Skeletal muscle and plasma concentrations of cefazolin

Surgical site infections are serious complications of surgery, particularly after orthopaedic surgery, where biomaterial infection has serious implications for the patient and poses a significant financial burden on society. Antibiotic prophylaxis is an important component of strategies to prevent surgical site infection, and although it has become part of routine practice before and during many surgical procedures, it has been insufficiently investigated.

The study published by Himebauch and colleagues¹ in this issue of the BJA is thus a very welcome and much needed addition to the literature on this topic. In their well written article the authors report skeletal muscle and plasma concentrations of Cefazolin during complex pediatric spinal surgery. These muscle concentrations are important, as insufficient concentrations may very well result in possible surgical site infections (SSI). Although data on the serum concentrations are well known, there are not many studies showing concentrations in the tissues surrounding the implant, which is where adequate antibiotic concentrations are necessary to prevent biofilm formation. The use of microdialysis in this study is innovative and safe and may represent an important adjunct in the quest to gain insight into the actual local tissue antibiotic concentrations.

The administration of prophylactic antibiotics is part of routine practice. Most commonly when permanently implanted biomaterial are placed, a cephalosporin is administered perioperatively. In large register-based studies of orthopaedic joint replacements, antibiotic prophylaxis has been associated with significantly reduced infection rates. Unfortunately the timing of administration before surgery, dosage and the administration of repeat perioperative dosage are debatable subjects, on which this article can cast some light. From the current article we can learn that in this vulnerable group of children with scoliosis, especially those with neuromuscular abnormalities, the concentrations are too low at the time of the incision. Also, given the duration of these operations, the local concentration of antibiotics decreases to an undesired low concentration during surgery. The measurements in table 3 show that the protection, especially against gram negative bacteria, is too low. Inadequate concentrations of antibiotics are not helpful in the prevention of biofilm formation, and may even induce bacterial resistance to antibiotics that are usually optimal for prophylactic treatment.

It is common knowledge that implanted biomaterials, such as those used in joint replacement are prone to infection. During the proceedings of the international consensus meeting on periprosthetic joint infection held in 2013, with virtually all the representatives of orthopaedic surgery present, consensus was reached on many subjects.² The efficacy of antimicrobial prophylaxis in preventing infections is a well-established,³ and preoperative i.v. antibiotic prophylaxis is regarded as the corner stone for the prevention of infection in all patients undergoing biomaterial implantation.

In operations that last for more than one h, an increasing infection rate is found even in the absence of implantation materials. Therefore more rigid treatment regimens for longer operations, and for high-risk patients, such as patients with diabetes, severe obesity and other risk factors, are introduced. It is also important that preoperative measurements for reduction of the risk for an infection, such as decolonization for MRSA and/or other MSSA bacteria in patients, are introduced and implemented.

After the insertion of a prosthesis into the human body a race between bacteria and host cells for the surface of the implant begins. If bacteria get the chance they will develop a so-called biofilm around the implant, a self-produced extracellular polymeric substance (slime layer). This biofilm protects the bacteria from the outside world, so that the immunological defense system if the patient has difficulty in sensing and attacking the bacteria inside the biofilm. Administered antibiotics may also have limited penetration into the surface of the biofilm, and frequently cannot reach the bacteria that are inside the biofilm. Therefore if an infection occurs in the presence of a biomaterial, such as a total hip prosthesis, the only way to eradicate this problem is the removal of the implant. It is clear from these data that antibiotic prophylaxis is not only needed at the start of the operation, but adequate concentrations of antibiotics should be present during the whole operation.³

A first or second generation cephalosporin (such as cefalozin or cefuroxime) should be administered for routine perioperative surgical prophylaxis. Isoxazolyl penicillin is used as an appropriate alternative. In patients with non-anaphylactic penicillin allergy, second generation cephalosporines are advised and in general can be used safely. Penicillin skin testing may be helpful in certain situations to clarify whether a patient has a true penicillin allergy. If a patient has a known anaphylactic penicillin allergy, vancomycin or clindamycin should be administered.

These antibiotics are chosen based on the coverage of gram-positive organisms and clinically important gram negative bacilli and anaerobic gram positive organisms. They also have an excellent distribution profile in bone, synovium, muscle and haematomas. The optimal prophylactic antibiotic regimen should preferably contain bactericidal antibiotics. The half-life of the chosen agent should be sufficient to provide cover for the important parts of the operation - at least the first two h of the operation, covering the time from incision to closure of the wound.^4–10

There is ongoing discussion on the required duration of adequate concentrations of antibiotics after the operation. Several researchers have found that in contrast to earlier regimes, a 24 h regimen was not associated with an increase in the infection rate when compared with a seven day or 48 h regimen.¹³ Studies are now addressing an even shorter duration of an adequate concentration of antibiotics after an operation.

The timing of administration before operation is critical. Optimal timing before surgery appears to be 60–30 min before the surgery.¹³ When using different agents for prophylaxis, timing of administration should be altered, to match the pharmacokinetics and dynamics of the agent. For vancomycin or fluoroquinolones for example, administration two h before surgery is probably better able to ensure an optimal concentration at surgical incision.

In patients where a tourniquet is used, then administration of the antibiotics at least ten min before inflation of the tourniquet, or directly after the release of the tourniquet, seem to be the optimal moments to ensure adequate concentrations in bone and fat.¹⁴

For longer duration procedures, an additional dose of antibiotics should be administered after two half-lives have elapsed since the administration of the first dose of the prophylactic agent.^15–17 Adequate antibiotic concentrations were found in bone after five min, and in fat after 10 min after i.v. administration of a repeat dose.¹⁴

Repeat dosing of antibiotics according to the guidelines should also be considered if there is a large volume of blood loss (>2000 ml) or administration of more than 2000 ml of fluid resuscitation. Because these are independent variables, re-doing should be considered as soon as one of the mentioned conditions is met.

For future research this means that not only the right timing (i.e. 30–60 min before the surgical incision) is required, but also that required concentrations of antibiotics may differ, in line with the operation undertaken, taking into account the duration of the procedure, the likely infecting organisms and the target tissue. Only local concentrations measured at the operation site and during the operation can confirm adequacy of applied doses and the need for additional doses to increase antibiotic concentrations. This study should therefore be regarded as the start for new studies that are urgently required to optimize the use of antibiotics during operations.

Declaration of interest

None declared.