Quinolone and Aminoglycoside Antibiotics

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Quinolone and Aminoglycoside Antibiotics

• Edgar Rios, Pharm.D., BCPS
• MHH Clinical Pharmacist
• UTHSCH Clinical Assistant Professor

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Overview

• Chemical Structure
• Classifications and spectrum of activity
• Mechanism of action and resistance
• Pharmacologic properties and pharmacodynamics
• Adverse effects
• Clinical uses

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Silver Nature Reviews Drug Discovery 6, 4155
(January 2007) doi10.1038 / nrd2202
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Mechanisms of resistance

• Alterations in target enzymes
• Chromosomally mediated
• Occur in 1 in 106 to 1 in 109 bacteria
• Resistance arises in a stepwise fashion
• Decreased permeation
• 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

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Pharmacodynamic Interactions
Peak/MIC
AUC/MIC
Concentration
MIC
Time
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Relationship Between AUC24/MIC and Efficacy of
Ciprofloxacin in Patients with Serious Bacterial
Infections
Forrest A, et al. AAC, 1993 37 1073-1081
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Proposing PK/PD limits for sensitivity
PK values PK/PD limits Breakpoints
(mg/L) Drug Daily Dose Cmax AUC Efficacy
EUCAST CLSI (mg/L) (mgh/L) (mg/L)
AUC/MIC (S-R) (S,I,R) Cipro 1000mg 2.5 24 0.2,0
.8 120,30 lt0.5,gt1 lt1,2,gt4 1500mg 3.6 32 160,40
Levo 500mg 4.0 40 0.3,0.9 133,44 lt1,gt2 lt2,4,gt8 M
oxi 400mg 3.1 35 0.2,0.7 175,50 lt0.5,gt1 lt2,4,gt8
(G-) lt1,2,gt4 (G)
Adapted with data from Clin Microbiol Infect
2005 11256-280 Emerging Infectious Diseases
2003 91-9
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Clinical Uses

• Indication Cipro Levo Moxi
• UTI X X
• Prostatitis X X
• Gonorrhea X
• Gastroenteritis X
• Intra-abdominal infection Xa Xb
• Respiratory tract infection X X X
• Bone and joint infection X
• Skin and skin structure infection X X X
• a In combination with metronidazole
• b As monotherapy

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Aminoglycosides

• Agent Source Year
• Streptomycin Streptomyces griseus 1944
• Neomycin Streptomyces fradiae 1949
• Kanamycin S. kanamyceticus 1957
• Paromomycin S. fradiae 1959
• Spectinomycin S. spectabilis 1962
• Gentamicin Micromonospora purpurea 1963
• and M. echinospora
• Tobramycin S. tenebrarius 1968
• Amikacin S. kanamyceticus 1971
• Netilmicin M. inyoensis 1975

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Mechanism of Action
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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

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Spectrum

• Gentamicin tobramycin lt amikacin
• Gram-negative organisms
• Fermenters and Pseudomonas aeruginosa
• Gram-positive organisms
• Staphylococcus spp. and Enterococci
• Miscellaneous

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Pharmacokinetics

• Absorption
• Not absorbed orally
• Must be given parenterally
• Distribution
• Poor into most tissues
• Elimination
• Renal

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Concentration vs Time-dependent Killing
Tobramycin
Ticarcillin
Time (hours)
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Peak/MIC Ratio and Clinical Response with
Aminoglycosides
Moore,et al. J Inf Disease, 1987 155(1) 93-98
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Does S Really Mean Sensitive?
Peak / MIC
Peak serum concentration
MIC Gent/Tobra Amikacin
0.25 32 84
0.5 16 40
1 8 20
2 4 10
4 2 5
8 1 2.5
16 0.5 1.25
32 0.25 0.625
64 0.125 0.3125
G/T 2 mg/kg 8 mcg/ml A 5 mg/kg 20 mcg/ml
CLSI breakpoints
S I R G/T lt4 8 gt16 A lt16 32 gt64
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Once Daily vs Traditional Dosing

• Whats the difference?
• Rational
• Concentration-dependent killing
• Post antibiotic effect
• Bacteria remains stunned even without any drug
• Allows for a drug free interval
• Less toxicity

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ODA vs Traditional Dosing
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Once Daily vs Traditional Dosing?

• Evidence for once daily
• Pneumonia, UTI, PID, IAI, bacteremia
• Lack of evidence for once daily
• Geriatric, CrCl lt20ml/min, obese, pregnant, burn,
  cystic fibrosis, ascites, osteomyelitis,
  enterococcal infections

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Once Daily Dosing

• Dose
• Gent/tobra 7 mg/kg (peak 20mcg/ml)
• Amikacin 15 mg/kg (peak 40mcg/ml)
• Interval every 24 hours (ClCr gt 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

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Antimicrob Agents Chemother. 199539650-55.
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Traditional DosingHow to dose?

• Based on volume of distribution (0.25-0.3 L/kg)
• Peak serum levels (mcg/ml)
• Pneumonia/sepsis soft tissue UTI
• Gent/tobra 6-10 5-7 4-6
• Amikacin 25-30 20-25 20
• Loading Dose Gent/tobra 2 - 3 mg/kg
• Amikacin 7.5 mg/kg
• Maintenance doses (mg/kg)
• Pneumonia/sepsis soft tissue UTI
• Gent/tobra 1.8-2 1.5
  1
• Amikacin 6.5 5.5 4
• Trough Levels (mcg/ml)
• Gent/tobra lt 2 Amikacin 4-10

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Traditional DosingWhat interval do I choose?

• Based on CrCl (renal function)
• CrCl (ml/min) t1/2 (hours) interval (hours)
• gt75 lt 3 8
• 51-75 3-4.4 12
• 25-50 4.5-8 24
• lt 25 gt 8 gt 24
• What do I monitor?
• Levels, renal function, ototoxicity

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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

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Bedside kinetics

• Typical Vd 0.25 0.3 L/kg
• Typical half life 2.5 -3 hours (with ClCr gt
  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

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Dosage Regime ManipulationPeaks/Troughs
Concentration Parameter Manipulation
P high, T OK 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