quinolone and aminoglycoside antibiotics edgar rios, pharm.d., bcps mhh clinical pharmacist uthsch...

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**