Study design
This study was a comparative, open label, prospective randomized clinical trial. It was performed to compare the efficacy, of a single dose prophylactic cefepime and ceftriaxone among patients underwent elective orthopedic surgery at BMC, Mwanza Tanzania.
Study population
The study population included all patients admitted at the BMC orthopedic wards and planned for elective orthopedic surgical procedure between June 2014 and February 2015 [15]. All orthopedic patients between 1 and 70 years of age planned for elective orthopedic surgery were considered eligible. However, patients with open contaminated fractures, history of any antibiotic use within 7 days preceding surgery, known history of hypersensitivity to beta-lactams, immunodeficiency disorders, HIV infection, pregnancy, diabetes or existing infection of soft tissue, bone or at the site of the fracture were excluded from the study.
Sample size estimation
The sample size was estimated using the formula published by Altman [16] and as used by Noordzij et al. [17]. The expected SSI rate estimates for ceftriaxone and cefepime were 2.3 % and 1.1 % respectively among patients as published by Del Rio et al. [18]. The conventional multipliers for alpha = 0.05 and multiplier for power = 0.90 were used and we considered a pre-study difference of more than 5 % between the two groups to be statistically significant. The sample size obtained was 208 patients (a minimum of 104 participants per group) and 10 % of this estimate was added to cover for non-response or loss to follow up, thus the required minimum sample size became 230 patients.
Randomization
Participants were assigned to one of two treatment groups, designated as “A” (ceftriaxone) and “B” (cefepime) using four digits, randomly generated computer numbers. Randomization to the two study arms was at 1:1 ratio. Each patient received 50 mg/kg (maximum 2 g) intravenous antibiotic given within 30 min before surgery. In case surgery lasted beyond 4 h or blood loss, surpassed 1500 mL the dose was repeated.
Null hypothesis
The treatment difference on the proportion of elective orthopedic surgery SSI in the two arms should be less or equal to ± 5 %.
Alternative hypothesis
The treatment difference on the proportion of elective orthopedic surgery SSI in the two arms should be more than ± 5 %.
Explanatory variables
Independent variables were demographic data (e.g. age, sex, and occupation), clinical presentation, ASA classification, type of orthopedic surgical procedure and implants used. In addition, duration of procedure, blood loss, type of anesthesia, wound closures, placement or removal of internal or external implants, and use of drains were also included.
Primary outcome measure
Surgical site infection was the primary end point carried out between day 3 and 30 after surgery. Two members of the orthopedic team alien to the study provided surveillance and clinical diagnosis of surgical site infection in the ward or SOPD. The CDC criteria of wound infection occurring at the incision site within 30 days after surgery and involving the skin, subcutaneous tissue, or muscle located above the fascial layer formed the basis for SSIs surveillance was used [19].
Surveillance continued for 30 days by making telephone calls and if patients reported any symptoms of wound infection patients were requested to return to the hospital for re-examination and specimen collection.
Microbiology laboratory studies
Wound discharge or pus were collected from infected surgical incisions using sterile cotton swabs without contaminating with skin commensals and was placed in a sterile bottle with transport media (Oxoid, UK). Collected samples were transported to laboratory within 1 h after being obtained. In the laboratory, specimens were registered and processed following standard laboratory procedures (SOPs) [20].
Isolates were identified using in-house biochemical tests as previously described [21, 22]. All isolates were subjected to antimicrobial drug susceptibility testing using disk diffusion method as stipulated by the Clinical Laboratory Standard Institute (CLSI) guidelines [23].
Data collection
Data were recorded on three different data sheets coded as Data Sheets A, B, and C. Data Sheet A focused on Contact information, socio-demographic information of the patient, morbid history and preoperative laboratory test results. The explanatory data captured included: age, gender, mechanism of injury, time to treatment, medical history and prior treatments, co-morbidities, smoking, alcohol use, andrecent history of antibiotic use. The attending doctor collected on or near the day of admission this information.
Sheet B contained intra-operative data regarding the treatments option for each injury, including the dates of the treatments, types of procedures, operative time, and blood loss, type of anesthesia, wound closure options, placement or removal of internal or external implants. This information on data sheet B was collectedintra-operatively corroborating with real time medical records by anesthetic and nursing staff.
Data Sheet C contained postoperative surveillance and follow-up information regarding progress, and subsequent treatment outcomes. In addition, the PI and researchassistants did transcribed phone conversations and completed progress charts during scheduled SOPD clinic visits.
Data management and statistical data analysis
Data were entered and cleaned using SPSS® version 21 (IBM Corporation) and re-assigned into STATA® Version 11 for analysis. The analysis of data involved hypothesis testing and comparison of study outcomes between cefepime and ceftriaxone groups. A statistical difference was established for a significant difference in cumulative incidence of surgical site infection between patients undergoing elective orthopedic surgery receiving peri-operative e ceftriaxone and cefepime regimen. Four parameters- cumulative incidence, incidence rate, 95 % confidence intervals and P-values were used to delineate results. Fisher’s Exact Test and P-value of analyzed data < 0.05 was considered to be statistically significant.
Cumulative incidence was calculated as the proportion of cases with SSI noted over total number of participants in each regimen under study. Incidence rate was computed by dividing the number of study subjects manifesting wound infection with total person follow-up days. Proportion test was done to determine the 95 % CI of the rates of SSI in two arms.
Data were summarized in form of proportions, and frequency tables, for categorical variables, while measures of central tendency were used to summarize continuous variables.
Ethical clearance
This trial did not involve new drugs but only determined the efficacy of a single dose regime of ceftriaxone and cefepime, however GCP and Declaration of Helsinki were observed. The study was cleared by CUHAS/BMC Research Ethics Committee with certificate no CRE/010/2014. An informed consent was obtained from participants after explaining the rationale of the study.