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Treatment of combat-related traumatic chronic osteomyelitis with tigecycline: a case series

Jamal Ahmad Wadi.1*, Yaseen Alastal 2, Hasan Tayyem, Mohd J. Al-Humaidi4

1*. Jordan Hospital and Medical Center 29 Adeeb Wahbah Street Amman, Jordan 11118. 2. Internal Medicine Department, The Specialty Hospital. 3. Pharmacy Department, The Specialty Hospital. 4. Surgical Department, The Specialty Hospital. * Correspondence:

jamalwadimd@yahoo.com

Abstract
Objective: to evaluate the efcacy of tigecycline treatmentin Combat-Related
Traumatic Chronic Osteomyelitis (CRTCO).

Methods: a retrospective study evaluates tigecycline the treatment of CRTCO.

Cases charts were reviewed for patients who were treated over the period 2011June 2012. During the tigecycline treatment period, orthopedic surgeons taking care of patients were not informed about the pending study.

Results: ten cases were included (one female and nine males), their mean age 45.5
years. The most common bones with CRTCO were the femur followed by the tibia. Microbiological diagnoses were obtained mostly from culture of bone biopsies and bone swabs. Bacteria isolated were identied as Acinetobacter spp. [6], Klebsiella pneumoniae [6], Escherichia coli [5], Pseudomonas aeruginosa [4], Enterococcus spp. [3] and Staphylococcu saureus. The mean duration of Tigecycline treatment was 35.7 days (range 21-91). Patients were treated with other antimicrobials prior to tigecycline for an approximate mean duration of 467 days (range2-1825) (how you obtained this data?). Reasons for switching to tigecycline were due to clinical failure in all patients, in addition to side effects and microbiological failure of previous regimen. Paired difference of the ESR for eight available patients pair was not signicant (p = 0.055), the same was observed for CRP (p = 0.9). There were seven (70%) clinically cured or improved patients with tigecycline treatment by the end of the study.

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Conclusion: CRTCO is a polymicrobial infection mostly caused by Gram-negative bacilli. The outcome of treating these patients with tigecycline is promising.

Introduction
Combat-related traumatic chronic osteomyelitis (CRTCO) is characterized by contaminated wounds; bones are usually shattered into many pieces, bone loss, shrapnel and the presence of necrotic bone and compromised soft tissues, occasional sinus tract with drainage. Surgical interventions are frequently needed, and the majority of patients need some form of prosthetic hardware to stabilize fractured bones, and infection is frequently polymicrobial, adding to management difculties. Bone biopsy for microbiological examination is of Under License of Creative Commons Attribution 3.0 License

the utmost importance. In addition, aspiration of occasionally existing uids surrounding the inammation would help in obtaining accurate microbiological diagnosis [1, 2, 3, 4]. During early 2011-June 2012, many Arab patients were referred to hospitals in Amman, Jordan for the management of complicated traumatic wounds with chronic osteomyelitis. Some referred patients had CRTCO, mostly infected with polymicrobial multidrug resistant bacterial infections. The treatment of these patients is tedious and most need parenteral broad-spectrum antimicrobials for extended periods.

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The normal accepted period of treatment for chronic osteomyelitis is six weeks, in conjunction with surgical debridement. Although a few reports found no signicant difference for regimens employed for less than six weeks. Nevertheless, the treatment duration of CRTCO remains undened and controversial [5, 6, 7]. Many antimicrobials are useful in the treatment of chronic osteomyelits with variable success rates, whether with parenteral or oral agents [8, 9]. In the last decade, the introduction of tigecycline has added to the antimicrobial armamentarium. Tigecycline belongs to the family of Glycylcyclines, a minocycline derivative, with extended-spectrum activity. This drug evades the resistance mechanisms that the parent compound was susceptible to, i.e., tetracycline-specic efux pump acquisition and ribosomal change [10]. Tigecyclines antimicrobial spectrum includes aerobic and anaerobic bacteria; including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumonaei as well as extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacteria [10, 11]. The labeled indications of tigecycline include complicated abdominal infections, skin and skin structure infections and mild to moderate community-acquired pneumonia [12-14]. The drug may be suitable for use in infections with multidrug resistant bacteria, and it has good bone concentration as well as good penetration in surrounding tissues due to its large volume of distribution. When tested by using single dose kinetic study in a rabbit bone model, infected bones have signicantly (P = 0.05) higher tigecycline concentrations [15]. This study investigates the effectiveness of tigecycline treatment in those patients with CRTCO and multidrug resistant (MDR) polymicrobial infections.

symptoms obviating the need to continue with other antimicrobials. Partially improved patients included those who had been mitigated, but judged by their orthopedic surgeon either not to be completely improved or were discharged with oral antimicrobials. Some patients were contacted by telephone few months after discharge and return to their home countries in order to follow up on their progress. Unimproved patients were those that were switched to other antimicrobials. Culture specimens were collected from bone biopsy, bone swabs or the immediate surrounding soft tissues uid aspiration or sinus-tract cultures. Culture specimens were processed in the hospital microbiology laboratory by inoculation into thioglycolate broth and incubation for ve days for the presence of bacterial growth; First sub culture of specimens from the broth was done after forty-eight hours of incubation by inoculation into MacConkey, chocolate agar and blood agar. Gram-positive bacteria colonies were tested for coagulase and are further identied and by Viteck II. Gram-negative lactose-fermenters grown on MacConkey were further identied with ViteckII, whereas Non-lacose fermenters were idented by oxidase reaction and then with Viteck II. Antibiotic susceptibility test was processed by the automated Viteck II (BioMrieux SA. F-69280Marcy lEtoile, France).

Statistical methods
Data were processed in Microsoft excel spread sheet. Isolated bacteria from different sources were considered based on the likelihood of the infecting pathogen/s .Odds ratio and relative risks were calculated for the likely isolated Gram-negative bacteria pathogen. SSPS was used for ESR and CRP, both measured before and after treatment, differences among each were calculated as paired ones. Two tailed t-student test and 95% condence interval were calculated for the paired differences. Signicance is considered for p< 0.05.

Materials and Methods

Study structure and patients
A retrospective study was conducted in the Specialty teaching hospital in Amman, Jordan. Patients who suffered from CRTCO were included. The aim was to evaluate tigecycline efcacy in the treatment of CRTCO. Cases were reviewed for all combat-traumatized patients who were admitted and treated over the period (2011-June 2012). Orthopedic surgeons taking care of patients prescribed tigecycline at their discretion on compassionate basis. Chronic osteomyelitis was dened based on criteria described by Maderet al., and by excluding patients who did not have diagnostic criteria of chronic osteomyelitis as described [1]. Clinical improvement was dened as a signicant clinical mitigation of the patients

Results
Ten cases were included in this study (one female and 9 men), with a mean age of 45.5 (range 20-70) years. Bones with CRTCO were; femur (6) patients, tibia (3), and one others. Microbiological diagnosis of infected patients was obtained by culturing bone biopsy specimens (4), bone swabs (4) and sinus swab ( Table 1). The following pathogens were recovered; Acinetobacter spp. [6], Klebsiella pneumonia [6], Escherichia coli [5], Pseudomonas aeruginosa [4], Enterococcus spp. [3], Staphylococcus aureus [1] and others bacteria species (3) ( Table 2). The mean tigecycline-treatment duration was 35.7 days (range 21-91). All patients were on other antimicrobials before receiving tigecycline with mean duration of 467 days (range 2-1825). Reasons for switching to tigecycline Under License of Creative Commons Attribution 3.0 License

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Table 1. Demography and characteristics of the ten patients with chronic osteomyelitis who were treated with tigecycline.
Duration Site of Source of of Osteomyelitis Culture tigecycline No. of Surgeries Reasons for switching to tigecycline Clinical failure and side effects of previous regimen Clinical & Microbiological failure

Case

Age

Gender

Prosthesis#

Improvement@

70

Male

21

Tibia

Bone

No

Yes (Partial)

34

Male

33*

Femur

Bone

Yes

Yes (Partial)

20

Male

40

Femur

Sinus

Yes

NA

Yes (Partial)

51

Male

21*

Others

Sinus

10

No

Clinical failure

No

64

Male

32

Femur

Bone

3.

Yes

Clinical failure

Yes

29

Male

28

Femur

Bone

NA

No

Clinical failure and side effects of previous regimen

Yes

59

Male

91*

Tibia

Bone

22

Yes

Clinical failure

No

39

Male

30*

Femur

Bone

No

Clinical failure and side effects of previous regimen Clinical and Microbiological Failure Clinical failure and side effects of previous regimen

No

23

Male

19

Tibia

Bone

No

Yes

10

66

Female

42*

Femur

Bone

Yes

Yes

@ Refer to text under Study structure and patients for denition of improvement. * Added antimicrobials to tigecycline included: Ceftazidime, Pipracillin/tazobactam, Ciprooxacine, Imipenem and Amikacin. # Prosthesis included plates, screws, intramedullary nails, wires, and external xators Mean and range of osteomyelitis diagnosis before switching to tigecycline: 467.37 (2 1825) days Patients mean age and range: 45.5 (20-70) years Mean and range duration of tigecycline treatment: 35.7 (21 -91) days NA: Not available

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Table 2. Number and frequency of microbiological isolationand their source frequency per microorganism in patients with chronic osteomyelitis who were treated with tigecycline
Microorganism Staphylococcus aureus Escherichia coli Pseudomonas aeruginosa Acinetobacter spp Klebsiella pneumoniae Enterococcus spp. Enterobacterspp Citrobacter spp. Bacterial Isolates Frequency and (%) 1 (3.57) 5 (17.85) 4 (14.28) 6 (21.42) 6 (21.42) 3 (10.71) 2 (7.14) 1 (3.57) Culture Sources Bone Biopsy Bone Biopsy 2 Bone Swab 2 Supercial Swab 1 Bone Biopsy 4 Bone Biopsy 4 Bone Swab 2 Bone Biopsy 4 Bone Swab 1 Sinus Swab 1 Bone Biopsy 2 Bone Swab 1 Bone Swab 1 Sinus Swab1 Bone Swab

Odds ratio for encountering a gram-negative bacteria = 69.4, Relative risk = 8.3 Monomicrobial isolation was in one patient with E. coli and the rest of patients showed polymicrobial growth pattern. Polymicrobial cultures came from all sources, mostly (60%) from bone biopsy.

Table 3. Number and rates of improvement in ten patients with chronic osteomyelitis treated with tigecycline.
Clinical Outcome* Improved Improved (partial) Not improved Tigecycline No. (%) 4 (40) 3 (30) 3 (30)

were seven cases (70%) and no data were available on follow up cultures three of them were partially improved; though described as improved and were discharged on oral treatment ( Table 3).

Discussion
War traumas usually involve fractured bones with complications including CRTCO. Caring for those patients is hampered by wound being contaminated by poor treatment conditions in the combat eld and initial treatment stations. Hence, referred patients often harbor MDR organisms [4, 17]. Our patients exhibited polymicrobial infections, dominated by MDR Gram-negative bacteria ( Table 2). A similar study has reported that coagulase-negative staphylococci accounted for 9% of all isolates recovered from patients with CRTCO during the Iraqi war [16, 17]. A review article by Murray and Hospenthal [18] had also shown similar patterns of predominant Gram-negative bacterial infections to those reported in this study The results of our cases demonstrate that seven (70%) of tigecycline-treated patients improved on follow-up for up to six months after end of treatment. A literature review of on CRTCO treatment did not reveal any studies addressing the treatment Under License of Creative Commons Attribution 3.0 License

* Refer to text under Study structure and patients for denition of improvement.

were due to clinical failure in all patients, in addition to side effects of previous regimen in four and persistence of infection in other patients. ESR paired differences for eight available values: Mean difference 25.6, DF = 7, Two-tailed t = 2.23, p = 0.055, 95% C.I. (- 0.73 to 51.98). Paired difference for CRP were; mean= 3.07, DF = 7, two-tailed t-test = 0.130, p = 0.9, and 95% C.I. (-53 to 59) ( Table 4). Numbers of surgeries were variable ranging from 1 to 22 surgeries including major dressing and debridement in a clinically treatmentfailed patient. Prosthesis (plates, screws, intramedullary nails and external xtures) were used in ve patients, one was among clinical failures ( Table 1). Clinically improved patients

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Table 4.  Laboratory inammatory parameters for the ten patients with chronic osteomyelitis who were treated with tigecycline, and their paired difference signicance tested by p-value and 95% condence interval.
Case Number 1 2 3 4$ 5 6 7$ 8$ 9 10 ESR before treatment NA 54 12 113 29 43 121 115 37 54 ESR Mean for the difference Degree of Freedom Two tailed t-test P Value 95% Condence Interval NA: Not available $: Cases clinically judged not improved 25.6 7 2.23 0.055 - 0.73 52 ESR after treatment NA 51.00 10.00 106.00 2.00 12.00 22.00 95.00 NA 38.00 CRP Before Treatment NA 145.0 2.6 26.0 8.7 37.0 111.0 16.3 3.9 89.9 CRP 3.07 7 0.130 0.9 -53 - 59 CRP After Treatment NA 120.00 2.90 8.20 32.00 3.00 23.00 163.00 NA 104.49 WBC 7.20 10.0 6.20 8.10 7.30 7.50 8.20 10.9 7.10 12.3

Paired Difference For Eight Patients With Available Paired ESR and CRP

outcomes of different antimicrobials. An interesting nding in our case series is that there was no signicant difference in paired comparisons for ESR (p = 0.055) and CRP (p = 0.9) in the seven patients in whom their clinical conditions improved completely by the end of therapy. In conclusion, CRTCO is a polymicrobial infection mostly caused by MDR Gram-negative bacilli. The outcome of treating CRTCO with tigecycline is promising, but controlled trials are needed to compare the efcacy of different antimicrobials in the treatment of these difcult-to-treat infections.

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