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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Orthop Clin North Am. 2021 Feb 10;52(2):93–101. doi: 10.1016/j.ocl.2020.12.002

Clinical Evidence of Current Irrigation Practices and the Use of Oral Antibiotics to Prevent and Treat Periprosthetic Joint Infection

Jason Zlotnicki 1, Alexandra Gabrielli 1, Kenneth L Urish 1, Kimberly M Brothers 1,✉
PMCID: PMC7990073  NIHMSID: NIHMS1655671  PMID: 33752842

Introduction

During total joint arthroplasty, the contamination of the operative field with bacteria has historically been thought to be the major cause of early, acute periprosthetic joint infection (PJI).1 Aimed at reducing this bacterial load, surgeons have engaged in the use of irrigation and other adjuvants during surgery and prior to wound closure. These additives have varied in type, concentration, and as well as mechanism for disrupting bacterial colonization. Antiseptics, antibiotic-infused irrigation, or soap-like surfactants are three main classifications for irrigation solutions.2 Oral antibiotics in the peri- and post-operative period have been explored, while new advances continue to emerge for the prevention and treatment of acute PJI. This review will examine some of the most widely-reported interventions; dilute betadine/povidone-iodine, chlorhexidine and hydrogen peroxide as lavage additives. Techniques for irrigation and extended oral antibiotic regimens will be presented. The role of irrigants in PJI for treatment of planktonic and biofilm bacteria will be discussed. Lastly, the newest advances in the field of adjuvants for prevention of PJI will be presented.

Betadine/Povidone-Iodine

Dilute betadine lavage has been demonstrated in the literature to decrease rates of postoperative infection in orthopaedic, urologic, cardiovascular, and general surgery procedures.3,4 This is due to the povidone-iodine contained within betadine, which releases free iodine in solution that is toxic to environmental microorganisms.5 The success of this technique was first widely demonstrated in total joint arthroplasty by Brown et al., in which the occurrence of PJI in the first 90 postoperative days was reduced from 0.97% to 0.15%, p = 0.04.6 Additional advantages included that it was inexpensive, simple, and readily available within most operating rooms. Although larger reviews of the clinical studies have questioned the utility of this intervention,7 further recent studies continue to demonstrate a potential role for dilute betadine irrigation in primary and revision arthroplasty.8 A most recent randomized control clinical study comparing a three-minute dilute betadine lavage to normal saline demonstrated a significant decrease in infection incidence (3.4% vs. 0.4%, p = 0.38).9 In the treatment of higher-risk PJI patients, dilute betadine has been demonstrated to be safe in combination with other substances including the antibiotic vancomycin.10 Although a role for further cocktails may have utility, dilute-betadine solution remains a possible option.

Chlorhexidine

Chlorhexidine products have also started to receive attention as a potential intra-operative irrigant for the reduction of bacterial contamination. Historically studied and used as preoperative skin disinfectant, 2% chlorhexidine gluconate demonstrated a significant reduction in deep surgical site infections in multiple studies.11,12 This is due to chlorhexidine existing in cation form at physiological pH, allowing it to bind to negatively charged bacterial membranes - this leads to both bacteriostatic and bactericidal effects at low and high concentrations, respectively.13 Despite the excellent data with preoperative skin cleansing, the data for intraoperative use has been inconsistent. A study by Frisch et al. did not detect any difference in infection reduction at 1 year with the use of chlorhexidine gluconate when comparing to dilute povidone-iodine as well as saline.14 In the case of a known infection, in vitro studies have shown a significant decrease in bacterial CFUs of biofilm forming Staphylococcal species.15 However, larger clinical studies are needed to detect a benefit for the use of chlorhexidine for the prevention and treatment of PJI. Older studies have demonstrated success with a combination of chlorhexidine and hydrogen peroxide,16 with theoretical benefit of a kill of a wider range of organisms with lower concentrations of each substance.

Hydrogen Peroxide

As cases of complex infection and resistant species arise, more aggressive debridement strategies are being tested for the treatment of colonized joints.17 This includes the use of hydrogen peroxide, which despite decades of use in wound treatment has only recently emerged in the treatment of total joint arthroplasty. Historically, hydrogen peroxide has been demonstrated to be widely effective in vivo in killing bacteria, through numerous pathways, including oxidative stress.18–20 Clinical studies have demonstrated mixed results across multiple surgical specialties, especially when used in isolation.21–23 Recent studies in total joint arthroplasty have demonstrated more success when used in combination with other antimicrobial irrigation fluids, specifically povidone-iodine. George et al. demonstrated excellent clinical outcomes in prevention of infection recurrence in n = 39 total joint arthroplasties (TJAs), at a mean of six years after single stage exchange arthroplasty, using a combination of povidone-iodine and diluted hydrogen peroxide.24 However, the complications of cytotoxicity and air embolism associated with the effervescence have been documented in the literature, with some suggesting no role for peroxide in orthopaedic surgical care.25,26

Overall, there are a number of clinical studies with variable results at adding povidone-iodine, chlorhexidine, or hydrogen peroxide to irrigants to prevent PJI. An important observation is the absence of clinical studies at using these adjuvants in the treatment of PJI. The use of bactericidal compounds would seem to be logical in the treatment of PJI, but appreciating that oxidative stress can induce biofilm antibiotic tolerance, as discussed below, may create a more complicated picture.

Pulse lavage versus Gravity Irrigation

Aside from adding antimicrobials and surfactants to irrigation fluid, study has been directed at the effect of irrigation delivery into the surgical wound bed. The American College of Surgeons has classified irrigation method as either high (i.e. pulsed lavage system) or low pressure (i.e. bulb syringe, gravity flow, etc.).27 An early study examining S. aureus inoculation removal in vitro demonstrated that high and low pressure were equivalent at early time points, but low pressure irrigation no longer had effect after 6 hours.28 While further studies demonstrated superiority of higher pressure irrigation,29 additional study demonstrated higher levels of tissue damage, larger bacterial burden rebound and the propagation of bacteria into deep tissues.30–32 Most recently, the Fluid Lavage of Open Wounds (FLOW) study, conducted in the investigation of open fractures, has shown no difference in re-operation rates between low and high pressure systems.28 Therefore, while high pressure systems may be more effective in decreasing bacterial counts, injury to local soft tissues and bacterial rebound must be taken into account in the care of surgical wound beds. Ultimately, the best available current evidence suggests that there is no difference between these two methods.

Oral Antibiotics for Prophylaxis and Treatment

In addition to the use of adjuvant irrigation techniques for high risk patients or known cases of PJI, the use of an extended post-operative oral antibiotic regimen has been theorized to provide benefit. In a study examining patients deemed high-risk for PJI on basis of specific risk factors, high-risk patients who did not receive a seven-day course of oral antibiotic on discharge were more than four times more likely to develop PJI.33 In this study, patients received cefadroxil 500 mg BID unless they tested positive for MRSA in pre-op assessment mandating the use of Bactrim DS BID. If they had documented anaphylaxis to cephalosporins, they were given 300 mg of clindamycin TID.33 In settings of known periprosthetic joint infection, debridement and antibiotics with implant retention (DAIR) and two stage exchange are the most common techniques used. Following the irrigation and debridement, systemic antibiotics are used for approximately 6 weeks, although IDSA guidelines allow for a range in treatment. Based on the high failure rate, almost 60%34, associated with DAIR procedures, the use of oral antibiotics for an undisclosed length of time has become increasingly popular. A recent large clinical study of DAIR procedures has strong evidence that extended use of oral antibiotics for one year can decrease failure rates, was not associated with increased adverse events, and provided guidelines for antibiotic stewardship, as treatment was only required for a defined time period35. The other common treatment for PJI includes two-stage exchange arthroplasty with reported success rates ranging from 67–91% depending on the definition of success.36 However, this leaves significant room for improvement in the eradication of infection and successful implant survival at later time points after two-stage. A recent multicenter randomized study examining a three-month course of oral antibiotics against no antibiotics demonstrated that the treatment group failed two-stage revision less frequently than those not receiving antibiotics (5% vs. 19%, p = 0.016).37 These findings are further supported by a more recent RCT demonstrating reduction of infection recurrence rate after a 3-month PO course following two-stage revision, 12.5% (antibiotics) vs. 28.6% (no antibiotics).38 Other groups have demonstrated the valuable role of tranexamic acid in reducing the rates of PJI, likely through decreasing the presence of a postoperative hematoma39. This highlights the need for continued study in the field of post-operative organism-directed antibiotic therapy, in addition to intra-operative strategies.

Biofilm antibiotic tolerance

Irrigation and debridement are the gold standard for management and treatment of PJI. However, this treatment fails in 60% of cases40. As bacteria multiply in infections they transition from the free-swimming or the planktonic form and cluster together to form large aggregates composed of an extracellular matrix called a biofilm. A biofilm can contain 1000 to 10,000 times more bacteria growing than in the planktonic form.41 In comparison to their planktonic counterparts, biofilms can be as much as 1000 times more resistant to biocides41,42. The biofilm extracellular matrix is largely responsible for this resistance. The biofilm extracellular matrix consists of polysaccharides, nucleic acids, and protein all of which are believed to contribute to antibiotic tolerance.42–44 Mandell et al. demonstrated the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were much higher in biofilms in comparison to planktonic bacteria in PJI clinical isolates of S. aureus.42,43,45 Similarly, Koch et al. demonstrated similar findings in PJI clinical isolates of Staphylococcus epidermidis and Cutibacterium acnes46. Antibiotic tolerance in PJI is believed to occur through 1) the development of bacterial persister cells47 that are able to survive in the presence of antibiotics,48 2) an overall decreased bacterial metabolism when in the biofilm state,49 and 3) the thick extracellular polymeric substance that binds and prevents drug penetration into the biofilm.43,50

Persister cells and toxin anti-toxin systems

Persister cells47 are a very small population of bacteria that are highly tolerant to antibiotics without undergoing any genetic changes.51 It is hypothesized that they are less sensitive to antibiotics because their cellular metabolism is dormant and thus not susceptible to antibiotic targets. Their antibiotic tolerance in the biofilm state is accomplished through toxin anti-toxin systems. This system is composed of a toxin that is able to disrupt an important cellular process and an anti-toxin that prevents toxin activation. The toxin and antitoxin form a complex in conditions of normal homeostasis. When the bacterium encounters an environmental stress (i.e. antibiotic treatment), the antitoxin disassembles from the toxin. The toxin becomes activated and disrupts bacterial metabolism to induce a state of dormancy.48,52,53 This system allows the bacteria to become tolerant to antibiotics. When treatment is stopped, the anti-toxin binds to the toxin resuming metabolic activities and antibiotic sensitivity. Toxin-antitoxin systems have been well studied in gram-negative bacteria. In Escherichia coli TA systems were identified to play a role in persistence and antibiotic tolerance.54 In Mycobacterium tuberculosis TA systems were shown to play a role in antibiotic tolerance, environmental stress adaptation and virulence.55 In studies by Ma et al. the Staphylococcus aureus TA system MazEF was demonstrated to play a role in biofilm formation, antibiotic tolerance, and infection.56

Oxidative Stress agents and biofilm antibiotic tolerance

Many studies have demonstrated the positive benefit of oxidative stress inducing agents in removal of biofilms. Schwecter et al. demonstrated disruption of methicillin-resistant S. aureus (MRSA) biofilms with chlorhexidine gluconate.57 Lineback et al. found hydrogen peroxide and sodium hypochlorite were more effective against S. aureus and Pseudomonas aeruginosa biofilms than quaternary ammonium compounds.58 However, given what has been previously discussed on effective irrigation solutions and biofilm antibiotic tolerance, oxidative stress inducing agents such as hydrogen peroxide, povidone-iodine, and chlorhexidine have also been demonstrated to inhibit bacterial metabolism49 thus increasing their tolerance to antibiotics.

Several studies have demonstrated the ability of these agents to be effective against planktonic bacteria but fail to significantly reduce the bacterial burden of biofilm bacteria.59 Rowe et al. demonstrated oxidative stress agents halt bacterial metabolism and induce persistence in S. aureus planktonic cells.60 In addition, several studies have demonstrated biofilm resistance to hydrogen peroxide.61–63 Elkins et al. found two catalases provided protection to P. aeruginosa biofilms when exposed to hydrogen peroxide.62 Hydrogen peroxide enhanced biofilm formation in a mucoid P. aeruginosa strain by promoting overproduction of alginate, a component of its extracellular matrix in a study by Tan et al.64 Leung and colleagues found after a 5 minute exposure of biofilms to clinically relevant concentrations of hydrogen peroxide, the majority of Candida albicans and E. coli biofilms were intact and alive.63 Tote et al. focused on several biocides and their ability to remove planktonic and biofilm bacteria.65 As expected the majority of the biocides could eliminate planktonic bacteria but failed to eliminate the biofilm. Povidone-iodine and hydrogen peroxide were effective enough with a 5 log reduction of planktonic P. aeruginosa after a 5 minute contact time. After treatment with povidone-iodine and hydrogen peroxide a 5 log reduction was observed in S. aureus planktonic growth after 5 and 15 minutes respectively. Of all the biocides tested in this study, sodium hypochlorite and hydrogen peroxide had the greatest activity on P. aeruginosa and S. aureus biofilms due to their ability to target both the biofilm biomass and the extracellular matrix. Hydrogen peroxide was able to reduce S. aureus biofilms by 89% after only 1 minute. This efficacy was not as rapid for P. aeruginosa but did result in complete eradication of biofilms after 60 minutes of treatment. Povidone iodine had a greater efficacy and reduced P. aeruginosa biofilms by 94% after only a 1 minute contact time. Chlorhexidine-digluconate was far more effective at targeting S. aureus resulting in an 84% decrease in viability after a 1 minute contact time in comparison to a 40% reduction in viability of P. aeruginosa biofilms. These differences in microbicidal activity are most likely due to the composition of the bacterial cell walls as S. aureus is a Gram-positive bacterium and P. aeruginosa is Gram-negative. Hardy et al. cautioned repeated exposure of S. aureus to biocides.66 Significant increases in antibiotic minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) were observed after repeated exposures of clinical isolates to chlorhexidine.

The impact of moving fluids on biofilm physiology

Many groups have focused on how the movement of fluids impact biofilm formation. Biofilms have been described as viscoelastic.67 Work by Böl et al. and Blauret et al. have demonstrated under certain conditions the same biofilm can behave as a fluid, a solid, or a mixture of the two.68,69 Flow cell experiments where growth media is flowed directly across a growing biofilm have shown that biofilms are able to rearrange their macroscopic structure in response to shear stressing forces to form more “drag-like” forms such as streamers or ripples.70 Biofilms with ripple or wavy patterns have been found growing inside endotracheal tubes71 and venous catheters.72 In an elegant study by Fabbri et al. the rippling effect of the biofilm was studied using a compressed air jet.73 Ripple-like structures were observed to form at the biofilm/fluid interface in Streptococcus mutans and Staphylococcus epidermidis. A wrinkly phenotype was observed to form rapidly in P. aeruginosa biofilms and was more resistant to disturbance by the air jet. The authors hypothesized these differences in biofilm phenotypes were likely due to differences in the extracellular matrix that formed each biofilm. These studies highlight how the extracellular matrix of the biofilm can allow it to survive elimination attempts such as irrigation in the context of orthopaedic infections.

As previously discussed high pressure systems may be more effective in decreasing bacterial burden. The role of high pressure (pulse lavage) irrigation in biofilm clearance was explored by Urish et al.74 S. aureus biofilms were grown on 3 different total knee arthroplasty materials cobalt chrome metal, polymethyl methacrylate (PMMA) and polyethylene. The biofilm biomass was quantified before and after pulse lavage irrigation. The biofilm was nearly eradicated from cobalt chrome metal, but PMMA and polyethylene only had a ten-fold reduction in biomass. These results indicate even after pulse lavage irrigation a significant amount of the biofilm remains on the implant surface. These results indicate under these circumstances antibiotic treatment would be unlikely to effectively eliminate infection.

Augmenting Current Therapies and Upcoming Technologies

In addition to organism-directed antibiotic antibiotics, therapies that can effectively eradicate biofilms are also necessary. Biofilms continue to be a problem due to their action as a barrier against mechanical debridement, antibiotics administration, and the effects of the host’s immune system. Treatment strategies surrounding biofilm infections involve optimizing and augmenting current treatment algorithms as well as investigating novel avenues that might aid in the eradication of biofilms. It has been established that rifampin may be an adjunct to use with other antibiotics for the treatment of PJI.75,76 Greimel et al. explored possible synergistic activities of rifampin combined with moxifloxacin using a mouse model of PJI.77 This study exhibited that the combination therapy has superior bactericidal effects compared to the monotherapy after 14 days of treatment.77 Beyond antibiotic adjuvants, additional novel therapies are being investigated. Specific nanoparticles are beginning to be identified as having passive antibiotic properties that could be beneficial in the treatment of PJI. Certain nanoparticles are able to lyse bacterial cells by increasing the concentrations of reactive oxygen species and decreased the integrity of the cell membrane and wall. Zaidi et al demonstrated that some inorganic nanoparticles (zinc oxide, silver, copper) have bactericidal modes of action and would be challenging for bacteria to develop resistance to.78 A rat model for MRSA wound infection showed faster wound healing and formation of collagen fibers using nanoparticles.79 This technology has yet to be tested in an in vivo PJI model but does show promise. Mandell et al. demonstrate a cationic antimicrobial peptide WLBU2 can effectively eliminate MSSA and MRSA clinical isolate biofilms.80,81 This peptide was still effective in the presence of bacteria with inhibited metabolism suggesting a promising future for its use as an antimicrobial therapy.80

Summary

In periprosthetic infection, dilute betadine, chlorhexidine, and hydrogen peroxide have been shown to be effective against treatment of planktonic bacteria. However, this treatment largely fails due to the presence of antibiotic tolerant biofilm. Repeated exposure to oxidative stress inducing biocides in irrigant solutions as well as reduced bacterial metabolism in the biofilm state contribute to this antibiotic tolerance. The use of antiseptics as irrigants should be carefully considered and only used when deemed necessary. Future studies focused on combination therapies of these antiseptics and eradication of biofilms should be explored.

Key Points:

  • Periprosthetic Joint Infection (PJI) is difficult to treat and a costly complication following total joint arthroplasty

  • Strategies aimed at reduction of PJI have great significance in the current health environment

  • Biofilm has a high tolerance to antibiotics, and this tolerance can be induced by oxidative stress

Synopsis:

In orthopaedic infections, the addition of hydrogen peroxide, povidone-iodine, and chlorhexidine can be added to irrigants to prevent and treat infection. There is a larger body of evidence that supports their use as a prophylaxis to prevent infection as compared to treating infection. Biofilm has a high tolerance to antimicrobials induced by oxidative stress.

Clinics Care Points.

  • The use of dilute-betadine or chlorhexidine solution as an additive to irrigation solution may prevent PJI, but further study is needed

  • Due to its mixed results for efficacy, the use of hydrogen peroxide as an irrigant requires further study

  • Both high (pulsed lavage systems) or low pressure irrigation are equivalent resulting in a reduction in biofilm mass

  • Oral antibiotics may prevent PJI in high risk patients following arthroplasty surgery and improve treatment outcomes in DAIR and two stage exchanges.

  • Biofilms are highly antibiotic tolerant

  • Antibiotic tolerance is mediated by toxin anti-toxin systems

  • Reduced bacterial metabolism contributes to antibiotic tolerance

  • Biofilms are largely resistant to forces applied to their outer surface limiting the effectiveness of irrigation and debridement

  • Combination therapies with irrigants and alternative strategies are necessary to eradicate biofilms in PJI

Footnotes

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