Pharmacology Exam IV PDF

Principles of Antimicrobial Therapy: Beta-Lactams I Selection of Antimicrobial Agents The drug must accumulate at the site of infection at therapeutic levels to treat an infection Factors ○ Microorganism identification and antimicrobial sensitivity ○ Site of infection ○ Severity of infection ○ Exist...

Principles of Antimicrobial Therapy: Beta-Lactams I Selection of Antimicrobial Agents The drug must accumulate at the site of infection at therapeutic levels to treat an infection Factors ○ Microorganism identification and antimicrobial sensitivity ○ Site of infection ○ Severity of infection ○ Existing patient factors ○ Safety of the antimicrobial agent ○ Cost of antimicrobial therapy Natural Barriers ○ Limit penetration of antibiotics to the site of infection ○ Lipid solubility and pKa of antibiotic Blood-Brain Barrier (a natural barrier that separates the CNS from the rest of the body) ○ Meningitis (must cross to treat) ○ Inflammation may facilitate antibiotic penetration across the BBB Status of the Patient Host factors ○ Immune system ○ Renal dysfunction - the drug can accumulate to become toxic ○ Hepatic dysfunction - the drug can accumulate to become toxic ○ Pregnancy - Certain antibiotics contraindicated (tetracycline, fluoroquinolones, aminoglycosides) ○ Lactation (tetracyclines can cross through breastmilk to nursing infant) ○ Poor perfusion ○ Age (tetracyclines contraindicated in children under the age of 8 because they bind calcium in newly formed teeth and bones) Chemotherapeutic Spectra: Species of microorganisms affected by a certain drug Categories ○ Narrow Spectrum Act on a single or limited group of microorganisms Isoniazid - only acts against mycobacterium like Tb Penicillin G - treats G+ bacteria ○ Extended Spectrum Effective against G+ and some G- bacteria Aminopenecillins - same activity as Penicillin G but also extended-spectrum to include some G- bacteria like E.coli ○ Broad Spectrum Affect a wide variety of microbial species (G+, G-, aerobic, and anaerobic) Tetracyclines and Chloramphenicol They can lead to resistance when used unnecessarily Can lead to superinfection by altering the nature of natural flora (Staph Aureus) Antibiotic Selection Most appropriate antibiotic for a given infection: ○ Most narrow-spectrum agent which is effective ○ Reduces potential development of resistance Strep pyogenes is highly resistant to tetracycline - broad spectrum; can be treated with any penicillin or cephalosporins Bacteriostatic vs. Bactericidal Drugs (STATIC vs. CIDAL) Bacteriostatic Agents: ○ Inhibit the growth and replication of bacteria at achievable serum levels ○ Block the bacteria from dividing ○ Limits the spread of infection ○ Hold infection in check until the immune system can come to take care of it Bactericidal agents ○ Kill bacteria ○ Decrease the total number of viable microorganisms Why does it matter? ○ You want to use a bactericidal for immunocompromised patients Antimicrobial Drug Combinations Treatment with a single agent ○ Reduces the possibility of superinfections ○ Decreases emergence of multi-drug resistant organisms ○ Minimizes potential toxicity Advantages and disadvantages of combination therapy ○ Advantages Certain combinations are synergistic: Beta-lactams and aminoglycosides (aminoglycosides are synergistic with any cell wall inhibitors) Vancomycin and aminoglycosides Sulfonamides and trimethoprim/pyrimethamine (inhibit the second step) Used for mixed infections (aerobic and anaerobic, G+ and G-) Used for serious infections (bacteremia, endocarditis, meningitis, pneumonia) Empiric therapy - treating a critically old patient that may not survive more than 48 hours (use broad spectrum or combo of broad-spectrum) Treatment of tuberculosis and leprosy Reduce the risk of microorganisms developing resistance ○ Disadvantages Certain combinations are antagonistic Bacteriostatic agents may interfere with the action of a bactericidal drug Certain antibiotics only work in the presence of actively proliferating microorganisms Cell wall inhibitors are the main bactericidal drugs and only work in the presence of actively dividing bacteria Antibiotic Resistance Bacteria are designated resistant or inherently resistant (G- rods are resistant to penicillin G that cannot cross the thick barrier) ○ If their growth is not inhibited by the maximum level of antibiotic tolerated by the host ○ Some microorganisms are inherently resistant Resistance develops due to: ○ Imprudent and inappropriate use of antibiotics The main misuse of antibiotics is using them to treat viruses - ANTIBIOTICS DO NOT WORK FOR VIRUSES BECAUSE THE TARGET SITES DO NOT EXIST ON VIRUSES Mechanisms involved in the development of antibiotic resistance: Genetic alterations ○ Spontaneous mutations of DNA May persist, be corrected, or be lethal If the cell survives; Mutations can be passed on to daughter cells producing resistant strains Example: Rifampin-resistant Mycobacterium tuberculosis This is why we treat Tb with a minimum combination of two drugs ○ DNA transfer of drug resistance Resistance properties are encoded into plasmids that are passed between cells Plasmids are passed between cell Passed between plasma of the same or different species producing different resistant species Altered protein expression ○ Modification of antibiotic target sites Both plasmids and mutations can alter target sites leading to resistance Alterations in target protein Induce resistance to certain antibiotics Alteration of penicillin-binding proteins in methicillin-resistant Staphylococcus aureus (MRSA) Staph is always producing a beta-lactamase MRSA is multi-drug resistant therefore NO penicillin can treat MRSA ○ Decreased accumulation of antibiotic Reduced accumulation causes decreased penetration: Antibiotic is unable to reach its site of action The pore that the antibiotic enters causes decreased penetration, the microorganism can also pick up a plasmid ○ Enzymatic inactivation of antibiotic Ability to destroy or inactivate the antibiotic This leads to the development of resistance Microorganism produces an enzyme that picks up a plasmid that inactivates the antibiotic Betamases - enzymes that inactivate beta-lactam inactivate many penicillins and cephalosporins FOCUS ON THE MOST COMMON MODE OF RESISTANCE TO EACH TYPE OF DRUG A question on synergistic combos, modes of resistance, several questions on mechanism of action and clinical use (Patient that is pregnant, four years old, has reduced hepatic function, and a patient that has reduced renal function) Complications of Antimicrobial Therapy Even though antibiotics exhibit selective toxicity the host may develop adverse side effects: The host may develop adverse effects: ○ Hypersensitivity (allergic) ○ Direct toxic effects (unrelated to antimicrobial effect) ○ Development of superinfections REWATCH 30-35 MIN Indications Contraindications Interactions Bacterial Cell Wall Inhibitors Beta-lactams (bactericidal and synergistic with aminoglycosides) ○ Penicillins (4 Groups) Standard penicillins Penicillin G - i.v., i.m. (G+ rods and streptococci, pneumococci) ○ Non-penicillinase-producing gram-positive bacteria (spirochetes, meningococci) ○ Can cross the blood-brain barrier ○ Neisseria meningitidis, Treponema pallidum, Leptospira ○ Syphilis, endocarditis, bacteremia, meningitis, anthrax, gas gangrene, actinomycosis ○ DOES NOT TREAT STAPH, CAN TREAT PNEUMOCOCCI Benzathine penicillin G - suspension (Bicillin L-A); i.m. depot injection ○ Depot is in muscle and slowly released over a long period ○ Used to treat Syphilis (ALL stages) Penicillin V - BY MOUTH! Oral form of penicillin G (narrow spectrum) ○ Streptococci ○ Pneumococci Antistaphylococcal penicillins Nafcillin Oxacillin Dicloxacillin Spectrum of Activity ○ Staphylococci and streptococci Bacteremia, endocarditis, meningitis, RTIs (pneumonia) UTIs, RTIs, skin and soft tissue infections, bone infections Best for skin and soft tissue infections because staph and strep are the two main causes of skin and soft tissue infections Extended-spectrum penicillins - aminopenicillins that have an amino group in the structure Amoxicillin (90% oral bioavailability) ○ - treat four of the main causes of RTIs, the drug of choice for otitis media because it is active against the four main causes ○ Used for peptic ulcer due to helicobacter pylori Ampicillin (50% oral bioavailability) ○ Used for meningitis ○ Used for streptococcal, pneumococcal, meningococcal and listeria meningitis ○ Given to treat gastroenteritis due to shigella and salmonella Same activity as Penicillin G plus increased G- activity Proteus mirabilis, E. coli, Haemophilus influenzae, Moraxella, Shigella, Salmonella, and Helicobacter pylori UTIs, RTIs, endocarditis prophylaxis, meningitis, gastroenteritis, peptic ulcer Antipseudomonal penicillin Piperacillin (broadest spectrum penicillin) ○ Same as amoxicillin with increased G-activity ○ Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter, Serratia, and Bacteroides fragilis ○ UTIs, RTIs, bacteremia, intra-abdominal infections MAIN SIDE EFFECTS OF PENICILLIN: Hypersensitivity Diarrhea Interstitial nephritis Neurotoxicity Platelet dysfunction Superinfections Pseudomembranous colitis ○ Cephalosporins ○ Carbapenems ○ Monobactam Peptides - inhibit cell wall synthesis to a different mechanism ○ Vancomycin ○ Bacitracin Others ○ Cyclosyrin ○ Phosphomycin Beta Lactams Target Site ○ PBPs Transpeptidase enzymes Beta lactams inhibit transpeptidase reaction (the third and final step in bacterial cell wall synthesis) Bactericidal ○ Time-dependent bactericidal activity because they require the bacteria to divide and multiply to work ○ Synergistic with aminoglycosides - almost always used with a cell wall inhibitor so you can reduce the dose of the aminoglycoside and reduce side effects like ototoxicity and nephrotoxicity Mechanism of Antibacterial Action ○ The target site for beta-lactams are penicillin-binding proteins that are transpeptidase enzymes ○ ALL STAPH PRODUCES PENICILLIN ○ Transpeptidase reaction is the formation of the peptide bridge, when a new cell wall is synthesized the transpeptidase protein forms the peptide bridges By inhibiting PBP, beta-lactam inhibits the formation of the peptide bridges Principles of Beta-Lactams II: Miscellaneous Peptide Antibiotics Penicillins Standard Penicillins Penicillin V Oral form of Penicillin G Treats oral and pharyngeal infections Only treats streptococci (strep pyogenes, agalactiae, etc.) and pneumococci (strep pneumoniae) ○ Penicillin G IV or IM administration Treats any G+ infection that does not produce beta-lactamase - bacteria, spirochetes, meningococci Neisseria meningitides, Treponema pallidum, Leptospira (IV) Syphilis, endocarditis, bacteremia, meningitis, anthrax, gas gangrene, actinomycosis (gas gangrene and actinomycosis are due to obligate anaerobe) Given IV to treat Leptospirosis due to leptospira ○ Benzathine Penicillin G - suspension depot i.m. injection (Bicillin L-A) Drug choice for ALL stages of Syphilis due to Treponema Polytum (1º, 2º, 3º Syphilis) Resistant to staphylococcal penicillinase Antistaphylococcal Penicillins - resistant to staphylococcal penicillinase (beta-lactamase) ○ Nafcillin - IV, serious RTIs ○ Oxacillin - IV, serious RTIs ○ Diploxicillin - acid-stable; minor UTIs, minor RTIs, bone infections Spectrum of Activity - Narrow Spectrum Treat Staphylococci and Streptococci Bacteremia Endocarditis, Meningitis, RTIs, UTIs SKIN AND SOFT TISSUE INFECTIONS, bone infections Staph and strep are infections of the skin and soft tissues Extended-spectrum Penicillins (Same as penicillin G and G-; G+ and G-) ○ Amoxicillin (90% bioavailability) #1 Prescribed Given orally for UTIs, RTIs (4 main causes of RTIs - strep pyogenes, strep pneumoniae, Haemophilus influenzae, Moraxella) Drug of choice for otitis media, endocarditis, meningitis, ○ Ampicillin (50% bioavailability) Availability is why it is the choice for gastroenteritis ○ G- Bacteria that can be treated: Proteus mirabilis, E.coli, Haemophilus influenzae, Moraxella, Shigella, Salmonella, and Helicobacter Pylori UTIs, RTIs, endocarditis prophylaxis, meningitis, gastroenteritis, peptic ulcer Antipseudomonal Penicillins ○ Piperacillin (Zosyn) Same activity as amoxicillin with increased G- activity Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobactor aerogenes, citribacter, serratia, and bacteroides fragilis Bacteroides fragilis - obligate anaerobe that most antibiotics do not treat UTIs, RTIs, bacteremia, intra-abdominal infections Good for intraabdominal because it treats most G- rods and Bacteroides fragilis Cephalosporins Bind to penicillin-binding proteins (PBP) Bactericidal drugs - time-dependent bactericidal activity because it requires time for the bacteria to divide and synthesize a new cell wall ALL CELL WALL INHIBITORS ARE SYNERGISTIC WITH AMINOGLYCOSIDES ○ By damaging the cell wall, these drugs increase access of aminoglycosides to their target site - 30S subunit 1st Generation: ○ Cephalexin (Oral) - 3rd most prescribed drug ○ Cefazolin (IV) Spectrum of Activity ○ ALL CEPHALOSPORINS are active against Staphylococci, Streptococci, and Pneumococci, Proteus, E.Coli, and Klebsiella pneumoniae (PEK) ○ Cephalosporins are resistant to penicillinase so they can treat staph infections ○ Cephalexin treats UTIs, RTIs, skin and soft tissue infections ○ Cephazolin treats surgical prophylaxis, bone infections, and endocarditis Staph is the cause of a post-surgical infection because it is on our skin 2nd Generation ○ Cefprozil (Cefzil) ○ Cefuroxime axetil (Ceftin) Spectrum of activity: ○ Same as 1st generation + Haemophilus influenzae and Moraxella catarrhalis (both RTI) ○ RTIs, UTIs, skin and soft tissue infections 2nd Generation Subtypes ○ Cephamycins: (backups to ceftriaxone for gonorrhea); advantage is gonorrhea and obligate anaerobes Cefoxitin Cefotetan Spectrum of Activity: ○ Same as 2nd generation + Neisseria gonorrhoeae, Bacteroides fragilis (G- obligate anaerobe), Clostridium perfringens (G+ obligate anaerobe) ○ Mixed anaerobic infections ○ Intraabdominal infections 3rd Generation ○ Ceftriaxone (BBB - IV) First line for Neisseria Gonorrhea Chancroid (Haemophilus Decree), Typhoid fever (Salmonella), Lyme disease (disseminated because it crosses the BBB) Meningitis, RTIs, UTIs, Bacteremia, bone infections, skin and soft tissue infections ○ Cefotaxime (BBB - IV) Meningitis, penicillin-resistant pneumococci, RTIs, UTIs Bacteremia, bone infections, skin and soft tissue infections ○ Ceftazidime (BBB - IV) PSEUDOMONAS AERUGINOSA Aminoglycoside with antipseudomonal cell wall inhibitor Causes UTIs that lead to polyenophritis and bacteremia UTIs, meningitis, bacteremia, pneumonia ○ Cefdinir Active against four RTIs, skin, and soft tissue infections ○ Cefixime (Only drug given orally for gonorrhea) Primarily used for Neisseria Gonorrhea Spectrum of Activity ○ Same as 2nd generation with increased G- activity (not G+) ○ THE FIVE FIRST-LINE DRUGS FOR GONORRHEA 4th Generation ○ Cefepime Spectrum of Activity ○ Broadest spectrum ○ All 3rd gen in one drug ○ PSEUDOMONAS, Enterobacter, Bacteroides UTIs, meningitis, bacteremia, pneumonia Intraabdominal infections 5th Generation ○ Ceftaroline fosamil Spectrum of Activity - binds to a different site on PBP ○ ONLY BETA LACTAM THAT CAN TREAT MRSA ○ VISA, VRSA, ENRTEROCOCCI, pneumococci, streptococci ○ PEcK, Haemophilus influenzae, Moraxella ○ Skin and soft tissue infections, CAP (community-acquired pneumonia) Cephalosporin Adverse Effects: ○ Hypersensitivity (most common) If a person has a serious allergic reaction to penicillin, cephalosporins are contraindicated ○ Disulfiram reaction ○ Nephrotoxicity ○ Superinfections Mechanisms of Resistance to Beta-Lactam Antibiotics Inactivation by beta-lactamase (Most common) ○ Penicillinase - inactivates penicillin ○ Cephalosporinase - inactivates cephalosporins Decreased accumulation ○ Reduced permeability or Efflux pump Modification of target PBPs ○ MRSA ○ Penicillin-resistant strep pneumoniae (PRSP) Interactions Probenecid ○ Inhibits renal tubular secretion of penicillins and cephalosporins ○ NOT nafcillin and ceftriaxone because they are excreted through the bile, NOT the kidney Safe to use in reduced renal function!! Contraindications ○ Previous beta-lactam allergy ○ Reduced renal function except for nafcillin and ceftriaxone Carbapenems Imipenem Meropenem Broadest spectrum beta-lactams ○ Commonly used for empiric therapy (treatment of critically ill), UTIs, RTIs IV administration Unintended Effects ○ Hypersensitivity ○ Diarrhea ○ Infusion site reactions ○ Seizures Monobactam Aztreonam ○ NOT cross-allergenic to beta-lactams ○ Aerobic G- activity ONLY Aerobic G- rods (all G- except Bacteroides) UTIs, bacteremia, intra-abdominal infections (when used with another drug) Other Cell Wall Inhibitors Peptides ○ Vancomycin - MOST IMPORTANT; WILL BE ON EXAM CELL WALL INHIBITOR - synergistic with aminoglycosides, bactericidal Polar tricyclic glycopeptide - not absorbed orally Narrow spectrum - ONLY G+ because it cannot enter the thick Gmembrane Important for the treatment of MRSA Inhibits cell wall synthesis Inhibits peptidoglycan chain polymerization Inhibits transpeptidase reaction Damages cell membranes Inhibits synthesis of cell membrane phospholipids G+ activity: MRSA, PRSP, enterococci Slow IV infusion for systemic G+ infections Oral for C. difficile and Staph aureus Ab-associated enterocolitis Mechanisms of Resistance to Vancomycin Decreased drug permeability = VISA (use a higher dose) Modification of vancomycin binding site = VRSA (No amount of vancomycin will work) Unintended effects: Infusion phlebitis Flushing and Shock (release of histamine when induced quickly) Ototoxicity ○ Bacitracin Inhibits incorporation of amino acids into bacterial cell wall Cyclic peptide mixture - cell wall inhibitor G+ activity Nephrotoxicity (from systemic use) Neosporin = Bacitracin, Polymyxin, and Neomycin ○ Polymyxin B Cationic basic peptide Disrupts bacterial cell membranes Aerobic G- activity Nephrotoxicity and neurotoxicity (from systemic use) ○ Daptomycin Cyclic lipopeptide IV Depolarizes bacterial cell membrane potential by forming potassium channels in G+ membranes - K+ ions leak out to depolarize membrane potential Spectrum of Activity G+ cocci ○ MRSA, VISA, and VRSA ○ VRE and streptococci Skin and soft tissue infections Bacteremia and endocarditis Pharmacokinetics Inactivated by pulmonary surfactant Majority eliminated by glomerular filtration Unintended effects: Myopathy Rhabdomyolysis with and without renal failure Jaundice and elevated hepatic enzymes Others ○ Cycloserine Inhibit peptidoglycan polymerization (lengthening) Analog of D-alanine Second - linen tuberculostatic agent Dose-related CNS toxicities and peripheral neuropathies ○ Fosfomycin Inhibit peptidoglycan polymerization (lengthening) Analog of PEP Acute cystitis/UTIs in females E.coli and enterococcus faecalis Tetracyclines, Macrolides, and Aminoglycosides Tetracyclines The broadest spectrum agents we have, which are only used to treat infections we cannot treat with a narrow spectrum agent ○ Used for conditions that cannot be treated with a cell wall inhibitor ○ Differ in pharmacokinetic characteristics Mechanisms of Resistance to Tetracyclines: ○ Decreased drug permeability (Efflux pump) ○ Altered target site (30S subunit) ○ Enzymatic inactivation Cross-resistance within class Pharmacokinetics: ○ Form nonabsorbable chelates with multivalent cations (Avoid antacids and dairy products) ○ Bound to tissues undergoing calcification (Bind to calcium) - this is why it is contraindicated in pregnant and children under 8 because they bind to calcium in newly formed teeth and bones ○ Hepatic glucuronidation (Excreted via kidneys) Unintended Effects ○ GI disturbances ○ Tooth discoloration and enamel dysplasia (Pregnant and children under 8) ○ Bone deformities and growth inhibition ○ Fata hepatotoxicity ○ Photosensitization (severe rash) ○ Superinfections ○ Fanconi syndrome - damaged renal tubules (outdated/expired tetracyclines) Contraindications ○ Renally impaired patients except for doxycycline ○ Hepatic ○ Pregnancy and nursing Doxycycline concentrates in nursing breastmilk ○ CHildren under 8 years old Three Main Drugs: ○ Tetracycline (Hydrocy group on B ring) Bind to 30S ribosomal RNA to inhibit bacterial protein synthesis Directly inhibits binding of amino acid-charged tRNA to the acceptor site of the mRNA-ribosomal complex (Blocks the addition of amino acids to growing peptides) Bacteriostatic - DO NOT KILL BACTERIA Can antagonize the activity of a cell wall inhibitor because bacteria need to divide to be treated by a bactericidal Spectrum of Activity Broad spectrum G+ and G Aerobic and Anaerobic Rickettsiae, chlamydiae (does not have a peptidoglycan cell wall that beta-lactams can inhibit), mycoplasma, and ureaplasma (the -plasmas do not have a cell wall, so it cannot be treated with a cell wall inhibitor) Acne Peptic ulcer disease - helicobacter pylori ○ Doxycycline (Hydroxy group on C ring) More commonly prescribed because it has favorable pharmacokinetic properties Rickettsial infections Chlamydial Infection Drug of Choice - urethritis, pneumoniae, psittacosis Ureaplasma urealyticum drug of choice (no cell wall) Mycoplasma pneumoniae (no cell wall) Lyme disease first line Vibrio cholerae first line Brucella first line Syphilis and leptospirosis backup Tetanus and gas gangrene backup Actinomycosis in penicillin-allergic patients Plasmodium falciparum (malaria) Excreted in bile and is safe to use in patients with reduced renal function ○ Minocycline Treats everything doxycycline can treat but we do not use it due to the adverse effects Meningococcal carrier state Nocardiosis (G+ rod causing cardiac lesions) Acne Unintended Effects Vestibular problems: vertigo, dizziness, and vomiting Pseudotumor cerebri - BIH with headache and blurred vision Macrolides - bind to 50S bacterial ribosomal subunit Wide spectrum of activity G+ and G Three Macrolides: ○ Erythromycin Half-life of 5 hours G+ infections in penicillin-allergic patients Strep pyogenes Listeria monocytogenes and Bacillus anthracis Clostridium perfringens and clostridium tetani Pharmacokinetics: Metabolized by microsomal enzymes (CYP3A4) Potential drug interactions with drugs that inhibit P450 system Unintended Effects: GI issues Cholestatic jaundice Transient deafness Cardiotoxicity (prolong QT rhythm) ○ Clarithromycin Helicobacter pylori Metabolized by microsomal enzymes (CYP3A4) Potential drug interactions with drugs that inhibit P450 system Pharmacokinetics Metabolite and parent drug excreted through kidney Accumulates in reduced renal function Used in reduced hepatic function ○ Azithromycin 68-hour heald life - takes about 10 days to be eliminated Pharmacokinetics: Metabolized by microsomal enzymes (CYP3A4) Potential drug interactions with drugs that inhibit P450 system Binds to the 50S subunit to block the translocation reaction and inhibit protein synthesis Bacteriostatic ○ G+ and G○ More commonly used to treat Chlamydia, Mycoplasma, Legionella, amd Ureaplasma All three macrolides are first-line drugs for: ○ Corynebacterium diphtheriae (G+ rod) ○ Mycoplasm pneumoniae ○ Legionella pneumophila Backup drugs for: ○ Ureaplasma reticulum ○ Borrelia (Lyme disease) Azithromycin and Erythromycin are good for STIs: ○ Chlamydia trachomatis ○ Haemophilus ducreyi (chancroid) ○ Neonatal chlamydial infections Azithromycin and Clarithromycin are good for RTIs: ○ Mycoplasm pneumoniae ○ Chlamidia pneumoniae ○ Mycobacterium avium intracellular complex (MAI complex) ○ Haemophilus Influenzae Clari Mechanisms of Resistance to Macrolides: Altered target site (50S subunit) ○ G+ bacteria Enzymatic inactivation ○ G- bacteria Decreased accumulation ○ Reduced permeability or efflux pump ○ Cross-resistance within class ○ MULTI-DRUG STREP PNEUMONIAE (if it develops resistance to one tetracycline it is to all, to one macrolide it is to all) Aminoglycosides - bind to 30S bacterial ribosomal subunit Used to treat aerobic G- rods and some G+ but not obligate anaerobes Oldest used and most serious side effects - ototoxicity and nephrotoxicity Only serious potentially life-threatening conditions When given orally, they are not absorbed Bind to the 30S subunit and block assembly of the of 50S to the 30S - functional ribosomal apparatus causing misreading of mRNA Concentration-Dependent bactericidal activity Synergistic with cell wall inhibitors Postantibiotic effects = prolonged bactericidal activity; greater efficacy with larger daily doses than multiple smaller doses (even after level falls below the MIC) Drugs: ○ Streptomycin ○ Gentamicin (more common) ○ Tobramycin (more common) 10 polar groups and only 16-18 carbons, with a pKa of 8.5 Not given orally because they are not absorbed ○ Amikacin (Broadest spectrum; resistant to the main mode of resistance, enzymatic inactivation) PEcK, Pseudomonas, Enterobactor Staphylococcus aureus and MRSA Bacteremia, endocarditis, meningitis, pneumonia, UTIs ○ Neomycin Topical for skin or ocular infections Orally not absorbed - bowel sterilization and hepatic coma Kills bacteria in the intestine to decrease the load on the liver When used systemically, it caused interstitial nephritis and tubular necrosis Why are aminoglycosides bactericidal and can be used with cell wall inhibitors while others are bacteriostatic and cannot be used with cell wall inhibitors? They are bactericidal because they irreversibly inhibit protein synthesis Tetracyclines and macrolides are reversible inhibitors of protein synthesis so they are bacteriostatic Aminoglycosides cont. Spectrum of Activity ○ Aerobic G- rods (any aerobic G- rod on the exam) Proteus, e.coli, klebsiella, haemophilus, moraxella, pseudomonas, citrobacter, helicobacter DO NOT treat Bacteroides (not obligate anaerobes) - Bacteroides fragilis or clostridium ○ Limited G+ activity Gnetomicin and neomycin can treat staphylococci and enterococci ○ Reserved for serious infections!! Due to the risk of nephrotoxicity and ototoxicity Mechanisms of Resistance ○ Enzymatic inactivation by acetylation (Most common) Decreased accumulation Lack of active transport mechanism Altered target site Cross-resistance within the class Amikacin increases resistance to inactivation Pharmacokinetics ○ Inadequate oral absorption ○ Glomerular filtration: Older patients have decreased renal function Required monitoring of plasma levels Prevent serious adverse effects Unintended Effects ○ Ototoxicity Auditory and vestibular Irreversible deafness, vertigo, and loss of balance ○ Nephrotoxicity Irreversible tubular necrosis Contraindications ○ Pregnancy Ototoxicity in the fetus ○ Reduced renal function - elderly