Abstract
This study investigated the clinical and microbiological characteristics of patients with recurrent bacteremia caused by the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex at a medical center. All ACB complex isolates associated with recurrent bacteremia were identified to the genomic species level using a 16S-23S rRNA gene intergenic spacer sequence-based method. Genotypes were determined by the random amplified polymorphic DNA patterns generated by arbitrarily primed PCR and by pulsotypes generated by pulsed-field gel electrophoresis. Relapse of infection was defined as when the genotype of the recurrent isolate was identical to that of the original infecting strain. Reinfection was defined as when the genospecies or genotype of the recurrent isolate differed from that of the original isolate. From 2006 to 2008, 446 patients had ACB complex bacteremia and 25 (5.6%) had recurrent bacteremia caused by the ACB complex. Among the 25 patients, 12 (48%) had relapse of bacteremia caused by A. nosocomialis (n = 7) or A. baumannii (n = 5). Among the 13 patients with reinfection, 5 (38.5%) had reinfection caused by different genospecies of the ACB complex. Most of the patients were immunocompromised, and most of the infection foci were catheter-related bloodstream infections. The overall in-hospital mortality rate was 33.3%. A. baumannii isolates had lower antimicrobial susceptibility rates than A. nosocomialis and A. pittii isolates. In conclusion, relapse of ACB complex bacteremia can develop in immunocompromised patients, especially those with central venous catheters. Molecular methods to identify the ACB complex to the genospecies level are essential for differentiating between reinfection and relapse of bacteremia caused by the ACB complex.
INTRODUCTION
Species in the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex, a group of bacteria comprising nonfermenting, aerobic, Gram-negative coccobacilli, are important nosocomial pathogens (18, 19). The prevalence of ACB complex-related health care infection has increased markedly in recent years, especially in intensive care units and in immunocompromised populations (4, 5, 12, 14, 15, 22). ACB complex infections carry high mortality rates and are associated with prolonged hospital stays and increased hospital costs (1, 3, 8, 14). Recent studies on the clinical features and outcomes of patients with ACB complex bacteremia have helped us better understand these life-threatening infections (1, 3, 6, 7, 9, 10, 12–14, 22, 23). Few studies, however, have reported on the prevalence of recurrent ACB complex bacteremia.
A. baumannii (genospecies 2), A. pittii (formerly known as Acinetobacter genospecies 3), and A. nosocomialis (formerly known as Acinetobacter genospecies 13TU) are genetically and phenotypically similar to A. calcoaceticus (Acinetobacter genospecies 1) and hence are grouped in the so-called ACB complex (11, 17, 20). Molecular methods are needed to identify members of the complex to the species level because each member has a distinct antimicrobial susceptibility profile and shows different clinical characteristics (3, 11, 14).
The aim of this retrospective study was to use molecular methods to differentiate between relapse and reinfection among patients with recurrent bacteremia caused by the ACB complex at a medical center during the period January 2006 to December 2008. The clinical features of patients with recurrent ACB complex bacteremia were also analyzed.
MATERIALS AND METHODS
Setting and patients.
The study was retrospectively conducted at the National Taiwan University Hospital (NTUH), a 2,500-bed tertiary-care center in northern Taiwan. Patients with repeated blood cultures positive for the ACB complex were identified from the computerized database of the bacteriology laboratory of the NTUH from January 2006 to December 2008. The clinical charts of all patients included in this study were reviewed. Information was collected on age, gender, and underlying immunocompromised conditions, including history of immunosuppressant drug use, diabetes mellitus, liver cirrhosis, end stage renal disease, and malignancy.
Microbiological investigation.
ACB complex isolates were initially identified by colony morphology, Gram staining, growth at 37°C, a negative oxidase test result, and oxidation of glucose. The Phoenix bacterial identification system (Becton, Dickinson Diagnostic Instrument Systems, Sparks, MD) was used to confirm the identities of the isolates. An array with six oligonucleotide probes based on the 16S-23S rRNA gene intergenic spacer (ITS) region was used to identify the isolates to the genospecies level, as previously described (2).
Antimicrobial susceptibility testing.
Antimicrobial susceptibilities to 13 agents (ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam, cefepime, imipenem, meropenem, doripenem, amikacin, gentamicin, ciprofloxacin, levofloxacin, colistin, and tigecycline) were determined using the agar dilution method and interpreted based on the criteria recommended by the Clinical and Laboratory Standards Institute (CLSI) (21). For isolates causing relapsing bacteremia, the MICs of original and relapsing isolates were compared.
Molecular typing.
The genotypes of the isolates were determined by pulsotypes generated by pulsed-field gel electrophoresis (PFGE) and the random amplified polymorphic DNA (RAPD) patterns generated by arbitrarily primed PCR (APPCR). APPCR was performed with two random oligonucleotide primers: M13 (5′-TTATGTAAAACGACGGCCAG-3′; Gibco BRL products, Gaithersburg, MD) and ERIC1 (5′-GTGAATCCCCAGGAGCTTACAT-3′; Gibco Bethesda Research Laboratories), as described previously (14, 21). For PFGE, DNA extraction and purification were also carried out as previously described (14). DNA was digested by the restriction enzyme SmaI, and the restriction fragments were separated in a CHEF-DRIII unit (Bio-Rad Laboratories, Hercules, CA) at 200 V for 27 h. Isolates were considered identical if they exhibited identical genotypes (pulsotypes and RAPD patterns).
Definitions.
Recurrence was defined in patients with evidence of ACB complex bacteremia after documentation of negative blood cultures or clinical improvement after completing a course of anti-ACB complex therapy (14 to 21 days). Recurrence was further classified as relapse or reinfection. Relapse of infection was defined as when the genospecies and genotype of the recurrent isolate were identical to those of the original infecting strain. Conversely, reinfection was defined as when the genospecies or genotype of the recurrent isolate differed from that of the original isolate. The patients with relapse of ACB complex bacteremia were defined as the study group, and the list of those patients was then matched with that for ACB complex bacteremia in our previous study (14). Patients with ACB complex bacteremia matched (2:1) for age, sex, and genospecies of the ACB complex of the study were defined as the control group. Pneumonia was defined in patients with purulent sputum cultures positive for the ACB complex and the presence of newly developed lung infiltrates. Catheter-related bloodstream infection (CRBSI) was defined as the presence of bacteremia and clinical manifestations of infection (i.e., fever, chills, and/or hypotension) in patients with intravenous catheters and no apparent source of bacteremia except the catheter (14). If no primary focus could be identified, the bacteremia was classified as bacteremia of unknown source.
Statistical analysis.
Data were analyzed using SPSS version 11.0 software. Continuous variables are expressed as mean ± standard deviation. Comparisons between continuous variables were analyzed using the Wilcoxon rank sum test or the independent t test as appropriate. Comparisons between or among categorical variables were made by the chi-square or Fisher's exact test. Statistical significance was set at a P value of <0.05.
RESULTS
Clinical characteristics of patients.
During the study period, 25 of 446 (5.6%) patients with ACB complex bacteremia had recurrent bacteremia caused by the ACB complex. Of the 25 patients, 7 (48%) had relapse of bacteremia caused by A. nosocomialis and 5 had relapse of bacteremia caused by A. baumannii. Of the 13 patients with reinfection, 5 (38.5%) had reinfection caused by different genospecies of the ACB complex (Table 1). The most common types of secondary episodes among the 12 patients with relapse of ACB complex bacteremia were CRBSI (n = 11), followed by bacteremia of unknown source (n = 1).
Table 1.
Species associated with ACB complex bacteremia reinfection and relapse
| Original ACB complex isolate | Recurrent ACB complex isolate | No. of patients with recurrent bacteremia caused by ACB complex |
|
|---|---|---|---|
| Relapse (n = 12) | Reinfection (n = 13) | ||
| A. baumannii | A. baumannii | 5 | 4 |
| A. nosocomialis | A. nosocomialis | 7 | 3 |
| A. pittii | A. pittii | 1 | |
| A. baumannii | A. nosocomialis | 3 | |
| A. nosocomialis | A. baumannii | 1 | |
| A. pittii | A. nosocomialis | 1 | |
The clinical characteristics of the patients with ACB complex bacteremia who had relapse of bacteremia (study group) and those who did not have relapse of bacteremia (control group) are summarized in Table 2. Diabetes mellitus and cancer were the most common underlying diseases, followed by heart failure and stroke. The presence of a central venous catheter was noted during the episodes of bacteremia in all patients with relapse and in about 83% of patients without relapse. Overall, there was no significant difference in these clinical characteristics, including underlying diseases, type of infection, and outcome, between the study and control groups. For the patients with relapse, the most commonly used antimicrobial agent was carbapenems (11 patients; 91.7%), followed by ampicillin-sulbactam (5; 41.7%) and aminoglycoside (3; 25%). Additionally, all of the patients with CRBSI in the study group underwent removal of the catheter and received antibiotics during the episodes. As for the outcome analysis, there was no significant difference in mortality rates between the control group (37.5%) and the study group (33.3%).
Table 2.
Comparision of clinical characteristics of patients with relapse bacteremia (study group) and without relapse of bacteremia (control group) caused by ACB complex
| Characteristic | Valuea |
P value | |
|---|---|---|---|
| Study group (n = 12) | Control group (n = 24) | ||
| Age (yr) | 51.9 ± 27.1 | 51.8 ± 26.0 | 0.992 |
| Male | 8 (66.7) | 16 (66.7) | 0.708 |
| Underlying disease | |||
| Diabetes mellitus | 6 (50.0) | 6 (25.0) | 0.261 |
| Active cancer | 5 (41.7) | 13 (54.1) | 0.728 |
| Congestive heart failure | 2 (16.7) | 0 (0.0) | 0.197 |
| Stroke | 2 (16.7) | 0 (0.0) | 0.197 |
| Liver cirrhosis | 1 (8.3) | 1 (4.2) | 0.791 |
| End-stage renal disease | 0 (0.0) | 6 (25.0) | 0.155 |
| Others | 2 (16.7)b | 1 (4.2)c | 0.523 |
| Use of central venous catheter | 12 (100.0) | 20 (83.3) | 0.247 |
| Recent surgery | 2 (16.7) | 4 (16.7) | 0.634 |
| Type of infection | |||
| Catheter related infection | 11 (91.7) | 14 (58.3) | 0.096 |
| Pneumonia | 0 (0.0) | 5 (20.8) | 0.234 |
| Bacteremia of unknown source | 1 (8.3) | 1 (4.2) | 0.791 |
| Intra-abdominal infection | 0 (0.0) | 1 (4.2) | 0.725 |
| Intensive care unit admission | 5 (41.7) | 14 (58.3) | 0.558 |
| Mechanical ventilation | 4 (33.3) | 14 (58.3) | 0.289 |
| Shock | 5 (41.7) | 5 (20.8) | 0.355 |
| In-hospital mortality | 4 (33.3) | 9 (37.5) | 0.904 |
Number (%) unless otherwise indicated.
Short-bowel syndrome.
Systemic lupus erythematosis.
Comparisons between patients with relapse due to A. baumannii and relapse due to A. nosocomialis.
Among the 12 patients with relapse of bacteremia due to the ACB complex, relapse was caused by A. nosocomialis in 7 (58.3%) patients and by A. baumannii in 5 (41.7%) patients. The majority of the patients were men, and diabetes mellitus and cancer were the most common underlying diseases. All of the patients had central venous catheters during the episodes of bacteremia. There were no significant differences between patients with relapse of bacteremia caused by A. nosocomialis and patients with relapse due to A. baumannii. The time from discontinuation of therapy to relapse ranged from 11 to 291 days (median, 49 days), and relapse of bacteremia occurred within 60 days after discontinuation of therapy in approximately half of the patients. The time from discontinuation of therapy to reinfection ranged from 9 to 439 days (median, 54 days). The longest period (439 days) occurred in a patient with an initial episode of A. pittii bacteremia and reinfection with A. nosocomialis. In contrast, the shortest periods were noted in a patient with an initial episode of A. nosocomialis and reinfection with a different strain of A. nosocomialis (9 days) and in another patient with a first episode of A. pittii bacteremia and reinfection with A. baumannii (9 days).
Antimicrobial susceptibilities.
The antimicrobial susceptibility patterns of the three genospecies of the ACB complex are compared in Table 3. A. baumannii had lower susceptibility rates than the other two species to all of the antimicrobials tested. All of the ACB complex isolates were susceptible to colisitn. A. baumannii isolates were less susceptible to ampicillin-sulbactam, piperacillin-tazobactam, cefepime, gentamicin, amikacin, ciprofloxacin, and levofloxacin than A. nosocomialis (P < 0.05). In a comparison of the MICs for original ACB complex isolates and those for isolates causing relapsing bacteremia (12 patients) (Table 4), original and relapsing isolates from 8 patients, 5 with A. nosocomialis and 3 with A. baumannii bacteremia, had a significant increase (>2-fold change) in the MIC. Isolates from two patients (patients 5 and 11) showed the most frequent MIC changes between the original and the recurrent isolates. The significant increases in MICs were most commonly found for ticarcillin-clavulanate, piperacillin-tazobactam, and cefepime. Imipenem was the only agent for which no significant MIC changes between the original and the recurrent isolate occurred.
Table 3.
In vitro susceptibilities of three genospecies of the ACB complex to 13 antimicrobial agents
| Bacterium (no of isolates) and antimicrobial agent | MIC (μg/ml) |
No. (%)a |
||||
|---|---|---|---|---|---|---|
| Range | 50% | 90% | S | I | R | |
| A. nosocomialis (18) | ||||||
| Ampicillin-sulbactam | 1–128 | 2 | 4 | 16 (89) | 0 (0) | 2 (11) |
| Ticarcillin-clavulanate | 2–>128 | 16 | 64 | 10 (56) | 6 (33) | 2 (11) |
| Piperacillin-tazobactam | 0.03–>128 | 0.03 | 0.25 | 16 (89) | 0 (0) | 2 (11) |
| Cefepime | 1–>128 | 2 | 8 | 16 (89) | 0 (0) | 2 (11) |
| Doripenem | 0.25–>32 | 0.25 | 0.5 | |||
| Meropenem | 0.25–>32 | 0.5 | 1 | 17 (94) | 0 (0) | 1 (6) |
| Imipenem | 0.25–>32 | 0.25 | 0.5 | 17 (94) | 0 (0) | 1 (6) |
| Gentamicin | 1–>128 | 2 | 4 | 16 (89) | 0 (0) | 2 (11) |
| Amikacin | 2–>128 | 8 | 8 | 16 (89) | 0 (0) | 2 (11) |
| Ciprofloxacin | 0.12–>128 | 0.25 | 0.5 | 16 (89) | 1 (6) | 1 (6) |
| Levofloxacin | 0.12–16 | 0.25 | 0.25 | 17 (94) | 0 (0) | 1 (6) |
| Colistin | 1–2 | 1 | 2 | 18 (100) | 0 (0) | 0 (0) |
| Tigecycline | 0.25–8 | 0.25 | 1 | 17 (94) | 0 (0) | 1 (6) |
| A. baumannii (17) | ||||||
| Ampicillin-sulbactam | 2–64 | 4 | 32 | 8 (47) | 2 (12) | 7 (41) |
| Ticarcillin-clavulanate | 8–>128 | 32 | >128 | 6 (35) | 3 (18) | 8 (47) |
| Piperacillin-tazobactam | 0.03–>128 | 32 | >128 | 7 (41) | 4 (24) | (35) |
| Cefepime | 1–>128 | 4 | >128 | 8 (47) | 4 (24) | 5 (29) |
| Doripenem | 0.25–32 | 1 | 16 | |||
| Meropenem | 0.25–32 | 1 | 16 | 13 (76) | 0 (0) | 4 (24) |
| Imipenem | 0.25–16 | 2 | 8 | 12 (71) | 3 (18) | 2 (11) |
| Gentamicin | 1–>128 | 2 | >128 | 8 (47) | 0 (0) | 9 (53) |
| Amikacin | 4–>128 | 32 | >128 | 7 (41) | 2 (11) | 8 (47) |
| Ciprofloxacin | 0.12–>128 | 16 | 64 | 6 (35) | 0 (0) | 11 (65) |
| Levofloxacin | 0.12–>32 | 4 | 8 | 7 (41) | 2 (11) | 8 (47) |
| Colistin | 0.05–2 | 1 | 1 | 17 (100) | 0 (0) | 0 (0) |
| Tigecycline | 0.25–16 | 0.5 | 8 | 14 (82) | 0 (0) | 3 (18) |
| A. pittii (3) | ||||||
| Ampicillin-sulbactam | 2–4 | |||||
| Ticarcillin-clavulanate | 8–16 | |||||
| Piperacillin-tazobactam | 0.03–16 | |||||
| Cefepime | 1–4 | |||||
| Doripenem | 0.25–0.5 | |||||
| Meropenem | 0.5–1 | |||||
| Imipenem | 0.25 | |||||
| Gentamicin | 1–2 | |||||
| Amikacin | 4 | |||||
| Ciprofloxacin | 0.12–0.25 | |||||
| Levofloxacin | 0.12 | |||||
| Colistin | 0.5–1 | |||||
| Tigecycline | 0.25–0.5 | |||||
S, susceptible; I, intermediate; R, resistant.
Table 4.
Changes of MICs between original and recurrent isolates of the ACB complex recovered from12 patients with relapsing bacteremia
| Antimicrobial agent | MIC (μg/ml) change in patient with relapsing bacteremiaa |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (A. nosocomialis)b | 2 (A. baumannii) | 3 (A. nosocomialis) | 4 (A. nosocomialis) | 5 (A. nosocomialis) | 6 (A. nosocomialis) | 7 (A. nosocomialis) | 8 (A. baumannii) | 9 (A. baumannii) | 10 (A. baumannii) | 11 (A. nosocomialis) | 12 (A. baumannii) | |
| Ampicillin-sulbactam | 2–16 | 2–8 | 1–1 | 1–1 | 1–64 | 2–2 | 64–64 | 4–8 | 32–64 | 8–4 | 2–8 | 2–2 |
| Ticarcillin-clavulanate | 64–64 | 8–16 | 32–32 | 8–8 | 32–>128 | 16–64 | 32–>128 | >128–>128 | >128–>128 | 64–>128 | 8–>128 | 8–16 |
| Piperacillin-tazobactam | 0.03–64 | 0.12–>128 | 0.03–0.03 | 0.03–0.03 | 0.03–>128 | 0.03–0.03 | 0.25–>0.12 | 4–16 | 64–128 | >128–>128 | 0.03–>128 | 0.03–0.03 |
| Cefepime | 1–16 | 1–4 | 2–2 | 8–4 | 2–128 | 4–2 | 2–2 | 4–8 | 16–32 | 16–64 | 2–128 | 2–2 |
| Doripenem | 0.5–8 | 0.25–0.25 | 0.25–0.25 | 0.25–0.25 | 0.5–4 | 0.25–0.5 | 0.25–0.5 | 4–4 | 2–2 | 16–32 | 0.25–2 | 0.25–0.25 |
| Meropenem | 0.5–16 | 0.5–0.25 | 0.25–0.25 | 0.5–0.5 | 1–16 | 0.5–0.5 | 0.5–0.5 | 4–4 | 2–2 | 16–>32 | 0.5–1 | 0.25–0.25 |
| Imipenem | 0.25–0.25 | 0.25–0.25 | 0.25–0.25 | 0.25–0.25 | 0.25–0. 5 | 0.25–0.25 | 0.25–0.25 | 8–16 | 2–2 | 16–32 | 0.25–0.5 | 0.25–0.25 |
| Gentamicin | 2–1 | 1–2 | 2–2 | 2–2 | 4–64 | 2–2 | 4–4 | 1–1 | >128–>128 | >128–>128 | 1–64 | 1–2 |
| Amikacin | 8–4 | 4–4 | 8–4 | 8–8 | 8–32 | 8–32 | 8–8 | 32–32 | >128–>128 | >128–>128 | 4–32 | 4–4 |
| Ciprofloxacin | 0.12–0.25 | 0.12–0.5 | 0.25–0.25 | 0.25–0.25 | 0.25–2 | 0.25–0.5 | 0.25–0.25 | 16–16 | 32–64 | >128–128 | 0.25–64 | 0.12–0.12 |
| Levofloxacin | 0.12–1 | 0.12–0.25 | 0.12–0.12 | 0.12–0.12 | 0.25–2 | 0.25–0.25 | 0.25–0.12 | 4–4 | 8–8 | 32–16 | 0.12–8 | 0.12–0.12 |
| Colistin | 1–1 | 0.5–4 | 2–1 | 1–2 | 2–2 | 1–2 | 2–2 | 2–2 | 1–1 | 0.5–1 | 2–2 | 1–2 |
| Tigecycline | 0.25–0.5 | 0.25–0.5 | 0.25–0.25 | 0.25–0.25 | 0.25–4 | 1–0.5 | 0.25–0.25 | 0.25–0.25 | 2–2 | 16–8 | 0.25–8 | 0.25–0.25 |
Values showing >2-fold MIC changes between original and relapsing isolates are in boldface.
Patient number and infecting genospecies.
DISCUSSION
To our knowledge, this is the first study to investigate the clinical characteristics of recurrent ACB complex bacteremia. During the study period, 25 (5.6%) patients with recurrent ACB complex bacteremia were identified from a total of 446 patients with bacteremia. Only 12 cases of relapse of ACB complex bacteremia were found, and CRBSI was the most common type of infection. Most of the patients had various immunocompromised conditions, including diabetes mellitus and cancer, and all of them had central venous catheters during the episodes of bacteremia. Our findings suggest that physicians should consider the possibility of relapse of ACB infection in immunocompromised patients with intravenous catheters. Although we tried to make a case-control study to identify the possible risk factor for relapse of ACB complex bacteremia, we did not find any significant factors for relapse based on these limited case numbers. Therefore, further large-scale study is needed to investigate the specific risk factors for relapse of ACB complex bacteremia. Additionally, we found that the times between discontinuation of therapy for first episodes of bacteremia and relapses of ACB complex bacteremia can be as long as 291 days. This may remind clinicians that ACB complex relapses can develop even several months after the first episode.
The pathogens causing relapse of bacteremia due to the ACB complex in this study were A. nosocomialis and A. baumannii. No cases of relapse were due to A. pittii. A previous study (3) demonstrated that genospecies 2 was associated with higher mortality than genospecies 13TU in patients with ACB bacteremia. However, we found that there was no significant difference in mortality rates between patients with relapse of bacteremia due to A. nosocomialis and patients with relapse caused by A. baumannii. One reason for the discrepancy in mortality between our study and that by Chuang et al. might be because of the small number of patients investigated in this study. Another reason might be the differences in study design. In our study, for example, we recruited only patients with recurrent ACB bacteremia, whereas in the study by Chuang et al. (3), the researchers focused on only one episode of ACB bacteremia.
In the current study, we demonstrated that the antibiotic susceptibility pattern varied according to the genospecies of the ACB complex. Significantly higher susceptible rates for ampicillin-sulbactam, piperacillin-tazobactam, cefepime, gentamicin, amikacin, ciprofloxacin, and levofloxacin were noted in A. nosocomialis than in A. baumannii. The finding is consistent with that reported in previous studies (3, 11, 14, 16, 17), which showed that A. baumannii isolates had higher levels of antibiotic resistance than A. nosocomialis. Because the isolates causing relapsing bacteremia tended (75%) to have higher MICs for commonly prescribed antimicrobial agents, physicians should be careful to choose appropriate antibiotics when facing the relapsing episodes of ACB bacteremia.
This study was a retrospective study of a small number of patients at a single medical center; therefore, no solid conclusions can be drawn. Nonetheless, this study is, to the best of our knowledge, the first study to investigate the clinical manifestation of recurrent ACB complex bacteremia. The results, therefore, provide some useful information about the issue.
In conclusion, relapse of bacteremia due to the ACB complex can develop in immunocompromised patients, especially patients with central venous catheters. Molecular methods are essential for identifying isolates of the ACB complex to the species level.
ACKNOWLEDGMENT
This study was supported by internal funding.
We have no conflicts of interest to declare.
Footnotes
Published ahead of print 3 July 2012
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