Trimethoprim-resistant Enterobacteriaceae in urinary tract infection
C.K. WONG, MD; G.K.M. HARDING, MD, FRCP[C]; A.R. RONALD, MD, FRCP[C]; SHIRLEY HOBAN,
Summary: The incidence of trimethoprim-resistant Enterobacteriaceae has not increased since the introduction of the combination trimethoprim-sulfamethoxazole (TMP-SMX) into clinical use at our centre in 1973. Using the minimum inhibitory concentration (MIC) as the index of trimethoprim resistance, this ranged from 1.6 to 800 pg I ml; for the majority of isolates it lay between 1.6 and 12.5 ug / ml. About half of these trimethoprim-resistant organisms were sensitive to sulfonamide. In vitro data suggest that organisms resistant to sulfonamide as well as to trimethoprim, where the MIC for the former drug is 3.1 /ug / ml or less, will be susceptible to the combination. More resistant organisms, i.e. those for which the MIC of trimethoprim is 6.2 ug / ml or more, often appear quite resistant to the combination. There is no evidence that previous therapy with TMP-SMX is a significant predisposing factor to infection with these organisms, although there is a significant correlation between previous TMP-SMX therapy and infection with organisms with a high level of trimethoprim resistance. Organisms harbouring R-factor resistance or thymine-dependent mutants were not encountered during the course of this study. Resume: Enterobacteriaceae resistants au trimethoprime dans les infections des voies urinaires Depuis les premiers essais cliniques dans notre centre, en 1973, de I'association trimethoprime-sulfamethoxazole (TMP-SMX), la frequence de resistance des Enterobacteriaceae au trimethoprime n'a pas augmente. Considerant la concentration inhibitrice minimum (CIM) comme I'index de la resistance au trimethoprime, elle variait de 1.6 a 800 ug I ml. Pour la majorite des isolats la CIM se situe entre 1.6 et 12.5 pg I ml. Pres de la moitie des organismes resistants au trimethoprime etaient sensibles au sulfonamide. Les donnees in vitro permettent de croire que les organismes qui sont resistants et au sulfonamide et au trimethoprime, quand la CIM pour le sulfonamide est de 3.1 ug I ml ou moins, seront sensibles a I'association. Les organismes plus resistants, i.e. ceux dont le CIM est 6.2 pg I ml ou plus, semblent souvent assez resistants a I'association. On ne possede aucun signe qu'un traitement prealable au TMP-SMX constitue un facteur predisposant a I'infection par ces organismes, meme si on a note une etroite correlation entre un traitement prealable au TMP-SMX et la frequence de I'infection par des organismes qui presentent From the departments of medical microbiology and medicine, University of Manitoba and Health Sciences Centre, Winnipeg This study was supported by a grant-in-aid from Burroughs Wellcome Ltd. Reprint requests to: Dr. C.K. Wong, Infectious diseases, Health Sciences Centre, 700 William Ave., Winnipeg, Man. R3E 0Z3
54S CMA JOURNAL/JUNE 14,
1975/VOL.
112
ART
une forte resistance au trimethoprime. Les organismes hebergeant le facteur R et les mutants thymino-dependants
n'ont pas ete constates durant le
cours
de la presente etude.
Trimethoprim in combination with sulfamethoxazole (TMPSMX) has emerged as a useful drug in the treatment and prophylaxis of urinary infections.1"7 The reported incidence of trimethoprim-resistant Enterobacteriaceae in clinical isolates has varied in different studies.8"13 Generally it has been low. There has been concern, however, that with the increased use of trimethoprim the percentage of organisms resistant to the drug may increase.10 Since October 1973 sensitivity to trimethoprim has been routinely monitored on all Enterobacteriaceae from urinary isolates at the General Centre, Health Sciences Centre, Win¬ nipeg. In this report we present data on the following: .The incidence of trimethoprim resistance. For the purpose of this study only Escherichia coli, Klebsiella species, En¬ terobacter species and Proteus species are included. .The degree of resistance of these organisms as determined by their minimal inhibitory concentration (MIC) to trimetho¬ prim and the correlation of the degree of trimethoprim resis¬ tance with the resistance to the combination of trimethoprim and sulfamethoxazole. .The mechanisms of trimethoprim resistance in these or¬ ganisms. . Predisposing factors to infection with these organisms, particularly with respect to previous therapy with trimethoprim. .The clinical correlates of urinary tract infection with these organisms in terms of the types and complications of the infections, their duration and outcome.
Materials and methods Patient population
The series was made up of all the inpatients at the Health Sciences Centre and outpatients treated at the outpatient clinics, in the emergency department and in the urinary tract infection clinic. A few urine cultures were also submitted from a nearby nursing home. Criteria of resistance
All urines were cultured on blood agar (Baltimore Biological Laboratories [BBL]) and MacConkey agar(BBL). Identification of species was according to routine bacteriologic tech¬ niques. Sensitivities were determined on Mueller-Hinton agar (BBL) using the Kirby-Bauer method. Discs containing 1.25 ug of trimethoprim and others containing 1.25 ug of trimethoprim and 23.75 ug of sulfamethoxazole were used. Organisms showing a zone size of less than 12 mm to trimethoprim and less than 14 mm to TMP-SMX were considered resistant.
f-wi
^W^^^W^M^$^MiMMfS.
Thymine-dependent mutants Two thymine-dependent mutants, an E. coli and an En¬ terobacter cloacae, were supplied through the courtesy of Dr. J.T. Smith of the school of pharmacy, University of London, England. These were cultured on all media used in this study.
iSS FIG. 1.Incidence of trimethoprim-resistant isolates (as determined disc diffusion) at 3-monthly periods. Table I.Incidence of trimethoprim-resistant urinary isolates*
*
By disc diffusion method (zone size
14 mm). Fifty of organisms were sensitive to sulfonamide (zone size > 18 mm); SMX
*
By disc diffusion method (zone size
C.K. WONG, MD; G.K.M. HARDING, MD, FRCP[C]; A.R. RONALD, MD, FRCP[C]; SHIRLEY HOBAN,
Summary: The incidence of trimethoprim-resistant Enterobacteriaceae has not increased since the introduction of the combination trimethoprim-sulfamethoxazole (TMP-SMX) into clinical use at our centre in 1973. Using the minimum inhibitory concentration (MIC) as the index of trimethoprim resistance, this ranged from 1.6 to 800 pg I ml; for the majority of isolates it lay between 1.6 and 12.5 ug / ml. About half of these trimethoprim-resistant organisms were sensitive to sulfonamide. In vitro data suggest that organisms resistant to sulfonamide as well as to trimethoprim, where the MIC for the former drug is 3.1 /ug / ml or less, will be susceptible to the combination. More resistant organisms, i.e. those for which the MIC of trimethoprim is 6.2 ug / ml or more, often appear quite resistant to the combination. There is no evidence that previous therapy with TMP-SMX is a significant predisposing factor to infection with these organisms, although there is a significant correlation between previous TMP-SMX therapy and infection with organisms with a high level of trimethoprim resistance. Organisms harbouring R-factor resistance or thymine-dependent mutants were not encountered during the course of this study. Resume: Enterobacteriaceae resistants au trimethoprime dans les infections des voies urinaires Depuis les premiers essais cliniques dans notre centre, en 1973, de I'association trimethoprime-sulfamethoxazole (TMP-SMX), la frequence de resistance des Enterobacteriaceae au trimethoprime n'a pas augmente. Considerant la concentration inhibitrice minimum (CIM) comme I'index de la resistance au trimethoprime, elle variait de 1.6 a 800 ug I ml. Pour la majorite des isolats la CIM se situe entre 1.6 et 12.5 pg I ml. Pres de la moitie des organismes resistants au trimethoprime etaient sensibles au sulfonamide. Les donnees in vitro permettent de croire que les organismes qui sont resistants et au sulfonamide et au trimethoprime, quand la CIM pour le sulfonamide est de 3.1 ug I ml ou moins, seront sensibles a I'association. Les organismes plus resistants, i.e. ceux dont le CIM est 6.2 pg I ml ou plus, semblent souvent assez resistants a I'association. On ne possede aucun signe qu'un traitement prealable au TMP-SMX constitue un facteur predisposant a I'infection par ces organismes, meme si on a note une etroite correlation entre un traitement prealable au TMP-SMX et la frequence de I'infection par des organismes qui presentent From the departments of medical microbiology and medicine, University of Manitoba and Health Sciences Centre, Winnipeg This study was supported by a grant-in-aid from Burroughs Wellcome Ltd. Reprint requests to: Dr. C.K. Wong, Infectious diseases, Health Sciences Centre, 700 William Ave., Winnipeg, Man. R3E 0Z3
54S CMA JOURNAL/JUNE 14,
1975/VOL.
112
ART
une forte resistance au trimethoprime. Les organismes hebergeant le facteur R et les mutants thymino-dependants
n'ont pas ete constates durant le
cours
de la presente etude.
Trimethoprim in combination with sulfamethoxazole (TMPSMX) has emerged as a useful drug in the treatment and prophylaxis of urinary infections.1"7 The reported incidence of trimethoprim-resistant Enterobacteriaceae in clinical isolates has varied in different studies.8"13 Generally it has been low. There has been concern, however, that with the increased use of trimethoprim the percentage of organisms resistant to the drug may increase.10 Since October 1973 sensitivity to trimethoprim has been routinely monitored on all Enterobacteriaceae from urinary isolates at the General Centre, Health Sciences Centre, Win¬ nipeg. In this report we present data on the following: .The incidence of trimethoprim resistance. For the purpose of this study only Escherichia coli, Klebsiella species, En¬ terobacter species and Proteus species are included. .The degree of resistance of these organisms as determined by their minimal inhibitory concentration (MIC) to trimetho¬ prim and the correlation of the degree of trimethoprim resis¬ tance with the resistance to the combination of trimethoprim and sulfamethoxazole. .The mechanisms of trimethoprim resistance in these or¬ ganisms. . Predisposing factors to infection with these organisms, particularly with respect to previous therapy with trimethoprim. .The clinical correlates of urinary tract infection with these organisms in terms of the types and complications of the infections, their duration and outcome.
Materials and methods Patient population
The series was made up of all the inpatients at the Health Sciences Centre and outpatients treated at the outpatient clinics, in the emergency department and in the urinary tract infection clinic. A few urine cultures were also submitted from a nearby nursing home. Criteria of resistance
All urines were cultured on blood agar (Baltimore Biological Laboratories [BBL]) and MacConkey agar(BBL). Identification of species was according to routine bacteriologic tech¬ niques. Sensitivities were determined on Mueller-Hinton agar (BBL) using the Kirby-Bauer method. Discs containing 1.25 ug of trimethoprim and others containing 1.25 ug of trimethoprim and 23.75 ug of sulfamethoxazole were used. Organisms showing a zone size of less than 12 mm to trimethoprim and less than 14 mm to TMP-SMX were considered resistant.
f-wi
^W^^^W^M^$^MiMMfS.
Thymine-dependent mutants Two thymine-dependent mutants, an E. coli and an En¬ terobacter cloacae, were supplied through the courtesy of Dr. J.T. Smith of the school of pharmacy, University of London, England. These were cultured on all media used in this study.
iSS FIG. 1.Incidence of trimethoprim-resistant isolates (as determined disc diffusion) at 3-monthly periods. Table I.Incidence of trimethoprim-resistant urinary isolates*
*
By disc diffusion method (zone size
14 mm). Fifty of organisms were sensitive to sulfonamide (zone size > 18 mm); SMX
*
By disc diffusion method (zone size
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