Aminoglycosides:

Dosing and Duration of

Therapy

William A. Craig, MD

University of Wisconsin and

Wm S. Middleton Memorial VA Hospital

Madison, WI USA

Time Course of Antibacterial Activity of Tobramycin and Ticarcillin Against

Pseudomonas aeruginosa

Time (hours)

0 2 4 6

Log

CF

U p

er T

high

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

4 mg/kg

12 mg/kg

20 mg/kg

0 2 4

300 mg/kg

800 mg/kg

2400 mg/kg

Tobramycin Ticarcillin

Craig and Gudmundsson 1996

Effect of Renal Impairment on the In-Vivo PAE of Amikacin

Normal Renal-Impaired

Organism Dose PAE (hr) PAE (hr)

P. aeruginosa 15 4.0 12.1

K. pneumoniae 15 3.4 12.3

90 7.4 -

Reddington and Craig, JAC 1995

Impact of Dosing Interval on Static Dose for Amikacin against K. pneumoniae and E. coliin Mice with Normal and Impaired Renal Function

Dosing Interval (Hours)3 6 12 24

Sta

tic D

ose (

mg/k

g/2

4 h

rs)

1

10

100

1000

K. pneumoniae

E. coliNormal T1/2=17 min

K. pneumoniae

E. coliRenal Impaired T1/2=104 min

Reddington and Craig, JAC 1995

Major Goal of Pharmacodynamics

Establish the PK/PD TARGET required

for effective antimicrobial therapy

- identify which PK/PD indice (T>MIC,

AUC/MIC, peak/MIC) best predicts in

vivo antimicrobial activity

- determine the magnitude of the

PK/PD parameter required for in vivo

efficacy (static effect, 1 or 2 log kill)

PK-PD Relationships for Amikacin with K. pneumoniae and S. marcescens

Q 6 hr Q 12 hr Q 24 hr Control

1 10 100 1000 10000-4

-2

0

2

4

AUC:MIC Ratio

Ch

an

ge

in

Lo

g (

CF

U/g

) o

ve

r 2

4 h

rs R2=0.852

0.1 1 10 100 1000

Cmax:MIC Ratio

R2=0.826

% Time > MIC

R2=0.766

0 20 40 60 80 100

Craig et al 2006 IDSA Abstract

PK/PD Indices: Aminoglycosides

AUC/MIC and Peak/MIC are important indices

determining efficacy of aminoglycosides in animal

infection models. A 24-hr AUC/MIC value of

100 along with a peak/MIC ratio 8-10 is

required for maximal efficacy.

A Peak/MIC ratio of 8-10 is required for 90%

efficacy in serious Gram-negative bacillary

infections in humans.

Relationship Between Peak/MIC Ratio and Efficacy of Aminoglycosides in Patientswith Gram-Negative Bacillary Infections

50

60

70

80

90

100

0-2.0 2.0-4.0 4.0-6.0 6.0-8.0 8.0-10.0 >10

Peak/MIC Ratio

P

erc

en

t E

ffic

acy

Moore et al. J Infect Dis 155:93, 1987

Efficacy of Tobramycin Monotherapy in Patients with Gram-Negative Bacillary

Infections

23 patients with nosocomial pneumonia or intra-abdominal infections

Clinical Cure

24 hr AUC/MIC > 110 80%

P<0.01 24 hr AUC/MIC < 110 47%

Smith et al. Clin Ther 2001; 23:1231

R²0.6451EXPOSURE & RESPONSE IN MAN

Tobramycin in Cystic Fibrosis Patients

Mouton JW, Jacobs N, Tiddens H, and Horrevorts AM. Pharmaco-

dynamics of tobramycin in patients with cystic fibrosis. Diagn Microbiol

Infect Dis. 2005;52:123-7.

R2=65% R2=60%

Optimizing Aminoglycosides for Nosocomial Pneumonia

Due to Gram-Negative Bacilli

• Study of 78 patients with nosocomial pneumonia

• Demonstrated a >90% probability of response in

fever and leukocytosis by 7 days if Cmax/MIC ratio

greater than or equal to 10

• Better correlation with peak/MIC than with AUC/MIC

Kashuba et al Antimicrob Agents Chemother 1999; 43:623

Aminoglycoside Monotherapy

• 27 trials in patients with urinary tract infections

aminoglycosides equally effective with competitors

• 9 trials in patients with non-urinary tract infections

higher rate of bacteriological failure with aminoglycosides

more nephrotoxic effects with aminoglycosides

Vidal et al. JAC 60:247, 2007

Combination vs Monotherapyfor Pseudomonas Bacteremia

• Prospective observational study of 200 cases

• 91% received appropriate antipseudomonal antibiotics: 70% combination

21% monotherapy

• Mortality: 27% combination therapy47% monotherapy

Hilfe et al, Am J Med 87:540, 1989

Combination vs Monotherapy for Pseudomonas Bacteremia

Therapy Mortality Percent

Combination Therapy 38 / 140 27%

Monotherapy 20 / 43 47%

Aminoglycosides 18 / 37 49%

Beta-Lactam 2 / 6 33%

Hilf et al, Am J Med 87:540, 1989)

Combination vs Monotherapyfor Pseudomonas Bacteremia

in Cancer Patients

Retrospective review of 410 episodes

Therapy Percent Cure

Combination Therapy 72%

Monotherapy

Aminoglycosides 29%

Beta-Lactam 70%

Bodey et al, Arch Intern Med 145:1621, 1985)

Combination vs Monotherapyfor Pseudomonas Bacteremia

• Prospective observational study in 2185 patients with gram-negative bacteremia

Therapy Mortality Percent

Combination Therapy 16 / 77 21%

Monotherapy

Aminoglycosides 10 / 36 28%

Beta-Lactam 20 / 95 21%

Leibovic et al, AAC 41:1127, 1997)

Conitnuous vs Intermittent Infusion of Oxacillin for Treatment of Staphylococcus

aureus Endocarditis

• Retrospective study: 78 CI vs 28 II

Continuous Intermittent

Infusion Infusion P-value

30-Day

Mortality 8% 10% 0.7

30-Day

Microbiologic 94% 79% 0.03

Cure

Gentamicin use: defervescence 2 days vs 4 days (P=0.02)

Hughes DW et al. AAC 2009; 53:2014

Once-Daily Dosing of Aminoglycosides

• 45 studies, mostly prospective, in over 6500 patients comparing once-daily with multiple daily dosing

• Slight non-significant enhancement in efficacy

• Of 9 meta-analyses (of different combinations of these 45 studies), 5 show a lower incidence of nephrotoxicity with once-daily dosing

Turnidge Inf Dis Clinics of N Amer 2003; 17:503

Aminoglycoside Nephrotoxicity

• Megalin is a lipoprotein on the brush border of renal tubular cells that binds aminoglycosides and is important for uptake of these drugs by pinocytosis

• Binding to megalin by aminoglycosides is saturable

• Animals deficient in megalin do not accumulate aminoglycosides in the kidney

• Once-daily dosing results in less uptake in human kidneys than thrice-daily or continuous infusion; nephrotoxicity occurs later with once-daily dosing –usually after 5-7 days; with longer courses the difference between regimens becomes smaller

Drug Metab Pharmacokin 2004;19:159; Rougier F et al AAC 2003; 47:1010

Hearing Loss and Vestibular Dysfunction with Aminoglcosides

Hearing Vestibular

Drug Loss Dysfunction

Amikacin 13.9% 7.4%

Gentamicin 8.3% 10.9%

Tobramycin 6.1% 3.5%

Kahlmeter & Dahlager, 1984; Ariano et al, 2008

Optimizing Use of Aminoglycosides

• Once daily treatment of 5-7 mg/kg (gentamicin, tobramycin) or 15-20 mg/kg (amikacin) for short periods (5-7 days)

• For non-urinary tract infections: Target attainment inadequate for monotherapy against organisms with MICs > 0.5 mg/L (gentamicin, tobramycin) or 2.0 mg/L (amikacin)

• Addition of aminoglycoside to ß-lactam rarely enhances efficacy except possibly for P. aeruginosa infections