Pharmacology Summary PDF

Pharmacology Summary Done By: Huthaifa Aboalhayyat Huthaifa Aboalhayyat Cell Wall Inhibitors PENICILLINS: Amoxicillin, Ampicillin, Dicloxacillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Ticarcillin....

Pharmacology Summary Done By: Huthaifa Aboalhayyat Huthaifa Aboalhayyat Cell Wall Inhibitors PENICILLINS: Amoxicillin, Ampicillin, Dicloxacillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Ticarcillin. :‫مجموعي ن يف جملة‬ ‫ن‬ ‫” ر‬ “Peter Picked a Ticket from bOx Am DiNa” / “‫بيت اختار تيكيت من صندوق عم دينا‬ ‫معلش انجليزي ع عربي بس هاد اللي طلع معي‬ Pe → Penicillin G + V Pi → Piperacillin Tic → Ticarcillin Ox → Oxacillin Am → Amoxicillin + Ampicillin Di → Dicloxacillin Na → Nafcillin CEPHALOSPORINS: 1st : Cephalexin, Cefadroxil, Cefazolin. 2nd : Cefuroxime, Cefotetan, Cefaclor, Cefoxitin. 3rd : Cefdinir, Cefixime, Cefotaxime, L Ceftazidime, Ceftriaxone, Ceftibuten. 4th : Cefepime. 5th : Ceftaroline. ‫هاد الفيديو بساعد كتت‬ https://youtu.be/t65fC2uVU1g?si=_nAS7_QcxkwqPNRq CARBAPENEMS: Doripenem, Ertapenem, Imipenem/cilastatin, Meropenem. "Do Every Important Move." Do → Doripenem E → Ertapenem Im → Imipenem/Cilastatin M → Meropenem Huthaifa Aboalhayyat MONOBACTAMS: Aztreonam. I. Antimicrobial Drugs Affecting Cell Wall Synthesis Target: Bacterial cell wall (contains peptidoglycan) o Not present in mammalian cells, making it a unique target for antibiotics. Effective Against: Actively growing bacteria with peptidoglycan cell walls o Ineffective against bacteria that do not have peptidoglycan (e.g., mycobacteria, protozoa, fungi, viruses). Major Drugs: o β-lactam antibiotics o Vancomycin o Daptomycin II. Penicillins Wide effectiveness and low toxicity but resistance limits use. Differences in side chains affect: o Antimicrobial spectrum o Stability to stomach acid o Hypersensitivity o Susceptibility to β-lactamases (enzymes that degrade them) A. Mechanism of Action Inhibit last step of cell wall synthesis (transpeptidation/cross-linkage): o Leads to weakened bacterial cell wall → lysis via osmotic pressure or autolysins. o Bactericidal (kills bacteria). o Works best on actively growing organisms. Huthaifa Aboalhayyat Key Mechanisms 1. Penicillin-binding proteins (PBPs): a. Inactivation of PBPs (enzymes involved in cell wall synthesis). b. Prevents cell wall formation and causes cell shape changes or lysis. 2. Inhibition of Transpeptidase: a. Penicillins block transpeptidase, which is needed for forming cross-links in peptidoglycan chains. 3. Autolysins: a. Autolysins degrade the cell wall in the presence of penicillin even without cell wall synthesis, leading to bacterial death. Resistance: Alterations in PBPs (e.g., MRSA resistance) can render penicillins ineffective. B. Antibacterial Spectrum of Penicillins Penicillin's Effectiveness: o Ability to cross the bacterial peptidoglycan cell wall and reach penicillin-binding proteins (PBPs) in the periplasmic space. o Factors influencing susceptibility: ▪ Size, charge, and hydrophobicity of the β-lactam antibiotic. Gram-Positive Bacteria: o Have easily traversable cell walls for penicillins. o Susceptible to penicillins in the absence of resistance. Gram-Negative Bacteria: o Have an outer lipopolysaccharide membrane that acts as a barrier to water-soluble penicillins. o Use porins (water-filled channels) in the membrane for penicillin entry. 1. Natural Penicillins: Source: Derived from Penicillium chrysogenum. o Penicillin G (benzyl-penicillin) and Penicillin V are the primary natural penicillins. Huthaifa Aboalhayyat Semisynthetic Penicillins: o Amoxicillin and Ampicillin (aminopenicillins) are chemically modified forms. Penicillin G: o Effective against gram-positive cocci, gram-positive bacilli, and spirochetes. o Susceptible to β-lactamases produced by resistant bacteria. o Drug of choice for: ▪ Gas gangrene (caused by Clostridium perfringens) ▪ Syphilis (caused by Treponema pallidum) Penicillin V: o Similar spectrum to Penicillin G. o Not used for bacteremia due to poor oral absorption. o More acid-stable than Penicillin G and often used orally for infections. 2. Antistaphylococcal Penicillins Penicillinase-resistant penicillins: o Methicillin, Nafcillin, Oxacillin, Dicloxacillin o Resistant to β-lactamase (penicillinase) produced by bacteria. Use: o Primarily for infections caused by penicillinase-producing staphylococci, including Methicillin-sensitive Staphylococcus aureus (MSSA). Note on Methicillin: o Not used clinically in the U.S. due to toxicity (interstitial nephritis). o Used in laboratory tests to identify methicillin-resistant Staphylococcus aureus (MRSA). MRSA: o Resistant to most β-lactam antibiotics, causing serious community and hospital-acquired infections. Activity: o Minimal to no activity against gram-negative infections. Huthaifa Aboalhayyat 3. Extended-Spectrum Penicillins Ampicillin and Amoxicillin: o Broad-spectrum antibiotics, effective against both gram-positive and gram-negative bacteria. Differences from Penicillin G: o Similar spectrum to Penicillin G, but more effective against gram-negative bacilli. Specific Uses: o Ampicillin: Drug of choice for Listeria monocytogenes and susceptible enterococcal species. o Amoxicillin: Used widely for respiratory infections and prophylactically in dentistry to prevent bacterial endocarditis in high-risk patients. Resistance Issues: o Resistance due to plasmid-mediated penicillinases (e.g., Escherichia coli and Haemophilus influenzae often resistant). Combination with β-lactamase Inhibitors: o Clavulanic acid or sulbactam protects amoxicillin and ampicillin from enzymatic degradation. o Extends their antimicrobial spectrum (e.g., MSSA resistance is overcome with inhibitors). 4. Antipseudomonal Penicillins Piperacillin and Ticarcillin: o Known as antipseudomonal penicillins due to their activity against Pseudomonas aeruginosa. o Available only in parenteral formulations (injections). o Piperacillin is the most potent of these antibiotics. Effective Against: o Many gram-negative bacilli. o Not effective against Klebsiella due to its penicillinase production. Combination with β-lactamase Inhibitors: o Ticarcillin + Clavulanic acid or Piperacillin + Tazobactam: Huthaifa Aboalhayyat ▪ Extends the antimicrobial spectrum to include penicillinase-producing organisms (e.g., Enterobacteriaceae and Bacteroides species). C. Resistance to Penicillins Natural Resistance: o Organisms lacking a peptidoglycan cell wall (e.g., Mycoplasma pneumoniae) or have cell walls impermeable to penicillins. Acquired Resistance: o Plasmid-mediated β-lactamases: Major clinical problem, leading to increased spread of resistant strains. Mechanisms of Resistance 1. β-Lactamase Activity: a. Enzymes that hydrolyze the β-lactam ring, inactivating the antibiotic. b. Constitutive or acquired: Most commonly acquired through plasmid transfer. c. Some β-lactam antibiotics resist β-lactamase hydrolysis and retain activity. d. Gram-positive bacteria secrete β-lactamases externally; gram-negative bacteria inactivate the drugs in the periplasmic space. 2. Decreased Permeability: a. Reduced penetration of the drug through the outer cell membrane prevents access to the PBPs. b. Efflux pumps can actively remove the drug from the bacterial cell (e.g., Klebsiella pneumoniae). 3. Altered PBPs: a. Modified PBPs with a lower affinity for β-lactam antibiotics. b. Results in the need for clinically unattainable concentrations of the drug to inhibit bacterial growth. c. Example: MRSA resistance to most β-lactam antibiotics. Huthaifa Aboalhayyat D. Pharmacokinetics of Penicillins 1. Administration Route of Administration: o IV or IM: Ampicillin + Sulbactam, Ticarcillin + Clavulanic Acid, Piperacillin + Tazobactam, Nafcillin, Oxacillin. o Oral only: Penicillin V, Amoxicillin, Dicloxacillin. o Oral or Parenteral: Some penicillins (e.g., Penicillin G). Depot Forms: o Procaine Penicillin G and Benzathine Penicillin G: ▪ Administered IM. ▪ Slowly absorbed, providing low, long-lasting levels in circulation. 2. Absorption Incomplete Absorption: o Most penicillins are incompletely absorbed orally, affecting intestinal flora. o Food reduces absorption of penicillinase-resistant penicillins, so take on an empty stomach. 3. Distribution Wide Body Distribution: o Crosses the placental barrier but is not teratogenic. o Poor penetration into bone or CSF unless sites are inflamed. o Inflamed meninges increase drug permeability into CSF. o Low levels in the prostate, making it ineffective for prostate infections. 4. Metabolism Minimal Metabolism: o Most β-lactam antibiotics are metabolized insignificantly. o Some penicillin G metabolism occurs in patients with impaired renal function. Huthaifa Aboalhayyat 5. Excretion Primary Route: o Renal excretion through tubular secretion and glomerular filtration. o Dosage adjustment required for patients with renal impairment. Exceptions: o Nafcillin and Oxacillin are metabolized in the liver (no renal adjustment needed). Probenecid Effect: o Competes for tubular secretion, increasing blood levels of penicillins. Breast Milk: Penicillins are excreted in breast milk. E. Adverse Reactions of Penicillins 1. Hypersensitivity Occurs in ~5% of patients; reactions range from rashes to angioedema and anaphylaxis. Cross-allergic reactions common among β-lactam antibiotics. Patient history is essential to assess severity and determine β-lactam safety. 2. Diarrhea Common due to disruption of intestinal flora balance. More frequent with incompletely absorbed or broad-spectrum penicillins. Risk of pseudomembranous colitis from Clostridium difficile and other organisms. 3. Nephritis Risk of acute interstitial nephritis, particularly with methicillin (no longer used clinically). 4. Neurotoxicity Can cause seizures if injected intrathecally or at very high blood levels. Huthaifa Aboalhayyat Epileptic patients at greater risk due to GABAergic inhibition by penicillins. 5. Hematologic Toxicities Decreased coagulation observed with high doses of piperacillin, ticarcillin, and nafcillin (also penicillin G). Cytopenias may develop with therapy >2 weeks; weekly blood count monitoring recommended. III. Cephalosporins β-lactam antibiotics, structurally and functionally related to penicillins. More resistant to certain β-lactamases compared to penicillins. Classified into five generations based on antibacterial spectrum and resistance to β-lactamases. A. Antibacterial Spectrum Ineffective against MRSA, L. monocytogenes, C. difficile, and enterococci (except advanced generation for MRSA). 1. First Generation Substitutes for penicillin G. Resistant to staphylococcal penicillinase (effective against MSSA). Effective against Proteus mirabilis, E. coli, K. pneumoniae (PEK bacteria). 2. Second Generation Broader gram-negative activity: H. influenzae, Enterobacter aerogenes, Neisseria species. Includes cephamycins (cefotetan, cefoxitin) active against Bacteroides fragilis (anaerobes). Reduced gram-positive activity compared to first generation. Not first-line due to increasing resistance in B. fragilis. 3. Third Generation Enhanced activity against gram-negative bacilli (e.g., Serratia marcescens). Huthaifa Aboalhayyat Key agents: o Ceftriaxone, cefotaxime: First-line for meningitis. o Ceftazidime: Active against P. aeruginosa (resistance increasing). Caution: Associated with collateral damage (antimicrobial resistance). 4. Fourth Generation Cefepime: Broad spectrum; effective against gram-positive (MSSA, streptococci) and gram-negative (e.g., Enterobacter, E. coli, K. pneumoniae, P. aeruginosa). Requires parenteral administration. Antibiogram testing recommended for P. aeruginosa treatment. 5. Advanced Generation Ceftaroline (prodrug: ceftaroline fosamil): Broad spectrum, unique structure. o Only β-lactam effective against MRSA (binds PBP2a) and S. pneumoniae (binds PBP2x). o Effective for complicated skin infections and community-acquired pneumonia. o Similar gram-negative coverage to ceftriaxone. o Lacks activity against P. aeruginosa, ESBL-producing Enterobacteriaceae, and A. baumannii. o Twice-daily IV dosing limits outpatient use. B. Resistance Resistance mechanisms are similar to penicillins. Not hydrolyzed by staphylococcal penicillinase, but susceptible to extended-spectrum β-lactamases (ESBLs). o E. coli and K. pneumoniae commonly associated with ESBLs. C. Pharmacokinetics 1. Administration Most cephalosporins require IV/IM administration due to poor oral absorption. Huthaifa Aboalhayyat Oral exceptions noted in Figure 38.12 (not listed here). 2. Distribution Distribute well into body fluids. Therapeutic CSF levels: Achieved only with select agents (e.g., ceftriaxone, cefotaxime). Cefazolin: Used as prophylaxis before surgery (effective against penicillinase-producing S. aureus and penetrates bone). All cephalosporins cross the placenta. 3. Elimination Tubular secretion/glomerular filtration: Most cephalosporins eliminated this way; doses require adjustment in renal dysfunction. Ceftriaxone: Excreted via bile; suitable for patients with renal insufficiency. D. Adverse Effects Generally well-tolerated, but allergic reactions can occur. Avoid use in patients with: o Anaphylaxis, Stevens-Johnson syndrome, or toxic epidermal necrolysis caused by penicillins. Cross-reactivity with penicillins: o Around 3%–5%, dependent on side chain similarity. o Highest cross-sensitivity with first-generation cephalosporins. IV. Other β-Lactam Antibiotics A. Carbapenems 1. Antibacterial Spectrum a. Active against β-lactamase–producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa (except some strains). Huthaifa Aboalhayyat b. Ertapenem lacks activity against P. aeruginosa, Enterococcus species, and Acinetobacter species. c. Resistant to most β-lactamases (except metallo-β-lactamases). 2. Pharmacokinetics a. Administered IV (ertapenem can also be IM). b. Penetrate body tissues/fluids, including CSF (e.g., meropenem effective in meningitis). c. Excreted via glomerular filtration. d. Imipenem requires coadministration with cilastatin to prevent formation of nephrotoxic metabolites. e. Dosage adjustment needed in renal insufficiency. f. Cefazolin: First-generation parenteral cephalosporin. Longer duration of action compared to other first-generation cephalosporins. Similar spectrum of action as other first-generation drugs. Good penetration into bone. g. Cephalexin: Prototype of first-generation oral cephalosporins. Effective against pharyngitis with oral administration. Dosage: Twice daily. h. Cefuroxime sodium: Prototype second-generation parenteral cephalosporin. Longer half-life compared to similar agents. Crosses the blood–brain barrier. Used for: Community-acquired bronchitis or pneumonia in the elderly, Patients who are immunocompromised. i. Cefuroxime axetil: Administered twice daily, this drug is well absorbed and is active against β-lactamase–producing organisms. j. Cefdinir + Cefixime: These are administered orally once daily. k. Cefotaxime: This penetrates well into the CSF. l. Ceftazidime: This is active against Pseudomonas aeruginosa. m. Ceftriaxone: Longest Half-Life: 6 to 8 hours, allows once-daily dosing. High Concentration: Achieves high levels in blood and cerebrospinal fluid (CSF). Effective Against Gonorrhea: Treats genital, anal, and pharyngeal penicillin-resistant Neisseria gonorrhoeae. Excretion: Eliminated via bile, suitable for patients with renal insufficiency. Bone Penetration: Shows good penetration into bone. n. Cefepime: This is active against Pseudomonas aeruginosa. 3. Adverse Effects a. Common: Nausea, vomiting, diarrhea. b. Rare: Eosinophilia, neutropenia. Huthaifa Aboalhayyat c. High doses of imipenem may cause seizures (less likely with other carbapenems). B. Monobactams (Aztreonam) Spectrum: Active against gram-negative pathogens, including Enterobacteriaceae and P. aeruginosa. o No activity against gram-positive organisms or anaerobes. Pharmacokinetics: Administered IV/IM; accumulates in renal failure. Adverse Effects: Low toxicity; may cause phlebitis, skin rash, or abnormal liver function tests. Special Feature: Minimal cross-reactivity with other β-lactams; safe for patients allergic to penicillins, cephalosporins, or carbapenems. V. β-Lactamase Inhibitors Examples: Clavulanic acid, sulbactam, and tazobactam. Contain a β-lactam ring but lack significant antibacterial activity. Mechanism: o Bind and inactivate β-lactamases, protecting β-lactamase-sensitive antibiotics. Used in combination with antibiotics (e.g., amoxicillin + clavulanic acid). Clavulanic acid alone: Minimal antibacterial activity. VI. Vancomycin Type: Tricyclic glycopeptide. Uses: o Treats life-threatening MRSA, MRSE, and enterococcal infections. o Oral form used for severe C. difficile colitis (not absorbed orally). o Prophylaxis for prosthetic device implantation in hospitals with high MRSA/MRSE rates. Dosing: Monitored via serum drug trough levels for safety and efficacy. Special Note: Reserved for β-lactam-resistant gram-positive infections or serious β-lactam allergy. Huthaifa Aboalhayyat VII. Daptomycin Type: Cyclic lipopeptide antibiotic. Mechanism: Bactericidal; concentration-dependent. Uses: o Treats resistant gram-positive organisms (MRSA, VRE). o Approved for complicated skin infections, bacteremia, and right-sided endocarditis. Limitations: o Ineffective for pneumonia (inactivated by pulmonary surfactants). o Not demonstrated effective for left-sided endocarditis. VIII. Telavancin Type: Lipoglycopeptide antibiotic; synthetic derivative of vancomycin. Mechanism: o Inhibits cell wall synthesis (like vancomycin). o Disrupts bacterial cell membrane (like daptomycin). Uses: o Treats complicated skin infections caused by resistant gram-positive organisms (e.g., MRSA). o Last-choice option for hospital-acquired/ventilator-associated pneumonia. Limitations: o Significant adverse effects (renal impairment, QTc prolongation, fetal harm in pregnancy). o Interferes with anticoagulation assays. IX. Fosfomycin Type: Synthetic derivative of phosphonic acid. Mechanism: Blocks cell wall synthesis by inhibiting peptidoglycan synthesis. Uses: o Urinary tract infections caused by E. coli or E. faecalis. Huthaifa Aboalhayyat o Single-dose treatment due to sustained urinary concentrations. Pharmacokinetics: Rapid absorption; excreted in active form in urine/feces. Adverse Effects: Diarrhea, vaginitis, nausea, headache. X. Polymyxins Types: Polymyxin B and colistin (polymyxin E). Mechanism: o Bind bacterial membranes, disrupting integrity (detergent-like action). o Bactericidal; concentration-dependent. Uses: o Active against gram-negative bacteria (P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter). o Salvage therapy for multidrug-resistant infections. Limitations: o Intrinsic resistance in Proteus and Serratia. o Toxicity: Nephrotoxicity, neurotoxicity (e.g., muscle weakness, slurred speech). Formulations: o Polymyxin B: Parenteral, ophthalmic, otic, topical. o Colistin: Prodrug (colistimethate sodium), IV or inhaled. Drug Name Category Mechanism of Action Therapeutic Uses Pharmacokinetics Adverse Effects Additional Notes Amoxicillin Penicillin Inhibits bacterial cell wall Broad-spectrum: Used for Well-absorbed orally, excreted Hypersensitivity Often combined with synthesis by binding to respiratory infections, urinary primarily in urine. May be reactions, clavulanic acid penicillin-binding proteins tract infections, and as combined with clavulanic acid diarrhea, nausea. (Augmentin) for (PBPs). prophylaxis for bacterial to resist β-lactamases. expanded spectrum. endocarditis. Ampicillin Penicillin Inhibits bacterial cell wall Used for infections caused by Poor oral absorption; may be Rash, diarrhea, Can be used in synthesis by binding to gram-positive bacilli, administered parenterally. Often hypersensitivity. combination with PBPs. enterococci, and Listeria combined with sulbactam for β- sulbactam (Unasyn). monocytogenes. lactamase resistance. Huthaifa Aboalhayyat Dicloxacillin Penicillin Resistant to β-lactamase; Used for penicillinase- Oral preparation available. Hypersensitivity Limited to inhibits bacterial cell wall producing staphylococcal reactions, nausea, staphylococcal synthesis by binding to infections. vomiting. infections due to PBPs. penicillinase resistance. Nafcillin Penicillin Resistant to β-lactamase; Effective against methicillin- Metabolized in the liver, does Neutropenia, Preferred for MSSA; not inhibits bacterial cell wall sensitive Staphylococcus not require renal adjustment. phlebitis, effective for gram- synthesis by binding to aureus (MSSA). hypersensitivity. negative bacteria. PBPs. Oxacillin Penicillin Resistant to β-lactamase; Treatment of staphylococcal IV or IM administration. Hypersensitivity Similar use and inhibits bacterial cell wall infections. reactions, spectrum to nafcillin. synthesis by binding to hepatotoxicity. PBPs. Penicillin G Penicillin Inhibits bacterial cell wall Effective for syphilis Poor oral bioavailability; Allergic reactions, The cornerstone of synthesis by binding to (Treponema pallidum), gas administered IV or IM. Excreted diarrhea, nephritis. penicillin therapy; depot PBPs. gangrene (Clostridium primarily by the kidneys. forms available (e.g., perfringens), and certain benzathine penicillin G). streptococcal infections. Penicillin V Penicillin Inhibits bacterial cell wall Used for mild infections like More acid-stable than penicillin Hypersensitivity Poor bioavailability limits synthesis by binding to pharyngitis. G; orally administered. reactions, use in severe infections. PBPs. gastrointestinal upset. Piperacillin Antipseudomo Extended-spectrum Effective against Pseudomonas Available only in parenteral Bleeding Combined with nal Penicillin activity, inhibits bacterial aeruginosa, enteric gram- formulations. Often combined tendencies, tazobactam (Zosyn) for cell wall synthesis. negative bacilli, and some with tazobactam for β- hypersensitivity. broader spectrum. anaerobes. lactamase resistance. Ticarcillin Antipseudomo Extended-spectrum Active against Pseudomonas Available parenterally; Hypersensitivity, Combined with nal Penicillin activity, inhibits bacterial aeruginosa and gram-negative frequently combined with increased bleeding clavulanic acid cell wall synthesis. bacilli. clavulanic acid for β-lactamase- risk. (Timentin) for extended producing organisms. coverage. Clavulanic β-Lactamase Inhibits β-lactamase Used in combination with No significant intrinsic Minimal adverse Protects antibiotics from acid Inhibitor enzymes, protecting β- amoxicillin or ticarcillin to treat antibacterial activity; used in effects. β-lactamase-producing lactam antibiotics from resistant bacterial infections. fixed combinations. bacteria. degradation. Sulbactam β-Lactamase Similar to clavulanic acid; Combined with ampicillin for Used parenterally; enhances the Minimal adverse Combined with Inhibitor inhibits β-lactamase enhanced spectrum of activity efficacy of β-lactam antibiotics. effects when ampicillin (Unasyn). enzymes. against resistant organisms. combined. Cefazolin 1st Gen Inhibits bacterial cell wall Surgical prophylaxis, MSSA IV or IM administration; excreted Hypersensitivity Commonly used for Cephalosporin synthesis. infections, and streptococcal in urine. reactions, orthopedic surgeries due infections. gastrointestinal to bone penetration. upset. Ceftriaxone 3rd Gen Inhibits bacterial cell wall Meningitis, gonorrhea, and High biliary excretion; long half- Hypersensitivity Does not require renal Cephalosporin synthesis. severe systemic infections. life allows once-daily dosing. reactions, biliary adjustment. sludge formation. Huthaifa Aboalhayyat Vancomycin Glycopeptide Inhibits bacterial cell wall MRSA infections, C. difficile Poor oral absorption; IV Red man Requires monitoring of synthesis by binding to D- colitis (oral formulation). administration for systemic syndrome, serum levels to avoid Ala-D-Ala terminus of infections; renal excretion. nephrotoxicity, toxicity. peptidoglycan precursors. ototoxicity. Daptomycin Lipopeptide Causes membrane Effective for MRSA, VRE, and Inactivated by pulmonary Myopathy, Monitor creatine depolarization and complicated skin infections. surfactants; not effective for rhabdomyolysis. phosphokinase (CPK) inhibits intracellular pneumonia. Renally excreted. levels during therapy. synthesis of DNA, RNA, and proteins. Aztreonam Monobactam Inhibits bacterial cell wall Gram-negative infections, Administered IV or IM; excreted Rash, liver enzyme Safe for use in patients synthesis; effective only especially in penicillin-allergic in urine. elevation. with severe penicillin against gram-negative patients. allergies. bacteria. Imipenem + Carbapenem Broad-spectrum β- Severe infections caused by IV administration; renally Seizures at high Combination prevents Cilastatin lactam; cilastatin resistant gram-positive, gram- excreted. doses, nephrotoxic metabolite prevents renal negative, and anaerobic gastrointestinal formation. metabolism of imipenem bacteria. upset. by dehydropeptidase. Polymyxin B Polymyxin Disrupts bacterial Salvage therapy for multidrug- Topical, IV, or IM administration. Nephrotoxicity, Resurgence in use due membrane integrity by resistant gram-negative neurotoxicity. to multidrug resistance. binding to phospholipids. infections. Colistin Polymyxin Disrupts bacterial Used in multidrug-resistant Administered via inhalation or Nephrotoxicity, Administered as membrane integrity; infections, including IV; excreted renally. neurotoxicity. colistimethate sodium prodrug form used for pneumonia. for systemic use. systemic infections. Fosfomycin Phosphonic Inhibits cell wall synthesis Treats uncomplicated urinary Rapid oral absorption; excreted Diarrhea, vaginitis, Single-dose therapy Acid Derivative by targeting UDP-N- tract infections caused by E. in active form in urine and feces. nausea, headache. effective for UTIs. acetylglucosamine coli and E. faecalis. enolpyruvyl transferase. Huthaifa Aboalhayyat Protein Synthesis Inhibitors TETRACYCLINES: Demeclocycline, Doxycycline, Minocycline, Tetracycline. "Demi Does Mini Tricks." Demi: Demeclocycline Does: Doxycycline Mini: Minocycline Tricks: Tetracycline GLYCYLCYCLINES: Tigecycline. AMINOGLYCOSIDES: Amikacin, Gentamicin, Neomycin, Streptomycin, Tobramycin. "Amir Gently Needs Strong Tools." Ami: Amikacin Gent: Gentamicin Ne: Neomycin Str: Streptomycin To: Tobramycin MACROLIDES/KETOLIDES: Azithromycin, Clarithromycin, Erythromycin, Telithromycin. "Azzy Clapped Every Time." Az: Azithromycin Cla: Clarithromycin Every: Erythromycin T: Telithromycin MACROCYCLIC: Fidaxomicin. LINCOSAMIDES: Clindamycin, OXAZOLIDINONES: Linezolid. OTHERS: Chloramphenicol, Quinupristin/Dalfopristin. Huthaifa Aboalhayyat I. Overview Antibiotics that inhibit bacterial protein synthesis by targeting ribosomes. Bacterial ribosomes: 30S and 50S subunits; mammalian ribosomes: 40S and 60S subunits. Selectivity for bacterial ribosomes reduces toxicity to host cells. High concentrations of some drugs (e.g., chloramphenicol, tetracyclines) may affect mitochondrial ribosomes due to structural similarity with bacterial ribosomes. II. Tetracyclines A. Mechanism of Action Enter bacteria via passive diffusion and an energy-dependent transport protein. Bind reversibly to the 30S ribosomal subunit. Inhibit bacterial protein synthesis by preventing tRNA binding to the mRNA–ribosome complex. B. Antibacterial Spectrum Bacteriostatic against gram-positive, gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. Common uses: o Acne. o Chlamydia infections (e.g., doxycycline). Typical therapeutic applications of tetracyclines: Disease Cause Key Features Treatment Lyme Disease Borrelia burgdorferi transmitted by Skin lesions, headache, fever, arthritis; bull's-eye rash (erythema migrans) Doxycycline tick bites hallmark feature Mycoplasma Mycoplasma pneumoniae ("walking Common in young adults or close-contact settings like camps; community- Macrolide or Pneumoniae pneumonia") acquired pneumonia doxycycline Cholera Vibrio cholerae ingested in fecally Diarrhea caused by enterotoxin; gastrointestinal infection Doxycycline + fluid contaminated food or water replacement Huthaifa Aboalhayyat Chlamydial Chlamydia trachomatis and Causes sexually transmitted infections (nongonococcal urethritis, pelvic Doxycycline or Infections Chlamydia psittaci inflammatory disease) or psittacosis (pneumonia, hepatitis, myocarditis) azithromycin Rocky Mountain Rickettsia rickettsii Fever, chills, aches, joint pain; early tetracycline response critical Tetracyclines Spotted Fever C. Resistance Efflux Pump: Most common mechanism; expels the drug from the cell, preventing intracellular accumulation. Enzymatic Inactivation: Bacteria produce enzymes that inactivate the drug. Ribosome Protection Proteins: Bacterial proteins prevent tetracyclines from binding to ribosomes. Selective Resistance: Resistance to one tetracycline does not imply resistance to all tetracyclines. D. Pharmacokinetics Absorption: o Adequately absorbed orally. o Decreased absorption with dairy, magnesium/aluminum antacids, or iron supplements (forms nonabsorbable chelates). o Doxycycline and minocycline available in oral and IV forms. Distribution: o Concentrates in bile, liver, kidney, gingival fluid, and skin. o Binds to calcified tissues (teeth, bones) and tumors with high calcium content. o Minocycline and doxycycline penetrate cerebrospinal fluid (CSF). o Minocycline achieves high levels in saliva and tears (useful for eradicating meningococcal carriers). o Crosses the placental barrier, concentrating in fetal bones and teeth. Elimination: o Tetracycline: Eliminated unchanged in urine. o Minocycline: Hepatic metabolism; minimal renal elimination. o Doxycycline: Eliminated via bile into feces (preferred in renal impairment). E. Adverse Effects Gastric discomfort: Huthaifa Aboalhayyat o Epigastric distress common. o Minimized by taking with food (non-dairy) or fluids and using capsules instead of tablets. Effects on calcified tissues: o Deposits in bones and teeth, causing discoloration and growth stunting in children. o Avoid in pediatric use. Hepatotoxicity: o Rare, occurs with high doses, particularly in pregnancy or preexisting liver/kidney issues. Phototoxicity: o Severe sunburn risk, especially with tetracycline and demeclocycline. o Patients should use sun protection. Vestibular dysfunction: o Dizziness, vertigo, tinnitus (common with minocycline; possible with doxycycline). Pseudotumor cerebri: o Rare intracranial hypertension (headache, blurred vision). o Reversible upon discontinuation. Contraindications: o Avoid in pregnant/breastfeeding women and children under 8 years. III. Glycylcyclines (Tigecycline) Overview Tigecycline is a derivative of minocycline and the first glycylcycline. Used for complicated skin/soft tissue infections and complicated intra-abdominal infections. A. Mechanism of Action Bacteriostatic action: o Binds reversibly to the 30S ribosomal subunit to inhibit protein synthesis. B. Antibacterial Spectrum Broad-spectrum activity includes: Huthaifa Aboalhayyat o Methicillin-resistant staphylococci (MRSA). o Multidrug-resistant streptococci. o Vancomycin-resistant enterococci (VRE). o Extended-spectrum β-lactamase-producing gram-negative bacteria. o Acinetobacter baumannii and anaerobic organisms. Not active against: o Morganella, Proteus, Providencia, Pseudomonas species. C. Resistance Developed to overcome tetracycline-resistant organisms (efflux pumps and ribosomal protection). Resistance still occurs, primarily due to efflux pump overexpression. D. Pharmacokinetics Administration: IV infusion. Distribution: High tissue penetration, low plasma concentration (poor for bloodstream infections). Elimination: Biliary/fecal route. Dose adjustments: o No adjustment for renal impairment. o Dose reduction required for severe hepatic dysfunction. E. Adverse Effects Common: Significant nausea and vomiting. Rare but serious: Acute pancreatitis (fatal cases reported). Other: o Elevated liver enzymes and serum creatinine. o Photosensitivity, pseudotumor cerebri. o Discoloration of permanent teeth (if used during tooth development). o Fetal harm (contraindicated in pregnancy). Huthaifa Aboalhayyat Drug interaction: o May reduce warfarin clearance and increase prothrombin time. o Monitor international normalized ratio (INR) closely with coadministration. IV. Aminoglycosides Overview Used for serious aerobic gram-negative bacilli infections. Limited by serious toxicities. Derived from Streptomyces sp. (-mycin) or Micromonospora sp. (-micin). A. Mechanism of Action Diffuse through porin channels and transported into cells via oxygen-dependent system. Bind to 30S ribosomal subunit, disrupting ribosome assembly or causing misreading of genetic code. Unique bactericidal action (concentration-dependent). o Target Cmax: 8–10× MIC. o Exhibit postantibiotic effect (PAE): Longer suppression with larger doses. Extended interval dosing (once daily) reduces nephrotoxicity and improves convenience. B. Antibacterial Spectrum Effective against aerobic gram-negative bacilli, including: o Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter sp. Often combined with β-lactam antibiotics for synergy (e.g., Enterococcus endocarditis). C. Resistance Mechanisms: o Efflux pumps. o Decreased uptake. Huthaifa Aboalhayyat o Plasmid-associated enzymes (modify/inactivate aminoglycosides). Amikacin is less vulnerable to resistance mechanisms. D. Pharmacokinetics 1. Absorption: a. Poor oral absorption → Parenteral administration required (except neomycin, used topically or orally). 2. Distribution: a. Hydrophilic → Variable tissue penetration. b. Low CSF penetration; intrathecal route used for CNS infections. c. Crosses the placenta → Accumulates in fetal plasma and amniotic fluid. 3. Elimination: a. 90% excreted unchanged in urine. b. Dose adjustment needed in renal dysfunction. E. Adverse Effects Overview: Therapeutic drug monitoring (e.g., gentamicin, tobramycin, amikacin) is critical to ensure proper dosing and minimize toxicities. Elderly patients are particularly vulnerable to nephrotoxicity and ototoxicity. 1. Ototoxicity: Vestibular and auditory damage linked to high plasma levels and prolonged treatment. Mechanism: Drug accumulates in inner ear fluids (endolymph and perilymph). Manifestations: o Deafness (may be irreversible). o Vertigo (especially with streptomycin). Risk Factors: o Concomitant use of ototoxic drugs (e.g., cisplatin, loop diuretics). o Use during pregnancy (can affect fetal development). Huthaifa Aboalhayyat 2. Nephrotoxicity Mechanism: Accumulation in proximal tubular cells disrupts calcium-mediated processes. Effects: o Ranges from mild, reversible renal impairment to severe, irreversible acute tubular necrosis. 3. Neuromuscular Paralysis: Cause: Rapid rise in drug concentrations (e.g., high doses infused quickly) or coadministration with neuromuscular blockers. At-Risk Populations: Patients with myasthenia gravis. Reversal: Administration of calcium gluconate or neostigmine. 4. Allergic Reactions Contact dermatitis commonly occurs with topically applied neomycin. V. Macrolides and Ketolides Overview Macrolides (e.g., erythromycin, clarithromycin, azithromycin) and ketolides (e.g., telithromycin) share structural similarities. Commonly used for patients allergic to penicillin. Ketolides are effective against macrolide-resistant gram-positive organisms. A. Mechanism of Action Bind irreversibly to the 50S ribosomal subunit, inhibiting protein synthesis. Bacteriostatic but can be bactericidal at higher doses. Share binding sites with clindamycin and chloramphenicol. B. Antibacterial Spectrum 1. Erythromycin: Effective against many penicillin G-susceptible organisms; alternative for penicillin-allergic patients. Huthaifa Aboalhayyat 2. Clarithromycin: a. Similar to erythromycin. b. Effective against Haemophilus influenzae, Helicobacter pylori, and intracellular pathogens (e.g., Chlamydia, Legionella). 3. Azithromycin: a. Less active against streptococci and staphylococci. b. More active against respiratory pathogens (e.g., H. influenzae, Moraxella). c. Preferred for urethritis (Chlamydia trachomatis) and Mycobacterium avium complex. 4. Telithromycin: a. Similar to azithromycin. b. Effective against macrolide-resistant organisms. C. Resistance Mechanisms 1. Reduced drug uptake by bacteria. 2. Presence of efflux pumps. 3. Decreased affinity of 50S ribosomal subunit due to methylation of ribosomal RNA. 4. Erythromycin esterases in gram-negative bacteria (e.g., Enterobacteriaceae). Telithromycin overcomes common resistance mechanisms. D. Pharmacokinetics 1. Administration: a. Erythromycin requires enteric-coated or esterified forms to avoid destruction by gastric acid. b. Food affects absorption: i. Decreases: Erythromycin, azithromycin. ii. Increases: Clarithromycin. c. IV forms available for erythromycin and azithromycin. 2. Distribution: a. Widely distributed, except in CSF. b. Azithromycin has the longest half-life and largest volume of distribution. Huthaifa Aboalhayyat 3. Metabolism: a. Erythromycin, telithromycin: Hepatic metabolism, CYP450 inhibitors. b. Clarithromycin: Partial hepatic metabolism, interacts with other drugs. 4. Excretion: a. Erythromycin, azithromycin: Excreted in bile. b. Clarithromycin: Excreted via both kidneys and liver (requires dosage adjustment in renal impairment). E. Adverse Effects of Macrolides and Ketolides 1. Gastric Distress and Motility: a. Most common side effect; can reduce patient compliance (especially with erythromycin). b. Clarithromycin and azithromycin are better tolerated. c. High doses of erythromycin induce smooth muscle contractions, sometimes used therapeutically for gastroparesis or postoperative ileus. 2. Cholestatic Jaundice: a. Associated with the estolate form of erythromycin (not used in the U.S.). b. Reported with other formulations as well. Huthaifa Aboalhayyat 3. Ototoxicity: a. Erythromycin: Transient deafness at high doses. b. Azithromycin: Rare cases of irreversible hearing loss. 4. Contraindications: a. Hepatic dysfunction: Use erythromycin, telithromycin, or azithromycin with caution due to accumulation in the liver. b. QTc prolongation: Risk of proarrhythmic conditions; avoid combining with other proarrhythmic agents. c. Telithromycin: Severe hepatotoxicity has restricted its use. 5. Drug Interactions: a. Erythromycin, telithromycin, and clarithromycin inhibit hepatic metabolism, leading to possible toxic accumulation of other drugs. b. Digoxin interaction: Increased digoxin absorption due to elimination of intestinal flora that inactivates the drug. VI. Fidaxomicin Mechanism of Action: o Acts on the sigma subunit of RNA polymerase, disrupting transcription and protein synthesis, leading to bacterial cell death. Spectrum of Activity: o Narrow spectrum, targeting gram-positive aerobes and anaerobes. o Primarily used for Clostridium difficile infections. Key Features: o Minimal systemic absorption; remains in the GI tract, making it ideal for gut infections. o No documented cross-resistance with other antibiotics. Adverse Effects: o Common: Nausea, vomiting, abdominal pain. o Rare: Hypersensitivity reactions (angioedema, dyspnea, pruritus). o Caution: Use with care in macrolide-allergic patients; anemia and neutropenia reported infrequently. Huthaifa Aboalhayyat VII. Chloramphenicol Mechanism of Action: o Binds to the bacterial 50S ribosomal subunit, inhibiting protein synthesis. o At high doses, it may inhibit mammalian mitochondrial ribosomes, causing bone marrow toxicity. Antibacterial Spectrum: o Effective against chlamydiae, rickettsiae, spirochetes, anaerobes. o Bacteriostatic but can be bactericidal depending on the dose and organism. Resistance: o Caused by enzymes that inactivate the drug, decreased penetration, or ribosomal binding site changes. Pharmacokinetics: o Administered IV; widely distributed, including the CSF. o Metabolized in the liver; excreted in urine. o Avoid in breastfeeding and adjust dose in liver dysfunction. Adverse Effects: a. Anemias: Dose-related anemia, hemolytic anemia (in G6PD deficiency), and aplastic anemia (independent of dose). b. Gray Baby Syndrome: i. Due to neonates' inability to metabolize and excrete the drug, causing mitochondrial toxicity. ii. Symptoms: Poor feeding, breathing issues, cardiovascular collapse, cyanosis, death. c. Drug Interactions: i. Inhibits hepatic oxidases, increasing levels of warfarin and phenytoin, potentiating their effects. VIII. CLINDAMYCIN Mechanism of Action: Similar to erythromycin; inhibits protein synthesis. Uses: Treats infections by gram-positive organisms (MRSA, Streptococcus) and anaerobes. Resistance: Cross-resistance with erythromycin; ineffective against C. difficile and some Bacteroides spp. Formulations: IV and oral; oral use limited due to GI intolerance. Huthaifa Aboalhayyat Pharmacokinetics: o Distributes well into body fluids (including bone). o Poor CSF entry. o Metabolized in liver; excreted in bile; minimal urinary excretion. o Accumulates in severe renal/hepatic failure. Adverse Effects: o Common: Diarrhea (risk of C. difficile-induced pseudomembranous colitis). o Skin rashes. o Treatment for C. difficile: Oral metronidazole or vancomycin. IX. QUINUPRISTIN/DALFOPRISTIN Mechanism of Action: o Synergistic binding to 50S ribosomal subunit; disrupts protein synthesis. o Bactericidal with prolonged post-antibiotic effect (PAE). Uses: o Primarily for E. faecium infections (bacteriostatic for VRE). o Ineffective against E. faecalis. Resistance: o Ribosomal methylation, enzymatic inactivation, and active efflux pumps. Pharmacokinetics: o IV administration (incompatible with saline). o Good intracellular penetration; poor CSF levels. o Metabolized in liver; excreted in feces. Adverse Effects: o Venous irritation (if not given via central line). o Hyperbilirubinemia (25%). o Arthralgia, myalgia. Huthaifa Aboalhayyat o CYP3A4 inhibition—risk of drug toxicities. X. LINEZOLID Mechanism of Action: o Binds to 23S rRNA of 50S ribosomal subunit; prevents formation of 70S initiation complex. Uses: o Gram-positive bacteria (MRSA, VRE, drug-resistant S. pneumoniae). o Effective against Corynebacterium spp., Listeria monocytogenes, and Mycobacterium tuberculosis. o Bacteriostatic (except bactericidal for Streptococci). o Alternative to daptomycin for VRE. o Not recommended for MRSA bacteremia. Resistance: o Reduced binding at the target site. o No cross-resistance with other protein synthesis inhibitors. Pharmacokinetics: o 100% oral absorption; IV available. o Widely distributed. o Metabolized via oxidation; excreted renally and non-renally. o No dose adjustment needed for renal/hepatic dysfunction. Adverse Effects: o Common: GI upset, headache, rash, thrombocytopenia (>10 days). o Rare: Serotonin syndrome (with MAOIs, SSRIs, tyramine foods). o Long-term use (>28 days): Irreversible peripheral neuropathy, optic neuritis. Huthaifa Aboalhayyat Drug Name Type Pharmacokinetics Mechanism of Action Uses Adverse Effects Resistance Demeclocycline Tetracycline Deposits in teeth and Inhibits protein synthesis Treats bacterial infections; Photosensitivity, Efflux pumps and bones, causing by binding to the 30S used off-label for SIADH. discoloration of teeth, ribosomal protection discoloration; excreted via ribosomal subunit. potential for stunted growth confer resistance. kidneys. in children. Doxycycline Tetracycline Excreted via bile; Inhibits protein synthesis Treats acne, Lyme disease, Phototoxicity, vestibular Resistance via efflux preferred in renal by binding to the 30S Chlamydia infections, and dysfunction, gastrointestinal pumps and ribosomal impairment; penetrates ribosomal subunit. gram-positive/negative upset, pseudotumor cerebri. protection. CSF. infections. Minocycline Tetracycline High levels in saliva and Inhibits protein synthesis Meningococcal carrier Vestibular side effects Resistance similar to tears; metabolized by binding to the 30S state, gram- (dizziness, vertigo), other tetracyclines. hepatically; penetrates ribosomal subunit. positive/negative phototoxicity. CSF. infections. Tetracycline Tetracycline Reduced absorption with Inhibits protein synthesis Acne, respiratory Hepatotoxicity, teeth Resistance dairy/antacids; excreted in by binding to the 30S infections, bacterial discoloration in children, mechanisms include urine; penetrates soft ribosomal subunit. infections. phototoxicity. efflux and enzymatic tissues. inactivation. Tigecycline Glycylcycline Poor plasma levels; high Inhibits protein synthesis Complicated skin/intra- Nausea, vomiting, acute Overexpression of tissue penetration; by binding to the 30S abdominal infections; pancreatitis, efflux pumps. eliminated via bile/feces. ribosomal subunit. MRSA, VRE infections. photosensitivity, fetal harm, tooth discoloration. Amikacin Aminoglycoside Administered IV; excreted Binds to 30S ribosomal Multidrug-resistant gram- Ototoxicity, nephrotoxicity, Enzymatic unchanged in urine. subunit, causing negative bacterial and potential modification of misreading of mRNA. infections. neuromuscular blockade. aminoglycoside. Gentamicin Aminoglycoside Poor CSF penetration; Binds to 30S ribosomal Pseudomonas infections, Nephrotoxicity, ototoxicity, Ribosomal binding excreted in urine; requires subunit, causing serious bacterial infections allergic reactions. alterations and monitoring in renal misreading of mRNA. (with β-lactams for enzymatic impairment. synergy). degradation. Neomycin Aminoglycoside Topical or oral use; poorly Binds to 30S ribosomal Bowel preparation, topical Contact dermatitis, Resistance involves absorbed systemically. subunit, causing skin infections. nephrotoxicity if systemic. enzymatic misreading of mRNA. modification. Streptomycin Aminoglycoside Administered IM; excreted Binds to 30S ribosomal Tuberculosis, plague, Ototoxicity (hearing loss, Ribosomal alterations in urine; accumulates in subunit, causing tularemia (in combination vertigo), nephrotoxicity. and enzymatic ear fluids. misreading of mRNA. therapy). resistance. Tobramycin Aminoglycoside Poor fat tissue Binds to 30S ribosomal Pseudomonas infections Nephrotoxicity, ototoxicity, Enzymatic penetration; excreted in subunit, causing (pneumonia, UTIs); often neuromuscular blockade. modification and urine. misreading of mRNA. used with β-lactams. decreased uptake mechanisms. Azithromycin Macrolide Long half-life; excreted in Binds to 50S ribosomal Respiratory infections, QT prolongation, Ribosomal binding bile; accumulates in subunit, inhibiting Chlamydia, H. influenzae, gastrointestinal upset, alterations and efflux tissues. translocation. MAC infections. hepatotoxicity. pumps. Huthaifa Aboalhayyat Clarithromycin Macrolide Metabolized in liver; Binds to 50S ribosomal H. pylori infections, Gastrointestinal upset, Resistance due to excreted in bile and urine. subunit, inhibiting intracellular pathogens hepatotoxicity, cytochrome methylation of binding translocation. (Legionella, Mycobacteria). P450 interactions. site. Erythromycin Macrolide Poor CSF penetration; Binds to 50S ribosomal Gram-positive infections, Cholestatic jaundice, QT Resistance via concentrated in liver; subunit, inhibiting penicillin alternative. prolongation, methylation and excreted in bile. translocation. gastrointestinal upset. efflux. Telithromycin Ketolide Metabolized in liver; Binds to 50S ribosomal Macrolide-resistant gram- Severe hepatotoxicity, QT Methylation of excreted in bile and urine; subunit, inhibiting positive strains. prolongation, visual ribosomal target site. poor CSF penetration. translocation. disturbances. Chloramphenicol Broad- Widely distributed; Binds to 50S ribosomal Life-threatening infections Aplastic anemia, gray baby Enzymatic spectrum therapeutic in CSF; subunit, inhibiting (meningitis). syndrome, drug interactions. inactivation of the metabolized hepatically. peptidyl transferase. drug. Clindamycin Lincosamide Metabolized hepatically; Binds to 50S ribosomal Gram-positive infections, Diarrhea, Resistance via poor CSF penetration; subunit, inhibiting MRSA, anaerobic bacteria. pseudomembranous colitis, ribosomal excreted in bile. translocation. skin rash. methylation. Linezolid Oxazolidinone Metabolized via oxidation; Binds to 23S rRNA of 50S MRSA, VRE, drug-resistant Thrombocytopenia, Reduced binding at penetrates tissues well; subunit, inhibiting 70S gram-positive infections. serotonin syndrome, optic ribosomal target site. no dose adjustment for initiation complex. neuropathy. renal impairment. Quinupristin/ Streptogramin Administered IV; Binds 50S ribosomal VRE, resistant gram- Venous irritation, Methylation of 23S Dalfopristin metabolized hepatically; subunit, disrupting positive cocci. hyperbilirubinemia, rRNA, enzymatic excreted in bile. protein elongation. arthralgia, myalgia. modifications. Fidaxomicin Macrocyclic Minimal systemic Inhibits RNA polymerase, Clostridium difficile Nausea, hypersensitivity Resistance due to antibiotic absorption; remains in GI disrupting bacterial infections. reactions, anemia. mutations in RNA tract. transcription. polymerase. Huthaifa Aboalhayyat Quinolones Folate Drugs Summary FLUOROQUINOLONES: Ciprofoxacin, Levofoxacin, Moxifoxacin, Nalidixic acid, Norfoxacin, Ofoxacin. "CIties LEad MOdern NAtions NOrth OFten." Ci→ Ciprofloxacin LE → Levofloxacin MO → Moxifloxacin NA → Nalidixic acid NO → Norfloxacin OF → Ofloxacin INHIBITORS OF FOLATE SYNTHESIS: Mafenide, Silversulfadiazine, Sulfasalazine. "MAny SILent SUrprises." MA → Mafenide SIL → Silversulfadiazine SU → Sulfasalazine INHIBITORS OF FOLATE REDUCTION: Pyrimethamine, Trimethoprim. COMBINATION OF INHIBITORS OF FOLATE SYNTHESIS AND REDUCTION: Cotrimoxazole (trimethoprim + sulfamethoxazole). URINARY TRACT ANTISEPTICS: Methenamine, Nitrofurantoin. I. FLUOROQUINOLONES Overview: o Nalidixic acid: Predecessor of fluoroquinolones. o Modern fluoroquinolones: Greater efficacy, broader spectrum, and better safety. o Issues: Associated with Clostridium difficile infections and antimicrobial resistance (e.g., methicillin-resistant staphylococci). o "Collateral damage": Similar to third-generation cephalosporins (e.g., ceftazidime). A. Mechanism of Action o Enter bacteria via porin channels. Huthaifa Aboalhayyat o Inhibit: ▪ DNA gyrase (topoisomerase II) → Relaxation of supercoiled DNA → DNA strand breakage. ▪ Topoisomerase IV → Interferes with chromosomal stabilization during cell division. o Gram-negative bacteria (e.g., Pseudomonas aeruginosa): ▪ Inhibition of DNA gyrase is more critical. o Gram-positive bacteria (e.g., Streptococcus pneumoniae): ▪ Inhibition of topoisomerase IV is more significant. Agent-Specific Activity: o Drugs with higher topoisomerase IV affinity (e.g., ciprofloxacin): Not suitable for S. pneumoniae. o Drugs with higher topoisomerase II affinity (e.g., moxifloxacin): Not suitable for P. aeruginosa. B. Antimicrobial Spectrum of Fluoroquinolones General Properties: o Bactericidal with AUC/MIC-dependent killing. o Effective against: ▪ Gram-negative organisms (E. coli, P. aeruginosa, H. influenzae). ▪ Atypical organisms (Legionellaceae, Chlamydiaceae). ▪ Gram-positive organisms (streptococci). ▪ Some mycobacteria (M. tuberculosis). o Ineffective for: ▪ Staphylococcus aureus, enterococcal infections, and syphilis. ▪ Limited utility against N. gonorrhoeae due to global resistance. o Levofloxacin and moxifloxacin: "Respiratory fluoroquinolones" with excellent activity against S. pneumoniae. Generational Classification: o 1st Generation: Nalidixic acid – narrow spectrum. o 2nd Generation: Ciprofloxacin, Norfloxacin – effective against gram-negative and atypical bacteria; significant intracellular penetration. Huthaifa Aboalhayyat o 3rd Generation: Levofloxacin – increased gram-positive activity. o 4th Generation: Moxifloxacin – effective against gram-positive and anaerobic organisms. C. Clinically Useful Fluoroquinolones 1. Norfloxacin: a. Rarely prescribed due to poor oral bioavailability and short half-life. b. Used for nonsystemic infections (UTIs, prostatitis, infectious diarrhea). 2. Ciprofloxacin: a. Best fluoroquinolone for P. aeruginosa; used in cystic fibrosis. b. Treats systemic infections, traveler’s diarrhea (E. coli), typhoid fever (Salmonella typhi), and as a second-line agent for tuberculosis. c. High bioavailability (~80%); oral and IV formulations interchangeable. d. Extended-release available for improved adherence. e. Typical therapeutic applications of fluoroquinolones: Disease Category Diseases Drugs Notes Anthrax Anthrax (postexposure Ciprofloxacin, Doxycycline Ciprofloxacin is the drug of choice. prophylaxis, treatment) Urinary Tract Uncomplicated and complicated Ciprofloxacin, Levofloxacin Effective in treating these infections. Infections UTIs Resistant Pneumonia, sinusitis Levofloxacin, Moxifloxacin, Levofloxacin is effective for β-lactam resistant Respiratory Ciprofloxacin infections; Ciprofloxacin has limited activity. Infections Gastrointestinal Acute diarrheal illnesses Ciprofloxacin Highly efficacious for infections caused by enteric Tract Infections pathogens. Anaerobic Infections General anaerobic infections Moxifloxacin Notable anti-anaerobic activity. 3. Levofloxacin: a. Replaced ofloxacin in clinical use. b. Broad spectrum: Treats prostatitis, skin infections, CAP, nosocomial pneumonia. Huthaifa Aboalhayyat c. Excellent activity against S. pneumoniae; 100% bioavailability; dosed once daily. 4. Moxifloxacin: a. Enhanced gram-positive (S. pneumoniae) and anaerobe activity (limited against B. fragilis). b. Poor activity against P. aeruginosa. c. Not indicated for UTIs due to lack of urine concentration. D. Resistance to Fluoroquinolones Primary Causes: o Chromosomal mutations in bacterial genes (e.g., gyrA or parC). o High resistance levels in gram-positive and gram-negative bacteria. Mechanisms of Resistance: o Altered Target: ▪ Mutations in DNA gyrase or topoisomerase IV decrease drug affinity. o Decreased Accumulation: ▪ Porin channel reduction: Fewer porin proteins limit drug entry. ▪ Efflux pumps: Actively remove drug from the cell. Cross-Resistance: Present among quinolones. E. Pharmacokinetics of Fluoroquinolones 1. Absorption: a. Oral absorption: i. Norfloxacin: 35–70%. ii. Other fluoroquinolones: 80–99%. b. Reduced absorption with: i. Sucralfate, antacids, iron, zinc, or calcium. c. IV and ophthalmic formulations available for ciprofloxacin, levofloxacin, moxifloxacin. 2. Distribution: a. Widely distributed in tissues and fluids, including bone, urine, kidney, prostatic tissue (not prostatic fluid), and lungs. Huthaifa Aboalhayyat b. Low cerebrospinal fluid (CSF) penetration (except ofloxacin). c. Accumulate in macrophages and leukocytes (active against intracellular organisms). 3. Elimination: a. Mostly renal excretion: Requires dose adjustment in renal dysfunction. b. Moxifloxacin: Excreted by the liver; no renal adjustment needed. F. Adverse Reactions of Fluoroquinolones Common Effects: o Nausea, vomiting, diarrhea, headache, dizziness, lightheadedness. Specific Concerns: o CNS Disorders: Use cautiously in epilepsy. o Peripheral Neuropathy and Glucose Dysregulation: Includes hypoglycemia and hyperglycemia. o Phototoxicity: ▪ Avoid sunlight; use sunscreen. ▪ Discontinue if phototoxicity occurs. o Cartilage Damage (Arthropathy): ▪ Observed in immature animals. ▪ Avoid in pregnancy, lactation, and children