STATE OF THE ART OF ANTIBIOTIC PROPHYLAXIS IN SURGERY

2. STATE OF THE ART OF ANTIBIOTIC PROPHYLAXIS IN SURGERY

2.1. Historical background

Based on a set of seminal studies, the background of the current policies of antimicrobial prophylaxis in surgery has been settled. The first studies to be

Antibiotic Policies: Theory and Practice. Edited by Gould and van der Meer Kluwer Academic / Plenum Publishers, New York, 2005

186 Jos W. M. van der Meer and Marjo van Kasteren mentioned within this context are—without doubt—the animal experiments by

Burke. In a series of elegant investigations, he investigated the timing of antibiotic prophylaxis (Burke, 1961). He produced surgical wounds in rats which he contaminated with Staphylococcus aureus. At various points in time

he administered antibiotics and discovered that wound infection could only be prevented if the antibiotics were given close to the time of inoculation.

A second landmark study was that of Weinstein and collaborators (Weinstein et al., 1975). In rats, these investigators showed that prophylaxis for abdominal surgery should be directed to both anaerobic bacteria and aerobic bacteria. When rats were intra-abdominally inoculated with intestinal flora, it was found that animals treated with antibiotics that were only effective against anaerobic bacteria (i.e., clindamycin), developed potentially lethal sepsis caused by aerobes; those animals treated with antibiotics that were selectively effective against aerobes, in contrast, would not develop sepsis but suffer from intra-abdominal abscesses (apparently mainly caused by anaerobes). Treatment with combined antibiotics prevented both types of problems. The importance of coverage of anaerobes and aerobes in clinical surgery was proposed by Nichols, who investigated regimens of oral antibiotic for prevention of wound infection after colonic surgery (Nichols et al., 1972). Thus, from these key studies the concept emerged that prophylaxis after abdominal surgery has to cover both anaerobes and aerobes.

The third group of landmark studies was that of Cruse and Foord. These investigators scrutinised the occurrence of surgical wound infections and determined the standards for the “acceptable” frequencies of wound infections after dirty surgery, contaminated surgery, so called clean-contaminated surgery, and clean surgery (Cruse and Foord, 1980). These investigations have set the stage for investigations looking into the effect of antibiotic prophylaxis in contaminated and clean-contaminated surgical procedures. The surgical classi- fication, given by Mayhall (1993) is presented here (Table 1). The percentages of post-operative wound infection without antibiotics range between 2% and 5% for clean wounds, around 10% for clean-contaminated wounds, and ⬎20% for contaminated wounds.

2.2. Principles of antibiotic prophylaxis in surgery

Taken together the studies discussed in the previous paragraphs have laid the foundations for the following principles in surgical prophylaxis:

● Antibiotic prophylaxis in surgery is mainly indicated for (clean-)contami- nated procedures

● The antibiotics to be selected for surgical prophylaxis should cover the microorganisms that predictably cause wound infection

Improving Prescribing in Surgical Prophylaxis 187

Table 1. Surgical wound classification Class

Description of the wound Clean

Elective, primary closure, without drains Non-traumatic, not infected, not inflamed Adequate asepsis Airways, GI tract, or genitourinary system not opened

Clean-contaminated Airways, GI tract, or genitourinary system opened under controlled conditions or without extraordinary contamination Oropharynx opened Vagina opened Urinary tract opened without positive urine culture Biliary tract opened without infected bile

Contaminated Open, traumatic wound (not older than 6 hr) Visible leakage from the GI tract GI tract or genitourinary system opened

with infected bile or urine Break in aseptic instrumentation Incision in area of acute, non-purulent inflammation

Dirty Surgery through traumatic wounds with necrotic tissue, foreign material or (faecal) contamination Traumatic wound with delayed treatment Perforated viscus detected Acute bacterial infection with pus detected at operation

Source: Adapted from Mayhall (1993).

● The antibiotics selected for prophylaxis should be present in adequate con-

centrations in the wound at the time that bacterial contamination occurs.

Commonly five more principles are added: ● The prophylactic antibiotics should be given for a short duration

● The antibiotics selected for this indication should not be used therapeutically ● The antibiotics selected should not readily lead to emergence of microbial

resistance ● The antibiotics used for surgical prophylaxis should be free of side effects

● The antibiotics used for surgical prophylaxis should be relatively cheap. Each of these principles will be discussed in a little more detail.

Antibiotic prophylaxis mainly in (clean-)contaminated procedures. It is gen- erally accepted that the main classes within the wound classification (Table 1) for which antibiotic prophylaxis is indicated are clean-contaminated and con- taminated wounds. However, there are clean surgical procedures in which a wound infection is such a disaster, that antibiotic prophylaxis is considered to be indicated. These are especially those procedures in which prosthetic material is

188 Jos W. M. van der Meer and Marjo van Kasteren implanted. Some surgical procedures with clean wounds meet with frequen-

cies of wound infection in the range of 8–20% (e.g., craniotomy and coronary bypass surgery). For these procedures antibiotic prophylaxis is considered acceptable.

Areas of uncertainty are abdominal hysterectomy and pulmonary surgery. For both procedures the clinical trials are equivocal (Boldt et al., 1999; Hemsell, 1991). Guidelines for prevention of infections in surgery have been published by several organsations, for example, the Centers for Disease Control in the United States (Mangram et al., 1999). In Table 2, the Dutch

Table 2. Surgical procedures for which perioperative antibiotic prophylaxis is indicated Clean wounds

ENT surgery

Stapedectomy Cochlear implant Implant/bone transplant nose

Neurosurgery

Craniotomy

Vascular surgery Application of prosthetic material Aorta reconstruction Vascular surgery with inguinal incision

Cardiac surgery Open-heart surgery, coronary bypass surgery, implantation

of prosthetic valve

Bone and joint surgery Implantation of prosthetic joints Osteosynthesis Amputation in ischaemic area

Clean-contaminated/contaminated Head and neck surgery

Incision of pharynx/oesophagus Neurosurgery

Surgery through naso-/oropharynx Thoracic surgery

Lobectomy en pulmonary resection Abdominal surgery

Stomach and duodenum surgery with hpochorhydria, disturbed motility or extreme overweight Biliary surgery for acute cholecystitis, stone in the common duct, age ⬎70 years, or obstructive jaundice Colonic or rectal surgery Appendectomy for appendicitis

Urogenital surgery Surgery of the urinary tract with non-sterile urine Vaginal/abdominal hysterectomy Secondary Caesarean section Manual removal of the placenta Abortion in second trimester or in first

trimester after PID Vulvectomy

Trauma

Open fracture Penetrating abdominal or thoracic trauma

Source: Adapted from van Kasteren et al. (2000).

Improving Prescribing in Surgical Prophylaxis 189 consensus (issued by the Working Party on Antibiotic Policy, SWAB) regard-

ing antibiotic prophylaxis in surgery is reproduced (van Kasteren et al., 2000). Prophylaxis to cover microorganisms that predictably cause wound infec- tion. Surgical wound infections are caused by endogenous and exogenous microflora. The endogenous microorganisms, the patient’s own flora, are dependent on the body site where the surgical procedure will take place. The antimicrobial susceptibility of the endogenous flora is dependent on the patient’s history (has the patient been exposed to resistant microorganisms, for example, methicillin-resistant S. aureus [MRSA], has the patient been using antibiotics recently?). This implies that antibiotic prophylaxis should be individualised, especially when there is a risk of resistant endogenous flora.

Exogenous microflora (transferred by medical personnel or by inanimate material) is generally not taken into account for the selection of the antimicro- bial drugs for prophylaxis: infections by these microorganisms should be pre- vented by hygienic measures. The choice of antibiotics should be aimed at optimal prophylaxis, not maximal.

Adequate antibiotic concentrations at the time of bacterial contamination. Since bacterial contamination of a surgical wound almost exclusively occurs between incision and closure, effective antibiotic concentrations should be present in the wound during that period. The literature on surgical prophylaxis has concentrated more on the presence of effective concentrations at the begin- ning of surgery than at time of closure (see next paragraph).

There has been quite some debate regarding the optimal time of giving the first antibiotic dose. Studies have provided evidence that administration within

2 hr before incision is effective (Classen et al., 1992). Given the rapidity of diffusion of antibiotics into tissues with adequate blood supply, it is probably better to shorten this time period to approximately 30 min.

The prophylactic antibiotics should be given for a short duration. There is general agreement that antibiotic prophylaxis in surgery should not be given for longer than 24 hr. A number of studies have compared administration of

a single dose versus 24 hr of administration and met with equal efficacy (Rowe-Jones et al., 1990; Wymenga et al., 1992). Despite the still insufficient power of these (large) studies, most authorities feel that a single dose of an antibiotic will suffice for surgical procedures that do not exceed 3–4 half-lives of the drug, provided there is no substantial blood loss and no use of extra-cor- poral circulation. Under the latter circumstances an extra dose of antibiotic shortly before the end of the operation is indicated.

Antibiotics selected for this indication should not be used therapeutically. This principle is of a somewhat lesser order than the others. It is mainly put forward for practical reasons. If an antibiotic is only used for prophylaxis, its use and compliance with guidelines is relatively easily monitored. In addition, since many antibiotics are effective in prophylaxis—provided they cover the

190 Jos W. M. van der Meer and Marjo van Kasteren microorganisms that are likely to cause the infection—it is unnecessary to use

new antibiotics. A drug like cefazolin is very suitable for the coverage of aerobic pathogens: its spectrum is sufficient, it has a relatively long half-life (90 min) and it is safe. It should be noted that this principle does not hold up as easily for anaerobic coverage. Here, metronidazole is often used and this drug cannot be avoided for therapy of anaerobic infections.

Antibiotics selected should not readily lead to emergence of microbial resis- tance. This general principle not only pertains to the effect of the antibiotic on the microflora of the patient, but also on that of the hospital environment (i.e., the operating theatre). Antibiotics that may readily induce resistance, for instance, through one-step mutation (macrolides, fucidic acid) are better avoided. Also, antibiotics with a very broad spectrum (such as carbapenems) should not be used in this setting: by destroying most of the endogenous flora, they pave the way for colonisation and subsequent infection by resistant hospital bacteria and also by fungi.

Antibiotics used for surgical prophylaxis should be free of side effects. One would preferably select antibiotics with which allergic reactions are rare. For this reason, penicillins are less suitable. Cephalosporins that are clearly less allergenic in general, can be used safely (Kelkar and Li, 2001). Although toxicity for most antibiotics is not a great problem if only a single dose is given, it is still wise to avoid aminoglycosides here. Wrong estimations of renal clearance and lean body mass are easily made and volume depletion and deterioration of renal function can occur during operation, all of which may enhance toxicity when more than one dose is given.

Antibiotics used for surgical prophylaxis should be relatively cheap. Cost containment is another reason to give preference to old (“off-patent”) drugs. Indirect costs also have to be taken into account and for this reason oral bowel preparations (containing for instance neomycin and erythromycin) have become less used.