2 g (3 g for patients over 120 kg)
Cefazolin is the most widely used antibiotic for PJI prophylaxis during the last decades in the USA and Europe . It is effective against gram-positive, aerobic gram-negative bacilli, and anaerobes. It also shows an excellent tissue availability within first minutes after its administration . Inhibitory concentrations are reached with doses as low as 1 g by intravenous (IV) administration. In 2015, Angthong et al.  reported that IV cefazolin at a dose of 2 g produced greater intraosseous concentrations overall than a dose of 1 g. However, higher intraosseous concentrations did not correlate with higher inhibitory effects. Despite its great advantages, cefazolin it is not effective against MRSA. For this, increased prevalence of MRSA should be taken into account to decide if cefazolin is the best option in our case. This is especially important as most of early PJI are caused by microorganism resistant to cefazolin .
However, clindamycin and vancomycin are appropriate options when cephalosporins are contraindicated (i.e., allergy) or when risk factors for antibiotic-resistant organism are present. Clindamycin adequately covers Staphylococcus spp. and Streptococcus spp. and is effective against many MRSA species as well, but vancomycin confers better coverage of MRSA. It is recommended for patients with known sensitivity to beta-lactams in regions with low prevalence of MRSA, when vancomycin would be indicated.
Vancomycin is also effective against streptococci, enterococci, and Clostridium and reaches good tissue concentration within the first minutes after its administration .
Quinolones are another alternative, with excellent cover against gram-positive and gram-negative bacteria. However, ciprofloxacin is not the best option, as resistance may develop relatively rapidly and because it favors Clostridium difficile colonization .
Gentamicin is also active against gram-negative and gram-positive bacteria. It is active against MRSA also. It can be used mixed with bone cement because it is heat stable. It can be also used in dual antibiotic prophylaxis .
Local microorganism resistance should be assessed to determine the proper prophylaxis. Microbiological and infectious diseases departments should continuously monitor the prevalence and resistance of different microorganisms. This is especially important with the cases of high prevalence of MRSA. Regarding this, even if vancomycin is not recommended for routine use in healthy people, its use should be considered when a TKA is performed in patients colonized by MRSA and penicillin allergies or when a high risk of MRSA infection exists . However, no clear evidence supporting routine dual antibiotic prophylaxis (i.e., cefazolin + vancomycin) in no high-risk patients exists, while complications (especially nephrotoxicity) are significantly increased . In 2003 Lazzarini et al.  found that TKA bone and soft tissue penetration of teicoplanin after regional prophylaxis with 200 mg was at least comparable with that achieved after systemic prophylaxis with 800 mg. Regional prophylaxis in TKA appeared to be safe and valuable. Higher dosages of teicoplanin seemed to be required to ensure coverage against coagulase-negative staphylococci.
As with other antibiotics, vancomycin use to treat pseudomembranous colitis has encouraged the development of vancomycin-resistant bacteria, including Staphylococcus spp. New antibiotics have been introduced to treat these bacteria, such as linezolid, daptomycin, and tigecycline. However, it seems to be reasonable to optimize antibiotic use and other methods of PJI prophylaxis to avoid increasing resistances.
This is especially important when treating nosocomial pathogens such as Escherichia coli, Klebsiella pneumonia, and Enterococcus spp. New resistances against third-generation cephalosporins, fluoroquinolones, or both have recently been reported . This is likely to jeopardize future effective prophylaxis as well as PJI treatment.
It is difficult to select an adequate prophylaxis for patients colonized or recently infected with multidrug-resistant pathogens. It is probably sufficient to cover pathogens, but other factors such as the immune status of the host and the proximity of the reservoir of the pathogen to the incision should be considered. In contrast to MRSA-colonized patients, where prophylaxis against MRSA is standard and evidence based, the ideal antibiotic for gram-negative pathogen-colonized patients is not well established . Patients must be covered on a case-by-case basis, considering the factors mentioned above.
In the special case of patients receiving therapeutic antimicrobials for a remote infection before surgery, elective TKA should be postponed.
5.7 Drug Administration
Some issues pertaining to administration should be considered. Classically, systemic administration should be done within the hour before the incision or the tourniquet inflation [7, 34]. In a study conducted by Steinberg et al., a decrease of 0.8% was seen if the antibiotic was administered within 30 min before incision or tourniquet inflation, in comparison when it was administered 30–60 min before . No differences were found when antibiotic administration was done 30 min before tourniquet inflation in comparison with 10 min before inflation . Classen et al. demonstrated that antibiotics administered during anesthetic induction were more effective than early administration (between 24 and 2 h before incision) or administration after surgery . So, for standard antibiotic prophylaxis, drug administration should be done within the hour before incision .
However, vancomycin should be administered over 60–120 min, in order to avoid a histaminergic reaction (red man syndrome), which can develop if the infusion is more rapid. Vancomycin should also be administered earlier as its penetration into the bone, synovium, and soft tissue is slower in comparison with cefazolin . Relating to administration, it is important to adjust doses to the patient’s weight. It has been noted that the standard 1 g of vancomycin could be insufficient for preventing MRSA infections in up to 69% of patients . Up to 69% of patients are underdosed with 1 g of vancomycin, and doses of 15 mg/kg are appropriated. It has also been recommended to start fluoroquinolone infusion within 2 h before incision .
It should be emphasized that prophylactic antibiotics should not be administered before incision or tourniquet inflation when a PJI is suspected and a TKA revision is encountered. Antibiotic prophylaxis should be delayed until intra-articular cultures are obtained in such cases.
In order to maintain adequate systemic concentration, administration should be repeated 4 h after the incision or when high blood loss (>2000 mL) is observed [24, 39, 40]. Antibiotic prophylaxis should be maintained until 24 h . Current evidence does not support any benefit of antibiotic prophylaxis beyond 24 h . Several studies have demonstrated no improvement on infection rates when the prophylaxis is maintained further than 24 h in clean surgery [42, 43], and, in fact, complications such as toxicity, Clostridium difficile infections, and development of resistances are consequences of unnecessary, prolonged prophylaxis [44, 45], increasing iatrogenia and costs [46, 47].
5.8 Staphylococcus aureus Screening and Decolonization
Staphylococcus aureus colonization is a known risk factor for PJI . Kalmeijer et al. demonstrated that nasal colonization was an independent risk factor for PJI . A recent study  showed an almost full individual concordance between Staphylococcus aureus genotypes in carriers who developed a deep SSI. This fact firmly supports transmission from the nose, skin surfaces, and other endogenous body areas as a possible route of infection.
Near 20% of the general population is Staphylococcus aureus carrier, and up to 4% of the population is colonized by MRSA [52, 53]. In the last decade, MRSA has changed from being exclusively nosocomial to community-acquired infection . While nasal colonization has decreased in the last decade in the USA, MRSA colonization has increased . A population may be classified according to three different patterns regarding their nasal colonization status: intermittent carriers (60%), persistent carriers (20%), and noncarriers (20%) .
The anterior nostrils are the main reservoir of Staphylococcus aureus in colonized individuals. Secondary reservoirs include the oropharynx, axillae, groin, perineum, forehead, and neck. These other sites should be encountered especially in the context of low-prevalent MRSA colonized population, where nasal cultures could not be sensitive enough for detection .
Given the consequences of infection, many studies regarding the management and decolonization of Staphylococcus aureus and MRSA carriers have been developed in recent years [49, 52]. Increased resistance to vancomycin has encouraged the development of screening programs and the change of antimicrobials as a consequence.
It has been demonstrated that preoperative screening of carrier condition and decolonization is effective  and a cost-effective procedure to decrease PJI rates [57–59].
Regarding the preoperative diagnosis of Staphylococcus aureus, cultures are still the standard method. Anterior nasal swab cultures are the most common sampling method, but as remarked before, other sites, such as the pharynx, groin, or wounds, could be more suitable in enhancing detection in low-prevalent carrier populations .
In recent years, polymerase chain reaction (PCR) has gained importance as an alternative to preoperative cultures in diagnosing carriers. It is also useful and effective in detecting MRSA [52, 59, 61]. It has been demonstrated to be sensitive, specific, and cost-effective in the diagnosis of carrier status and seems to be the best test in comparison to others . It is more sensitive and faster than traditional cultures and currently constitutes the gold standard for Staphylococcus aureus detection .
Decolonization has been done classically with intranasal mupirocin. It is applied on colonized high-risk patients for perioperative PJI, decreasing perioperative infection rates . But this is controversial, as other well-designed studies do not demonstrate differences between mupirocin administration or not . Therefore, as it is an antibiotic, and, even if resistances have been rarely reported , its overuse could lead to resistance development . This is why it is not recommended as empiric preoperative prophylaxis in patients without surveillance . It has been estimated that prior mupirocin exposure increase nasal colonization ninefold in MRSA carriers .
Although optimal timing and duration of administration are not standardized, it is thought that 5 days of treatment are required to be effective. Treatment compliance in this situation can be low . Multiple colonization sites are another risk factor for decolonization failure.
In recent years, povidone-iodine has emerged as an alternative to decolonization with intranasal mupirocin . It is effective to eradicate mupirocin-resistant Staphylococcus aureus . It can be applied on the day of the surgery and does not develop resistances, being at least as effective as mupirocin is .
Other alternatives to mupirocin decolonization have been proposed. Two percent chlorhexidine body shower has demonstrated mixed results. While it seems to be effective as monotherapy, better results have been observed when used as adjunct to mupirocin protocols . An advantage is that a shower covers other sites of Staphylococcus aureus colonization. None of them have been as extensively studied as mupirocin, and further studies are needed.
To date, PCR has gained importance in Staphylococcus aureus carrier screening, as well as decolonization of carriers with nasal povidone-iodine.
Decolonization is not permanent . When a patient has been colonized, a high risk of recolonization exists, and, if mupirocin was used, increased risk of resistances exists . So if a patient is undergoing subsequent procedures, screening for carrier status and, eventually, decolonization, should be done.
5.9 Antibiotic-Loaded Bone Cement
Polymethyl methacrylate (PMMA) bone cement is widely used and represents the standard for TKA fixation to bone. Bone cement has the capacity to release antibiotic molecules during hours or even days. This capacity is increased as the porosity is increased . In recent years, adding antibiotics into bone cement has been encouraged as a way to increase bone and surgical site antibiotic concentration and liberation, especially in the revision setting, where cement spacers and antibiotic-loaded bone cement are widely used [71, 72]. However, although the evidence for the use of antibiotic-loaded bone cement in TKA looks favorable, it has not been confirmed by recent studies , and available data from different national registries remain controversial .
Added antibiotics can alter bone cement properties and should comply with several criteria . They should be heat stable, water-soluble, and bactericide allowing for gradual elution and avoiding allergic reaction .
Aminoglycosides (e.g., gentamicin, tobramycin) fit these criteria. Other antibiotics such as vancomycin, erythromycin, or colistin have been also used. The association of tobramycin and vancomycin is of interest, as its elution is improved if they are associated .
Adding further doses of antibiotics to cement should be considered carefully, in order to not alter the mechanical properties of PMMA. In a classical study by Lautenschlager et al. , 10 g of gentamicin added to 60 g of cement resulted in decreased strength and mechanical properties. As a general principle, the higher the dose, the higher the elution of the antibiotic from the cement while the worse the mechanical resistance [77, 78]. It is not clear what is the ideal concentration of antibiotic with no repercussion on mechanical strength and microbiological effectiveness . However, increased risk of mechanical failure with the use of antibiotic cement has not been demonstrated in the clinical setting . No differences between prepackaged cement with antibiotic and manual blended cement powder with antibiotic in the operating room have been demonstrated .
Toxicity and selection pressure of flora and development of resistances are also potential adverse effects of antibiotic load bone cement . While adverse effects such as local bone cell toxicity and nephrotoxicity have been reported, these remain rare, as the dose of antibiotics is usually low.
In a study from the Canadian joint registry , no differences in 2-year revision rates for TKA were observed between patients with antibiotic-loaded bone cement and conventional bone cement. This has been also observed in other studies .
Antibiotic loading of bone cement increases the overall cost of TKA. In a study conducted by Gutowski et al. , they investigated the clinical and cost-effectiveness of the use of antibiotic-loaded cement for primary TKA by comparing the rate of infection in 3048 TKAs performed without loaded cement over a 3-year period versus the incidence of infection after 4830 TKAs performed with tobramycin-loaded cement over a later period of time of a similar duration. Depending on the type of antibiotic-loaded cement that was used, its cost in all primary TKAs ranged between USD $2112.72 and USD $112606.67 per case of infection that was prevented. It has been estimated that the treatment of one case of PJI varies from 50,000 to 100,000$ . Taking into account that antibiotic-loaded cements are more economical than managing PJI, we could use them especially when we are facing a case with high risk of infection .
Antibiotic prophylaxis is not a cost-free action. As with all medicines, antibiotics can result in adverse effects. Antibiotic administration under the adequate dosage/levels could lead to increasing resistances and partial treatment of infections . As we have described before, increasing microbial resistance is one of the main problems we face.
Antibiotic overuse could also result in Clostridium difficile infection. In a study reported by Campbell et al. on inpatient hospitalization, antibiotics for urinary tract infections and the use of proton pump inhibitors were identified as risk factors for Clostridium difficile infection in orthopedic patients . Longer duration of prophylaxis and the usage of multiple agents have also been identified as risk factors .
Even rare, anaphylactic reactions to cephalosporins can occur (beta-lactams are the most frequent antibiotics causing anaphylactic reactions), as with other beta-lactam antibiotics.
Type 1 (immunoglobulin E (IgE)-mediated) allergic reactions to beta-lactams are uncommon. They usually occur within 30–60 min after administration and can pose a life-threatening emergency. In this situation, cephalosporins, penicillins, or carbapenems should be avoided.
However in other non-IgE-mediated allergic reactions against penicillins such as anaphylaxis, urticarial, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis, cephalosporin and carbapenem use could be safe . Patients should be questioned about their history of allergies before drug administration. It is also important to determine whether an antibiotic allergy is true or not, to avoid wrong administration of other drugs and possible resistance development.
Other more common reactions with beta-lactam administration include skin rash, eosinophilia, diarrhea, or Clostridium difficile infection. As previously stated, clindamycin is a good alternative when beta-lactams are not indicated. The typical and most severe adverse effect of clindamycin is Clostridium difficile diarrhea. Other adverse effects are skin rash or abdominal pain.
Regarding vancomycin, a histamine release can occur with fast infusion. This reaction includes pruritus, erythema, and hypotension (red man syndrome). It can be avoided with slow infusion. Nephrotoxicity and ototoxicity are other side effects of vancomycin but rare (<1%). If anaphylaxis or intolerance to vancomycin is present, daptomycin constitutes a good alternative.
Prophylactic antibiotics should cover at least the most prevalent bacteria-producing postoperative infection. They should reach high enough concentrations (at least the minimum inhibitory concentration) in the serum and bone and maintain this over time. Doses should be repeated to keep appropriate concentrations. For standard antibiotic prophylaxis, drug administration should be done within the first hour before incision. Cefazolin (1–3 g depending on body weight every 2–5 h) is the most widely used antibiotic for PJI prophylaxis during the last decades in the USA and Europe. It is effective against gram-positive, aerobic gram-negative bacilli, and anaerobes. In spite of its great advantages, cefazolin is not effective against MRSA. For this reason, a high prevalence of MRSA should be kept in mind to determine if cefazolin is the best option in our case. However, clindamycin (90 mg every 3–6 h) and vancomycin (15/kg every 6–12 h) are adequate alternatives when cefazolin is contraindicated (i.e., allergy) or when risk factors for antibiotic-resistant organisms are present.