Acinetobacter Baumannii-related Osteomyelitis: Clinical and Epidemiological Characterization
Conditions: Osteomyelitis
Sponsor: University of Sao Paulo

COVER PAGE 
Title: Acinetobacter baumannii - related osteomyelitis: clinical and epidemiological 
characterization 
NCT number: NCT03559530 
Date: 08/18/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FINAL REPORT 
Study title: Acinetobacter baumannii - related osteomyelitis: clinical and epidemiological 
characterization 
Pfizer Tracking Number: WI176466 
The initial database consisted of 262 patients with bone tissue culture positive for 
Acinetobacter baumannii submitted to surgical procedures to treat osteomyelitis at the Instituto 
de Ortopedia e Traumatologia da HCFMUSP from January 2007 to December 2015. From this 
total, it was possible to collect data for 171 patients for analysis. Here is a description of the 
reason for not including 91 patients: 
- non-location of medical records: 44 patients; 
- culture results were not considered for treatment: 29 patients; 
- duplicate cases in the database: 8 patients; 
- cultures showing other species of Acinetobacter: 7 patients; 
- cultures harvested at the time of initial treatment of cases of exposed fractures and 
considered as contamination / colonization: 3 patients. 
The descriptive analysis of the total sample (171 patients) and the result of the 
comparison between the cases of patients with extensively drug resistant (XDR) isolates treated 
with tigecycline and colistin (65 patients) are described in the following report and represents 
the largest case series of osteomyelitis related to A. baumannii ever described. The study 
protocol was registered in clinicaltrials.gov (NCT03559530). 
 
 

1. Descriptive analysis of the Acinetobacter baumannii osteomyelitis database 
1.1. Demographics of 171 patients (percentage and absolute numbers) 
• Average age: 43.2 years 
• Male sex: 78.4% (134) 
• Any comorbidity present: 33.9% (58) 
o Sistemic hypertension: 21.1% (36) 
o  Neoplasia: 3.5% (6) 
o Diabetes mellitus: 10.5% (18) 
o HIV infection: 1.2% (2) 
o Rheumatoid arthritis: 4.7% (8) 
o Systemic lupus erythematosus: 0.6% (1) 
o Other rheumatological conditions: 1,2% (2) 
o Use of immunosuppressive drugs: 3.5% (6) 
 
• Epidemiological background 
o Smoking: 6.4% (11) 
o Alcohol abuse: 5.8% (10) 
o Ilicit drug use: 0.6% (1) 
o Previous surgical site infection in the affected segment: 25.1% (43) 
o Prior orthopedic surgery: 43.3% (74) 
 
• Affected segment 
o Hip: 24.6% (42) 

o Leg: 21.6% (37) 
o Thigh: 15.8% (27) 
o Spine: 14.6% (25) 
o Foot and ankle: 9.4% (16) 
o Knee: 8.2% (14) 
o Arm: 2.3% (4) 
o Forearm: 1.8% (3) 
o Hand and wrist: 1.2% (2) 
o elbow: 0.6% (1) 
 
• Co-infection agents present: 72.5% (124) 
o S. aureus: 19.4% (24) 
o Coagulase-negative Staphylococcus spp.: 19.4% (21) 
o Klebsiella pneumoniae: 16.1% (20) 
o Pseudomonas aeruginosa: 17.7% (22) 
o Candida spp .: 0.8% (1) 
o Enterococcus spp .: 28.2% (35) 
 
 
 
 
 
 

• Antibiogram of A. baumannii isolates for the 171 patients included (table 1). 
Table 1 –Antibiogram for A. baumannii samples from the 171 patients included. 
Antimicrobial 
Susceptibility 
Not tested 
Amikacin 
61,4% (105) 
0,6% (1) 
Ampicillin/sulbactam 
43,3% (74) 
0% (0) 
Cefepime 
15,8% (27) 
1,2% (2) 
Ceftazidime 
14% (24) 
5,8% (10) 
Ciprofloxacin 
14,6% (25) 
5,8% (10) 
Imipenem 
35,1% (60) 
0,6% (1) 
Meropenem 
33,3% (57) 
4,1% (7) 
Colistin 
63,7% (109) 
33,9% (58) 
Tigecycline 
47,4% (81) 
38% (65) 
Gentamicin 
58,5% (100) 
0% (0) 
 
Table 2 and Figures 1 to 7 below show the evolution of the susceptibility profiles of A. 
baumannii isolates against the main antimicrobials tested during the period in which the 
patients included in the study were treated. Tigecycline is not included in this analysis because  
A. baumannii susceptibility to this antimicrobial was extrapolated from breakpoints for 
enterobacteria during the study period, according to Clinical and Laboratory Standards Institute 
(CLSI) criteria. 
 
 
 
 

Table 2 – Percentage of A. baumannii isolates susceptible to main antimicrobials tested during the study period 
Amikacin 
Ampi/Sulb 
Cefepime 
Ceftazidime 
Ciprofloxacin 
Carbapenem 
Gentamicin 
2007 
29 
79 
14 
14 
14 
43 
50 
2008 
23 
73 
14 
9 
9 
55 
45 
2009 
29 
59 
18 
18 
12 
47 
76 
2010 
79 
37 
5 
11 
11 
37 
53 
2011 
58 
27 
19 
15 
15 
27 
65 
2012 
80 
50 
25 
20 
25 
45 
55 
2013 
84 
29 
16 
16 
16 
26 
68 
2014 
91 
18 
9 
9 
9 
9 
36 
2015 
82 
18 
18 
9 
18 
18 
64 
 
 
Figure 1 – Evolution of the susceptibility profile of isolates of A. baumannii to amikacin over study period 
 
29
23
29
79
58
80
84
91
82
0
10
20
30
40
50
60
70
80
90
100
2007
2008
2009
2010
2011
2012
2013
2014
2015
TSAAmica

 
Figure 2 – Evolution of the susceptibility profile of isolates of A. baumannii to ampicillin/sulbactan  
over study period 
 
 
Figure 3 – Evolution of the susceptibility profile of isolates of A. baumannii to cefepime over study period 
 
 
79
73
59
37
27
50
29
18
18
0
10
20
30
40
50
60
70
80
90
2007
2008
2009
2010
2011
2012
2013
2014
2015
TSAUnasyn
14
14
18
5
19
25
16
9
18
0
5
10
15
20
25
30
2007 2008 2009 2010 2011 2012 2013 2014 2015
TSACefepime

 
Figure 4 – Evolution of the susceptibility profile of isolates of A. baumannii to ceftazidime over study period 
 
 
Figure 5 – Evolution of the susceptibility profile of isolates of A. baumannii to ciprofloxacin over study period 
 
14
9
18
11
15
20
16
9
9
0
5
10
15
20
25
2007 2008 2009 2010 2011 2012 2013 2014 2015
TSACeftazidime
14
9
12
11
15
25
16
9
18
0
5
10
15
20
25
30
2007 2008 2009 2010 2011 2012 2013 2014 2015
TSACiprofloxacino

 
Figure 6 – Evolution of the susceptibility profile of isolates of A. baumannii to carbapenems (imipenem  
and meropenem) over study period 
 
 
Figure 7 – Evolution of the susceptibility profile of isolates of A. baumannii to gentamicin over study period 
 
 
• Classification of osteomyelitis 
o Post traumatic: 64.9% (111) 
o Contiguous: 29.8% (51) 
o Spine osteomyelitis: 2.9% (5) 
43
55
47
37
27
45
26
9
18
0
10
20
30
40
50
60
2007 2008 2009 2010 2011 2012 2013 2014 2015
Carbapenem
50
45
76
53
65
55
68
36
64
0
10
20
30
40
50
60
70
80
90
2007 2008 2009 2010 2011 2012 2013 2014 2015
TSAGentamicina

o  Hematogenic: 2.3% (4) 
o Acute: 52.6% (90) 
o Chronic: 47.4% (81) 
 
• Previous open fracture: 36.8% (63). Open fracture classification according to Gustilo and 
Anderson 
o No registeredclassification : 22.2% (14) 
o II: 4.8% (3) 
o IIIa: 14.3% (9) 
o IIIb: 44.4% (28) 
o IIIc: 14.3% (9) 
• Neuropathic foot infection: 2.9% (5) 
• Decubitus ulcer infection: 16.4% (28) 
• Closed fracture: 9.4% (16) 
• ASA score: 
o ASA I: 35.1% (60) 
o ASA II: 51.5% (88) 
o ASA III: 13.5% (23) 
• need for muscle or skin flap repair during osteomyelitis treatment: 32.2% (55) 
• Negative pressure therapy: 25.1% (43) 
• Hyperbaric oxygen therapy: 1.2% (2) 
• Average number of surgical procedures  for treatment: 3.5 

• Antimicrobial use 
o Prior to diagnosis of A. baumannii infection: 90.6% (155) 
o Use of combination therapy (two active drugs) for A. baumannii: 2.9% (5) 
o Treatment groups: 
o Colistin: 19.9% (34) 
o Ampicillin / Sulbactam: 18.7% (32) 
o Tigecycline: 18.1% (31) 
o Aminoglycosides: 15.2% (26) 
o Quinolone: 14% (24) 
o Carbapenem: 10.5% (18) 
o Aminoglycoside + tigecycline: 1.2% (2) 
o Aminoglycoside + Colistin: 0.6% (1) 
o 3th and 4th generation cephalosporins: 0.6% (1) 
o Sulfamethoxazole / trimethoprim: 0.6% (1) 
o Tigecycline + Colistin: 0.6% (1) 
• OPAT: 14% (24) 
• Average length of antimicrobial treatment time: 72.6 days 
• Average length of hospital stay: 77.9 days 
• Adverse events 
o Some adverse event: 21.6% (37) 
o Change of microbial drug due to adverse event: 3.5% (6) 
 
 
 

• Outcome 
o After 1 year (favorable X unfavorable) 
o Favorable: 53.8% (92) 
o After 1 year (detailed) 
o Remission: 53.8% (92) 
o Relapse: 15.2% (26) 
o Amputation: 14.6% (25) 
o Loss of follow-up: 12.3% (21) 
o Death related to A. baumannii infection: 3.5% (6) 
o Death not related to A. baumannii infection: 0.6% (1) 
2. Comparative analysis of cases of osteomyelitis by A. baumannii XDR treated with 
either colistin or tigecycline 
For this analysis, the 65 patients with  XDR A. baumannii -related osteomyelitis, always 
resistant to carbapenems, treated with colistin or tigecycline were included. The choice of 
antimicrobial was at the discretion of the attending physicians responsible for each patient 
during their hospitalization and was not influenced by this study, since this is a retrospective 
analysis.  
Baseline characteristics of each group were compared, according to : 
- 
demographic variables and clinical characteristics already described above,  
- 
tincidence of adverse events related to the treatment and  
- 
outcomes of the patients according to the antimicrobial used. 
Quantitative characteristics were described according to groups using summary 
measures (mean ± standard deviation or median (minimum; maximum) and compared between 
groups using Student's t-tests or Mann-Whitney tests. Qualitative characteristics of the patients 

were described according to groups using absolute and relative frequencies, association 
between groups were tested using chi-square or exact tests (Fisher's exact test or likelihood 
ratio test). The software used for the analysis was Microsoft-SPSS for Windows version 20.0. 
Microsoft Excel 2003 was the software used for data tabulation. Tests were performed at a 
significance level of 5%. 
Table 3 shows the distribution of the 65 patients according to each treatment group 
(colistin or tigecycline) regarding demographic variables and clinical characteristics. In the group 
of patients treated with tigecycline, the frequency of men was statistically lower than in the 
group treated with colistin (p = 0.028). In the group of patients treated with tigecycline, there 
were also predominance of smokers (p = 0.021) and patients with chronic osteomyelitis (p = 
0.036). 
Table 3 - Distribution of patients with XDR A. baumannii osteomyelitis according to demographic and clinical characteristics and comparison 
according to treatment group (colistin or tigecycline). 
Variable 
Treatment group 
Total (N = 65) 
p 
Colistin (N = 34) 
Tigecycline (N = 31) 
Sex (Male) 
29 (85,3) 
19 (61,3) 
48 (73,8) 
0,028 
Age (years) 
40,6 ± 19,1 
46,8 ± 18,9 
43,6 ± 19,1 
0,193** 
Length of hospital stay (days) 
74,5 (13; 331) 
64 (0; 226) 
70 (0; 331) 
0,948£ 
Charlson index 
0 (0; 5) 
1 (0; 7) 
0 (0; 7) 
0,083£ 
Presence of comorbidity 
10 (29,4) 
13 (41,9) 
23 (35,4) 
0,292 
Systemic hypertension 
6 (17,6) 
9 (29) 
15 (23,1) 
0,277 
Neoplasia 
2 (5,9) 
3 (9,7) 
5 (7,7) 
0,663* 
Diabetes 
4 (11,8) 
2 (6,5) 
6 (9,2) 
0,674* 
HIV 
0 (0) 
2 (6,5) 
2 (3,1) 
0,224* 
Rheumatoid arthritis 
2 (5,9) 
1 (3,2) 
3 (4,6) 
>0,999* 
Systemic lupus erythematosus 
0 (0) 
0 (0) 
0 (0) 
a 
Ankylosing spondylitis 
0 (0) 
0 (0) 
0 (0) 
a 
Other rheumatic diseases 
0 (0) 
1 (3,2) 
1 (1,5) 
0,477* 
Use of immunosuppressive drugs 
1 (2,9) 
1 (3,2) 
2 (3,1) 
>0,999* 
Chemotherapy 
0 (0) 
0 (0) 
0 (0) 
a 
Chronic Renal Disease 
0 (0) 
0 (0) 
0 (0) 
a 
Previous SSI in the affected segment 
10 (29,4) 
7 (22,6) 
17 (26,2) 
0,531 
Injectable drug abuse 
0 (0) 
1 (3,2) 
1 (1,5) 
0,477* 
Smoking 
0 (0) 
5 (16,1) 
5 (7,7) 
0,021* 
Alcohol abuse 
2 (5,9) 
4 (12,9) 
6 (9,2) 
0,413* 
Previous orthopedic surgery in the affected segment 
10 (29,4) 
14 (45,2) 
24 (36,9) 
0,189 
Affected Segment 
  
  
  
0,414 
   Lower limbs 
29 (85,3) 
24 (77,4) 
53 (81,5) 
  
   Upper limbs 
5 (14,7) 
7 (22,6) 
12 (18,5) 
  
Other agents detected 
24 (70,6) 
21 (67,7) 
45 (69,2) 
0,804 

Classification of osteomyelitis Lima and Zumiotti 
  
  
  
0,841# 
   Post-traumatic 
23 (67,6) 
19 (61,3) 
42 (64,6) 
  
   Contiguity 
7 (20,6) 
9 (29) 
16 (24,6) 
  
   Hematogenic 
2 (5,9) 
2 (6,5) 
4 (6,2) 
  
   Spine 
2 (5,9) 
1 (3,2) 
3 (4,6) 
  
Time classification of osteomyelitis 
  
  
  
0,036 
   Acute 
22 (64,7) 
12 (38,7) 
34 (52,3) 
  
   Chronic 
12 (35,3) 
19 (61,3) 
31 (47,7) 
  
Antecedent of open fracture 
17 (50) 
10 (32,3) 
27 (41,5) 
0,147 
Infection in pressure ulcer 
6 (17,6) 
4 (12,9) 
10 (15,4) 
0,736* 
Antecedent of closed fracture 
1 (2,9) 
4 (12,9) 
5 (7,7) 
0,184* 
ASA Classification 
  
  
  
0,189 
   I 
11 (32,4) 
8 (25,8) 
19 (29,2) 
  
   II 
20 (58,8) 
15 (48,4) 
35 (53,8) 
  
   III 
3 (8,8) 
8 (25,8) 
11 (16,9) 
  
Number of surgical procedures for treatment 
3 (1; 12) 
3 (1; 9) 
3 (1; 12) 
0,510£ 
Presence of implant 
6 (17,6) 
3 (9,7) 
9 (13,8) 
0,480* 
Need to remove the implant 
4 (11,8) 
9 (29) 
13 (20) 
0,082 
Need for soft tissue repair 
10 (29,4) 
8 (25,8) 
18 (27,7) 
0,746 
Use of negative pressure therapy 
12 (35,3) 
6 (19,4) 
18 (27,7) 
0,151 
Hyperbaric oxygen use 
1 (2,9) 
0 (0) 
1 (1,5) 
>0,999* 
Pain 
6 (17,6) 
7 (22,6) 
13 (20) 
0,619 
Hyperemia 
9 (26,5) 
4 (12,9) 
13 (20) 
0,172 
Local elevated temperaure 
2 (5,9) 
1 (3,2) 
3 (4,6) 
>0,999* 
Fistula 
19 (55,9) 
19 (61,3) 
38 (58,5) 
0,659 
Edema 
1 (2,9) 
4 (12,9) 
5 (7,7) 
0,184* 
Fever 
4 (11,8) 
9 (29) 
13 (20) 
0,082 
Use of antimicrobial before A. baumannii infection 
34 (100) 
30 (96,8) 
64 (98,5) 
0,477* 
Other antimicrobials used 
29 (85,3) 
23 (74,2) 
52 (80) 
0,264 
Need for OPAT 
4 (11,8) 
9 (29) 
13 (20) 
0,082 
Baseline Creatinine 
0,69 ± 0,36 
0,82 ± 0,54 
0,75 ± 0,45 
0,260** 
Full treatment lenght (days) 
42,5 (1; 193) 
42 (9; 193) 
42 (1; 193) 
0,438£ 
Data expressed as n (%), mean ± SD or median (min, max.); Chi-square test; * Fisher's exact test; # Likelihood ratio test; ** Student's t-test; £ Mann-Whitney test; a There 
are no cases to estimate 
 
 
 
Regarding the registered adverse events, table 4 shows the comparison between the 
two treatment groups. It is possible to observe that the general incidence of adverse events was 
higher in the group of patients treated with colistin (p = 0.047), as well as the incidence of renal 
impairment (p = 0.003). The incidence of nausea and vomiting was higher in the group of 
patients treated with tigecycline (p = 0.046). 
 
 

Table 4 - Comparison of incidence of adverse events during treatment for patients receiving colistin or tigecycline 
Variable 
Treatment group 
Total (N = 65) 
p 
Colistin (N = 34) 
Tigecycline (N = 31) 
Overall adverse events 
23 (67,6) 
13 (41,9) 
36 (55,3) 
0,047 
Renal impairment 
20 (58,8) 
7 (22,6) 
27 (41,5) 
0,003 
Liver abnormalities 
1 (2,9) 
1 (3,2) 
2 (3,1) 
>0,999* 
Nausea 
0 (0) 
4 (12,9) 
4 (6,2) 
0,046* 
Neural alterations 
0 (0) 
0 (0) 
0 (0) 
a 
Skin rash 
1 (2,9) 
0 (0) 
1 (1,5) 
>0,999* 
Other 
5 (14,7) 
2 (6,4) 
7 (10,7) 
0,430 
Data expressed as n (%) or mean ± SD; Chi-square test; * Fisher's exact test; ** Student's t-test; a There are no cases 
to estimate 
 
Due to the characteristics of the osteomyelitis evolution, the treatment outcome was 
assessed based on the patient's evaluation 12 months after the end of the treatment. Evaluated 
outcomes were remission of the infection (absence of signs and symptoms compatible with 
osteomyelitis activity), relapse (patient returning with signs and symptoms of infection up to 12 
months after treatment), amputation, death and loss of follow-up. The outcomes were also 
evaluated in a dichotomous way, being considered remission as a favorable outcome and 
recurrence, amputation and death and as unfavorable outcomes. Patients who presented loss 
of follow-up were analyzed in two ways: as a separate outcome and as part of unfavorable 
outcomes. There were no significant differences between the two treatment groups in these 
analyzes, as can be seen in Tables 5 and 6. 
Table 5 - Distribution of the outcomes after 12 months of treatment according to the antimicrobial group 
Outcome 
Treatment group 
Total (N = 65) 
p 
Colistin (N = 34) 
Tigecycline (N = 31) 
Remission 
15 (44,1) 
12 (38,7) 
27 (41,5) 
0,801 
Death 
2 (5,8) 
3 (9,6) 
5 (7,7) 
0,663 
Recidive 
5 (14,7) 
6 (19,3) 
11 (16,9) 
0,744 
Amputation 
7 (20,6) 
2 (6,45) 
9 (13,8) 
0,152 
Loss of follow-up 
5 (14,7) 
8 (25,8) 
13 (20) 
0,355 
Data expressed as n (%); Chi-square test to estimate 
  
  
  
 
 

Table 6 - Dichotomic distribution of the outcomes after 12 months of treatment according to the antimicrobial 
group  
Outcome 
Treatment group 
Total (N = 65) 
p 
Colistin (N = 34) 
Tigecycline (N = 31) 
Outcome  
  
  
  
0,535 
    Unfavorable 
14 (41,2) 
11 (35,5) 
25 (38,5) 
  
    Favorable 
15 (44,1) 
12 (38,7) 
27 (41,5) 
  
    Loss of follow-up 
5 (14,7) 
8 (25,8) 
13 (20) 
  
Outcome  
  
  
  
0,659 
    Unfavorable 
19 (55,9) 
19 (61,3) 
38 (58,5) 
  
    Favorable 
15 (44,1) 
12 (38,7) 
27 (41,5) 
  
Data expressed as n (%); Chi-square test to estimate 
  
  
  
 
Analysis of presented data allows us to conclude that, in this sample of patients studied, 
tigecycline presented a better safety profile than colistin for the treatment of osteomyelitis 
related to XDR carbapenem resistant A. baumannii. Both antimicrobial presented similar 
efficacy. The data presented in this report will be submitted for scientific publication.