Pharmacology and Therapeutics (P.11) PDF

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES PHARMACOLOGY LECTURE LECTURER: Dr. Paul Tang DATE: February 13, 2024 TOPIC OUTLINE I. Tetracyclines a. Tetracycline b. Doxycycline c. Minocycline d. Tigecycline I...

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES PHARMACOLOGY LECTURE LECTURER: Dr. Paul Tang DATE: February 13, 2024 TOPIC OUTLINE I. Tetracyclines a. Tetracycline b. Doxycycline c. Minocycline d. Tigecycline II. Macrolides a. Erythromycin b. Clarithromycin c. Azithromycin III. Lincosamides a. Clindamycin IV. Chloramphenicol V. Streptogramins a. Quinupristin- dalfopristin VI. Oxazolidinones a. Linezolid b. Tedizolid TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES Basic features: Inhibit bacterial protein synthesis by binding and interfering with ribosomes Most are bacteriostatic Few are bactericidal I. TETRACYCLINE (TCN) a. b. c. d. TETRACYCLINE DOXYCYCLINE MINOCYCLINE TIGECYCLINE Tetracycline o has a higher renal clearance, o it will pass through the kidneys o need to adjust the dose o chelate divalent metal ions, which can interfere with their absorption and activity Free tetracyclines o crystalline amphoteric substances of low solubility Hydrochlorides o more soluble o acidic and fairly stable MODE AND MECHANISM OF ACTION Broad-spectrum bacteriostatic antibiotics inhibit protein synthesis enter microorganisms by a. Passive diffusion b. energy- dependent process of active transport Susceptible organisms concentrate the drug intracellularly bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex prevents addition of amino acids to the growing peptide TETRA = TRENTA (30s)  Active against many Gram (+) and Gram (-) bacteria, o anaerobes, o rickettsiae, o chlamydiae, o mycoplasmas If strains are resistant to: Tetracycline They may be susceptible to: 1. Doxycycline 2. Minocycline 3. Tigecycline RESISTANCE Three mechanisms of resistance to tetracycline analogs: 1. Impaired influx or increased efflux by an active transport protein pump; 2. Ribosome protection due to production of proteins that interfere with Tetracycline binding to the ribosome; and 3. Enzymatic inactivation PHARMACOKINETICS: (ADME) BASIC CHEMICAL STRUCTURE OF TETRACYCLINE Parent compound: Tetracycline Subtypes of tetracycline: differentiated by compounds attached to the different side chains (R5, R6 and R7) Kidney disease: know the renal clearance to know if you have to adjust the dose to be given or not I.A. Minocycline, Doxycycline, Metacycline o o have smaller renal clearance no need to adjust the dose. ABSORPTION: after oral administration a. Tetracycline: 60– 70% b. Doxycycline & Minocycline: 95–100% Tigecycline poorly absorbed orally administered intravenously Tetracycline: portion of an orally administered dose remains in the gut lumen, alters intestinal flora, and is excreted in the feces. mainly occurs in the upper small intestine 40–80% bound by serum proteins impaired by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which contain multivalent cations; and by alkaline pH N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 1|7 PCC SOM 2026 o o PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES Tetracycline: administered on an empty stomach Doxycycline and Minocycline: not impaired by food I.B. TIGECYCLINE DISTRIBUTION: Distributed widely to tissues and body fluids o except for CSF: 10–25% of those in serum Cross the placenta and excreted in breast milk Result of chelation with calcium: o bind to and damage growing bones and teeth METABOLISM: Shortens the half-life of Tetracycline and Doxycycline by 50% due to the induction of hepatic enzymes that metabolize the drugs: o Carbamazepine, o Phenytoin, o Barbiturates, and o Chronic Alcohol ingestion broad spectrum and many tetracycline resistant strains are susceptible to tigecycline because it is not affected by the common resistance determinants intravenous administration only Chief adverse: nausea, and vomiting Approved for treatment of o skin and skin structure infection, o intra-abdominal infections, o community acquired pneumonia ADVERSE REACTIONS (TETRACYCLINES) ELIMINATION: Excreted mainly in bile and urine Concentrations in bile > serum by tenfold Urine excretion (TCN): 10-15% by glomerular filtration Fecal excretion: 10-40% Non-renal excretion: Do not accumulate significantly in renal failure, requiring no dosage adjustment 1. Doxycycline 2. Tigecycline Short-acting: Tetracycline Long-acting: a. Doxycycline: 6-8 hours half-life b. Minocycline: 16-18 hours half-life Tigecycline: 36 hours half-life Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon Most adverse effects are due to direct toxicity of the drug or to alteration of microbial flora Alter the normal gastrointestinal flora, with suppression of susceptible coliform organisms and overgrowth of Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia, and Candida readily bound to calcium deposited in newly formed bone or teeth in young children When given during pregnancy it can be deposited in the fetal teeth, leading to: o fluorescence, o discoloration, and o enamel dysplasia Deposited in bone cause deformity or growth inhibition Not usually given to children of age 8 and below Can impair hepatic function, especially during pregnancy, in patients with preexisting liver disease, and when high doses are given intravenously CLINICAL USES: Drug of choice o Rickettsiae and Borrelia Spp o Rocky Mountain spotted fever o Lyme disease Excellent drugs for the treatment of o Mycoplasma pneumoniae o Chlamydiae o Spirochetes o Helicobacter pylori: Gastric, duodenal ulcer Cholera: stop the shedding of vibrio Tetracycline + other antibiotics o Plague, Tularemia, and Brucellosis Prophylaxis of Protozoal Infections, (P. falciparum) Other uses include treatment of: o Acne o Exacerbations Of Bronchitis, o Community-Acquired Pneumonia, o Leptospirosis, and o some Non-Tuberculous Mycobacterial Infections (e.g., Mycobacterium marinum) Minocycline o 100 mg orally BID for 5 days, o eradicate the meningococcal carrier state If strains are resistant to: (meningococcal strains) Minocycline They may be susceptible to: 1. 2. Ciprofloxacin Rifampicin All forms of tetracycline in general are mainly in capsule form more than in tablet form. II. MACROLIDES a. Erythromycin b. Clarithromycin c. Azithromycin Group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached Prototype Erythromycin Semisynthetic derivatives 1. Clarithromycin 2. Azithromycin II.A. ERYTHROMYCIN General structure is the macrolide ring and the sugars o Desosamine o Cladinose Solubility: o Poorly soluble in water (0.1%) o Dissolves readily in organic solvents Stability: o stable at 4°C o lose activity rapidly at 20°C and at acid pH N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 2|7 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES dispensed as various esters and salts antibacterial action of erythromycin and other macrolides may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms Activity is enhanced at alkaline pH. Inhibition of protein synthesis by binding to the 50S ribosomal RNA The binding site is near the peptidyl transferase center, and peptide chain elongation (i.e., transpeptidation) is prevented by blocking of the polypeptide exit tunnel active against Gram (+) organisms o Mycoplasma pneumoniae, o L pneumophila, o Chlamydia trachomatis, o Chlamydophila psittaci, o Chlamydophila pneumoniae, o H. pylori, o Listeria monocytogenes, o Certain mycobacteria also are susceptible Gram-negative organisms such as o Neisseria spp, o Bordetella pertussis, o Bartonella henselae, o Bartonella quintana o Rickettsia species, o Treponema pallidum, and o Campylobacter species RESISTANCE TO ERYTHROMYCIN usually plasmid-encoded 3 general mechanisms have been identified: 1. Reduced permeability of the cell membrane or active efflux; 2. Production (by enterobacteriaceae) of esterases that hydrolyze macrolides; 3. Modification of the ribosomal binding site (socalled ribosomal protection) by chromosomal mutation or by a macrolide inducible or constitutive methylase most important resistance mechanisms in Gram (+) 1. Efflux 2. Methylase production: confers resistance to structurally unrelated but mechanistically similar compounds such as Clindamycin Cross-resistance is complete between erythromycin and the other macrolides PHARMACOKINETICS Destroyed by stomach acid administered with enteric coating Food interferes with the absorption Stearate and ethyl succinate formulations are fairly acidresistant and somewhat better absorbed Normal serum half-life: 1.5 hours Half-life + anuria: 5 hours, adjustment for renal failure is not necessary Bile excretion: Large amounts of administered dose Urine excretion: only 5% of administered dose Traverses the placenta and reaches the fetus. CLINICAL USES: Traditional drug of choice in Corynebacterial Infections (diphtheria, corynebacterial sepsis, erythrasma) and in respiratory, neonatal, ocular, or genital chlamydial infections Useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci emergence of resistance has limited its use given orally or intravenously ADVERSE REACTIONS: Anorexia, nausea, vomiting, and diarrhea are common. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason for selecting an alternative to erythromycin Can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity rxn Most patients recover from this, but hepatitis recurs if the drug is re-administered other allergic reactions: fever, eosinophilia, and rashes Metabolites inhibit cytochrome P450 enzymes II.B. CLARITHROMYCIN Derived from erythromycin by addition of a methyl group Improved acid stability and oral absorption has activity against: o Mycobacterium avium complex (more active) o Mycobacterium leprae, o Toxoplasma gondii, and o H influenzae Erythromycin resistant streptococci and staphylococci are also resistant to clarithromycin Longer half-life, penetrates most tissues well, with concentrations equal to or exceeding serum concentrations Metabolized in the liver and partially eliminated in the urine 14- hydroxyclarithromycin, o major metabolite o has antibacterial activity o eliminated in the urine, o hence, dosage must be adjusted in patients with compromised kidney function II.C. AZITHROMYCIN Derived from erythromycin addition of methylated nitrogen into the lactone ring Its spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin highly active against Chlamydia spp although in produced in relatively low serum concentrations, it penetrates into most tissues (except CSF) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100- fold Half-life about 3 days rapidly absorbed and well tolerated orally do not alter bioavailability but delay absorption and reduce peak serum concentrations o Aluminum antacid o Magnesium antacids N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 3|7 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES Does NOT inactivate cytochrome P450 enzymes Electrocardiographic QT interval prolonged by macrolide antibiotics due to an effect on potassium ion channels Torsade’s De Pointes Arrhythmia: QT interval prolongation Dosage of Azithromycin: 500mg once a day for 3 days only III. LINCOSAMIDES III.A. CLINDAMYCIN a chlorine-substituted derivative of lincomycin antibiotic that is elaborated by Streptomyces lincolnensis inhibits protein synthesis interfering with the formation of initiation complexes and with aminoacyl translocation reactions. Binding subunit: 50S subunit of the bacterial ribosome, identical with that for erythromycin ADVERSE EFFECTS: CLINDAMYCIN IV. A. Susceptible Organism Resistant Organism 1. Streptococci 1. Enterococci 2. Staphylococci 2. Gram-negative aerobes 3. Pneumococci Resistance to clindamycin, which generally confers crossresistance to macrolides, is due to: 1. Mutation of the ribosomal receptor site; 2. Modification of the receptor by a constitutively expressed methylase 3. Enzymatic inactivation of clindamycin Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane PHARMACOKINETICS: CLINDAMYCIN about 90% protein-bound penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells Metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. o Normal half-life: about 2.5 hours, o Px with anuria: increasing to 6 hours No dosage adjustment is required for renal failure QUINUPRISTIN-DALFOPRISTIN treatment of skin and soft tissue infections caused by o Streptococci and Staphylococci o Bacteroides spp and other anaerobes o Group A Streptococcus ▪ in conjunction with penicillin G ▪ Toxic Shock Syndrome ▪ Necrotizing Fasciitis Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur Administration of clindamycin is a risk factor for Diarrhea and Colitis due to Clostridium difficile STREPTOGRAMINS CLINICAL USE: CLINDAMYCIN Combined with an aminoglycoside or cephalosporin to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, o Septic Abortion, o Pelvic Abscesses, or o Pelvic Inflammatory Disease; and o Lung and Periodontal Abscesses For prophylaxis of Endocarditis in patients with specific valvular heart disease who are undergoing certain dental procedures Together with primaquine, it is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients combination of two streptogramins: in a 30:70 ratio a. Quinupristin, a streptogramin B b. Dalfopristin, a streptogramin A Active against Gram-positive cocci, including o multidrug-resistant strains of streptococci, o penicillin-resistant strains of S pneumoniae, o methicillin-susceptible and resistant strains of staphylococci, and o E faecium (but not Enterococcus faecalis) Resistance is due to: 1. Quinupristin: modification of the binding site (MLS-B type resistance), 2. Dalfopristin: enzymatic inactivation or efflux Administered intravenously; rapidly metabolized Half-life o Quinupristin: 0.85 hours o Dalfopristin: 0.7 hours Elimination is principally by the fecal route Dose adjustment is not necessary for renal failure, peritoneal dialysis, or hemodialysis Patients with hepatic insufficiency may not tolerate the drug at usual doses Both significantly inhibit CYP3A4, which metabolizes Warfarin, Diazepam, Quetiapine, Simvastatin, and Cyclosporine, among many others Approved for treatment of infections caused by o Staphylococci or o Vancomycin-Resistant Strains of E. Faecium Principal toxicities are infusion-related events, such as pain at the infusion site, and an arthralgia-myalgia syndrome N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 4|7 PCC SOM 2026 V. PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES lives of these drugs (phenytoin, tolbutamide, chlorpropamide, and warfarin) CHLORAMPHENICOL Crystalline chloramphenicol is a neutral, Stable compound Soluble in alcohol but poorly soluble in water Widely distributed to virtually all tissues and body fluids, including the CNS and CSF Bacteriostatic by binding reversibly to the 50S subunit of the bacterial ribosome → inhibits peptide bond formation Chloramphenicol acetyltransferase, Cause of significant resistance a plasmid-encoded enzyme that inactivates the drug Chloramphenicol succinate, prodrug used for parenteral administration highly water soluble hydrolyzed in vivo to yield free chloramphenicol Most of the drug is inactivated either by: 1. conjugation with glucuronic acid (1’ in liver) 2. reduction to inactive aryl amines Urine excretion: elimination of inactive degradation products Bile and fecal excretion: elimination of a small amount of active drug Dosage should be reduced since they clear chloramphemicol less well → Dosage should be reduced. 1. Newborns less than a week old and 2. Premature infants also clear chloramphenicol less well Broad-spectrum and active against o aerobic G(+) & G(-) o anaerobic G(+) & G(-) o active also against Rickettsiae but not Chlamydiae Treatment of serious Rickettsial Infections o Typhus and o Rocky Mountain spotted fever Alternative to a β-lactam antibiotic for the treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin VI. OXAZOLIDIONES VI.A LINEZOLID A member of the OXAZOLIDINONE CLASS of synthetic antimicrobials. Active against Gram-positive organisms: o staphylococci, streptococci, enterococci, o Gram-positive anaerobic cocci, and o Gram positive rods such as Corynebacteria, Nocardia spp, and L monocytogenes o Mycobacterium tuberculosis bacteriostatic agent: primarily bactericidal agent: streptococci Indicated for o Vancomycin-Resistant E. faecium Infections, o Health Care– Associated Pneumonia, o Community- Acquired Pneumonia, and o complicated and uncomplicated skin and soft tissue infections caused by susceptible Gram (+) bacteria Off-label uses of linezolid include treatment of o Multi-Drug Resistant Tuberculosis o Nocardia infections ADVERSE REACTION: LINEZOLID Due to linezolid induced inhibition of mitochondrial protein synthesis, adverse effects include: o Thrombocytopenia (most common) o Anemia and neutropenia (most commonly in patients with a predisposition to or underlying bone marrow suppression) o Optic and peripheral neuropathy and lactic acidosis ADVERSE REACTIONS: CHLORAMPHENICOL Gastrointestinal disturbances, including nausea, vomiting, and diarrhea but are rare in children Dose-related reversible suppression of red cell production at dosages >50 mg/kg/d after 1–2 weeks Aplastic anemia, a rare consequence of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, it occurs more frequently with prolonged use. tends to be irreversible and can be fatal may respond to bone marrow transplantation or immunosuppressive therapy Gray Baby Syndrome When infants are given dosages >50 mg/kg/d, the drug may accumulate with vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs resulting in prolonged half- VI.B. TEDIZOLID An active moiety of the prodrug tedizolid phosphate, a next-generation oxazolidinone With high potency against Gram-positive bacteria, including Methicillin-Resistant S Aureus Potential advantages over linezolid include increased potency against staphylococci longer half-life of 12 hours, allowing once- daily dosing May be associated with a decreased risk of marrow suppression. It is thought to have a lower risk of serotonergic toxicity N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 5|7 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES CHECKPOINT! DERIVATIVE CLASS/ PARENT CMPD 1. 2. Tigecycline Azithromycin a. b. Tetracycline Macrolides 3. Tedizolid c. Oxazolidinones 4. 5. Quinupristin Clindamycin d. e. Streptogramins Lincosamides DESCRIPTION i. ii. iii. iv. v. Not affected by common resistant determinants Can cause Torsade’s De Pointes Arrythmia Potential advantage over Linezolid of increased potency against Staphylococcus Streptogramin B Elaborated by Streptomyces lincolnensis CLINICAL APPLICATION DRUG 1. 2. 3. 4. 5. CLINICAL APPLICATION Clindamycin + Penicillin G Clindamycin + Primaquineane Quinupristin + Dalfopristin Tetracycline Erythromycin a. b. c. d. e. Active against Group A Streptococcus Active against P. jiroveci pneumonia in AIDS Active against E. faecium but not E. faecalis Rocky Mountain Spotted Fever Corynebacterium infection and Chlamydia TOXICITIES TOXICITY 1. 2. 3. 4. 5. 6. DRUGS Torsades de Pointes Arrythmia Gray baby Syndrome Aplastic Anemia Gastro intestinal “intolerance” Colitis due to C. difficile Optic + Lactic Acidosis + Peripheral neuropathy a. b. Azithromycin Chloramphenicol c. d. e. Erythromycin Clindamycin Linezolid MECHANISM OF ACTION DRUGS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Minocycline Tigecycline Doxycycline Clarythromycin Erythromycin Azithromycin Quinupristin Linezolid Tedizolid Dlfopristin MECHANISM OF ACTIONS a. Prevents bacterial protein synthesis by binding to the 30s ribosomal subunit b. Prevents bacterial protein synthesis by binding to the 50s ribosomal subunit c. Prevents bacterial protein synthesis by binding to the 23s ribosomal RNA of 50s subunit Every answer is lined up in the same row alongside the question. N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 6|7 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.11 TETRACYCLINES, MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL, STREPTOGRAMINS, & OXAZOLIDINONES N OT E TA K E R : A B U L E N C I A | BAC WA D E N | B A L D O S | BA S T I A N | C U TAY | F E R R E R | S A N G DA A N Page 7|7