Final Project Association Between Co-trimoxazole Resistance and Febrile Urinary Tract Infection Caused by E.

coli Acquired in the Healthcare Setting

Alex Smithson. MD. Santa Coloma Gramenet, Barcelona, Catalonia

INTRODUCTION
E. coli is responsible for most febrile urinary tract infections (FUTI) in men The prostate is the organ most frequently involved in males with FUTI Co-trimoxazole reaches high concentrations in the prostate and is considered, together with quinolones, the first therapeutic choice in males with FUTI The widespread use co-trimoxazole has led to an increasing resistance to cotrimoxazole among E. coli isolates It has been demonstrated an association between resistance to quinolones and acquisition of the FUTI in the healthcare setting (Smithson A, et al, Eur J Clin Microbiol 2012) The possible association between co-trimoxazole resistance among E. coli strains causing FUTI in males and acquisition of the infection in the healthcare setting has not been evaluated

RESEARCH QUESTION
Measure the prevalence of co-trimoxazole resistance in our sample of E. coli strains causing FUTI in males Evaluate the possible association between co-trimoxazole resistance among the E. coli strains causing FUTI in males and acquisition of the infection in the healthcare setting
Study

the correlation between co-trimoxazole resistance and other

clinical variables in our sample of males with FUTI caused by E. coli

METHODOLOGY-I

Ambispective cross-sectional study in which we collected data

from male patients aged > 18 years with a FUTI caused by E. coli. FUTI was defined as an armpit temperature > 38C and one or more symptoms of urinary infection Clinical variables recorded were: age, dementia, healthcareassociated urinary tract infection, diabetes mellitus, chronic kidney failure, cirrhosis, neoplasia, chronic obstructive lung disease, heart failure, the Charlson comorbidity index, antibiotic treatment, presence of urinary tract abnormalities or prior urinary infection The study was approved by the hospital Ethics Committee

METHODOLOGY-II
Urine

samples were obtained from clean-catch midstream urine

or from urinary catheters and cultured on MacConkey agar Positive urine cultures were defined by bacterial growth > 103 colony forming units/mL. Susceptibilities to amoxicillin, amoxicillin-clavulanate acid, cefuroxime, gentamicin, pipemidic acid, ciprofloxacin, co-trimoxazole and fosfomycin were tested by agar disk diffusion method according to the CLSI criteria Intermediate and resistant E. coli strains to either of the antimicrobials tested were grouped together for data analysis

METHODOLOGY-III
Qualitative data are expressed as number (percentages).

Quantitative data are expressed as mean (+ standard deviations). Continuous variables are compared by the ANOVA test. Categorical data were compared by using the Chi-square test. Statistical significance was defined as a two-tailed P value of < 0.05. Statistical analysis was carried out by the program SPSS (version 20; SPSS, Inc., Chicago, IL)

RESULTS-I
297 patients with FUTI due to E. coli were included in the study

71 out of 284 (25%) (13 missing values) of the FUTI were caused by co-trimoxazole resistant E. coli strains The clinical characteristics (univariate analysis) of the 297 patients included its shown in the Table posted in Assignment 3 Males with FUTI caused by co-trimoxazole resistant E. coli strains were more likely to have acquired the infeccion in the healthcare setting (31%) than patients with a FUTI caused by cotrimoxazole susceptible E. coli strains (18.8%) (X2 4.65, df 1, P = 0.03)

RESULTS-II

Males with FUTI caused by co-trimoxazole resistant E. coli

strains were also more likely to have received prior antimicrobial treatment (42.3%) compared to patients with a FUTI caused by cotrimoxazole susceptible E. coli strains (21.8%) (X2 11.28, df 1, P = 0.001) (Figure 1) Co-trimoxazole resistant E. coli strains with a higher frequency were resistant to other antimicrobials such as amoxicillin, amoxicillin-clavulanic, cefuroxime, ceftriaxone, gentamicin, fosfomycin and ciprofloxacin (Figure 2) when compared to their cotrimoxazole susceptible counterparts

Figure 1. Relationship between co-trimoxazol resistance and previous antimicrobial treatment

80,0%

Prior antimicrobial treatment

P = 0.001

0 1

60,0%

Porcentaje

42.3%

0= Abscence of previous antibiotic treatment 1= Previous antibiotic treatment

40,0%

21.8%

20,0%

0,0% 0 1

Co-trimoxazole

0= Co-trimoxazol susceptible E. coli 1= Co-trimoxazol resistant E. coli

Figure 2. Relationship between co-trimoxazol resistance and ciprofloxacin susceptibility pattern in the E. coli strains
Ciprofloxacino; R=1/S=0/I=2
80,0%

P < 0.001

64.8%

0 1

0= ciprofloxacin susceptible E. coli strain

60,0%

Porcentaje

1= ciprofloxacin resistant E. coli strain

40,0%

25.8%

20,0%

0,0% 0 1

Co-trimoxazole

0= co-trimoxazole susceptible E. coli strain 1= co-trimoxazole resistant E. coli strain

RESULTS-III
Patients

with an infection caused by co-trimoxazole resistant E.

coli strains had higher heart rates (104.6 + 18 bpm) than those patients with an infection caused by co-trimoxazole susceptible E. coli strains (96.4 + 17.8 bpm) (P = 0.001) Figure 1 shows the Box Plot of the variable heart rate in patients with FUTI caused by co-trimozole resistant and in those with FUTI caused by co-trimoxazole susceptible E. coli strains No statistical significant differences were found in co-trimoxazole resistant and susceptible strains regarding other quantitative variables

Figure 3. Relationship between heart rate and co-trimoxazol susceptibility

200

P = 0.001
150 2 59 6

37

Heart rate

100

124 50

0 0 1

o - t r25th i m oand x a z75th o l e ;percentiles R=1/S=0 Data are represented as medians (horizontalC bar), (boxes), and 10th and 90th percentiles (bars). Significant differences between groups are indicated (ANOVA). 0= Co-trimoxazole susceptible E. coli strains; 1= Co-trimoxazole resistant E. coli strains

DISCUSSION-I
The prevalence of co-trimoxazole resistant E. coli observed in our study was below the 40% observed in previous studies (Smithson A, et al, Reviews in Medical Microbiology, 2003). This could be due to a decrease in the consumption of co-trimoxazol over the years and thus a lower selective antimicrobial pressure Similarly to what was observed with ciprofloxacin (Smithson A, et al, Eur J Clin Microbiol 2012), co-trimoxazole resistance was associated with FUTI acquired in the healthcare setting and with previous antimicrobial treatment

DISCUSSION-II
Empirical treatment with co-trimoxazole should be avoided particularly in pacients with FUTI acquired in the healthcare setting and in those with prior antimicrobial treatment Co-trimoxazole resistance was associated with resistance to other antimicrobials, mainly with ciprofloxacin resistance. This could be explained because genes encoding for antimicrobial resistance frequently are clustered together in genetic fragments called pathogenicity islands (Hacker J, et al, Annu Rev Microbiol 2000)

DISCUSSION-III
The fact that FUTI caused by co-trimoxazole resistant E. coli strains had higher heart rates than those urinary infections caused by co-trimoxazole susceptible E. coli strains is, somehow, surprising This could be due to a higher frequency of atrial fibrillation in elderly people. Males with FUTI caused by co-trimoxazole resistant E. coli strains were older (differences were not statistical significant) than FUTI caused by co-trimoxazole susceptible E. coli strains, although this is just an speculation as the variable atrial fibillation was not recorded in the study

POTENTIAL LIMITATIONS OF THE STUDY

Some of the patients were recorded retrospectively The criteria of healthcare-associated urinary tract infection has not been universally accepted and has not been supported by prospective studies We have analyzed an apparent miscellaneous group of males with FUTI, but as stated by the Guidelines on Urological Infections from the European Association of Urology, most men with FUTI have in fact an acute prostatitis (Available at: http:// w w w. u r o w e b . o r g/ f i l e a d m i n / t x _ e a u g u i d e l i n e s / 2 0 0 9 / F u l l / Urological_Infections.pdf)

Peso Dividir archivo

<ninguno> <ninguno> 297

SYNTAX-I
Casos utilizados

Quantitative variable

Tiempo de procesador Tiempo transcurrido Dimensiones solicitadas Casillas disponibles

00:00:00,19 00:00:00,00 2 131072

to_de_datos1] /Users/alexsmithson/Desktop/Curso estadstica coursera/FUTI.sav Pgina 1

SYNTAX-II
Quantitative variables
GET FILE='/Users/alexsmithson/Desktop/Curso estadstica coursera/FUTI.sav'. DATASET NAME Conjunto_de_datos1 WINDOW=FRONT. T-TEST GROUPS=TMSX(1 0) /MISSING=ANALYSIS /VARIABLES=Age DaysHospit Charlson MBP BPM Leucocytes Creatinine DURATIONATB /CRITERIA=CI(.95).

Prueba T

Figure 1

Notas 01-MAY-2013 17:21:47

Resultados creados Comentarios

Entrada de grficos. Datos * Generador GGRAPH ... /GRAPHDATASET NAME="graphdataset" VARIABLES=TMSX COUNT()[name="COUNT"] PreviousAntimicrobial MISSING=LISTWISE REP Conjunto_de_datos1 /GRAPHSPEC SOURCE=INLINE. BEGIN GPL SOURCE: s=userSource(id("graphdataset")) Filtro <ninguno> DATA: TMSX=col(source(s), name("TMSX"), unit.category()) Peso <ninguno> DATA: COUNT=col(source(s), name("COUNT")) Dividir archivo <ninguno> DATA: PreviousAntimicrobial=col(source(s), name("PreviousAntimicrobial"), unit.category()) 297 COORD: rect(dim(1,2), cluster(3,0)) GUIDE: axis(dim(3), label("Co-trimoxazole")) GUIDE: axis(dim(2), label("Porcentaje")) GUIDE: legend(aesthetic(aesthetic.color.interior), label("Prior antimicrobial treatment")) SCALE: linear(dim(2), include(0)) ELEMENT: interval(position(summary.percent(PreviousAntimicrobial*COUNT*TMSX, base.coordinate(dim(3)))), color.int Casos utilizados END GPL.

GrficoG
Notas Resultados creados Sintaxis Comentarios 01-MAY-2013 20:39:32

SYNTAX-III
Figure 2

GET FILE='/Users/alexsmithson/Desktop/Curso estadstica coursera/FUTI.sav'. DATASET NAME Conjunto_de_datos1 WINDOW=FRONT. * Generador de grficos. GGRAPH /GRAPHDATASET NAME="graphdataset" VARIABLES=TMSX COUNT()[name="COUNT"] CIPRO MISSING=LISTWISE REPORTMISSING=NO /GRAPHSPEC SOURCE=INLINE. BEGIN GPL SOURCE: s=userSource(id("graphdataset")) DATA: TMSX=col(source(s), name("TMSX"), unit.category()) DATA: COUNT=col(source(s), name("COUNT")) DATA: CIPRO=col(source(s), name("CIPRO"), unit.category()) COORD: rect(dim(1,2), cluster(3,0)) GUIDE: axis(dim(3), label("Co-trimoxazole")) GUIDE: axis(dim(2), label("Porcentaje")) GUIDE: legend(aesthetic(aesthetic.color.interior), label("Ciprofloxacino; R=1/S=0/I=2")) SCALE: linear(dim(2), include(0)) ELEMENT: interval(position(summary.percent(CIPRO*COUNT*TMSX, base.coordinate(dim(3)))), color.interior(CIPRO), shap END GPL.

GrficoG
Notas Resultados creados Comentarios Entrada Datos ... Conjunto_de_datos1 Filtro Peso <ninguno> <ninguno> 02-MAY-2013 17:43:34

SYNTAX-IV
Figure 3
* Generador de grficos. GGRAPH /GRAPHDATASET NAME="graphdataset" VARIABLES=TMSX BPM MISSING=LISTWISE REPORTMISSING=NO /GRAPHSPEC SOURCE=INLINE. BEGIN GPL SOURCE: s=userSource(id("graphdataset")) DATA: TMSX=col(source(s), name("TMSX"), unit.category()) DATA: BPM=col(source(s), name("BPM")) DATA: id=col(source(s), name("$CASENUM"), unit.category()) GUIDE: axis(dim(1), label("Co-trimoxazole; R=1/S=0")) GUIDE: axis(dim(2), label("Heart rate")) SCALE: linear(dim(2), include(0)) ELEMENT: schema(position(bin.quantile.letter(TMSX*BPM)), label(id)) END GPL.

GrficoG
Notas Resultados creados Comentarios Entrada Datos ... Conjunto_de_datos1 Filtro Peso Dividir archivo <ninguno> <ninguno> <ninguno> 297 Sintaxis 01-MAY-2013 17:44:17

Acknowledgments
I would like to acknowledge the Emergency Department of the Fundaci Hospital de lEsperit Sant, Santa Coloma Gramenet, Barcelona, Catalonia, for all their support in the development of the study Thank you all!!!