Acinetobacter Baumannii-related Osteomyelitis: Clinical and Epidemiological Characterization

Acinetobacter baumannii is an opportunist pathogen that has become increasingly important over recent years as a cause of nosocomial infections. Ventilator-associated pneumonia, central line-associated bloodstream infection and bone and soft tissue infections secondary to open fractures are among the conditions most associated with this agent .

Attention is drawn not only to the increasing incidence of this agent over the last few years but also to the rapid worsening of its susceptibility to antimicrobial agents, including carbapenems. Few therapeutic options are available for treating pan-resistant strains: colistin and tigecycline has been used, but resistance to these options frequently emerges in clinical practice. Taking into account the fact that fewer new antimicrobial agents are being validated and introduced into clinical practice, the growing prevalence of isolates with these high levels of resistance is becoming a matter of increasing concern.

Certain risk factors have also been correlated with infection related to A. baumannii. The most important are prolonged hospitalization in intensive care units and use of invasive devices. Another important risk factor is severe trauma: A. baumannii is associated with invasive infections, including osteomyelitis following open fracture reduction. Studies that included military personnel and civilians involved in the recent conflicts in Iraq and Afghanistan have shown high prevalence of A. baumannii as causative agent in cases of osteomyelitis secondary to traumatic injuries. Also, in Brazil, a retrospective study that analyzed 101 cases of osteomyelitis due to Gram-negative bacilli showed that A. baumannii was the second most prevalent agent and that it had a high degree of antimicrobial resistance, particularly to carbapenems.

The objectives of this retrospective study are: 1. clinically and epidemiologically characterize 241 patients with osteomyelitis related to A. baumannii who were admitted at the Institute of Orthopedics and Traumatology, Hospital das Clínicas, University of São Paulo; 2. to describe the antimicrobial susceptibility profile of A. baumannii strains isolated; 3. to evaluate the patients' outcomes (remission, recurrence, limb amputation or death) according to the antimicrobial treatment used, including tigecycline; 4. to compare efficacy and safety profiles of tigecycline, colistin and ampicillin-sulbactan among patients with carbapenem-resistant A. baumannii related osteomyelitis.

INTRODUCTION Acinetobacter baumannii is an opportunist pathogen that has become increasingly important over recent years as a cause of nosocomial infections (1,2). Ventilator-associated pneumonia, central line-associated bloodstream infection and bone and soft tissue infection secondary to open fractures are among the conditions most associated with this agent.

Attention is drawn not only to the increasing incidence of this agent over the last few years but also to the rapid worsening of its susceptibility to antimicrobial agents, including carbapenems. Among the striking characteristics of this species is its high capacity to develop antimicrobial resistance. The most important types of resistance are, firstly, intrinsic resistance related to the association between diminished permeability of the external membrane and constitutive expression of efflux pumps; and secondly, acquisition of genetic elements, which might be resistance genes or insertion elements that, in association with the chromosomal genes of this bacterium, can trigger expression of resistance and great ability to survive in the environment, which is commonly related to production of biofilm (7). All these characteristics have been correlated with emergence of multiresistant and pan-resistant strains of A. baumannii. Few therapeutic options are available for treating pan-resistant strains: colistin and tigecycline has been used, but resistance to these options frequently emerges in clinical practice. Taking into account the fact that fewer new antimicrobial agents are being validated and introduced into clinical practice, the growing prevalence of isolates with these high levels of resistance is becoming a matter of increasing concern. The formerly abundant flow of provision of new antibiotics of ever-broader spectrum has been shown to be a non-renewable resource.

Certain risk factors have also been correlated with occurrence of A. baumannii. The most important are prolonged hospitalization in intensive care units and use of invasive devices .Another important risk factor is severe trauma: A. baumannii is associated with invasive infections, including osteomyelitis following open fracture reduction. Studies that included military personnel and civilians involved in the recent conflicts in Iraq and Afghanistan have shown high prevalence of A. baumannii as causative agent in cases of osteomyelitis secondary to traumatic injuries. Also, in Brazil, a retrospective study that analyzed 101 cases of osteomyelitis due to Gram-negative bacilli showed that A. baumannii was the second most prevalent agent, showing a high profile of antimicrobial resistance, particularly to carbapenems.

At the Institute of Orthopedics and Traumatology, Hospital das Clínicas, University of São Paulo, a Brazilian reference center that provides care for high-complexity orthopedic cases, 241 cases of osteomyelitis related to A. baumannii were treated between 2007 and 2014. All cases had microbiological confirmation, with positive cultures of bone tissue.

OBJECTIVES

1. Clinical and epidemiological characterization of 241 cases of osteomyelitis related to A. baumannii who were admitted at the Institute of Orthopedics and Traumatology, Hospital das Clínicas, University of São Paulo;
2. To describe the antimicrobial susceptibility profile of A. baumannii strains isolated;
3. To evaluate the patients' outcomes (remission, recurrence, limb amputation or death) according to the antimicrobial treatment used, including tigecycline.
4. To compare efficacy and safety profiles of tigecycline, colistin and ampicillin-sulbactan among patients with carbapenem-resistant A. baumannii related osteomyelitis.

METHODS This study will include data about all 241 patients with A. baumannii-related osteomyelitis admitted at our institution from 2007 to 2014. According to the institution´s protocol, diagnosis of osteomyelitis was based on the clinical history, infectious signs and symptoms and positive culture of bone tissue for A. baumannii. Bone samples were obtained from biopsy fragments identified as bone or medullary canal tissue (cortical bone and medullary canal aspirates) obtained through surgical procedures. All specimens were sent to the microbiology laboratory in thioglycolate culturing medium. The first reading was made 24 hours after incubation started and if the samples showed bacterial growth, the material was seeded in blood agar and MacConkey agar media. Bacterioscopic examinations were also performed. Subsequently, Gram-negative bacteria were identified by means of Vitek. Non-fermenting and Gram-positive bacteria were identified manually and a susceptibility test was performed using disk-diffusion. The minimum inhibitory concentrations were released in accordance with the CLSI criteria.

The following variables will be collected and analyzed for clinical characterization and outcomes evaluation:

• Gender;
• Age;
• Affected bones;
• Time of disease symptoms until hospital admission;
• Osteomyelitis-related symptoms;
• Previous antimicrobial use (before A. baumannii-positive culture);
• Classification of osteomyelitis (according to Waldwogel´s system);
• Presence of comorbidities (diabetes mellitus, active neoplasia, HIV infection, intravenous drug use, smoking, peripheral venous/arterial disease, alcoholism, open fracture, previous orthopedic surgery, imunossupressive conditions);
• ASA score;
• A. baumannii susceptibility profile;
• Antimicrobial drugs prescribed for A. baumannii-related infection;
• Antimicrobial drugs prescribed for concomitant infections;
• Antimicrobial-related side effects;
• Creatinine evolution following A. baumannii-related infection treatment;
• ESR, CPR and hemogram evolution following A. baumannii-related infection treatment;
• AST and ALT evolution following A. baumannii-related infection treatment;
• Radiological evolution of affected bone following A. baumannii-related infection treatment;
• Outcomes 6-month after A. baumannii-related infection treatment (disease remission, amputation of the affected limb, infection relapse, death and loss to follow-up). Disease remission will be defined as absence of signs of infection at the end of follow-up period.

Data analysis will be descriptive for all above mentioned variables among the 241 patients with A. baumanni-related osteomyelitis. Among those with infection related to carbapenem resistant-isolates, the variables concerning safety and efficacy of chosen antimicrobial regimen, colistin, ampicillin-sulbactan or tigeciclyne (antimicrobial-related side effects; creatinine evolution; ESR, CPR and hemogram evolution will be compared using chi-square test or Fisher's exact test for categoric variables and ANOVA test for continuous variables. Radiological variables and outcomes will be compared using chi-square test or Fisher's exact test.

Inclusion Criteria:

1. Microbiologically confirmed osteomyelitis related to Acinetobacter baumannii

Exclusion Criteria:

1. Impossibility to review data in medical records;
2. Culture results with A. baumannii considered as colonization.