Lecture 6 - Introduction to Antibiotics (Part 2) PDF

Lecture 6 — Introduction to Antibiotics (Part 2) Dr. Ed El Sayed NURS 342 Objectives General mechanism action of DNA synthesis inhibitors and anti-mycobacterial agents Minimum inhibitory concentration vs. Minimum bactericidal concentration Time dependent vs. Concentration dependent antimicrobial act...

Lecture 6 — Introduction to Antibiotics (Part 2) Dr. Ed El Sayed NURS 342 Objectives General mechanism action of DNA synthesis inhibitors and anti-mycobacterial agents Minimum inhibitory concentration vs. Minimum bactericidal concentration Time dependent vs. Concentration dependent antimicrobial action Bacteriostatic vs Bactericidal antibiotics Empiric vs Targeted antibiotic therapy Basics of antimicrobial pharmacokinetics 1. Bacterial DNA Synthesis Inhibitors This class inhibit bacteria by targeting key steps in nucleic acid synthesis during the replication cycle Subdivided into two classes: A. Loading… Antimetabolites (pseudo-analogs) B. Direct enzyme inhibitors blocking synthesis of DNA A. Antimetabolites Sulfamethoxazole + Trimethoprim (SMX/TMP) Sulfamethoxazole is a structural analog of para-amino benzoic acid (PABA) PABA is acted on by bacterial enzyme dihydropteroate synthase (DHPS) to synthesize DNA Sulfamethoxazole will therefore compete with PABA for DHPS and stop DNA synthesis Trimethoprim is a structural analog of folate Folate is acted on by bacterial dihydrofolate reductase (DHFR) to synthesize DNA Trimethoprim will therefore compete with folate for DHFR and stop DNA synthesis SMX+TMP work synergistically to prevent bacterial DNA synthesis Loading… TMP+SMX combo is active against Gram positive and Gram negative infections - - Also active against MRSA infections - - T NO reliable pseudomonas coverage - TMP+SMX is FIRST LINE option for E. coli (e.g. urinary tract infections), pneumocystis pneumonia (PCP) and toxoplasmosis in immunocompromised patients (e.g. AIDS) An analog of SMX (sulfonamide) is used topically to treat burn victims neomyack sulfuramide basitracin Toxicity: GI disturbances Hypersensitivity reactions and rash Neutropenia Anemia — higher risk in persons with glucose 6-phosphate dehydrogenase (G6PD) deficiency Hyperkalemia (caution with other drugs that are also associated with hyperkalemia) 2. Direct enzyme inhibitors I. Fluoroquinolones (FQ): - Ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, ofloxacin - Work by inhibiting bacterial topoisomerase II (aka DNA gyrase) II. - Metronidazole: Prodrug, forms reactive free radicals that are directly toxic to DNA III. Nitorfurantoin: (Mixed DNA and ribosomal inhibitor) I. Fluoroquinolone (FQ) FQ are mainly active against Gram negative infections Used FIRST LINE in osteomyelitis (only if the bacteria is sensitive) The “respiratory FQ” are levofloxacin and moxifloxacin Ciprofloxacin is an option to treat urinary tract infections Ofloxacin is used topically as ear drops for otic infections Only agent active against MRSA is delafloxacin Only agent active against anaerobic infection on its own is moxifloxacin FQ toxicity: GI disturbances Tendon rupture (Achilles heel) QT prolongation Hypoglycemia (especially in elderly or diabetes patients) FQs are NOT used in pregnancy or children (bone toxicity) II. Metronidazole Mainly active against anaerobic infections (below the diaphragm) First line treatment for trichomonas vaginalis infection and bacterial vaginosis (BV) Also used in combination with FQ to treat intra-abdominal infections (e.g. fistulas in Loading… patients with inflammatory bowel disease) Not used first line anymore to treat uncomplicated C. diff infection (now reserved for severe cases) Toxicity: GI distress Meningitis III. Nitrofurantoin Broad spectrum, active against Gram positive and negative organisms Used primarily in urinary tract infections For frequent recurrence — use long term as prevention Unique toxicity: Pulmonary fibrosis 3. Mycobacterial Inhibitors These are antibiotics with specificity to mycobacteria species Drug Rifapentine+isoniazid is for latent TB Dapsone is for leprosy (in combo with rifampin) All of them cause hepatotoxicity Unique toxicity DNA synthesis inhibitor Induction of hepatic enzymes Discoloration of body fluids Isoniazid Mycolic acid cell wall inhibitor Neuropathy (must coadminister with vitamin B6 (pyridoxine) Pyrazinamide Unknown Arthritis Ethambutol Mycolic acid cell wall inhibitor Retinitis Rifampin/Rifapentine Rifampin, Isoniazid, Pyrazinamide and Ethambutol (RIPE) are for active tuberculosis (TB) Mechanism of action Dapsone DNA synthesis inhibitor Hemolysis Methemoglobinemia · “Rifampin urine” Antibiotic Summary I. Minimum Inhibitory Concentration vs Minimum Bactericidal Concentration Minimum Inhibitory Concentration (MIC): The concentration of antibiotic that inhibits visible bacterial growth at 24 hours of growth in specific media and under specific conditions. Minimum Bacteriostatic Concentration (MBC): The concentration of antibiotic that results in a 1,000-fold reduction in bacterial density at 24 hours of growth in specific media and under specific conditions. II. Bacteriostatic vs Bactericidal Bacteriostatic: An antibiotic that slows down the growth of bacteria Bactericidal: An antibiotic that kills bacteria If the MBC:MIC ratio is less than or equal to 4, the antibiotic is considered bactericidal against the organism being tested If the MBC:MIC ratio is greater than 4, the antibiotic is considered bacteriostatic against the organism being tested Theoretically increasing the concentration of a bacteriostatic antibiotic high enough will turn it in to bactericidal (this is possible in the lab/test tube, but not in clinic/patients because of toxicity!) III. Time dependent vs. Concentration dependent killing Time dependent killing: The LONGER the antibiotic concentration stays above MIC, the greater the extent of killing (higher concentrations above MIC has minimal effect) — examples are beta-lactams, macrolides, linezolid and sulfamethoxazole Concentration dependent killing: The HIGHER the antibiotic concentration is above the MIC, the greater the extent of killing (longer durations above MIC has minimal effect) — examples are fluoroquinolones, aminoglycosides and glycopeptides Tetracyclines exhibit both time and concentration dependent killing IV. Empiric vs Targeted Therapy Empiric Tx: At the time of clinical presentation, the causative organism is unknown, so a broad spectrum antibiotic is used until lab data (culture, PCR, sensitivity, etc.) comes back Targeted Tx: A narrow spectrum antibiotic is selected based on the known identity and sensitivity of the causative organism The advantage of using empiric therapy is rapid initiation of antibiotics to control infection, prevent further transmission and worsening of disease The disadvantage is that many other organisms (including normal flora) are killed and the resistance risk is high V. Basics of Antimicrobial Pharmacokinetics Loading dose (LD): The amount of drug needed to achieve a therapeutic level in the body. The is a one-time administration. Maintenance dose (MD): The among of drug needed to uphold the steady state concentration of the drug in the body at therapeutic level (Css means rate of drug in = rate of drug out). This is usually a recurrent dose throughout the duration of therapy. Bioavailability (F): The actual amount of drug reaching the systemic circulation (ranges from 0-1). Intravenous drugs have F=1, for oral drugs F