Prophylactic Antibiotics

                                Dr. KS Dhillon

Introduction

Wound infections are the commonest hospital-acquired infections in patients undergoing surgery [1]. Such infections lead to increased antibiotic usage, increased costs, and prolonged hospitalization [2]. Prophylactic antibiotics can reduce the risk of postoperative wound infections. Inapprioate antibiotic use can increase the risk of emergence of antimicrobial resistance. Hence, judicious use of antibiotics in the hospital is essential.

The original surgical antibiotic prophylaxis experiments were performed in pigs about 40 years ago. The results concluded that the most effective period for prophylaxis begins the moment bacteria gain access to the tissues and the antibiotic are not effective after the bacteria has been in the tissues for more than three hours [3]. Since then there have been several other studies in animals and in humans. Now the principles of antibiotic prophylaxis have become an accepted part of surgical practice [4].

About 30-50% of antibiotics used in hospital practice are for surgical prophylaxis. However, between 30% and 90% of this antibiotic prophylaxis use is inappropriate. Most often the antibiotic is either given at the wrong time or continued for too long [5]. There, however, remains controversy as to the duration of prophylaxis needed and also as to which specific surgical procedures should receive prophylaxis [4].

Indications

Preoperative antibiotic prophylaxis involves the administration of antibiotics prior to performing surgery to decrease the risk of postoperative infections. The evidence that supports the routine use of preoperative prophylactic antibiotics continues to grow. A 2008 study highlighted the effectiveness of prophylactic antibiotics in patients undergoing total hip and knee replacement. It showed an 8% reduction in the absolute risk of wound infection and an 81% relative risk reduction as compared to patients who had no prophylaxis [6]. In patients undergoing, artificial implant or foreign body implantation as part of the procedure, bone grafting procedures, and other surgeries with extensive dissections, prophylactic antibiotics are routinely used.

The timing of antibiotic administration varies. The goal of preoperative systemic prophylactic antibiotics administration is to have a high concentration in the tissues at the start of the operation and during surgery [7,8]. 

The antibiotic must be given at least 30 minutes, but no greater than 60 minutes before the skin incision is made [7,9,10]. The antibiotic must be given 15-45 min before the inflation of a tourniquet [11].

The most common organisms that cause surgical site infections include [12]:

• Staphylococcus aureus

• Staphylococcus epidermidis

• Aerobic streptococci

• Anaerobic cocci

Other organisms, such as Cutibacterium acnes, are often isolated in the postoperative infections following shoulder surgery.

Preoperative antibiotic selection is usually based on the anatomic region where the surgical procedure is to be carried out. When determining appropriate antibiotic selection, the goal is to ensure that the most common organisms are targeted. Several factors are taken into consideration when selecting the preoperative antibiotic. These include: 

• Cost

• Safety

• Ease of administration

• Pharmacokinetic profile

• Bacteriocidal activity

• Hospital resistance patterns

 By addressing these factors during antibiotic selection, surgical site infections are minimized. Surgical site infections constitute a significant factor that drives negative patient-reported outcomes and independent risk factors for increasing the financial burden [13].

Cefazolin is most often used for surgical prophylaxis in patients who have no history of beta-lactam allergy. It is not used for operation at surgical sites in which the most probable organisms are not covered by cefazolin. 

Patients who are allergic to cefazolin are given clindamycin or vancomycin for prophylaxis. Most patients who are allergic to beta-lactam are able to tolerate cefazolin. 

In patients with MRSA colonization, vancomycin is the alternative unless additional antibiotics are required for gram-negative or anaerobic organisms [14]. Multiple options are available for patients requiring additional microbe coverage, including cefazolin plus metronidazole, cefoxitin, or ertapenem. These additional antibiotic options are based on specific surgical sites and patient-specific antibiotic resistance [15].

Weight-based dosing is followed as per standardized protocol. The antibiotic administration should be done within 1 hour of skin incision and continue for 24 hours postoperatively. Patients in whom the surgical duration is greater than 4 hours and in patients with estimated blood loss of over 1,500 ml, intraoperative dosing of antibiotics would be required [16]. The weight-based guidelines include the following [17]:

• Cefazolin: 2 g (3 g for weight >120 kg) -- adult surgical prophylaxis guidelines.

• Vancomycin: 15 mg/kg

Wound Classifications 

Wound types can be classified as clean, clean-contaminated, contaminated, or dirty/infected [18]. Clean wounds are not infected, without inflammation, and are primarily closed. Clean-contaminated wounds involve the genital, respiratory, alimentary, and urinary tract.  Contaminated wounds include open, fresh accidental wounds, and those with non-purulent inflammation. Contaminated wounds also include procedures with breaks in sterile technique or gross spillage from the gastrointestinal tract. Dirty or infected wounds are old traumatic wounds with devitalized tissue, existing clinical infection, and those with perforated viscera.

During clean procedures, skin florae such as coagulase-negative staphylococci (Staphylococcus epidermidis or Staphylococcus aureus) are the predominant pathogens in the infection site. In the clean-contaminated procedures, the most commonly found organisms causing surgical site infections are skin flora, gram-negative rods, and Enterococci [19].

Skin Preparation 

Preoperatively basic infection control strategies have to be followed. The instruments have to be sterilized, and skin preparation is done. Methicillin resistant Staphylococcus aureus [MRSA] decolonization, appropriate hair removal, and skin antiseptic preparation done [20].  Regarding the latter, it is recommended that patients about to undergo surgery perform a combination of a standard soap and water shower and chlorhexidine gluconate cloth wash before surgery.

Murray et al [21] in a study showed that the combined protocol of soap and water shower and chlorhexidine gluconate cloth wash resulted in a 3-fold reduction in colony count for coagulase-negative Staphylococcus (CNS), a significant decrease in positive cultures for CNS and Corynebacterium, as well as a significant decrease in bacterial burden compared to soap and water shower alone.

Some hospitals carry out nasal swab screening for MRSA weeks before

elective arthroplasty procedures and treat those who are positive. Positive MRSA culture can be treated with either 2% mupirocin to the nares twice daily for five days preoperatively or they can be treated with 5% povidone-iodine solution to each nostril for 10 seconds per nostril, 1 hour prior to surgery, in addition to vancomycin administration at the time of the surgery [22,23].

Splenectomized Patients

Infection control in splenectomized patients requires special attention.  

In 1996, the British Committee for Standards in Haematology published Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen [24], that are considered to reflect best-practice. These recommendations were updated in 2002 [25], and

consist of the following key elements:

1. All splenectomized patients should receive pneumococcal immunization and revaccination. If not previously immunized they should also receive Haemophilus influenzae type B and meningococcal C vaccine. Yearly influenza immunization is recommended.

2. Lifelong prophylactic antibiotics are recommended, or at least the first two years after splenectomy. In case of suspected or proven infection patients should be given systemic antibiotics and be admitted to a hospital.

3. All patients should be educated about the risks of infection and the risk associated with traveling (such as becoming infected by Plasmodium falciparum) and unusual infections (i.e. dog bites). Patient records should be labeled to indicate the risk.

Mechanism of Action

Multiple antibiotic classes are used in preoperative antibiotic prophylaxis. The antibiotics utilized are bactericidal. Bacteriostatic drugs are usually not used. Bactericidal drugs kill the targeted organisms instead of just preventing the multiplication of the bacteria. Certain antibiotics can exhibit bacteriostatic or bactericidal properties depending on bacterial sensitivity and antibiotic concentration. Clindamycin for example is bacteriostatic at lower doses, but at higher doses, it has bactericidal properties. For surgery, the intent is to ensure the bactericidal concentration has been reached in the blood and tissues before the incision is made.

Antibiotic Administration

Most of the preoperative prophylactic antibiotics are administered intravenously (IV). The timing of administration, redosing, duration of prophylactic therapy, and dosing in obese patients are important components in the prevention of surgical site infections [26]. The unnecessary use of antibiotics should be avoided to diminish adverse effects and antibiotic resistance. 

Antibiotics are given within 30 to 60 minutes of a surgical incision. There are exceptions to this rule and these include vancomycin and levofloxacin, which require administration within 120 minutes of the incision due to longer administration times. If a patient is already on an antibiotic for another infection before surgery and that antibiotic is appropriate for surgical prophylaxis, an extra dose of the antibiotic can be administered within 60 minutes of the incision. If the patient is already receiving vancomycin and has renal failure, cefazolin should be used before the surgery instead of an extra vancomycin dose [27].

Redosing of antibiotics is important depending on the half-life of the particular antibiotic used. Renal dysfunction and extensive burns can impact the half-life of an antibiotic. Cefazolin and cefoxitin would have to be administered more than once, depending on the length of the procedure. A perioperative dose of cefazolin has to be administered again four hours after the initial preoperative dose. Cefoxitin should be administered again two hours later. Redosing antibiotics have to be considered in patients with significant blood loss or dilution during surgery. 

Prophylactic antibiotics should be discontinued within 24 hours unless there is an infection. There is some controversy regarding the duration of therapy postoperatively following cardiothoracic surgery. There are two meta-analyses that compared 24 hours versus 48 hours as the cut-off in patients undergoing cardiac surgeries. They found that there was a significant decrease in surgical site infections with the extended duration [28].

The most recent CDC guidelines state that additional prophylactic antibiotics should not be administered after the surgical incision is closed in patients undergoing clean and clean-contaminated procedures. This recommendation applies to patients with or without a drain after the surgical site is closed.

Weight-based dosing is recommended when cefazolin, vancomycin, and gentamicin are used in adult surgical prophylaxis. Cefazolin 2 g is the current recommended dose for prophylaxis except for patients weighing greater than or equal to 120 kg, who should receive 3 g. There is some literature which states that cefazolin 2 g  should be sufficient for an adult of any weight.

The vancomycin dose is 15 mg/kg, and the gentamicin dose is 5 mg/kg. Other prophylactic antibiotic dosing regimens in adults are clindamycin 900 mg, cefoxitin 2 gm, and ertapenem 1 gm. All prophylactic antibiotics for children are dosed based on mg per kg of body weight. Pediatric dose for cefazolin is 30 mg/kg and for vancomycin, it is 15 mg/kg. 

Adverse Effects

Limiting the duration of antibiotics usage is important. Antimicrobial usage can alter the hospital and patient's bacterial flora. This can lead to colonization and the development of resistance. The excessive use of vancomycin can increase the risk of developing vancomycin-resistant enterococcus.

Contraindications

Beta-lactam antibiotics are commonly used for surgical prophylaxis. It is crucial to identify when such antibiotics are contraindicated. If a patient has an immunoglobulin (IgE) mediated allergy to penicillin, then penicillins, cephalosporins, and carbapenems cannot be used for prophylaxis. A type 1 reaction would include anaphylaxis, urticaria, or bronchospasm that occurs 30 to 60 minutes following the administration of the antibiotic. Carbapenems and cephalosporins are considered safe in patients who have not had a type-1 reaction, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Obtaining a good allergy history from each patient is vital to determine whether the patient's allergy is real. 

Monitoring

Surgical site infections can occur for various reasons, including incorrect antibiotic usage. The correct antibiotic dosage, timing of the initial dose, and timing of any applicable redosing are major factors to keep in mind to ensure best practices are followed when considering antibiotic prophylaxis practices.

Monitoring should ensure no surgical site infections occur due to increasing local antibiotic resistance. Antibiotic selection should be reviewed to avoid using antibiotics that result in new or worsening resistance patterns. An institution can choose to use cefoxitin instead of ertapenem in colorectal surgeries so as to avoid excessive usage of the carbapenem class especially if there is an escalating number of carbapenem-resistant organisms [29].

Toxicity

No apparent toxicities are known with the recommended doses of antibiotics. This is mainly due to the limited duration of antibiotic exposure in surgical prophylaxis.

Conclusion

Antibiotic prophylaxis for surgery is an effective management strategy for reducing postoperative infections. This is on condition that appropriate antibiotics are given at the correct time for appropriate durations and for appropriate surgical procedures. Most often surgical antibiotic prophylaxis is given as a single intravenous dose as soon as the patient is stabilized under anesthesia, prior to skin incision. It is important to use a narrow spectrum antibiotic that is appropriate for the type of surgery to be carried out. Hospital surgical antibiotic prophylaxis protocols should be regularly reviewed, as the endemicity of multi-resistant bacteria in certain units or hospitals are subject to frequent change.

References

1. Horan TC, Culver DH, Gaynes RP, Jarvis WR, Edwards JR, Reid CR. Nosocomial infections in surgical patients in the United States, January 1986 - June 1992. Infect Control Hosp Epidemiol 1993; 14:73-80.

2. McGowan JE Jr. Cost and benefit of perioperative antimicrobial prophylaxis: methods for economic analysis. Rev Infect Dis 1991;13(Suppl 10): S879-89.

3. Burke JF. The effective period of preventative antibiotic action in experimental incisions and dermal lesions. Surgery 1961;50:161-8.

4. Patchen Dellinger E, Gross PA, Barrett TL, Krause PJ, Martone WJ, McGowan JE Jr, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Clin Infect Dis 1994;18:422-7.

5. Dettenkofer M, Forster DH, Ebner W, Gastmeier P, Ruden H, Daschner FD. The practice of perioperative antibiotic prophylaxis in eight German hospitals. Infection 2002;30:164-7.

6. AlBuhairan B, Hind D, Hutchinson A. Antibiotic prophylaxis for wound infections in total joint arthroplasty: a systematic review. J Bone Joint Surg Br. 2008 Jul;90(7):915-9.

7. Tarchini G, Liau KH, Solomkin JS. Antimicrobial Stewardship in Surgery: Challenges and Opportunities. Clin Infect Dis. 2017 May 15;64(suppl_2): S112-S114. 

8. W-Dahl A, Robertsson O, Stefánsdóttir A, Gustafson P, Lidgren L. Timing of preoperative antibiotics for knee arthroplasties: Improving the routines in Sweden. Patient Saf Surg. 2011 Sep 19;5:22.

9. Gyssens IC. Preventing postoperative infections: current treatment recommendations. Drugs. 1999 Feb;57(2):175-85.

10. Galandiuk S, Polk HC, Jagelman DG, Fazio VW. Re-emphasis of priorities in surgical antibiotic prophylaxis. Surg Gynecol Obstet. 1989 Sep;169(3):219-22.

11. Stefánsdóttir A, Robertsson O, W-Dahl A, Kiernan S, Gustafson P, Lidgren L. Inadequate timing of prophylactic antibiotics in orthopedic surgery. We can do better. Acta Orthop. 2009 Dec;80(6):633-8.

12. Tan TL, Gomez MM, Kheir MM, Maltenfort MG, Chen AF. Should Preoperative Antibiotics Be Tailored According to Patient's Comorbidities and Susceptibility to Organisms? J Arthroplasty. 2017 Apr;32(4):1089-1094.e3. 

13. Varacallo MA, Mattern P, Acosta J, Toossi N, Denehy KM, Harding SP. Cost Determinants in the 90-Day Management of Isolated Ankle Fractures at a Large Urban Academic Hospital. J Orthop Trauma. 2018 Jul;32(7):338-343.

14. Bosco JA, Slover JD, Haas JP. Perioperative strategies for decreasing infection: a comprehensive evidence-based approach. Instr Course Lect. 2010;59:619-28.

15. Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, Fish DN, Napolitano LM, Sawyer RG, Slain D, Steinberg JP, Weinstein RA., American Society of Health-System Pharmacists. Infectious Disease Society of America. Surgical Infection Society. Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013 Feb 01;70(3):195-283.

16. Dehne MG, Mühling J, Sablotzki A, Nopens H, Hempelmann G. Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques. Orthopedics. 2001 Jul;24(7):665-9. 

17. Clark JJC, Abildgaard JT, Backes J, Hawkins RJ. Preventing infection in shoulder surgery. J Shoulder Elbow Surg. 2018 Jul;27(7):1333-1341.

18. Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, Reinke CE, Morgan S, Solomkin JS, Mazuski JE, Dellinger EP, Itani KMF, Berbari EF, Segreti J, Parvizi J, Blanchard J, Allen G, Kluytmans JAJW, Donlan R, Schecter WP., Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 2017 Aug 01;152(8):784-791.

19. Pfeffer I, Zemel M, Kariv Y, Mishali H, Adler A, Braun T, Klein A, Matalon MK, Klausner J, Carmeli Y, Schwaber MJ. Prevalence and risk factors for carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae among patients prior to bowel surgery. Diagn Microbiol Infect Dis. 2016 Jul;85(3):377-380.

20. Chauveaux D. Preventing surgical-site infections: measures other than antibiotics. Orthop Traumatol Surg Res. 2015 Feb;101(1 Suppl): S77-83.

21. Murray MR, Saltzman MD, Gryzlo SM, Terry MA, Woodward CC, Nuber GW. Efficacy of preoperative home use of 2% chlorhexidine gluconate cloth before shoulder surgery. J Shoulder Elbow Surg. 2011 Sep;20(6):928-33.

22. Phillips M, Rosenberg A, Shopsin B, Cuff G, Skeete F, Foti A, Kraemer K, Inglima K, Press R, Bosco J. Preventing surgical site infections: a randomized, open-label trial of nasal mupirocin ointment and nasal povidone-iodine solution. Infect Control Hosp Epidemiol. 2014 Jul;35(7):826-32. 

23. Campbell KA, Stein S, Looze C, Bosco JA. Antibiotic stewardship in orthopaedic surgery: principles and practice. J Am Acad Orthop Surg. 2014 Dec;22(12):772-81.

24. (1996) Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Working Party of the British Committee for Standards in Haematology Clinical Haematology Task Force. BMJ. 312:430-434.

25. Davies JM, Barnes R, Milligan D (2002) Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2:440-3.

26. Chen X, Brathwaite CE, Barkan A, Hall K, Chu G, Cherasard P, Wang S, Nicolau DP, Islam S, Cunha BA. Optimal Cefazolin Prophylactic Dosing for Bariatric Surgery: No Need for Higher Doses or Intraoperative Redosing. Obes Surg. 2017 Mar;27(3):626-629.

27. Unger NR, Stein BJ. Effectiveness of pre-operative cefazolin in obese patients. Surg Infect (Larchmt). 2014 Aug;15(4):412-6.

28. Mertz D, Johnstone J, Loeb M. Does duration of perioperative antibiotic prophylaxis matter in cardiac surgery? A systematic review and meta-analysis. Ann Surg. 2011 Jul;254(1):48-54. doi: 10.1097/SLA.0b013e318214b7e4. PMID: 21412147.

29. Deierhoi RJ, Dawes LG, Vick C, Itani KM, Hawn MT. Choice of intravenous antibiotic prophylaxis for colorectal surgery does matter. J Am Coll Surg. 2013 Nov;217(5):763-9.