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. 2017 Aug 24;61(9):e00931-17. doi: 10.1128/AAC.00931-17

Multicenter Study of Clinical Features of Breakthrough Acinetobacter Bacteremia during Carbapenem Therapy

Yi-Tzu Lee a,b, Yung-Chih Wang c,d, Shu-Chen Kuo e, Chung-Ting Chen a,b, Chang-Pan Liu f,g, Yuag-Meng Liu h, Te-Li Chen i,j, Ya-Sung Yang d,✉
PMCID: PMC5571354  PMID: 28674056

ABSTRACT

Breakthrough Acinetobacter bacteremia during carbapenem therapy is not uncommon, and it creates therapeutic dilemmas for clinicians. This study was conducted to evaluate the clinical and microbiological characteristics of breakthrough Acinetobacter bacteremia during carbapenem therapy and to assess the efficacy of various antimicrobial therapies. We analyzed 100 adults who developed breakthrough Acinetobacter bacteremia during carbapenem therapy at 4 medical centers over a 6-year period. Their 30-day mortality rate was 57.0%, and the carbapenem resistance rate of their isolates was 87.0%. Among patients with carbapenem-resistant Acinetobacter bacteremia, breakthrough bacteremia during carbapenem therapy was associated with a significantly higher 14-day mortality (51.7% versus 37.4%, respectively; P = 0.025 by bivariate analysis) and a higher 30-day mortality (P = 0.037 by log rank test of survival analysis) than in the nonbreakthrough group. For the treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy, tigecycline-based therapy was associated with a significantly higher 30-day mortality (80.0%) than those with continued carbapenem therapy (52.5%) and colistin-based therapy (57.9%) by survival analysis (P = 0.047 and 0.045 by log rank test, respectively). Cox regression controlling for confounders, including severity of illness indices, demonstrated that treatment with tigecycline-based therapy for breakthrough Acinetobacter bacteremia was an independent predictor of 30-day mortality (hazard ratio, 3.659; 95% confidence interval, 1.794 to 7.465; P < 0.001). Patients with breakthrough Acinetobacter bacteremia during carbapenem therapy posed a high mortality rate. Tigecycline should be used cautiously for the treatment of breakthrough Acinetobacter bacteremia that develops during carbapenem therapy.

KEYWORDS: Acinetobacter, bacteremia, carbapenem, breakthrough, tigecycline

INTRODUCTION

Acinetobacter species have become major nosocomial pathogens associated with high mortality in immunocompromised hosts (1). Carbapenems, such as imipenem, meropenem, and doripenem, are preferred agents for treating serious Acinetobacter infections (2, 3). However, the emergence of carbapenem-resistant Acinetobacter spp. threatens the efficacy of these agents for the treatment of health care-associated infections (2, 4). In addition, carbapenem treatment itself is a risk factor for the development of infections caused by carbapenem-resistant Acinetobacter species (2, 5, 6).

Clinical and microbiological features of breakthrough Gram-negative bacteremia during carbapenem therapy have been reported (7), but clinical data specific for Acinetobacter spp. are limited. The recommended therapy for carbapenem-resistant Acinetobacter spp. was combinations of carbapenem and colistin (2). However, it is unknown whether these regimens or those with other antimicrobials, such as tigecycline, that are active against carbapenem-resistant Acinetobacter spp. are appropriate for treating breakthrough Acinetobacter bacteremia during carbapenem therapy. Furthermore, the determinants of carbapenem resistance among the causative microorganisms have not yet been elucidated. Therefore, this study was conducted to evaluate the clinical and microbiological features of breakthrough Acinetobacter bacteremia during carbapenem therapy and to assess the clinical efficacy of various antimicrobial regimens for breakthrough Acinetobacter bacteremia.

RESULTS

We reviewed the charts and medical records of 1,352 patients who had Acinetobacter bacteremia during the study period. Of these, 100 patients met the inclusion criteria, after excluding 1,252 patients for various reasons (see Fig. S1 in the supplemental material). The study population included 53 patients who received meropenem, 44 patients who received imipenem, and 3 patients who received doripenem therapy for more than 48 h before the onset of Acinetobacter bacteremia and who had a viable first isolate. All patients received carbapenem therapy with a dosage appropriate for end-organ(s) function. The treatment durations with imipenem, meropenem, and doripenem before the onset of Acinetobacter bacteremia were 9.8 ± 10.7, 10.2 ± 6.2, and 12.0 ± 6.5 days, respectively (P = 0.589). The infections that were treated with carbapenems prior to Acinetobacter bacteremia were caused by Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter, Citrobacter, and Serratia species, which were all susceptible to carbapenems. None were caused by Acinetobacter species. There was no significant difference in 14-day or 30-day mortality after the onset of Acinetobacter bacteremia based on the bacterial species that caused infections prior to the Acinetobacter bacteremia.

The carbapenem-resistant rate was high (87.0%) among Acinetobacter isolates that caused breakthrough bacteremia during carbapenem therapy, and it may have been a confounding factor that influenced patient outcomes (8). Thus, we sought to compare the patients with breakthrough Acinetobacter bacteremia during carbapenem therapy caused by carbapenem-resistant strains (n = 87) and nonbreakthrough Acinetobacter bacteremia caused by carbapenem-resistant strains (n = 265) (Table 1). Patients with breakthrough bacteremia were more likely to receive appropriate antimicrobial therapy for their carbapenem-resistant Acinetobacter bacteremia than the nonbreakthrough group. They received a carbapenem in combination with colistin or tigecycline as an effective regimen more frequently than the nonbreakthrough group. The Acute Physiology and Chronic Health Evaluation (APACHE) II scores and 14-day mortality rate were significantly higher in the breakthrough group than in the nonbreakthrough group, but there was no significant difference in 30-day mortality rates between the two patient groups by bivariate analysis. Survival analysis revealed that the breakthrough group had a significantly higher 30-day mortality than the nonbreakthrough group (P = 0.037, by log rank test; Fig. 1). Breakthrough bacteremia during carbapenem therapy is an independent risk factor for 14-day mortality (Table S1), but not for 30-day mortality (odds ratio [OR], 1.551; 95% confidence interval [CI], 0.864 to 2.783; P = 0.141), among patients with carbapenem-resistant Acinetobacter bacteremia. Carbapenem-resistant Acinetobacter isolates causing breakthrough bacteremia had resistance rates of commonly used antimicrobials similar to those causing nonbreakthrough bacteremia, except for a significantly lower rate of sulbactam resistance, and they were less likely to carry the carbapenemase gene-associated ISAba1-blaOXA-23-like genetic structure (Table 1). The imipenem and meropenem MICs were not significantly different between the 2 groups (P = 0.321 and 0.871, respectively). Among carbapenem-resistant isolates of Acinetobacter baumannii, the isolates causing breakthrough bacteremia were more likely to carry the ISAba1-blaOXA-51-like structure than those causing nonbreakthrough bacteremia (Table 1). The tigecycline MICs were not significantly different between the 2 groups (P = 0.424). For the treatment of carbapenem-resistant Acinetobacter bacteremia, none of the antimicrobial regimens was associated with significantly higher or lower 14-day and 30-day mortality (Table S2), and none of the antimicrobial regimens was an independent risk factor associated with 14-day or 30-day mortality by the logistic regression model (14-day mortality, Table S1; 30-day mortality, data not shown) or Cox regression model (data not shown) in the multivariable analysis. Subgroup analysis among patients with nonbreakthrough carbapenem-resistant Acinetobacter bacteremia yielded similar results (data not shown).

TABLE 1.

Univariate comparison between patients with breakthrough Acinetobacter bacteremia during carbapenem therapy and nonbreakthrough Acinetobacter bacteremia caused by carbapenem-resistant strains

Characteristica Breakthrough carbapenem resistant (n = 87) Nonbreakthrough carbapenem resistant (n = 265) P value
Demographic characteristics
    Age (median [IQR]) (yr) 69 (53–80) 72 (58–81) 0.192
    Male sex 51 (58.6) 186 (70.2) 0.062
    Recent ICU stay 49 (56.3) 124 (46.8) 0.156
    Bacteremia acquired in ICU 60 (69.0) 120 (45.3) <0.001
    Length of hospitalization before bacteremia (median [IQR]) (days) 21 (13–34) 22 (10–39) 0.624
Comorbid conditions
    Alcoholism 3 (3.4) 13 (4.9) 0.770
    Liver cirrhosis 8 (9.2) 44 (16.6) 0.130
    Chronic obstructive pulmonary disease 28 (32.2) 48 (18.1) 0.009
    Chronic kidney disease 32 (36.8) 101 (38.1) 0.924
    Type 2 diabetes mellitus 31 (35.6) 97 (36.6) 0.972
    Hypertension 37 (42.5) 108 (40.8) 0.868
    Coronary artery disease 14 (16.1) 31 (11.7) 0.379
    Congestive heart failure 21 (24.1) 50 (18.9) 0.363
    Cerebrovascular accident 18 (20.7) 51 (19.2) 0.890
    Collagen vascular disease 3 (3.4) 8 (3.0) 0.737
    Immunosuppressant therapy 11 (12.6) 26 (9.8) 0.585
    Solid tumor 13 (14.9) 71 (26.8) 0.035
    Hematological malignancy 8 (9.2) 8 (3.0) 0.032
    Chemotherapy 7 (8.0) 14 (5.3) 0.494
    Neutropenia 7 (8.0) 11 (4.2) 0.165
    Trauma 4 (4.6) 9 (3.4) 0.743
    Burn 1 (1.1) 5 (1.9) 1.000
    Recent surgery 21 (24.1) 57 (21.5) 0.716
Charlson comorbidity index (median [IQR]) 4 (2–6) 4 (2–6) 0.919
Invasive procedures
    Arterial catheter 40 (46.0) 108 (40.8) 0.465
    Central venous catheter 49 (56.3) 139 (52.5) 0.614
    Ventilator use 70 (80.5) 163 (61.5) 0.002
    Hemodialysis 18 (20.7) 58 (21.9) 0.932
    Thoracic drain 10 (11.5) 18 (6.8) 0.239
    Abdominal drain 11 (12.6) 25 (9.4) 0.514
Sources of bacteremia
    Pneumonia 42 (48.3) 99 (37.4) 0.094
    Catheter 18 (20.7) 46 (17.4) 0.590
    Urinary tract infection 1 (1.1) 10 (3.8) 0.305
    Intra-abdominal infection 6 (6.9) 16 (6.0) 0.975
    Wound 2 (2.3) 11 (4.2) 0.532
    Primary bacteremia 18 (20.7) 83 (31.3) 0.077
Antimicrobial therapy after bacteremia onset
    Appropriate antimicrobial therapy 32 (36.8) 56 (21.1) 0.005
    Effective regimensb
        Colistin 18 (56.3) 43 (75.4) 0.102
        Tigecycline 12 (37.5) 15 (26.3) 0.389
        Fluoroquinolone 7 (21.9) 9 (15.8) 0.667
        Sulbactam 2 (6.3) 4 (7.0) 1.000
        Carbapenem + colistin 16 (50.0) 11 (19.3) 0.005
        Carbapenem + tigecycline 6 (18.8) 2 (3.5) 0.023
        Carbapenem + sulbactam 2 (6.3) 1 (1.8) 0.293
        Colistin + tigecycline 4 (12.5) 12 (21.1) 0.471
Outcome
    Shock 29 (33.3) 89 (33.6) 1.000
    APACHE II score (median [IQR]) 26 (19–32) 24 (17–30) 0.023
    14-day mortality 45 (51.7) 99 (37.4) 0.025
    30-day mortality 54 (62.1) 132 (49.8) 0.062
Species causing bacteremia
    A. baumannii 52 (59.8) 184 (69.4) 0.125
    A. nosocomialis 24 (27.6) 66 (24.9) 0.722
    A. pittii 10 (11.5) 8 (3.0) 0.004
    A. soli 0 (0.0) 4 (1.5) 0.576
Microbiological characteristics of causative microorganisms
    Nonsusceptibility to:
        Amikacin 46 (52.9) 117 (44.2) 0.196
        Ampicillin-sulbactam 52 (59.8) 192 (72.3) 0.036
        Cefepime 75 (86.2) 246 (92.9) 0.094
        Ceftazidime 78 (89.7) 250 (94.3) 0.208
        Piperacillin-tazobactam 83 (95.4) 258 (97.4) 0.475
        Ciprofloxacin 67 (77.0) 223 (84.2) 0.176
        Levofloxacin 70 (80.5) 221 (83.4) 0.642
        Colistin 0 (0.0) 6 (2.3) 0.343
        Tigecycline 31 (35.6) 94 (35.5) 1.000
    Isolates harboring ISAba1-blaOXA-51-like 20 (23.0) 38 (14.3) 0.085
        A. baumannii isolates harboring ISAba1-blaOXA-51-like/total no. of isolates harboring ISAba1-blaOXA-51-like (%) 18/52 (36.7) 32/184 (17.4) 0.013
    Isolates harboring ISAba1-blaOXA-23-like 37 (42.5) 168 (63.4) 0.001
        A. baumannii isolates harboring ISAba1-blaOXA-23-like/total no. of isolates harboring ISAba1-blaOXA-23-like (%) 21/52 (40.4) 147/184 (79.9) <0.001
    Isolates harboring IS1008 (or IS1006)-ΔISAba3-blaOXA-58-like 6 (6.9) 8 (3.0) 0.120
    Isolates harboring blaOXA-24-like 11 (12.6) 16 (6.0) 0.076
    Isolates harboring blaIMP-like 5 (5.7) 5 (1.9) 0.072
    Isolates harboring blaVIM-like 3 (3.4) 5 (1.9) 0.414
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a

Data are presented as the number (%), unless otherwise indicated. IQR, interquartile range; ICU, intensive care unit; APACHE II, Acute Physiology and Chronic Health Evaluation II.

b

Each item denotes the corresponding antimicrobial agent alone or in combination with other antimicrobial agent(s). For example, “colistin” denotes “colistin alone or in combination with other antimicrobial agent(s).” The numbers in parentheses denote the percentage of patients who received the corresponding antimicrobial agent alone or in combination with other antimicrobial agent(s) among the patients who received appropriate antimicrobial therapy.

FIG 1.

FIG 1

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Comparison of Kaplan-Meier survival curves at 30 days among patients with breakthrough and nonbreakthrough carbapenem-resistant Acinetobacter bacteremia during carbapenem therapy.

The overall 30-day mortality rate of breakthrough Acinetobacter bacteremia during carbapenem therapy was 57.0%. The baseline demographics, clinical, and microbiological characteristics of survivors and nonsurvivors at 30 days after breakthrough Acinetobacter bacteremia are shown in Table 2. There were no significant differences between survivors and nonsurvivors in terms of comorbid conditions, the regimen and length of carbapenem therapy before bacteremia, and the appropriateness of antimicrobial therapy after the onset of bacteremia. Among the 20 patients with catheter-related infections as the source of bacteremia, early removal of the catheter within 48 h of bacteremia onset was not associated with a lower 30-day mortality (P = 0.921). A Cox proportional regression analysis was performed to see if any regimen was associated with a better or worse outcome (Table 3). It revealed that tigecycline-based therapy (hazard ratio [HR], 3.659; 95% CI, 1.794 to 7.465; P < 0.001), higher APACHE II score at bacteremia onset (HR, 1.049; 95% CI, 1.020 to 1.080; P = 0.001), and catheter-related infection as a source of bacteremia (HR, 1.984; 95% CI, 1.075 to 3.660; P = 0.028) were independent risk factors associated with 30-day mortality. Patients receiving colistin and tigecycline combination therapy with or without other antimicrobial(s) were excluded from the following analysis that compared tigecycline-based and colistin-based therapies. The Kaplan-Meier survival analysis revealed that the 30-day mortality rate was significantly higher in patients receiving tigecycline-based therapy than in those continuing carbapenem therapy without any concomitant antimicrobial(s) (P = 0.047, by log rank test) and those receiving colistin-based therapy (P = 0.045, by log rank test) (Fig. 2). The APACHE II scores were not significantly different among patients receiving tigecycline-based therapy, continued carbapenem therapy, and colistin-based therapy (P = 0.828 in a comparison of 3 therapies; tigecycline-based therapy versus continued carbapenem therapy, P = 0.554; tigecycline-based therapy versus colistin-based therapy, P = 0.861) (Table S3). In the tigecycline-based therapy group, most patients (11/15) received concomitant antimicrobial(s) with tigecycline. Among 100 Acinetobacter isolates causing breakthrough bacteremia, 40.0% were inhibited at 1 mg/liter and 71.0% at 2 mg/liter tigecycline (MIC50, 2 mg/liter; MIC90, 4 mg/liter). The case patients were treated continuously with a carbapenem without combination with other antimicrobial agent(s) after the onset of breakthrough Acinetobacter bacteremia due to the following reasons. First, some of the causative Acinetobacter isolates of breakthrough Acinetobacter bacteremia were susceptible to carbapenems. Second, the case patients may have been treated continuously with a carbapenem before the blood culture reported carbapenem-resistant Acinetobacter spp. Third, the case patients may have been treated continuously with a carbapenem even though the blood culture reported carbapenem-resistant Acinetobacter spp. because they improved after receiving carbapenem therapy. There was no significant difference in patient outcomes based on the reasons for continuous treatment with carbapenem monotherapy after the onset of breakthrough Acinetobacter bacteremia.

TABLE 2.

Univariate comparison between 30-day survivors and nonsurvivors in patients with breakthrough Acinetobacter bacteremia during carbapenem therapy

Characteristica All (n = 100) Survivors (n = 43) Nonsurvivors (n = 57) P value
Demographical characteristics
    Age (median [IQR]) (yr) 70.5 (53.25–80.75) 75 (55–83) 66 (52–79.5) 0.215
    Male sex 62 (62.0) 22 (51.2) 40 (70.2) 0.083
    Recent ICU stay 58 (58.0) 26 (60.5) 32 (56.1) 0.819
    Bacteremia acquired in ICU 66 (66.0) 27 (62.8) 39 (68.4) 0.707
    Length of hospitalization before bacteremia (median [IQR]) (days) 21.5 (13.25–36.5) 25 (15–37) 21 (11.5–36) 0.477
    Comorbid conditions
    Alcoholism 4 (4.0) 0 (0.0) 4 (7.0) 0.132
    Liver cirrhosis 9 (9.0) 4 (9.3) 5 (8.8) 1.000
    Chronic obstructive pulmonary disease 32 (32.0) 12 (27.9) 20 (35.1) 0.585
    Chronic kidney disease 38 (38.0) 18 (41.9) 20 (35.1) 0.629
    Type 2 diabetes mellitus 34 (34.0) 14 (32.6) 20 (35.1) 0.959
    Hypertension 42 (42.0) 19 (44.2) 23 (40.4) 0.857
    Coronary artery disease 17 (17.0) 10 (23.3) 7 (12.3) 0.239
    Congestive heart failure 24 (24.0) 12 (27.9) 12 (21.1) 0.577
    Cerebrovascular accident 19 (19.0) 11 (25.6) 8 (14.0) 0.230
    Collagen vascular disease 4 (4.0) 3 (7.0) 1 (1.8) 0.312
    Immunosuppressant therapy 12 (12.0) 3 (7.0) 9 (15.8) 0.302
    Solid tumor 16 (16.0) 8 (18.6) 8 (14.0) 0.733
    Hematological malignancy 10 (10.0) 4 (9.3) 6 (10.5) 1.000
    Chemotherapy 8 (8.0) 4 (9.3) 4 (7.0) 0.722
    Neutropenia 8 (8.0) 2 (4.7) 6 (10.5) 0.460
    Trauma 4 (4.0) 3 (7.0) 1 (1.8) 0.312
    Burn 1 (1.0) 1 (2.3) 0 (0.0) 0.430
    Recent surgery 25 (25.0) 14 (32.6) 11 (19.3) 0.200
Charlson comorbidity index (median [IQR]) 4 (2–5.75) 4 (2–6) 4 (2–5) 0.816
Invasive procedures
    Arterial catheter 43 (43.0) 19 (44.2) 24 (42.1) 0.997
    Central venous catheter 55 (55.0) 26 (60.5) 29 (50.9) 0.453
    Ventilator use 76 (76.0) 30 (69.8) 46 (80.7) 0.303
    Hemodialysis 20 (20.0) 9 (20.9) 11 (19.3) 1.000
    Thoracic drain 11 (11.0) 2 (4.7) 9 (15.8) 0.109
    Abdominal drain 14 (14.0) 8 (18.6) 6 (10.5) 0.389
Sources of bacteremia
    Pneumonia 49 (49.0) 21 (48.8) 28 (49.1) 1.000
    Catheter 20 (20.0) 6 (14.0) 14 (24.6) 0.289
    Urinary tract infection 1 (1.0) 1 (2.3) 0 (0.0) 0.430
    Intra-abdominal infection 6 (6.0) 2 (4.7) 4 (7.0) 0.697
    Wound 2 (2.0) 2 (4.7) 0 (0.0) 0.182
    Primary bacteremia 22 (22.0) 11 (25.6) 11 (19.3) 0.612
Carbapenem therapy before bacteremia
    Imipenem 44 (44.0) 23 (53.5) 21 (36.8) 0.145
    Meropenem 53 (53.0) 18 (41.9) 35 (61.4) 0.083
    Doripenem 3 (3.0) 2 (4.7) 1 (1.8) 0.576
Length of carbapenem therapy before bacteremia (median [IQR]) (days) 9 (5–13) 9 (4–13) 9 (5–14) 0.829
Antimicrobial therapy after bacteremia onsetb
    Appropriate antimicrobial therapy 44 (44.0) 23 (53.5) 22 (38.6) 0.201
    Continued carbapenem monotherapy 59 (59.0) 28 (65.1) 31 (54.4) 0.382
    Colistin-based therapyc 19 (19.0) 8 (18.6) 11 (19.3) 1.000
    Tigecycline-based therapy 15 (15.0) 3 (7.0) 12 (21.1) 0.095
    Fluoroquinolone-based therapy 9 (9.0) 3 (7.0) 6 (10.5) 0.728
    Sulbactam-based therapy 5 (5.0) 3 (7.0) 2 (3.5) 0.649
    Carbapenem- and colistin-based therapyc 17 (17.0) 7 (16.3) 10 (17.5) 1.000
    Outcome
    Shock 34 (34.0) 11 (25.6) 23 (40.4) 0.183
    APACHE II score (median [IQR]) 26 (18–31.75) 22 (17–29) 28 (21–33) 0.014
Species causing bacteremia
    A. baumannii 53 (53.0) 17 (39.5) 36 (63.2) 0.032
    A. nosocomialis 30 (30.0) 15 (34.9) 15 (26.3) 0.481
    A. pittii 13 (13.0) 9 (20.9) 4 (7.0) 0.080
    A. soli 2 (2.0) 1 (2.3) 1 (1.8) 1.000
Microbiological characteristics of causative microorganisms
    Isolates harboring ISAba1-blaOXA-51-like 22 (22.0) 8 (18.6) 13 (22.8) 0.793
    Isolates harboring ISAba1-blaOXA-23-like 37 (37.0) 11 (25.6) 26 (45.6) 0.065
    Isolates harboring IS1008 (or IS1006)-ΔISAba3-blaOXA-58-like 6 (6.0) 0 (0.0) 6 (10.5) 0.036
    Isolates harboring blaOXA-24-like 11 (11.0) 6 (14.0) 5 (8.8) 0.523
    Isolates harboring blaIMP-like 5 (5.0) 4 (9.3) 1 (1.8) 0.162
    Isolates harboring blaVIM-like 4 (4.0) 2 (4.7) 2 (3.5) 1.000
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a

Data are presented as the number (%), unless otherwise indicated. IQR, interquartile range; ICU, intensive care unit; APACHE II, Acute Physiology and Chronic Health Evaluation II.

b

An antimicrobial agent (or antimicrobial agents)-based therapy denotes the corresponding antimicrobial agent(s) alone or in combination with other antimicrobial agent(s).

c

Only intravenous colistin was included. Inhaled colistin was not included.

TABLE 3.

Cox regression analyses of prognostic factors associated with 30-day mortality among patients with breakthrough Acinetobacter bacteremia during carbapenem therapy

Variable Univariate analysis
 Multivariate analysis
HR (95% CI)a P HR (95% CI)a P
APACHE II scoreb 1.044 (1.015–1.074) 0.003 1.049 (1.020–1.080) 0.001
Recent surgery 0.508 (0.262–0.983) 0.044
Catheter-related infection 1.842 (1.003–3.384) 0.049 1.984 (1.075–3.660) 0.028
Bacteremia due to A. baumannii 1.866 (1.086–3.205) 0.024
Bacteremia due to A. pittii 0.422 (0.153–1.167) 0.097
Tigecycline-based therapy 2.142 (1.124–4.082) 0.021 3.659 (1.794–7.465) <0.001
Appropriate therapy 0.637 (0.373–1.088) 0.099
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a

HR, hazard ratio; CI, confidence interval.

b

APACHE II, Acute Physiology and Chronic Health Evaluation II.

FIG 2.

FIG 2

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Comparison of Kaplan-Meier survival curves at 30 days among patients who received continued carbapenem therapy, colistin-based therapy, and tigecycline-based therapy for their breakthrough Acinetobacter bacteremia (tigecycline-based therapy versus continued carbapenem therapy, P = 0.047 by log rank test; tigecycline-based therapy versus colistin-based therapy, P = 0.045 by log rank test).

Tigecycline-based therapy was independently associated with a poor outcome in patients with breakthrough Acinetobacter bacteremia during carbapenem therapy but not in patients with carbapenem-resistant Acinetobacter bacteremia or nonbreakthrough carbapenem-resistant Acinetobacter bacteremia. Among patients with carbapenem-resistant Acinetobacter bacteremia who were treated with tigecycline-based therapy, the breakthrough group had a significantly higher 14-day mortality (78.6% [11/14] versus 36.4% [12/33], respectively; P = 0.020) and a higher 30-day mortality but without reaching statistical significance (78.6% [11/14] versus 42.4% [14/33], respectively; P = 0.051) than the nonbreakthrough group. There were no significant differences in demographic characteristics, underlying diseases, Charlson comorbidity index (P = 0.831), invasive procedures, sources of bacteremia, including pneumonia (50.0% [7/14] versus 51.5% [17/33]; P = 1.000), APACHE II scores (P = 0.369), bacterial species and tigecycline MICs (P = 0.654) of causative pathogens, or the percentage and regimens of combination therapy between the 2 groups.

DISCUSSION

This multicenter study was designed to assess the clinical features of breakthrough Acinetobacter bacteremia during carbapenem therapy and to evaluate the clinical outcomes among patient groups receiving different antimicrobial therapies. Breakthrough Acinetobacter bacteremia during carbapenem therapy was associated with a high mortality rate and high carbapenem resistance rate. Among patients with carbapenem-resistant Acinetobacter bacteremia, the breakthrough group was associated with significantly higher 14-day mortality than the nonbreakthrough group, even though the breakthrough group was more likely to receive appropriate antimicrobial therapy. For the treatment of patients with breakthrough bacteremia, tigecycline-based therapy was independently associated with a poor outcome.

Breakthrough Acinetobacter bacteremia during carbapenem therapy is not uncommon in patients. However, its clinical impact has not yet been determined. In addition, patients with breakthrough bacteremia during carbapenem therapy are sometimes excluded from the study population of carbapenem-resistant Acinetobacter bloodstream infections in outcome analysis (9), despite the high prevalence of carbapenem resistance among their Acinetobacter isolates. This study provides the first data on the clinical significance of breakthrough Acinetobacter bacteremia during carbapenem therapy. We found that in the carbapenem-resistant subgroup, breakthrough bacteremia was associated with a higher 14-day mortality than with nonbreakthrough bacteremia. For 30-day mortality, survival analysis revealed that the breakthrough group had a higher mortality rate. Overall, the breakthrough group was associated with a poorer outcome than the nonbreakthrough group in carbapenem-resistant Acinetobacter bacteremia. The unfavorable outcome is not a result of inappropriate antimicrobial therapy, because patients with breakthrough bacteremia are more likely to receive appropriate antimicrobial therapy for their carbapenem-resistant Acinetobacter bacteremia than those in the nonbreakthrough group, such as a carbapenem in combination with colistin or tigecycline. Since they had already received a carbapenem, it was reasonable to add colistin or tigecycline when symptoms/signs of bacteremia occurred.

Tigecycline is often used for the treatment of carbapenem-resistant Acinetobacter infections or as a salvage therapy for Acinetobacter infections with carbapenem treatment failure. However, our results do not support the use of a tigecycline-based regimen for the treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy. The similarity of APACHE II scores among patient groups receiving different regimens and the finding that tigecycline-based therapy remains an independent mortality risk factor after controlling for severity of illness indices exclude disease severity as a confounder to explain the difference in mortality. Possible explanations include the bacteriostatic property of tigecycline, the relatively high MICs of tigecycline of our study isolates that were unachievable by the currently approved dose of tigecycline in serum (10), a low AUC/MIC ratio when the currently approved dose is used (11–16), and a high prevalence of hospital-acquired pneumonia as a source of bacteremia in breakthrough Acinetobacter bacteremia during carbapenem therapy (14, 17). Since there were no differences in patient characteristics, tigecycline MICs, and the percentage of pneumonia between breakthrough and nonbreakthrough groups of carbapenem-resistant Acinetobacter bacteremia, the reasons for the association of tigecycline-based therapy with more unfavorable outcomes in the breakthrough group require further investigation.

Although all the study isolates were susceptible to colistin, colistin alone or in combination with other antimicrobial agents was still associated with a high mortality rate. It is suggested that susceptibility to colistin cannot ensure successful treatment. The current colistin susceptibility breakpoint of 2 mg/liter may not be adequate, based on its pharmacokinetic properties, such as inadequate plasma levels and potential for development of resistance (2). Whether colistin is effective for certain subgroups of patients and whether colistin combined with other antimicrobials, such as rifampin, can improve patient outcomes are yet to be determined. In addition, only patients who received the standard dose of carbapenem therapy were included in the current study. Maximizing carbapenem dosing or prolonging infusion may be associated with better patient outcomes, since these strategies have improved the probability of attaining pharmacodynamic targets (3, 18). Further studies are needed to evaluate if these strategies can prevent or treat breakthrough Acinetobacter bacteremia during carbapenem therapy.

Among the mechanisms of carbapenem resistance in Acinetobacter spp., the most notable is the expression of class D carbapenemases (1, 2). Although carbapenem-resistant Acinetobacter isolates causing breakthrough bacteremia during carbapenem therapy were less likely to carry the ISAba1-blaOXA-23-like structure than the nonbreakthrough group, the ISAba1-blaOXA-23-like structure was still the most prevalent carbapenem resistance determinant in both groups. The ISAba1-blaOXA-23-like genetic structure was often contained in transposons which were carried by conjugative plasmids, facilitating its widespread in Acinetobacter isolates in recent years (19, 20). Of greater interest is that the carbapenem-resistant A. baumannii isolates causing breakthrough bacteremia are more likely to carry the ISAba1-blaOXA-51-like structure. It has been suggested that carbapenem therapy may be a risk factor for rapid acquisition of A. baumannii isolates harboring the ISAba1-blaOXA-51-like structure. The universal chromosomal location of blaOXA-51-like genes in A. baumannii (21) and the wide distribution of the insertion sequence ISAba1 in the A. baumannii genome (22) may facilitate the transposition of ISAba1 upstream of blaOXA-51-like genes to confer a high level of carbapenem resistance (23).

The major limitations of this study are its retrospective design and intrinsic selection bias. The strengths of this study are the inclusion of a large number of patients from multiple medical centers located in representative regions of Taiwan using stringent inclusion criteria, recent isolates, and detailed characterization of resistance markers among breakthrough and nonbreakthrough carbapenem-resistant isolates. Our findings provide clinicians with outcome data of breakthrough Acinetobacter bacteremia during carbapenem therapy.

In conclusion, patients with breakthrough Acinetobacter bacteremia during carbapenem therapy posed a high mortality rate. Compared to continued carbapenem- or colistin-based therapy, tigecycline-based therapy was associated with higher mortality. Further studies are required to determine the optimal treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy.

MATERIALS AND METHODS

Hospital setting and study population.

This retrospective study was conducted from January 2010 to December 2015 at 4 medical centers in Taiwan: Changhua Christian Hospital (CCH; 1,676 beds) in central Taiwan, Mackay Memorial Hospital (MMH; 2,055 beds) in northern Taiwan, Taipei Veterans General Hospital (TVGH; 2,900 beds) in northern Taiwan, and Tri-Service General Hospital (TSGH; 1,712 beds) of the National Defense Medical Center in northern Taiwan. Patients with at least one positive blood culture for Acinetobacter spp. who had symptoms and signs of infection were recruited into the study. For patients with ≥2 positive blood cultures, only the first blood culture was included. Patients <20 years of age and those with incomplete medical records were excluded. Case patients were defined as individuals whose blood cultures grew Acinetobacter spp. and who had been receiving a type II carbapenem (e.g., imipenem, meropenem, or doripenem) as monotherapy for at least 48 h before breakthrough bacteremia. The case patients were treated with a carbapenem before the onset of breakthrough Acinetobacter bacteremia as definite antimicrobial treatment for infections which were not caused by Acinetobacter spp. and were caused by carbapenem-susceptible microorganisms, such as pneumonia caused by carbapenem-susceptible Pseudomonas aeruginosa, or urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Patients who received ertapenem and those whose blood cultures yielded the same Acinetobacter spp. prior to breakthrough bacteremia were excluded. Among the patients with carbapenem-resistant Acinetobacter bacteremia, the nonbreakthrough group was defined as those who did not receive any type II carbapenem therapy within 48 h before the onset of bacteremia. All patients who fulfilled the criteria were included in the study. The protocol was approved by the hospitals' institutional review boards (IRB) (CCH, IRB no. 140514; MMH, IRB no. 14MMHIS125; TVGH, IRB no. 2014-07-006CC; and TSGH, IRB no. 1-103-05-100).

Data collection and definitions.

The medical records of the patients were reviewed retrospectively and analyzed. Patients were assessed for demographic characteristics, duration of hospitalization, stay in the intensive care unit (ICU), comorbidities, invasive procedures at the time of bacteremia onset, and time of receipt, dose, and route of therapy with individual antimicrobial drugs. Recent stay in the ICU was defined as being within 2 weeks of the first positive blood culture. Episodes of bloodstream infection were considered to be acquired in the ICU if they appeared beyond 48 h after ICU admission. Immunosuppressive therapy was defined as use of immunosuppressive agents within 2 weeks or use of corticosteroids at a dosage equivalent to or higher than 15 mg of prednisolone daily for 1 week within 4 weeks before the onset of bacteremia. Chemotherapy was defined as administration of cytotoxic agents within 6 weeks before onset of bacteremia. Recent surgery was defined as operations performed within 4 weeks before the onset of bacteremia. The source of bacteremia was determined according to the definitions of the U.S. Centers for Disease Control and Prevention (24). The severity of infection was evaluated using the Acute Physiology and Chronic Health Evaluation (APACHE) II score within 24 h before the onset of bacteremia. Appropriate antimicrobial therapy was defined as administration of at least one antimicrobial agent to which the causative pathogen was susceptible in vitro within 24 h after the onset of bacteremia for a minimum of 24 h, with an approved route and dosage appropriate for end-organ(s) function. Antimicrobial therapy that did not meet this definition was considered inappropriate. Monotherapy with an aminoglycoside was not considered an appropriate therapy. An antimicrobial agent (or antimicrobial agents)-based therapy was defined as treatment with the antimicrobial agent(s) alone or in combination with another antimicrobial agent(s). Continued carbapenem therapy was defined as maintaining treatment with the carbapenem that the patient had received before the onset of breakthrough Acinetobacter bacteremia without any concomitant antimicrobial agent(s). The dose of colistin was 5 mg/kg colistin base activity loading, followed by 5 mg/kg/day colistin base activity divided over 8 or 12 h in patients with normal renal function. For those with impaired renal function, the dosage was adjusted according to renal function, as previously described (25, 26). The loading dose of tigecycline was 100 mg, followed by a maintenance dose of 50 mg every 12 h. The all-cause 14-day and 30-day mortality rates were used as the endpoints and were defined as death occurring within 14 and 30 days after the date of bacteremia onset, respectively. For patients who were discharged before the 30-day limit, the status was determined by a review of outpatient records or by contacting the patient directly.

Bacterial identification, clonal study, antimicrobial susceptibility testing, and detection of carbapenem resistance determinants.

The initial isolate was used for the microbiological studies. The bacteria were phenotypically identified as Acinetobacter spp. using the Vitek 2 system (bioMérieux, Marcy l'Étoile, France). Acinetobacter baumannii was identified by a multiplex PCR method (10). Isolates identified as non-baumannii Acinetobacter spp. were further identified to the genomic species level by 16S-23S ribosomal DNA intergenic spacer sequence analysis, as previously described (27). The MICs of carbapenems, tigecycline, and colistin and the antimicrobial susceptibilities of other agents were determined by agar dilution according to the Clinical and Laboratory Standards Institute (CLSI) (28). Multidrug resistance (MDR) was defined as resistance to any one agent in at least 3 of the following classes of antimicrobials: aminoglycosides, carbapenems, antipseudomonal cephalosporins, β-lactam–β-lactamase inhibitor combinations, and fluoroquinolones.

Multiplex PCR assays were performed to detect the carbapenem-hydrolyzing class D β-lactamase (CHDL) genes (blaOXA-23-like, blaOXA-24-like, blaOXA-51-like, blaOXA-58-like, and blaOXA-143-like) (29). Metallo-β-lactamases were detected by phenotypic methods and PCR assays, including the multiplex PCR with primers specific for the blaIMP, blaVIM, blaSIM, blaSPM, and blaGIM-1 genes (30), and the PCR assay detecting the presence of blaNDM-1 (31). The upstream locations of insertion sequences (ISs) ISAba1 of the blaOXA-51-like or blaOXA-23-like gene and IS1008 or IS1006 upstream of the blaOXA-58-like gene were analyzed by PCR mapping (23, 30, 32–34).

Statistical analysis.

PASW for Windows version 18 (SPSS, Chicago, IL, USA) was used for all data analyses. The χ2 test with Yates correction or Fisher's exact test was used to compare categorical data. Continuous variables were analyzed using the Mann-Whitney U test or two-sample t test. The Wilcoxon signed-rank test was used to determine statistically significant differences between paired samples. The time to mortality, defined as the interval between the onset of bacteremia and death, was analyzed using the Kaplan-Meier survival analysis, and the log rank test was used to compare univariable survival distributions between different groups of patients. A logistic regression model was used to explore independent prognostic factors associated with 14-day and 30-day mortality of patients with Acinetobacter bacteremia caused by carbapenem-resistant strains. A Cox proportional hazard regression model was used to explore independent prognostic factors associated with the 30-day mortality of patients with breakthrough Acinetobacter bacteremia during carbapenem therapy. Univariable analyses were performed separately for each risk factor to ascertain the odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI). All biologically plausible variables with a P value of <0.10 in the univariable analysis were considered for inclusion in the logistic regression model or Cox regression model in the multivariable analysis. A P value of <0.05 was considered statistically significant.

Supplementary Material

Supplemental material
supp_61_9_e00931-17__index.html (793B, html)

ACKNOWLEDGMENTS

This work was supported by grants from Taipei Veterans General Hospital (grants V105B-005 and V106B-002 [to Y.-T.L.]), Tri-Service General Hospital (grants TSGH-C105-112 [to Y.-C.W.], TSGH-105-113 [to Y.-S.Y.], and TSGH-C106-096 [to Y.-S.Y.]), the National Defense Medical Center (grants MAB-106-076 [to Y.-C.W.] and MAB-106-098 [to Y.-S.Y.]), and the Ministry of Science and Technology (grants MOST 104-2314-B-075-043-MY3 [to Y.-T.L.], MOST 105-2314-B-016-039-MY3 [to Y.-C.W.], and MOST 105-2628-B-016-003-MY2 [to Y.-S.Y.]). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

We declare no relevant conflicts of interest related to this article.

Footnotes

Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00931-17.

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