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Keywords:

  • Inhaled colistin methanesulfonate;
  • multidrug-resistant Acinetobacter baumannii

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

Clin Microbiol Infect 2012; 18: 870–876

Abstract

Repeated isolation of multidrug-resistant Acinetobacter baumannii (MDRAB) from respiratory secretions poses a great challenge for infection control. We conducted a retrospective case–control study to evaluate the efficacy and adverse effect of inhaled colistin methanesulfonate (CMS) in the eradication of MDRAB from the respiratory tract. Patients who were admitted to Taipei Veterans General Hospital between February 2009 and June 2010, had at least two sets of monomicrobial culture of MDRAB from respiratory secretions, and remained in hospital for at least 14 days after the first isolation of MDRAB (index day) were included. Patients who received intravenous CMS were excluded. Patients who received CMS inhalation for ≥3 days were selected as cases whereas the controls were matched for age and Acute Physiology and Chronic Health Evaluation II score. Thirty-nine cases and controls were identified. The duration of CMS inhalation was 10.9 ± 3.6 days. The use of inhaled CMS was the only independent factor associated with the eradication of MDRAB within 14 days after the index day (OR 266.33; 95% CI 11.26–6302.18, p <0.001), and shortened the duration of MDRAB recovery from the respiratory tract by 13.3 ± 1.45 days. The adverse effects were similar for both groups. The increase of colistin minimal inhibitory concentrations in the last isolate compared with the index isolate from the same patient did not differ between the two groups. In conclusion, our study demonstrated that inhaled CMS enhanced the eradication of MDRAB from the respiratory tract without significant clinical adverse effect or impact on colistin resistance.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

The three phenotypically undifferentiated Acinetobacter baumannii complex (Abc) have become important nosocomial pathogens [1]. Among them, A. baumannii is the most challenging for healthcare institutions globally because of its multidrug resistance and proneness to cause outbreaks that are difficult to control [2]. The major infection caused by A. baumannii is nosocomial pneumonia and A. baumannii can also colonize respiratory tracts [3]. Acinetobacter baumannii pneumonia is associated with a high mortality rate (36–66.7%) and increases length of hospital stay [3–5]. Colonization by A. baumannii is also associated with subsequent A. baumannii infection and increases patient morbidity, mortality and length of hospital stay [6–8]. In addition, strict and costly infection control measures are always needed to contain the outbreak [3,9]. As a result, the eradication of A. baumannii may prevent the adverse clinical consequences and decrease the vast expenditure of infection control [6,7].

Colistin is one of the limited drugs of choice for the treatment of multidrug-resistant A. baumannii (MDRAB) with favourable clinical outcomes [10–12]. The colistin is modified to a less toxic derivative, colistin methanesulfonate (CMS), for intravenous use [13]. The CMS can also be delivered through inhalation. The efficacy of inhaled colistin in the eradication of Pseudomonas aeruginosa has been reported [14,15]. A few studies assessed the efficacy of inhaled colistin in addition to the concomitant intravenous use of different antibiotics on the outcome of patients with pneumonia caused by gram-negative bacilli [16–18]. These studies also assessed the efficacy of inhaled colistin on bacterial eradication, but the results were controversial [16,19]. Although the major causative pathogens in these studies were Abc, other gram-negative bacilli were also included [11,12,16–19]. The impact of therapy might vary among different pathogens [1]. Moreover, Abc comprises three different species that are different in terms of their antibiotic (including colistin) susceptibility patterns [20,21] and possibly their pathogenicity [1]. The heterogenicity of the pathogens might complicate the interpretation of the results.

In this study, we conducted a case–control study to evaluate whether in patients with or without concomitant intravenous antibiotic therapy, the addition of inhaled CMS can enhance the eradication of MDRAB from the respiratory tract.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

Patient population

Taipei Veterans General Hospital is a 2900-bed tertiary centre in Taiwan. According to the guideline for infection control in our hospital, patients with MDRAbc cultured from respiratory secretions received isolation and strict contact precaution measures until three subsequent cultures from respiratory secretions, which were performed every 3–5 days, revealed a negative result for MDRAbc. During the isolation, patients might receive inhaled CMS for the eradication of the MDRAbc according to the individual decision of the physicians in charge. The dosage of inhaled CMS was 2 million international units (IU) (= 160 mg CMS) twice per day, regardless of the patients’ renal function. The CMS was reconstructed in 5–7 mL sterile normal saline and delivered via a jet nebulizer with an oxygen flow of 8 L/min in patients without ventilator support. For patients with ventilator support, the inhaled CMS was delivered by means of the T-bird AVS (Bird Products, Palm Springs, CA, USA). The extra cost of the isolation room per patient in Taipei Veterans General Hospital was about US$ 120 (double room without roommate) or US$ 180 (single room) per day.

This retrospective matched case–control study (ratio 1 : 1) assessed all adult patients (aged ≥18 years) who were admitted from February 2009 to June 2010 and with at least two sets of culture from respiratory secretions that showed the monomicrobial growth of MDRAB. The day when the first MDRAB was isolated was defined as the index day, and the first isolate was defined as the index isolate. Patients were excluded if they died or left hospital within 14 days after the index day or their respiratory secretion could not be collected regularly because the outcome of interest could not be assessed. Patients were selected as case patients when they had received inhaled CMS for ≥3 days after the index day. Control patients were those who did not receive inhaled CMS and were selected based on the following matching criteria: age (±5 years), Acute Physiology and Chronic Health Evaluation (APACHE) II score (±4 points) [19]. Patients included in the study could have received concomitant intravenous antibiotics except CMS, as use of intravenous CMS might complicate the interpretation of results. In selecting the control patients, the investigators did not know the outcomes. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (2011-04-026IC).

Data collection and definition

Clinical data were retrospectively collected by reviewing the medical records. Multidrug resistance was defined as isolates non-susceptible to all of the following antibiotics, including carbapenems, anti-pseudomonas cephalosporins, anti-pseudomonas penicillins, fluoroquinolones, aminoglycosides, tetracycline and trimethoprim/sulfamethoxazole. The MDRAB could be either susceptible to colistin, tigecycline or sulbactam. Pneumonia was diagnosed as previously described [22].

Early eradication was defined if at least two consecutive cultures from the respiratory secretions revealed no growth of MDRAB and no MDRAB was recovered from subsequent cultures, which were performed every 3–5 days until 14 days after the index day. For patients with early eradication, recurrence/recolonization was defined as the recovery of MDRAB 14 days after the index day. For patients without early eradication, if the MDRAB continued to be isolated till the end of the follow up or the 28th day after the index day, the persistent isolation of MDRAB was considered.

Adverse effects were recorded. Haemodynamic instability was considered when inotropic agents were mandated, and bronchospasm when a bronchodilator therapy was needed. Nephrotoxicity was defined as an increase in baseline creatinine of ≥44.2 μM for patients with normal renal function, ≥20% increase for those with previous renal dysfunction, or a decline in renal function that required renal replacement therapy. If the patients underwent pre-existing renal replacement therapy or the use of a mechanical ventilator on the index day, they were excluded from the evaluation of nephrotoxicity and adverse respiratory effect, respectively.

Microbiological studies

The Abc was phenotypically identified using the API ID 32GN system (bioMérieux, Marcy l’Etoile, France) and then identified to the genomic species using a multiplex-PCR method [23]. The antimicrobial susceptibilities were performed by disk diffusion tests. The MICs of colistin were determined by an agar dilution test using colistin sulfate (Sigma Aldrich, St Louis, MO, USA) [24]. The genetic relationship of the isolates was determined by pulsed-field gel electrophoresis, as previously described [25].

Statistical analysis

A univariate analysis was performed using a Student’s t-test/Mann–Whitney U-test, or Fisher’s exact tests/Pearson chi-square test, as appropriate. A multivariate analysis was performed to assess the relationship between the predictor variables and the outcomes of interest. All analyses were performed using the Statistical Package for the Social Sciences version 18.0 (SPSS, Chicago, IL, USA). A value of p <0.05 was considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

During the study period, 1020 patients experienced MDRAbc growth from respiratory secretions. Among 291 patients who had monomicrobial growth of MDRAbc and had stayed in hospital for ≥14 days, 49 patients had received CMS inhalation therapy for ≥3 days but not concomitant intravenous CMS. Ten patients were excluded because the bacteria were identified as other Acinetobacter species. Finally, 39 patients were available as cases and 39 corresponding controls were identified. The duration of the inhaled CMS therapy was 10.9 ± 3.6 days. The demographic data, underlying diseases and invasive procedures are listed in Tables 1 and 2 (Supplementary data). A comparable portion of patients in case and control groups (10/39 vs 8/39, p <0.591) had received intravenous antibiotic therapy (either for MDRAB pneumonia or other infections) that had an in vitro activity against the MDRAB.

Table 1.   Characteristics of the study patientsa
CharacteristicsCase (= 39)Control (= 39)p
  1. aData are presented as number (%) of patients, unless stated otherwise.

  2. bIndex day was defined as the first day when the multi-drug resistant Acinetobacter baumannii was isolated from respiratory secretion.

  3. SD, standard deviation; APACHE, acute physiology and chronic health evaluation.

Age, mean years ± SD78 ± 13.181.3 ± 10.20.227
Sex, male34 (87.2)26 (66.7)0.032
APACHE II score at index dayb, mean ± SD20.0 ± 6.221.1 ± 4.50.349
APACHE II score at day 14 after index day, mean ± SD20.4 ± 6.420.5 ± 4.90.943
Colonization23 (59.0)27 (69.2)0.345
Pneumonia16 (41.0)12 (30.8)0.345
Stay in intensive care unit28 (71.8)33 (84.6)0.170
Hospitalization day prior to index day, mean days ± SD62.8 ± 135.943.5 ± 130.00.523
Table 2.   Predisposing factors and invasive procedures use of study patientsa
CharacteristicsCase (= 39)Control (= 39)p
  1. aData are presented as number (%) of patients, unless stated otherwise.

  2. bPredisposing factors with a prevalence of <5% in both groups was not shown.

  3. PAOD, peripheral arterial occlusive disease; SD, standard deviation.

Predisposing factorsb
 Chronic renal disease23 (59.0)19 (48.7)0.364
 Bed-ridden22 (56.4)21 (53.8)0.820
 Hypertension16 (41.0)18 (46.2)0.648
 Diabetes mellitus15 (38.5)11 (28.2)0.337
 Chronic lung diseases14 (35.9)16 (41.0)0.642
 Cerebrovascular diseases13 (33.3)11 (28.2)0.624
 Congestive heart failure12 (30.8)11 (28.2)0.804
 Coronary artery disease12 (30.8)6 (15.4)0.107
 Steroid use11 (28.2)19 (48.7)0.063
 Solid organ tumor9 (23.1)6 (15.4)0.389
 Major operation6 (15.4)2 (5.1)0.135
 Collagen disease4 (10.3)3 (7.7)0.692
 Renal replacement therapy3 (7.7)3 (7.7)>0.99
 Liver cirrhosis3 (7.7)1 (2.6)0.305
 Chemotherapy2 (5.1)1 (2.6)0.556
 PAOD2 (5.1)0 (0)0.152
 Trauma1 (2.6)2 (5.1)0.556
Invasive procedures use
 Nasogastric tube36 (92.3)38 (97.4)0.305
 Foley catheter23 (59.0)30 (76.9)0.089
 Mechanical ventilation15 (38.5)23 (59.0)0.070
 Duration of mechanical ventilation prior to index day, mean days ± SD5.7 ± 6.77.9 ± 6.60.137
 Central venous catheterization13 (33.3)16 (41.0)0.482
 Tracheostomy10 (25.6)10 (25.6)>0.99
 Arterial catheterization5 (12.8)11 (28.2)0.092
 Abdominal drainage1 (2.6)0 (0)0.314
 Total parental nutrition0 (0)2 (5.1)0.152
Previous intravenous antibiotic use38 (97.4)31(79.5)0.013
 Carbapenems18 (46.2)7 (17.9)0.008
 Sulbactam or ampicillin/sulbactam9 (23.1)5 (12.8)0.238
 Tigecycline9 (23.1)2 (5.1)0.023
 Anti-pseudomonas beta-lactams24 (61.5)23 (59.0)0.817
 Ciprofloxacin or levofloxacin9 (23.1)10 (25.6)0.792
 Aminoglycosides2 (5.1)2 (5.1)>0.99
Concomitant intravenous antibiotic use32 (82.1)31 (79.5)0.774
 Carbapenems18 (46.2)6 (15.4)0.003
 Sulbactam or ampicillin/sulbactam11 (28.2)12 (30.8)0.804
 Tigecycline10 (25.6)8 (20.5)0.591
 Anti-pseudomonas beta-lactams9 (23.1)16 (41.0)0.089
 Ciprofloxacin or levofloxacin2 (5.1)9 (23.1)0.023
 Aztreonam1 (2.6)0 (0)0.314
 Aminoglycosides1 (2.6)0 (0)0.314

During the subsequent cultures, the last cultures positive for MDRAB in the case group were at day 8.2 ± 6.4 after the index day, but were at day 21.5 ± 4.5 (p <0.001) in the control group. The extra expenditure to cover the isolation room fees because of the prolonged isolation of the control group was around US$ 1596 ± 174 to 2394 ± 261 per patient. In contrast, the extra expenditure for the inhaled CMS in the case group was US$ 115 ± 38 per patient. The early eradication rate within 14 days after the index day of MDRAB isolation from respiratory secretions (Table 3) was higher in the case group than in the control group (84.6% vs 10.3%; p <0.001). In the subgroup analysis of patients with colonization or pneumonia, the early eradication rates were both higher in the case group than control group [95.7% (22/23) vs 7.4% (2/27), p <0.001; 68.8% (11/16) vs 16.7% (2/12), p 0.009]. Among the cases with early eradication, 78.8% continued to be free of respiratory colonization and/or infection from MDRAB. In patients without early eradication, the percentage of patients who experienced persistent isolation of MDRAB in the two groups was similar (50% (3/6) vs 57.1% (20/35)); p >0.99].

Table 3.   Outcomes and adverse effects of patients in the case and control groupsa
CharacteristicsCase (= 39)Control (= 39)p
  1. aData are presented as number (%) of patients, unless stated otherwise.

  2. bNot all of the last isolates were available from the case and control groups.

  3. MIC, minimal inhibitory concentration.

Microbiological outcome
 Eradication within 14 days33 (84.6)4 (10.3)<0.001
 Recurrence/recolonization7/33 (21.2)0/4 (0)0.570
 Persistent isolation3/6 (50)20/35 (57.1)>0.99
Change of colistin MIC between the last isolate and the index isolate from the same patient
 1–2-fold increase8/28 (28.6)b4/30 (13.3)b0.152
Cumulative adverse effects at day 14 after index day
 Hemodynamic instability4 (10.3)4 (10.3)>0.99
 Acute renal failure6/36 (16.7)7/36 (19.4)0.759
 Need for renal replacement therapy2/36 (5.6)2/36 (5.6)>0.99
 Need for intubation4/24 (16.7)2/16 (12.5)0.718
Cumulative adverse effects at day 28 after index day
 Hemodynamic instability7 (17.9)5 (12.8)0.530
 Acute renal failure11/36 (30.6)9/36 (25.0)0.599
 Need for renal replacement therapy3/36 (8.3)2/36 (5.6)0.643
 Need for intubation5/24 (20.8)3/16 (18.8)0.872
Clinical outcome
 28-day mortality5 (12.8)4 (10.3)0.723
 In-hospital mortality16 (41.0)13 (33.3)0.482

To investigate whether the inhaled CMS was an independent factor associated with the early eradication of MDRAB, other factors associated with the early eradication (Table 4) were entered into the multivariate analysis. Only the use of inhaled CMS was the independent factor associated with the early eradication of MDRAB (OR 266.33; 95% CI 11.26–6302.18, p <0.001).

Table 4.   Factors associated with the early eradication of multidrug-resistant Acinetobacter baumanniia
VariablesSuccessful eradication (= 37)No eradication (= 41)pMultivariate OR (95% CI)p
  1. aData are presented as number (%) of patients, unless stated otherwise.

  2. OR, odds ratio; CI, confidence interval; SD, standard deviation; CMS, colistin methanesulfonate.

Age, mean years ± SD76.3 ± 14.082.7 ± 8.40.018 0.465
Chronic lung disease9 (24.3)21 (51.2)0.015 0.090
Steroid use10 (27.0)20 (48.8)0.049 0.925
Use of arterial catheterization4 (10.8)12 (29.3)0.044 0.805
Use of nasogastric tube33 (89.2)41 (100)0.031 >0.99
Duration of mechanical ventilator use prior to index day, mean days ± SD4.84 ± 6.258.56 ± 6.650.013 0.114
Previous use of carbapenem17 (45.9)8 (19.5)0.012 0.612
Previous use of tigecycline9 (24.3)2 (4.9)0.014 0.971
Concomitant use of ciprofloxacin or levofloxacin0 (0)11 (26.8)<0.001 >0.99
CMS inhalation33 (89.2)6 (14.6)<0.001266.33 (11.26–6302.18)<0.001

The incidence of haemodynamic instability, need for intubation, or nephrotoxicity did not differ between the case and control groups (Table 3). No bronchospasm was observed in either group. The 28-day and in-hospital mortality rate did not differ between the two groups.

The index isolates in the case and control groups belonged to 28 and 23 different pulsotypes, respectively (data not shown). No specific pulsotype was found. All of the index isolates were resistant to imipenem, ceftazidime, cefoperazone, cefepime, piperacillin/tazobactam, ciprofloxacin, levofloxacin, gentamicin, tetracycline and trimethoprim/sulfamethoxazole. Seventy-five isolates (96.2%) were also resistant to sulbactam. Seventy index isolates (89.7%) showed a susceptibility to colistin, with the MIC ranging from 0.5 to 2 mg/L. Eight isolates were resistant to colistin (with MIC of 4 mg/L (seven isolates) and 8 mg/L (one isolate)), among which six were in the case group and two in the control group (15.4% vs 5.1%, p 0.135). Five of the six case patients harbouring the colistin-resistant MDRAB had their isolates eradicated within 14 days whereas neither of the two control patients did. Overall, the early eradication rate within 14 days between patients with colistin-resistant or colistin-susceptible isolates was similar (5/8 (62.5%) vs 32/70 (45.7%), p 0.368). The early eradication of colistin-resistant and colistin-susceptible isolates did not differ in the case group (5/6 (83.3%) vs 28/33 (84.8%), p 0.925).

The last positive MDRAB isolates from 28 case patients and 30 control patients were available. Sixteen (57.1%) last isolates in the case group belonged to the same pulsotype as their index isolates, whereas in the control group 13 (43.3%) isolates did (Supplementary data). The proportion of last isolates with increased colistin MIC compared with the index isolates from the same patients did not differ significantly between the two groups (Table 3). Two follow-up isolates from each group had colistin MIC at resistant levels. In the case group, both were eradicated within 14 days. In the control group, one was eradicated within 14 days and the other persisted at day 28 after the index day.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

To the best of our knowledge, this was the first matched case–control study focusing on the efficacy of inhaled CMS in the eradication of respiratory MDRAB, which was identified to the genomic species level. We found that inhaled CMS enhanced the eradication of MDRAB from the respiratory tract and was not associated with significant adverse effects or the emergence of colistin resistance.

The inhaled CMS shortened the duration of MDRAB recovery from the respiratory tract by 13.3 ± 1.45 days. Fourteen days after the index day, a significant number of case patients had their MDRAB eradicated. Although there were some differences in the background between the two groups, the multivariate analysis identified that inhaled CMS was still the only independent factor associated with early eradication. In 78.8% of the case patients who had the early eradication of MDRAB, the culture remained negative after cessation of the inhaled CMS, indicating that the negative culture that resulted during CMS inhalation was not merely the result of the carryover effect of CMS.

The high microbiological eradication rate in our study was consistent with previous cohort studies and one comparative study [11,12,16–18]. However, a recent comparative study using 1 million IU twice daily of colistin showed no microbiological benefit [19]. The high dose of inhaled CMS might explain part of the high eradication rate in our study. A peak concentration approaching 40 mg/L has been found after inhalation of a single dose of 2 million IU colistin [14]. The eradication of index isolates that had colistin MIC at resistant levels might also be due to the high concentration in the airway. The best delivery method for inhaled CMS has not been confirmed. The results of our study indicated that the current preparation and delivery method might be adequate for the eradication of the respiratory MDRAB.

One of the benefits of the early eradication of MDRAB from the respiratory tract by inhaled CMS was decreased hospital cost, at least those resulting from the isolation ward fee. In our hospital, this meant a saving of at least US$ 1596 ± 174 to 2394 ± 261 per patient. This certainly underestimated the costs, especially those resulting from manpower, which were hard to estimate, and the disposable consumables used in the contact precautions. Nevertheless, the benefit of inhaled CMS in other countries, including those with lower incidences of MDRAB colonization and different infection control policies, cannot be extrapolated. In addition, it remains to be determined whether there is any other benefit resulting from the eradication of MDRAB, including the prevention of subsequent infection and the containment of an outbreak.

There was no associated bronchospasm, which would mandate the use of a bronchodilator, in our study. The incidence of serious respiratory events (need for intubation) and nephrotoxicity was similar between the two groups, which was in agreement with most previous clinical studies [11,16,17,19]. The systemic adverse effects of colistin were avoided because of the low systemic concentration of colistin after inhalation [14].

Unexpectedly, the isolates recovered from the subsequent culture revealed different pulsotypes compared with the index isolates in half of the patients in both groups. The results indicated the complexity of A. baumannii colonization that could only be detected with molecular epidemiology tools. The change of colistin MIC between the two groups did not differ significantly. Two colistin-resistant isolates in the case group emerged but both were eradicated. The high concentration of colistin over MIC of the isolate might be responsible for the rarity of the emergence of resistance and the eradication of the resistant isolates. The other reason for the scarcity of emergence of colistin resistance in A. baumannii, especially in vivo, is that colistin resistance in A. baumannii may be associated with a loss of biological fitness and the intrinsic instability of the resistance [26–28].

In our study consisting mostly of colonized patients (59% in the case group and 69.2% in the control group), we did not assess the efficacy of inhaled CMS on patients’ clinical outcomes, including success in infection. Moreover, after excluding patients with early mortality (within 14 days), we only assessed 28-day and in-hospital mortality in our study. Not surprisingly, the inhaled CMS did not reduce the mortality of patients mostly with colonization.

In conclusion, our study demonstrated that inhaled CMS offered a microbiological benefit in patients with MDRAB from the respiratory tract and decreased need for expenditure on isolation. No significant clinical adverse effect or emergence of resistance was associated with CMS inhalation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

This work was supported by Taipei Veterans General Hospital (V100C-025 and V10E4-005), National Science Council (NSC98-2314-B-010-010-MY3), and Yen Tjing Ling Medical Foundation (CI-99-18).

Transparency Declaration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

T.L.C. has received speaker honoraria from Bayer, Daiichi Sankyo Merck, Pfizer and TTY Biopharm. All other authors declared that they have no conflict of interest.

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
  10. Supporting Information

Figure S1. The index and last isolates from the same case patients were aligned side by side and designated as a and b after the numbering of the strains.

Figure S2. The index and last isolates from the same case patients were aligned side by side and designated as a and b after the numbering of the strains.

Figure S3. The index and last isolates from the same control patients were aligned side by side and designated as a and b after the numbering of the strains.

Figure S4. The index and last Isolates from the same control patients were aligned side by side and designated as a and b after the numbering of the strains. An exception is strain no 20a and 20b, which was not in order because of a loading mistake during performing PFGE.

Figure S5. The index and last isolates from the same case or control patients were.

Table S1. The antibiotics used for the treatment of 12 patients with MDRAB pneumonia in control group and their outcomes.

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CLM_3682_sm_supplementarydata.doc815KSupporting info item

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