Download Antibiotics II

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**