Are All Q

Quinolones Equal
q
with Regard
g to Resistance?
A PK/PD Perspective

Abraham Simatupang
p of Pharmacology
Dept gy
School of Medicine – Universitas Kristen
Indonesia, Jakarta
farmakologiuki@yahoo com
farmakologiuki@yahoo.com
 Optimal antibiotic
usage

Efficacy
ffi Toxicity
i i Resistance
i
Introduction
‡ Antimicrobial resistance is a global pandemic
‡ Initially was a nosocomial infections →
community-acquired (eg. S. pneumoniae, H.
influenzae, M. catarrhalis, E. coli, Staph aureus)
Contributing factors to resistance:
1. Overuse of antimicrobials – human, veterinary,
agricultural
2. Low dosages
3. Improper dosing frequency
4. Extended duration of therapy
5. Prophylactic use
6
6. Clinical trials excluding patients w/ resistant
pathogens
7. Clinical trials which focus only
y on clinical
outcomes
Hospitalized patients Community-acquired
pathogens
‡Vancomycin resistant Enterococci ‡Ampicillin/amoxicllin resistant H.
influenza

‡Methicillin resistant S. aureus ‡Trimethoprim/sulfamethoxazole

resistant H. influenza
‡Glycopeptide
Gl copeptide resistant
esistant S.
S aureus
a e s ‡Ampicillin/amoxicllin
Ampicillin/amo icllin resistant
esistant M.
M
catarrhalis

‡Extended spectrum beta-

beta ‡Methicilin resistant S.
S aureus
lactamases (ESBLs)

‡Pseudomonas aeruginosa and ‡Penicillinand multiple drug

other afermentors resistant S. pneumoniae
Acinebacter spp
‡Fluoroquinolone (older classes)
S
Stenotrophomonas
h maltophilia
l hili
resistant S. pneumoniae

‡Multi resistant coagulase

coagulase- ‡Ampicillin/TMP/SMX resistant
negative staphylococci E.coli
Current estimate of resistance to ciprofloxacin
among isolates recovered from hospitals in the
USA

Jacoby; CID 2005; 41:S120-6.

Important PK/PD
/ Measures
AUC:MIC
Cmax:MIC
 PK/PD parameters predictive of antimicrobial
efficacy based on unbound plasma levels

Jacobs MR: Int J Infect Diseases 2003; 7: Suppl. 1

Magnitude
g of PK/PD
/ measures predictive
p of efficacyy for
select antibiotic classes vs some pathogens
Magnitude
M i d off
Pertinent PK/PD variable
Drug/Drug class
variable correlated with
efficacy
Beta lactams Time > MIC ≥ 40%-50% of
dosing interval

Fluoroquinolones vs 24-hour AUC:MIC ≥ 90-125

Gr – bacteria

Fluoroquinolones vs 24-hour AUC:MIC ≥ 30-40

S pneumoniae
S.

Data from: Ambrose et al. Antimirob Agents

g Chemother 2001;45:2793-7;
; ; Forrest et al. Antimicrob
Agents Chemother 1993; 37: 1073-81; Craig & Andes. Pediatr Infect Dis 1996;15: 255-9.
Estimated fluroquinolones potency in vivo against Gram + and Gram - bacteria

Pharmacodynamics of major fluoroquinolones against S. pneumoniae

Allen GPet al. Antimicrob Agents Chemother 2003; 47: 2606–2614.

What
h is resistance?
‡ Genotype
G t
The bacteria carry certain resistance
elements
l t
‡ Phenotype
The bacteria has an increased MIC in
comparison with the wild type
‡ Clinical
The bacteria are able to multiply
p y in
humans in the presence of drug
concentrations achievable during therapy
Cars O. Dept. Medical Science-Uppsala, Sweden
 Antibiotic exposure
p

Clinical failure and/or

Bacterial persistance
Infecting bacterial population

Selection of resistant bacterial

R
subpopulations

Normal microflora
Gradual change
In susceptibility
Selective amplification of resistant
mutants
Time

MIC

2 IN 1 BILLION 200 IN 1 BILLION Immuno compromised 20.000 IN 1 BILLION

state
Prior infection

Acute infection/failed
therapy
Prior antibiotic exposure
Healthy immune
system Potential
clearance Immune Threshold
Breached
Primary target of quinolones for
S pneumoniae
S. i

Principal
p
Fl
Fluoroquinolones
i l
Target
Topoisomera
se IV (parC, Cipro Norflox Trova Levo
parE)

DNA gyrase
Spar Moxi Gemi Gare Grepa Gati
(gyrA,, gyrB)
(gy gy )

Drlica & Malik. Curr Topics Med Chem. 2003; 3: 1349-64.

PD indices
d used
d in resistance studies
d
‡ Cmax/MIC
C /MIC ‡ T>
T MPC

‡ Cmax/MPC ‡ TMSW

‡ AUC/MIC ‡ AUCMSW

‡ AUC/MPC
Mutant prevention concentration (MPC)
‡ the antimicrobial drug concentration threshold
that would require an organism to simultaneously
possess two resistance mutations for growth in
the presence of the drug.
‡ the drug concentration that prevents the growth
of first-step resistant mutants or the MIC of the
most resistant organism present in the
heterogeneous bacterial population when tested
against >109 organisms.
‡ Th MIC off the
The h most resistant
i first
fi step resistant
i
cell present in a bacterial population → to
understand how resistant population
p p
emerge, approach to reduce the likelihood
of selecting for resistance, to compare
q
fluoroquinolone p
potency y
Blondeau et al. J of Chemother 2004; 16: Suppl 3: 1-19
MPC measurement

Drug conc required to

inhibit the growth of these
first-step resistant
mutants

Y. D
Y Dong ett al.l (1999) A
Antimicrob
ti i b A Agents
t Ch
Chemother
th . 43
43:1756
1756 - 58.
58 TTested
t d th
the
concept through studies of M. tuberculosis & S. aureus against fluoroquinolone
Mutant selection
l window
d (MSW)
S

Cmax
Concept of Mutant selection window
(Drlica & Zhao, 2004)

Eradication of first mutants

Concentration

MPC

Selection of first mutants MSW

MIC

No therapeutic effect

Ti
Time following
f ll i administration
d i i t ti
Relationshipp of serum concentration of
gatifloxacin to MPC for Streptococcus
pneumoniae.
i
Relationshipp of serum concentration of
gemifloxacin to MPC for Streptococcus
pneumoniae.
i
Relationship of serum concentration of
levofloxacin to MPC for Streptococcus
pneumoniae

Fisher et al , 1999. Blondeau et al , ACC 2001, Hansen et al, 2003.

Relationship of serum concentration of
moxifloxacin to MPC for S. pneumoniae

Wise,, R. Clin Drug

g Invest 1999;; 17:365-387.
Blondeau et al, ACC 2001, Hansen et al 2003.
 MPC/MIC
/ ratios
Drug MIC MPC SI

Gemiflox 0.03 0.5 16

Levoflox 1 8 8

Moxiflox 0.25 1 4

Adapted from D. Croisier, 2005; Bondeau et al 2001; Hansen et al 2003

MPC/MIC
/ ratios in relation
l to PK??
Drug MIC MPC SI Cmax

Gemiflox 0.03 0.5 16 ≈ 1.5

(320 mg)

≈6
L
Levoflox
fl 1 8 8
(500 mg)

≈4
Moxiflox 0.25 1 4
(400 mg)
Low practical breakpoints are necessary...
necessary
Proposed PK/PD upper
Typical T i l PK values
Typical l limit of sensitivity
(ug/ml) for
Drug daily
Cmax in mg/L AUC24h
dosage t t l/f
total/free (
(mg x h/L) Effi
Efficacy
Prevention
of resistance
(dose) total/free
1.4/1.1
Norfloxacin 800 mg
(400 mg PO)
14/11 0.1-0.4 0.1

2.5/1.75
Ciprofloxacin 1000 mg
(500 mg PO)
24/18 0.2-0.8 0.2

4/3
Ofloxacin 400 mg
(400 mg PO)
40/30 0.3-0.9 0.4

4/2.8
Levofloxacin 500 mgg
(500 mg PO)
40/28 0.3-0.9 0.3

3.1/1.8
Moxifloxacin 400 mg
(400 mg PO)
35/21 0.2-0.7 0.2
Breakpoint
k issues…
PK/PD breakpoints (mg/L) NCCLS
Dosage
Drug break-
(mg/24 h) AUC/MIC*
Peak/MIC** points
po ts
(24h)

Norfloxacin 800 mg 0.1 0.2 <4

Ciprofloxacin 1000 mg 0.1 0.2 <1

Ofloxacin 400 mg 0.2-0.4 0.3-0.4 <2

Levofloxacin 500 mg 0.4 0.4-0.5 <2

Gatifloxacin 400 mg 03
0.3 04
0.4 <2

Moxifloxacin 400 mg 0.4 0.4 <2

* AUC/MIC=125; Peak/MIC=10
CONCLUSIONS
S S
‡ Certain
C t i d
dosage regimens
i are clearly
l l
associated with a risk for selective
enrichment of a resistant subpopulation
‡ The selective pressure varies between
bacterial species
species, antibiotics,
antibiotics and
resistance mechanisms
‡ The pharmacodynamic indices to minimize
resistance will vary due to infectious site,
bacterial species,
species and resistance
mechanisms
Potentiall clinical
l l implications
l
‡ Avoid monotherapy with drugs where Cmax does
not reach the MPC or where the MSW is very long
‡ Adj t dosages
Adjust d regimens
i (dose,
(d dose
d interval)
i t l) to
t
reduce the TMSW
‡ Include studies on prevention of resistance early
in drug development:
Preferred properties:
- low mutation rate
- High fitness cost of mutants
- Narrow MSW