Correlations of Antibiotic Use and Carbapenem Resistance in

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Correlations of Antibiotic Use and Carbapenem Resistance in Enterobacteriaceae 1

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Milena McLaughlin1, 2, M. Renee Advincula1, Michael Malczynski2, Chao Qi2, 3, Maureen 3

Bolon, MD2,3, Marc H. Scheetz1, 2# 4

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1Midwestern University, 555 31st Street, Downers Grove, IL, USA 6

2Northwestern Memorial Hospital, 251 E Huron Street, Chicago, IL, USA 7

3Northwestern University, 303 E Superior Street, Chicago, IL, USA 8

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Running Title: Antibiotic Consumption and CIRE 10

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Key Words: antibiotic, Carbapenem Intermediate or Resistant Enterobacteriaceae, CIRE, 12

correlation, consumption 13

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#Correspondence and Reprint Author: Marc Scheetz, PharmD, MSc, Midwestern University 15

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

IL, 60515, Phone: 630-515-6116, Fax: 630-515-6958, Email: [email protected] 17

18

Manuscript word count: 1,002 Abstract word count: 75 19

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Copyright © 2013, American Society for Microbiology. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00607-13 AAC 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, the 22

clinical relationship between antibiotic consumption and the epidemiology of CIRE remains 23

unclear. This study sought to analyze temporal antibiotic consumption trends for relationships 24

with incident CIRE. In total, 310,892 DOT and 55 de-duplicated CIRE were analyzed. When 25

conservative corrections were applied for multiple comparisons, carbapenem class use and 26

piperacillin/tazobactam use retained significant positive and negative relationships with the 27

incidence of CIRE, respectively. 28

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Carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE) are of increasing concern and 30

have rapidly spread globally [1-3] and in the United States [4-6]. The Midwestern United States 31

has not been spared from the emergence of CIRE. The first reported isolates of CIRE were 32

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 and 34

resistance in non-fermentative Gram-negative organisms [8-11] and carbapenem-resistant 35

Klebsiella pneumoniae [12]; the contribution of antibiotic consumption to CIRE incidence 36

remains unclear. As CIRE are incident in the Midwestern United States, we used this optimal 37

opportunity to analyze temporal antibiotic consumption trends for relationships with incident 38

CIRE. 39

40

This study was performed at Northwestern Memorial Hospital (NMH), an 897-bed, tertiary 41

academic medical center located in Chicago, IL. Broad-spectrum Gram-negative antibiotics with 42

a potential for influencing CIRE and in use at NMH were included in the analysis. Consumption 43

was measured as days of therapy (DOT) per 1,000 patient days [13]. DOTs were aggregated 44

quarterly from January 1, 2006 through December 31, 2010. Quarterly compilation allowed 45

capture of immediate and time delayed effects of antimicrobial use on resistance [14, 15]. These 46

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

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

moxifloxacin), glycylcyclines (tigecycline), and polymxins (colistin methanesulfonate). Only 49

antibiotics achieving relevant systemic concentrations were captured; any antibiotic prescribed as 50

an ophthalmic solution, ointment, or enema was excluded from the study. Antibiotics with 51

formulary status throughout the entire time period were analyzed individually. Since the 52


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preferred carbapenem(s) changed at our institution during the study period, carbapenems were 53

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 rate 57

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 manufacturer’s instructions (bioMerieux, St. Louis, MO). 60

CIRE were defined as isolates with a carbapenem minimum inhibitory concentration (MIC) ≥ 2 61

mg/L. 62

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Antibiotic use and CIRE incidence were assessed for trends utilizing the Chi-square test for trend 64

with EpiInfo v3.5.3 (Centers for Disease Control and Prevention, Atlanta, GA). Correlations 65

between CIRE incidence and antibiotic consumption were assessed with Spearman’s correlations 66

using Intercooled Stata Version 11.1 (Statacorp, College Station, TX). Bonferroni corrections 67

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 the 69

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 were 71

analyzed. Antibiotic use showed increasing trends during the analysis period for the carbapenem 72

class (p<0.001). Aztreonam (p<0.001), cefepime (p=0.003), ceftazidime (p<0.001), moxifloxacin 73

(p<0.001), and piperacillin/tazobactam (p<0.001) had decreasing trends over the study analysis 74

period. Ciprofloxacin, colistin, and tigecycline usage were found to be consistent throughout the 75

study period (p>0.05 for all). 76

77

A total of 27,818 isolates were identified as Enterobacteriaceae out of which there were 55 de-78

duplicated CIRE. The following organism types were identified as CIRE: Klebsiella 79

pneumoniae (n=47, 85.5%), Escherichia coli (n=4, 7.3%), Enterobacter cloacae (n=2, 3.6%), 80

Enterobacter aerogenes (n=1, 1.8%), and Klebsiella oxytoca (n=1, 1.8%). CIRE isolates/1000 81

patient days increased significantly as a function of time (p<0.001) per the Chi-square test for 82

trend. 83

84

There was a positive correlation between CIRE incidence and the carbapenem class (r=0.62, 85

p=0.004) (Figure 1); the association remained significant when the analysis was corrected for 86

multiple comparisons (i.e. significance at the level of ≤ 0.0056). CIRE isolates/1000 patient days 87

increased as a mathematical function of all carbapenem DOT/1000 patient days (y = 88

0.0077+0.1307/(1+exp(-(x-23.6967)/ 0.0109)), r2=0.64) (Figure 2)). This equation identified a 89

sharp increase in the number of CIRE/1000 patient days after exceeding 22 carbapenem 90

DOTs/1000 patient days. 91

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There was a negative correlation with ceftazidime (r=-0.52, p=0.018), piperacillin/tazobactam 93

(r=-0.64, p=0.0021), and moxifloxacin (r=-0.51, p=0.022) usage. When the analysis was 94

corrected for multiple comparisons among these negative correlations (i.e. significance at the 95

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 in 98

Enterobacteriaceae. Previous epidemiological studies with select Gram-negative organisms 99

support our findings. One study analyzed carbapenem use and found that carbapenem use and 100

carbapenem-resistant K. pneumoniae increased simultaneously [12]. The correlation of 101

carbapenem exposure and antimicrobial resistance has also been reported in case-control studies 102

[16, 17]. These analyses found that progression to CIRE is likely the result of multi-factorial 103

process in respect to antibiotic exposure; our study corroborates these results and may indicate 104

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 disk 107

diffusion because minimum inhibitory concentrations were not available for analysis. Thus, these 108

numbers may slightly underreport CIRE incidence. Second, these data are epidemiologic in 109

nature and cannot confirm or disprove causality. However, the statistical power gained with 110

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 from 112

imipenem/cilastatin to meropenem in mid 2007, though CIRE incidence largely occurred in the 113

presence of meropenem use. This modification should improve validity since the use of each 114

individual carbapenem varied depending on formulary status. Fourth, our institution actively 115


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screens for nosocomial organism outbreaks. There was one outbreak of CRE involving three 116

patients; however, this represented a very small portion (5.5%) of isolates studied. Thus, our 117

results are unlikely biased by horizontal organism transfer. Lastly, this study was conducted at a 118

single large institution in Chicago, IL. Results may not apply to other areas where different 119

pathogens predominate ecologically. 120

121

The incidence of CIRE is increasing at our institution and was associated with increasing 122

carbapenem class use and decreasing piperacillin/tazobactam use. Further research is needed to 123

elucidate if knowledge of associations between antibiotic consumption and CIRE may be used to 124

design interventions that slow CIRE spread. 125


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Acknowledgements: None. 126

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Financial Support Statement: This work was supported in part by a Midwestern University 128

Student Research Grant. Midwestern University had no part in the design and conduct of the 129

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

or approval of the manuscript. 131

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Financial disclosures: All authors have no relevant conflicts of interest or financial conflicts to 133

disclose. 134

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Corresponding Author: Marc Scheetz, PharmD, MSc, Midwestern University Chicago College 136

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

630-515-6116, Fax: 630-515-6958, Email: [email protected] 138

139

Portions of this research were presented at the 51st Interscience Conference on Antimicrobial 140

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


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Figure Legends 207

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Figure 1. All carbapenem DOT/1000 patient days and CIRE/1000 patient days 209

DOT = days of therapy 210

CIRE = Carbapenem-intermediate or -resistant Enterobacteriaceae 211

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Figure 2. CIRE isolates/1000 patient days vs. all carbapenem DOT/1000 patient days 213

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

r2=0.64 215

CIRE = Carbapenem-intermediate or -resistant Enterobacteriaceae 216

DOT = days of therapy 217


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Correlations of Antibiotic Use and Carbapenem Resistance in

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