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Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint infection: a retrospective study of 39 patients
Accepted Manuscript Title: Suppressive antibiotic therapy with oral doxycycline for staphylococcus aureus prosthetic joint infections: a retrospective study of 39 patients Author: Pradier M, Nguyen S, Robineau O, Titecat M, Blondiaux N, Valette M, Loïez C, Beltrand E, Dézeque H, Migaud H, Senneville E PII: DOI: Reference:
S0924-8579(17)30228-5 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.04.019 ANTAGE 5168
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
16-10-2016 27-4-2017
Please cite this article as: 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 infections: a retrospective study of 39 patients, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint
2
infections: a retrospective study of 39 patients
3 4
Pradier M1, Nguyen S1,2, Robineau O1,2, Titecat M2, Blondiaux N1, Valette M1, Loïez C2, Beltrand
5
E1, Dézeque2 H, Migaud H2, Senneville E1,2
6 7
University Department of Infectious Diseases
8
Faculty of Medicine of Lille University II, Lille, France
9
Gustave Dron Hospital
10
135 rue du Président Coty
11
59200 Tourcoing, France
12 13
Corresponding author : Eric Senneville, MD, PhD
14
Tel.: +33 (0)3 20 694 848; fax: +33 (0)3 20 694 496
15
E-mail address: [email protected]
16 17 18
Running title : doxycycline for suppressive antibiotic therapy
19
Page 1 of 26
20
Highlights
21
22 23
physicians
24 25
28
suppressive antibiotic therapy aims to prolong remission in patient treated for prosthetic joint infection with higher risk of relapse and/or failure
26 27
suppressive antibiotic therapy for prosthetic joint infections is diversely considered by
patients treated with suppressive antibiotic therapy should distinguished from those receiving a palliative antibiotic therapy
doxycycline is safe and efficient in patients who are candidates for suppressive antibiotic therapy in this setting
29
Abstract
30
Purpose :
31
To describe the use of oral doxycycline as suppressive antibiotic therapy (SAT) in patients with
32
Staphylococcus aureus periprosthetic (hip or knee) joint infections.
33
Patients and methods :
34
Medical charts of all patients with surgical revisions for S. aureus hip or knee prosthetic joint
35
infections who were given doxycycline-based SAT because of a high risk of failure of various
36
origins were reviewed. Data regarding tolerability and effectiveness of doxycycline-based SAT
37
were analyzed.
38
Results :
39
Thirty-nine patients of mean age 66.1 ± 16.3 years received doxycycline-based SAT in the period
40
from January 2006 to January 2014. Prosthetic joint infections involved the hip in 23 (58.9%)
41
patients, and the knee in 16 (41.1%), and were qualified as early in 15 patients (38.4%).
42
Methicillin-resistant S. aureus accounted for 28.2% of the total number of bacterial strains
43
identified. All included patients had surgery which consisted in debridement and implant
44
retention in 33 of them (84.6%).
2 Page 2 of 26
45
Adverse events likely attributable to SAT were reported in 6 patients (15.4%), leading to SAT
46
discontinuations in two of them (5.1%). Twenty-nine patients remained event-free (74.4%), and
47
10 (25.6%) failed including 8 (20.5%) relapses, and 2 (5.1%) superinfections. Overall, 8 out of
48
the 10 failure cases were related to a doxycycline-susceptible pathogen.
49 50
Conclusions :
51
Our results suggest that oral doxycycline used as SAT in patients treated for S. aureus hip or knee
52
prosthetic joint infections has an acceptable tolerability and effectiveness, and appears to be a
53
reasonable option in this setting.
54 55
Keywords : Periprosthetic joint infection, suppressive antibiotic therapy, Staphylococcus aureus,
56
palliative antibiotic therapy, doxycycline, bacterial resistance
57 58
3 Page 3 of 26
59
Introduction
60
Periprosthetic joint infections require both surgical intervention and antibiotic therapy conducted
61
at the light of the most recent guidelines for the management of these potentially life-threatening
62
infections (1,2). Suppressive antibiotic therapy (SAT) differs from the curative antibiotic therapy
63
in that it aims to increase the chance of retaining a functional prosthesis in patients with lower
64
probability of remission due to suboptimal surgery and/or curative antibiotic therapy, and/or bad
65
general status. So far, there has been no consensus on the definition, use of SAT, or optimal
66
antibiotic choice and duration. Doxycycline appears to be an attractive candidate for SAT due to
67
its high oral bioavailability close to 100% (3), high bone concentration (4), long half-life (5),
68
acceptable tolerance including as prolonged therapy even in elderly patients (6,7), and low cost,
69
not exceeding 1 to 5€ per day. Doxycycline is active against most Gram-positive cocci, including
70
methicillin-resistant staphylococci (8). Data on the use of oral cyclines as SAT in patients with
71
prosthetic joint infections are scarce although the Infectious Diseases Society of America (IDSA)
72
recommends cyclines as the preferred antibiotics for SAT in prosthetic joint infections due to
73
methicillin-resistant Staphylococcus aureus (MRSA) (2). The objectives of the present study are
74
to describe the tolerance and the effectiveness of oral doxycycline used as SAT for S. aureus hip
75
or knee prosthetic joint infections in patients treated with surgical revision but were considered to
76
be at higher risk of failure given their suboptimal antibiotic therapy, suboptimal surgical
77
management and/or poor general conditions.
78 79
Material and methods
80
Study design and population
81
The present retrospective study was performed at the national French reference center for
82
complex osteo-articular infections of the North West region (Gustave Dron hospital of Tourcoing
83
and Roger Salengro hospital of Lille). Medical charts of all adult patients with PJI (hip and knee) 4 Page 4 of 26
84
who received oral doxycycline-based SAT from January 2006 to January 2014 were reviewed.
85
All patients included in the study had surgical management including debridement, antibiotics
86
and implant retention (DAIR), arthroplastic resection or 1-2 step implant exchange. Therapeutic
87
strategies were decided for each patient during multidisciplinary meetings gathering orthopedic
88
surgeons, infectious disease consultants, microbiologists, and anesthesiologists. In each case, the
89
patient was aware of the different therapeutic options and took part in the final decision.
90 91
Definitions
92
PJI was defined according to the IDSA guidelines criteria of PJI (2). PJI was classified as early
93
(i.e., infection within three months of arthroplasty), delayed (i.e., 3-12 months after arthroplasty)
94
or late (i.e., more than 12 months after arthroplasty) (2). Remission was defined as the absence of
95
signs of infection assessed at least 24 months after the end of the curative treatment and then at
96
the last contact with the patient. Failure was defined as any other outcome including death except
97
when it was not in relation with the PJI. Relapse was defined as the occurrence of PJI at the initial
98
site due to the same bacterial species (based on the antibiotic susceptibility profile) with or
99
without acquisition of resistance to doxycycline, and superinfection as a new infection at the
100
initial
101
webster.com/dictionary/relapse#medicalDictionary;
102
dictionary/superinfection#medicalDictionary).
site
due
to
an
organism
distinct
of
initial
strain
(https://www.merriam-
https://www.merriam-webster.com/
103 104
Microbiology
105
The diffusion agar technique was used to assess the susceptibility profile of all pathogens
106
identified from peroperative samples to antibiotics by using the procedure and interpretation of
107
the susceptibility tests proposed by the Comité de l’Antibiogramme de la Société Française de
5 Page 5 of 26
108
Microbiologie;
109
microbiologie.org).
annual
guides
from
2006
to
2014
recommandations
(www.sfm-
110 111
Surgical management and curative antibiotic therapy
112
DAIR was used in patients with a well-fixed prothesis, no sinus tract, and for whom the infection
113
had been diagnosed within 4 weeks after implantation or the delay from the onset of the
114
infectious symptoms and reintervention was less than 3 weeks (1,2); DAIR was also indicated in
115
patients with poor overall condition for whom no alternative surgery would have been acceptable
116
despite a time from implantation to revision and/or a duration of the infection prior revision
117
exceeding the current recommended deadlines. In all DAIR cases, the mobile parts (polyethylene)
118
of the prosthesis were changed. In the other cases, the indications of one or two-stage exchange
119
(1/2SE) followed the current recommendations (1,2). In cases of re-implantation of a new
120
prosthesis, the duration of antibiotic therapy depended on the results of intraoperative sample
121
cultures (i.e., 2 weeks in case of negative culture results if antibiotic therapy had been stopped at
122
least 2 weeks prior to the intervention, and 6 to 12 weeks in case of positive culture results). New
123
implants were mostly uncemented. Arthroplastic resection (AR) was performed in patients for
124
whom joint replacement would not have produced any functional benefit. All surgical procedures
125
were performed without antibiotic prophylaxis. A combination of antimicrobial agents
126
administered intravenously was begun intraoperatively immediately after samples were taken. It
127
consisted
128
piperacillin/tazobactam, aztreonam, or imipenem) and a second antimicrobial agent active against
129
methicillin-resistant staphylococci (vancomycin or daptomycin). The empirical post-operative
130
antibiotic therapy was continued until the results of intraoperative sample cultures were available
131
and was then modified in accordance with the culture results (curative antibiotic therapy).
132
Antibiotics were selected based on the patient's characteristics and administered following the
133
recommendations of Zimmerli et al. (9). After discharge from the hospital, the patients were
of
a
broad
spectrum
β-lactam
agent
(e.g.,
cefotaxime,
cefepime,
6 Page 6 of 26
134
followed-up by both the referring surgeon and the infectious disease consultant one month after
135
discharge and at the end of antibiotic treatment. The total duration of the curative antimicrobial
136
therapy was 6 weeks to 6 months, according to the pathogen and the prosthesis involved, then
137
followed by the suppressive therapy. Patients were candidates for SAT if they (i) had been
138
operated sub-optimally (e.g. removal of the infected implants not feasible, incomplete or
139
performed outside recommended deadlines), (ii) had received non-optimal curative antibiotic
140
therapy (e.g. impossibility to use rifampicin combinations), (iii) underwent complex orthopedic
141
surgery exposing to limb-threatening conditions in case of relapse, or (iv) had profound
142
immunosuppression (e.g. chemotherapy for cancer) or poor overall condition (e.g. severe cardiac,
143
liver renal, neurologic diseases) exposing to a higher risk of failure.
144 145
Suppressive antibiotic therapy (SAT)
146
SAT was debuted in patients who were considered in remission at the end of the curative
147
treatment but were considered at higher risk of failure (cf above). A specific information was
148
provided to the patients regarding the rational of this unconventional treatment and the expected
149
benefit on their outcome as well as the potential adverse events related to prolonged use of oral
150
doxycycline therapy. A particular attention was paid to the skin and digestive potential toxicity
151
and drug-drug interactions. Doxycline-based SAT was considered only in patents without known
152
contra-indications especially allergy and gastro-duodenal ongoing diseases which were eliminated
153
by fibroscopic assessment if indicated. Until the results of the study reported by Byren et al. were
154
published, the majority of our patients were proposed a two-year duration of doxycycline-based
155
SAT (10). From the beginning of 2010 we took into account Byren et al.'s recommendations and
156
asked the patients to continue SAT (i.e. continued SAT) as long as they had the infected
157
prosthesis.
158 159
Follow-up 7 Page 7 of 26
160
Patients were then followed-up by their referring surgeon once annually for a minimum of 2
161
years. All the patients under SAT were seen in consultation by the infectious diseases consultant
162
twice a year where the efficacy and the tolerability of SAT were assessed. We systematically
163
asked the patients to note the number of missing doses during the period between two
164
consultations. Missing data on patient outcome after the end of antibiotic treatment were obtained
165
by telephone contact with the patient himself/herself or his/her General Practitioner, or when
166
applicable, by reviewing medical records in cases of readmission.
167 168
Statistical analysis
169
An intention-to-treat analysis was performed in the present study (i.e. all patients treated by
170
doxycycline-based SAT including those who received less than 6 months of SAT) in order to
171
avoid any underestimation of failures. The Fisher-exact test or Pearson chi-square test was used
172
for categorical data, whereas the Student test was used for continuous data.
173 174
Ethical considerations
175
All patients’ collected data were anonymized and recorded on a standardized form preventing any
176
personal identification according to procedures defined by the French information protection
177
commission (Commission Nationale de l’Informatique et des Libertés-CNIL); approval from the
178
Institutional Review Board of the G. Dron hospital (Espace Ethique, N° of the approval : 2016/6)
179
was obtained.
180 181
Results
182
Patients
183
During the study period, we identified 82 patients who were given SAT for a PJI of whom 43
184
were excluded as they had non staphylococcal PJIs (n=41) and/or were treated with other 8 Page 8 of 26
185
antibiotics than doxycycline (i.e. cotrimoxazole in two patients, minocycline in two, amoxicillin
186
in one and clindamycin in one). The demographic characteristics of the included patients are
187
reported in Table 1. Thirty-nine patients of mean age 66.1 ± 16.3 years were finally included in
188
the present study. The mean delay from implantation to PJI management was 7.36 ± 6.4 months
189
(range 1-25) and 15 patients (38.4%) had early prosthetic joint infections. Nineteen out of 39
190
patients (48.7%) had immunosuppression, including neoplasia in 5 of them (12.8%).
191 192
Microbiology
193
A total of 50 different strains were identified from peroperative samples (Table 2). Polymicrobial
194
infections were recorded in 9 patients (23.1%) and involved coagulase negative staphylococci
195
(CoNS) in 5 cases. Eleven S. aureus (28.2%) and 3 CoNS (60%) were resistant to methicillin.
196
Resistance to rifampicin was recorded in 15 S. aureus (38.4%) and in one (20%). CoNS.
197 198
Surgical management
199
Surgical management consisted in DAIR for 32 patients (82.1%) or in implant exchange for 7
200
patients (17.9%) including 4SE (10.2%) and 3SE (7.7%).
201 202
Curative antibiotic therapy
203
Most patients (71.8%) were treated with rifampicin-combinations for curative antibiotic.
204
Rifampicin combined with levofloxacin was the most frequently prescribed regimen (35.9%)
205
(Table 3). The mean duration of curative antibiotic treatment was 102.8 ± 48.6 days.
206 207
Suppressive antibiotic therapy
208
The indications of SAT included (i) suboptimal surgery or curative antibiotic therapy (n=26 and
209
6, respectively), (iii) complex orthopedic surgery (n=4), and (iv) immunosuppressive status (n=3).
210
In particular, 15 patients with poor overall condition were treated with DAIR although the time 9 Page 9 of 26
211
from implantation to revision exceeded the 4 week deadline currently recommended and received
212
suboptimal antibiotic therapy. The mean SAT duration was 675.3 ± 619.1 days (range 508-842).
213
Thirteen patients (33.3%) were proposed a two-year duration of SAT and 26 (67.7%) a continued
214
SAT. Ten adverse events likely attributable to SAT were reported in 6 patients (15.4%), including
215
photosensitization (n=4), and nausea/vomiting (n=2, all were improved by changing the daily
216
administration into two divided doses of 100mg). SAT discontinuations, all due to cycline-
217
induced skin problems were recorded in 2 patients (5.1%). Overall, missing doses of antibiotics
218
were reported between 0 and 5 missing doses per 6 months of treatment (data not shown).
219 220
Follow-up
221
The mean duration of the event-free period was 994.4 ± 736.2 days (range 795-1193). Three
222
patients (7.7%) died during the study period including one while receiving SAT. None of these
223
deaths was related to the PJI (one pulmonary embolism, one neoplasia and one hospital-acquired
224
pneumonia). Twenty-nine patients remained event-free (74.4%), and 10 (25.6%) failed including
225
8 (20.5%) relapses, and 2 (5.1%) superinfections. The pathogens responsible for the
226
superinfection cases were S. epidermidis. Failure was recorded after a mean delay of 310.2 ± 566
227
(range 47-668) days following the beginning of SAT. All of the failure cases were diagnosed
228
while the patients were under SAT. Among patients with relapsing infection, S. aureus remained
229
susceptible to doxycycline in seven of these eight cases whereas doxycycline-resistant S.
230
epidermidis was identified in one of the two superinfection cases. Overall, 8 out of the 10 failure
231
cases were related to a doxycycline-susceptible pathogen. Continued SAT was associated with a
232
better rate of remission than 2-year SAT (Table 5).
233
10 Page 10 of 26
234
Discussion
235
The present study is the first to report a series of patients with hip or knee prosthetic joint
236
infections treated uniformly with doxycycline-based SAT. The choice of doxycycline for our
237
patients receiving SAT was based on the high oral bioavailability of doxycycline, its high bone
238
diffusion and the data available regarding its tolerability even in long-term treatments reported in
239
other settings such as rheumatology and dermatology (5,11,12). Of note, doxycycline is
240
recommended for suppressive antibiotic therapy by both the IDSA and the International
241
Consensus Meeting committee for MRSA-related prosthetic joint infections (1,2). There are,
242
however, no data focusing on the efficacy of SAT by oral doxycycline, mainly because patients
243
are treated in the available published studies on SAT, with varied antibiotic regimens (e.g.,
244
cyclines, β-lactams, clindamycin, fluoroquinolones, cotrimoxazole, and rifampicin) whose
245
outcomes are analyzed globally with no analysis performed according to the type of antibiotic
246
used (10,1319). Furthermore, in previous studies, the indications of SAT as well as the definitions
247
of treatment failure, and the choice of curative antibiotic therapy preceding SAT are
248
heterogeneous, making comparisons of these studies very difficult.
249
In our study, the use of cycline-based SAT in patients with hip or knee prosthetic joint
250
infections was associated with a remission rate of 71.8% which is relatively high when compared
251
to the results of previous studies on SAT (10,13-19). In addition, this value of remission rate
252
favorably compares with that of previous series of patients with prosthetic joint infections who
253
received optimal medical and surgical treatments which significantly differs from our patients
254
(20-23). The optimal duration of SAT in patients treated for prosthetic joint infections is a subject
255
of debate. Until the results reported by Byren et al. became available by the end of 2009, we used
256
to maintain SAT for two years (10). Since the beginning of 2010, we have asked our patients to
257
prolong SAT as long as the infected implants remain in place given the high risk of relapsing
258
infection reported by Byren et al. in these patients following the cessation of SAT (10). The better
11 Page 11 of 26
259
remission rate in our patients treated with continued versus 2-year SAT is consistent with the
260
results reported previously by Byren et al. although the patients' clinical status and the antibiotics
261
used as SAT are quite different in the two studies (109). Of note, no change in the surgical or in
262
the curative and suppressive antibiotic therapy occurred during the study period that may have
263
influenced our results.
264
The wide range of remission rates reported in previous studies on SAT (i.e., 8 to 91%) illustrates
265
the absence of consensus on the definition of SAT (10,13-19). In our center we consider SAT as
266
an adjunctive treatment in patients who could not benefit of the most appropriate medical and
267
surgical treatments for various reasons. We only propose SAT to patients treated sub-optimally
268
but are in remission at the end of the curative treatment in order to compensate what we consider
269
to be a higher risk of failure when compared to that of patients treated optimally (24). Of note,
270
since we decided to propose SAT to our selected patients we have observed no refusal of them.
271
We do not use antibiotics in patients with chronic failure of hip or knee prosthetic joint infections
272
especially in case of fistula especially because we consider it is likely to favor the closing of the
273
fistula and therefore to expose the patient to a high risk of pus retention and therefore sepsis. We
274
think that prolonged antibiotic therapy prescribed in failure patients or in patients unable to
275
undergo surgery is more a palliative treatment than a suppressive therapy. The merge of patients
276
treated with a palliative therapy with other patients treated with SAT is likely to underestimate the
277
real efficacy of SAT. We therefore propose to differentiate "palliative" patients from other
278
patients treated with SAT.
279
PJI involving the hip was associated with a better outcome which is consistent with the recent
280
study of Siqueira et al. (18). The tendency towards a longer length of curative antibiotic therapy
281
we recorded in SAT failure patients (p=0.06) may be due to the fact that physicians tended to
282
propose longer curative antibiotic treatments in the patients they considered to be at higher risk
283
of failure. Neither the microbiological origin nor the surgical option (i.e., retention versus
284
removal of the infected implants) did not significantly influence the patients' outcome (Table 4), 12 Page 12 of 26
285
as it was reported by Siqueira et al. (18). Doxycycline was preferred to minocycline where the
286
pathogen(s) was(were) susceptible to doxycycline because of the irreversible hyperpigmentation
287
that can be seen with prolonged administration of minocycline (25) and the risk or more severe
288
adverse events such as drug rash with eosinophilia and systemic symptoms (DRESS syndrome) or
289
severe acute hepatitis (26,30). The tolerability profile of cycline-based SAT in our patients
290
favorably compares with that of the previous studies on prolonged oral cycline therapy in other
291
settings (,11, 12, 287). Skin problems were the most common adverse effects related to cycline-
292
based SAT, followed by nausea/vomiting but no cases of esophageal ulcers were reported in our
293
patients (29). Of note, no case of Clostridium difficile-associated diarrhea was recorded in our
294
patients which differs from previous studies using β-lactam agents or cotrimoxazole as SAT
295
(13,17). Overall, the patients' compliance to cycline-based SAT was high with a very low number
296
of missing doses recorded at each consultation. Of note, among failure patients, 8 of them were
297
found to be infected with a bacterial strain fully susceptible to doxycycline. We have no
298
explanation for this other than the limits of this therapeutical option, noting however that the
299
persistence of the infected material did not significantly influence the chance of remission in our
300
series of patients. Finally, despite the long exposure to cycline agents, the acquisition of
301
resistance to this class of antibiotics was recorded in only 1 out of 39 (2.6%) patients which is
302
consistent with the limited effects of cyclines antibiotic therapy on the host microbiota including
303
the risk of induced C. difficile diarrhea (30-32). However, this illustrates the potential negative
304
effect of prolonged antibiotic therapy which justifies a multidisciplinary discussion before
305
proposing this unconventional prolonged antibiotic administration.
306
The present study has some limitations related to its retrospective design and the small size of the
307
studied population. Its strengths are essentially the homogeneous protocols of treatment applied to
308
our patients followed by the same multidisciplinary team and the fact that SAT was only based on
309
a single antibiotic class which is likely to have reduced data interpretation biases.
310 13 Page 13 of 26
311
In conclusion, the results of the present study suggest that oral doxycycline use as SAT for
312
patients treated initially with suboptimal management of PJI is safe and is associated with an
313
acceptable rate of remission of infection with a low risk of emergence of bacterial resistance in
314
case of failure. Our results also show that SAT discontinuation expose patients with hip or knee
315
prosthetic joint infections to a higher risk of relapse of infection which confirms previous
316
recommendations from Byren et al. to maintain SAT as long as possible (10).
317 318
Acknowledgments
319
Thanks to Mr Philippe Choisy and Mr Marc Digumber for their technical assistance
320
Author contributions
321
SE and NS initiated and designed the study; PM, BE, DH, MH collected the data; VM analyzed
322
the data; TM, BN and LC recorded microbiological data; PM, NS, RO, BE, DH, MH, SE had a
323
role in patient care; DH, MH and BE critically reviewed the manuscript written by PM, NS and
324
SE; all of the authors approved the final version of the manuscript.
325 326
Declarations
327
Funding: No funding
328
Competing Interests: The authors report no conflicts of interest in this work
329
Ethical Approval: Approval from the Institutional Review Board of the G. Dron hospital
330
(Espace Ethique, N° of the approval : 2016/6) was obtained
331
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12. Smith K, Leyden JJ. Safety of Doxycycline and Minocycline: A Systematic Review. Clin Ther 2005;27:1329–42.
380 381 382
13. Segreti J, Nelson JA, Trenholme GM. Prolonged suppressive antibiotic therapy
for
infected orthopedic prostheses. Clin Infect Dis 1998;27:711–3.
383 16 Page 16 of 26
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14. Rao N, Crossett LS, Sinha RK, Le Frock JL. Long-term suppression of infection in total joint arthroplasty. Clin Orthop Relat Res 2003;414:55–60.
386 387 388
15. Goulet JA, Pellicci PM, Brause BD, Salvati EM. Prolonged suppression of infection in total hip arthroplasty. J Arthroplasty 1988;3:109–16.
389 390 391
16. Tsukayama DT, Wicklund B, Gustilo RB. Suppressive antibiotic therapy in chronic prosthetic joint infections. Orthopedics 1991;14:841–4.
392 393
17. Prendki V, Zeller V, Passeron D, Desplaces N, Mamoudy P, Stirnemann J, et al.. Outcome
394
of patients over 80 years of age on prolonged suppressive antibiotic therapy for at least 6
395
months for prosthetic joint infection. Int J Infect Dis 2014;29:184–9.
396 397
18. Siqueira MB, Saleh A, Klika AK, O’Rourke C, Schmitt S, Higuera CA, et al.. Chronic
398
Suppression of Periprosthetic Joint Infections with Oral Antibiotics Increases Infection-
399
Free Survivorship. J Bone Joint Surg Am 2015;97:1220–32.
400
19. Koeppe J, Johnson S, Morroni J, Siracusa-Rick C, Armon C. Suppressive Antibiotic
401
Therapy for Retained Infected Prosthetic Joints: Case Series and Review of the Literature.
402
Infect Dis Clin Pract 2008;16:224–29.
403 404
20. Aboltins CA, Page MA, Buising KL,Jenney AW, Daffy JR, Choong PF, et al.Treatment of
405
staphylococcal prosthetic joint infections with debridement, prosthesis retentionand oral
406
rifampicin and fusidic acid. Clin Microbiol Infect 2007;13:586–91.
407
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408
21. Lora-Tamayo J, Murillo O, Iribarren JA, Soriano A, Sanchez-Somolinos M, Baraia-
409
Etxaburu JM, et al.; REIPI Group for the Study of Prosthetic Infection. A large
410
multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus
411
aureus prosthetic joint infections managed with implant retention. Clin Infect Dis
412
2013;56:182–94.
413 414
22. Cobo J, Garcia San Miguel L, Euba G, Rodrıguez D, Garcıa-Lechuz JM, Riera M , et al..
415
Early prosthetic joint infection: outcomes with debridement and implant retention
416
followed by antibiotic therapy. Clin Microbiol Infect 2011;17:1632–7.
417 418
23. Senneville E, Joulie D, Legout L, Valette M, Dezèque H, Beltrand E, et al.. Outcome and
419
Predictors of Treatment Failure in Total Hip/Knee Prosthetic Joint Infections Due to
420
Staphylococcus aureus. Clin Infect Dis 2011;53:334–40.
421
24. Betsch BY, Eggli S, Siebenrock KA, Täuber MG, Mühlemann K. Treatment of joint
422
prosthesis infection in accordance with current recommendations improves outcome. Clin
423
Infect Dis 2008;46:1221–6.
424 425 426
25. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980;244:1103–6.
427 428
26. Lawrenson RA, Seaman HE, Sundström A, Williams TJ, Farmer RD. Liver damage
429
associated with minocycline use in acne: a systematic review of the published literature
430
and pharmacovigilance data. Drug Saf 2000;23:333–49.
431
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432
27. Lan J, Lahoti A, Lew DB. A severe case of minocycline-induced DRESS resulting in liver
433
transplantation and autoimmune sequelae. Ann Allergy Asthma Immunol 2016;116:367–
434
8.
435 436
28. Meropol SB, Chan KA, Chen Z, Finkelstein JA, Hennessy S, Lautenbach E, et al..
437
Adverse events associated with prolonged antibiotic use. Pharmacoepidemiol Drug Saf
438
200;17:523-32.
439 440
29. Dağ MS, Öztürk ZA, Akın I, Tutar E, Çıkman Ö, Gülşen MT. Drug-induced esophageal
441
ulcers: case series and the review of the literature. Turk J Gastroenterol 2014;25:180–4.
442
30. Hung YP, Lee JC, Lin HJ, Liu HC, Wu YH, Tsai PJ, et al.. Doxycycline and Tigecycline:
443
Two Friendly Drugs with a Low Association with Clostridium difficile Infection.
444
Antibiotics (Basel) 2015;4:216–22.
445 446
31. Doernberg SB, Winston LG, Deck DH, Chambers HF. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis 2012;55:615–20.
447 448 449
32. Turner RB, Smith CB, Martello JL, Slain D. Role of doxycycline in Clostridium difficile infection acquisition. Ann Pharmacother 2014;48:772–6.
450
19 Page 19 of 26
451
Table 1 : Characteristics of 39 patients with knee or hip prosthetic joint infections treated with
452
oral doxycycline-based suppressive antibiotic therapy Characteristics Male, n of pts (%)
15 (38.4)
Female, n of pts (%)
24 (61.6)
Age, years, mean ± SD (range)
66.1 ± 16.3 (18-91)
≥75 yo (%)
14 (35,9)
50-75 yo (%)
20 (51.2)
<50 yo (%)
5 (12.8)
Weight, kg ± SD
82.6 ± 22.9
BMI, mean ± SD, kg.m-2 (n=70)
30.7 ± 7.5
Immunosuppression, n of pts (%)
19 (48.7)
- diabetes mellitus
4 (10.2)
- neoplasia
5 (12.8)
- rheumatoid arthritis
6 (15.4)
- corticosteroid therapy
1 (2.5)
- chronic renal failure
3 (7.7)
- none
42 (53.9)
Location of PJI, n of pts (%) - hip
23 (58.9)
- knee
16 (41.1)
Clinical symptoms at the time of diagnosis of PJI, n of pts (%) - fever (data available for 26 patients)
11 (42.3)
- pus (data available for 28 patients)
17 (60.7)
- sinus tract (data available for 31 patients)
13 (41.9)
20 Page 20 of 26
Delay from symptoms to surgery; months, mean ± SD (range)
7.42 ± 6.97 (1-27)
Type of infection, n of pts (%) - early
15 (38.4)
- delayed
17 (43.5)
- late
7 (17.9)
Number of previous surgery, mean ± SD 453
1.13 ± 1.61
N of pts : number of patients; yo : years old; BMI : body mass index; SD : standard deviation
454
21 Page 21 of 26
455
Table 2 : Bacterial pathogens isolated from peroperative samples of prosthetic joint infections in
456
39 patients treated with doxycycline-based suppressive antibiotic therapy Microorganism
N° of strains (% of the total)
Gram positive cocci
46 (92)
Staphylococci
44 (88)
Staphylococcus aureus
39 (78)
MSSA
28 (56)
MRSA
11 (22)
CoNS
5 (10)
Staphylococcus epidermidis
3 (6)
Staphylococcus lugdunensis
1 (2)
Staphylococcus warneri
1 (2)
Group G streptococci
1 (2)
Enterococcus faecalis
1 (2)
Aerobic Gram negative bacilli
3 (6)
Enterobacteriaceae
2 (4)
Citrobacter koseri
1 (2)
Escherichia coli
1 (2)
Pseudomonas aeruginosa
1 (2)
Anaerobes
1 (2)
Propionibacterium acnes
1 (2)
Total number of strains
50 (100%)
457 458
22 Page 22 of 26
459
Table 3 : Characteristics of the curative antibiotic initial treatment in 39 patients treated with
460
doxycycline-based antibiotic suppressive therapy Curative antibiotic therapy
N° of patients (%)
Combination with rifampicin
28 (71.8)
- rifampicin / fluoroquinolonesa
14 (35.9)
- rifampicin / cycline
6 (15.4)
- rifampicin / otherb
8 (20.5)
Without rifampicin, n (%)
11 (28.2)
- fluoroquinolones / otherc
3 (7.7)
- cyclines / otherd
4 (10.3)
- otherse
4 (10.3)
461
a
Levofloxacin (n=14)
462
b
Cotrimoxazole (n=5); Imipenem (n=1); Amoxicillin (n=1); Linezolid (n=1)
463
c
Clindamycin (n=2), Fusidic acid (n=1)
464
d
Clindamycin (n=2), Teicoplanin (n=2)
465
e
Linezolid (n=3), Clindamycin (n=1)
23 Page 23 of 26
466
Table 4 : Bivariate analysis comparing the characteristics of 39 patients treated by doxycycline-
467
based suppressive antibiotic therapy according to the outcome (i.e., remission versus failure) Variables
Remission
Failure group
P
group (n=29)
(n=10)
value
Age
68.6 ± 14.7
60.0 ± 19.2
0.14
Male
10 (34.4%)
5 (50%)
0.38
BMI (n=70)
30.3 ± 7.50
31.7 ± 7.65
0.61
- knee
10 (34.4%)
6 (60%)
0.15
- hip
18 (62.1%)
5 (50%)
0.50
Mean delay from implantation; months, ±SD
7.1 ± 6.70
8.09 ± 5.82
0.42
Previous surgery
0.89 ± 1.37
1.73 ± 2.05
0.12
Prosthesis
Microbiology
0.51
- MSSA
22 (75.8%)
6 (60%)
0.34
- MRSA
7 (24.1%)
4 (40%)
0.34
- CoNS
3 (10.3%)
2 (20%)
0.43
6 (20.7%)
3 (30%)
0.55
- diabetes mellitus
3 (10.3%)
1 (10%)
0.97
- rheumatoid polyarthritis
4 (13.8%)
2 (20%)
0.64
- chronic renal failure
2 (6.9%)
1 (10%)
0.75
- corticosteroid therapy**
1 (3.4%)
0
---
- neoplasia
3 (10.3%)
2 (20%)
0.44
- none
7 (24.1%)
3 (30%)
0.71
- polymicrobial Immunosuppression
24 Page 24 of 26
DAIR
25 (86.2%)
7 (70%)
0.25
136.45
0.02
Curative antibiotic therapy - mean duration, days ±SD
89,6
- rifampicin combinations
± 30.09
± 69.30
21 (65.6%)
7 (70%)
0.88
3 (10.3%)
1 (10%)
0.98
2(6.9%)
0
---
Adverse events - photosensitization - gastro-intestinal 468
MSSA, methicillin susceptible S. aureus; MRSA, methicillin-resistant S. aureus ; CoNS,
469
coagulase-negative staphylococci
470
* : hip versus knee prosthesis
471
** : ≥ 10mg/d for > 3 months
472
25 Page 25 of 26
473
Table 5 : Compared outcome of 39 patients treated with 2-year versus continued doxycycline-
474
based suppressive antibiotic therapy (SAT) for knee or hip prosthetic joint infections Outcome
2 year SAT
Continued SAT
P
(n=10)
(n=29)
Discontinuation for SAT-related adverse effect
1 (10%)
2 (6.9%)
0.75
Death
1 (10%)
2 (6.7%)
0.75
Failure
5 (50%)
5 (17.2%)
0.04
value
475 476 477 478
26 Page 26 of 26
S0924-8579(17)30228-5 http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.04.019 ANTAGE 5168
To appear in:
International Journal of Antimicrobial Agents
Received date: Accepted date:
16-10-2016 27-4-2017
Please cite this article as: 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 infections: a retrospective study of 39 patients, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint
2
infections: a retrospective study of 39 patients
3 4
Pradier M1, Nguyen S1,2, Robineau O1,2, Titecat M2, Blondiaux N1, Valette M1, Loïez C2, Beltrand
5
E1, Dézeque2 H, Migaud H2, Senneville E1,2
6 7
University Department of Infectious Diseases
8
Faculty of Medicine of Lille University II, Lille, France
9
Gustave Dron Hospital
10
135 rue du Président Coty
11
59200 Tourcoing, France
12 13
Corresponding author : Eric Senneville, MD, PhD
14
Tel.: +33 (0)3 20 694 848; fax: +33 (0)3 20 694 496
15
E-mail address: [email protected]
16 17 18
Running title : doxycycline for suppressive antibiotic therapy
19
Page 1 of 26
20
Highlights
21
22 23
physicians
24 25
28
suppressive antibiotic therapy aims to prolong remission in patient treated for prosthetic joint infection with higher risk of relapse and/or failure
26 27
suppressive antibiotic therapy for prosthetic joint infections is diversely considered by
patients treated with suppressive antibiotic therapy should distinguished from those receiving a palliative antibiotic therapy
doxycycline is safe and efficient in patients who are candidates for suppressive antibiotic therapy in this setting
29
Abstract
30
Purpose :
31
To describe the use of oral doxycycline as suppressive antibiotic therapy (SAT) in patients with
32
Staphylococcus aureus periprosthetic (hip or knee) joint infections.
33
Patients and methods :
34
Medical charts of all patients with surgical revisions for S. aureus hip or knee prosthetic joint
35
infections who were given doxycycline-based SAT because of a high risk of failure of various
36
origins were reviewed. Data regarding tolerability and effectiveness of doxycycline-based SAT
37
were analyzed.
38
Results :
39
Thirty-nine patients of mean age 66.1 ± 16.3 years received doxycycline-based SAT in the period
40
from January 2006 to January 2014. Prosthetic joint infections involved the hip in 23 (58.9%)
41
patients, and the knee in 16 (41.1%), and were qualified as early in 15 patients (38.4%).
42
Methicillin-resistant S. aureus accounted for 28.2% of the total number of bacterial strains
43
identified. All included patients had surgery which consisted in debridement and implant
44
retention in 33 of them (84.6%).
2 Page 2 of 26
45
Adverse events likely attributable to SAT were reported in 6 patients (15.4%), leading to SAT
46
discontinuations in two of them (5.1%). Twenty-nine patients remained event-free (74.4%), and
47
10 (25.6%) failed including 8 (20.5%) relapses, and 2 (5.1%) superinfections. Overall, 8 out of
48
the 10 failure cases were related to a doxycycline-susceptible pathogen.
49 50
Conclusions :
51
Our results suggest that oral doxycycline used as SAT in patients treated for S. aureus hip or knee
52
prosthetic joint infections has an acceptable tolerability and effectiveness, and appears to be a
53
reasonable option in this setting.
54 55
Keywords : Periprosthetic joint infection, suppressive antibiotic therapy, Staphylococcus aureus,
56
palliative antibiotic therapy, doxycycline, bacterial resistance
57 58
3 Page 3 of 26
59
Introduction
60
Periprosthetic joint infections require both surgical intervention and antibiotic therapy conducted
61
at the light of the most recent guidelines for the management of these potentially life-threatening
62
infections (1,2). Suppressive antibiotic therapy (SAT) differs from the curative antibiotic therapy
63
in that it aims to increase the chance of retaining a functional prosthesis in patients with lower
64
probability of remission due to suboptimal surgery and/or curative antibiotic therapy, and/or bad
65
general status. So far, there has been no consensus on the definition, use of SAT, or optimal
66
antibiotic choice and duration. Doxycycline appears to be an attractive candidate for SAT due to
67
its high oral bioavailability close to 100% (3), high bone concentration (4), long half-life (5),
68
acceptable tolerance including as prolonged therapy even in elderly patients (6,7), and low cost,
69
not exceeding 1 to 5€ per day. Doxycycline is active against most Gram-positive cocci, including
70
methicillin-resistant staphylococci (8). Data on the use of oral cyclines as SAT in patients with
71
prosthetic joint infections are scarce although the Infectious Diseases Society of America (IDSA)
72
recommends cyclines as the preferred antibiotics for SAT in prosthetic joint infections due to
73
methicillin-resistant Staphylococcus aureus (MRSA) (2). The objectives of the present study are
74
to describe the tolerance and the effectiveness of oral doxycycline used as SAT for S. aureus hip
75
or knee prosthetic joint infections in patients treated with surgical revision but were considered to
76
be at higher risk of failure given their suboptimal antibiotic therapy, suboptimal surgical
77
management and/or poor general conditions.
78 79
Material and methods
80
Study design and population
81
The present retrospective study was performed at the national French reference center for
82
complex osteo-articular infections of the North West region (Gustave Dron hospital of Tourcoing
83
and Roger Salengro hospital of Lille). Medical charts of all adult patients with PJI (hip and knee) 4 Page 4 of 26
84
who received oral doxycycline-based SAT from January 2006 to January 2014 were reviewed.
85
All patients included in the study had surgical management including debridement, antibiotics
86
and implant retention (DAIR), arthroplastic resection or 1-2 step implant exchange. Therapeutic
87
strategies were decided for each patient during multidisciplinary meetings gathering orthopedic
88
surgeons, infectious disease consultants, microbiologists, and anesthesiologists. In each case, the
89
patient was aware of the different therapeutic options and took part in the final decision.
90 91
Definitions
92
PJI was defined according to the IDSA guidelines criteria of PJI (2). PJI was classified as early
93
(i.e., infection within three months of arthroplasty), delayed (i.e., 3-12 months after arthroplasty)
94
or late (i.e., more than 12 months after arthroplasty) (2). Remission was defined as the absence of
95
signs of infection assessed at least 24 months after the end of the curative treatment and then at
96
the last contact with the patient. Failure was defined as any other outcome including death except
97
when it was not in relation with the PJI. Relapse was defined as the occurrence of PJI at the initial
98
site due to the same bacterial species (based on the antibiotic susceptibility profile) with or
99
without acquisition of resistance to doxycycline, and superinfection as a new infection at the
100
initial
101
webster.com/dictionary/relapse#medicalDictionary;
102
dictionary/superinfection#medicalDictionary).
site
due
to
an
organism
distinct
of
initial
strain
(https://www.merriam-
https://www.merriam-webster.com/
103 104
Microbiology
105
The diffusion agar technique was used to assess the susceptibility profile of all pathogens
106
identified from peroperative samples to antibiotics by using the procedure and interpretation of
107
the susceptibility tests proposed by the Comité de l’Antibiogramme de la Société Française de
5 Page 5 of 26
108
Microbiologie;
109
microbiologie.org).
annual
guides
from
2006
to
2014
recommandations
(www.sfm-
110 111
Surgical management and curative antibiotic therapy
112
DAIR was used in patients with a well-fixed prothesis, no sinus tract, and for whom the infection
113
had been diagnosed within 4 weeks after implantation or the delay from the onset of the
114
infectious symptoms and reintervention was less than 3 weeks (1,2); DAIR was also indicated in
115
patients with poor overall condition for whom no alternative surgery would have been acceptable
116
despite a time from implantation to revision and/or a duration of the infection prior revision
117
exceeding the current recommended deadlines. In all DAIR cases, the mobile parts (polyethylene)
118
of the prosthesis were changed. In the other cases, the indications of one or two-stage exchange
119
(1/2SE) followed the current recommendations (1,2). In cases of re-implantation of a new
120
prosthesis, the duration of antibiotic therapy depended on the results of intraoperative sample
121
cultures (i.e., 2 weeks in case of negative culture results if antibiotic therapy had been stopped at
122
least 2 weeks prior to the intervention, and 6 to 12 weeks in case of positive culture results). New
123
implants were mostly uncemented. Arthroplastic resection (AR) was performed in patients for
124
whom joint replacement would not have produced any functional benefit. All surgical procedures
125
were performed without antibiotic prophylaxis. A combination of antimicrobial agents
126
administered intravenously was begun intraoperatively immediately after samples were taken. It
127
consisted
128
piperacillin/tazobactam, aztreonam, or imipenem) and a second antimicrobial agent active against
129
methicillin-resistant staphylococci (vancomycin or daptomycin). The empirical post-operative
130
antibiotic therapy was continued until the results of intraoperative sample cultures were available
131
and was then modified in accordance with the culture results (curative antibiotic therapy).
132
Antibiotics were selected based on the patient's characteristics and administered following the
133
recommendations of Zimmerli et al. (9). After discharge from the hospital, the patients were
of
a
broad
spectrum
β-lactam
agent
(e.g.,
cefotaxime,
cefepime,
6 Page 6 of 26
134
followed-up by both the referring surgeon and the infectious disease consultant one month after
135
discharge and at the end of antibiotic treatment. The total duration of the curative antimicrobial
136
therapy was 6 weeks to 6 months, according to the pathogen and the prosthesis involved, then
137
followed by the suppressive therapy. Patients were candidates for SAT if they (i) had been
138
operated sub-optimally (e.g. removal of the infected implants not feasible, incomplete or
139
performed outside recommended deadlines), (ii) had received non-optimal curative antibiotic
140
therapy (e.g. impossibility to use rifampicin combinations), (iii) underwent complex orthopedic
141
surgery exposing to limb-threatening conditions in case of relapse, or (iv) had profound
142
immunosuppression (e.g. chemotherapy for cancer) or poor overall condition (e.g. severe cardiac,
143
liver renal, neurologic diseases) exposing to a higher risk of failure.
144 145
Suppressive antibiotic therapy (SAT)
146
SAT was debuted in patients who were considered in remission at the end of the curative
147
treatment but were considered at higher risk of failure (cf above). A specific information was
148
provided to the patients regarding the rational of this unconventional treatment and the expected
149
benefit on their outcome as well as the potential adverse events related to prolonged use of oral
150
doxycycline therapy. A particular attention was paid to the skin and digestive potential toxicity
151
and drug-drug interactions. Doxycline-based SAT was considered only in patents without known
152
contra-indications especially allergy and gastro-duodenal ongoing diseases which were eliminated
153
by fibroscopic assessment if indicated. Until the results of the study reported by Byren et al. were
154
published, the majority of our patients were proposed a two-year duration of doxycycline-based
155
SAT (10). From the beginning of 2010 we took into account Byren et al.'s recommendations and
156
asked the patients to continue SAT (i.e. continued SAT) as long as they had the infected
157
prosthesis.
158 159
Follow-up 7 Page 7 of 26
160
Patients were then followed-up by their referring surgeon once annually for a minimum of 2
161
years. All the patients under SAT were seen in consultation by the infectious diseases consultant
162
twice a year where the efficacy and the tolerability of SAT were assessed. We systematically
163
asked the patients to note the number of missing doses during the period between two
164
consultations. Missing data on patient outcome after the end of antibiotic treatment were obtained
165
by telephone contact with the patient himself/herself or his/her General Practitioner, or when
166
applicable, by reviewing medical records in cases of readmission.
167 168
Statistical analysis
169
An intention-to-treat analysis was performed in the present study (i.e. all patients treated by
170
doxycycline-based SAT including those who received less than 6 months of SAT) in order to
171
avoid any underestimation of failures. The Fisher-exact test or Pearson chi-square test was used
172
for categorical data, whereas the Student test was used for continuous data.
173 174
Ethical considerations
175
All patients’ collected data were anonymized and recorded on a standardized form preventing any
176
personal identification according to procedures defined by the French information protection
177
commission (Commission Nationale de l’Informatique et des Libertés-CNIL); approval from the
178
Institutional Review Board of the G. Dron hospital (Espace Ethique, N° of the approval : 2016/6)
179
was obtained.
180 181
Results
182
Patients
183
During the study period, we identified 82 patients who were given SAT for a PJI of whom 43
184
were excluded as they had non staphylococcal PJIs (n=41) and/or were treated with other 8 Page 8 of 26
185
antibiotics than doxycycline (i.e. cotrimoxazole in two patients, minocycline in two, amoxicillin
186
in one and clindamycin in one). The demographic characteristics of the included patients are
187
reported in Table 1. Thirty-nine patients of mean age 66.1 ± 16.3 years were finally included in
188
the present study. The mean delay from implantation to PJI management was 7.36 ± 6.4 months
189
(range 1-25) and 15 patients (38.4%) had early prosthetic joint infections. Nineteen out of 39
190
patients (48.7%) had immunosuppression, including neoplasia in 5 of them (12.8%).
191 192
Microbiology
193
A total of 50 different strains were identified from peroperative samples (Table 2). Polymicrobial
194
infections were recorded in 9 patients (23.1%) and involved coagulase negative staphylococci
195
(CoNS) in 5 cases. Eleven S. aureus (28.2%) and 3 CoNS (60%) were resistant to methicillin.
196
Resistance to rifampicin was recorded in 15 S. aureus (38.4%) and in one (20%). CoNS.
197 198
Surgical management
199
Surgical management consisted in DAIR for 32 patients (82.1%) or in implant exchange for 7
200
patients (17.9%) including 4SE (10.2%) and 3SE (7.7%).
201 202
Curative antibiotic therapy
203
Most patients (71.8%) were treated with rifampicin-combinations for curative antibiotic.
204
Rifampicin combined with levofloxacin was the most frequently prescribed regimen (35.9%)
205
(Table 3). The mean duration of curative antibiotic treatment was 102.8 ± 48.6 days.
206 207
Suppressive antibiotic therapy
208
The indications of SAT included (i) suboptimal surgery or curative antibiotic therapy (n=26 and
209
6, respectively), (iii) complex orthopedic surgery (n=4), and (iv) immunosuppressive status (n=3).
210
In particular, 15 patients with poor overall condition were treated with DAIR although the time 9 Page 9 of 26
211
from implantation to revision exceeded the 4 week deadline currently recommended and received
212
suboptimal antibiotic therapy. The mean SAT duration was 675.3 ± 619.1 days (range 508-842).
213
Thirteen patients (33.3%) were proposed a two-year duration of SAT and 26 (67.7%) a continued
214
SAT. Ten adverse events likely attributable to SAT were reported in 6 patients (15.4%), including
215
photosensitization (n=4), and nausea/vomiting (n=2, all were improved by changing the daily
216
administration into two divided doses of 100mg). SAT discontinuations, all due to cycline-
217
induced skin problems were recorded in 2 patients (5.1%). Overall, missing doses of antibiotics
218
were reported between 0 and 5 missing doses per 6 months of treatment (data not shown).
219 220
Follow-up
221
The mean duration of the event-free period was 994.4 ± 736.2 days (range 795-1193). Three
222
patients (7.7%) died during the study period including one while receiving SAT. None of these
223
deaths was related to the PJI (one pulmonary embolism, one neoplasia and one hospital-acquired
224
pneumonia). Twenty-nine patients remained event-free (74.4%), and 10 (25.6%) failed including
225
8 (20.5%) relapses, and 2 (5.1%) superinfections. The pathogens responsible for the
226
superinfection cases were S. epidermidis. Failure was recorded after a mean delay of 310.2 ± 566
227
(range 47-668) days following the beginning of SAT. All of the failure cases were diagnosed
228
while the patients were under SAT. Among patients with relapsing infection, S. aureus remained
229
susceptible to doxycycline in seven of these eight cases whereas doxycycline-resistant S.
230
epidermidis was identified in one of the two superinfection cases. Overall, 8 out of the 10 failure
231
cases were related to a doxycycline-susceptible pathogen. Continued SAT was associated with a
232
better rate of remission than 2-year SAT (Table 5).
233
10 Page 10 of 26
234
Discussion
235
The present study is the first to report a series of patients with hip or knee prosthetic joint
236
infections treated uniformly with doxycycline-based SAT. The choice of doxycycline for our
237
patients receiving SAT was based on the high oral bioavailability of doxycycline, its high bone
238
diffusion and the data available regarding its tolerability even in long-term treatments reported in
239
other settings such as rheumatology and dermatology (5,11,12). Of note, doxycycline is
240
recommended for suppressive antibiotic therapy by both the IDSA and the International
241
Consensus Meeting committee for MRSA-related prosthetic joint infections (1,2). There are,
242
however, no data focusing on the efficacy of SAT by oral doxycycline, mainly because patients
243
are treated in the available published studies on SAT, with varied antibiotic regimens (e.g.,
244
cyclines, β-lactams, clindamycin, fluoroquinolones, cotrimoxazole, and rifampicin) whose
245
outcomes are analyzed globally with no analysis performed according to the type of antibiotic
246
used (10,1319). Furthermore, in previous studies, the indications of SAT as well as the definitions
247
of treatment failure, and the choice of curative antibiotic therapy preceding SAT are
248
heterogeneous, making comparisons of these studies very difficult.
249
In our study, the use of cycline-based SAT in patients with hip or knee prosthetic joint
250
infections was associated with a remission rate of 71.8% which is relatively high when compared
251
to the results of previous studies on SAT (10,13-19). In addition, this value of remission rate
252
favorably compares with that of previous series of patients with prosthetic joint infections who
253
received optimal medical and surgical treatments which significantly differs from our patients
254
(20-23). The optimal duration of SAT in patients treated for prosthetic joint infections is a subject
255
of debate. Until the results reported by Byren et al. became available by the end of 2009, we used
256
to maintain SAT for two years (10). Since the beginning of 2010, we have asked our patients to
257
prolong SAT as long as the infected implants remain in place given the high risk of relapsing
258
infection reported by Byren et al. in these patients following the cessation of SAT (10). The better
11 Page 11 of 26
259
remission rate in our patients treated with continued versus 2-year SAT is consistent with the
260
results reported previously by Byren et al. although the patients' clinical status and the antibiotics
261
used as SAT are quite different in the two studies (109). Of note, no change in the surgical or in
262
the curative and suppressive antibiotic therapy occurred during the study period that may have
263
influenced our results.
264
The wide range of remission rates reported in previous studies on SAT (i.e., 8 to 91%) illustrates
265
the absence of consensus on the definition of SAT (10,13-19). In our center we consider SAT as
266
an adjunctive treatment in patients who could not benefit of the most appropriate medical and
267
surgical treatments for various reasons. We only propose SAT to patients treated sub-optimally
268
but are in remission at the end of the curative treatment in order to compensate what we consider
269
to be a higher risk of failure when compared to that of patients treated optimally (24). Of note,
270
since we decided to propose SAT to our selected patients we have observed no refusal of them.
271
We do not use antibiotics in patients with chronic failure of hip or knee prosthetic joint infections
272
especially in case of fistula especially because we consider it is likely to favor the closing of the
273
fistula and therefore to expose the patient to a high risk of pus retention and therefore sepsis. We
274
think that prolonged antibiotic therapy prescribed in failure patients or in patients unable to
275
undergo surgery is more a palliative treatment than a suppressive therapy. The merge of patients
276
treated with a palliative therapy with other patients treated with SAT is likely to underestimate the
277
real efficacy of SAT. We therefore propose to differentiate "palliative" patients from other
278
patients treated with SAT.
279
PJI involving the hip was associated with a better outcome which is consistent with the recent
280
study of Siqueira et al. (18). The tendency towards a longer length of curative antibiotic therapy
281
we recorded in SAT failure patients (p=0.06) may be due to the fact that physicians tended to
282
propose longer curative antibiotic treatments in the patients they considered to be at higher risk
283
of failure. Neither the microbiological origin nor the surgical option (i.e., retention versus
284
removal of the infected implants) did not significantly influence the patients' outcome (Table 4), 12 Page 12 of 26
285
as it was reported by Siqueira et al. (18). Doxycycline was preferred to minocycline where the
286
pathogen(s) was(were) susceptible to doxycycline because of the irreversible hyperpigmentation
287
that can be seen with prolonged administration of minocycline (25) and the risk or more severe
288
adverse events such as drug rash with eosinophilia and systemic symptoms (DRESS syndrome) or
289
severe acute hepatitis (26,30). The tolerability profile of cycline-based SAT in our patients
290
favorably compares with that of the previous studies on prolonged oral cycline therapy in other
291
settings (,11, 12, 287). Skin problems were the most common adverse effects related to cycline-
292
based SAT, followed by nausea/vomiting but no cases of esophageal ulcers were reported in our
293
patients (29). Of note, no case of Clostridium difficile-associated diarrhea was recorded in our
294
patients which differs from previous studies using β-lactam agents or cotrimoxazole as SAT
295
(13,17). Overall, the patients' compliance to cycline-based SAT was high with a very low number
296
of missing doses recorded at each consultation. Of note, among failure patients, 8 of them were
297
found to be infected with a bacterial strain fully susceptible to doxycycline. We have no
298
explanation for this other than the limits of this therapeutical option, noting however that the
299
persistence of the infected material did not significantly influence the chance of remission in our
300
series of patients. Finally, despite the long exposure to cycline agents, the acquisition of
301
resistance to this class of antibiotics was recorded in only 1 out of 39 (2.6%) patients which is
302
consistent with the limited effects of cyclines antibiotic therapy on the host microbiota including
303
the risk of induced C. difficile diarrhea (30-32). However, this illustrates the potential negative
304
effect of prolonged antibiotic therapy which justifies a multidisciplinary discussion before
305
proposing this unconventional prolonged antibiotic administration.
306
The present study has some limitations related to its retrospective design and the small size of the
307
studied population. Its strengths are essentially the homogeneous protocols of treatment applied to
308
our patients followed by the same multidisciplinary team and the fact that SAT was only based on
309
a single antibiotic class which is likely to have reduced data interpretation biases.
310 13 Page 13 of 26
311
In conclusion, the results of the present study suggest that oral doxycycline use as SAT for
312
patients treated initially with suboptimal management of PJI is safe and is associated with an
313
acceptable rate of remission of infection with a low risk of emergence of bacterial resistance in
314
case of failure. Our results also show that SAT discontinuation expose patients with hip or knee
315
prosthetic joint infections to a higher risk of relapse of infection which confirms previous
316
recommendations from Byren et al. to maintain SAT as long as possible (10).
317 318
Acknowledgments
319
Thanks to Mr Philippe Choisy and Mr Marc Digumber for their technical assistance
320
Author contributions
321
SE and NS initiated and designed the study; PM, BE, DH, MH collected the data; VM analyzed
322
the data; TM, BN and LC recorded microbiological data; PM, NS, RO, BE, DH, MH, SE had a
323
role in patient care; DH, MH and BE critically reviewed the manuscript written by PM, NS and
324
SE; all of the authors approved the final version of the manuscript.
325 326
Declarations
327
Funding: No funding
328
Competing Interests: The authors report no conflicts of interest in this work
329
Ethical Approval: Approval from the Institutional Review Board of the G. Dron hospital
330
(Espace Ethique, N° of the approval : 2016/6) was obtained
331
References
332
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9. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med 2004;351:1645–54.
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10. Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, et al.. One hundred
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15. Goulet JA, Pellicci PM, Brause BD, Salvati EM. Prolonged suppression of infection in total hip arthroplasty. J Arthroplasty 1988;3:109–16.
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16. Tsukayama DT, Wicklund B, Gustilo RB. Suppressive antibiotic therapy in chronic prosthetic joint infections. Orthopedics 1991;14:841–4.
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17. Prendki V, Zeller V, Passeron D, Desplaces N, Mamoudy P, Stirnemann J, et al.. Outcome
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23. Senneville E, Joulie D, Legout L, Valette M, Dezèque H, Beltrand E, et al.. Outcome and
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Predictors of Treatment Failure in Total Hip/Knee Prosthetic Joint Infections Due to
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Staphylococcus aureus. Clin Infect Dis 2011;53:334–40.
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24. Betsch BY, Eggli S, Siebenrock KA, Täuber MG, Mühlemann K. Treatment of joint
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31. Doernberg SB, Winston LG, Deck DH, Chambers HF. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis 2012;55:615–20.
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32. Turner RB, Smith CB, Martello JL, Slain D. Role of doxycycline in Clostridium difficile infection acquisition. Ann Pharmacother 2014;48:772–6.
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19 Page 19 of 26
451
Table 1 : Characteristics of 39 patients with knee or hip prosthetic joint infections treated with
452
oral doxycycline-based suppressive antibiotic therapy Characteristics Male, n of pts (%)
15 (38.4)
Female, n of pts (%)
24 (61.6)
Age, years, mean ± SD (range)
66.1 ± 16.3 (18-91)
≥75 yo (%)
14 (35,9)
50-75 yo (%)
20 (51.2)
<50 yo (%)
5 (12.8)
Weight, kg ± SD
82.6 ± 22.9
BMI, mean ± SD, kg.m-2 (n=70)
30.7 ± 7.5
Immunosuppression, n of pts (%)
19 (48.7)
- diabetes mellitus
4 (10.2)
- neoplasia
5 (12.8)
- rheumatoid arthritis
6 (15.4)
- corticosteroid therapy
1 (2.5)
- chronic renal failure
3 (7.7)
- none
42 (53.9)
Location of PJI, n of pts (%) - hip
23 (58.9)
- knee
16 (41.1)
Clinical symptoms at the time of diagnosis of PJI, n of pts (%) - fever (data available for 26 patients)
11 (42.3)
- pus (data available for 28 patients)
17 (60.7)
- sinus tract (data available for 31 patients)
13 (41.9)
20 Page 20 of 26
Delay from symptoms to surgery; months, mean ± SD (range)
7.42 ± 6.97 (1-27)
Type of infection, n of pts (%) - early
15 (38.4)
- delayed
17 (43.5)
- late
7 (17.9)
Number of previous surgery, mean ± SD 453
1.13 ± 1.61
N of pts : number of patients; yo : years old; BMI : body mass index; SD : standard deviation
454
21 Page 21 of 26
455
Table 2 : Bacterial pathogens isolated from peroperative samples of prosthetic joint infections in
456
39 patients treated with doxycycline-based suppressive antibiotic therapy Microorganism
N° of strains (% of the total)
Gram positive cocci
46 (92)
Staphylococci
44 (88)
Staphylococcus aureus
39 (78)
MSSA
28 (56)
MRSA
11 (22)
CoNS
5 (10)
Staphylococcus epidermidis
3 (6)
Staphylococcus lugdunensis
1 (2)
Staphylococcus warneri
1 (2)
Group G streptococci
1 (2)
Enterococcus faecalis
1 (2)
Aerobic Gram negative bacilli
3 (6)
Enterobacteriaceae
2 (4)
Citrobacter koseri
1 (2)
Escherichia coli
1 (2)
Pseudomonas aeruginosa
1 (2)
Anaerobes
1 (2)
Propionibacterium acnes
1 (2)
Total number of strains
50 (100%)
457 458
22 Page 22 of 26
459
Table 3 : Characteristics of the curative antibiotic initial treatment in 39 patients treated with
460
doxycycline-based antibiotic suppressive therapy Curative antibiotic therapy
N° of patients (%)
Combination with rifampicin
28 (71.8)
- rifampicin / fluoroquinolonesa
14 (35.9)
- rifampicin / cycline
6 (15.4)
- rifampicin / otherb
8 (20.5)
Without rifampicin, n (%)
11 (28.2)
- fluoroquinolones / otherc
3 (7.7)
- cyclines / otherd
4 (10.3)
- otherse
4 (10.3)
461
a
Levofloxacin (n=14)
462
b
Cotrimoxazole (n=5); Imipenem (n=1); Amoxicillin (n=1); Linezolid (n=1)
463
c
Clindamycin (n=2), Fusidic acid (n=1)
464
d
Clindamycin (n=2), Teicoplanin (n=2)
465
e
Linezolid (n=3), Clindamycin (n=1)
23 Page 23 of 26
466
Table 4 : Bivariate analysis comparing the characteristics of 39 patients treated by doxycycline-
467
based suppressive antibiotic therapy according to the outcome (i.e., remission versus failure) Variables
Remission
Failure group
P
group (n=29)
(n=10)
value
Age
68.6 ± 14.7
60.0 ± 19.2
0.14
Male
10 (34.4%)
5 (50%)
0.38
BMI (n=70)
30.3 ± 7.50
31.7 ± 7.65
0.61
- knee
10 (34.4%)
6 (60%)
0.15
- hip
18 (62.1%)
5 (50%)
0.50
Mean delay from implantation; months, ±SD
7.1 ± 6.70
8.09 ± 5.82
0.42
Previous surgery
0.89 ± 1.37
1.73 ± 2.05
0.12
Prosthesis
Microbiology
0.51
- MSSA
22 (75.8%)
6 (60%)
0.34
- MRSA
7 (24.1%)
4 (40%)
0.34
- CoNS
3 (10.3%)
2 (20%)
0.43
6 (20.7%)
3 (30%)
0.55
- diabetes mellitus
3 (10.3%)
1 (10%)
0.97
- rheumatoid polyarthritis
4 (13.8%)
2 (20%)
0.64
- chronic renal failure
2 (6.9%)
1 (10%)
0.75
- corticosteroid therapy**
1 (3.4%)
0
---
- neoplasia
3 (10.3%)
2 (20%)
0.44
- none
7 (24.1%)
3 (30%)
0.71
- polymicrobial Immunosuppression
24 Page 24 of 26
DAIR
25 (86.2%)
7 (70%)
0.25
136.45
0.02
Curative antibiotic therapy - mean duration, days ±SD
89,6
- rifampicin combinations
± 30.09
± 69.30
21 (65.6%)
7 (70%)
0.88
3 (10.3%)
1 (10%)
0.98
2(6.9%)
0
---
Adverse events - photosensitization - gastro-intestinal 468
MSSA, methicillin susceptible S. aureus; MRSA, methicillin-resistant S. aureus ; CoNS,
469
coagulase-negative staphylococci
470
* : hip versus knee prosthesis
471
** : ≥ 10mg/d for > 3 months
472
25 Page 25 of 26
473
Table 5 : Compared outcome of 39 patients treated with 2-year versus continued doxycycline-
474
based suppressive antibiotic therapy (SAT) for knee or hip prosthetic joint infections Outcome
2 year SAT
Continued SAT
P
(n=10)
(n=29)
Discontinuation for SAT-related adverse effect
1 (10%)
2 (6.9%)
0.75
Death
1 (10%)
2 (6.7%)
0.75
Failure
5 (50%)
5 (17.2%)
0.04
value
475 476 477 478
26 Page 26 of 26