Quinolones. Drugs: norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin Mechanism of action:
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1 Quinolones Drugs: norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin Mechanism of action: Inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topoisomerase IV rapid cell death Post antibiotic effect: lasts 1 to 2 hours, increases with increasing concentration Mechanism of resistance: Chromosomal: Alter target enzymes: DNA gyrase and topoisomerase IV Decreased drug penetration: Pseudomonas, E. coli Plasmid: seen in some K. pneumoniae and E. coli Mutations in both target enzymes are needed to produce significant resistance
2 Quinolones Parent drug: nalidixic acid
3 Classification Quinolones (1 st generation) Highly protein bound Mostly used in UTIs Fluoroquinolones (2 nd, 3 rd and 4 th generation) Modified 1 st generation quinolones Not highly protein bound Wide distribution to urine and other tissues; limited CSF penetration.
4 Generation Drug Names Spectrum 1st 2nd 3rd 4th nalidixic acid cinoxacin norfloxacin ciprofloxacin enoxacin ofloxacin levofloxacin sparfloxacin moxifloxacin gemifloxacin *trovafloxacin Gram- but not Pseudomonas species Gram- (including Pseudomonas species), some Gram+ (S. aureus) and some atypicals Same as 2 nd generation with extended Gram+ and atypical coverage Same as 3 rd generation with broad anaerobic coverage *withdrawn from the market in 1999
5 Mechanism of Action Dual MOA: 1. Inhibition of bacterial DNA Gyrase (Topoisomerase II) 1. Formation of quinolone-dna-gyrase complex 2. Induced cleavage of DNA 2. Inhibition of bacterial Topoisomerase IV 1. Mechanism poorly understood Mechanism of DNA Gyrase
6 Mechanism of Action
7 Quinolones [Conc] > serum: Prostate tissue Stool Bile Lung Neutrophils Macrophages Kidneys [Conc] < serum: Prostatic tissue fluid Bone CSF
8 Quinolones Drug interactions: absorption: Al3+, Mg2+, and Ca2+ antacids CYP450 inhibition potential drug interactions for ciprofloxacin (Ex) can increase warfarin exposure (real changes in INR are rare, but monitor) Adverse effects: GI: Nausea, vomiting CNS: HA, dizziness, confusion, insomnia, delerium, hallucinations, seizure (rare) Cardiovascular: Torsades de pointes (rare) Musculoskeletal: Rupture of tendon (rare) Neurologic: Polyneuropathy (rare)
9 Quinolones PK/PD Bactericidal antibiotics Show both time-dependent and a combination of time- dependent and concentration dependent killing Time-Dependent vs. Concentration-Dependent Killing
10 Ciprofloxacin Administration [Usual Dosage]: IV, PO [ mg q 8-12h] Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor activity against Strep. pneumoniae. Indications: -- Nosocomial pneumonia -- Intra-abdominal infections Uncomplicated/complicated UTI Anthrax exposure and prophylaxis Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases absorption -- Increased effects of warfarin ADRs QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis
11 Levofloxacin Brand Name: Levaquin, Quixin Administration [Usual Dosage]: IV, PO and ophthalmic [ mg q24h] Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens, Mycobacterium tuberculosis Indications: Chronic bronchitis and CAP -- Nosocomial pneumonia SSTIs Intra-abdominal infections Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases absorption ADRs Blood glucose disturbances in DM patients QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis
12 Moxifloxacin Brand Name: Avelox, Vigamox Administration [Usual Dosage]: IV, PO and ophthalmic [400mg q24h] Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) & atypicals (L. pneumophila, C pneumonia & M. pneumoniae), Mycobacterium tuberculosis, gram-negative anaerobes Indications: Chronic bronchitis CAP Bacterial conjuctivitis Sinusitis Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases absorption Safety and efficacy not established in patients <18 y.o. ADRs Blood glucose disturbances in DM patients QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis
13 Resistance Mechanisms Mutations that enhance antibiotic efflux capability Bacterial chromosomal mutations for genes that encode for bacterial DNA gyrase and Topo IV Mutations in outer membrane porins (Gram-)
14 Metronidazole Mechanism of action: Enters bacteria via cell diffusion Activated via single reduction step by bacteria forms radicals reacts with nucleic acid cell death Spectrum of activity: Anaerobic bacteria Microaerophilic bacteria Protozoa Resistance: Rare Mechanism: decreased activation ( redox reaction) of drug
15 Metronidazole Indications*: Anaerobe infections C. difficile H. pylori Bacterial vaginosis Trichomonas vaginitis Amebiasis Giardiasis Drug interactions: EtOH Antacids CyA/tacrolimus Lithium Phenytoin Rifampin Warfarin * Dose can vary by indication
16 Metronidazole Distribution into tissue: Therapeutic levels: PMNs Unobstructed biliary tract Pancreas CSF Empyema fluid Peritoneal fluid Hepatic abscess Pelvic tissues Vaginal/seminal fluid Adverse Effects: GI: N, V, epigastric distress Metallic taste Darkening of urine Peripheral neuropathy Pancreatitis Hepatitis Fever Reversible neutropenia
17 Tetracyclines Broad-spectrum activity Includes aerobic G+ and G-, atypicals [Rickettsia spp, treponema spp, chlamydia spp, and others] Little to no effect on fungi or viruses Tetracycline Doxycycline* Minocycline Tigecycline
18 Mechanism of Action Passive diffusion
19 Mechanism of Action Once inside the cell Bind 30S ribosomal subunit Blocks binding of aminoacyl-trna to acceptor site on mrna-ribosome complex Protein synthesis is inhibited = bacteriostatic effect
20 Tetracycline Dosing: Adult: mg PO q6h Peds: mg/kg/d q6h Food and milk decrease absorption about 50% Administer at least 1-2 hours prior to or 4 hours after antacid or vitamins due to chelation [Al 3+, Mg 2+, Ca 2+, Fe 2+ ] m
21 Tetracycline Dosage forms: Capsule: 250, 500 mg Tablet: 250, 500 mg Suspension: 125 mg/5 ml Adverse Effects: Photosensitivity Discoloration of teeth N/V/D Candidal superinfection Hepatotoxicity
22 Tetracycline - Special Populations Pregnancy Category D Enters breast milk Renal insufficiency CrCl: ml/min: every 8-12 hours CrCl: ml/min: every hours CrCl: <10 ml/min: every 24 hours Hepatic insufficiency Avoid use If necessary, maximum 1g/day
23 Doxycycline Dosing: Adults: mg/day in 1-2 divided doses PO or IV Peds: > 45 kg use adult dosing < 45 kg: 2-5 mg/kg/day in 1-2 divided doses. [Max. 200 mg/day] Give with meals to decrease GI upset Take with water and sit up for 30 minutes to avoid esophageal irritation
24 Doxycycline Dosage forms: Capsules Hyclate, monohydrate: Adverse Effects 50, 100 mg Coated pellets: 75,100 Discoloration of teeth mg Diarrhea Variable release: 40mg - 30 immediate and 10 Rash delayed Photosensitivity Injection: 100 mg Suspension: Urticaria 25mg/5mL Tablet: Hyclate: 100 mg Monohydrate: 50,75,100 mg Delayed-release coated pellets: 75,100 mg
25 Pregnancy Doxycycline - Special Populations Category D, but use in pregnancy and Use in children single 5-7 day course for RMSF is safe Renal Insufficiency No adjustment necessary
26 Tigecycline Dosing: Adults: initial dose of 100 mg. Maintenance dose: 50 mg q12h x 5-14 days. FDA indications: complicated SSTIs and intraabdominal infections
27 Tigecycline Dosage forms: Injection: 50 mg Administration Infuse over mins through dedicated line or via Y-site. Stable in D5W or NS Adverse Effects: N/V/D Hypertension Edema Hypotension Headache Rash Pruritus Local irritation
28 Tigecycline - Special Populations Pregnancy Category D Not recommended - crosses placenta Renal Insufficiency No dosage adjustment required Hepatic Impairment Severe: initial dose 100 mg followed by 25 mg q12h
29 Tigecycline Aerobic and facultative gram negative organisms: Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella species Anaerobic organisms: Bacteroides species (including fragilis) Clostridium perfringens Peptostreptococcus micros
30 Tigecycline Distribution: [Gall bladder], [Colon], [Lung] > [Serum] [Bone], [Synovial fluid] < [Serum] Elimination: Mostly feces/biliary excretion (59%) Some excretion in urine (33%) Adverse Effects (incidence): Nausea (29.5%) Vomiting (19.7%) Diarrhea (12.7%) Local reaction (9.0%)
31 TMP/SMX Good activity against Gr (+) and Gr (-) organisms: MRSA, very active against PCP. Covers Stenotrophomonas maltophila, Nocardia, and enteric gram-negative rods. Exceptions: Pseudomonas aeruginosa, Group A strep, enterococcus, Gr (-) anaerobes. MOA: Sulfamethoxazole interferes with bacterial folic acid synthesis and growth via inhibition of dihydrofolic acid formation from paraaminobenzoic acid; trimethoprim blocks the production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. Use with caution in pts with severe G6PD deficiency Toxicity: GI upset, rash can progress to SJS and TEN, thrombocytopenia, leucopenia, hepatitis; hyperkalemia SMX:TMP is a 5:1 ratio, in oral and IV dosage forms mg/kg (of TMP) daily, in 2 to 4 divided doses (q 6 h) for PCP, Nocardia, Stenotrophomonas, GNR; DS 2 BID for MRSA.
32 Colistin (polymyxin E) MOA: binds to lipopolysaccharide on outer cell wall of GNR; permeability change in cell envelope; leakage of cell content. Formulation, IV: colistimethate hydrolyzed to colistin. PK/PD: negligible oral absorption, predominant renal elimination; concentration-dependent activity.
33 Colistin Spectrum: aerobic gram-negative rods, including Acinetobacter, Ps. aeruginosa, Stenotrophomonas. NOT active against: Burkholdaria, Proteus, Serratia, Brucella, gram-negative anaerobes, gram-positive cocci Adverse effects: ATN; Neurotoxicity dizziness, weakness, vertigo, visual changes, confusion, ataxia.
34 Colistin Dosing regimens (poorly defined): 2.5 to 5 mg/kg/day in 2-4 doses For SCr : 160 mg q 12h SCr : 160 mg q 24 h SCr > 2.6: 160 mg q 36 h Hemodialysis: Load with 160 mg, then 80 mg after each dialysis.
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