Lecture 14 - Bactericidal Inhibitors of DNA-RNA

‭Bactericidal Inhibitors of DNA/RNA‬ ‭‬ F ● ‭ luoroquinolones (ciprofloxacin)‬ ‭●‬ ‭Cyclic lipopeptides (daptomycin)‬ ‭●‬ ‭Metronidazole (flagyl)‬ ‭Fluoroquinolones‬ ‭●‬ ‭Prototype: Ciprofloxacin (Cipro)‬ ‭MOA‬ ‭ ‬ I‭ nhibits bacterial DNA enzymes needed for replication and cell division‬ ● ‭●‬ ‭DNA gyrase:‬‭Responsible for coiling of DNA strand‬ ‭●‬ ‭Topoisomerase IV:‬‭Responsible for separation of daughter‬‭strands of DNA‬ ‭Uses‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ actericidal‬‭and‬‭broad-spectrum‬ B ‭Primarily‬‭aerobic gram-negative‬‭(‬‭Salmonella‬‭,‬‭E. coli‬‭,‬‭Klebsiella‬‭)‬ ‭Some aerobic gram-positive, especially for inhaled bacteria (Anthrax)‬ ‭S. aureus‬‭,‬‭N. gonorrhea‬‭,‬‭C. diff‬‭are resistant‬ ‭Ciprofloxacin‬ ‭Pharmacokinetics/Dynamics‬ ‭●‬ ‭Rapidly absorbed‬‭orally‬ ‭●‬ ‭High concentration in urine, stool, bile, saliva, bone, and prostate‬ ‭○‬ ‭Effective to treat respiratory and urinary tract infections‬ ‭●‬ ‭Low levels in CSF; not a good option‬ ‭●‬ ‭Half-life = 4 hours‬ ‭○‬ ‭Short duration of action‬‭, more frequent dosing‬ ‭●‬ ‭Metabolized by the liver‬ ‭●‬ ‭Excreted by the kidneys‬ ‭Adverse Effects‬ ‭●‬ ‭GI:‬‭N/V/D, abdominal pain‬ ‭●‬ ‭CNS:‬‭Dizziness, headache, confusion, restlessness‬ ‭○‬ ‭Higher risk in older adults; can cause falls‬ ‭●‬ ‭Superinfection‬‭:‬‭Candida‬‭,‬‭C. diff‬ ‭○‬ ‭Broad-spectrum‬ ‭●‬ ‭Significant phototoxicity‬ ‭●‬ ‭Most concerning‬‭(but rare):‬‭Tendon rupture‬ ‭○‬ ‭Black box warning‬ ‭Tendinitis/Tendon Rupture‬ ‭●‬ ‭Rare (1/10,000)‬ ‭●‬ ‭Usually affects the Achilles tendon‬ ‭●‬ ‭Early S/S:‬‭Tendon pain, swelling, inflammation‬ ‭●‬ ‭Reversible‬‭if identified early‬ ‭○‬ ‭Should be reported right away‬ ‭●‬ ‭Avoid ciprofloxacin in patients:‬ ‭○‬ ‭< 18 years old or > 60 years old‬ ‭○‬ ‭Transplant patients‬ ‭○‬ ‭Patients taking glucocorticoids‬ ‭●‬ ‭Pregnancy/lactation:‬‭Alternative drug preferred‬ ‭Drug and Food Interactions‬ ‭●‬ ‭Absorption reduced by‬‭chelate formation‬‭: Aluminum,‬‭magnesium, iron, calcium, zinc‬ ‭○‬ ‭Similar to tetracyclines‬ ‭○‬ ‭Dietary sources and OTC preparations‬ ‭●‬ ‭Ciprofloxacin is a‬‭P450 inhibitor‬‭and increases plasma‬‭levels of:‬ ‭○‬ ‭Theophylline (narrow therapeutic index)‬ ‭○‬ ‭Macrolides‬ ‭○‬ ‭Warfarin‬ ‭○‬ ‭Tinidazole (an antifungal drug)‬ ‭Considerations for Administration‬ ‭●‬ ‭Cation interactions: Administer cations 2 hours before or 6 hours after (chelates)‬ ‭●‬ ‭Possible drug interactions: Close monitoring‬ ‭●‬ ‭Patient education:‬ ‭○‬ ‭S/S of tendinitis‬ ‭○‬ ‭Phototoxicity: Protective measures‬ ‭●‬ ‭Increased risk for secondary infections‬ ‭Metronidazole (Flagyl)‬ ‭MOA‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ reaks apart DNA helical structure to prevent nucleic acid synthesis, causing cell death‬ B ‭Prodrug:‬‭Must be absorbed by bacteria and converted‬‭to its active form‬ ‭Only‬‭anaerobes‬‭can complete this conversion‬ ‭Bactericidal‬‭to anaerobic organisms and protozoans‬‭only‬ ‭Pharmacokinetics‬ ‭●‬ ‭Metabolized by CYP3A4‬ ‭Therapeutic Indications‬ ‭●‬ ‭C. difficile‬‭,‬‭Gardnerella vaginosis‬‭(bacterial vaginosis)‬ ‭○‬ ‭Commonly employed to treat mild-moderate‬‭C. diff‬‭infections‬ ‭○‬ ‭Prophylactic use prior to surgery‬ ‭●‬ ‭Protozoal infections (i.e. giardia, trichomoniasis)‬ ‭Adverse Effects‬ ‭●‬ ‭Common:‬ ‭○‬ ‭Headache‬ ‭○‬ ‭Xerostomia‬ ‭○‬ ‭Metallic taste‬ ‭○‬ ‭GI disturbances:‬‭Nausea‬ ‭○‬ ‭CNS:‬‭Dizziness, decreased appetite‬ ‭○‬ ‭Disulfiram reaction with‬‭alcohol‬ ‭■‬ ‭Similar to cephalosporins‬ ‭●‬ ‭Rare:‬‭Stevens-Johnson Syndrome‬ ‭ atient Education Exercise‬ P ‭You are caring for a patient who will be discharged with a prescription for metronidazole 500 mg‬ ‭PO BID x 7 days.‬ ‭1.‬ ‭How often will the patient take the metronidazole and for how long?‬ ‭a.‬ ‭Twice a day for 7 days‬ ‭2.‬ ‭What side effects would you be sure to prioritize in your education?‬ ‭a.‬ ‭Stevens-Johnson syndrome, disulfiram reaction, dizziness, xerostomia‬ ‭3.‬ ‭When should the patient contact the provider?‬ ‭a.‬ ‭Upon the onset of any adverse effects, including uncommon ones, such as signs of‬ ‭an allergic reaction, abnormal urination, vaginal itching/discharge, redness or‬ ‭white patches in mouth/throat, ringing in ears, pelvic pain, confusion, irritability,‬ ‭depression, weakness, rapid heart rate‬ ‭4.‬ ‭What would you recommend the patient do if experiencing xerostomia?‬ ‭a.‬ ‭Remain hydrated; keep water with you but have access to the restroom‬ ‭b.‬ ‭Have food/snacks that induce salivation (ex. Hard candy)‬ ‭5.‬ ‭What other education would you provide to this patient?‬ ‭a.‬ ‭Avoid concurrent consumption of alcohol‬ ‭b.‬ ‭Metronidazole may be contraindicated if less than 12 weeks pregnant, on dialysis,‬ ‭or following a sodium-free diet‬ ‭c.‬ ‭Take with food if administration causes an upset stomach‬ ‭d.‬ ‭If taken in liquid form, shake well before use‬ ‭e.‬ ‭If a dose is missed, take it as soon as possible‬ ‭Antimycobacterial Agents: Tuberculosis‬ ‭Tuberculosis (TB)‬ ‭●‬ ‭Estimated 10 million people with TB in 2020‬ ‭○‬ ‭1.1 million children‬ ‭○‬ ‭~7,000-8,000 new cases in the U.S. annually‬ ‭●‬ ‭⅓ of world population is infected with TB‬ ‭●‬ ‭13th leading cause of death in the world‬ ‭○‬ ‭TB killed more than 1.5 million people in 2020‬ ‭●‬ ‭TB incidence is falling about 2% per year‬ ‭●‬ ‭Mortality has fallen 22% in the past 15 years‬ ‭Pathogenesis‬ ‭●‬ ‭Mycobacterium tuberculosis‬ ‭●‬ ‭May be limited to the lungs or may disseminate‬ ‭●‬ ‭Bacteria are latent in most cases; significant population with latent TB‬ ‭●‬ ‭When the disease is active, morbidity is significant‬ ‭Primary (Initial) Infection‬ ‭●‬ ‭Transmitted from person to person‬ ‭○‬ ‭Inhalation of infected, aerosolized sputum‬ ‭●‬ ‭Initial infection in the lungs‬ ‭○‬ ‭Can spread to the blood, spine, or kidneys‬ ‭●‬ ‭Immunity usually develops within a few weeks‬ ‭●‬ ‭90% of normal immune systems never develop clinical or radiologic evidence of TB‬ ‭○‬ ‭Individuals likely harbor the bacteria for life‬ ‭●‬ ‭If the immune system fails to control the primary infection, TB develops‬ ‭○‬ ‭Necrosis and cavitation of lung tissue‬ ‭■‬ ‭Cavitation: Formation of large air pockets‬ ‭○‬ ‭Severe destruction of lung tissue‬ ‭●‬ ‭Reactivation:‬‭Renewal of dormant tubercle bacilli‬ ‭○‬ ‭60% of new infections may be caused by reactivation‬ ‭Goal of TB Treatment‬ ‭●‬ ‭Eliminate symptoms and prevent relapse by killing tubercle bacilli that are actively‬ ‭dividing as well as those that are “resting”‬ ‭Drug Resistance and Treatment‬ ‭●‬ ‭Resistance is a major obstacle to treatment‬ ‭○‬ ‭Mono-resistance‬ ‭○‬ ‭Poly-resistance‬ ‭ ‬ ‭Multidrug-resistant TB (MDR TB)‬ ○ ‭○‬ ‭Extensively drug-resistant TB (XDR TB)‬ ‭○‬ ‭Rifampicin resistance (RR)‬ ‭ ‬ ‭Treatment must‬‭always include 2+ drugs‬‭to which the‬‭infecting organism is sensitive‬ ● ‭●‬ ‭Inadequate drug therapy is the primary cause of resistance‬ ‭Causes of Inadequate Drug Therapy‬ ‭●‬ ‭Poor patient adherence‬ ‭○‬ ‭Accessibility‬ ‭○‬ ‭Regimen is too long/complicated‬ ‭○‬ ‭Cost of therapy‬ ‭●‬ ‭Inadequacy‬ ‭○‬ ‭Duration is too short‬ ‭■‬ ‭To kill actively dividing and dormant bacilli‬ ‭○‬ ‭Inconsistent dosing‬ ‭○‬ ‭Dosage is too low‬ ‭○‬ ‭Too few drugs in combination‬ ‭●‬ ‭Directly observed therapy (DOT)‬ ‭First-Line Antimycobacterial Drugs‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ I‭ soniazid (Isotamine)‬ ‭Rifampin (Rifadin)‬ ‭Pyrazinamide‬ ‭Ethambutol (Myambutol)‬ ‭Isoniazid‬ ‭‬ B ● ‭ actericidal: To active‬‭ly dividing bacteria‬ ‭●‬ ‭Bacteriostatic: To dormant‬‭TB organisms‬ ‭○‬ ‭So immune system can target them‬ ‭●‬ ‭Indication: Active and latent TB‬ ‭○‬ ‭Reserve for‬‭non-resistant‬‭forms of‬‭M. tuberculosis‬‭only‬ ‭●‬ ‭MOA: Suppresses growth by inhibiting synthesis of mycolic acid‬ ‭●‬ ‭Resistance is increasing; spontaneous mutation during treatment‬ ‭●‬ ‭Multi-drug approach‬‭required‬ ‭Adverse Effects‬ ‭●‬ ‭Most common:‬‭Peripheral neuropathy‬ ‭○‬ ‭S/S: Symmetrical paresthesias in hands/feet‬ ‭○‬ ‭Clumsiness, unsteadiness, muscle aches‬ ‭○‬ ‭Treatment:‬‭Vitamin B6‬‭(Pyridoxine)‬ ‭‬ H ● ‭ epatotoxicity‬‭: Risk increases with age‬ ‭●‬ ‭CNS effects:‬‭Optic neuritis‬‭, seizures, dizziness,‬‭ataxia, depression‬ ‭Drug Interactions‬ ‭●‬ ‭Strong P450 inhibitor‬‭of several enzymatic families‬ ‭○‬ ‭Causes multiple interactions‬ ‭●‬ ‭Alcohol‬‭: Increases risk for liver injury‬ ‭Considerations for Administration‬ ‭●‬ ‭Monitor liver function monthly‬ ‭○‬ ‭Look for elevated aminotransferase (AST) and alanine aminotransferase (ALT)‬ ‭●‬ ‭Education about S/S of hepatotoxicity‬ ‭○‬ ‭Anorexia‬ ‭○‬ ‭Fatigue‬ ‭○‬ ‭Jaundice‬ ‭○‬ ‭Alcohol use‬ ‭○‬ ‭Report signs if they occur‬ ‭●‬ ‭Report signs of neuropathy‬ ‭Rifampin (Rifadin)‬ ‭‬ B ● ‭ road-spectrum‬‭antibiotic;‬‭bactericidal‬ ‭●‬ ‭MOA: Inhibits DNA/RNA enzymes to suppress RNA synthesis = no protein synthesis‬ ‭Therapeutic Use:‬ ‭●‬ ‭Tuberculosis‬ ‭●‬ ‭Leprosy‬ ‭●‬ ‭S. aureus‬‭infections‬ ‭Adverse Effects‬ ‭●‬ ‭Discoloration of body fluids‬ ‭●‬ ‭Hepatotoxicity‬ ‭●‬ ‭Hepatitis (rare)‬ ‭Drug Interactions‬ ‭●‬ ‭Induces P450‬‭; can hasten drug metabolism, reducing‬‭effectiveness‬ ‭○‬ ‭Oral contraceptives‬ ‭○‬ ‭Warfarin‬ ‭○‬ ‭Drugs for HIV infection‬ ‭●‬ ‭Alcohol‬‭can increase risk of hepatotoxicity‬ ‭Considerations for Administration‬ ‭●‬ ‭Monitor liver function (ALT/AST)‬ ‭Patient Education‬ ‭●‬ ‭S/S of hepatitis‬ ‭●‬ ‭Discoloration of body fluids‬ ‭●‬ ‭Alternate form of birth control‬ ‭●‬ ‭Potential drug interactions‬ ‭Pyrazinamide‬ ‭‬ M ● ‭ OA: Inhibit fatty acid synthesis‬ ‭●‬ ‭Bactericidal‬‭to‬‭M. tuberculosis‬ ‭Therapeutic Use‬ ‭●‬ ‭Tuberculosis‬ ‭●‬ ‭Used in combination therapy to treat active TB‬ ‭Adverse Effects‬ ‭●‬ ‭Hepatotoxicity:‬‭Increased risk when used in combination‬‭with isoniazid or rifampin‬ ‭●‬ ‭Has caused hepatitis‬ ‭○‬ ‭S/S: Malaise, anorexia, N/V, jaundice‬ ‭●‬ ‭Polyarthralgias:‬ ‭○‬ ‭Affect ~40% of patients‬ ‭○‬ ‭Can be dose-dependent‬ ‭●‬ ‭Hyperuricemia:‬‭Abnormally high levels of uric acid‬‭in the blood‬ ‭●‬ ‭Photosensitivity‬ ‭Considerations for Administration‬ ‭●‬ ‭Close monitoring of liver function‬ ‭●‬ ‭ALT/AST baseline an Q2 weeks‬ ‭●‬ ‭Educate patient about S/S hepatitis‬ ‭●‬ ‭Polyarthralgias‬ ‭○‬ ‭Manage with NSAIDs‬ ‭○‬ ‭May need to decrease dose‬ ‭Ethambutol (Myambutol)‬ ‭‬ M ● ‭ OA: Inhibits an enzyme leading to impairment of cell wall synthesis‬ ‭●‬ ‭Bacteriostatic‬‭: Active only against mycobacteria‬ ‭●‬ ‭Pharmacokinetics:‬‭Minimal hepatic‬‭metabolism‬ ‭Adverse Effects‬ ‭●‬ ‭Most significant:‬‭Optic neuritis‬ ‭○‬ ‭Blurred vision, disturbance of color vision, narrow visual field‬ ‭○‬ ‭Symptoms resolve with discontinuation‬ ‭○‬ ‭Not recommended in patients < 8 years old‬ ‭●‬ ‭Allergic reactions (dermatitis, pruritus)‬ ‭●‬ ‭GI upset‬ ‭●‬ ‭Confusion‬