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Risk Factors Associated With Imipenem-Resistance Among Isolated Gram -Negative Bacteria From Patients in Sanandaj Hospitals, Iran


1 Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, IR Iran
2 Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, IR Iran
3 Department of Microbiology, Kurdistan University of Medical Sciences, Sanandaj, IR Iran
*Corresponding author: Rashid Ramazanzadeh, Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, IR Iran. Tel: +98-9143104424, Fax: +98-8716664674, E-mail: .
Avicenna Journal of Clinical Microbiology and Infection. 3(1): e29989 , DOI: 10.17795/ajcmi-29989
Article Type: Brief Report; Received: Jun 13, 2015; Revised: Nov 7, 2015; Accepted: Nov 15, 2015; epub: Jan 23, 2016; collection: Feb 2016

Abstract


Background: The use of imipenem antibiotics against Gram-negative bacteria is growing, but the incidence of imipenem-resistant bacteria is also increasing.

Objectives: The aim of this study was to determine the risk factors for imipenem resistance in patients with Gram-negative bacteria infections.

Patients and Methods: An imipenem minimum inhibitory concentrations (MIC) test was done using the E-test, and a survey of different risk factors of imipenem resistance in 374 patients who were infected solely by Gram-negative bacteria was performed.

Results: Of the 374 isolated, 134 were imipenem resistant, and 240 were sensitive to imipenem. The resistance rate was more common in males and in patients with intensive care unit (ICU) admission, trauma-induced infections, a history of antibiotic use, the need for ventilator support, or central venous catheter insertion, and in nosocomial infections.

Conclusions: Our results showed the rate of effects of different risk factors on imipenem resistance. Regarding the studied risk factors, appropriate programs must be set in place to control and prevent imipenem resistance in Gram-negative bacteria.

Keywords: Risk Factors; Imipenem; Gram- Negative Bacteria; Drug Resistance

1. Background


The antimicrobial resistance of bacteria leads to problems in controlling and treating infections (1). Drug resistance can result in treatment failure, increased morbidity and mortality (especially in critically ill patients), prolonged hospitalization, and higher healthcare costs (2). The risk factors for imipenem resistance in patients have been determined in many studies (1), and different studies have shown the resistance to imipenem in various bacteria. Zilberberg et al. (3) In the US, used a systematic literature review to show that imipenem-resistant bacteria was present in 14.6% of the isolates of patients with pneumonia. In another study, Sorin et al. (4). Also in the US, demonstrated that the nosocomial transmission of imipenem-resistant Pseudomonas aeruginosa is related to bronchoscopy, which is associated with improper connection to the steris systems. Also, Huang et al. (2) In Taiwan, reported that, in 329 patients with Acinetobacter nosocomialis bacteremia, 20.4% showed no susceptibility to imipenem.

2. Objectives


We conducted this study to identify the risk factors related to imipenem resistance in Gram-negative bacteria isolated from patients of Sanandaj hospitals, in Iran.

3. Patients and Methods


3.1. Study Population and Specimen Types

We conducted a descriptive, analytic, cross-sectional study on clinical isolates, obtained from patients of Sanandaj Hospitals, located in the Kurdistan province of Iran (from January 2007 through January 2010). Isolates were collected from clinical samples, including the bloodstream, the respiratory tract, skin and soft tissues, and urinary tract infections. On the basis of this study, patients that had at least one imipenem-resistant isolate were considered as cases, and patients who were infected by sensitive isolates during the duration of this study were defined members of the control group, when considering a particular condition related to risk factors during study time.


3.2. Microbiological Methods

All clinical samples were routinely cultured on MacConkey and blood agar (Merck, Germany) plates. Blood samples were cultured in Castaneda blood culture bottles. Isolates were identified at the species level using standard biochemical tests and microbiological methods. Only one isolate per patient was included in this study.


3.3. Antibiotic Susceptibility Testing

Imipenem minimum inhibitory concentration (MIC) tests were done using E-test strips (AB Biodisk, Swede) according to National Committee for Clinical Laboratory Standards (NCCLS); Imipenem-sensitive ≤ 4 mg/lit, imipenem-resistant ≥ 16 mg/lit (5).


3.4. Risk Factor Detection

For each patient, the following clinical data were collected prospectively in a checklist of different parts, including demographic data, diagnosis at admission, type of clinical ward, current remedy for the patient, history of using antimicrobial agents, isolation site of the bacteria, the presence of mono or poly microbial infections, clinical outcome, and underling diseases. The sources of all clinical specimens were noted in this study, and the results of laboratory tests were compared and matched with the checklists.


3.5. Statistical Analysis

We compared the characteristics of this study using a univariate analysis, and variables were entered in a logistic regression analysis. The chi-square or Fisher’s exact test was used for the comparison of dichotomous variables. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. Statistical analyses were performed using the software program SPSS 16 for Windows (P values ≤ 0.05) (SPSS Inc., Chicago, IL, USA).

4. Results


In this study, 374 Gram-negative bacterium isolates were considered for evaluation. Therefore, 134 (35.8%) patients were considered as the case and 240 (64.1%) patients were considered the control. The majority of isolates were taken from female patients: 231 (61.7%). Results showed that imipenem sensitivity in females (67.09%) was more prevalent than in the males (55.24%). Intensive care unit (ICU) admission, trauma-induced infections, a history of antibiotic use, the need to ventilator support or for the insertion of central venous catheter, and nosocomial infections significantly increased the risk of imipenem resistance in Gram-negative bacteria. Univariate analyses of potential risk factors for imipenem-resistant isolates indicated cefepim use (68.42%) as the potential risk factor for the resistance of Gram-negative bacteria to imipenem, with a CI of 95% (0.09 - 0.69) and P = 0.00 (Table 1).


Table 1.
Table 1.
The Frequency of Risk Factors and Imipenem Sensitivitya

5. Discussion


This is the first study on risk factors related to imipenem resistance in Gram-negative bacteria in Sanandaj Hospitals, Iran. In our study, the results of the statistical tests performed on 374 patients over four years showed that there are significant statistical differences between the studied risk factors and imipenem resistance (P values < 0.05). In Zavascki’s study, there was not a significant statistical correlation (P value ≥ 0.05) between gender and imipenem resistance in P. aeruginosa, which is not similar to our study, but there was a significant statistical correlation between mechanical ventilation and imipenem resistance (P value ≤ 0.05) (6). Different Gram-negative bacteria could serve as a reservoir of beta lactamase genes, so it is possible that those mobile genetic elements, such as plasmids that carry antibiotic-resistant genes, spread among bacteria, from strain to strain, and in different species of Gram-negative bacilli (7). The reasons for antibiotic resistance, especially β-lactam antibiotics, vary, but drug inactivation (by β-lactamases), insensitivity of the target (altered penicillin-binding proteins), decreased permeability (altered Gram-negative outer-membrane porins), and active efflux are some of them. Also, bacteria strains that produce Extended-Spectrum β- Lactamases (ESBLs) are capable of degrading the expanded-spectrum cephalosporins and monobactams, and show multidrug resistance to more than one antibiotic (8). Our study’s identification of an ICU stay as a strong risk factor for imipenem-resistance was not unexpected [OR = 8.32, CI95% (4.94 – 14.01)], since it had been identified as such in Onguru’s and Lee’s (P value ≤ 0.005) studies as well (1, 9). In general, it can be concluded that the causes of emergence and the spread of antibiotic-resistant bacteria in healthcare facilities (HCFs) are multifactorial. Some of these factors are: widespread use of antibiotics, cross-transmission from patient to patient, inappropriate or poor infection control measures, inter-hospital transfer of resistance, the acquisition of organisms from the hospital environment, a community contribution of resistance, and so on (10). A limitation of this study is that we were unable to assess the role of patient-to-patient transmission, so this can be considered a bias among our results. In conclusion, this study showed different risk factors for imipenem resistance. However, our results suggest that the risk factors for imipenem resistance are strongly related to ICU stay in patients. Extensive use of other broad-spectrum antibiotics also increases the risk of imipenem resistance, so appropriate programs must be set in place to control and prevent such resistance in patients with these risk factors. There is hope that more studies will be done on the mentioned risk factors and the “how” of gaining antibiotic resistance in bacteria.

Acknowledgments

This is part of MD student (Roghaye Mehrdel) thesis. Authors wish to extend their gratitude to the Kurdistan University of Medical Sciences for supporting the project. We thank the Microbiology laboratory staff of the Beasat and Toohid Hospitals for their technical support.

Footnotes

Authors’ Contribution: Roghaye Mehrdel carried out the study and collected data. Behzad Mohsenpour and Rashid Ramazanzadeh supervised the study, participated in designing and conducting it, and in the preparation of the manuscript. Tayyebeh Faraji, Milad Masaeli and Samaneh Rouhi conducted research and prepared the manuscript. All the authors have studied and approved the content of the present manuscript and participated in revising the paper.
Funding/Support: This study was funded and supported by the cellular and molecular research center and the microbiology department of the Kurdistan University of Medical Sciences, Sanandaj, Iran.

References


Table 1.

The Frequency of Risk Factors and Imipenem Sensitivitya

Risk Factors Imipenem- Sensitiveb Imipenem Resistantb Total P Value OR
Lower Upper
Gender
Male 79 (55.24) 64 (44.75) 143
Female 155 (67.09) 76 (32.90) 231 .02 .39 0.92
Underlying disease
Yes 23 (54.76) 19 (45.23) 42
No 211 (63.55) 121 (36.64) 332 .31 .36 1.32
Previous treatment with antibiotics
Yes 14 (50) 14 (50) 28
No 220 (63.58) 126 (36.41) 346 .16 .26 1.24
ICU stay
Yes 28 (43.75) 36 (56.25) 64
No 205 (66.34) 104 (33.65) 309 .00 .22 0.68
Ventilator support
Yes 24 (37.50 ) 40 (62.50 ) 64
No 209 (67.63 ) 100 (32.36 ) 309 .00 .16 0.50
Trauma-induced infections
Yes 18 (39.13 ) 28 (60.86 ) 46
No 216 (65.85 ) 112 (34.14 ) 328 .00 .17 0.62
Need for central venous catheter
Yes 9 (32.14) 19 (67.85) 28
No 225 (65.02) 121 (34.97) 346 .00 .11 0.58
Blood transfusion
Yes 31 (44.28) 39 (55.71) 70
No 203 (66.77) 101 (33.22) 304 .00 .23 0.67
Nosocomial infection
Yes 23 (38.98) 36 (61.01) 59
No 211 (66.98) 104 (33.01) 315 .00 .17 0.55
Antibiotic use in the past 14 days
Yes 12 (41.37) 17 (58.62) 29
No 222 (64.34) 123 (35.65) 345 .01 .18 0.84
Cefepim use
Yes 6 (31.57) 13 (68.42) 19
No 228 (64.22) 127 (35.77) 355 .00 .09 0. 69
a OR: 95% confidence interval, these p-values stand and OR for comparison between males and females, and Yes and No.
b Data are presented as No. (%).