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Quinolone and Aminoglycoside Antibiotics Edgar Rios, Pharm.D., BCPS MHH Clinical Pharmacist UTHSCH Clinical Assistant Professor Overview Chemical Structure Classifications and spectrum of activity Mechanism of action and resistance Pharmacologic properties and pharmacodynamics Adverse effects Clinical uses Silver Nature Reviews Drug Discovery 6, 41–55 (January 2007) | doi:10.1038 / nrd2202 Mechanisms of resistance Alterations in target enzymes Decreased permeation Chromosomally mediated Occur in 1 in 106 to 1 in 109 bacteria Resistance arises in a stepwise fashion Changes in porins (OmpF) Efflux pumps (MexAB-OprM) Low to intermediate levels of resistance Can effect other drugs Plasmid meditated resistance qnr gene Protects DNA gyrase and topoisomerase IV Low level resistance Pharmacodynamic Interactions Concentration Peak/MIC AUC/MIC MIC Time Relationship Between AUC24/MIC and Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infections % Efficacy 100 80 60 40 20 0 0-62.5 62.5-125 125-250 250-500 >500 24-Hour AUC/MIC Clinical Microbiologic Forrest A, et al. AAC, 1993; 37: 1073-1081 Proposing PK/PD limits for sensitivity PK values Drug Breakpoints (mg/L) EUCAST Cmax AUC Efficacy (mg/L) (mg*h/L) (mg/L) AUC/MIC (S-R) (S,I,R) 1000mg 2.5 24 0.2,0.8 120,30 <0.5,>1 <1,2,>4 1500mg 3.6 32 Levo 500mg 4.0 40 0.3,0.9 133,44 <1,>2 <2,4,>8 Moxi 400mg 3.1 35 0.2,0.7 175,50 <0.5,>1 <2,4,>8 (G-) Cipro Daily Dose PK/PD limits CLSI 160,40 Adapted with data from: Clin Microbiol Infect 2005; 11:256-280 Emerging Infectious Diseases 2003; 9:1-9 <1,2,>4 (G+) Clinical Uses Indication UTI Prostatitis Gonorrhea Gastroenteritis Intra-abdominal infection Respiratory tract infection Bone and joint infection Skin and skin structure infection a In combination with metronidazole b As monotherapy Cipro X X X X Xa X X X Levo X X Moxi X Xb X X X Aminoglycosides Agent Streptomycin Neomycin Kanamycin Paromomycin Spectinomycin Gentamicin Tobramycin Amikacin Netilmicin Source Streptomyces griseus Streptomyces fradiae S. kanamyceticus S. fradiae S. spectabilis Micromonospora purpurea and M. echinospora S. tenebrarius S. kanamyceticus M. inyoensis Year 1944 1949 1957 1959 1962 1963 1968 1971 1975 Mechanism of Action Resistance Alteration in ribosomal binding sites Mycobacterial resistance to streptomycin Altered uptake Staph spp. and Pseudomonas aeruginosa Aminoglycoside modifying enzymes Plasmids and transposons Confer cross resistance Amikacin least effected Spectrum Gentamicin = tobramycin < amikacin Gram-negative organisms Fermenters and Pseudomonas aeruginosa Gram-positive organisms Staphylococcus spp. and Enterococci Miscellaneous Pharmacokinetics Absorption Not absorbed orally Must be given parenterally Distribution Poor into most tissues Elimination Renal Concentration vs Time-dependent Killing Log10 Colony Forming Units/ml Tobramycin Ticarcillin 9 Control 8 1/8 MIC 7 1/2 MIC 1 MIC 6 4 MIC 5 16 MIC 4 64 MIC 3 2 0 2 4 6 8 0 Time (hours) 2 4 6 8 Response Rate (%) Peak/MIC Ratio and Clinical Response with Aminoglycosides 100 90 80 70 60 50 2 4 6 8 10 12+ Maximum Peak / MIC ratio Moore,et al. J Inf Disease, 1987; 155(1): 93-98 Does “S” Really Mean Sensitive? Peak / MIC Gent/Tobra Amikacin Peak serum concentration MIC G/T: 2 mg/kg = 8 mcg/ml 0.25 0.5 1 32 16 8 84 40 20 2 4 8 4 2 1 10 5 2.5 16 32 64 0.5 0.25 0.125 1.25 0.625 0.3125 A: 5 mg/kg = 20 mcg/ml CLSI breakpoints S I R G/T <4 8 >16 A <16 32 >64 Once Daily vs Traditional Dosing What’s the difference? Rational Concentration-dependent killing Post antibiotic effect Bacteria remains “stunned” even without any drug Allows for a drug free interval Less toxicity Concentration (mcg/ml) ODA vs Traditional Dosing 25 20 15 10 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Times (Hours) ODA Traditional Once Daily vs Traditional Dosing? Evidence for once daily Pneumonia, UTI, PID, IAI, bacteremia Lack of evidence for once daily Geriatric, CrCl <20ml/min, obese, pregnant, burn, cystic fibrosis, ascites, osteomyelitis, enterococcal infections Once Daily Dosing Dose Gent/tobra = Amikacin = Interval: 7 mg/kg 15 mg/kg (peak ~ 20mcg/ml) (peak ~ 40mcg/ml) every 24 hours (ClCr > 60ml/min) every 36 hours (ClCr 40 – 60ml/min) Monitor Level 6 – 14 hours after starting the infusion Trough (needs to be undetectable), renal function Antimicrob Agents Chemother. 1995;39:650-55. Traditional Dosing How to dose? Based on volume of distribution (0.25-0.3 L/kg) Peak serum levels (mcg/ml) Pneumonia/sepsis Gent/tobra 6-10 Amikacin 25-30 Loading Dose: Gent/tobra Amikacin Maintenance doses (mg/kg): Pneumonia/sepsis Gent/tobra 1.8-2 Amikacin 6.5 Trough Levels (mcg/ml) Gent/tobra < 2 Amikacin 4-10 soft tissue 5-7 20-25 UTI 4-6 20 2 - 3 mg/kg 7.5 mg/kg soft tissue 1.5 5.5 UTI 1 4 Traditional Dosing What interval do I choose? Based on CrCl (renal function) CrCl (ml/min) t1/2 (hours) >75 <3 51-75 3-4.4 25-50 4.5-8 < 25 >8 What do I monitor? Levels, renal function, ototoxicity interval (hours) 8 12 24 > 24 Conclusion Fluoroquinolones Broad-spectrum but differences Resistance increasing Concentration dependent killing (AUC/MIC) Well tolerated Aminoglycosides Resurgence because of resistance Mainly gram negative activity Concentration dependent killing (Peak/MIC) Serious toxicities Bedside kinetics Typical Vd = 0.25 – 0.3 L/kg Typical half life = 2.5 -3 hours (with ClCr > 60ml/min) Wt: 80kg Goal peak: 10 mg/L LD = (80kg * 0.3 L/kg) * 10 mg/L = 240 mg At 3 half lives Conc = (10/2) = (5/2) = (2.5/2) = 1.25 Goal trough: 1mg/L MD = (10 mg/L – 1 mg/L) * 24 L = 216 ~ 220 mg Dosage Regime Manipulation: Peaks/Troughs Concentration Parameter P high, T OK Manipulation Decrease dose P low, T OK Increase dose** P OK, T high Increase interval P OK, T low Decrease interval P high, T high Decrease dose, Increase interval P low, T low Increase dose, decrease interval ** Trough may increase**