Antimicrob. Agents Chemother. 2013 McLaughlin AAC.00607 13

8/13/2019 Antimicrob. Agents Chemother. 2013 McLaughlin AAC.00607 13

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Correlations of Antibiotic Use and Carbapenem Resistance inEnterobacteriaceae1

2

Milena McLaughlin1, 2

, M. Renee Advincula1, Michael Malczynski

2, Chao Qi

2, 3, Maureen3

Bolon, MD2,3

, Marc H. Scheetz1, 2

#4

5

1Midwestern University, 555 31

stStreet, Downers Grove, IL, USA6

2Northwestern Memorial Hospital, 251 E Huron Street, Chicago, IL, USA7

3Northwestern University, 303 E Superior Street, Chicago, IL, USA8

9

Running Title: Antibiotic Consumption and CIRE10

11

Key Words: antibiotic, Carbapenem Intermediate or ResistantEnterobacteriaceae, CIRE,12

correlation, consumption13

14

#Correspondence and Reprint Author: Marc Scheetz, PharmD, MSc, Midwestern University15

Chicago College of Pharmacy, Department of Pharmacy Practice, 555 31stSt., Downers Grove,16

IL, 60515, Phone: 630-515-6116, Fax: 630-515-6958, Email: [email protected]

18

Manuscript word count: 1,002 Abstract word count: 7519

20

Copyright 2013, American Society for Microbiology. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00607-13AAC Accepts, published online ahead of print on 8 July 2013


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Abstract (unstructured)21

Epidemiological studies have shown a link between carbapenem use and resistance; however, the22

clinical relationship between antibiotic consumption and the epidemiology of CIRE remains23

unclear. This study sought to analyze temporal antibiotic consumption trends for relationships24

with incident CIRE. In total, 310,892 DOT and 55 de-duplicated CIRE were analyzed. When25

conservative corrections were applied for multiple comparisons, carbapenem class use and26

piperacillin/tazobactam use retained significant positive and negative relationships with the27

incidence of CIRE, respectively.28

29


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Carbapenem-intermediate or -resistantEnterobacteriaceae (CIRE) are of increasing concern and30

have rapidly spread globally [1-3] and in the United States [4-6]. The Midwestern United States31

has not been spared from the emergence of CIRE. The first reported isolates of CIRE were32

Klebsiella pneumoniae,and mobile genetic plasmids have subsequently spread to other Gram-33

negative rods [7]. While epidemiological studies have shown a link between carbapenems and34

resistance in non-fermentative Gram-negative organisms [8-11] and carbapenem-resistant35

Klebsiella pneumoniae [12]; the contribution of antibiotic consumption to CIRE incidence36

remains unclear. As CIRE are incident in the Midwestern United States, we used this optimal37

opportunity to analyze temporal antibiotic consumption trends for relationships with incident38

CIRE.39

40

This study was performed at Northwestern Memorial Hospital (NMH), an 897-bed, tertiary41

academic medical center located in Chicago, IL. Broad-spectrum Gram-negative antibiotics with42

a potential for influencing CIRE and in use at NMH were included in the analysis. Consumption43

was measured as days of therapy (DOT) per 1,000 patient days [13]. DOTs were aggregated44

quarterly from January 1, 2006 through December 31, 2010. Quarterly compilation allowed45

capture of immediate and time delayed effects of antimicrobial use on resistance [14, 15]. These46

antibiotics included beta-lactams (aztreonam, cefepime, ceftazidime, ertapenem,47

imipenem/cilastatin, meropenem, piperacillin/tazobactam), fluoroquinolones (ciprofloxacin,48

moxifloxacin), glycylcyclines (tigecycline), and polymxins (colistin methanesulfonate). Only49

antibiotics achieving relevant systemic concentrations were captured; any antibiotic prescribed as50

an ophthalmic solution, ointment, or enema was excluded from the study. Antibiotics with51

formulary status throughout the entire time period were analyzed individually. Since the52


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preferred carbapenem(s) changed at our institution during the study period, carbapenems were53

analyzed as a combinatorial class.54

55

All isolates were obtained from clinical cultures from January 1,2006 through December 31,56

2010. Only the first isolate per patient per quarter was included in the study, and incidence rate57

was calculated by standardizing the at risk population to 1000 patient hospitalized days.58

Susceptibility testing for all isolates was performed with the Vitek 2 system using the AST-59

GN25 (22230) card and following manufacturers instructions (bioMerieux, St. Louis, MO).60

CIRE were defined as isolates with a carbapenem minimum inhibitory concentration (MIC) 261

mg/L.62

63

Antibiotic use and CIRE incidence were assessed for trends utilizing the Chi-square test for trend64

with EpiInfo v3.5.3 (Centers for Disease Control and Prevention, Atlanta, GA). Correlations65

between CIRE incidence and antibiotic consumption were assessed with Spearmans correlations66

using Intercooled Stata Version 11.1 (Statacorp, College Station, TX). Bonferroni corrections67

were applied to correct for multiple comparisons with p< 0.0056 (i.e. p= 0.05/9 comparisons)68

being considered significant.Significant relationships were further assessed using the69

Marquardt-Levenberg algorithm (SigmaPlot 12, Systat Software Inc., San Jose, CA).70


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During the study period, a total of 310,892 DOT and 6,753 DOT/1000 patient days were71

analyzed. Antibiotic use showed increasing trends during the analysis period for the carbapenem72

class (p


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There was a negative correlation with ceftazidime (r=-0.52, p=0.018), piperacillin/tazobactam93

(r=-0.64, p=0.0021), and moxifloxacin (r=-0.51, p=0.022) usage. When the analysis was94

corrected for multiple comparisons among these negative correlations (i.e. significance at the95

level of 0.0056), only the correlation with piperacillin/tazobactam remained significant.96

97

We found that increasing carbapenem use was correlated with increasing resistance in98

Enterobacteriaceae.Previous epidemiological studies with select Gram-negative organisms99

support our findings. One study analyzed carbapenem use and found that carbapenem use and100

carbapenem-resistantK. pneumoniae increased simultaneously[12]. The correlation of101

carbapenem exposure and antimicrobial resistance has also been reported in case-control studies102

[16, 17]. These analyses found that progression to CIRE is likely the result of multi-factorial103

process in respect to antibiotic exposure; our study corroborates these results and may indicate104

that replacing several antibiotics with the class of carbapenems is potentially problematic.105

106

Limitations to our study should be noted. First, we excluded organisms only tested by disk107

diffusion because minimum inhibitory concentrations were not available for analysis. Thus, these108

numbers may slightly underreport CIRE incidence. Second, these data are epidemiologic in109

nature and cannot confirm or disprove causality. However, the statistical power gained with110

epidemiologic analyses allowed us to stratify and analyze individual antibiotic associations.111

Third, carbapenems were analyzed as a class due to a change in formulary from112

imipenem/cilastatin to meropenem in mid 2007, though CIRE incidence largely occurred in the113

presence of meropenem use. This modification should improve validity since the use of each114

individual carbapenem varied depending on formulary status. Fourth, our institution actively115


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screens for nosocomial organism outbreaks. There was one outbreak of CRE involving three116

patients; however, this represented a very small portion (5.5%) of isolates studied. Thus, our117

results are unlikely biased by horizontal organism transfer. Lastly, this study was conducted at a118

single large institution in Chicago, IL. Results may not apply to other areas where different119

pathogens predominate ecologically.120

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The incidence of CIRE is increasing at our institution and was associated with increasing122

carbapenem class use and decreasing piperacillin/tazobactam use. Further research is needed to123

elucidate if knowledge of associations between antibiotic consumption and CIRE may be used to124

design interventions that slow CIRE spread.125


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Acknowledgements:None.126

127

Financial Support Statement: This work was supported in part by a Midwestern University128

Student Research Grant. Midwestern University had no part in the design and conduct of the129

study; collection, management, analysis, and interpretation of the data; and preparation, review,130

or approval of the manuscript.131

132

Financial disclosures:All authors have no relevant conflicts of interest or financial conflicts to133

disclose.134

135

Corresponding Author: Marc Scheetz, PharmD, MSc, Midwestern University Chicago College136

of Pharmacy, Department of Pharmacy Practice, 555 31stSt., Downers Grove, IL, 60515, Phone:137

630-515-6116,Fax: 630-515-6958, Email: [email protected]

139

Portions of this research were presented at the 51

st

Interscience Conference on Antimicrobial140

Agents and Chemotherapy (Chicago, IL, September 19, 2011)141


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Figure Legends207

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Figure 1. All carbapenem DOT/1000 patient days and CIRE/1000 patient days209

DOT = days of therapy210

CIRE = Carbapenem-intermediate or -resistantEnterobacteriaceae211

212

Figure 2. CIRE isolates/1000 patient days vs. all carbapenem DOT/1000 patient days213

f = 0.0077+0.1307/(1+exp(-(x-23.6967)/ 0.0109))214

r2=0.64215

CIRE = Carbapenem-intermediate or -resistantEnterobacteriaceae216

DOT = days of therapy217


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