Seasonality of Antibiotic Resistance and Correlation with Antibiotic Use
Lova SunCDDEP
Summer 2010
Questions• Is antibiotic resistance of different bacteria
seasonal? (E coli, MRSA, VRE)– TSN Database
• Do prescription levels of antibiotics which might be driving this resistance also show seasonal trends?– IMS Database
• Is antibiotic prescription seasonality temporally correlated to seasonality of resistant bugs, perhaps with time lag?– Cross-correlation analysis, time-series regressions,
Granger causality
Part I: E. coliIs E. Coli Antibiotic Resistance Seasonal?
Resistance to Ampicillin: Winter Peak Resistance to Ciprofloxacin: Winter Peak
-.01
-.005
0.0
05.0
1.0
15R
esid
uals
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1date
Polynomial Detrended E. coli Resistance to Cipro
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Res
idua
lsLo
g P
erio
dogr
am
0.00 0.10 0.20 0.30 0.40 0.50Frequency
Evaluated at the natural frequencies
Sample spectral density function: Ampicillin Resistance
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Res
idua
lsLo
g P
erio
dogr
am
0.00 0.10 0.20 0.30 0.40 0.50Cycles per month
Evaluated at the natural frequencies
Spectral Density Function: E. coli resistance to Cipro
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Res
idua
lsLo
g P
erio
dogr
am
0.00 0.10 0.20 0.30 0.40 0.50Frequency
Evaluated at the natural frequencies
Spectral density function: Ciprofloxacin Resistance
-.02
-.01
0.0
1.0
2R
esid
uals
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1date
Polynomial Detrended Ampicillin Resistance
Are Prescriptions of these Antibiotics Seasonal? -2
0000
00-1
0000
000
1000
000
2000
000
Res
idua
ls
1998m1 2000m1 2002m1 2004m1 2006m1 2008m1Date in months
Detrended Aminopenicillin Prescriptions
-500
000
050
0000
1000
000
Res
idua
ls
1998m1 2000m1 2002m1 2004m1 2006m1 2008m1Date in months
Detrended Quinolone Prescriptions
Aminopenicillin Prescriptions: Winter Peak Fluoroquinolone Prescriptions: Winter Peak
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Res
idua
lsLo
g P
erio
dogr
am
0.00 0.10 0.20 0.30 0.40 0.50Frequency
Evaluated at the natural frequencies
Sample spectral density function: Ampicillin Prescriptions
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Res
idua
lsLo
g P
erio
dogr
am
0.00 0.10 0.20 0.30 0.40 0.50Frequency
Evaluated at the natural frequencies
Spectral density function: Quinolone Prescriptions
Prescription-Resistance Correlations: Detrended Data
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns o
f det
rend
ed rx
s an
d re
s
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram between Ampicillin Prescriptions and Resistance
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns d
etre
nded
rxs-
res
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram between Quinolone Prescriptions and Cipro Resistance
-500
000
050
0000
1000
000
Qui
nolo
ne P
resc
riptio
n R
esid
uals
-.01
-.005
0.0
05.0
1.0
15C
ipro
Rei
stan
ce R
esid
uals
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1date
Resistance to Cipro Quinolone Prescriptions
Unlagged Detrended Cipro Resistance and Quinolone Prescriptions
Ampicillin (1-month lag Correlation = 0.7816) Ciprofloxacin (Unlagged Correlation = 0.4310)
-200
0000
-100
0000
010
0000
020
0000
0A
mpi
cilli
n P
resc
riptio
n R
esid
uals
-.02
-.01
0.0
1.0
2A
mpi
cilli
n R
esis
tanc
e R
esid
uals
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1date
Ampicillin Resistance Ampicillin Prescriptions
Nonlagged Ampicillin Prescription-Resistance
Part II: MRSAIs MRSA a seasonal bug?
5000
1000
015
000
2000
025
000
MR
SA
_dis
chge
s
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1 2007m1date
Total MRSA Discharges, based on NHDS and TSN
Not Combined. But…
HA- and CA-MRSA Seasonality-.0
4-.0
20
.02
.04
Res
idua
ls
1999m1 2000m1 2001m1 2002m1 2003m1 2004m1 2005m1 2006m1date
poly detrended HAMRSA proportion of SA
-.04
-.02
0.0
2.0
4R
esid
uals
2002m1 2003m1 2004m1 2005m1 2006m1date
deg 4 poly detrended CAMRSA proportion of SA
2500
030
000
3500
040
000
4500
050
000
(sum
) cel
lulit
is
1 2 3 4 5 6 7 8 9 10 11 12DischargeMonth
Total Cellulitis/Abcess SA Discharges, 99-05
6500
070
000
7500
080
000
8500
0se
pt_p
neum
1 2 3 4 5 6 7 8 9 10 11 12DischargeMonth
Total Pneumonia + Septicemia MRSA Discharges by Month, 99-05
HA-MRSA: Winter Peak CA-MRSA: Summer Peak
TSN
Dat
aN
HDS
Data
Possible Antibiotic Drivers of HA-MRSA
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns o
f det
rend
ed rx
s an
d H
A-M
RS
A
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram between Quinolone Prescriptions and Prop HA-MRSA
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns o
f det
rend
ed rx
s an
d H
A-M
RS
A
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram between Macrolide Prescriptions and Prop HA-MRSA
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns o
f rxs
_det
rend
ed a
nd p
rop_
HA
_pol
y_re
sid
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram Cephalosporin Rxs and HA-MRSA
Pres
crip
tion
Seas
onal
ity:
Win
ter P
eaks
Corr
elati
on: P
resc
riptio
ns
and
HA-M
RSA
Quinolones: 2-month lag (Correlation 0.5810)
Macrolides: 1-month lag(Correlation 0.6699)
Cephalosporins: 1-month lag (Correlation 0.6713)
-100
0000
-500
000
050
0000
1000
000
Res
idua
ls
-.04
-.02
0.0
2.0
4R
esid
uals
1998m1 2000m1 2002m1 2004m1 2006m1 2008m1Date in months
HA-MRSA Cephalosporin Prescriptions
Detrended Cephalosporin Prescriptions + HA-MRSA
-200
0000
020
0000
040
0000
0R
esid
uals
-.04
-.02
0.0
2.0
4R
esid
uals
1998m1 2000m1 2002m1 2004m1 2006m1 2008m1Date in months
HA-MRSA Macrolide Prescriptions
Detrended Macrolide Prescriptions 99-07 + HA-MRSA
-500
000
050
0000
1000
000
Res
idua
ls
-.04
-.02
0.0
2.0
4R
esid
uals
1998m1 2000m1 2002m1 2004m1 2006m1 2008m1date
HA-MRSA Quinolone Prescriptions
Detrended Quinolone Prescriptions 99-07 + HA-MRSA
Possible Antibiotic Driver of CA-MRSA
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
cros
s-co
rrel
atio
ns o
f det
rend
ed d
ata
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram Staph Penicillin Prescriptions and CA-MRSA, 02-06
Staph Penicillin Prescriptions: Summer Peak
1-month lag (Correlation 0.6371)
-100
00-5
000
050
0010
000
Res
idua
ls
-.04
-.02
0.0
2.0
4R
esid
uals
2002m1 2003m1 2004m1 2005m1 2006m1 2007m1Date in months
Residuals Staph-Penicillin Prescriptions
Detrended Staph-Penicillin Prescriptions + CA-MRSA
Part III: Vancomycin-Resistant EnterococciVRE Seasonality and Correlation with HA-MRSA
-.04
-.02
0.0
2.0
4.0
6R
esid
uals
1999m1 2000m7 2002m1 2003m7 2005m1 2006m7date
Frac-Poly Detrended Enterococci Resistance to Vancomycin
-.04
-.02
0.0
2.0
4.0
6
1999m1 2000m7 2002m1 2003m7 2005m1 2006m7date
VRE Detrended HA-MRSA Detrended
Detrended HA-MRSA and VRE, 99-06
-1.0
0-0
.50
0.00
0.50
1.00
-1.0
0-0
.50
0.00
0.50
1.00
Cro
ss-c
orre
latio
ns o
fdet
rend
ed v
alue
s
-12-11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12Lag
Cross-correlogram Detrended HA-MRSA and VRE
Vancomycin Resistance: Winter Peak
VRE and HA-MRSA:Correlation = 0.6431No time lag
Conclusions• Both antibiotic resistance and prescriptions are
seasonal• After a 1-2 month lag (presumably the time it takes for
antibiotic use to select for resistant strains), antibiotic prescriptions are significantly correlated with (and perhaps drive) resistance
• CA- and HA-MRSA have opposite seasonal peaks, with different antibiotics or other factors driving each type
• MRSA, an indicator of vancomycin use, is correlated with VRE
• Implications for hospital infection control and prescription policies
Acknowledgements
• Prof. Ramanan Laxminarayan• Prof. Bryan Grenfell• Eili Klein• Mike Eber