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Antibiotic Choice: The Synergistic Effect of Single vs Dual Antibiotics
The Journal of Arthroplasty 35 (2020) S19eS23
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Antibiotic Choice: The Synergistic Effect of Single vs Dual Antibiotics Nequesha S. Mohamed, MD a, Wayne A. Wilkie, DO a, Ethan A. Remily, DO a, James Nace, DO a, Ronald E. Delanois, MD a, *, James A. Browne, MD b a b
Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital, Baltimore, MD Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 September 2019 Received in revised form 1 November 2019 Accepted 3 November 2019
Introduction: This review summarizes single vs dual antibiotic cement literature, evaluating for synergistic activity with dual antibiotics. Methods: A systematic review was performed for literature regarding dual antibiotics in cement, identifying 13 studies to include for review. Results: Many in vitro studies reported higher elution from cement and/or improved bacteria inhibition with dual antibiotics, typically at higher dosages with a manual mixing technique. Limited clinical data from hip hemiarthroplasties and spacers demonstrated that dual antibiotics were associated with improved infection prevention and higher intra-articular antibiotic concentrations. Conclusion: In addition to broader pathogen coverage, several studies document synergy of elution and increased antibacterial activity when dual antibiotics are added to cement. Limited clinical evidence suggests that dual antibiotic cement may be associated with reduced infection rates. © 2019 Elsevier Inc. All rights reserved.
Keywords: dual antibiotics antibiotic cement antibiotic synergy antibiotic elution dual antibiotic cement
Periprosthetic joint infections (PJIs) are an uncommon but challenging complication for orthopedic surgeons [1]. Treatment success can range from 65% to 90% depending on various factors such as patient comorbidities, duration of infection, and the presence or absence of polymicrobial organisms [2]. The utilization of antibiotic-laden cement (ALC), which delivers antibiotics directly into the joint, has become a common adjunct to treat and prevent PJI in arthroplasty patients [3]. Commercially available single antibiotic cements typically contain an aminoglycoside such as tobramycin to prevent infections by Gram negative organisms [4]. However, they have poor coverage of some Gram positive organisms, which comprise 86%-90% of all PJIs [5]. Additionally, the
This article is published as part of a supplement supported by an educational grant from OsteoRemedies, LLC. One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2019.11.002. * Reprint requests: Ronald E. Delanois, MD, Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital, 2401 West Belvedere Avenue, Baltimore, MD, 21215. https://doi.org/10.1016/j.arth.2019.11.002 0883-5403/© 2019 Elsevier Inc. All rights reserved.
dosage of single antibiotic cement may be inadequate to prevent PJI, leading to a reinfection rate as high as 24% in previously treated patients [6]. To improve antibiotic delivery, surgeons have explored increasing the number and types of antibiotics utilized in ALCs [7]. Dual antibiotics have been incorporated into ALCs for many years. Vancomycin is the most common antibiotic added to aminoglycoside ALCs and improves the spectrum of coverage to include methicillin-resistant Gram positive organisms [7]. A secondary effect of these combinations is a higher and longer lasting elution of both drugs [8,9]. This synergism between vancomycin and aminoglycosides has been recognized and extensively studied for decades. The mechanism behind this effect may be due to “passive opportunism,” where the second antibiotic appears to act as a soluble passive additive, increasing the porosity and available surface area for elution [8]. The advantage of enhanced elution is the ability to maintain intra-articular antibiotic concentrations above the minimal inhibitory concentration for a longer period of time, thereby preventing polymicrobial pathogen colonization [6,10,11]. However, several concerns have been raised regarding antibiotic utilization in ALCs. The levels of antibiotics necessary to achieve therapeutic concentrations can be quite high, and renal injury could occur with sustained exposure in the weeks subsequent to ALC implantation, in addition to the risk of antibiotic resistance [12,13].
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Table 1 Level I Evidence Studies. Study
Year
Antibiotics
Cohorts
Outcomes
Results
Sprowson et al [10]
2016
G þ Cli
448 patients: 0.5 g G 400 patients: 1 g G þ 1 g Cli
Deep and superficial SSI rates
Deep SSI: G ¼ 3.5%, G þ Cli ¼ 1.1% Deep and superficial SSI: G ¼ 5.3%, G þ Cl ¼ 1.7%
Cli, clindamycin; G, gentamicin; g, gram; SSI, surgical site infection.
The concentration of antibiotics in ALC may also negatively affect the intrinsic cement properties, increasing the risk of mechanical failure [14]. Moreover, the cost of dual antibiotics can be a limiting factor, although ALC utilization may reduce annual care costs in patients with a 5% postoperative risk of PJI [15]. Despite concerns about the high-doses of antibiotics required for ALCs to be efficacious, some evidence has shown them to be relatively safe for arthroplasty patients, with systemic levels often being undetectable and bacterial resistance decreased with supratherapeutic local drug concentrations [16]. Currently, the growing incidence of antibiotic resistance and polymicrobial infections has led many surgeons to revisit the antibiotics utilized in ALC. Many surgeons prefer single antibiotic cement, though synergistic elution may render dual antibiotics a more desirable treatment option and provide a broader spectrum of coverage. Thus, the purpose of this review is to summarize studies comparing dual antibiotics in bone cement, and to evaluate increased synergistic activity over single antibiotic cement. Specifically, we review studies reporting elution characteristics and/or infection rates with the utilization of 2 antibiotics in ALC.
evaluate antibiotic characteristics; they assessed only the properties of bone cement; they were systematic reviews or metaanalyses of other studies; they were unavailable in English; or the full text was not available. Eligible Studies Initial searches of the PubMed, EMBASE, and Cochrane Library databases returned 6011 publications. After application of the inclusion and exclusion criteria, 10 manuscripts remained. Additionally, the references of the included studies were searched for further studies, leading to the inclusion of another 3 studies. Study Data Included studies were stratified by level of clinical evidence, with in vitro studies categorized as the lowest level of evidence and randomized control trials categorized as level I studies. Where applicable, studies were assessed on antibiotics utilized, local antibiotic concentrations, infection rates, and elution characteristics.
Methods Results Publication Sources Level I Studies A systematic review of the PubMed, EMBASE, and Cochrane Library databases was performed for literature pertaining to the utilization of dual antibiotics in cement. Reports published in any time frame regarding this topic were identified with various key words and Boolean operators. Queries were performed in August 2019. The following strings were utilized in each database search: ((“antibiotic” OR “dual antibiotics” OR “antibiotic-laden” OR “antibiotic-impregnated”) AND (“cement” OR “bone cement” OR “cement spacer” OR “spacer”)) OR ((“antibiotic” OR “dual antibiotics” OR “antibiotic-laden” OR “antibiotic-impregnated”) AND (“elution”) AND (“arthroplasty” OR “joint”)). Study Selection Articles were included in this systematic review if they compared the use of biologic cement with 2 or more antibiotics to biologic cement with a single antibiotic or to the same antibiotics in varied concentrations; they were written in English; and a full text article was available. Articles were excluded if they did not contain at least 1 cohort receiving dual antibiotics in cement; they did not
There was 1 level I study comparing single antibiotics to dual antibiotics in ALC (Table 1). Sprowson et al [10] performed a quasirandomized controlled trial treating 848 hip fracture patients with cemented hemiarthroplasty, randomizing patients to receive either low-dose single antibiotic impregnated or high-dose dual antibiotic impregnated cement. There were 448 patients who received single antibiotic cement mixed with 0.5 g of gentamicin and 400 patients who received dual antibiotic cement mixed with 1 g of clindamycin and 1 g of gentamicin. The primary outcome, incidence of a deep surgical site infection (SSI), was significantly lower in the dual antibiotic group (1.1%) when compared to the single antibiotic group (3.5%, P ¼ .041). The dual antibiotic group also had significantly lower infection rates than the single antibiotic group when deep and superficial SSIs were combined (1.7% vs 5.3%, P ¼ .009). Summary of Level I Studies This study appears to have sufficient patient numbers and a randomized prospective design to support the utilization of dual
Table 2 Level II Evidence Studies. Study
Year Antibiotics Cohorts
Savage et al [11] Masri et al [6]
2019 G þ Cla 1998 T þ V
Outcomes
108 patients: 0.5 g G Deep and superficial SSI rates 98 patients: 1 g Cla þ 1 g G Intra-articular antibiotic (1) 1 g V, 2.4 g T elution (2) 1 g V, 3.6 g T (3) 1.5 g V, 2.4 g T (4) 1.5 g V, 3.6 g T
Results Deep SSI: G ¼ 2.9%, G þ Cla ¼ 0.0%. Superficial SSI: G ¼ 3.7%, G þ Cla ¼ 5.1% T 3.6 g had highest elution with no influence on V V eluted slowly, and elution dependent on T dose V highest elution with T 3.6 g
Cla, clarithromycin; G, gentamicin; g, gram; SSI, surgical site infection; T, tobramycin; V, vancomycin.
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Table 3 Level III Evidence Studies. Study
Year
Antibiotics
Cohorts
Outcomes
Results
Tyas et al [17]
2018
G þ Cli
681 patients: 0.5 g G 1260 patients: 1 g G þ 1 g Cli
Deep SSI
G ¼ 3.4% G þ Cli ¼ 1.2% Polymicrobial infections
Cli, clindamycin; G, gentamicin; g, gram; SSI, surgical site infection.
antibiotics for infection prevention. However, the difference in antibiotic concentrations is a limitation that could suggest that high-dose single antibiotic cement may perform similarly to dual antibiotic cement. Another weakness is the quasi-randomization with group allocation, which was done for pragmatic reasons but weakens the quality of results compared to a true conventional randomized control trial. Despite these limitations, this level I study provides evidence that high-dose dual antibiotic impregnated cement is correlated with a reduced incidence of SSI when compared to standard low-dose single antibiotic-loaded bone cement. Level II Studies There were 2 level II studies included in this review (Table 2). A study assessing deep and superficial SSI was performed by Savage et al [11] with femoral neck fracture patients undergoing hip arthroplasty receiving either single or dual ALC. They retrospectively collected 108 patients for the single antibiotic (0.5 g gentamicin) group, and prospectively enrolled 98 patients in the dual antibiotic (1 g clarithromycin þ1 g gentamicin) group. Their results demonstrated that the single antibiotic group had a deep SSI rate of 2.9%, while the dual antibiotic group had a deep SSI rate of 0.0%. However, the single antibiotic group had a superficial SSI rate of 3.7% compared to the dual antibiotic group who had a superficial SSI rate of 5.1%. In a prospective study of 49 patients undergoing a 2-stage revision for PJI, Masri et al [6] evaluated intra-articular levels of vancomycin and tobramycin in ALC spacers to determine if the previously described synergism between the 2 antibiotics existed in vivo. The ALC was loaded with 1.2-4.8 g of tobramycin and 1-2 g of vancomycin. The intra-articular concentrations of tobramycin and vancomycin were measured at the time the spacer was removed (mean of 118 days following implantation). They reported the highest elution of tobramycin with 3.6 g per bone cement package (P ¼ .011). Vancomycin elution was not as good and the dose of vancomycin did not appear to influence the concentration. Vancomycin elution appeared to be dependent on the dose of tobramycin, with the highest elution of vancomycin reached when 3.6 g of tobramycin was added to the cement (P ¼ .007). These results suggest that vancomycin should not be used alone in ALC due to its poor elution characteristics and confirm the synergistic effect between the 2 antibiotics. Summary of Level II Studies The Savage study demonstrates improved deep infection prevention with dual antibiotics, which is arguably more important than superficial infection prevention, as superficial SSI can be influenced by many factors, including wound closure techniques, dressings, and patient self-care. However, the different doses of antibiotics could have played a role in the different infection rates. An evaluation of ALC with similar antibiotic doses would have more weight on the efficacy of dual antibiotics. Moreover, they also raise the concern of increased dual antibiotic costs, though it may be offset by the reduction in further treatments. In contrast, the Masri
study utilized different antibiotic concentrations to find the best combination for infection eradication. Unfortunately, their small sample size may cast some doubt on the reproducibility of the results. Another limitation is the change in cement they made early in the study, which could have altered elution characteristics and infection rates. Despite these limitations, both of these studies have suggested potential clinical benefits to dual antibiotic cement and have laid the groundwork for further large-scale clinical studies. Level III Studies There was 1 level III study identified that assessed single and dual antibiotics (Table 3). A study by Tyas et al [17] retrospectively reviewed 1941 hemiarthroplasties with deep SSI who were implanted with low-dose single or high-dose dual ALC. In total, 681 hemiarthroplasties were performed with cement containing 0.5 g of gentamicin, and 1260 hemiarthroplasties were performed with cement containing 1 g of gentamicin and 1 g of clindamycin. They demonstrated an infection rate of 3.4% and 1.2% for single antibiotic and dual antibiotic cement, respectively (P ¼ .003). Most of these infections were polymicrobial, with Staphylococcus epidermidis as the most commonly isolated organism. Dual antibiotic spacers eliminated all Staphylococcus aureus and Corynebacterium infections. Some resistance to both antibiotics was noted, although this proportion was still lower than the proportion of infections resistant to the single antibiotic. Summary of Level III Studies This study suggests reduced infection rates with dual antibiotic cement, and had large numbers to support their findings. As with previous studies performed on this topic, the comparison of lowdose single antibiotic to high-dose dual antibiotics is a limitation, as it could be argued that a high-dose single antibiotic spacer may perform similarly to dual antibiotics. Additionally, the retrospective design is not as strong as the prospective study data, and the variation of hosts included after termination of the original study could have altered the infection profiles. However, the resistance profiles seem to indicate that despite the dosage, the dual antibiotic spacers were able to eradicate more organisms due to the extended coverage, highlighting their efficacy and synergy. Lowest Level of Evidence Studies There were 9 in vitro studies assessing antibiotic elution from bone cement (Table 4). The antibiotics evaluated included vancomycin, gentamicin, tobramycin, imipenem-cilastatin, clindamycin, ceftazidime, and fluconazole. Li et al [18] displayed reduced vancomycin elution with gentamicin, as compared to vancomycin alone (P < .001), while vancomycin did not have a reciprocal influence on gentamicin elution. Another study by Bertazzoni Minelli et al [7] revealed that antibiotic combinations inhibited all bacterial growth, showing synergistic activity against multiresistant strains. Commercially prepared vancomycin and gentamicin ALCs were compared to manually mixed ALCs by Frew et al [19], demonstrating significantly higher
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Table 4 Lowest Level of Evidence Studies (In vitro). Study
Year
Antibiotics
Antibiotic Cohorts
Outcomes
Results
Li et al [18]
2019
GþV
Antibiotic elution and antibacterial activity
2 g V, 2 g G eluted 50% less V than 2 g V V did not affect G elution 2 g V, 2 g G had best antibacterial activity (no growth)
Bertazzoni Minelli et al [7]
2011
GþV
Antibacterial activity
4.5 g G, 4.5 g V inhibited all bacterial growth, including multiresistant bacteria 4.5 g G, 4.5 g V prevented biofilm formation
Frew et al [19]
2017
GþV
(1) (2) (3) (4) (5) (6) (7) (8) (9) (1) (2) (3) (4) (1)
Antibiotic elution
G and V elution significantly higher with 0.5 g G (premix), 2 g V (all manual)
Penner et al [8]
1996
TþV
Antibiotic elution
V elution 103% greater in 1 g V, 2.4 g T T elution 68% greater in 1 g V, 2.4 g T
Slane et al [9]
2018
TþV
Antibiotic elution
T 3 g, V 2 g resulted in significantly higher elution
Klekamp et al [20]
1999
TþV
Antibiotic elution
V decreased the elution of T T did not affect the elution of V
Boelch et al [21]
2017
GþV G þ Cli
Antibiotic elution
1.0 g G (premix), 1.0 g Cli (premix) eluted more G after 48 h 0.5 g G (premix), 2.0 g V (manual) eluted more V
Cerretani et al [22]
2002
V þ IC
Antibiotic elution
V þ IC demonstrated increased elution of V
Martínez-Moreno et al [23]
2017
Ce þ F
Antibiotic elution and bioactivity
453% increase in Ce and 648% increase in F in treatment dosages Increased bioactivity of treatment dose
0 g G, 0 g V 0 g G, 1 g V 0 g G, 2 g V 0 g G, 4 g V 1 g G, 0 g V 2 g G, 0 g V 4 g G, 0 g V 1 g G, 1 g V 2 g G, 2 g V 0 g G, 0 g V 4.5 g G, 0 g V 0 g G, 4.5 g V 4.5 g G, 4.5 g V 0.5 g G (premix), 2 g V (premix) (2) 0.5 g G (premix), 2 g V (gradual manual) (3) 0.5 g G (premix), 2 g V (all manual) (1) 1 g V (2) 2.4 g T (3) 1 g V, 2.4 g T (1) 0 g T, 0 g V (2) 1.5 g T, 0 g V (3) 3 g T, 0 g V (4) 0 g T, 1.5 g V (5) 0 g T, 3 g V (6) 1 g T, 1 g V (7) 2 g T, 2 g V (8) 3 g T, 3 g V (9) 3 g T, 1 g V (10) 3 g T, 2 g V (11) 1 g T, 3 g V (12) 2 g T, 3 g V (1) 1.2 g T (2) 2.4 g T (3) 1 g V (4) 2 g V (5) 3 g V (6) 1 g V, 1.2 g T (1) No antibiotics (2) 0.5 g G (premixed) (3) 0.5 g G (premixed), 2.0 g V (premixed) (4) 0.5 g G (premix), 2.0 g V (manual) (5) 1.0 g G (premix), 1.0 g Cli (premix) (1) 2 g V (3 groups) (2) 2 g V þ 2 g IC (3 groups) (1) 1 g Ce, 1 g F: prophylaxis (2) 4 g Ce, 4 g F: treatment
Ce, ceftazidime; Cli, clindamycin; F, fluconazole; G, gentamicin; g, gram; IC, imipenem-cilastatin; T, tobramycin; V, vancomycin.
elution of gentamicin (P ¼ 1.56 104) and vancomycin (P ¼ 2.02 105) from manually mixed cement, presumably due to increased porosity. Penner et al [8] tested vancomycin and tobramycin release, finding that elution of vancomycin and tobramycin was 103% greater and 68% greater in dual combinations, respectively. Similar results were presented by Slane et al [9], who found that mixing tobramycin with vancomycin resulted in significantly higher elution of both antibiotics (P < .001), additionally observing a synergistic effect on tobramycin elution with the addition of vancomycin. A study by Klekamp et al [20] discovered that vancomycin decreased the elution of tobramycin, while tobramycin did not have a reciprocal effect. Boelch et al [21] showed that a gentamicin and clindamycin combination eluted significantly more gentamicin than other combinations (P < .05), and vancomycin eluted more in combination. Cerretani et al [22] assessed the
elution of vancomycin and vancomycin with imipenem-cilastatin, demonstrating increased elution of vancomycin with imipenemcilastatin when compared to vancomycin alone (P < .05). Another study assessing ceftazidime and fluconazole in bone cement by Martínez-Moreno et al [23] indicated a 453% increase in ceftazidime and a 648% increase in fluconazole with treatment dosages over prophylaxis dosages. Summary of Lowest Level of Evidence Studies Limitations were noted in some of these studies. The Li and Klekamp studies found decreased elution with dual antibiotics, though Li demonstrated that dual combinations limited bacterial growth better than single antibiotics, while Klekamp’s study only tested the lowest concentrations of antibiotics and performed their
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study under conditions which may have limited cement porosity and elution. Boelch did not test manually added clindamycin combinations, as they did with their vancomycin group. MartínezMoreno’s study assessed an antifungal agent, an uncommon PJI pathogen. Still, these studies all suggest the importance of high-dose antibiotics and cement characteristics in elution synergy. Bertazzoni Minelli’s study demonstrated that dual antibiotics synergistically inhibited the growth of bacteria resistant to both antibiotics. Cerretani’s study found that antibiotic elution was greater in combination regardless of cement type. In terms of synergy, Penner’s study posits that dual antibiotics in ALC dissolve more when mixed together, leaving a larger surface area for more antibiotics to elute from, leading to the observed synergism. This theory is referenced by other in vitro studies. However, true comparisons of elution characteristics are limited, as these studies utilized different protocols, cement mixtures, and antibiotics. Multiple factors influence how antibiotics elute from ALCs and these studies could all be replicated with similar conditions to determine the optimal dual antibiotic combination. Nonetheless, dual antibiotics appear to have superior elution characteristics and improved inhibition of bacterial growth in vitro. Conclusion This review found that several in vitro and in vivo studies support the benefits of dual antibiotic bone cement, with synergy of drug elution and improved antibacterial activity. However, there are worries of toxic antibiotic concentrations and negative side effects which restrict their utilization. Additionally, concerns have been raised over the potential for increased antibiotic resistance, and no benefit in primary cases. Despite these concerns, surgeons have been incorporating dual antibiotics in ALC for years with great success in treating infected joints. Broader pathogen coverage and increased elution rates make dual antibiotic cement spacers an attractive option in the treatment of PJI. More level I studies assessing the benefits of high-dose single and dual antibiotic cements are needed to truly elucidate the best option for infection prevention and treatment.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
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Antibiotic Choice: The Synergistic Effect of Single vs Dual Antibiotics Nequesha S. Mohamed, MD a, Wayne A. Wilkie, DO a, Ethan A. Remily, DO a, James Nace, DO a, Ronald E. Delanois, MD a, *, James A. Browne, MD b a b
Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital, Baltimore, MD Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 September 2019 Received in revised form 1 November 2019 Accepted 3 November 2019
Introduction: This review summarizes single vs dual antibiotic cement literature, evaluating for synergistic activity with dual antibiotics. Methods: A systematic review was performed for literature regarding dual antibiotics in cement, identifying 13 studies to include for review. Results: Many in vitro studies reported higher elution from cement and/or improved bacteria inhibition with dual antibiotics, typically at higher dosages with a manual mixing technique. Limited clinical data from hip hemiarthroplasties and spacers demonstrated that dual antibiotics were associated with improved infection prevention and higher intra-articular antibiotic concentrations. Conclusion: In addition to broader pathogen coverage, several studies document synergy of elution and increased antibacterial activity when dual antibiotics are added to cement. Limited clinical evidence suggests that dual antibiotic cement may be associated with reduced infection rates. © 2019 Elsevier Inc. All rights reserved.
Keywords: dual antibiotics antibiotic cement antibiotic synergy antibiotic elution dual antibiotic cement
Periprosthetic joint infections (PJIs) are an uncommon but challenging complication for orthopedic surgeons [1]. Treatment success can range from 65% to 90% depending on various factors such as patient comorbidities, duration of infection, and the presence or absence of polymicrobial organisms [2]. The utilization of antibiotic-laden cement (ALC), which delivers antibiotics directly into the joint, has become a common adjunct to treat and prevent PJI in arthroplasty patients [3]. Commercially available single antibiotic cements typically contain an aminoglycoside such as tobramycin to prevent infections by Gram negative organisms [4]. However, they have poor coverage of some Gram positive organisms, which comprise 86%-90% of all PJIs [5]. Additionally, the
This article is published as part of a supplement supported by an educational grant from OsteoRemedies, LLC. One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2019.11.002. * Reprint requests: Ronald E. Delanois, MD, Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital, 2401 West Belvedere Avenue, Baltimore, MD, 21215. https://doi.org/10.1016/j.arth.2019.11.002 0883-5403/© 2019 Elsevier Inc. All rights reserved.
dosage of single antibiotic cement may be inadequate to prevent PJI, leading to a reinfection rate as high as 24% in previously treated patients [6]. To improve antibiotic delivery, surgeons have explored increasing the number and types of antibiotics utilized in ALCs [7]. Dual antibiotics have been incorporated into ALCs for many years. Vancomycin is the most common antibiotic added to aminoglycoside ALCs and improves the spectrum of coverage to include methicillin-resistant Gram positive organisms [7]. A secondary effect of these combinations is a higher and longer lasting elution of both drugs [8,9]. This synergism between vancomycin and aminoglycosides has been recognized and extensively studied for decades. The mechanism behind this effect may be due to “passive opportunism,” where the second antibiotic appears to act as a soluble passive additive, increasing the porosity and available surface area for elution [8]. The advantage of enhanced elution is the ability to maintain intra-articular antibiotic concentrations above the minimal inhibitory concentration for a longer period of time, thereby preventing polymicrobial pathogen colonization [6,10,11]. However, several concerns have been raised regarding antibiotic utilization in ALCs. The levels of antibiotics necessary to achieve therapeutic concentrations can be quite high, and renal injury could occur with sustained exposure in the weeks subsequent to ALC implantation, in addition to the risk of antibiotic resistance [12,13].
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Table 1 Level I Evidence Studies. Study
Year
Antibiotics
Cohorts
Outcomes
Results
Sprowson et al [10]
2016
G þ Cli
448 patients: 0.5 g G 400 patients: 1 g G þ 1 g Cli
Deep and superficial SSI rates
Deep SSI: G ¼ 3.5%, G þ Cli ¼ 1.1% Deep and superficial SSI: G ¼ 5.3%, G þ Cl ¼ 1.7%
Cli, clindamycin; G, gentamicin; g, gram; SSI, surgical site infection.
The concentration of antibiotics in ALC may also negatively affect the intrinsic cement properties, increasing the risk of mechanical failure [14]. Moreover, the cost of dual antibiotics can be a limiting factor, although ALC utilization may reduce annual care costs in patients with a 5% postoperative risk of PJI [15]. Despite concerns about the high-doses of antibiotics required for ALCs to be efficacious, some evidence has shown them to be relatively safe for arthroplasty patients, with systemic levels often being undetectable and bacterial resistance decreased with supratherapeutic local drug concentrations [16]. Currently, the growing incidence of antibiotic resistance and polymicrobial infections has led many surgeons to revisit the antibiotics utilized in ALC. Many surgeons prefer single antibiotic cement, though synergistic elution may render dual antibiotics a more desirable treatment option and provide a broader spectrum of coverage. Thus, the purpose of this review is to summarize studies comparing dual antibiotics in bone cement, and to evaluate increased synergistic activity over single antibiotic cement. Specifically, we review studies reporting elution characteristics and/or infection rates with the utilization of 2 antibiotics in ALC.
evaluate antibiotic characteristics; they assessed only the properties of bone cement; they were systematic reviews or metaanalyses of other studies; they were unavailable in English; or the full text was not available. Eligible Studies Initial searches of the PubMed, EMBASE, and Cochrane Library databases returned 6011 publications. After application of the inclusion and exclusion criteria, 10 manuscripts remained. Additionally, the references of the included studies were searched for further studies, leading to the inclusion of another 3 studies. Study Data Included studies were stratified by level of clinical evidence, with in vitro studies categorized as the lowest level of evidence and randomized control trials categorized as level I studies. Where applicable, studies were assessed on antibiotics utilized, local antibiotic concentrations, infection rates, and elution characteristics.
Methods Results Publication Sources Level I Studies A systematic review of the PubMed, EMBASE, and Cochrane Library databases was performed for literature pertaining to the utilization of dual antibiotics in cement. Reports published in any time frame regarding this topic were identified with various key words and Boolean operators. Queries were performed in August 2019. The following strings were utilized in each database search: ((“antibiotic” OR “dual antibiotics” OR “antibiotic-laden” OR “antibiotic-impregnated”) AND (“cement” OR “bone cement” OR “cement spacer” OR “spacer”)) OR ((“antibiotic” OR “dual antibiotics” OR “antibiotic-laden” OR “antibiotic-impregnated”) AND (“elution”) AND (“arthroplasty” OR “joint”)). Study Selection Articles were included in this systematic review if they compared the use of biologic cement with 2 or more antibiotics to biologic cement with a single antibiotic or to the same antibiotics in varied concentrations; they were written in English; and a full text article was available. Articles were excluded if they did not contain at least 1 cohort receiving dual antibiotics in cement; they did not
There was 1 level I study comparing single antibiotics to dual antibiotics in ALC (Table 1). Sprowson et al [10] performed a quasirandomized controlled trial treating 848 hip fracture patients with cemented hemiarthroplasty, randomizing patients to receive either low-dose single antibiotic impregnated or high-dose dual antibiotic impregnated cement. There were 448 patients who received single antibiotic cement mixed with 0.5 g of gentamicin and 400 patients who received dual antibiotic cement mixed with 1 g of clindamycin and 1 g of gentamicin. The primary outcome, incidence of a deep surgical site infection (SSI), was significantly lower in the dual antibiotic group (1.1%) when compared to the single antibiotic group (3.5%, P ¼ .041). The dual antibiotic group also had significantly lower infection rates than the single antibiotic group when deep and superficial SSIs were combined (1.7% vs 5.3%, P ¼ .009). Summary of Level I Studies This study appears to have sufficient patient numbers and a randomized prospective design to support the utilization of dual
Table 2 Level II Evidence Studies. Study
Year Antibiotics Cohorts
Savage et al [11] Masri et al [6]
2019 G þ Cla 1998 T þ V
Outcomes
108 patients: 0.5 g G Deep and superficial SSI rates 98 patients: 1 g Cla þ 1 g G Intra-articular antibiotic (1) 1 g V, 2.4 g T elution (2) 1 g V, 3.6 g T (3) 1.5 g V, 2.4 g T (4) 1.5 g V, 3.6 g T
Results Deep SSI: G ¼ 2.9%, G þ Cla ¼ 0.0%. Superficial SSI: G ¼ 3.7%, G þ Cla ¼ 5.1% T 3.6 g had highest elution with no influence on V V eluted slowly, and elution dependent on T dose V highest elution with T 3.6 g
Cla, clarithromycin; G, gentamicin; g, gram; SSI, surgical site infection; T, tobramycin; V, vancomycin.
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Table 3 Level III Evidence Studies. Study
Year
Antibiotics
Cohorts
Outcomes
Results
Tyas et al [17]
2018
G þ Cli
681 patients: 0.5 g G 1260 patients: 1 g G þ 1 g Cli
Deep SSI
G ¼ 3.4% G þ Cli ¼ 1.2% Polymicrobial infections
Cli, clindamycin; G, gentamicin; g, gram; SSI, surgical site infection.
antibiotics for infection prevention. However, the difference in antibiotic concentrations is a limitation that could suggest that high-dose single antibiotic cement may perform similarly to dual antibiotic cement. Another weakness is the quasi-randomization with group allocation, which was done for pragmatic reasons but weakens the quality of results compared to a true conventional randomized control trial. Despite these limitations, this level I study provides evidence that high-dose dual antibiotic impregnated cement is correlated with a reduced incidence of SSI when compared to standard low-dose single antibiotic-loaded bone cement. Level II Studies There were 2 level II studies included in this review (Table 2). A study assessing deep and superficial SSI was performed by Savage et al [11] with femoral neck fracture patients undergoing hip arthroplasty receiving either single or dual ALC. They retrospectively collected 108 patients for the single antibiotic (0.5 g gentamicin) group, and prospectively enrolled 98 patients in the dual antibiotic (1 g clarithromycin þ1 g gentamicin) group. Their results demonstrated that the single antibiotic group had a deep SSI rate of 2.9%, while the dual antibiotic group had a deep SSI rate of 0.0%. However, the single antibiotic group had a superficial SSI rate of 3.7% compared to the dual antibiotic group who had a superficial SSI rate of 5.1%. In a prospective study of 49 patients undergoing a 2-stage revision for PJI, Masri et al [6] evaluated intra-articular levels of vancomycin and tobramycin in ALC spacers to determine if the previously described synergism between the 2 antibiotics existed in vivo. The ALC was loaded with 1.2-4.8 g of tobramycin and 1-2 g of vancomycin. The intra-articular concentrations of tobramycin and vancomycin were measured at the time the spacer was removed (mean of 118 days following implantation). They reported the highest elution of tobramycin with 3.6 g per bone cement package (P ¼ .011). Vancomycin elution was not as good and the dose of vancomycin did not appear to influence the concentration. Vancomycin elution appeared to be dependent on the dose of tobramycin, with the highest elution of vancomycin reached when 3.6 g of tobramycin was added to the cement (P ¼ .007). These results suggest that vancomycin should not be used alone in ALC due to its poor elution characteristics and confirm the synergistic effect between the 2 antibiotics. Summary of Level II Studies The Savage study demonstrates improved deep infection prevention with dual antibiotics, which is arguably more important than superficial infection prevention, as superficial SSI can be influenced by many factors, including wound closure techniques, dressings, and patient self-care. However, the different doses of antibiotics could have played a role in the different infection rates. An evaluation of ALC with similar antibiotic doses would have more weight on the efficacy of dual antibiotics. Moreover, they also raise the concern of increased dual antibiotic costs, though it may be offset by the reduction in further treatments. In contrast, the Masri
study utilized different antibiotic concentrations to find the best combination for infection eradication. Unfortunately, their small sample size may cast some doubt on the reproducibility of the results. Another limitation is the change in cement they made early in the study, which could have altered elution characteristics and infection rates. Despite these limitations, both of these studies have suggested potential clinical benefits to dual antibiotic cement and have laid the groundwork for further large-scale clinical studies. Level III Studies There was 1 level III study identified that assessed single and dual antibiotics (Table 3). A study by Tyas et al [17] retrospectively reviewed 1941 hemiarthroplasties with deep SSI who were implanted with low-dose single or high-dose dual ALC. In total, 681 hemiarthroplasties were performed with cement containing 0.5 g of gentamicin, and 1260 hemiarthroplasties were performed with cement containing 1 g of gentamicin and 1 g of clindamycin. They demonstrated an infection rate of 3.4% and 1.2% for single antibiotic and dual antibiotic cement, respectively (P ¼ .003). Most of these infections were polymicrobial, with Staphylococcus epidermidis as the most commonly isolated organism. Dual antibiotic spacers eliminated all Staphylococcus aureus and Corynebacterium infections. Some resistance to both antibiotics was noted, although this proportion was still lower than the proportion of infections resistant to the single antibiotic. Summary of Level III Studies This study suggests reduced infection rates with dual antibiotic cement, and had large numbers to support their findings. As with previous studies performed on this topic, the comparison of lowdose single antibiotic to high-dose dual antibiotics is a limitation, as it could be argued that a high-dose single antibiotic spacer may perform similarly to dual antibiotics. Additionally, the retrospective design is not as strong as the prospective study data, and the variation of hosts included after termination of the original study could have altered the infection profiles. However, the resistance profiles seem to indicate that despite the dosage, the dual antibiotic spacers were able to eradicate more organisms due to the extended coverage, highlighting their efficacy and synergy. Lowest Level of Evidence Studies There were 9 in vitro studies assessing antibiotic elution from bone cement (Table 4). The antibiotics evaluated included vancomycin, gentamicin, tobramycin, imipenem-cilastatin, clindamycin, ceftazidime, and fluconazole. Li et al [18] displayed reduced vancomycin elution with gentamicin, as compared to vancomycin alone (P < .001), while vancomycin did not have a reciprocal influence on gentamicin elution. Another study by Bertazzoni Minelli et al [7] revealed that antibiotic combinations inhibited all bacterial growth, showing synergistic activity against multiresistant strains. Commercially prepared vancomycin and gentamicin ALCs were compared to manually mixed ALCs by Frew et al [19], demonstrating significantly higher
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Table 4 Lowest Level of Evidence Studies (In vitro). Study
Year
Antibiotics
Antibiotic Cohorts
Outcomes
Results
Li et al [18]
2019
GþV
Antibiotic elution and antibacterial activity
2 g V, 2 g G eluted 50% less V than 2 g V V did not affect G elution 2 g V, 2 g G had best antibacterial activity (no growth)
Bertazzoni Minelli et al [7]
2011
GþV
Antibacterial activity
4.5 g G, 4.5 g V inhibited all bacterial growth, including multiresistant bacteria 4.5 g G, 4.5 g V prevented biofilm formation
Frew et al [19]
2017
GþV
(1) (2) (3) (4) (5) (6) (7) (8) (9) (1) (2) (3) (4) (1)
Antibiotic elution
G and V elution significantly higher with 0.5 g G (premix), 2 g V (all manual)
Penner et al [8]
1996
TþV
Antibiotic elution
V elution 103% greater in 1 g V, 2.4 g T T elution 68% greater in 1 g V, 2.4 g T
Slane et al [9]
2018
TþV
Antibiotic elution
T 3 g, V 2 g resulted in significantly higher elution
Klekamp et al [20]
1999
TþV
Antibiotic elution
V decreased the elution of T T did not affect the elution of V
Boelch et al [21]
2017
GþV G þ Cli
Antibiotic elution
1.0 g G (premix), 1.0 g Cli (premix) eluted more G after 48 h 0.5 g G (premix), 2.0 g V (manual) eluted more V
Cerretani et al [22]
2002
V þ IC
Antibiotic elution
V þ IC demonstrated increased elution of V
Martínez-Moreno et al [23]
2017
Ce þ F
Antibiotic elution and bioactivity
453% increase in Ce and 648% increase in F in treatment dosages Increased bioactivity of treatment dose
0 g G, 0 g V 0 g G, 1 g V 0 g G, 2 g V 0 g G, 4 g V 1 g G, 0 g V 2 g G, 0 g V 4 g G, 0 g V 1 g G, 1 g V 2 g G, 2 g V 0 g G, 0 g V 4.5 g G, 0 g V 0 g G, 4.5 g V 4.5 g G, 4.5 g V 0.5 g G (premix), 2 g V (premix) (2) 0.5 g G (premix), 2 g V (gradual manual) (3) 0.5 g G (premix), 2 g V (all manual) (1) 1 g V (2) 2.4 g T (3) 1 g V, 2.4 g T (1) 0 g T, 0 g V (2) 1.5 g T, 0 g V (3) 3 g T, 0 g V (4) 0 g T, 1.5 g V (5) 0 g T, 3 g V (6) 1 g T, 1 g V (7) 2 g T, 2 g V (8) 3 g T, 3 g V (9) 3 g T, 1 g V (10) 3 g T, 2 g V (11) 1 g T, 3 g V (12) 2 g T, 3 g V (1) 1.2 g T (2) 2.4 g T (3) 1 g V (4) 2 g V (5) 3 g V (6) 1 g V, 1.2 g T (1) No antibiotics (2) 0.5 g G (premixed) (3) 0.5 g G (premixed), 2.0 g V (premixed) (4) 0.5 g G (premix), 2.0 g V (manual) (5) 1.0 g G (premix), 1.0 g Cli (premix) (1) 2 g V (3 groups) (2) 2 g V þ 2 g IC (3 groups) (1) 1 g Ce, 1 g F: prophylaxis (2) 4 g Ce, 4 g F: treatment
Ce, ceftazidime; Cli, clindamycin; F, fluconazole; G, gentamicin; g, gram; IC, imipenem-cilastatin; T, tobramycin; V, vancomycin.
elution of gentamicin (P ¼ 1.56 104) and vancomycin (P ¼ 2.02 105) from manually mixed cement, presumably due to increased porosity. Penner et al [8] tested vancomycin and tobramycin release, finding that elution of vancomycin and tobramycin was 103% greater and 68% greater in dual combinations, respectively. Similar results were presented by Slane et al [9], who found that mixing tobramycin with vancomycin resulted in significantly higher elution of both antibiotics (P < .001), additionally observing a synergistic effect on tobramycin elution with the addition of vancomycin. A study by Klekamp et al [20] discovered that vancomycin decreased the elution of tobramycin, while tobramycin did not have a reciprocal effect. Boelch et al [21] showed that a gentamicin and clindamycin combination eluted significantly more gentamicin than other combinations (P < .05), and vancomycin eluted more in combination. Cerretani et al [22] assessed the
elution of vancomycin and vancomycin with imipenem-cilastatin, demonstrating increased elution of vancomycin with imipenemcilastatin when compared to vancomycin alone (P < .05). Another study assessing ceftazidime and fluconazole in bone cement by Martínez-Moreno et al [23] indicated a 453% increase in ceftazidime and a 648% increase in fluconazole with treatment dosages over prophylaxis dosages. Summary of Lowest Level of Evidence Studies Limitations were noted in some of these studies. The Li and Klekamp studies found decreased elution with dual antibiotics, though Li demonstrated that dual combinations limited bacterial growth better than single antibiotics, while Klekamp’s study only tested the lowest concentrations of antibiotics and performed their
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study under conditions which may have limited cement porosity and elution. Boelch did not test manually added clindamycin combinations, as they did with their vancomycin group. MartínezMoreno’s study assessed an antifungal agent, an uncommon PJI pathogen. Still, these studies all suggest the importance of high-dose antibiotics and cement characteristics in elution synergy. Bertazzoni Minelli’s study demonstrated that dual antibiotics synergistically inhibited the growth of bacteria resistant to both antibiotics. Cerretani’s study found that antibiotic elution was greater in combination regardless of cement type. In terms of synergy, Penner’s study posits that dual antibiotics in ALC dissolve more when mixed together, leaving a larger surface area for more antibiotics to elute from, leading to the observed synergism. This theory is referenced by other in vitro studies. However, true comparisons of elution characteristics are limited, as these studies utilized different protocols, cement mixtures, and antibiotics. Multiple factors influence how antibiotics elute from ALCs and these studies could all be replicated with similar conditions to determine the optimal dual antibiotic combination. Nonetheless, dual antibiotics appear to have superior elution characteristics and improved inhibition of bacterial growth in vitro. Conclusion This review found that several in vitro and in vivo studies support the benefits of dual antibiotic bone cement, with synergy of drug elution and improved antibacterial activity. However, there are worries of toxic antibiotic concentrations and negative side effects which restrict their utilization. Additionally, concerns have been raised over the potential for increased antibiotic resistance, and no benefit in primary cases. Despite these concerns, surgeons have been incorporating dual antibiotics in ALC for years with great success in treating infected joints. Broader pathogen coverage and increased elution rates make dual antibiotic cement spacers an attractive option in the treatment of PJI. More level I studies assessing the benefits of high-dose single and dual antibiotic cements are needed to truly elucidate the best option for infection prevention and treatment.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
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