Antibiotic Prophylaxis in the Prevention of Surgical Site Infections After Selected Urgent Abdominal Surgical Procedures
Antibiotic Prophylaxis in the Prevention of Surgical Site Infections After Selected Urgent Abdominal Surgical Procedures
Aim of prospective randomized a placebo controlled study is to prove that in case of acute
 surgical procedure due to appendicitis, ileus of small bowel and perforation of small bowel
 and stomach appropriately administered antibiotic prophylaxis is effective with lower
 incidence of infection in surgical site and comparable risk of development of other
 nosocomial infections versus group without antibiotic prophylaxis. Secondary aim is to
 determine risk of developing nosocomial infection in the above mentioned group of patients,
 identify group of patients which does not benefit from prophylaxis, and compile financial
 costs for antibiotic prophylaxis and treatment of nosocomial infections and thus the
 background for the recommended procedure with regards that such prospective study does not
 exist in the Czech Republic.
Introduction Infection related to surgical procedure was always considered the main cause of
 mortality end morbidity in surgical patients. ATB prophylaxis has become the breakthrough in
 surgical praxis in terms of prevention of surgical postoperative complications (Surgical Site
 Infection - SSI) and radical improvement of surgical results. ATB prophylaxis prior to
 intervention procedures presents however 1/3 of costs for medicinal products and it is also
 potentially hazardous. Even single use of antibiotic agent can be a cause for development of
 nosocomial infection with indispensable mortality and costly treatment. Several
 recommendation in worldwide literature have been presented during the last 10 years which
 concerned indications and route of administration of antibiotics prior to scheduled or acute
 surgical procedure; indications for acute procedures broaden and it increases the consumption
 of antibiotics. Excessive pre-hospital and hospital exposure to antibiotics is however
 related to development of microbial resistance which shows in higher incidence of nosocomial
 infections (health care - associated infection - HAI) - urinary infections, pneumonia,
 catheter infection and another diseases such as Clostridium colitis caused by highly virulent
 type. Moreover some studies suggest bad compliance in dosing and timing of antibiotic
 prophylaxis which causes only the negative effect of prophylaxis without positive affection
 of SSI. This knowledge and disagreement led us to elaboration of protocol for prospective
 randomized placebo controlled study which could be the base for correct surgical praxis in
 investigator's conditions.

 Aim of the project The aim of this prospective randomized placebo controlled study is to
 prove the positive effect of antibiotic prophylaxis on the incidence of SSI in patients with
 comparable risk of developing other nosocomial infections in case of acute abdominal
 procedures for diagnosis such as appendicitis, ileus of small bowel and stomach or small
 bowel perforation and thus with exclusion of tertiary peritonitis. Secondary aim is to
 identify the group of patients in which risk of developing nosocomial infection exceeds
 benefit of ATB prophylaxis. Tertiary aim is to assess whether preoperative microbial
 screening has its significance for reduction of HAI. After comparing the financial cost of
 therapy (including SSI and HAI generally) it will be possible to submit background for
 proposal of recommended procedure for administration of antibiotic prophylaxis in the most
 common acute surgical procedures with regard to risk factors for genesis of nosocomial
 infections. Such prospective randomized placebo controlled study has not been conducted in
 the Czech Republic; further study with similar target group of patients (very common in
 surgical praxis) has not been published in world literature.

 Hypothesis Correctly administered antibiotic prophylaxis prior to acute abdominal procedures
 reduces frequency of SSI. It can increase the frequency of severe nosocomial infections in
 risk group of patients. rational use of antibiotic prophylaxis should however lead to
 reduction of incidence of nosocomial infections with clinical and socioeconomic impacts
 including prevention of feared severe infections associated with health care (HAI).

 Methodology

 Method is aimed at:

 1. Assessing the effect of risks to development of nosocomial infections on behalf of
 patient (ASA, morbidity, relevance of the actual disease, microbial screening targeted
 on community infection, BMI, previous hospitalization in health care facility).

 2. Assessing perioperative influence on the genesis of nosocomial infections (correct
 administration of ATB prophylaxis- protocol control, perioperative influences - blood
 loss, body temperature, extend of inflammation, SIRS sings, duration of surgery, ICU
 stay, microbial profile, analgesia, physiotherapy, complications assessment).

 3. Assessing the influence of ATB if those are correctly administered on the genesis of SSI
 in acute procedures (length of hospitalization, length of treatment and complications).

 4. Long term and socioeconomic impacts of SSI (60 days follow up, life quality assessment),
 standard proposal. After completion of patient monitoring the analysis of cost for
 hospitalization including medication, surgery and postoperative outpatient control will
 be conducted using the hospital information system.

 Appropriate patients to be enrolled in the study are all patients with following diagnosis
 operated at the site: Acute appendicitis (classical or laparoscopy appendectomy), ileus of
 the small bowel (adhesiolysis, enterotomy with suction or resection of small bowel),
 perforated stomach or duodenal ulcer (classical excision of the ulcer and suture of the GIT
 wall), i.e. patients without stercoral peritonitis. Patient will be definitely included if
 they signed the preoperative informed consent form which they were able to understand well
 and whose diagnosis was confirmed during surgery. Patients will be excluded if they are
 younger than 18 years of age, pregnant females, and patients with known allergy to
 administered ATB and also if their mental state does not allow appropriate instruction and
 signing of the informed consent and further patients who used ATB in the course of last 2
 weeks.

 Preoperative care, actual surgical procedure and subsequent postoperative care are not the
 direct subject of study and will be conducted according to so far known procedures.

 Patient will be administered therapeutic agent (antibiotic) or placebo in form of intravenous
 infusion 60 minutes prior the surgical procedure due to suspicion of the above mentioned
 diagnosis. If the surgery lasts for more than 3 hours, the infusion will be repeated. After
 analysis of the most common pathogens in individual clinical diagnosis, microbiologist chose
 following preparations: Acute appendicitis - Cefuroxim (Zinacef 1.5 g) + Ornidazol (Avrazor
 1g), perforated ulcer - Aminopenicillin + inhibitor (Amoksiklav 2.4 g) + Fluconazole 800mg
 i.v., ileus of small bowel - Cefuroxim (Zinacef 1.5 g) + Metronidazol (Avrazor 1g). Surgeon
 will confirm the definite diagnosis during surgery which will confirm the definite inclusion
 in the study. Surgeon will not be present dilution or administration of the agent. Nobody
 from patient's attending study personnel will not be able to distinguish whether the patient
 was administered antibiotic or saline solution. The prophylaxis will be extended for 24 hours
 in common half-dosage according to publication sources.

 Randomization will be conducted using generator of random numbers. This sequence will be
 incorporated in simple digital patient database internet access to which will be password
 protected. One educated ICU nurse will enter only basic patients´ data and system itself will
 determine whether to prepare placebo or diluted antibiotic. Since that moment this
 information will be confidential and software will be accessible only for entering other
 monitored parameters. Dividing into individual groups will be conducted in interim controls
 after six months intervals and final division after completion of study. Totally there will
 be 2 major groups and 6 subgroups and those 3 subgroups according to individual diagnosis
 each one with 1 control group. If severe complication (allergy reaction) occurs, the
 principle investigator can uncover the blinding using specific password; system entry will
 automatically mean exclusion of the patient from study.

 Patients will be discharge from the hospital based on criteria (agreement of the patient,
 without signs of severe infection (SIRS), sufficient oral intake, sufficient analgesia with
 oral analgesics, would treatable in the outpatient department); patient will be treated as
 outpatients in case of complications; patients will be questioned on the phone in case of
 uncomplicated course and they will be ask to fill out life quality questionnaire (SF36) on
 the day 30 and 60.

 Demographic data on included patient and monitored data will be recorded into special cards
 and transmitted in the specifically created software to further processing.

 Investigators assume to include total of 500 patients during 3 years.

 Time schedule:

 1. year of the project: creation of the randomization program, personnel education,
 software creation, inclusion of 130 patients with appendicitis diagnosis, 18 patients
 with ileus of small bowel and 35 patients with perforation of ulcerous disease. Data
 processing. Results will be evaluated at the end of the year.

 2. year of the project: Inclusion of 130 patients with appendicitis diagnosis, 18 patients
 with ileus of small bowel and 35 patients with perforation of ulcerous disease. Data
 analysis will be performed and subgroup analysis and partial results will be processed
 and presented.

 3. year of the project: Inclusion of 90 patients with appendicitis diagnosis, 14 patients
 with ileus of small bowel and 30 patients with perforation of ulcerous disease. Follow
 up termination. Definite data collection, analysis, results evaluation including
 financial analysis. Standard proposal. Presentation in national and international
 forums, publications.

 Principle investigator will apply the created protocol and will continuously control its
 compliance including schedule, will process interim data, will evaluate data compliance with
 literature and will prepare their presentation and publication and will process final
 results. 2nd co-worker is guarantees the microbiological part of the project; 3rd and 4th
 co-workers will collect rather large amount of data and will enter them in created system.
 5th and 6th co-workers will control including appropriate patients in study (it means acute
 procedure), % of included patients out of number of suitable patients is an important
 criterion for significance of gathered data. They also cooperate in presentation data
 processing. 7th co-worker controls correctness of data collection. 5 specifically educated
 independent nurses who do not attend the patient (24 hour service) will prepare infusions for
 patients according to acquired randomization data - placebo or monitored group.
 Administrative worker will select data from the information system and patients´ files, file
 and selects study cards and supervises their correct completion.

 Means of data collection Data collection will be conducted in terms of preoperative
 examination: Demographic data (age, diagnosis, co-morbidity expressed by score - ASA, BMI,
 blood count, CRP), microbiology samples for detection of influence of community pathogens,
 especially presence of multiresistant pathogens - Clostridium difficile will be sought.

 In course of surgery: evaluation of perioperative finding, SSI risk 0-3 point; contamination
 scoring I-IV, body temperature monitoring (BT), blood loss (including weighing of screens),
 length of surgery.

 In postoperative period will be recorded: number of transfusion preparations, number of days
 on UPV, days at ICU, oral intake, physiotherapy, invasive inlets (peripheral venous catheter,
 permanent urinary catheter, nasogastric tube, drains) and quality of analgesia (Visual Analog
 Scale - VAS).

 On discharge: samples collection for microbiological examination, record of SSI incidence and
 other HAI defined according to criteria of National Healthcare Safety Network (NHSN),
 completion of assessment of life quality questionnaire (SF36).

 After discharge: complications will be recorded till day 30 and 60 (SSI and HAI), life
 quality assessment. After completion of patient monitoring the analysis of cost for
 hospitalization including medication, surgery and postoperative outpatient control will be
 conducted using the hospital information system.

 Statistics:

 Morbidity which ranges from 15 to 20%, investigators consider 10% as clinically significant
 reduction. Minimal extent of each collection is 118 when considering 5% level of significance
 for single sided test and test power 70%; minimal extent of each collection for portion of
 nosocomial infection 6-10% is 234 in case of clinically significant decrease by 5%. Estimates
 of numbers required for detection of clinical difference of two days (standard deviation
 estimate 2.6 for appendicitis respectively 3.2 for perforation and 2.3 for ileus of small
 bowel) lead to values 36, 47 a 25 people in each group. Total number for each set is 250
 people and it fulfills the above mention criteria and ranges 175, 50 and 25 in each subgroup
 are sufficient. Group homogeneity will be compared based on descriptive statistical methods;
 risk factors will be evaluated using regression analysis and multivariant analysis. When
 comparing basic factors p<0.05 will be considered as clinically significant in case of above
 given test power.

 Patient informed consent (short version, complete version was approved by ethics committee
 and is enclosed in appendix): Study description: Each surgical procedure has its own risk so
 called postoperative infectious complications. One possibility how to prevent those
 complications is the preventive administration of antibiotics just prior the procedure - so
 called antibiotic (ATB) prophylaxis. There is no clear evidence for positive effect of ATB
 prophylactic use in some acute surgical procedures. On the other hand introduction of ATB
 prophylaxis has its complications. Aim of study: Aim of the study is the recommendation
 whether in given cases administration of ATB prophylaxis has positive effect on reduction of
 incidence of postoperative infectious complications and whether this benefit is higher than
 risks related to ATB administration. Inclusion in study and conductance: Single inclusion is
 only based on the decision of patient (approximately 500 patients). Study participation will
 be offered to patients who will be operated on due to acute appendicitis, perforated stomach
 or duodenal ulcer or due to ileus of small bowel. Pregnant and lactating females are excluded
 from the study. After patient's consent with study participation the intravenous preparation
 will be administered which contains active substance (antibiotic) or placebo (only saline
 solution). Both administered substances are registered preparations administered for given
 purpose in general praxis. The chance of application of either active preparation and or
 placebo is 50:50. Patient will be telephonically inquired about concrete postoperative
 complications on day 30 and 60 after surgery. If there is suspicion on complication, patient
 will be examined and treated using standard procedure. He will be further asked for
 completion of questionnaire about life quality. Health risks: This study is not related to
 practically any excessive risk. ATB and placebo administration does not in any way influence
 the surgical procedure or postoperative care. Non-invasive sample collection for cultivation
 (urine collection, sputum collection -secretion from respiratory tract mucosa, smear from
 throat and stool). Compensation for bodily harm: If patient obliges to study physician's
 instructions and her/his team and health damage of patient occurs as a result of
 administration of any preparation, the study sponsor will cover all cost for treatment of
 this damage which is not covered by patient's health insurance. Patient's declaration: I,
 undersigned, agree with my participation in study. I am older than 18 years of age. I was
 informed in detail about the aim of study, its procedures and what it is expected from me.
 Study physician explained me the expected benefits and possible health risks. I acknowledge
 that conducted study is an investigation activity. Study is randomized and therefore I
 acknowledge possibility of random assignment into individual groups which differ in therapy.
 I fully understood and I have the opportunity to ask additional questions which were
 satisfactory answered to me. I informed study conducting physician about all my diseases and
 medications which I have been taking over the last 28 days and also about medication which I
 currently take. I declare that I do know that I am pregnant at time of inclusion in the
 study. I understood that I can discontinue or withdraw my participation in the study at any
 time without affecting course of my further treatment. My personal data will be kept in full
 confidentiality after study enrollment according to applicable laws in the Czech Republic.
 Based on my given consent my original medical information could be accessed to authorized
 acquired data by sponsor representatives, independent ethics committees and international or
 local competent authorities (The State Institute for Drug Control in the Czech Republic).
 Confidentiality protection of personal data is guaranteed for those cases. There will not be
 any cost to me for my participation in study and concomitantly study enrollment is not
 related to any financial reward. I understood that my name will never be present in reports
 about this study. (date, name, signature) Cooperation Working site of co-worker participates
 in postgraduate education; co-worker is recognized surgical expert and therefore he is
 guarantee for correct study conductance and results applications in praxis; the cooperation
 will be confirmed by agreement.

 Discussion Investigator's working site will conduct internal retrospective study dealing with
 SSI in patients with appendicitis and stomach ulcer perforation. 180-200 acute appendectomies
 will be performed every year with SSI frequency 2.5 - 18.5% according to contamination. Group
 of patient with stomach ulcer perforation will be evaluated similarly (n=42) with SSI 14.3%,
 total morbidity 35% and mortality 11.9%. All of those data correlate with results from the
 world literature however it is possible that after retrospective assessment correct
 monitoring of ATB prophylaxis (40% compliance) and patient stratification will reduce the
 frequency of complications.

 Information Working site of designer performs hundreds of the above given operations which a
 presumption for completion of the study aims. Especially young surgeon will participate in
 this study who will manage methodology of hospital care as well as surgery under supervision
 of experienced physician and will educated for patients´ monitoring. Statistical evaluation
 will be performed by professional statistician. Principle investigator has numerous
 experiences with clinical studies and she/she published his/her results in journals. Other
 specific equipment is not necessary for study procedure.

 Conclusion Proposed prospective randomized double blinded study will provide clear results
 assessing effect of administration of ATB prophylaxis on the incidence of SSI and other HAI
 in case of the most common acutely performed surgical procedures. Risk factor analysis and
 costs for treatment will aid to determine group of patients who will benefit from prophylaxis
 and vice versa.

 Expected results and significance of the project Project results will be used as background
 for establishing recommended procedure of antibiotic prophylaxis administration in surgery.
 Standardized protocol will be introduced for patients monitoring including monitorzation of
 nosocomial infections which is can be applied in general surgical praxis. Simple universal
 software will be created in terms of study which manages patient database and thus enables
 rapid concurrent assessment of health care quality. Respective reduction of nosocomial
 infections frequency should result in significant economic benefit for surgical praxis. With
 regard that similar complex prospective study has not been published in national and
 international magazines, publication in impact journal; socioeconomic analysis will be
 published especially in national medical journals so it would be easily accessible.

 Project should aid the prevention of nosocomial infections (HAI) and reduction of their
 genesis and thus to increase surgical care, shorten hospitalization and should have impact on
 the whole society.
Inclusion Criteria:

 -  patient older > 18 years

 -  Patient indicated for emergent surgery for:

 acute appendicitis / perforated gastric or duodenal ulcer / small bowel obstruction

 -  The patient can understand the aim of the study and sign informed consent (including
 language barriers)

 -  The diagnose is confirmed intraoperatively

 Exclusion Criteria:

 -  Refused the participation in the study and

 -  uninsured self-payers

 -  Patients with known allergy to the substance administered during the study or chronic
 medication contraindicated with study drug

 -  Pregnant or breastfeeding women

 -  Use of antibiotics in the last 2 weeks

 -  Known serious illness (heart failure, renal failure, liver failure, CNS disorders)

 -  Signs of infectious mononucleosis and risk of infectious endocarditis