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Evaluation of Antimicrobial Resistance Rates in Klebsiella Isolates/Klebsiella Izolatlarinin Antimikrobiyal Direnc Oranlarinin Degerlendirilmesi.

Introduction

Klebsiella is an important genus of the Enterobacteriaceae family which causes community-acquired infections as well as nosocomial infections [1]. Present in small amounts in normal flora, Klebsiella spp. may cause colonization and subsequent infection in cases of prolonged hospitalization, invasive procedures such as urinary or central venous catheterization, history of prior surgery, or use of broad-spectrum antibiotics [2,3]. It has been known for the last four or five decades that Gram-negative bacteria are more common causes of nosocomial infections [4]. Today, knowing the resistance pattern of the bacterial agent has become more important than knowing whether it is Gram-negative or Gram-positive.

Klebsiella bacteria may develop different mechanisms of antibiotic resistance. Among them, the most common is extended-spectrum beta-lactamase (ESBL) production [5]. Another form is carbapenem resistance [6]. Resistant bacteria lead to prolonged hospitalization, loss of labor, high costs, and high mortality.

Intensive care patients are critical patterns who require early and effective treatment. Therefore, each hospital must be aware of its specific bacterial resistance rates and initiate empirical treatment accordingly. The aim of this study was to determine the resistance profiles of Klebsiella bacteria isolated from various sample types in various clinical samples in the intensive care units (ICUs) of our setting and contribute to policies regarding the appropriate use of antibiotics.

Materials and Methods

Resistance rates of Klebsiella spp. strains isolated from clinical samples of patients residing in ICUs of the Kahramanmaras Sutcu Imam University Faculty of Medicine between January 2014 and June 2017 were analysed retrospectively. Blood, urine, bronchoalveolar lavage, tracheal aspirate culture (TAC), cerebrospinal fluid, pleural fluid, peritoneal fluid, drainage fluid, and wound site samples were cultured. Cerebrospinal fluid, pleural fluid, peritoneal fluid, drainage fluid, and wound site samples were analysed within the category of 'others' because they were fewer in number. The study included only patients aged 18 years or older who were treated in ICUs. For patients with multiple isolates, only the first strain isolated was included in the analysis.

Clinical samples received by the microbiology laboratory were inoculated on 5% sheep blood agar (RTA, Turkey) and EMB agar (RTA, Turkey) and incubated at 37 [degrees]C for 18-24 hours. Colonies showing Gram-negative bacilli in Gram staining and were identified as oxidase negative, lactose positive, and mucoid producing on culture medium were suspended at a turbidity of 0.5 McFarland. Identification and antibiotic susceptibility tests were done in accordance with "European Committee on Antimicrobial Susceptibility Testing" (EUCAST) recommendations using a Phoenix 100 (Becton Dickinson, USA) system. Extended-spectrum beta-lactamase-producing organisms were identified based on susceptibility to aztreonam, third and fourth generation cephalosporins (cefpodoxime 8 [micro]g/mL, ceftazidime 8 [micro]g/mL) alone and/or in the presence of beta-lactamase inhibitors (ceftriaxone/clavulanic acid 2 [micro]g/mL, cefotaxime/clavulanic acid 2 [micro]g/mL, ceftazidime/clavulanic acid 2 [micro]g/mL). Imipenem, meropenem, and ertapenem minimum inhibitor concentration values were tested and metallo-beta-lactamase producing strains were considered carbapenem-resistant.

Statistical Analysis

SPSS v.17.0 software package (SPSS Inc, Chicago, Illinois, USA) was used in statistical analyses of the data obtained from the study. Continuous data were summarized as mean and standard deviation, while categorical data were expressed as number and percentage. Student's t-test was used in comparisons of continuous variables between independent groups. The chi-square ([chi square]) test was used when comparing categorical values between independent groups. Statistical significance level was accepted as p<0.05.

Results

The mean age of the 443 patients was 66.0[+ or -]20.2 years (minimum-maximum, 19-102 years); 56.9% (n=252) were male and 43.1% (191) were female.

Of the samples from which Klebsiella was isolated, 31.8% (n=141) were TAC, 23.7% (n=105) were blood, 23.3% (n=103) were urine, 9.0% (n=40) were sputum, and 12.2% (n=54) were other sample types.

The three most common units where Klebsiella-positive cultures were performed were the Anesthesia ICU with 56.9% (n=252), the Internal Medicine ICU with 16.9% (n=75), and the Neurology ICU with 10.4% (n=46). Data pertaining to all units are summarized in Table 1.

In terms of the distribution of Klebsiella species, Klebsiella pneumoniae accounted for the large majority of cases (89.7%, n=397). This was followed by K. oxytoca (7%, n=31), K. ozaenae (2.9%, n=13), K. granulomatis (0.2%, n=1), and K. ornithinolytica (0.2%, n=1).

Extended-spectrum beta-lactamase-positive strains accounted for 54.4% (n=241) of the cases, while 45.6% (n=202) were ESBL-negative.

The antibiotic susceptibility rates of the K. pneumoniae and K. oxytoca strains are presented in Table 2.

The mean duration of hospital stay was 47.04[+ or -]40.7 days (minimum-maximum, 1-220 days). Hospital stays were slightly longer in ESBL-positive cases (47.65[+ or -]39.6 days) compared to ESBL-negative cases (46.31[+ or -]42.0 days), but the difference was not statistically significant (p=0.729).

The mortality rate was 54.4% while the remaining 45.6% of the patients were discharged with full recovery. All deaths occurred at the hospital, on day 42.3[+ or -]34.7 of hospitalization. The mortality rate was 60.2% among patients with ESBL-positive Klebsiella versus 47.5% among patients with ESBL-negative Klebsiella ([chi square], p=0.008). In addition, the mortality rate was 55.7% among patients with carbapenem-resistant Klebsiella and 53.8% among patients with non-carbapenem-resistant Klebsiella ([chi square], p=0.717). The association between culture types and patient mortality is shown in Table 3.

Discussion

Drug resistance in Gram-negative bacteria is a serious global concern. Extended-spectrum beta-lactamases are most often produced by Escherichia coli and Klebsiella spp., which are members of Enterobacteriaceae family [7,8]. Extended-spectrum beta-lactamase-producing bacteria are not only resistant to penicillin, but to many cephalosporins and monobactams as well. They may also develop resistance to other drug groups such as quinolones, tetracyclines, aminoglycosides, and carbapenems [9-11].

While the prevalence of ESBL-producing Klebsiella is increasing in Turkey and eastern Europe, it is on a downward trend in western Europe. Antimicrobial resistance patterns may vary between regions, hospitals, and even units within the same hospital. Therefore, each hospital must know its specific antimicrobial resistance profile. Rates of ESBL-producing Klebsiella vary widely in the literature, too. Temiz et al. [12] detected ESBL-producing Klebsiella at rates of 65.1% in samples obtained from ICUs, inpatient units, and outpatient units (68.3% in K. pneumoniae isolates and 10.7% in K. oxytoca isolates). Parlak et al. [13] reported ESBL-positive K. pneumoniae in 67% of samples obtained from inpatient units and the ICU. Guducuoglu et al. [14] reported this rate to be 49%. In the HITIT-2 study involving 6 centers in Turkey, the prevalence of ESBL-producing K. pneumoniae was 32.3%, with only 16.2% in ICUs [15]. The International Nosocomial Infection Control Consortium report for Turkey summarized data from 19 hospitals between 2003 and 2012 [16]. It was determined in the study that ceftriaxone-and ceftazidime-resistant K. pneumoniae strains accounted for 55.7% of central catheter-related bloodstream infections, 46.3% of ventilator-associated pneumonia, and 50.0% of catheter-related urinary tract infections in the ICU. The ESBL-positive Klebsiella ratio in our study was 54.4%.

Beta-lactam/beta-lactamase inhibitors may be preferred for infections caused by ESBL-producing bacteria. In a study by Kuzucu et al. [17], 68% of ESBL-producing K. pneumoniae isolates were found to be piperacillin/tazobactam resistant. This rate was 32% in another study [18], and was 22.3% in the HITIT-2 study [15]. The results of our study were similar to those of Kuzucu et al. [17]. Resistance to beta-lactam/beta-lactamase inhibitors is increasing.

In severe/systemic infections caused by ESBL-producing Klebsiella spp., drugs should be chosen based on susceptibility patterns. In their 2005-2006 analysis, Guducuoglu et al. [14] observed no carbapenem resistance among ESBL-positive K. pneumoniae isolates. There was also no resistance to carbapenem in three of the centers (Akdeniz, Hacettepe, and Dokuz Eylul Universities) involved in the multicenter HITIT-2 study conducted in 2004-2005. However, carbapenem resistance was detected at a rate of 1.3% in the other three centers [15]. More recently, a study by Saygili Pekinturk and Akgunes [19] reported imipenem resistance rates of 2%, 7%, 0%, 38%, and 50% respectively in the years 2011-2015. Although numerous previous studies demonstrated carbapenem susceptibility of ESBL-positive Klebsiella isolates, current evidence shows that carbapenem resistance is becoming more prevalent among ESBL-positive Klebsiella isolates. We also found high resistance to carbapenems in the ESBL-positive K. pneumoniae strains in our study, with rates of 40.3% for ertapenem, 30.5% for meropenem, and 29.7% for imipenem.

In ESBL-positive infections, drugs in the quinolone group may be used as an alternative to beta-lactam/beta-lactamase inhibitors or carbapenems [20]. However, previous studies have generally reported high quinolone resistance rates. Parlak et al. [13] determined ciprofloxacin resistance rates of 11%, 8%, 13%, 35%, and 36% in ESBL-positive K. pneumoniae isolates between 2006 and 2010. In another study, the average ciprofloxacin resistance in the years 2011-2015 was 46% (no data for 2011; 48%, 24%, 52%, and 58% respectively for the remaining years) [19]. In another study by Nepal et al. [21], ciprofloxacin resistance of ESBL-positive K. pneumoniae isolates was 46.2%. In our study, the rate of ciprofloxacin resistance in ESBL-positive K. pneumoniae isolates was much higher than the rates reported in the literature.

We detected higher rates of antibiotic resistance in the ESBL-positive Klebsiella isolates in our study compared to resistance rates in the literature. This may be attributed to the fact that all of the patients included in this study were ICU patients.

Conclusion

In order to overcome the problem of resistance in ESBL-positive Klebsiella spp., each hospital should be aware of its specific resistance rates and the infection control committee should conduct regular surveillance. Units with high resistance rates should be evaluated for deficiencies, and remedial measures and training should be implemented. Furthermore, cultures and antibiotic susceptibility tests should be utilized more diligently before initiating antibiotics. Policies for the rational use of antibiotics should be established in light of this information in order to reduce resistance rates.

Ethics

Ethics Committee Approval: Retrospective study.

Informed Consent: Retrospective study.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Concept: S.N., S.A., Design: S.N., S.A., A.R.S., Data Collection or Processing: B.T., S.N., Analysis or Interpretation: S.N., A.R.S., Literature Search: S.N., A.R.S., Writing: S.N., S.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

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[15.] Gur D, Gulay Z, Akan OA, Aktas Z, Kayacan CB, Cakici O, Erac B, Gultekin M, Ogunc D, Soyletir G, Unal N, Uysal S. Resistance To Never Beta-lactams and Related ESBL Types in Gram-negative Nosocomial Isolates in Turkish Hospitals: Results of the Multicentre Hitit Study. Mikrobiyol Bul. 2008;42:537-44.

[16.] Leblebicioglu H, Erben N, Rosenthal VD, Atasay B, Erbay A, Unal S, Senol G, Willke A, Ozgultekin A, Altin N, Bakir M, Oncul O, Ersoz G, Ozdemir D, Yalcin AN, Ozdemir H, Yildizdas D, Koksal I, Aygun C, Sirmatel F, Sener A, Tuna N, Akan OA, Turgut H, Demiroz AP, Kendirli T, Alp E, Uzun C, Ulusoy S, Arman D. International Nosocomial Infection Control Consortium (INICC) national report on device-associated infection rates in 19 cities of Turkey, data summary for 2003-2012. Ann Clin Microbiol Antimicrob. 2014;13:51.

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[19.] Saygili Pekinturk N, Akgunes A. Extended spectrum beta-lactamase production and antibiotic resistance of Escherichia coli and Klebsiella spp. isolated from hospitalized patients: data of 2011-2015. Turk Hij Den Biyol Derg. 2017;74:221-8.

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iD Selcuk NAZIK (1), iD Bircan TOPAL (2), iD Ahmet Riza SAHIN (1), iD Selma ATES (1)

(1) Kahramanmaras Sutcu Imam University Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Kahramanmaras, Turkey

(2) Kahramanmaras Sutcu Imam University Faculty of Medicine, Infection Control Committee Nursing, Kahramanmaras, Turkey

Address for Correspondence/Yazisma Adresi: Selcuk Nazik MD, Kahramanmaras Sutcu Imam University Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Kahramanmaras, Turkey

Phone: +90 505 501 91 61 E-mail: dr.selcuknazik@hotmail.com ORCID: orcid.org/0000-0003-0587-0104

Received/Gelis Tarihi: 30.10.2017 Accepted/Kabul Tarihi: 05.02.2018

Cite this article as: Nazik S, Topal B, Sahin AR, Guler S. Evaluation of Antimicrobial Resistance Rates in Klebsiella Isolates. Mediterr J Infect Microb Antimicrob. 2018;7:8.

DOI: 10.4274/mjima.2018.8
Table 1. Distribution of Klebsiella isolates according to hospital unit
and sample type [n (%)]

                             Blood       Urine       TAC

Anesthesia ICU               77 (30.6)   34 (13.5)   93 (36.9)
Internal medicine ICU        11 (14.7)   42 (56.0)    6 (8.0)
General surgery ICU           3 (16.7)    2 (11.1)    1 (5.6)
Neurology ICU                 4 (8.7)    17 (37)     18 (39.1)
Pulmonary ICU                 1 (4.0)     2 (8.0)    18 (72.0)
Neurosurgery ICU              7 (41.2)    4 (23.5)    4 (23.5)
Cardiovascular surgery ICU    0 (0)       0 (0)       1 (50.0)
Coronary ICU                  2 (25.0)    2 (25.0)    0 (0)
Total (n)                   105         103         141

                            Sputum     Other (*)  Total

Anesthesia ICU              27 (10.7)  21 (8.3)   252 (100)
Internal medicine ICU        4 (5.3)   12 (16.0)   75 (100)
General surgery ICU          2 (11.1)  10 (55.6)   18 (100)
Neurology ICU                1 (2.2)    6 (13.0)   46 (100)
Pulmonary ICU                2 (8.0)    2 (8.0)    25 (100)
Neurosurgery ICU             0 (0)      2 (11.8)   17 (100)
Cardiovascular surgery ICU   1 (50.0)   0 (0)       2 (100)
Coronary ICU                 3 (37.5)   1 (12.5)    8 (100)
Total (n)                   40         54         443

(*) Includes cerebrospinal fluid, pleural fluid, peritoneal fluid,
drainage fluid, and wound site samples. TAC: Tracheal aspirate culture,
ICU: Intensive care unit

Table 2. Antibiotic susceptibility rates of K. pneumoniae and K.
oxytoca strains

Antibiotic               K. pneumoniae [n (%)]
                         n=397
                         ESBL (+) n=226  ESBL (-) n=171  p (*)

Piperacillin/tazobactam  144 (63.7)      80 (46.8)       0.001
Ceftriaxone              226 (100)       85 (49.7)       0.000
Cefepime                 226 (100)       78 (45.6)       0.000
Ceftazidime              226 (100)       83 (48.5)       0.000
Gentamicin               125 (55.3)      70 (40.9)       0.005
Amikacin                  43 (19.0)      32 (18.7)       0.937
Ciprofoxacin             167 (73.9)      74 (43.3)       0.000
Ertapenem                 91 (40.3)      53 (31.0)       0.057
Imipenem                  67 (29.7)      44 (25.7)       0.389
Meropenem                 69 (30.5)      43 (25.1)       0.238
TMP-SMX                  173 (76.5)      85 (49.7)       0.000
Tigecycline               68 (30.1)      18 (10.5)       0.000
Colistin                  21 (9.3)        9 (5.30)        0.133

Antibiotic               K. oxytoca [n (%)]
                         n=31
                         ESBL (+) n=8  ESBL (-) n=23  p (*)

Piperacillin/tazobactam  5 (62.5)      6 (26.1)       0.064
Ceftriaxone              8 (100)       7 (30.4)       0.001
Cefepime                 8 (100)       7 (30.4)       0.001
Ceftazidime              8 (100)       5 (21.7)       0.000
Gentamicin               1 (12.5)      5 (21.7)       0.569
Amikacin                 0 (0)         2 (8.7)        0.389
Ciprofoxacin             3 (37.5)      4 (17.4)       0.241
Ertapenem                1 (12.5)      4 (17.4)       0.746
Imipenem                 0 (0)         3 (13.0)       0.282
Meropenem                0 (0)         3 (13.0)       0.282
TMP-SMX                  7 (87.5)      5 (21.7)       0.001
Tigecycline              0 (0)         1 (4.3)        0.549
Colistin                 0 (0)         0 (0)          -

(*) Chi-square test was used for intergroup comparisons. ESBL:
Extended-spectrum beta-lactamase, TMP-SMX: Trimetoprim
-sulfamethoxazole, p<0.05 was considered significant

Table 3. The relationship between culture type and mortality of cases
[n (%)]

Culture type               Outcome                Total
                           Discharged  Death

Blood                      42 (40.0)   63 (60.0)  105 (100)
Urine                      58 (56.3)   45 (43.7)  103 (100)
Tracheal aspirate culture  58 (41.1)   83 (58.9)  141 (100)
Sputum                     16 (40.0)   24 (60.0)   40 (100)
Other (*)                  28 (51.9)   26 (48.1)   54 (100)

(*) Includes cerebrospinal fluid, pleural fluid, peritoneal fluid,
drainage fluid, and wound site samples
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Title Annotation:RESEARCH ARTICLE / ARASTIRMA
Author:Nazik, Selcuk; Topal, Bircan; Sahin, Ahmet Riza; Ates, Selma
Publication:Mediterranean Journal of Infection, Microbes and Antimicrobials
Article Type:Report
Date:Jan 1, 2018
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