Suppressive Antibiotics for Prosthetic Joint Infections

I have to admit, this is not a very sexy topic to write about. Indeed, next to diabetic foot infections, these tend to, shall we put it, do not arouse my interest. Nevertheless as the population ages, more and more people will end up with a knee or hip replacement and you are more likely to see it, so whether you find these infections fascinating or not, you should probably have pretty darn good understanding of the various therapeutic options that are available. The topics of diagnosis and general treatment will be the topic of another post; for now, lets focus on the role of suppressive antibiotics.

The use of suppressive antibiotics tends to be of consideration following either a one stage exchange (which is not typically used in the US) or debridement and implant retention (DAIR, in other words, joint washout with the prosthetic joint left in place). There is no consensus as  to how long to maintain suppressive therapy, with one review noting this ranges from several months following surgery to indefinite therapy (1). Indeed, the guidelines do not seem to come to a consensus in this issue. Looking at a direct quote from the 2013 IDSA guidelines (2):

“The panel could not agree on the use and duration of chronic suppression following the induction course of intravenous antimicrobial therapy in non-staphylococcal PJI or following a 3- to 6-month course of quinolone or other companion drug/rifampin in staphylococcal PJI treated with [DAIR.] Some members…would never use chronic suppression therapy….others would recommend the use of chronic suppression in all cases of PJI treated with [DAIR].” 

IDSA PJI Guidelines, 2013

In the previously mentioned review, the strategy most commonly used was 3-6 months of suppressive therapy for PJI managed with DAIR with longer duration for staphylococcal infection. The data supporting suppressive therapy for PJI is sparse and usually in the form of cohort studies. For instance, one multicenter, observational cohort study of 108 patients with PJI found that suppressive antibiotics following a DAIR approach was associated with higher survival probability at 12 months (3)

Notably, there was no difference in survival probability if antibiotics were extended beyond 12 months. In this cohort, 52% of patients had an infection with staphylococcus. Another retrospective study found that 3 months, but not 6 months of suppressive antibiotics following DAIR approach, was associated with a greater likelihood of treatment success (4):

As noted above, Staph aureus is associated with less likelihood of treatment success. A smaller retrospective study of 99 patients who underwent DAIR procedure found that the 2-year survival rate free of treatment failure was 60% (95% CI 50-70%) in a population where 89% received suppressive antibiotics (5). While it is difficult to tell the benefits of suppressive antibiotics in this population given the lack of control group, the authors performed a multivariate analysis and concluded the presence of a sinus tract, and duration of symptoms >8d prior to debridement along with Staph aureus were associated with increase rate of treatment failure:

A similar retrospective study in 23 patients undergoing hip PJI debridement found that 56.5% of patients who received suppressive antibiotic therapy did not recur at the end of 33 months (6). Not surprisingly, those with staph aureus had worse outcomes:

Interestingly, in the subset of patients who got suppressive antibiotics immediately after IV antibiotics, these tended to do better when compared to those who had a period free of antibiotics:

A  of 7 studies evaluating 424 patients found an overall success rate for suppressive therapy of 

75% across all 7 studies (7) with a median duration of suppression of around 63.5 months. Unfortunately, all of these studies were retrospective with and all but one did not have a non-suppressive antibiotic group. Furthermore, the indication for suppressive antibiotics differed across these studies (though most of them occurred in the setting of DAIR), so it is difficult to draw any meaningful conclusions. 2 other studies suggest benefit, however. One small retrospective (8) analysis focusing on streptococcal PJI found that suppressive antibiotics were associated with less recurrences, though the number of patients was rather small at only 39:

A multicenter, prospective RCT (9)  found that a 3-month course of suppressive PO antibiotics following a two-stage exchange was associated with decreased treatment failure (5% vs 19%, HR 4.37, 95% CI 1.297-19.748), though it is to be noted this involved a more “thorough” manner of source control. 

One interesting finding came from a multicenter retrospective series of PJI managed with DAIR in Oxford, UK (10). A total of 112 patients were managed with DAIR followed by a mean duration of 1.5yr of PO antibiotics, with 20 of them having treatment failure (12 after stopping antibiotics and 8 while on antibiotics; HR 4.3, 95% CI 1.4-12.8). Notably,the risk of failure increases after stopping antibiotics to more than 4-fold, even when examining the rate of failure in all patients under follow-up at 500 days (HR 1.4, 95% Ci 0.5-3.9). In other words, the rate of failure after stopping antibiotics relatively soon after a DAIR is the same as that after a significant time period after DAIR. This represents an early period of high risk in the first 3 months (HR 7.0, 95% CI 1.5-33) which drops over the following 3 months. All that to say, it seems suppressive antibiotic delay the time for recurrence rather than prevent it. 

What are the risk factors for recurrence during suppression?

As far as I can tell, the presence of sinus tract (i.e a really bad infection), and staph aureus tend to come up as significant risk factors. Indeed, in the previously mentioned retrospective cohort, those with Staph infections were more likely to have clinical failure, as well as those who had a CRP >80 (OR 6, 95% CI 0.81-44; 4)

Of interest, open surgery was actually more favorable compared to arthroscopic and seems that primary debridement tends to do better as well. In another study (5), Staph aureus had a HR of 5.14 for failure.

A multicenter retrospective study of 302 patients evaluated factors associated with failure following a DAIR approach for PJI (11). Age <70, upper limb PJI, and etiology other than gram positive cocci were associated with increase risk of failure for this approach. Notably, the use of rifampin was not associated with success of PJI in GPCs (HR 1.13, 95% CI 0.25-5.16). The overall rate of success at 2 years was 75%, while at 5 years it was 50%. A single center retrospective cohort of 21 patients found that suppressive therapy was more successful in those who had either a hip or knee PJI, had Staph epi as a primary infection, or had a standard prosthesis compared to a tumor prosthesis (12):

What do we make of this? As mentioned previously, the guidelines on this do not have a clear recommendation for suppressive therapy and high quality data is lacking. Needless to say, it seems that, if a patient is able to tolerate PO therapy, then suppressive antibiotics following a DAIR procedure for staphylococcus is a reasonable approach for a minimum of 6 months. It could be argued that all DAIR procedures would warrant at least a short period of suppressive therapy, with more resistant organisms warranting a longer course. Again, this is dependent on the patients risk of further surgery (i.e. elderly/immunosuppressed patients who would not do well with another surgery, then this is a reasonable option). In those who are younger and are able to tolerate further procedures, you could make the argument that the risk of antibiotic therapy may not be warranted. Certainly for staphylococcal infections it should be strongly considered. One retrospective analysis did find that doxycycline had a favorable profile with 74.4% of these having no recurrence of infections (13). A summary of recommended PO antibiotics is as follows:

Notice that linezolid does not make an appearance here, with cirpofloxacin being only used for Pseudomonas. This is because of the toxicity associated with them, especially linezolid which can cause serotonin syndrome, myelosuppression, and peripheral neuropathy. 

References:

1. Tande AJ, Gomez-Urena EO, Berbari EF, Osmon DR. Management of Prosthetic Joint Infection. Infect Dis Clin North Am. 2017 Jun;31(2):237-252. doi: 10.1016/j.idc.2017.01.009. Epub 2017 Mar 30. PMID: 28366224.
2. Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, Rao N, Hanssen A, Wilson WR; Infectious Diseases Society of America. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013 Jan;56(1):e1-e25. doi: 10.1093/cid/cis803. Epub 2012 Dec 6. PMID: 23223583.
3. Shah NB, Hersh BL, Kreger A, Sayeed A, Bullock AG, Rothenberger SD, Klatt B, Hamlin B, Urish KL. Benefits and Adverse Events Associated With Extended Antibiotic Use in Total Knee Arthroplasty Periprosthetic Joint Infection. Clin Infect Dis. 2020 Feb 3;70(4):559-565. doi: 10.1093/cid/ciz261. PMID: 30944931.
4. Keller SC, Cosgrove SE, Higgins Y, Piggott DA, Osgood G, Auwaerter PG. Role of Suppressive Oral Antibiotics in Orthopedic Hardware Infections for Those Not Undergoing Two-Stage Replacement Surgery. Open Forum Infect Dis. 2016 Aug 30;3(4):ofw176. doi: 10.1093/ofid/ofw176. PMID: 27747252; PMCID: PMC5063553.
5. Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM, Harmsen SW, Mandrekar JN, Osmon DR. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis. 2006 Feb 15;42(4):471-8. doi: 10.1086/499234. Epub 2006 Jan 5. PMID: 16421790.
6. Leijtens B, Weerwag L, Schreurs BW, Kullberg BJ, Rijnen W. Clinical Outcome of Antibiotic Suppressive Therapy in Patients with a Prosthetic Joint Infection after Hip Replacement. J Bone Jt Infect. 2019 Nov 6;4(6):268-276. doi: 10.7150/jbji.37262. PMID: 31966956; PMCID: PMC6960024.
7. Malahias MA, Gu A, Harris EC, Adriani M, Miller AO, Westrich GH, Sculco PK. The Role of Long-Term Antibiotic Suppression in the Management of Peri-Prosthetic Joint Infections Treated With Debridement, Antibiotics, and Implant Retention: A Systematic Review. J Arthroplasty. 2020 Apr;35(4):1154-1160. doi: 10.1016/j.arth.2019.11.026. Epub 2019 Dec 9. PMID: 31955984.
8. Renz N, Rakow A, Müller M, Perka C, Trampuz A. Long-term antimicrobial suppression prevents treatment failure of streptococcal periprosthetic joint infection. J Infect. 2019 Sep;79(3):236-244. doi: 10.1016/j.jinf.2019.06.015. Epub 2019 Jul 13. PMID: 31310778.
9. Frank JM, Kayupov E, Moric M, Segreti J, Hansen E, Hartman C, Okroj K, Belden K, Roslund B, Silibovsky R, Parvizi J, Della Valle CJ; Knee Society Research Group. The Mark Coventry, MD, Award: Oral Antibiotics Reduce Reinfection After Two-Stage Exchange: A Multicenter, Randomized Controlled Trial. Clin Orthop Relat Res. 2017 Jan;475(1):56-61. doi: 10.1007/s11999-016-4890-4. PMID: 27387759; PMCID: PMC5174034.
10. Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, Gundle R, Berendt A. One hundred and twelve infected arthroplasties treated with ‘DAIR’ (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother. 2009 Jun;63(6):1264-71. doi: 10.1093/jac/dkp107. Epub 2009 Mar 31. Erratum in: J Antimicrob Chemother. 2011 May;66(5):1203. Erratum in: J Antimicrob Chemother. 2013 Dec;68(12):2964-5. PMID: 19336454; PMCID: PMC2680346.
11. Escudero-Sanchez R, Senneville E, Digumber M, Soriano A, Del Toro MD, Bahamonde A, Del Pozo JL, Guio L, Murillo O, Rico A, García-País MJ, Rodríguez-Pardo D, Iribarren JA, Fernández M, Benito N, Fresco G, Muriel A, Ariza J, Cobo J. Suppressive antibiotic therapy in prosthetic joint infections: a multicentre cohort study. Clin Microbiol Infect. 2020 Apr;26(4):499-505. doi: 10.1016/j.cmi.2019.09.007. Epub 2019 Sep 17. PMID: 31539638.
12. Wouthuyzen-Bakker M, Nijman JM, Kampinga GA, van Assen S, Jutte PC. Efficacy of Antibiotic Suppressive Therapy in Patients with a Prosthetic Joint Infection. J Bone Jt Infect. 2017 Jan 15;2(2):77-83. doi: 10.7150/jbji.17353. PMID: 28529867; PMCID: PMC5423578.
13. Pradier M, Nguyen S, Robineau O, Titecat M, Blondiaux N, Valette M, Loïez C, Beltrand E, Dézeque H, Migaud H, Senneville E. Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint infection: a retrospective study of 39 patients. Int J Antimicrob Agents. 2017 Sep;50(3):447-452. doi: 10.1016/j.ijantimicag.2017.04.019. Epub 2017 Jun 28. PMID: 28668689.