Treatment Outcome of Bacteremia Due to Non–Carbapenemase-producing Carbapenem-Resistant Klebsiella pneumoniae Bacteremia: Role of Carbapenem Combination Therapy

Clinical Therapeutics/Volume xxx, Number xxx, xxxx

Treatment Outcome of Bacteremia Due to NoneCarbapenemase-producing CarbapenemResistant Klebsiella pneumoniae Bacteremia: Role of Carbapenem Combination Therapy Nan-Yao Lee 1,2,3; Chin-Shiang Tsai 1,2; Ling-Shan Syue 1,2; Po-Lin Chen 1,2,3; Chia-Wen Li 1,2; Ming-Chi Li 1,2; and Wen-Chien Ko 1,2,3 1

Division of Infectious Diseases, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 2Center for Infection Control, National Cheng Kung University Hospital, Tainan, Taiwan; and 3Department of Medicine, College of Medicine, National Cheng Kung University Tainan, Tainan, Taiwan ABSTRACT Purpose: Infections caused by carbapenemaseproducing Klebsiella pneumoniae are emerging causes of morbidity and mortality worldwide. Optimal treatment for nonecarbapenemase-producing carbapenem-resistant K pneumoniae (nCP-CRKP) bacteremia remains undefined. The goal of this study was to assess the clinical outcome, predictors of mortality, and therapeutic strategy of carbapenems for nCP-CRKP bacteremia. Methods: A retrospective study of monomicrobial bacteremia caused by nCP-CRKP, at a medical center between 2010 and 2015 was conducted. CRKP which was defined as a minimum inhibitory concentration (MIC) of
2 for ertapenem or
4 mg/L for meropenem, or imipenem. Multiplex polymerase chain was applied to detect carbapenemase genes. The patients definitively treated with combination therapy were compared with monotherapy using a propensity scoreematched analysis to assess therapeutic effectiveness. The primary end point was the 30-day crude mortality and clinical prognostic factors were assessed. Findings: Overall 171 patients met criteria were eligible for the study and their overall 30-day mortality rate was 38.6%. The multivariate logistic regression analysis showed that combination therapy was associated with a lower 30-day mortality rate (adjusted odds ratio [aOR], 0.11; 95% CI, 0.03e0.43; P ¼ 0.001) and less clinical (aOR, 0.21; 95% CI, 0.08e0.58; P ¼ 0.003) and microbiologic (aOR, 0.36; 95% CI, 0.19e0.71; P ¼ 0.003) failure.

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However, the 30-day mortality rate in the cases infected by a pathogen with a meropenem MIC 8 mg/L receiving carbapenem-containing or carbapenem-sparing combination regimens was similar (15 of 58 [25.9%] vs 5 of 20 [23.3%]; P ¼ 1.0). Implications: Combination therapy, regardless of carbapenem-containing or carbapenem-sparing, with one or more active agents improved survival more than monotherapy and was more effective in patients with critical illness. (Clin Ther. 2020; 42:XXXeXXX) © 2020 Elsevier HS Journals, Inc. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Key words: Carbapenem-resistant, Klebsiella pneumoniae, Enterobacteriaceae, bloodstream infection, combination therapy, MICs.

INTRODUCTION Increasing antibiotic resistance among Enterobacteriaceae is a growing public health crisis that makes many health careeassociated infections untreatable with current antibiotics.1e3 Carbapenemresistant Klebsiella pneumoniae (CRKP) has emerged as a global threat over the past decade. Phenotypic resistance to carbapenems is typically caused by 2 major mechanisms: (1) extended-spectrum b-

Accepted for publication January 7, 2020 https://doi.org/10.1016/j.clinthera.2020.01.004 0149-2918/$ - see front matter © 2020 Elsevier Inc. All rights reserved.

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Clinical Therapeutics lactamases or AmpC b-lactamase combined with structural mutations such as outer membrane protein deficiency, efflux pump overproduction, or alterations in penicillin-binding proteins (nonecarbapenemaseproducing K pneumoniae); or (2) production of carbapenemases that hydrolyze carbapenem antibiotics (carbapenemase-producing K pneumoniae).4e7 These pathogens often harbor genes conferring resistance to multiple antibiotic classes in addition to beta-lactams.5,6 Invasive infections due to CRKP are associated with poor outcomes, with mortality rates of 40%e70% in patients with bloodstream infections, compared with 20%e30% among matched patients with bloodstream infections due to carbapenem-susceptible isolates.6,8e10 However, the prevalence of nonecarbapenemaseproducing K pneumoniae among CRKP isolates (nCP-CRKP) is >60% in national surveillance (68.6%) and reported clinical studies (61%).11,12 The optimal treatment for nCP-CRKP infections is important for outcome and may be different from treatment for infections caused by carbapenemaseproducing CRKP (CP-CRKP). The clinical role of carbapenem monotherapy and combination therapy for invasive infections due to CRKP with or without carbapenemase production is not well defined.11,13 The retrospective studies of bloodstream infections caused by CRKP found that patients receiving combination therapy were more likely to survive than patients receiving monotherapy.14e17 Regardless of resistant mechanisms, some carbapenem-resistant Enterobacteriaceae (CRE) isolates remained phenotypically susceptible to carbapenems. Esterly et al18 have evaluated clinical outcomes of patients with gram-negative bacteremia using a predictive model according to carbapenem MIC stratification. This study showed that patients infected by an organism that had a meropenem or imipenem MIC <2 mg/L had better outcomes after adjustment for confounding variables. Such a finding raises the question of the relative impact of resistance gene and phenotypic susceptibility. Moreover, in the absence of well-designed comparative studies, the role of carbapenem-based therapy remains undefined. Herein, we conducted a clinical study to assess the clinical outcome and predictors of mortality and

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compared monotherapy and carbapenem combination therapy for nCP-CRKP bacteremia.

MATERIALS AND METHODS Study Population and Data Collection The cases of K pneumoniae bacteremia were reviewed from the microbiology database at National Cheng Kung University Hospital (NCKUH) between August 2010 and August 2015. If a patient experienced more than one bacteremic episode, only the first episode was included. The study was approved by the NCKUH Institutional Review Board (ER-100-182). Included were adults (age
20 years) fulfilling both criteria: clinically significant bacteremia with compatible sepsis syndrome and parenteral antibiotic therapy administered for >48 h before the end of antibiotic therapy or death, and with adequate doses as recommended by the Clinical and Laboratory Standards Institute (CLSI), according to the susceptibility categories.19 For carbapenem-based therapy, the dosage of carbapenems was as follows: ertapenem 1 g every 24 h, imipenem 500 mg every 6 h or 1 g every 8 h, and meropenem 1 g every 8 h. The strategy of extended infusion (over 3 h) of 1e2 g meropenem every 8 h was indicated for patients infected by an isolate with a meropenem or imipenem MIC >2 mg/ L. Patients with polymicrobial bacteremia were excluded. Antimicrobial therapy administered within 72 h after bacteremia onset was regarded as empirical therapy; therapy administered afterward was regarded as definitive therapy. Also, definitive antimicrobial therapy was defined as antimicrobial therapy that was continued or commenced on the day that the antibiogram results were reported to the clinicians and which was started no later than 72 h after the index positive blood sample for culture had been drawn. Appropriate therapy was defined as the receipt of either combination therapy or monotherapy, if the causative isolate was in vitro susceptible to one of the prescribed drugs. The combination therapy was defined as the receipt of more than one agent as definitive therapy during therapeutic course. The prescriptions of antibiotic agents were approved by infectious disease specialists

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N.-Y. Lee et al. and pharmacists for their indications and dosages in the study hospital.

Microbiology and Antimicrobial Susceptibilities The VITEK 2 system (bioMerieux, Marcy-l'Etoile, France) was used for species identification and antimicrobial susceptibility testing. MICs of antibiotics were determined by using the broth microdilution method and interpreted according to the CLSI breakpoints; MICs of colistin and tigecycline were interpreted by using the breakpoints established by the European Committee on Antimicrobial Susceptibility Testing.20 Using the definition of CRE from the Centers for Disease Control and Prevention, carbapenem resistance was defined as being in vitro resistant to at least one of ertapenem (MIC
2 mg/L), imipenem (MIC
4 mg/ L), or meropenem (MIC
4 mg/L).21 In addition, an Enterobacteriaceae isolate that harbors a carbapenemase gene was also referred to as CRE, regardless of carbapenem MICs. Bacterial genomic DNA was extracted, and multiplex polymerase chain reaction was applied to detect carbapenemase (blaKPC, blaVIM, blaIMP, blaNDM, and blaOXA) genes.22 The K pneumoniae isolates that harbor a carbapenemase gene were excluded.

Clinical Outcomes Clinical information was retrieved from medical charts and collected in a case record form. Bacteremia was defined as the isolation of organisms in at least one blood culture with compatible clinical features. Patients receiving antimicrobial therapy for >48 h with adequate dosage were included for assessment of outcome. The primary outcome was the crude 30-day mortality rate. Secondary outcomes included total hospital length of stay after bacteremia onset and clinical and microbiologic failure during hospitalization. The severity of underlying medical illness was graded as being rapidly fatal, ultimately fatal, or nonfatal, stratified according to the McCabe score.23 The severity of bacteremia was graded on the day of bacteremia onset by using the Pitt bacteremia score, and critical illness was defined as a Pitt bacteremia score
4 points.24 Immunocompromising conditions included the presence of HIV infection; receipt of chemotherapy, immunomodulatory

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therapy, or corticosteroid therapy for at least 7 days within 1 month before bacteremia onset; or absolute neutrophil count <100 cells/mL at bacteremia onset. Clinical failure was defined as initial antimicrobial therapy that failed to resolve sepsis symptoms or signs or if a fatal outcome ensued after at least 5 days. The detection of K pneumoniae bacteremia after antimicrobial therapy for at least 72 h was regarded as microbiologic failure.

Statistical Analyses Data were analyzed by using SPSS software for Windows version 22.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Continuous variables are expressed as median and interquartile range (IQR) and were compared by using the ManneWhitney U test or Student t test. Categorical variables are expressed as the percentages of total numbers of patients and were compared by using the Fisher exact test or c2 test. Independent predictors for 30-day mortality were identified by means of logistic regression analysis. Variables with a P value  0.1, as determined by the univariate analysis, were included in the multivariate logistic regression analysis. KaplaneMeier survival curves were compared by using the log-rank test, and a Cox proportional hazards model was applied for the survival analysis, adjusted for confounding variables. A P value < 0.05 was considered statistically significant, and all tests were two-tailed. Due to the differences in baseline characteristics and the absence of random allocation to treatment groups in our study, a propensity score matching method was used to minimize the differences between both groups. Propensity scores were calculated by a multivariate logistic regression model in which the dependent variable was a binary indicator of combination therapy or monotherapy. The covariates to generate the propensity score included age, sex (male), preexisting conditions (liver cirrhosis, endstage renal disease requiring dialysis, chronic obstructive pulmonary disease, congestive heart failure with an ejection fraction <45%, diabetes mellitus, or immunocompromising conditions), Pitt bacteremia score, intensive care unit stay on day 1 of bacteremia, and source of bacteremia. The 1:1 nearest neighbor matching without replacement was performed with a caliper width of 0.20. Standardized

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Clinical Therapeutics mean biases were tested to ensure balance after propensity score matching between the combination therapy and monotherapy.

RESULTS Patient Population A total of 171 patients met the inclusion criteria for the analyses of microbiologic and clinical outcome (Figure 1). The characteristics of patients receiving monotherapy (n ¼ 93) or combination therapy (n ¼ 78) are summarized in Table I. There were no statistically significant differences in terms of age, sex, or comorbidity among patients treated with monotherapy or combination therapy, except that patients with an underlying rapidly fatal disease stratified according to the McCabe score, critical illness, or bacteremic pneumonia were more likely to receive combination therapy. During hospitalization, 88 patients died, resulting in an in-hospital mortality rate of 51.5% and a 30-day crude mortality rate of 38.6%. Male patients accounted for 63.7% (109 patients), and all had one or more comorbidities. Their median age was 72 years (interquartile range [IQR], 57e82 years). The median duration of hospitalization before the onset of bacteremia was 15 days (IQR, 4e41 days).

Figure 1.

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Vascular catheter-related infections (46 patients [26.9%]) and primary bacteremia (n ¼ 43 [25.1%]) were the major sources of bacteremia, followed by pneumonia (n ¼ 41 [24.0%]), urinary tract infections (n ¼ 24 [14.0%]), skin and soft tissue infections (n ¼ 19 [11.1%]), and intra-abdominal infections (n ¼ 8 [4.7%]). The vast majority (92.4%) of K pneumoniae isolates were susceptible to colistin. The susceptible rate of meropenem, imipenem, and ertapenem was 64.3%, 57.3%, and 6.4%, respectively. Of note, 139 (81.3%) isolates showed discordant susceptibilities (ie, an isolate was resistant to one carbapenem but susceptible to the others).

Antibiotic Therapy and Outcome As shown in Table I, the 30-day mortality rate was higher in those receiving monotherapy than in those receiving combination therapy (46 [49.5%] of 93 vs 20 [25.6%] of 78; P ¼ 0.002). Also, there was a higher clinical failure rate (42 [45.2%] of 93 vs 18 [23.1%] of 78; P ¼ 0.004), microbiologic failure rate (23 [24.7%] of 93 vs [6.4%] 5 of 78; P ¼ 0.002), and longer hospital stay (median, 22 vs 21 days; P ¼ 0.02) among those receiving monotherapy than among those receiving combination therapy. The 30-

Study flow of included patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae bacteremia.

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Table I.

Baseline characteristics of 171 adults with monomicrobial carbapenem-resistant Klebsiella pneumoniae bacteremia treated with combination therapy or monotherapy.

Characteristics

Whole cohort

Propensity score-matched cohort

Monotherapy Combination P values Monotherapy Combination P values group, n¼93 therapy group, group, n¼70 therapy group, n¼70 n¼78 Age, median (IQR), year Gender, male Length of hospital before bacteremia, median (IQR), day Comorbidity Diabetes mellitus Chronic kidney disease Malignancy Liver cirrhosis Severity of underlying disease (McCabe classification) Rapidly fatal None or non-rapidly fatal Pitt bacteremia score,
4 points Source of bacteremia Vascular catheterrelated infection Primary bacteremia Intra-abdominal infection Pneumonia Skin and soft-tissue infection Urosepsis Hospital stay of survivors, median (IQR), days Appropriate definitive therapy Clinical failure Microbiological failure Sepsis-related mortality

72 (56e81)

71 (60e82)

0.66

71 (54e79)

70 (58e78)

0.79

57 (61.3) 20 (4e44)

52 (66.7) 15 (5e31)

0.52 0.4

44 (62.9) 21 (4e44)

46 (65.7) 14 (4e34)

0.86 0.41

59 (63.4) 33 (35.5)

45 (57.7) 23 (29.5)

0.53 0.42

40 (57.1) 23 (32.9)

42 (60.0) 23 (32.9)

0.86 0.99

29 (31.2) 13 (14.0)

21 (26.9) 12 (15.4)

0.61 0.83 0.03

25 (35.7) 6 (8.6)

17 (24.3) 10 (14.3)

0.20 0.43 0.99

6 (6.5) 87 (93.5)

14 (17.9) 64 (82.1)

6 (8.6) 64 (91.4)

6 (8.6) 64 (91.4)

23 (46.2)

57 (73.1)

<0.001

28 (40.0)

29 (41.4)

0.99

27 (29.0)

19 (24.4)

0.6

22 (31.4)

19 (27.1)

0.71

25 (26.9) 6 (6.5)

18 (23.1) 2 (2.6)

0.6 0.29

20 (28.6) 0 (0)

18 (25.7) 2 (2.9)

0.85 0.50

14 (15.1) 9 (9.7)

27 (34.6) 10 (12.8)

0.004 0.63

16 (22.9) 7 (10.0)

17 (24.3) 10 (14.3)

0.99 0.61

15 (16.1) 22 (14e54)

9 (11.5) 21 (12e52)

0.51 0.02

9 (12.9) 16 (10e19)

9 (12.9) 15 (10e18)

0.99 0.02

80 (86.0)

72 (92.3)

0.23

63 (90.0)

65 (92.9)

0.76

42 (45.2) 23 (24.7) 41 (44.1)

18 (23.1) 5 (6.4) 18 (23.1)

0.004 0.002 0.006

33 (47.1) 14 (20.0) 32 (45.7)

14 (20.0) 5 (7.1) 14 (20.0)

0.001 0.046 0.002

(continued on next page)

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Clinical Therapeutics

Table I.

(Continued )

Characteristics

Whole cohort

Propensity score-matched cohort

Monotherapy Combination P values Monotherapy Combination P values group, n¼93 therapy group, group, n¼70 therapy group, n¼70 n¼78 30-day mortality In-hospital mortality

46 (49.5) 51 (54.8)

20 (25.6) 37 (47.4)

0.002 0.36

35 (50,0) 38 (54.3)

15 (21.4) 29 (41.4)

0.001 0.18

Data are given as numbers (percentages), unless otherwise specified. SD indicates standard deviation; IQR, interquartile range.

day mortality rate of combination therapy was significantly reduced in critically ill patients (38 [88.4%] of 43 vs 14 [37.8%] of 37; P < 0.001). In the multivariate logistic regression analysis, 30day mortality was independently associated with critical illness (Pitt bacteremia score
4 points at bacteremia onset; adjusted odds ratio [aOR], 9.15; 95% CI, 3.63e23.08; P < 0.001), pneumonia (aOR, 6.05; 95% CI, 1.93e18.98; P ¼ 0.002), a rapidly fatal underlying disease (aOR, 6.54; 95% CI, 1.37e31.1; P ¼ 0.02), appropriate definitive therapy (aOR, 0.06; 95% CI, 0.009e0.43; P ¼ 0.005), or

Table II. Variables

combination therapy (aOR, 0.11; 95% CI, 0.03e0.43; P ¼ 0.001) (Table II). Otherwise, patients receiving combination therapy were associated with less clinical (aOR, 0.21; 95% CI, 0.08e0.58; P ¼ 0.003) and microbiologic (aOR, 0.36; 95% CI, 0.19e0.71; P ¼ 0.003) failure. The KaplaneMeier survival analysis also favored combination therapy (aOR, 0.24; 95% CI, 0.13e0.43; P < 0.001, using the Cox regression model). Seventy pairs of patients with monotherapy and those with combination therapy could be matched on the basis of the propensity score at the ratio of 1:1.

Risk factors of 30-day crude mortality among 171 adults with monomicrobial carbapenem-resistant Klebsiella pneumoniae bacteremia. Survivors Non-survivors (n ¼ 105) (n ¼ 66)

Age; median (IQR), years 70 (56e78) Pneumonia 15 (14.3) Urosepsis 20 (6.1) Pitt bacteremia score
4 28 (26.7) points Rapidly fatal underlying 5 (4.8) disease Meropenem MIC > 1(0.01) 8 mg/L Colistin-based therapy 42 (40.0) Appropriate therapy 102 (97.1) Combination therapy 58 (55.2)

73 26 4 52

Univariate analysis OR (95% CI)

Multivariate analysis

P values

OR (95% CI)

P values

(63e85) e 0.03 1.01 (0.98e1.03) 0.73 (39.4) 3.9 (1.89e8.15) <0.001 6.05 (1.93e18.98) 0.002 (19.0) 0.27 (0.08e0.8) 0.02 0.15 (0.04e0.54) 0.004 (78.8) 10.2 (4.91e21.23) <0.001 9.15 (3.63e23.08) <0.001

13 (19.7)

4.91 (1.66e14.5)

12 (18.2)

1.2 (1.08e1.36)

17 (25.8) 50 (75.8) 20 (30.3)

0.52 (0.27e1.02) 0.09 (0.03e0.33) 0.35 (0.18e0.68)

0.004 6.54 (1.37e31.1) <0.001

2.3 (2.0e275.9)

0.07 0.87 (0.23e3.32) <0.001 0.06 (0.009e0.43) 0.002 0.11 (0.03e0.43)

0.02 0.01 0.84 0.005 0.001

Data are given as number (percentage) unless otherwise specified. Ellipses indicate not available. OR indicates odds ratio, CI confidence interval, and IQR interquartile range.

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Table III.

Standardized mean differences of co-variables between the combination and monotherapy groups. Data are given as number (percentage), unless otherwise specified.

Covariable

Age, median (IQR), y Male sex ICU stay Comorbidity Diabetes mellitus Chronic kidney disease Malignancy Liver cirrhosis McCabe classification Pitt bacteremia score
4 points Pneumonia

Whole Cohort

Propensity ScoreeMatched Cohort

Monotherapy Group, n ¼ 93

Combination Therapy Group, n ¼ 78

SMD

Monotherapy Group, n ¼ 70

Combination Therapy Group, n ¼ 70

SMD

72 (56e81) 57 (61.3) 42 (45.2)

71 (60e82) 52 (66.7) 38 (48.7)

0.68 0.11 0.07

71 (54e79) 44 (62.9) 33 (47.9)

70 (58e78) 46 (65.7) 30 (42.1)

0.05 0.06 0.08

59 33 29 13 85 43

45 23 21 12 68 37

(57.7) (29.5) (26.9) (15.4) (87.2) (47.4)

0.12 0.07 0.09 0.04 0.36 0.02

40 23 25 6 64 28

42 23 17 10 64 29

(60.0) (32.9) (24.3) (14.3) (91.4) (41.4)

0.06 0.03 0.02 0.01 0.08 0.03

27 (34.6)

0.26

16 (22.9)

17 (24.3)

0.03

(63.4) (35.5) (31.2) (14.0) (91.4) (46.2)

14 (15.1)

(57.1) (32.9) (35.7) (8.6) (91.4) (40.0)

ICU ¼ intensive care unit; IQR ¼ interquartile range; SMD ¼ standardized mean differences.

The standardized mean differences of many variables were >10% before matching and became <10% after matching (Table III). After propensity score matching, combination therapy continued to be associated with a lower 30-day mortality rate compared with those receiving monotherapy (21.4% vs 50.0%; P ¼ 0.001) (Table I). Most patients (153 [89.5%] of 171) received at least 1 active agent for bacteremia (Table IV). Within various in vitro antimicrobial activities for combination therapy, the aOR of 30-day mortality of individuals receiving definitive combination therapy that was not in vitro active was 0.61 (95% CI, 0.22e1.71; P ¼ 0.35), one active agent was 0.29 (95% CI, 0.15e0.56; P < 0.001), and two active agents was 0.07 (95% CI, 0.009e0.52; P ¼ 0.01). These values are compared with those receiving appropriate definitive monotherapy as the reference in the Cox regression model after adjustment for confounding variables (Figure 2). Combination therapy, either carbapenemcontaining (15 [25.9%] of 58 vs 25 [44.4%] of 54; P ¼ 0.048) or carbapenem-sparing (5 [25.0%] of 20 vs 22 [56.4%] of 39; P ¼ 0.029) regimens, fared

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better than monotherapy. For those receiving definitive combination therapy, the 30-day mortality rate of those receiving a carbapenem-containing regimen was similar to that of a carbapenem-sparing regimen (15 [25.9%] of 58 vs 5 [23.3%] of 20; P ¼ 1.0). Of note, among carbapenem-containing combination therapy, the 30-day mortality rate increased from 0% in the causative isolates with meropenem MIC <0.5 mg/L to 80.0% in those with MIC >8 mg/L (linear-by-linear association, P < 0.001) (Figure 3), and it was lower than that among adults with monotherapy in corresponding MIC categories. In other words, carbapenemcontaining combination therapy heralded a better prognosis than carbapenem monotherapy for the isolates with an MIC of 0.5e8 mg/L.

DISCUSSION The use of combination therapy for the management of infections caused by CRE was explored with the objective of determining the potential synergistic or additive effects of certain combinations of antimicrobial agents.25 We aimed to compare the outcomes for patients treated with monotherapy

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Clinical Therapeutics

Table IV. Antimicrobial regimens for 171 patients with carbapenem-resistant Klebsiella pneumoniae bacteremia Antimicrobial regimens Appropriate Therapy Combination therapy Carbapenem*-containing regimens Carbapenem/amikacin Carbapenem/colistin Meropenem/ciprofloxacin Carbapenem-sparing regimens Colistin/ciprofloxacin Colistin/amikacin Colistin/cefepime Cefepime/amikacin Piperacillin-tazobactam/ amikacin Ciprofloxacin/amikacin Monotherapy Colistin Cefepime Carbapenem Ciprofloxacin Piperacillin-tazobactam Inappropriate therapy (no active agent) Combination therapy Ciprofloxacin/imipenem Meropenem/amikacin Monotherapy Levofloxacin Ertapenem Cefepime Piperacillin-tazobactam

No. of patients (%) 153 (89.5) 73 (42.7) 55 (32.2) 7 46 2 18

(4.1) (26.9) (1.2) (10.5)

2 3 2 7 2

(1.2) (1.8) (1.2) (4.1) (1.2)

2 80 1 18 59 1 1 18

(1.2) (46.8) (0.6) (10.5) (34.5) (0.6) (0.6) (10.5)

5 3 2 13 2 2 3 6

(2.9) (1.8) (1.2) (7.6) (1.2) (1.2) (1.8) (3.6)

Data are given as number (percentage). *Imipenem or meropenem. Dosages of antibiotic for CrCl > 50 mL/min as following; amikacin (7.5mg/kg every 12 h); colistin (100-150 mg every 12h); ciprofloxacin (400 mg every 8-12 h); cefepime (1-2g every 8 h); piperacillin-tazobactam (4.5g every 6 h).

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Figure 2.

Survival analysis for adults receiving combination therapy with 2 active agents (n ¼ 16), 1 active agent (n ¼ 137), and without active agents (n ¼ 5) compared with those receiving monotherapy with 1 active agent (reference, black solid line, n ¼ 80). aOR ¼ adjusted odds ratio.

versus combination therapy after the adjustment of confounders. Treatment with monotherapy was associated with worse clinical and microbiologic outcomes than combination therapy in propensity scoreematched analyses. Compared with monotherapy, combination therapy independently heralded a lower 30-day mortality rate regardless of carbapenem. The protective effect of combination therapy was noted among patients with critical illness. Moreover, the mortality rate increased as the meropenem MIC of the causative isolates increased in the cases of carbapenem-based therapy. Studies including patients with infections caused by carbapenemase-producing Enterobacteriaceae show that the benefits of combination therapy are more pronounced in patients with critical illness.17,26,27 In a more detailed analysis of the effect of combination therapy, the impact on survival of combination

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Figure 3.

The 30-day mortality rates of patients with monomicrobial nonecarbapenemase-producing carbapenem-resistant Klebsiella pneumoniae stratified according to meropenem MICs and therapeutic strategies.

therapy varied among different sources of infections, and the benefits declined when noncritical urosepsis was the source.17 This finding would support the crucial role of combination therapy for the treatment of infections with substantial mortality, such as bacteremic pneumonia. According to CDC's CRE definition, most of our nCP-CRKP isolates were resistant to ertapenem but remained susceptible to imipenem or meropenem, a finding similar to that in previous surveillance studies.28,29 Other than the production of carbapenemases, the mechanisms mediating carbapenem resistance in K. pneumoniae are complex and may be associated with modification in the outer membrane permeability, or up-regulation of efflux pumps with or without hyper-production of AmpC beta-lactamases or ESBLs.4,29,30 Irrespective of the complexity of resistant mechanisms of CRE, combination therapy would provide synergism, and

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can be one of the strategies to overcome resistance before the disclosure of precise resistance mechanisms. Most of our patients treated by carbapenem monotherapy experiencing clinical failure were infected by the isolates with a meropenem MIC of > 0.5 mg/L. The susceptible MIC threshold of current CLSI guideline for Enterobacteriaceae isolates (i.e., 1 mg/L for meropenem or imipenem) has been speculated to be too high for nCP-CRKP, since clinical success was more likely, if the MIC value of meropenem or imipenem was less than 1 mg/L.18 More clinical studies are necessary to assess the optimal susceptible breakpoint for carbapenemresistant Enterobacteriaceae. Colistin was most in vitro active against nCP-CRKP isolates in our study, but the morality rate in those with colistin monotherapy was unacceptably high (100%), as previous reports.25,31 Though up to now there are no randomized controlled trials comparing combination

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Clinical Therapeutics therapy with monotherapy for patients with CRE infections,25 many data support the superiority of combination therapy (at least two agents in vitro active against the causative pathogen) over monotherapy (one in vitro active agent), in terms of patient survival for invasive CRE infections.15,32 The recent introduction of a novel cephalosporin (cefiderocol), ß-lactamase inhibitors (avibactam, vaborbactam, and relebactam), aminoglycoside (plazomicin), and synthetic tetracycline (eravacycline), provided additional therapeutic options for CRE infections.13,33 Surveillance data showed in vitro antibacterial activity of these new agents against CRE, and could support their clinical use for the treatment of serious infections due to noncarbapenemase-producing isolates.13 An unfavorable outcome was independently predicted by four factors in the present study. Three factors, i.e., presence of underlying rapidly fatal disease, bacteremic pneumonia, and a critical illness, were related to clinical status at infection onset, in accordance with previous studies.15,16,34,35 Another factor, a modifiable one, was the appropriateness of antibiotic therapy. To address carbapenem-based therapy for nCP-CRKP bacteremia, our analysis may be unique from previous studies in that 30-day mortality was correlated with meropenem MICs, even within the susceptible range. In the MIC range of 0.5e8 mg/L, there was a correlation of MIC value and clinical outcome in the cases of carbapenem combination therapy. However, for the causative isolates with a carbapenem MIC of < 0.5 mg/L or > 8 mg/L, more clinical studies are warranted to clarify the role of combination therapy. As previous studies, for those infected by the carbapenem-resistant isolates, the combinations of a carbapenem with colistin, high-dose tigecycline, an aminoglycoside, or fosfomycin, confer better therapeutic outcomes.36,37 While the receipt of appropriate definitive therapy, especially combination regimens, provides survival benefit which was more evident for the cases of carbapenem-based regimens consisting of two or even three antibiotics, even within susceptible category of meropenem (0.5e1 mg/L). However, there are limited data evaluating the suitable breakpoints of carbapenem-based combinations to predict a favorable outcome.10 Tumbarello et al. demonstrated that combination

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therapy with two or more active agents including meropenem was associated with a better outcome for infections caused by K. pneumoniae carbapenemase (KPC)-producing isolates with a meropenem MIC of  8 mg/L.17 Likewise, our data demonstrated that adults infected by the isolates with a meropenem MIC of 1e8 mg/L and treated by meropenem-based combination therapy fared well. There were several limitations in our work. First, our patients often had multiple comorbidities and advanced age and had an increased risk of all-cause mortality. However, we conducted a multivariable regression analysis correcting for age, comorbidities, source of infection, and disease severity. Second, our nCP-CRKP isolates were selected based on the exclusion of the isolates with the prevalent genes mediating carbapenemase production. However, we aimed to study the amendable variables to improve the outcome of those with bloodstream infections caused by MICdefined nCP-CRKP. The previous studies provides clinical evidences supporting the MIC-based therapeutic approach,38e40 for which the knowledge of resistance mechanisms is not necessary. Finally, since only clinical data regarding the hospitalization period were available, we can analyze the in-hospital outcome and long-term outcome of different treatment groups remains undefined. In spite of the above limitations, this study includes a large adult cohort of nCP-CRKP bloodstream infections and can provide useful information to optimize antimicrobial approaches for the treatment of such difficult-to-treat infections. In conclusion, our clinical data illustrated worse outcomes in adults with nCP-CRKP bacteremia, as meropenem MICs of the causative isolates increased. Carbapenem-containing or carbapenem-sparing combination regimens involving one or more drugs with in vitro activity against the bacteremic isolate may be more effective than monotherapy. Furthermore, carbapenem monotherapy should be limited in the bacteremic events caused by the isolates of low meropenem MIC (< 0.5 mg/L), and carbapenem-containing combination regimens are preferred for nCP-CRKP bacteremia caused by the isolates with a meropenem MIC of 1-8 mg/L.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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N.-Y. Lee et al.

ACKNOWLEDGMENTS This study was supported by the grants from the Ministry of Health and Welfare, Taiwan (MOHW106-TDU-B-211-113003), and National Cheng Kung University Hospital (NCKUH-10306007 and NCKUH-10802042). Drs. Lee and Ko conceived the study; Drs. Tsai, Chen, C.-W. Li, Syue, and M.-C. Li provided data collection and statistical and analytic support; Drs. Lee and Chen performed the laboratory work; Drs. Lee and Ko analyzed the data; and Dr. Lee prepared the manuscript. All authors reviewed and edited the manuscript.

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Address correspondence to: Wen-Chien Ko, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng Li Road, 704, Tainan, Taiwan. E-mail: [email protected]

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