Background
Klebsiella pneumoniae is a major nosocomial pathogen that causes pneumonia, urinary tract infections, and bacteremia [
1]. The widespread use of broad-spectrum cephalosporins over the last several decades has resulted in extended-spectrum β-lactamase (ESBL)–producing strains of
K. pneumoniae becoming endemic in hospitals worldwide [
2,
3]. ESBLs hydrolyze β-lactam antibiotics such as penicillins and most cephalosporins, thereby conferring resistance to these drugs [
4,
5]. Thus, ESBL-producing
K. pneumoniae are usually resistant to at least one extended-spectrum cephalosporin [
6]. Delays in effective treatment result in worse outcomes including increased length of hospital stays, hospitalization costs, and mortality compared to infections caused by non-ESBL producing strains [
6]. The burden caused by these strains is particularly high in Korean hospitals, where approximately 53% of
K. pneumoniae infections are caused by ESBL-producing strains [
7].
To overcome this β-lactamase–mediated resistance and to enhance the efficacy of β-lactam antibiotics, β-lactam/β-lactamase inhibitor (BLBLI) combinations such as ampicillin/sulbactam and piperacillin/tazobactams have been introduced in clinical practice [
8]. Although these drugs are effective in treating infections caused by ESBL-producing organisms [
8,
9], carbapenems have largely remained the treatment of choice [
2,
11], as studies have reported conflicting results regarding the relative efficacy of therapy with BLBLIs compared to that with carbapenems [
12]. However, the emergence of carbapenemase-producing
Enterobacteriaceae [
13,
14] has increased the need to utilize carbapenem-sparing treatment options, such as BLBLIs, for ESBL-related infections [
10,
11]. However, it is now a growing concern that the increased use of BLBLIs will likely lead to increased resistance to these drugs [
15,
16]. One previous molecular study supports this concern, indicating that the use of BLBLIs selects for point mutants in TEM penicillinases resistant to inhibitors [
17].
Although there is a generally well-established link between overall antibiotic use and resistance within hospitals [
18,
19], information is still lacking on the relationship between BLBLI consumption and antibiotic resistance in
K. pneumoniae. In this study, we examined the temporal association between the consumption of antibiotics commonly used in hospitals, particularly BLBLIs, third-generation cephalosporins, and fluoroquinolones, and antimicrobial resistance in
K. pneumoniae. This study aimed to increase understanding of the relationship between the use of and resistance to BLBLIs to improve decision-making and policies on the use of BLBLIs as a carbapenem-sparing option.
Results
The average annual number of antibiotics prescriptions during the study period was 69,100 (range 27,371–84,128) for all BLBLIs; 53,300 (range 22,789–70,514) for all third-generation cephalosporins; and 28,536 (range 12,324–35,368) for all fluoroquinolones (Table
1). There was no significant trend in prescribing rates over the study period.
Table 1
Average quarterly number of antibiotic prescriptions in a tertiary hospital from 2012 to 2016
β-lactam/β-lactamase inhibitors | 68,907 (53,899–80,221) | 72,725 (63,235–84,128) | 71,561 (68,880–76,537) | 63,638 (27,371–80,928) | 68,512 (64,378–71,719) |
Third-generation cephalosporins | 63,304 (60,238–70,514) | 64,784 (60,468–67,074) | 51,578 (44,996–54,267) | 39,007 (22,789–46,250) | 45,999 (44,346–47,384) |
Fluoroquinolones | 29,300 (26,233–33,663) | 31,621 (28,920–35,297) | 27,582 (21,069–35,286) | 25,900 (12,324–32,129) | 28,195 (19,737–35,368) |
The yearly numbers of
K. pneumoniae isolates from 2012 to 2016 for this analysis were 1524, 1609, 1585, and 1754. The mean rates of
K. pneumoniae resistance to piperacillin/tazobactam, ceftazidime, and levofloxacin were 41% (range 22–49), 34% (range 14–44), and 30% (range 23–44), respectively (Table
2). There was a stable trend in resistance rates against ceftazidime and levofloxacin; however, the resistance rate against piperacillin/tazobactam significantly increased from 34% (range: 22–46) in 2012 to 46% (range: 43–49) in 2016; (
p < 0.01).
Table 2
Quarterly antimicrobial resistance in K. pneumoniae in a tertiary hospital from 2012 to 2016
Piperacillin/Tazobactam | 33.75 (22.00–46.00) | 42.50 (40.00–45.00) | 41.00 (39.00–45.00) | 40.25 (30.00–46.00) | 46.00 (43.00–49.00) |
Ceftazidime | 40.75 (38.00–44.00) | 38.50 (36.00–42.00) | 28.75 (26.00–31.00) | 27.00 (14.00–35.00) | 36.00 (33.00–38.00) |
Levofloxacin | 28.50 (27.00–32.00) | 29.00 (27.00–31.00) | 26.25 (23.00–30.00) | 32.50 (27.00–44.00) | 33.00 (30.00–36.00) |
In a bivariate analysis, the lagged (two quarters) quarterly number of all BLBLI prescriptions significantly correlated with
K. pneumoniae resistance to piperacillin/tazobactam (β = 0.66;
p < 0.01), ceftazidime (β = 0.54;
p = 0.02), and levofloxacin (β = − 0.60;
p = 0.01). Similarly, the lagged quarterly number of all third-generation cephalosporin prescriptions significantly correlated with
K. pneumoniae resistance to ceftazidime (β = 0.64;
p < 0.01; two quarters) and levofloxacin (β = 0.50;
p = 0.03; one quarter). The lagged quarterly number of all quinolone prescriptions correlated with
K. pneumoniae resistance to ceftazidime (β = 0.14;
p < 0.01; two quarters), although there was no significant association with levofloxacin resistance (β = 0.23;
p = 0.35) (Table
3).
Table 3
Cross-correlation coefficients between quarterly antibiotics prescriptions and quarterly isolation rates of antibiotic-resistant K pneumoniae from 2012 to 2016
β-lactam/β-lactamase inhibitors | 0.66 p < 0.01 2 quarters lag | 0.54 p = 0.02 2 quarters lag | −0.60 p = 0.01 2 quarters lag |
Third-generation cephalosporins | −0.11 p = 0.65 - | 0.64 p < 0.01 2 quarters lag | 0.50 p = 0.03 1 quarter lag |
Fluoroquinolones | 0.26 p = 0.29 - | 0.14 p < 0.01 2 quarters lag | 0.23 p = 0.35 - |
Discussion
The emergence of ESBL-producing
K. pneumoniae strains and the increasing rates of carbapenem resistance have reduced therapeutic options for infections caused by these organisms [
2,
6,
10]. BLBLIs such as piperacillin/tazobactam have been suggested as alternatives to carbapenems [
10,
11,
12] and may be comparable in efficacy to carbapenems against ESBL-producing
K. pneumoniae infections [
34]. However, although the evidence for their use as an alternative to carbapenems has been conflicting [
12], their use has been increasing. This has led to increasing concern about resistance, which undermines the efficacy of these drugs [
12].
To improve policies around the potential replacement of carbapenems with BLBLIs, it is important to examine the relationship between BLBLI use and antimicrobial resistance using a seasonal analysis, which previous studies used to demonstrate the linkage between seasonality and antibiotic use [
22,
35].
The greatest positive temporal association was found between all BLBLI utilization and piperacillin/tazobactam resistance in
K. pneumoniae. However, no significant correlation was found for the use of the third-generation cephalosporins and fluoroquinolone. This was presumably due to the selection pressure of antibiotic use on the prevalence of resistant isolates. This finding is consistent with results of a previous study that identified a significant correlation between piperacillin/tazobactam use and subsequent piperacillin/tazobactam resistance in
Enterobacteriaceae [
36].
We also found that ceftazidime resistance in
K. pneumoniae temporally correlated with prescriptions for all BLBLIs, all third-generation cephalosporins, and all fluoroquinolones. Consistent with our findings, a previous report indicated that the presence of ceftazidime-resistant
Klebsiella spp
. is significantly positively associated with cephalosporin and fluoroquinolone use at the hospital level [
37]. Regarding the positive association between fluoroquinolone use and the prevalence of ceftazidime resistance to
K. pneumoniae, this may be explained by the transferrable plasmid (qnr gene) among ESBL-producing strains which leads to quinolone resistance [
38]. Thus, these correlations are likely due to the ability of ESBLs to confer resistance to multiple classes of antibiotics [
39].
However, we did not find an association between levofloxacin resistance in
K. pneumoniae and the consumption of quinolones; this result was in contrast to some previous reports which found that increasing fluoroquinolone use was associated with rising incidence of quinolone resistance in
Enterobacteriaceae [
40,
41]. Additionally, we found that levofloxacin resistance in
K. pneumoniae was negatively associated with all BLBLI utilization and positively associated with third-generation cephalosporin utilization. These results may be due to the low level of fluctuation from the quarterly number of fluoroquinolones used, and the low magnitude of utilization likely affected the resistance emergence rates [
42].
This is the first study to describe the temporal relationship between BLBLI use and the resistance to them in
K. pneumoniae in a tertiary level hospital. The strong correlations reported in our study suggest that replacing carbapenems with BLBLIs is not an ideal long-term solution, as resistance is likely to spread rapidly. A previous study in Korea showed that broad-spectrum penicillins including BLBLIs were more frequently prescribed than narrow-spectrum penicillins [
43]. Another study demonstrated that this is presumably due to the physician’s desire to avoid missing an unlikely or unidentified resistant pathogen [
44]. Thus, BLBLIs should be suggested to be used with caution as a carbapenem-sparing option. Further research is needed to evaluate the impact of antimicrobial stewardship programs to balance the use and resistance across drug classes.
Although the results from our study were significant, there are some limitations. First, the study was ecological in nature and may not represent biological associations at the individual level. However, ecological studies are often used to suggest the relationship between use of an antibiotic and resistance to that antibiotic on population level [
35,
45]. Second, we used the total number of antibiotics prescriptions as a measure of antibiotic consumption instead of using defined daily doses (DDDs) in this study. However, a previous study indicated that evaluating the total number of antibiotics prescriptions is a useful method to measure the strength of the relationship between antibiotic consumption and antibiotic resistance [
41], and DDDs are typically highly correlated with the total number of prescriptions. Third, other factors such as the inconsistency of the patient population, transferred patients having resistant organisms from different hospitals, possible epidemics, and infection control measures during the study the period may have affected the level of resistance in our findings.