quinolone and aminoglycoside antibiotics edgar rios, pharm.d., bcps mhh clinical pharmacist uthsch...
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Quinolone and Quinolone and Aminoglycoside AntibioticsAminoglycoside Antibiotics
Edgar Rios, Pharm.D., BCPSEdgar Rios, Pharm.D., BCPS
MHH Clinical PharmacistMHH Clinical Pharmacist
UTHSCH Clinical Assistant ProfessorUTHSCH Clinical Assistant Professor
OverviewOverview
Chemical StructureChemical StructureClassifications and spectrum of activityClassifications and spectrum of activityMechanism of action and resistanceMechanism of action and resistancePharmacologic properties and Pharmacologic properties and
pharmacodynamicspharmacodynamicsAdverse effectsAdverse effectsClinical usesClinical uses
Silver Nature Reviews Drug Discovery 6, 41–55 (January 2007) | doi:10.1038 / nrd2202
Mechanisms of resistanceMechanisms of resistance Alterations in target enzymesAlterations in target enzymes
Chromosomally mediatedChromosomally mediated Occur in 1 in 10Occur in 1 in 1066 to 1 in 10 to 1 in 1099 bacteria bacteria Resistance arises in a stepwise fashionResistance arises in a stepwise fashion
Decreased permeationDecreased permeation Changes in porins (OmpF)Changes in porins (OmpF) Efflux pumps (MexAB-OprM)Efflux pumps (MexAB-OprM) Low to intermediate levels of resistanceLow to intermediate levels of resistance Can effect other drugsCan effect other drugs
Plasmid meditated resistancePlasmid meditated resistance qnr geneqnr gene Protects DNA gyrase and topoisomerase IV Protects DNA gyrase and topoisomerase IV Low level resistanceLow level resistance
Pharmacodynamic InteractionsPharmacodynamic Interactions
MIC
Con
cent
rati
on
Time
Peak/MIC
AUC/MIC
Relationship Between AUCRelationship Between AUC2424/MIC and Efficacy /MIC and Efficacy
of Ciprofloxacin in Patients with Serious of Ciprofloxacin in Patients with Serious Bacterial InfectionsBacterial Infections
0
20
40
60
80
100
% E
ffic
acy
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 Proposing PK/PD limits for sensitivitysensitivity
PK values PK/PD limits Breakpoints (mg/L)
Drug Daily Dose Cmax AUC Efficacy EUCAST CLSI
(mg/L) (mg*h/L) (mg/L) AUC/MIC (S-R) (S,I,R)
Cipro 1000mg 2.5 24 0.2,0.8 120,30 <0.5,>1 <1,2,>4
1500mg 3.6 32 160,40
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-)
<1,2,>4 (G+)Adapted with data from:
Clin Microbiol Infect 2005; 11:256-280
Emerging Infectious Diseases 2003; 9:1-9
Clinical UsesClinical Uses
IndicationIndication CiproCipro LevoLevo MoxiMoxi
UTIUTI XX XX
ProstatitisProstatitis XX XX
GonorrheaGonorrhea XX
GastroenteritisGastroenteritis XX
Intra-abdominal infectionIntra-abdominal infection XXaa XXbb
Respiratory tract infectionRespiratory tract infection XX XX XX
Bone and joint infectionBone and joint infection XX
Skin and skin structure infectionSkin and skin structure infection XX XX XX
aa In combination with metronidazole In combination with metronidazolebb As monotherapy As monotherapy
AminoglycosidesAminoglycosides
AgentAgent SourceSource YearYearStreptomycinStreptomycin Streptomyces griseusStreptomyces griseus 19441944NeomycinNeomycin Streptomyces fradiaeStreptomyces fradiae 19491949KanamycinKanamycin S. kanamyceticusS. kanamyceticus 19571957ParomomycinParomomycin S. fradiaeS. fradiae 19591959SpectinomycinSpectinomycin S. spectabilisS. spectabilis 19621962GentamicinGentamicin Micromonospora purpureaMicromonospora purpurea 19631963
and and M. echinosporaM. echinosporaTobramycin Tobramycin S. tenebrariusS. tenebrarius 19681968Amikacin Amikacin S. kanamyceticusS. kanamyceticus 19711971Netilmicin Netilmicin M. inyoensisM. inyoensis 19751975
Mechanism of ActionMechanism of Action
ResistanceResistanceAlteration in ribosomal binding sitesAlteration in ribosomal binding sites
Mycobacterial resistance to streptomycinMycobacterial resistance to streptomycin
Altered uptakeAltered uptakeStaphStaph spp. and spp. and Pseudomonas aeruginosaPseudomonas aeruginosa
Aminoglycoside modifying enzymesAminoglycoside modifying enzymesPlasmids and transposonsPlasmids and transposonsConfer cross resistanceConfer cross resistanceAmikacin least effectedAmikacin least effected
SpectrumSpectrum
Gentamicin = tobramycin < amikacinGentamicin = tobramycin < amikacin
Gram-negative organismsGram-negative organismsFermenters and Fermenters and Pseudomonas aeruginosaPseudomonas aeruginosa
Gram-positive organismsGram-positive organismsStaphylococcusStaphylococcus spp. and Enterococci spp. and Enterococci
MiscellaneousMiscellaneous
PharmacokineticsPharmacokinetics
AbsorptionAbsorptionNot absorbed orallyNot absorbed orallyMust be given parenterallyMust be given parenterally
DistributionDistributionPoor into most tissuesPoor into most tissues
EliminationEliminationRenalRenal
Concentration vs Time-dependent Concentration vs Time-dependent KillingKilling
2
3
4
5
6
7
8
9
0 2 4 6 8
Log
10 C
olon
y F
orm
ing
Un
its/
ml
0 2 4 6 8
Control
1/8 MIC
1/2 MIC
1 MIC
4 MIC
16 MIC
64 MIC
Tobramycin Ticarcillin
Time (hours)
Peak/MIC Ratio and Clinical Peak/MIC Ratio and Clinical Response with AminoglycosidesResponse with Aminoglycosides
Moore,et al. J Inf Disease, 1987; 155(1): 93-98
50
60
70
80
90
100
2 4 6 8 10 12+
Maximum Peak / MIC ratio
Resp
onse
Rate
(%
)
Does “S” Really Mean Sensitive?Does “S” Really Mean Sensitive?
MICMIC Gent/TobraGent/Tobra AmikacinAmikacin
0.250.25 3232 8484
0.50.5 1616 4040
11 88 2020
22 44 1010
44 22 55
88 11 2.52.5
1616 0.50.5 1.251.25
3232 0.250.25 0.6250.625
6464 0.1250.125 0.31250.3125
S I R
G/T <4 8 >16
A <16 32 >64
G/T: 2 mg/kg = 8 mcg/ml
A: 5 mg/kg = 20 mcg/ml
Peak / MIC Peak serum concentration
CLSI breakpoints
Once Daily vs Traditional DosingOnce Daily vs Traditional Dosing
What’s the difference?What’s the difference?
RationalRational Concentration-dependent killingConcentration-dependent killingPost antibiotic effectPost antibiotic effect
Bacteria remains “stunned” even without any drugBacteria remains “stunned” even without any drugAllows for a drug free intervalAllows for a drug free interval
Less toxicityLess toxicity
ODA vs Traditional DosingODA vs Traditional Dosing
0
5
10
15
20
25
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Times (Hours)
Con
cent
ratio
n (m
cg/m
l)
ODA Traditional
Once Daily vs Traditional Dosing?Once Daily vs Traditional Dosing?Evidence for once dailyEvidence for once daily
Pneumonia, UTI, PID, IAI, bacteremiaPneumonia, UTI, PID, IAI, bacteremia
Lack of evidence for once dailyLack of evidence for once dailyGeriatric, CrCl <20ml/min, obese, pregnant, Geriatric, CrCl <20ml/min, obese, pregnant,
burn, cystic fibrosis, ascites, osteomyelitis, burn, cystic fibrosis, ascites, osteomyelitis, enterococcal infectionsenterococcal infections
Once Daily DosingOnce Daily Dosing
DoseDose
Gent/tobra =Gent/tobra = 7 mg/kg7 mg/kg (peak ~ 20mcg/ml)(peak ~ 20mcg/ml)
Amikacin =Amikacin = 15 mg/kg15 mg/kg (peak ~ 40mcg/ml)(peak ~ 40mcg/ml)
Interval:Interval: every 24 hours (ClCr > 60ml/min)every 24 hours (ClCr > 60ml/min) every 36 hours (ClCr 40 – 60ml/min)every 36 hours (ClCr 40 – 60ml/min)
MonitorMonitorLevel 6 – 14 hours after starting the infusionLevel 6 – 14 hours after starting the infusionTrough (Trough (needs to be undetectableneeds to be undetectable), renal function), renal function
Antimicrob Agents Chemother. 1995;39:650-55.
Traditional DosingTraditional DosingHow to dose?How to dose?
Based on volume of distributionBased on volume of distribution (0.25-0.3 L/kg) (0.25-0.3 L/kg)
Peak serum levels (mcg/ml)Peak serum levels (mcg/ml)Pneumonia/sepsisPneumonia/sepsis soft tissuesoft tissue UTIUTI
Gent/tobraGent/tobra 6-106-10 5-7 5-7 4-64-6AmikacinAmikacin 25-3025-30 20-25 20-25 2020
Loading Dose:Loading Dose: Gent/tobraGent/tobra 2 - 3 mg/kg2 - 3 mg/kgAmikacinAmikacin 7.5 mg/kg7.5 mg/kg
Maintenance doses (mg/kg):Maintenance doses (mg/kg):Pneumonia/sepsisPneumonia/sepsis soft tissuesoft tissue UTIUTI
Gent/tobraGent/tobra 1.8-21.8-2 1.5 1.5 1 1AmikacinAmikacin 6.56.5 5.5 5.5 4 4
Trough Levels (mcg/ml)Trough Levels (mcg/ml)Gent/tobra < 2Gent/tobra < 2 Amikacin 4-10Amikacin 4-10
Traditional DosingTraditional DosingWhat interval do I choose?What interval do I choose?
Based on CrCl (renal function)Based on CrCl (renal function)
CrCl (ml/min)CrCl (ml/min) t1/2 (hours)t1/2 (hours) interval (hours)interval (hours)
>75>75 < 3 < 3 88
51-7551-75 3-4.4 3-4.4 1212
25-5025-50 4.5-8 4.5-8 2424
< 25< 25 > 8 > 8 > 24> 24
What do I monitor?What do I monitor?
Levels, renal function, ototoxicityLevels, renal function, ototoxicity
ConclusionConclusion
FluoroquinolonesFluoroquinolones Broad-spectrum but differencesBroad-spectrum but differences Resistance increasingResistance increasing Concentration dependent killing (AUC/MIC)Concentration dependent killing (AUC/MIC) Well toleratedWell tolerated
AminoglycosidesAminoglycosides Resurgence because of resistanceResurgence because of resistance Mainly gram negative activityMainly gram negative activity Concentration dependent killing (Peak/MIC)Concentration dependent killing (Peak/MIC) Serious toxicitiesSerious toxicities
Bedside kineticsBedside kinetics
Typical Vd =Typical Vd = 0.25 – 0.3 L/kg 0.25 – 0.3 L/kg
Typical half life =Typical half life = 2.5 -3 hours (with ClCr > 60ml/min) 2.5 -3 hours (with ClCr > 60ml/min)
Wt: 80kgWt: 80kg Goal peak: 10 mg/LGoal peak: 10 mg/L
LD = (80kg * 0.3 L/kg) * 10 mg/L = 240 mgLD = (80kg * 0.3 L/kg) * 10 mg/L = 240 mg
At 3 half lives Conc = (10/2) = (5/2) = (2.5/2) = 1.25At 3 half lives Conc = (10/2) = (5/2) = (2.5/2) = 1.25
Goal trough: 1mg/LGoal trough: 1mg/L
MD = (10 mg/L – 1 mg/L) * 24 L = 216 ~ 220 mgMD = (10 mg/L – 1 mg/L) * 24 L = 216 ~ 220 mg
Dosage Regime Manipulation:Dosage Regime Manipulation:Peaks/TroughsPeaks/Troughs
Concentration Concentration ParameterParameter
ManipulationManipulation
P high, T OKP high, T OK Decrease doseDecrease dose
P low, T OKP low, T OK Increase dose**Increase dose**
P OK, T highP OK, T high Increase intervalIncrease interval
P OK, T lowP OK, T low Decrease intervalDecrease interval
P high, T highP high, T high Decrease dose, Increase intervalDecrease dose, Increase interval
P low, T lowP low, T low Increase dose, decrease intervalIncrease dose, decrease interval
** Trough may increase**