Pharmacology & Medicinal Chemistry III Lecture #12 PDF

Pharmacology & Medicinal Chemistry III Lecture #12 Miscellaneous Antibacterial Agents Today’s Outline: I. Bacitracin II. Polymixin B and Colistimethate III. Daptomycin IV. Rifaximan V. Mupirocin Read for this lecture: Goodman and Gilman – Chapte...

Pharmacology & Medicinal Chemistry III Lecture #12 Miscellaneous Antibacterial Agents Today’s Outline: I. Bacitracin II. Polymixin B and Colistimethate III. Daptomycin IV. Rifaximan V. Mupirocin Read for this lecture: Goodman and Gilman – Chapter 59 Learning Objectives for Miscellaneous Antibacterial Agents Lecture By the end of this lecture, you should be able to… Describe the mechanism of action of drugs in this lecture. Describe the antibacterial spectrum for these medications. Identify common and severe adverse events associated with administration of these medications. Identify routes of administration and how the drugs of this lecture are excreted. Explain why Daptomycin is NOT an effective treatment for pulmonary infections. I. Bacitracin  Bacitracin – Structure and Mechanism of Action Chapter 55, Goodman and Gilman, 12th ed. Mechanism of Action Inhibits synthesis of the _____________________ by interfering with the transport of peptidoglycan subunits across the cell membrane. Bacitracin – Antibacterial Spectrum, Adverse Effects, and Other Antibacterial Spectrum Many _________________ Bacteria Adverse Effects Little (with topical administration) Nephrotoxicity (with systemic administration).  Renal function must be monitored with IM administration Other Renal excretion Topical, ophthalmic, and IM (restricted) administration - Often combined with other compounds (Neosporin – Neomycin, Polymixin B, and II. Polymixin B and Colistimethate  Polymixin B and Colistimethate – Structure Polymixin B Comprised of a mixture of Polymixin B1 and Polymixin B2 Chapter 55, Goodman and Gilman, 12th ed. Colistimethate (pro-drug) Converted to _______ (Polymixin E) Related structure to Polymixin B olymixins are amphipathic. ct like detergents. http://  Polymixin B and Colistimethate – Mechanism of Action Mechanism of Action - Interact with certain phospholipids Disrupt the bacterial __________________________________ (in Gram negative bacteria), forming abnormally large openings through which cellular components can leak out. Has affinity for some bacteria cell membranes over others (specificity). Figure 12.4, Foundations in Microbiology, 7th  Polymixin B and Colistimethate – Antibacterial Spectrum Most _________________bacteria - Includes E. coli, Salmonella, Bordetella, Shigella, and Pseudomonas aeruginosa - Used especially to treat bacteria resistant to other antibiotics. Not effective against Gram positive bacteria. Resistance is common, so these drugs are usually used in combination therapies. Usually reserved for MDR pathogens (for systemic use) due to adverse effects  Polymixin B and Colistimethate – Adverse Side effects are Effects few for topical administration, due to lack of absorption. Extremely _________________ (if parenteral administration)- Monitor closely. Neurotoxicity – (includes dizziness, numbness, vertigo)  Neuromuscular blockade leading to respiratory paralysis  Polymixin B and Colistimethate – Other Notes _________________; poorly absorbed through mucous membranes Used to treat infections of the skin, mucous membranes, eyes, and ears. - Polymixin B - Opthalmic, otic, and topical are available. Often in combination with other compounds A component of Neosporin - Colistin – otic administration Polymixin B is available for IV, IM. Colistin is also available for oral, IV, IM, and inhalation. - Oral - Can be used prophylactically before GI surgery. - Systemic - for last-line therapy (due to adverse III. Daptomycin Daptomycin – Structure Chapter 55, Goodman and Gilman, 12th ed.  Daptomycin - Mechanism of Action Binds to bacterial membranes leading to their depolarization and loss of __________________________________ This leads to the inhibition of bacterial metabolism, including DNA, RNA, and protein synthesis. Bactericidal Figure 43.10 Basic and Clinical Pharmacology, 14 Daptomycin – Antibacterial Spectrum and Resistance Antibacterial Spectrum _________________ Bacteria Effective against MRSA, VRSA, and other drug- resistant Gram positive bacteria. Resistance Little  Daptomycin – Adverse Effects and Other Adverse Effects Muscle pain / weakness- Damage to the musculoskeletal system Diarrhea, vomiting Anemia Other Administered intravenously (poorly absorbed orally; toxic to muscles when injected intramuscularly). Mostly excreted in urine. Daptomycin is NOT a good choice for V. Rifaximin  Rifaximin – Mechanism of Action RNA synthesis inhibitor  Targets bacterial DNA-dependent _________________  Structurally similar to Rifamycins (which will be covered with the anti- mycobacterial drugs)  Rifaximin – Other Oral administration is available.  However, minimal absorption occurs (under normal conditions), so it is used to treat infections in the GI tract. Targets a broad spectrum of bacteria. Generally well tolerated Indicated for traveler’s diarrhea and IBS w/diarrhea If diarrhea worsens following extended use of Rifaximin (>2 months), it may be due to an adverse event (Clostridium difficile infection). IV. Mupirocin  Mupirocin – Structure and Mechanism of Action Chapter 55, Goodman and Gilman, 12th ed. Mechanism of Action Inhibits _________________ - Thereby inhibiting protein synthesis - Reversible - Bactericidal Activity against Gram positive bacteria (e.g. Staphylococcus aureus, including MRSA) and several Gram negative bacteria.  Mupirocin - Resistance  _________ level of resistance When resistance is present, it is usually due to: - Mutations in the isoleucyl tRNA synthetase that decrease its affinity for mupirocin. - The acquisition of an extra copy of the isoleucyl tRNA synthetase gene (that codes for an altered form of the enzyme)  Mupirocin - Other  Mupirocin is rapidly metabolized and inactivated upon entry into the body.  For topical and intranasal use ‐ E.g. to decolonize MRSA from nasal passages  Absorption through intact skin or skin lesions is minimal.  Adverse effects - May cause irritation at site of application. - Headache - Systemic issues are very rare due to its rapid inactivation.  Which one of the following pairs of drugs has the most similar mechanism of action? A. Polymixin B and Streptogramin B. Mupirocin and Penicillin G C. Bacitracin and Vancomycin D. Daptomycin and Oxacillin