1 Introduction

The current widespread use of cephalosporins in order to reduce the incidence of wound and soft tissue infections as well as infections around orthopedic implants following orthopedic operations was well established in many clinical trials that clearly demonstrated their effectiveness in reducing infections. Rosenfeld et al.¹ reported that cefoxitin achieved and sustained therapeutic bone levels after a single 1 gr bolus injection in patients that underwent elective hip or knee surgery. They concluded that “first-generation cephalosporins, such as cephalothin or cefazolin, have been the preferred chemo-prophylactic agents because of their excellent anti-staphylococcal activity and lack of appreciable toxicity”.

The current recommendations are to administer intravenously a first or a second generation cephalosporin enough time before surgery in order to achieve serum and tissue bactericidal levels when the incision is made.^2,3 Cefazolin is the most frequently used agent,² whereas allergic patients receive clindamycin or vancomycin.³

Several protocol modifications are being researched for high risk patients (obesity, diabetes mellitus, smoking, renal failure, autoimmune disease and nasal colonization with methicillin sensitive Staphylococcus aureus or methicillin resistant Staphylococcus aureus [MRSA]). When extended oral 7 day postoperative antibacterial treatment in addition to the regular protocol was administered to high risk patients undergoing total joint arthroplasty there was notable reduction in incidence of infection.⁴ Other authors investigated the use of dual anti-Staphylococcal antibiotics including vancomycin against MRSA. The success rate of this protocol is unclear but an improvement in infection rate in revision surgery was demonstrated by some⁵ but not by other investigators.⁶ The incidence of acute kidney injury was higher in the dual protocol group.⁷

Naturally, antibiotic prophylaxis should be effective against the common pathogens that produce postoperative infections. Current trends in bacterial resistance and the increased incidence of methicillin resistant Staphylococci can render the use of 1st or 2nd generation cephalosporins nearly useless.⁸ One recent study found 30% of infections after joint replacements as polymicrobial; Gram-negative and Gram-positive combinations. Among monomicrobial infections 43% were Staphylococcus aureus (4% methicillin-resistant).⁹ Coagulase negative staphylococci were 30% of infections after knee prosthesis and 19% after hip prosthesis. Gram-negative bacteria were noted in 17% of hip and knee replacement infections.⁹ A study from Spain of total joint arthroplasties found an increase in Gram-negative infections, from 21% to 67%.⁹Staphylococcus aureus remains the most common organism after fracture surgery, but methicillin resistance is becoming more common and can even surpass in certain areas the sensitive species.¹⁰ Coagulase negative staphylococci are also prevalent and are methicillin resistant in 80–90% of cases.¹⁰ The incidence of multi-drug resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii is increasing¹⁰ as well as the incidence of gastrointestinal tract organisms, including Escherichia coli, Enterobacter, Enterococci, Klebsiella and Proteus.¹⁰

The aim of our study was to determine whether the use of 1st or 2nd generation cephalosporins for prophylaxis in orthopedic surgery is still effective against the current infecting organisms. We have retrospectively analysed the post-operative tissue, synovial fluid, pus, wound and blood cultures and antibiotic resistance after orthopedic operations in our department during the 2014–2015 and 2018–2019 calendar years for comparison.

2 Materials and methods

This retrospective study was approved by our institutional review board and a waiver of informed consent was granted. All medical record data were collected at one tertiary care center. The hospital information system was queried for all the patients that underwent orthopedic operations in our institution between 2014-2015 and 2018–2019 and had positive post-operative tissue, synovial fluid, pus, wound or blood cultures up to 6 months postoperatively using MDClone platform (MDClone, Israel). We then narrowed the analysis to patients that underwent primary hip and knee joint replacement and trauma surgery. For each included patient all positive cultures were retrieved from the microbiology laboratory. All cultures were analysed for antibiotic resistance and susceptibility. Positive cultures that appeared later than 6 months after surgery were considered to be due to haematogenous spread and not included. Skin and epidemiological survey cultures (nose, rectum) were not included, as they are considered to be unreliable representations of the real infecting organism. Patients not allergic to penicillin or cephalosporins received perioperative intravenous cefazolin. Patients with open fractures received cefazolin for 3 days and gentamicin for one day. Allergic patients received clindamycin or vancomycin instead of cefazolin according to surgeon's preference. All joint replacement surgery is performed at our institution using positive-pressure surgical helmet systems.

3 Results

8790 orthopedic operations were performed in 2014–2015 (52.55% men) and 8706 in 2018–2019 (49.62% men). The average age of the patients (±standard deviation) was 53.69 (±22.64) during the first period and 52.69 (±22.55) during the second. The distribution of operations that were included in the study is shown in Table 1.

The proportions of various bacteria for each surgery group are shown in Table 2. Trauma operations include internal and/or external fixation of closed or open fractures. Hip hemiarthroplasties were included in the trauma group, while non-elective total hip replacements performed for proximal femoral fracture were included in the total joint group. Only primary joint replacements were included.

Staphylococcus aureus, Staphylococcus epidermidis and other Staphylococci comprise a large proportion of positive cultures; mean 51.1% for all study groups. Staphylococcus epidermidis particularly was noted in 25.4% and 21.8% for joint replacements and 13.2% and 12.9% for trauma operations in the 2 periods respectively. The mean incidence of Gram-negative bacteria was 39.6% for all study periods. Polymicrobial Gram-negative and Gram-positive or several Gram-negative or Gram-positive bacteria combinations were found in 35% of joint replacements in the first period and 15.9% in the second; in trauma surgery it had an incidence of 38.46% and 36.98% respectively.

Bacterial resistance.

Oxacillin resistance has increased both for Staphylococcus aureus and Staphylococcus epidermidis (coagulase negative) between the two periods. Up to 83% of Staphylococci epidermidis were found resistant in the second period in all study groups (Table 3, Fig. 1). 33.49% of all Staphylococci were oxacillin resistant in the first period and 53.85% in the second.

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Fig. 1 An increase in oxacillin resistance of Staphylococci is seen in the second period, up to 83% of Staphylococcus epidermidis.

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Vancomycin resistance: In the first period (2014–15) no bacteria from all study groups were resistant to vancomycin. In the second period (2018–19) one patient (1.88% of cultures tested for vancomycin) was infected with vancomycin resistant Enterococcus faecium found in a bone culture after internal fixation of a tibia and fibula fracture (Table 4).

No staphylococci resistant to linezolid were found in both periods.

Advanced 3rd generation cephalosporin (Ceftazidime) resistance among the gram neative bacteria was 11–22% (Table 5).

Gentamicin resistance increased for staphylococci and decreased for Gram-negative organisms (Table 6) between the study periods.

The resistance to clindamycin increased between the study periods up to 45% of all bacteria tested (Table 7).

4 Discussion

Prophylactic antibiotic treatment certainly reduces the incidence of postoperative infections in orthopedics. But if the same reduction can be achieved by the use of ultra-sterile theatres, controlling risk factors or by other means, the use of antibiotics may be questionable. The liberal use of cephalosporins causes selection of resistant bacteria and when infection does occur, it occurs with organisms that are more difficult to eradicate and fuels the never-ending race with developing bacterial resistance. Surprisingly, almost 50 years after Boyd's, Burke's and Colton's paper¹¹ the basic recommendations for prophylactic antibiotic treatment in orthopedic surgery has resulted in minimal change.

Recent publications show an increase in methicillin/oxacillin resistant Staphylococci, up to 90% for coagulase negative Staphylococci. As Staphylococci remain prevalent in infections after orthopedic operations and methicillin resistant Staphylococci and many Gram-negative bacteria are also resistant to 1st generation cephalosporins, their use might become less efficient. Increase in incidence of Gram-negative bacteria necessitates the use of antibiotics that are active against those organisms. 1st generation cephalosporins are active against Proteus mirabilis, some Escherichia coli and Klebsiella pneumoniae, but are inefficient against Pseudomonas aeruginosa, Acinetobacterbaumannii, Bacteroidesfragilis, Enterobacter, indole-positive Proteus mirabilis, or Serratia marcescens; Thus decreasing the usefulness of 1st generation cephalosporins for prophylaxis even more. 2nd generation cephalosporins provide some additional protection against Gram-negative bacteria but are less effective against Staphylococci. Our work showed a comparable trend of an increase in oxacillin resistance of Staphylococci, and high incidence of non-gastrointestinal Gram-negative bacteria and gastrointestinal bacteria with some decrease in joint replacement surgery. Nevertheless the mean incidence of Gram-negative bacteria was 39.6% in our study.

Vancomycin resistance is currently rare but it might become a problem in the future as bacteria acquire resistance. Heteroresistant vancomycin-intermediate Staphylococcus aureus is more common already and probably will become a more serious problem in the near future. We have demonstrated that clindamycin resistance is increasing and the common use of clindamycin as an alternative prophylactic drug in cephalosporin allergic patients should be re-considered. The choice of vancomycin for this purpose is also problematic, due to absence of activity against Gram-negative bacteria. Vancomycin was found generally to be less effective as a prophylactic agent.⁶ Some hospitals are already recommending combining aminoglycosides in their prophylaxis protocols,¹² though nephrotoxicity and ototoxicity are a significant drawback, especially during concurrent use with vancomycin.

Our study must be interpreted in light of certain limitations. As all of the patients in our study received prophylactic antibiotics, it is impossible to know about the infections that were prevented with these. The study's retrospective nature presents an additional limitation. As we examined the local bacterial flora, it is difficult to extrapolate bacteria from other locations. We counted positive cultures, and patients that had more than one positive culture may be overrepresented in the statistic. Finally, Bacteria that are difficult to grow may be underrepresented relatively to bacteria that grow easily in a medium.

5 Conclusion

The optimal antibiotic to be used in perioperative prophylaxis in orthopedic surgery should be active against methicillin-resistant Staphylococci and also to provide at least reasonable protection against Gram-negative organisms. It should achieve and sustain bactericidal concentrations in serum, bone and soft tissues when the incision is made and during the operation. Bacteria should not be able to easily acquire resistance to that antibiotic, as it is intended for massive use. We can conclude that the use of 1st or 2nd generation cephalosporins for prophylaxis in orthopedic surgery does not provide the necessary protection anymore and a new consensus should be achieved, considering geographic variations in pathogen incidence and stratification by risk of infection for different patients.

Funding

No funding was received for this paper.

Conflicts of interest/Competing interests

All authors declared no conflict of interest.

Ethics approval

Approved by our institutional ethics committee.

Consent to participate

Not applicable.

Consent for publication (include appropriate statements)

Was sent to corresponding author.

Availability of data and material (data transparency)

All data is digitally saved and available for review.

Trial registration number and date of registration

0826-20-TLV- December 27, 2020.

Authors' contributions

•Conceptualization: EK.•Data curation: EK.•Formal analysis: EK, MD.•Methodology: EK, YW.•Validation: MD.•Writing - original draft: EK, SM.•Writing - review & editing: EK, SM, YW, MD.