Secondary outcomes:
Out of the 205 patients with isolated Klebsiella organisms in the
ICU during the study duration, 122 (59.5 %) were carbapenem-resistant
(CRK). Those CRK were resistant to imipenem in 97 patients, to meropenem
in 62 patients, or resistant to both in 51 patients.
The pre-intervention CRK isolates was reported in 52 isolates (85.2 %)
compared to 70 isolates (48.6 %) in the post-intervention period. These
differences were statistically significant with OR (95% CI) of 0.164
(0.075-0.357), P < 0.001.
Among the 61 patients in the pre-intervention period, no patients were
in grade 1 (0 %), while 9 (14.8 %) and 52 patients (85.2 %) had grade
2 and 3 resistance respectively compared to 13 (9 %), 61 (42.4 %) and
70 (48.6 %) of the 144 of the post-intervention periods had resistance
of grade 1, 2, and 3 respectively (P < 0.001). This pattern
showed a decreased prevalence of CRK (grade 3) at the expense of
increased grades 1 and 2 Klebsiella species.
One-way ANOVA (Levene’s Test of equality of error variances p-value
> 0.05) showed that the difference in carbapenem
consumption reported with the different Klebsiella grades was
significant (F=4.8, P=0.009). It was 31.9 ± 3 DDD / 1000 patient-days
with grade 1 compared to 31.7 ± 10.1 and 36.5 ± 11.8 DDD / 1000
patient-days with grades 2 and 3 respectively. Moreover, post-hoc
analysis using Turkey’s test for pairwise comparison found a significant
difference between grade 2 and 3 (P=0.01) (Figure 2).
Figure 2: The relationship between Klebsiella resistance grades
and carbapenems consumption.
Two ordinal logistic regression models were used. The first model with a
fit parallel line test (χ2 = 1.97, P = 0.16)
showed that Klebsiella species were more likely to be in a lower
category of resistance significantly after implementation of the ASP
with OR (95 % CI) of 6.3 (2.88 – 13.73). The second model with a fit
parallel line test (χ2 = 0.275, P = 0.6) showed
that that Klebsiella species were more likely be in a lower
category of resistance with a decrease in carbapenems use with OR (95 %
CI) of 1.04 (1.012 – 1.07).
4. DISCUSSIONS:
Multidrug-resistant bacteria are shown to be caused by antibiotics abuse
in the healthcare facilities (Cantón, Horcajada, Oliver, Garbajosa, &
Vila, 2013) especially in ICUs (Prabaker & Weinstein, 2011). We
hypothesized that the application of ASP within the ICU including the
preauthorization of restricted antibiotics list, the timeout for
de-escalation, and the timeout for early discontinuation with other
different elements can decrease the consumption of different antibiotics
especially carbapenems, and consequently decrease the prevalence of the
CRK species. We conducted an observational study to measure the
carbapenem consumption within the ICU of a tertiary hospital in an
Egyptian rural area after the implementation of ASP elements and
compared this consumption with that prior to the program implementation.
We also evaluated the impact of the carbapenem consumption on theKlebsiella species resistance pattern.
The implementation of the ASP in our study significantly decreased the
carbapenem utilization, where it caused a decrease in the carbapenem use
by 31.6 % compared to 22% in another study (Elligsen et al., 2012). A
previously reported stewardship program decreased carbapenem utilization
from 300 to 20 DDD / month (Simmons, Sherman, & Crosmun, 2016), which
is not like our results that could be because of the different units
used for carbapenem consumption.
Another study found that the ASP decreased the consumption of meropenem
from 90.5 to 24.96 and imipenem from 6.5 to 2.3 in terms of DDD / 1000
patients-days (Jaggi, Sissodia, & Sharma, 2012).
Other impacts of ASP were studied, and it was concluded that the
application of the program caused a significant decrease in the
inappropriate antibiotic use from 18.5 % to 11.4 % (Maeda et al.,
2016) and the implementation of antibiotic restriction policy decreased
the total broad-spectrum antibiotic days. (Rimawi, Mazer, Siraj, Gooch,
& Cook, 2013). Moreover, the prospective audit and feedback elements of
the ASP were seen to be of utmost importance in applying of the program
in many studies (Lesprit, Landelle, & Brun-Buisson, 2013; D. H. Solomon
et al., 2001). One study applied an easy-to-use electronic
preauthorization system within ASP that was seen to significantly
decrease the cephalosporins use by 39 % (Buising et al., 2008). Other
earlier programs that restricted the use of cephalosporins caused an 18
% decrease in hospital prescription of cephalosporins (Hanberger,
Skoog, Ternhag, & Giske, 2014).
Appropriate antibiotics selection and time to de-escalation from
carbapenems or antipseudomonal antibiotics was studied after ASP
implementation and it was found that ASP significantly improved time to
de-escalation and appropriateness of antibiotics (Bookstaver et al.,
2017). We didn’t however analyze the impact of the different program
elements separately due to the small sample size. The decrease in
carbapenem consumption in our study might indicate compliance to
restricted antibiotics policy, shorter time to antibiotics
de-escalation, appropriate duration, and optimum dosing.
We reported a 59.5 % prevalence of CRK in our study. Other studies in
Egypt reported similar prevalence ranging from 44 % up to more than 63
% (Amer et al., 2016; El Kholy & El Manakhly, 2018; Metwally et al.,
2013). Additionally, out of 80 Klebsiella pneumoniae isolates
obtained from hospitalized patients at Menoufia University Hospitals,
the resistance to imipenem and meropenem was observed in 62.5 and 56.2
respectively(Melake et al., 2016).
We reported a significant decrease in the prevalence of the CRK after
the implementation of the ASP interventions. Viñau Lopez et al. found a
decrease in resistance of Klebsiella pneumoniae after ASP
implementation in a tertiary hospital from 46 % to 38 % (Jaggi et al.,
2012). Other studies reported that the applying of ASP with a shorter
antibiotic course was shown to decrease antibiotic-resistant
superinfection from 38 % to 14 % (Srinivasan, 2017).
Others showed that interventions
that decreased excessive antibiotic use, decreased the antibiotic
resistance pattern, and even improve clinical outcomes (Davey et al.,
2013). Despite that Elligsen et al showed that the ASP interventions
decreased meropenem resistance, they didn’t show a significant
difference in the clinical outcome in terms of mortality or length of
stay (Elligsen et al., 2012).
We also found that higherklebsiella resistance grades were associated with higher
carbapenem consumption. Horikoshi et al showed a positive correlation
between days on carbapenems and carbapenems resistance in the pediatric
population (Horikoshi et al., 2017). Another case-control study
involving Klebsiella pneumoniae bloodstream infection found that
carbapenem use caused 9.98 fold increase in the odds of acquiring
carbapenem resistance (Yuan et al., 2020). Carbapenem exposure within
one month before the onset of bloodstream infection was found by other
authors to be the only risk factor for developing CRK infection (Liu et
al., 2019).
Despite that the reduced
antibiotic consumption could be the direct outcome of applying ASP, its
long-term impact might include several clinical and economic impacts.
Mortality reduction and decrease hospital length of stay as outcomes to
ASP had been also studied. The ASP implementation caused up to a 54 %
reduction in mortality with an OR of 2.17 (Conway et al., 2017) and
decreased length of hospitalization (Horikoshi et al., 2017). These
results were, however, not reproduced in a meta-analysis including 11
studies (Lindsay et al., 2019).
Our study was limited by the small sample size. We did not study the
impact of the program on clinical outcomes in terms of mortality and
length of stay. The authors considered that changes related to the
clinical outcome may require a longer duration to be evident. It is of
significance to study a sub-analysis of the effect of the different
elements of the ASP. This, however, requires a larger sample size, and
accordingly, the authors studied the impact of the program as a bundle.
CONCLUSION
Applying antibiotic stewardship programs including preauthorization of
restricted antibiotics, timeouts of de-escalation and discontinuation,
and implementing hospital-specific guidelines could reduce the
unnecessary carbapenems use in the ICU with a subsequent decrease in the
emergence of the Klebsiella resistant strains.