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