Carbapenem Breakpoints for <i>Acinetobacter baumannii</i> Group: Supporting Clinical Outcome Data from Patients with Bacteremia

<div><p>The carbapenem breakpoints set by different organizations for <i>Acinetobacter</i> are discordant, but supporting clinical data are lacking. This study aimed to provide the first clinical outcome data to support the carbapenem breakpoints for <i>Acinetobacter baumannii</i> (Ab) group in patients with bacteremia. This study included 117 adults who received carbapenems for treatment of Ab group bacteremia in Taipei Veterans General Hospital over an 8-year period. We analyzed 30-day mortality rates among patient groups acquiring isolates with different carbapenem minimal inhibitory concentrations (MICs). The carbapenem MIC breakpoint derived from classification and regression tree (CART) analysis to delineate the risk of 30-day mortality was between MICs of ≤ 4 mg/L and ≥ 8 mg/L. Mortality rate was higher in patients acquiring isolates with carbapenem MIC ≥ 8 mg/L than ≤ 4 mg/L, by bivariate (54.9% [28/51] vs 25.8% [17/66]; <i>P</i> = 0.003) and survival analysis (<i>P</i> = 0.001 by log-rank test). Multivariate analysis using logistic regression and Cox regression models including severity of illness indices demonstrated that treating patients with Ab group bacteremia caused by isolates with a carbapenem MIC ≥ 8 mg/L with carbapenem was an independent predictor of 30-day mortality (odds ratio, 5.125; 95% confidence interval [CI], 1.946–13.498; <i>P</i> = 0.001, and hazard ratio, 2.630; 95% CI, 1.431–4.834; <i>P</i> = 0.002, respectively). The clinical outcome data confirmed that isolates with MIC ≤ 4 mg/L were susceptible to carbapenem, and those with MIC ≥ 8 mg/L were resistant in patients with Ab group bacteremia.</p></div

Univariate comparison between patients acquiring <i>Acinetobacter baumannii</i> group with carbapenem MIC ≤ 4mg/L and MIC ≥ 8mg/L.

<p>Univariate comparison between patients acquiring <i>Acinetobacter baumannii</i> group with carbapenem MIC ≤ 4mg/L and MIC ≥ 8mg/L.</p

Logistic regression analysis of prognostic factors associated with 30-day mortality among patients treated with carbapenem for <i>Acinetobacter baumannii</i> group bacteremia.

<p>Logistic regression analysis of prognostic factors associated with 30-day mortality among patients treated with carbapenem for <i>Acinetobacter baumannii</i> group bacteremia.</p

Thirty-day mortality rate of patients with <i>Acinetobacter baumannii</i> (Ab) group bacteremia in different susceptibility categories.

<p>The rate was significantly lower in those with carbapenem minimal inhibitory concentration (MIC) ≤ 4 mg/L comparing to those with carbapenem MIC ≥ 8 mg/L.</p

Comparison of Kaplan–Meier survival curves, at 30 days, between patients with <i>Acinetobacter baumannii</i> group bacteremia caused by isolates having minimal inhibitory concentration (MIC) ≤ 4 mg/L or ≥ 8 mg/L.

<p>Comparison of Kaplan–Meier survival curves, at 30 days, between patients with <i>Acinetobacter baumannii</i> group bacteremia caused by isolates having minimal inhibitory concentration (MIC) ≤ 4 mg/L or ≥ 8 mg/L.</p

Cox regression analysis of prognostic factors associated with 30-day mortality among patients treated with carbapenem for <i>Acinetobacter baumannii</i> group bacteremia.

<p>Cox regression analysis of prognostic factors associated with 30-day mortality among patients treated with carbapenem for <i>Acinetobacter baumannii</i> group bacteremia.</p

Table_1_Biofilm formation is not an independent risk factor for mortality in patients with Acinetobacter baumannii bacteremia.docx

In the past decades, due to the high prevalence of the antibiotic-resistant isolates of Acinetobacter baumannii, it has emerged as one of the most troublesome pathogens threatening the global healthcare system. Furthermore, this pathogen has the ability to form biofilms, which is another effective mechanism by which it survives in the presence of antibiotics. However, the clinical impact of biofilm-forming A. baumannii isolates on patients with bacteremia is largely unknown. This retrospective study was conducted at five medical centers in Taiwan over a 9-year period. A total of 252 and 459 patients with bacteremia caused by biofilm- and non-biofilm-forming isolates of A. baumannii, respectively, were enrolled. The clinical demographics, antimicrobial susceptibility, biofilm-forming ability, and patient clinical outcomes were analyzed. The biofilm-forming ability of the isolates was assessed using a microtiter plate assay. Multivariate analysis revealed the higher APACHE II score, shock status, lack of appropriate antimicrobial therapy, and carbapenem resistance of the infected strain were independent risk factors of 28-day mortality in the patients with A. baumannii bacteremia. However, there was no significant difference between the 28-day survival and non-survival groups, in terms of the biofilm forming ability. Compared to the patients infected with non-biofilm-forming isolates, those infected with biofilm-forming isolates had a lower in-hospital mortality rate. Patients with either congestive heart failure, underlying hematological malignancy, or chemotherapy recipients were more likely to become infected with the biofilm-forming isolates. Multivariate analysis showed congestive heart failure was an independent risk factor of infection with biofilm-forming isolates, while those with arterial lines tended to be infected with non-biofilm-forming isolates. There were no significant differences in the sources of infection between the biofilm-forming and non-biofilm-forming isolate groups. Carbapenem susceptibility was also similar between these groups. In conclusion, the patients infected with the biofilm-forming isolates of the A. baumannii exhibited different clinical features than those infected with non-biofilm-forming isolates. The biofilm-forming ability of A. baumannii may also influence the antibiotic susceptibility of its isolates. However, it was not an independent risk factor for a 28-day mortality in the patients with bacteremia.</p

Supplemental Material, Supplemental_Table_1 - Risk of Mortality of Catheter-Related Bloodstream Infections Caused by <i>Acinetobacter</i> Species

<p> Supplemental Material, Supplemental_Table_1 for Risk of Mortality of Catheter-Related Bloodstream Infections Caused by <i>Acinetobacter</i> Species by Yi Lee, Yi-Tzu Lee, Yung-Chih Wang, Chung-Ting Chen, Jun-Ren Sun, Chang-Pan Liu, Yuan-Meng Liu, Shu-Chen Kuo, Chun-Hsiang Chiu, Ya-Sung Yang, Jung-Chung Lin, and Te-Li Chen in Journal of Intensive Care Medicine </p

Tandem duplication of the <i>bla</i>_NDM-1 gene in pKPX-1 and pECX-1.

<p>(<b>A</b>) Diagrammatic representation of the analysis of <i>bla</i>_NDM-1 copy number by Southern blot. The probe is shown with a red arrow, and the tandem duplication of the 8588-bp repeat is indicated by the bracket. The asterisks indicate the methylated <i>Nru</i>I sites. The sizes of <i>Bam</i>HI or <i>Hind</i>III digested fragments depend on the copy number of the repeat. The pound sign indicates 79.1 kb and 71.8 kb for <i>Bam</i>HI and <i>Hind</i>III restrictions, respectively, when there are 8 copies of the tandem repeat, as in the case of pECX-1. (<b>B</b>) Sequencing read distribution and Southern analysis of the <i>bla</i>_NDM-1 region for pECX-1. The upper panel shows the relative coverage depth of the repeat region and its flanking sequences. The average coverage of <i>bla</i>_NDM-1 is 7–8 fold of those sequences of the immediately adjacent regions, suggesting that there are eight copies of the repeat. As shown in the lower panel, Southern analysis confirms this model of tandem duplication. (<b>C</b>) <i>Bla</i>_NDM-1 copy number variation detected by the Southern analysis. Sequence depth of the region revealed an average of 3–4 copies of the repeat sequence in pKPX. <i>Bam</i>HI and <i>Hind</i>III digestion gave a series of ladder bands, corresponding to different copy numbers of the repeat. By contrast, <i>Avr</i>II and <i>Nru</i>I both deliberated a single major band of 8.6 kb, representing the unit length of the tandem repeats.</p

Sequence analysis of KPX plasmids.

<p>Two circular sequences are shown for the organization of pKPX-1 (<b>A</b>) and pKPX-2 (<b>B</b>). Mapping shotgun sequencing reads of pECX-1 to the pKPX-1 is indicated by the red half-circle. A large part of the plasmid, corresponding to the nucleotide positions 23,125 to 145,377 of pKPX-1, was not found in pECX-1. Only the part on the left side, totaling 128,191-bp, is retained. Two genes encoding chloramphenicol and amikacin resistance were identified by functional library screening. Their positions in the deleted region are indicated. Nucleotides are numbered according to the replication origin. Genes are color coded: yellow, β-lactamase; red, antimicrobial resistance associated; blue, plasmid replication and partitioning; black, transposases or IS elements; and white, other coding sequences of miscellaneous features. The arrows on the open reading frames (ORFs) indicate the gene orientation. Gene clusters involved in gene transfer or mobility are marked in green. <i>Xba</i>I and <i>Avr</i>II restriction sites are shown inside the circle.</p