Abstract
This meta-analysis was conducted to assess mortality, clinical and microbiological response following antibiotic therapy among patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. Fifty-four observational studies involving 3195 CRKP-infected patients who received antibiotic treatment were included. We found combination therapy to be associated with lower mortality than monotherapy, but no differences in clinical and microbiological response. Among the various combination therapies, no significant differences in mortality, clinical and microbiological response were found. Moreover, clinical outcomes did not differ significantly among various monotherapies. This report describes the data related to the article entitled: “A systematic review and meta-analysis of treatment outcomes following antibiotic therapy among patients with carbapenem-resistant Klebsiella pneumoniae infections”.
Keywords: Antibiotic resistance, Carbapenem-resistant, Infectious diseases, Pharmacotherapy, Klebsiella pneumoniae
Subject | Infectious diseases |
Specific subject area | Antibiotic efficacy against carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. |
Type of data | Table Chart Figure |
How data were acquired | Systematic review and meta-analysis |
Data format | Raw data and analyzed data |
Parameters for data collection | Outcomes (mortality, clinical and microbiological response) among antibiotic-treated patients with carbapenem-resistant Klebsiella pneumonia (CRKP) infections. |
Description of data collection | The data presented is based on fifty-five articles (54 studies) selected based on a systematic literature review that involved searches performed in Medline, Embase, Cochrane Central, and the International Pharmaceutical Abstracts databases from their inception to December 2018. |
Data source location | Monash University, Melbourne, Australia |
Data accessibility | Data are with this article |
Related research article | Agyeman AA, Bergen PJ, Rao GG, Nation RL, Landersdorfer CB A systematic review and meta-analysis of treatment outcomes following antibiotic therapy among patients with carbapenem-resistant Klebsiella pneumoniae infections International Journal of Antimicrobial Agents. |
Value of the Data
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1. Data
Based on the inclusion criteria, out of 1863 articles initially screened, fifty-five articles (54 studies) reporting treatment outcomes among antibiotic-treated CRKP-infected patients were included in the meta-analysis (Fig. 1). The included studies were of good quality as per their quality appraisal scores (Table 1) which were evaluated using the Newcastle-Ottawa scale (NOS) for nonrandomized trials included in meta-analyses [1].
Table 1.
Article No. | First author, year | Criteria for quality assessment |
Total quality score | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Selection |
Comparability |
Outcome/Exposure |
||||||||
1 | 2 | 3 | 4 | 1 | 2 | 3 | ||||
1 | Alexander, 2012 [2] | * | n.a | * | * | n.a | * | * | * | 6 |
2 | Bergamasco, 2012 [3] | * | n.a | * | * | n.a | * | * | * | 7 |
3 | Brizendine, 2015 [4] | * | * | * | * | * * | * | * | * | 9 |
4 | Capone, 2013 [5] | * | n.a | * | * | n.a | * | * | - | 5 |
5 | Cprek, 2016 [6] | * | n.a | * | * | n.a | * | * | * | 6 |
6 | Daikos, 2009 [7] | * | * | * | * | ** | * | * | * | 9 |
7 | Daikos, 2014 [8] | * | n.a | * | * | n.a | * | * | * | 6 |
8 | Dubrovskaya, 2013 [9] | * | n.a | * | * | n.a | * | * | * | 6 |
9 | Gomez-Simmonds, 2016 [10] | * | n.a | * | * | n.a | * | * | * | 6 |
10 | Ji, 2015 [11] | * | n.a | * | * | n.a | * | * | * | 6 |
11 | Machuca, 2017 [12] | * | n.a | * | * | n.a | * | * | * | 6 |
12 | Michalopoulos, 2010 [13] | * | n.a | * | * | n.a | * | * | * | 6 |
13 | Mouloudi, 2010 [14] | * | * | - | - | ** | * | * | n.a | 6 |
14 | Nguyen, 2010 [15] | * | n.a | * | * | n.a | * | * | * | 6 |
15 | Qureshi, 2012 [16] | * | n.a | * | * | n.a | * | * | * | 6 |
16 | Qureshi, 2014 [17] | * | * | * | * | ** | * | * | * | 9 |
17 | Sanchez-Romero, 2012 [18] | * | * | * | * | ** | * | - | * | 8 |
18 | Satlin, 2011 [19] | * | n.a | * | * | n.a | * | * | * | 6 |
19 | Souli, 2008 [20] | * | n.a | * | * | n.a | * | * | * | 6 |
20 | Souli, 2010 [21] | * | n.a | * | * | n.a | * | * | * | 6 |
21 | Souli, 2017 [22] | * | n.a | * | * | n.a | * | * | * | 6 |
22 | Shields, 2016a [23] | * | n.a | * | * | n.a | * | * | * | 6 |
23 | Trecarichi, 2016 [24] | * | * | * | * | ** | * | * | * | 9 |
24 | Tumbarello, 2012 [25] | * | n.a | * | * | n.a | * | * | * | 6 |
25 | Tumbarello, 2015 [26] | * | n.a | * | * | n.a | * | * | * | 6 |
26 | Vardakas, 2015 [27] | * | n.a | * | * | n.a | * | * | * | 6 |
27 | Venugopalan, 2017 [28] | * | * | * | * | ** | * | * | n.a | 8 |
28 | Weisenberg, 2009 [29] | * | n.a | * | * | n.a | * | - | * | 5 |
29 | Daikos, 2007 [30] | * | * | - | - | ** | * | * | n.a | 6 |
30 | Maltezou, 2009 [31] | * | n.a | * | * | n.a | * | * | * | 6 |
31 | Navarro-San, 2013 [32] | * | n.a | * | * | n.a | * | * | * | 6 |
32 | Di Carlo, 2013 [33] | * | n.a | * | * | n.a | * | * | * | 6 |
33 | Balandin, 2014 [34] | * | n.a | * | * | n.a | * | * | * | 6 |
34 | Kontopidou, 2014 [35] | * | n.a | * | * | n.a | * | * | * | 6 |
35 | McLaughlin, 2014 [36] | * | * | - | * | ** | * | * | n.a | 7 |
36 | Pontikis, 2014 [37] | * | n.a | * | * | n.a | * | * | * | 6 |
37 | Mammina, 2010 [38] | * | n.a | * | * | n.a | * | * | * | 6 |
38 | Oliva, 2017 [39] | * | n.a | * | * | n.a | * | * | * | 6 |
39 | Gonzalez-Padilla, 2015 [40] | * | n.a | * | * | n.a | * | * | * | 6 |
40 | Neuner, 2011 [41] | * | n.a | * | * | n.a | * | * | * | 6 |
41 | Falagas, 2007 [42] | * | * | - | * | ** | * | * | n.a | 7 |
42 | Sbrana, 2013 [43] | * | n.a | * | * | n.a | * | * | * | 6 |
43 | Papadimitriou-Olivgeris, 2017 [44] | * | * | - | * | ** | * | * | n.a | 7 |
44 | Falcone, 2016 [45] | * | n.a | * | * | n.a | * | * | * | 6 |
45 | Liao, 2017 [46] | * | n.a | * | * | n.a | * | - | * | 5 |
46 | De Pascale, 2017 [47] | * | * | - | - | ** | * | * | n.a | 6 |
47 | Freire, 2015 [48] | * | * | * | * | ** | * | * | * | 9 |
48 | Hussein, 2013 [49] | * | * | - | * | ** | * | * | n.a | 7 |
49 | Simkins, 2014 [50] | * | * | - | * | ** | * | * | n.a | 7 |
50 | Shields, 2016b [51] | * | n.a | * | * | n.a | * | * | * | 6 |
51 | Russo, 2018 [52] | * | * | - | * | ** | * | * | n.a | 7 |
52 | Su, 2018 [53] | * | n.a | * | * | n.a | * | * | * | 6 |
53 | Varotti, 2017 [54] | * | * | - | * | ** | * | * | n.a | 7 |
54 | Pouch, 2015 [55] | * | * | - | * | ** | * | * | n.a | 7 |
55 | Duani, 2018 [56] | * | * | - | * | ** | * | * | n.a | 7 |
*Fulfillment of items within a section; n.a, not applicable.
1.1. Mortality
The data showed that the overall pooled mortality rate among the CRKP-infected patients treated with antibiotics was 37.2% (95% CI 33.1–41.4%; I2 = 76.8%) (Fig. 2). Sub-group analyses based on geographic region (North America: 30.4%, 95% CI 20.9–40.8%, I2 = 80.4%; other: 39.5%, 95% CI 35.1–44.1%, I2 = 74.7%), publication years (≤2012: 40.8%, 95% CI 31.4–50.6%; I2 = 67.2%; 2013–2018: 36.1%, 95% CI 31.5–40.8%, I2 = 79.8%) and study design (retrospective: 37.5%, 95% CI 32.6–42.5%, I2 = 79.1%: prospective: 35.4%, 95% CI 28.2–42.9%; I2 = 56.6%) did not result in significant reduction in heterogeneity levels for the pooled mortality rates. Moreover, funnel plot visualization showed no evidence of publication bias (Fig. 3).
Compared to combination therapy, monotherapy was associated with a higher likelihood of mortality (odds ratio [OR] 1.45, 95% CI 1.18–1.78; I2 = 0.0%) (Fig. 4). However, there were no significant differences in the likelihood of mortality between CRKP-infected patients treated with 2-drug and ≥3-drug combination regimens (Fig. 5) or between the combination containing and sparing regimens of carbapenems (Fig. 6), polymyxins (Fig. 7), aminoglycosides (Fig. 8) and tigecycline (Fig. 9). Moreover, there were no significant differences in the likelihood of mortality between the various monotherapies (Table 2). The comparison of the mortality outcomes across the various antibiotic combination regimens did not change when the analysis was restricted to 14- and 30-day mortality (Table 3).
Table 2.
Outcome | No. of studies pooled | No. of patients | Odds Ratio (OR) (95% CI) | Heterogeneity of included studies |
---|---|---|---|---|
Mortality | ||||
Carbapenem vs polymyxin | 7 | 98 | 0.83 (0.29–2.40) | 18.3%, p = 0.290 |
Carbapenem vs aminoglycoside | 10 | 110 | 1.83 (0.67–4.97) | 11.3%, p = 0.339 |
Carbapenem vs tigecycline | 8 | 103 | 1.43 (0.56–3.69) | 0.0%, 0.540 |
Polymyxin vs aminoglycoside | 11 | 377 | 1.10 (0.70–1.71) | 0.0%, p = 0.557 |
Polymyxin vs tigecycline | 11 | 422 | 0.84 (0.56–1.25) | 0.0%, p = 0.788 |
Aminoglycoside vs tigecycline | 11 | 188 | 0.53 (0.27–1.04) | 0.0%, p = 0.980 |
Clinical response | ||||
Carbapenem vs polymyxin | No pooled data (1 datapoint) | – | – | – |
Carbapenem vs aminoglycoside | 3 | 19 | 0.75 (0.08–7.08) | 0.0%, p = 0.592 |
Carbapenem vs tigecycline | 3 | 27 | 0.92 (0.14–5.91) | 0.0%, p-0.554 |
Polymyxin vs aminoglycoside | 2 | 50 | 1.10 (0.13–9.61) | 28.7%, p = 0.236 |
Polymyxin vs tigecycline | 4 | 69 | 2.27 (0.46–11.27) | 0.0%, p = 0.564 |
Aminoglycoside vs tigecycline | 3 | 56 | 2.58 (0.79–8.41) | 0.0%, p = 0.997 |
Microbiological response | ||||
Carbapenem vs polymyxin | No pooled data (0 datapoint) | – | – | – |
Carbapenem vs aminoglycoside | No pooled data (1 datapoint) | – | – | – |
Carbapenem vs tigecycline | No pooled data (1 datapoint) | – | – | – |
Polymyxin vs aminoglycoside | No pooled data (1 datapoint) | – | – | – |
Polymyxin vs tigecycline | 2 | 50 | 2.76 (0.87–8.68) | 0.0%, p = 0.344 |
Aminoglycoside vs tigecycline | 2 | 65 | 3.00 (0.60–15.1) | 0.0%, p = 0.580 |
Table 3.
Mortality | No. of studies pooled | No. of patients | Odds Ratio (OR) (95% CI) | Heterogeneity of included studies |
---|---|---|---|---|
By 14-day | ||||
Monotherapy vs combination | 8 | 935 | 1.42 (1.06–1.90); p = 0.020 | I2 = 0.0%; p = 0.907 |
2-drug vs ≥ 3-drug combination | 8 | 490 | 0.91 (0.59–1.41); p = 0.674 | I2 = 0.0%; p = 0.844 |
Carbapenem-containing vs carbapenem-sparing | 4 | 65 | 1.39 (0.31–6.16); p = 0.664 | I2 = 0.0%; p = 0.700 |
Polymyxin-containing vs polymyxin-sparing | 5 | 114 | 1.45 (0.50–4.16); p = 0.491 | I2 = 0.0%; p = 0.531 |
Aminoglycoside-containing vs aminoglycoside-sparing | 6 | 117 | 0.46 (0.17–1.24); p = 0.125 | I2 = 0.0%; p = 0.504 |
Tigecycline-containing vs tigecycline-sparing | 5 | 106 | 1.70 (0.60–4.78); p = 0.315 | I2 = 0.0%; p = 0.890 |
By 28-day or 30-day | ||||
Monotherapy vs combination | 14 | 763 | 1.54 (1.09–2.17); p = 0.015 | I2 = 1.2%; p = 0.436 |
2-drug vs ≥ 3-drug combination | 13 | 555 | 0.91 (0.59–1.42); p = 0.684 | I2 = 9.2%; p = 0.353 |
Carbapenem-containing vs carbapenem-sparing | 11 | 470 | 0.65 (0.37–1.12); p = 0.123 | I2 = 14.2%; p = 0.309 |
Polymyxin-containing vs polymyxin-sparing | 12 | 457 | 1.33 (0.64–2.75); p = 0.446 | I2 = 53.8%; p = 0.014 |
Aminoglycoside-containing vs aminoglycoside-sparing | 13 | 545 | 0.99 (0.58–1.67); p = 0.956 | I2 = 27.0%; p = 0.172 |
Tigecycline-containing vs tigecycline-sparing | 11 | 507 | 1.09 (0.48–2.45); p = 0.844 | I2 = 56.1%; p = 0.012 |
The bold values represent the significant results.
1.2. Clinical response
The data showed that the overall pooled clinical response rate among the CRKP-infected patients treated with antibiotics was 69.0% (95% CI 60.1–78.2%; I2 = 82.8%) (Fig. 10). Sub-group analyses based on geographic region (North America: 64.9%, 95% CI 50.1–78.5%, I2 = 80.4; other: 72.4%, 95% CI 60.0–83.4%; I2 = 85.4%), publication years (≤2012: 73.9%, 95% CI 57.1–88.0%; I2 = 82.5%; 2013–2018: 66.3%, 95% CI 54.9–76.9%, I2 = 83.6%) and study design (retrospective: 67.1%, 95% CI 55.5–77.7%, I2 = 84.4%: prospective: 79.7%, 95% CI 63.2–92.6%; I2 = 59.4%) did not result in significant reduction in heterogeneity levels for the pooled clinical response rate. Moreover, direct observation of the funnel plot did not show any obvious evidence of publication bias (Fig. 11).
There was no significant difference in the clinical response rate between monotherapy and combination regimens (Fig. 12), nor between 2-drug and ≥3-drug combination regimens (Fig. 13). Furthermore, no significant differences were noted in the pooled clinical response between combination containing and sparing regimens of carbapenems (Fig. 14), polymyxins (Fig. 15), aminoglycosides (Fig. 16) and tigecycline (Fig. 17). Moreover, there were no significant differences in the likelihood of clinical response between the various monotherapies (Table 2).
1.3. Microbiological response
The data showed that the overall pooled microbiological response rate among the CRKP-infected patients treated with antibiotics was 63.7% (95% CI 53.7–74.1%; I2 = 82.1%) (Fig. 18). Sub-group analyses based on geographic region (North America: 71.6%, 95% CI 63.6–79.1%, I2 = 48.7%; other: 53.9%, 95% CI 34.5–72.7%, I2 = 86.7%), publication years (≤2012: 67.8%, 95% CI 49.1–84.2%; I2 = 82.6%; 2013–2018: 62.2%, 95% CI 49.3–74.4%, I2 = 80.9%) and study design (retrospective: 63.2%, 95% CI 51.6–74.1%, I2 = 81.9%; prospective: 78.8%, 95% CI 60.6–92.9%; I2 = 68.0%) did not result in significant reduction in heterogeneity levels for the pooled microbiological response rate. Moreover, as per the funnel plot visualization, there was no obvious presence of publication bias (Fig. 19).
There was no significant difference in the microbiological response rate between monotherapy and combination regimens (Fig. 20), nor between 2-drug and ≥3-drug combination regimens (Fig. 21). Furthermore, no significant differences were noted in the pooled microbiological response between combination containing and sparing regimens of carbapenems (Fig. 22), polymyxins (Fig. 23), aminoglycosides (Fig. 24) and tigecycline (Fig. 25). Moreover, there were no significant differences in the likelihood of clinical response between the various monotherapies (Table 2).
2. Experimental design, materials and methods
2.1. Search strategy
In this article, treatment outcomes (mortality, clinical and microbiological response) among antibiotic-treated CRKP-infected patients were reviewed based on published literature. More specifically, a thorough systematic literature search was conducted in Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and the International Pharmaceutical Abstracts databases from their inception to December 26 2018 using the using search terms such as Klebsiella pneumoniae, antibiotic therapy and carbapenem resistance. The full search strategy is presented in Table 4. The database searches were also supplemented by manual reference screening of the included articles.
Table 4.
|
3. Methodological quality assessment
All studies that met the selection criteria were assessed for quality via the Newcastle-Ottawa scale (NOS) for nonrandomized trials included in meta-analyses [1]. Studies achieving a NOS score of ≥5 were deemed to be of sufficient quality for inclusion in the review.
3.1. Inclusion and exclusion criteria
All studies addressing treatment outcomes for patients with infections caused by CRKP who received antibiotic therapy were eligible for inclusion. Studies involving both infected and colonized patients were included if the treatment outcomes of the infected patients could be separately extracted. Studies were excluded if they were based upon case reports or case series of <10 patients, focused on children or were in vitro or animal studies. Conference abstracts and meeting reports were also excluded.
3.2. Data extraction
A pre-designed data extraction form was used to collect relevant data. The extracted information included study details (first author, publication year, sample size, period, design, and country), population characteristics (gender distribution, mean age, site of infection etc.), antibiotic susceptibility testing (AST), details of antibiotic regimen, treatment outcomes (mortality, clinical response, and microbiological response) and any reported adverse events. All-cause mortality evaluated at end of patient follow-up was the primary outcome measurement. We additionally extracted data specifically for 14-day and 30-day mortality. The secondary outcomes were clinical response, microbiological response and adverse events. Due to the lack of standard and uniform criteria for the assessment and reporting of clinical response and microbiological response we adopted the definitions as employed in individual studies. The articles’ screening and selection process was conducted according to the PRISMA Guidelines [57].
3.3. Data analysis
The overall all-cause mortality, clinical response and microbiological response rates were determined via meta-analysis proportion. The meta-analysis was performed using the Freeman-Tukey double arcsine transformed proportions to stabilize the variance [58]. A random-effects (DerSimonian and Laird) model was used in the meta-analysis due to the anticipated heterogeneity across studies. For the comparative assessment of treatment outcomes following specific antibiotic therapies, the effect measure was expressed as odds ratios (ORs). Cochran's Q test and the Ι2 statistic were used to quantify the presence of statistical heterogeneity [59]. I2 values of 25%, 50%, and 75% were considered to be low, moderate, and high degrees of heterogeneity, respectively. To examine the potential sources of heterogeneity in the pooled mortality, clinical and microbiological response rates, we performed subgroup analyses based on the following characteristics: geographic region (North America vs. other), publication years (≤2012 vs. 2013–2018) and study design (prospective vs. retrospective). The presence of publication bias was assessed by direct observation of funnel plots and quantified with Egger's regression test [60]. To examine the robustness of our pooled estimates, leave-one-out sensitivity analyses were performed. A study was considered influential if the pooled estimate without it was outside the 95% CIs of the overall pooled estimate. All analyses were performed using Stata 15/IC (StataCorp LP, College Station, Texas, USA). P-value <0.05 was considered as statistically significant.
Acknowledgments
The authors are grateful to Dr. Richard Ofori-Asenso of the Department of Epidemiology and Preventive Medicine, Monash University for cross-checking the extracted data and to Dr. Jenni Ilomaki of the Centre for Medicine Use and Safety, Monash University for constructive review of the manuscript. AAA is supported by a Monash Graduate Scholarship and Monash International Postgraduate Research Scholarship for her doctoral studies. CBL was supported by an Australian National Health and Medical Research Council (NHMRC) Career Development Fellowship (APP1062509). The funders had no role in the research design, data collection, analysis and interpretation, or the decision to submit the work for publication.
Conflict of Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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