistance (low genetic barrier)
Efavirenz: CNS side effects (vivid dreams, dizziness, depression) particularly at initiation; teratogenic (neural tube defects - avoid in 1st trimester)

Protease Inhibitors (PIs): RITONAVIR, DARUNAVIR, ATAZANAVIR

Mechanism: Inhibit HIV aspartyl protease which cleaves polyprotein precursors (Gag-Pol) into functional viral proteins. Inhibition produces non-infectious viral particles.
Pharmacokinetic Boosting: Low-dose ritonavir potently inhibits CYP3A4, markedly increasing levels of co-administered PIs. Cobicistat is a newer pharmacokinetic enhancer (no antiviral activity). This is why darunavir is given as darunavir/ritonavir or darunavir/cobicistat.
Adverse Effects: Metabolic syndrome - hyperlipidemia, insulin resistance, lipodystrophy (fat redistribution); GI intolerance; multiple drug interactions

Integrase Strand Transfer Inhibitors (INSTIs): DOLUTEGRAVIR, BICTEGRAVIR, RALTEGRAVIR, ELVITEGRAVIR

Mechanism: Inhibit HIV integrase - blocks strand transfer step, preventing integration of viral DNA into host cell chromosomal DNA. Very high genetic barrier to resistance (dolutegravir, bictegravir).
Current preferred regimens: Dolutegravir or bictegravir-based - preferred WHO/DHHS first-line due to potency, tolerability, and high resistance barrier. Dolutegravir associated with neural tube defects when used in early pregnancy (caution; benefit/risk discussion required).

ACYCLOVIR and Antiherpesvirus Drugs

Mechanism: Acyclovir is a guanosine analog prodrug:
  1. Phosphorylated to acyclovir monophosphate by viral thymidine kinase (TK) - present only in herpesvirus-infected cells (selectivity mechanism)
  2. Further phosphorylated to triphosphate by cellular kinases
  3. Acyclovir triphosphate competitively inhibits viral DNA polymerase and acts as a chain terminator (no 3'-OH)
Selectivity is high because human TK phosphorylates acyclovir ~200× less efficiently than viral TK.
Drugs and Spectrum:
  • Acyclovir/Valacyclovir: HSV-1, HSV-2, VZV
  • Ganciclovir/Valganciclovir: CMV (more potent vs. CMV than acyclovir; also requires viral kinase UL97)
  • Famciclovir: HSV, VZV
  • Foscarnet: Acyclovir-resistant HSV/VZV (TK-deficient mutants), CMV (pyrophosphate analog, does NOT require viral kinase)
  • Cidofovir: CMV retinitis in AIDS; HSV; also poxviruses
Clinical Correlations:
  • HSV encephalitis: IV acyclovir 10 mg/kg q8h (medical emergency - start empirically)
  • VZV (chickenpox, zoster): Valacyclovir or acyclovir (early treatment reduces duration)
  • CMV prophylaxis (transplant): Valganciclovir
  • Acyclovir resistance: Usually TK mutation in immunocompromised - treat with foscarnet or cidofovir

NEURAMINIDASE INHIBITORS: OSELTAMIVIR (TAMIFLU), ZANAMIVIR

Mechanism: Inhibit influenza virus neuraminidase (sialidase) - the surface enzyme that cleaves sialic acid from host cell receptors and newly formed virions. Without neuraminidase, newly assembled virus particles remain tethered to the host cell and to each other, preventing viral spread.
Clinical use: Treatment within 48h of symptom onset (reduces illness by ~1 day in uncomplicated influenza); important for hospitalized, high-risk (elderly, immunocompromised, pregnant), or severe cases. Also used for post-exposure prophylaxis.
Resistance: H275Y mutation in neuraminidase (H1N1 oseltamivir resistance during 2008-2009)
Baloxavir marboxil: Newer cap-dependent endonuclease inhibitor - single oral dose for uncomplicated influenza

KEY RESISTANCE MECHANISMS - Summary

MechanismExample
Beta-lactamase productionMRSA, ESBL-producing E. coli
Altered PBP (mecA/PBP2a)MRSA
Modified ribosomal targetVRE (D-Ala-D-Lac), linezolid-resistant VRE
Efflux pumpsFluoroquinolone resistance, macrolide resistance
Enzymatic modification of drugAminoglycoside-modifying enzymes
Reduced permeability (OMP loss)Carbapenem resistance in gram-negatives
Target gene mutationRifampicin (rpoB), fluoroquinolones (gyrA/parC), isoniazid (katG/inhA)
Altered metabolic pathwaySulfonamide resistance

CLINICAL CORRELATION MNEMONICS

Antibiotics that cover anaerobes (above AND below diaphragm): CAMPEN - Carbapenems, Amoxicillin-clavulanate, Metronidazole, Piperacillin-tazobactam, rEquires knowing Clindamycin (above only), cefoxitiN/cefotetan
Antibiotics NOT to use in pregnancy:
  • Tetracyclines (teeth, bone - 2nd/3rd trimester)
  • Fluoroquinolones (cartilage - though evidence weak)
  • Sulfonamides (kernicterus in neonates - 3rd trimester)
  • Aminoglycosides (ototoxicity in fetus)
  • Chloramphenicol (Grey baby syndrome in neonates)
  • Rifampicin (teratogenic)
Beta-lactam allergy: cross-reactivity
  • Penicillin → cephalosporin: ~1-2% true cross-reactivity (based on identical side chains, not beta-lactam ring)
  • Penicillin → carbapenem: ~1%
  • Penicillin → aztreonam: no cross-reactivity (except aztreonam ↔ ceftazidime - shared R1 side chain)
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14e; Katzung's Basic and Clinical Pharmacology, 16e; Jawetz Melnick & Adelberg's Medical Microbiology, 28e
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