Antibiotic prophylaxis in obese patients submitted to bariatric surgery . A systematic review

PURPOSE: To review the use of cefazolin in prophylaxis of surgical wound infection (SSI) in bariatric surgery (BS). METHODS: A systematic review was performed from October to November, 2013 using the following databases: The Cochrane Library, Medline, LILACS, and EMBASE. The inclusion criteria were randomized clinical trials and observational studies that were evaluated by two independent reviewers. RESULTS: Nine hundred and sixty one titles were recovered after preliminary analysis (title and abstract), seven studies remained for final analysis. There were three clinical trials (one with SSI, and two with antibiotic levels as the outcome), and four were observational studies (three cohorts and one case-control, all had SSI as the outcome). After administration of 1g or 2 g, levels of cefazolin in serum and tissue were suboptimal according to two studies. Results from observational studies indicated that different antibiotics were used for prophylaxis of SSI in BS and that use of other drugs may be associated with higher rates of SSI. CONCLUSION: The use of cefazolin for surgical wound infection prophylaxis in bariatric surgery is recommended, however further studies are needed in order to refine parameters as initial dose, redose, moment of administration and lasting of prophylaxis.


Introduction
Obesity is considered a chronic disease and is reaching epidemic proportions in developed and developing countries 1,2 .
It represents an important burden of disease from clinical and public health perspective 3 .A long term strategy is required for its prevention and it must be managed with a comprehensive approach 1 .Obesity is associated to increase mortality and morbidity 1,4 , and this condition is frequently not controlled by diet and pharmacologic therapy.Bariatric surgery, however, is being shown to be more effective in sustained weight reduction 5 which increases the demand for surgical intervention in these patients 6 .
Although obesity is considered a risk factor for nosocomial infections 4,7 particularly surgical site infection (SSI), there were few studies that have evaluated this specific factor among patients submitted to bariatric surgery 7,8 .It is considered one of the most common complications in bariatric surgery 5,9 , and its magnitude may be underestimated 5 .The frequency of SSI in obese patients ranges from 1-21.7% after bariatric surgeries 4,5,7,10,11 , depending on the surgical technique applied 7 .It is important to consider that in these studies there is a poor standardization of antibiotic agents and its posology.
The factors that have been associated to an increase in the risk of post-surgical infections are usually identified as the evaluation of individual risk of the patient, the transoperatory period and procedures that are carried out 9 .Surgical site and prevailing microorganisms drive the antibiotic choice for prophylaxis 9 .The most frequent species isolated from postsurgical infections in bariatric surgery are Staphylococcus spp 10,12 and Streptococcus species 7,10 .
First generation cephalosporin's, due to spectrum, safety and experience of use, are the choice in the prophylaxis of most of surgeries 4 .A recent guideline issued by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Surgical Infection Society and the Society for Health Care Epidemiology of America recommends cefazolin for procedures involving entry into lumen of gastrointestinal tract (as in bariatric surgery), with strength of evidence "A" 13 .This drug is, indeed, widely employed 4,5,8,11,14,15 .
Despite the recommendations indicating the use of cefazolin, other drugs and regimens are also employed.In a large observational study, a total of 37 different antibiotic regimens were found for prevention of SSI in bariatric surgery 7 , indicating that, although cefazolin is the most recommended drug, other options are widely used.
Cefazolin presents a half-life of two hours, giving protection for longer surgeries.It has anti-staphylococcal activity and is the preferred agent in gastrointestinal surgeries in high risk patients (i.e.obesity) 4 .Besides, it is a low cost drug.According to some authors, 2g of cefazolin should be administered in morbidly obese patients; however there is a concern if this dose is sufficient for all patients, considering that average corporal weight is variable as it has increased in the last years 4,7,14,15 .
There is a need of qualified information not only about the agent to be employed, but also about dosage, moment of administration, posology and pharmacokinetic profile of the drug.The present scenario permits to observe the use of different antimicrobial agents, with different posology without consistent evidence, promoting conditions to an increase in bacterial resistance and related costs 4 .
The objective of this study was to review the use of cefazolin in the prophylaxis of surgical wound infection in bariatric surgery.

Methods
A systematic review was carried out from October to November, 2013searching the following databases: The Cochrane Library, Medline, LILACS and EMBASE.The first choice in terms of type of publication was randomized clinical trial and then quasi-experiment.Observational studies were also searched in order to identify those articles that had less risk of bias.After a preliminary recovery, titles and abstracts were examined by two independent reviewers.Cases of disagreement were evaluated by a third reviewer.
To evaluate the quality of reporting in observational studies and clinical trial studies STROBE 16 CONSORT statements 17 were respectively employed.

Results
Nine hundred and sixty one (961) titles were identified using the search strategy.The preliminary analysis of title and scope excluded 903 studies.After analysis of the abstract of the 58 remaining studies, 52 were considered inadequate.The remaining six studies, together with one additional included by the references analysis, were integrally analyzed.Among the three clinical trials, one had SSI as the outcome.SSI was the outcome of the four observational studies.

Clinical trials
The use of cefazolin for antibiotic prophylaxis in BS was for the first time supported by a study published more than thirty years ago by Pories et al. 11 .It was a double blind prospective randomized clinical trial with two arms: one group of patients received cefazolin intravenously, 1g 2 hours prior to surgery, at induction of anesthesia, and then 0.5g every 6 hours for 48 hours while the other group received a placebo.The study was interrupted previously than planned due to evidence that SSI was significantly less frequent in the group that received cefazolin (1/27=4% in the cefazolin group versus 5/23=21% in the placebo group, p<0.05).
The study became a state of the art on the antibiotic prophylaxis for BS and since this study cefazolin is being widely used on this procedure.We have not identified any new article since the Pories' one, in which cefazolin was confronted to placebo.
Other trials had levels of antibiotic as the outcome.Forse et al. 15 investigated the effect of the mode of administration of cefazolin (1g intramuscular, subcutaneous or intravenous) on drug serum and adipose tissue concentration and found that for all morbidly obese patients levels were significantly lower when compared to those of control (non-obese patients).It was also evident that levels were below the minimal inhibitory concentration, independent of the mode of administration.Only when patients received intravenous 2g of cefazolin prophylaxis were both serum and adipose tissue levels achieved.In a subsequent segment of the study, morbidly obese patients received 2g of cefazolin and SSI rate dropped to 5.6% compared to the previous rate of 16.5%.Levels of cefazolin were measured by Edmiston Jr et al. 14 in patients receiving 2g of cefazolin preoperatively, followed by a second dose at 3 hours in patients assigned in three groups, according to BMI.Therapeutic tissue levels were achieved in 48.1% (BMI= 40-49), 28.6% (BMI= 50-59), and 10.2% (BMI≥60), indicating that the dosing strategy may fail to provide adequate prophylaxis.
A synthesis of all clinical trials included on this review are shown on Table 1, and quality of reporting studies is shown on Table 2.

Observational studies
Three cohort and one case-control studies have described the issue of antibiotic prophylaxis in BS.The first one, a retrospective cohort, was published as a letter 18 .It did not find significant differences in rates of SSI in patients receiving 1 or 2 g of cefazolin (rates of SSI = 7.69% in the group receiving 1g and 10.3% 2g of cefazolin).The authors emphasized that there was a lack of standardization in the prescribing, administration, and duration of antibiotic prophylaxis.
In another retrospective, single center cohort 5 , with 269 individuals submitted to Roux-en-Y gastric bypass, the rate of SSI observed was 20%.Epidural analgesia and delayed antibiotic prophylaxis administration (after incision) increased the odds of SSI (1.6 and 1.9, respectively).Gender, age, BMI, duration of surgery, and diabetes, on the other hand, had no effect on SSI.
In a large (2,012 patients) prospective multicenter (nine community hospitals in the USA) cohort, with 82% of laparoscopic procedures, the overall rate of SSI was 1.4% in patients submitted to BS 7 .A total of 37 different antibiotic regimens were observed and SSI rate was higher in patients receiving vancomycin prophylaxis (relative risk = 9.4; 95% confidence interval = 3.1 -26.1, p=0.005), when compared to patients that received other antibiotics.It is interesting to observe that cefazolin was administered as the single agent in less than half of the surgeries that had antimicrobial prophylaxis recorded (864/1,989; 43%).Recently, a case-control study was used to identify factors associated to SSI in patients following Roux-en Y gastric bypass 9 .
RCT: randomized clinical trial SSI: surgical site infection Each case of SSI (n=91) was matched with three controls (n=273) in the investigation.After multivariate analysis, use of prophylaxis with antibiotics other than cefazolin (OR, 4.2; 95% CI: 1.47-11.7) was identified as a risk factor for SSI.Other variables that had a significant association with SSI included duration of surgery and comorbidities as diagnosis of bipolar disorder and sleep apnea.
The authors proposed a score to improve stratification of risk for SSI after BS.

Discussion
Cefazolin has been routinely used in the prophylaxis of infection in bariatric surgery in guidelines of hospitals worldwide Even though, there are few well designed studies available in the scientific literature to provide support for issues such as initial dose, need and rational for redose, moment of administration and lasting of prophylaxis.Only one study was placebo controlled and had SSI as the outcome.Two studies 14,15 had levels of antibiotic as the outcome and both find that levels of antibiotic in tissues were suboptimal and this observation appears consonant with the recent recommendation of an increased dose (3g) for patients weighing ≥120 kg 13 .
Observational studies were also rather heterogeneous.
Mehta's study 18 has, among its limitations, a small sample size (26 and 29 for 1 or 2 g of cefazolin, respectively).The cohort by Freeman 7 points out the high diversity and lack of standardization in antibiotic prophylaxis.The study presented some weaknesses (observational design, low rates of SSI, patients were not directly contacted during post-discharge surveillance), however strengths like multicenter design, prospective and standardized collection of data must be considered.Finally, the case-control study which was included in this review indicated that, besides use of antibiotics other than cefazolin, other variables had a significant association with SSI (duration of surgery and comorbidities as diagnosis of bipolar disorder and sleep apnea) 9 The influence in SSI of variables that are not related to antibiotic use had been identified previously in Christou's cohort 5 that showed that use of an epidural catheter for analgesia increased the risk for SSI.
Currently it would not be reasonable a placebo controlled clinical trial in this context, as the 1981 Pories' study 11 showed a significant reduction of rates of SSI and there is no antimicrobial agent that presents the necessary characteristics to replace cefazolin with some potential advantage in bariatric surgery.There is a need to emphasize that two observational studies showed that prophylactic use of antibiotics other than cefazolin were significantly associated with SSI 4,7 .

Conclusion
The use of cefazolin for surgical wound infection prophylaxis in bariatric surgery is recommended, however further studies are needed in order to refine parameters as initial dose, redose, moment of administration and lasting of prophylaxis.

CHART 1 -CHART 2 -
Terms employed (Chart 1): Mesh terms: bariatric surgery, gastric bypass, antibiotic prophylaxis, surgical site infection, cefazolin, and as free term, surgical wound infection -access: October 2013 DeCS terms: bariatric surgery, gastric bypass, antibiotic prophylaxis, cefazolin, surgical wound infection -access: October 2013 EMTREE terms: bariatric surgery, antibiotic prophylaxis, cefazolin -access: November 2013No limits were applied in the search.We also analyzed references included in articles selected (Chart 2).Databases strategy search.Flow chart of databases search.

TABLE 1 -
Articles identified and selected -clinical trials.

TABLE 2 -
Evaluation of clinical trials quality parameters according Consort statement. (cont.)

Table 3
presents a summary of observational studies and Table4shows evaluation according to Strobe Statements.