# Efficacy and safety of co-trimoxazole in device-related bone and joint infections: a CRIOGO multicentre case-control study

Raphaël Lecomte¹,²*, Colin Deschanvres ID ¹,², Amandine Le Bourgeois³, Géraldine Bart⁴, Rafaël Mahieu⁵, Gwénaël Le Moal⁶, Séverine Ansart⁷, Nathalie Asseray¹,², Louise Ruffier d'Epenoux⁸, Stéphane Corvec ID ⁸,⁹ and David Boutoille ID ¹,² on behalf of the CRIOGO network†

¹Department of Infectious Diseases, CHU Hôtel-Dieu, Nantes, France; ²Centre d'Investigation Clinique, Unité d'Investigation Clinique 1413 INSERM, CHU Nantes, France; ³Department of Hematology, CHU Hôtel-Dieu, Nantes, France; ⁴Department of Rheumatology and Internal Medicine, Percy Military Training Hospital, Paris, France; ⁵Department of Infectious Diseases, CHU Angers, Angers, France; ⁶Department of Infectious Diseases, CHU de Poitiers, Poitiers, France; ⁷Department of Infectious Diseases, CHU Brest, Brest, France; ⁸Department of Bacteriology, CHU Nantes, Nantes, France; ⁹INSERM, INCIT U1302, Université de Nantes, CHU Nantes, Nantes, France

*Corresponding author. E-mail: raphael.lecomte@chu-nantes.fr
†Members are listed in the Acknowledgements section.

Received 18 June 2024; accepted 30 August 2024

**Objectives:** Co-trimoxazole could be an alternative antibiotic to treat device-related bone and joint infection (BJI) but there are few published data about its efficacy and safety in this complex scenario to treat infection. The objective was to compare the outcome of patients with device-related BJI treated with an antibiotic regimen including co-trimoxazole versus a regimen without co-trimoxazole.

**Methods:** This multicentre case-control study included consecutive adult patients diagnosed with device-related BJI. Each patient receiving co-trimoxazole was included in the co-trimoxazole group and was matched with two control patients, with stratification on microbial aetiology and age. The primary outcome was composite and defined by death or treatment failure during the follow-up.

**Results:** In this study, 150 patients were included, 50 in the co-trimoxazole group and 100 in the control group. The rate of reaching the primary endpoint was 18% in the co-trimoxazole group (9/50 cases) versus 21% in the control group (21/100) (P=0.66). Co-trimoxazole use was not associated with an unfavourable outcome in the multivariate analysis (adjusted OR 0.8, 95% CI 0.31-2.06, P=0.64). Although no significant difference was observed in premature discontinuation of treatment due to an adverse event between both groups (14 versus 12%, P=0.73), treatment-related adverse events were significantly more frequently reported in patients of the co-trimoxazole group than the control group [34% (17/50) versus 18% (18/100), P=0.03].

**Conclusions:** Co-trimoxazole appears to be an effective alternative for the treatment of BJI, even when it occurs on a device, but the safety profile requires close monitoring of adverse effects.

## Introduction

Bone and joint infections (BJIs) are associated with a high morbidity, particularly when they occur on devices.¹ Treatment is based on surgery, followed by prolonged antibiotic therapy, associated with numerous adverse effects.²,³ For the treatment of Gram-positive infections, a rifampicin-based regimen is recommended,²,⁴ but its use is limited by numerous drug interactions and adverse effects. Fluoroquinolones are indicated as the first-line treatment for Gram-negative infections, but the

tendinopathies induced and emergence of fluoroquinolone resistance also restrict their use.⁵,⁶ In BJI, there are currently few or no published data on the efficacy and safety of the other available antimicrobial agents.

Co-trimoxazole, an association of trimethoprim with sulfamethoxazole, has been used for many years and is active against some *Streptococcus* spp. and most *Staphylococcus* spp., including strains with methicillin resistance but also against Gram-negative bacteria.⁷⁻¹⁰ Co-trimoxazole has good bioavailability, which allows oral administration and is an economic alternative.¹¹
However, co-trimoxazole is known for toxicity, such as cutaneous, haematological and hepatic toxicity. In BJI, co-trimoxazole use is uncommon for two main reasons: (i) there are very few efficacy data published in the literature,¹²⁻¹⁴ particularly for device-associated BJI; and (ii) the duration of treatment is particularly long for these infections,² increasing the risk of adverse effects.

The study objective of this study was to compare the outcome of patients with device-related BJI treated with an antibiotic regimen including co-trimoxazole versus a regimen without co-trimoxazole, in terms of efficacy and safety.

# Patients and methods

## Patients

This retrospective case-control study was performed using patient data from four University hospitals of the Centres de Référence pour les Infections Ostéo-articulaires du Grand Ouest (CRIOGO) network: Angers, Brest, Poitiers and Nantes. Patients were screened from the 'French registry for complex bone and joint infections' database, a centralized online secure database gathering the electronic case report forms (eCRFs) filled for every patient that has been discussed in multidisciplinary meetings. This database is a recognized national database that has already demonstrated the quality of its data.¹⁵ All consecutive adult patients diagnosed with a device-related BJI between 2011 and 2012 were screened for this study.

Patients were included if they had criteria for the diagnosis of acute device-related BJI confirmed by the local multidisciplinary meeting. This diagnosis was based on clinical signs and symptoms of BJI associated with a positive bacteriological culture of the surgical samples. The bacteriological results were considered positive when at least one culture yielded a strict pathogen (*Staphylococcus aureus*, *Pseudomonas aeruginosa*, Enterobacteriaceae and anaerobes) or when two cultures yielded a strain that was a skin commensal (such as CoNS or *Cutibacterium acnes*).² Patients treated with co-trimoxazole had to have an infection with at least one co-trimoxazole-susceptible bacterium. Conversely, patients treated with other antibiotics (control group) or with polymicrobial infections could have infections with co-trimoxazole-resistant bacteria.

Exclusion criteria were: (i) absence of surgery, (ii) BJI without a device, (iii) relapse of a previous infection, (iv) absence of microbiological documentation, (v) pregnancy, (vi) neuromeningeal infection, (vii) skin and soft tissue infection; and (viii) BJI palliative treatment.

Each included patient receiving at least one dose of co-trimoxazole was included in the co-trimoxazole group and was matched with two control patients (i.e. patients with antibiotic regimens without co-trimoxazole). This matching was stratified according to age (±5 years) and microbial aetiology: monomicrobial staphylococcal infection versus other types of infection (other microorganism infection or polymicrobial). Patients in the co-trimoxazole group were recruited from the four CRIOGO centres, while control patients were recruited from the Nantes centre only.

## Data

Date of inclusion was defined by the day of septic surgery, which could be debridement with retention, exchange or removal of the device. In all centres, the choice of antibiotic regimens was based on the same protocols: surgery with microbiological samples followed by empirical parenteral antibiotic treatment with piperacillin/tazobactam and linezolid. With the microbiological results, the definitive treatment was determined by the local team.

All data were collected from electronic medical records of the initial hospitalization and follow-up medical consultations. All patients were

from referral centres, and surgical reports and multidisciplinary meetings reports were obligatorily available (legal requirement).

## Outcomes

The primary outcome was composite and defined by death or treatment failure during the follow-up. Treatment failure was defined by persistence or relapse of clinical signs of infection and/or surgery with perioperative signs of infection and/or positive tissue culture after antibiotic treatment.

Secondary outcomes were death, treatment failure, infection cure with major functional sequelae (defined by amputation or arthrodesis), adverse events reported by the physician, and premature antibiotic discontinuation due to side effects.

## Statistical analysis

Cases and controls were described using numbers and percentages for qualitative variables, and mean and standard deviation and/or median and IQR for quantitative variables. The McNemar test was used to compare cases and controls for qualitative variables, and paired t-test and Wilcoxon's signed-rank test were used for quantitative variables.

To study the association between exposure factors and the occurrence of unfavourable outcome, univariate and multivariate analyses were performed using conditional logistic regression, estimating ORs and 95% CIs. We included in the model the factors associated with failure classically described in the literature, excluding matching factors.

A two-sided *P* value of less than 5% was considered to indicate statistical significance for all analyses. Statistical analyses were performed with R software (R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/).

## Ethics

This study was declared to CNIL (Commission Nationale de l'Informatique et des Libertés) on 26 September 2014 with the number 1796321. In accordance with French law on retrospective studies of anonymized data, informed consent was not required.

# Results

## Patient population

In this study, 150 patients were included, 50 in the co-trimoxazole group and 100 in the control group. Age, sex and comorbidities were similar in both groups and are detailed in Table 1. Prosthetic joint infections accounted for 42% of cases (63/150) and osteosynthesis material infections for the other 58% (87/150). The most frequently identified pathogens were *S. aureus* [40.1% of cases (61/150), with methicillin resistance in 9 cases (14.7%)] followed by Gram-negative bacilli [29.3% of cases (44/150), more frequent in the co-trimoxazole group (*P*=0.04)] and CoNS in 18.6% of cases (28/150). Polymicrobial infections were found in 27% of the BJI (41/150). All of them were surgically treated before receiving an antibiotic combination, with a median follow-up of 22.4 months (range 12.8-30.2). Among prosthesis-related BJI, 32% were treated by debridement, antibiotics and implant retention (DAIR) (20/63), 60% by prosthesis replacement (38/63) and 8% by permanent removal of the prosthesis (5/63), while 48% of osteosynthesis infections required material removal (42/87), debridement in 30% of cases (26/87) and exchange in 19% (17/87) (two missing data).

Treatment with a fluoroquinolone (*P*<0.01), rifampicin (*P*=0.04) and clindamycin (*P*=0.01) was less frequent in the co-trimoxazole group than in the control group. However, there was
<table><caption>**Table 1.** Baseline characteristics</caption><thead><tr><th></th><th>Co-trimoxazole group (N=50)</th><th>Control group (N=100)</th><th>P value</th></tr></thead><tbody><tr><td>Age, years, median (IQR)</td><td>64 (48-83)</td><td>65 (49-76)</td><td>0.39</td></tr><tr><td>Male sex, n (%)</td><td>30 (60)</td><td>62 (62)</td><td>0.81</td></tr><tr><td>Comorbidity</td><td></td><td></td><td></td></tr><tr><td>Charlson CI, median (IQR)</td><td>3 (1-5)</td><td>2.5 (1-4)</td><td>0.62</td></tr><tr><td>Diabetes, n (%)</td><td>5 (10)</td><td>9 (9)</td><td>0.84</td></tr><tr><td>Malignancy, n (%)</td><td>5 (10)</td><td>15 (15)</td><td>0.40</td></tr><tr><td>Obesity, n (%)</td><td>4 (8)</td><td>9 (9)</td><td>0.84</td></tr><tr><td>Chronic renal failure, n (%)</td><td>3 (6)</td><td>7 (7)</td><td>0.82</td></tr><tr><td>Cardiopathy, n (%)</td><td>11 (22)</td><td>15 (15)</td><td>0.29</td></tr><tr><td>Microorganisms, n (%)</td><td></td><td></td><td></td></tr><tr><td>S. aureus</td><td>15 (30)</td><td>46 (46)</td><td>0.06</td></tr><tr><td>CoNS</td><td>13 (26)</td><td>15 (15)</td><td>0.10</td></tr><tr><td>Enterococcus sp.</td><td>4 (8)</td><td>4 (4)</td><td>0.30</td></tr><tr><td>Streptococcus sp.</td><td>2 (4)</td><td>7 (14)</td><td>0.47</td></tr><tr><td>Gram-negative bacteria</td><td>20 (40)</td><td>24 (24)</td><td>0.04</td></tr><tr><td>Enterobacter sp.</td><td>12 (24)</td><td>8 (8)</td><td>0.01</td></tr><tr><td>Escherichia coli</td><td>5 (10)</td><td>9 (9)</td><td>0.99</td></tr><tr><td>P. aeruginosa</td><td>0</td><td>7 (7)</td><td>0.13</td></tr><tr><td>Proteus sp.</td><td>5 (10)</td><td>2 (2)</td><td>0.08</td></tr><tr><td>Other Gram-negative bacteria</td><td>2 (4)<sup>a</sup></td><td>5 (5)<sup>b</sup></td><td>0.99</td></tr><tr><td>Other</td><td>9 (9)</td><td>22 (22)</td><td>0.57</td></tr><tr><td>Polymicrobial</td><td>15 (30)</td><td>26 (26)</td><td>0.60</td></tr><tr><td>Surgical treatment, n (%)</td><td></td><td></td><td></td></tr><tr><td>Prosthetic joints</td><td>25 (50)</td><td>38 (38)</td><td>0.16</td></tr><tr><td>Debridement with implant retention</td><td>9 (18)</td><td>11 (11)</td><td>0.23</td></tr><tr><td>One-stage exchange</td><td>8 (16)</td><td>16 (16)</td><td>0.99</td></tr><tr><td>Two-stage exchange</td><td>6 (12)</td><td>8 (8)</td><td>0.58</td></tr><tr><td>Permanent removal</td><td>2 (4)</td><td>3 (3)</td><td>0.75</td></tr><tr><td>Osteosynthesis<sup>c</sup></td><td>25 (50)</td><td>62 (62)</td><td>0.16</td></tr><tr><td>Removal</td><td>12 (24)</td><td>30 (30)</td><td>0.44</td></tr><tr><td>Exchange</td><td>5 (10)</td><td>12 (12)</td><td>0.72</td></tr><tr><td>Debridement with retention</td><td>8 (16)</td><td>18 (18)</td><td>0.76</td></tr><tr><td>Antibiotic treatment (definitive treatment)</td><td></td><td></td><td></td></tr><tr><td>Bitherapy<sup>d</sup>, n (%)</td><td>49 (98)</td><td>91 (91)</td><td>0.11</td></tr><tr><td>Fluoroquinolone, n (%)</td><td>24 (48)</td><td>76 (76)</td><td>&lt;0.01</td></tr><tr><td>Rifampicin, n (%)</td><td>13 (26)</td><td>43 (43)</td><td>0.04</td></tr><tr><td>Clindamycin, n (%)</td><td>4 (8)</td><td>25 (50)</td><td>0.01</td></tr><tr><td>Duration, days, median (IQR)</td><td>95 (80-106)</td><td>91 (58-109)</td><td>0.25</td></tr></tbody></table>

CI, comorbidity index; MRCNS, methicillin-resistant CoNS; MSCNS, methicillin-susceptible CoNS.

<sup>a</sup>Klebsiella pneumoniae (n=1), Serratia marcescens (n=1).

<sup>b</sup>K. pneumoniae (n=2), S. marcescens (n=1), Acinetobacter sp. (n=1), Citrobacter koseri (n=1).

<sup>c</sup>Two missing data about the type of surgical treatment.

<sup>d</sup>Definitive therapy (exclusion of post-operative probabilistic treatment).

<table><caption>**Table 2.** Outcomes</caption><thead><tr><th></th><th>Co-trimoxazole group (N=50)</th><th>Control group (N=100)</th><th>P value</th></tr></thead><tbody><tr><td>Primary outcome, n (%)</td><td></td><td></td><td></td></tr><tr><td>Death or treatment failure</td><td>9 (18)</td><td>21 (21)</td><td>0.66</td></tr><tr><td>Secondary outcomes, n (%)</td><td></td><td></td><td></td></tr><tr><td>Treatment failure</td><td>7 (14)</td><td>17 (17)</td><td>0.64</td></tr><tr><td>Death</td><td>2 (4)</td><td>4 (4)</td><td>0.99</td></tr><tr><td>Major sequelae</td><td>8 (16)</td><td>8 (8)</td><td>0.13</td></tr><tr><td>Adverse events<sup>a</sup></td><td>17 (34)</td><td>18 (18)</td><td><strong>0.03</strong></td></tr><tr><td>PAD</td><td>7 (14)</td><td>12 (12)</td><td>0.73</td></tr></tbody></table>

Bold values correspond to significant values (P < 0.05).

PAD, premature antibiotic discontinuation due to adverse events.

<sup>a</sup>Patients with one or more adverse events.

no difference in terms of the use of dual therapy (P=0.11) or the duration of treatment (P=0.25). In the co-trimoxazole group, the median delay between the septic revision surgery and the introduction of co-trimoxazole was 7 days (IQR 4.5-14). No patient received treatment for less than 21 days (premature discontinuation due to adverse events), and the median duration of co-trimoxazole treatment was 83 days (IQR 52-92). In patients with normal renal function (n=40), co-trimoxazole dosage was 320/1600 mg/day for 23 patients (57.5%), 480/2400 mg/day for 11 patients (27.5%) and 640/3200 mg/day for 6 patients (15%).

## Efficacy

The rate of primary endpoint (death or failure) was 18% in the co-trimoxazole group (9/50 cases) versus 21% in the control group (21/100) (P=0.66). There were no differences in any of the secondary efficacy endpoints between the two groups: mortality [4% (2/50) versus 4% (4/100), P=0.99], failure [14% (7/50) versus 17% (17/100), P=0.64] and infection cure with major functional sequelae [16% (8/50) versus 8% (8/100), P=0.13] (Table 2).

The primary outcome (death or failure) was not different according to the dosage of co-trimoxazole [13% (3/23) if the dosage was 320/1600 mg/day compared with 9% (1/11) if the dosage was 480/2400 mg/day and 16.6% (5/6) if the dosage was 640/3200 mg/day]. Similarly, the prognosis was no different whether co-trimoxazole was used in combination with a fluoroquinolone [primary outcome: 17% (4/24)] or with another antibiotic [primary outcome: 16% (4/25)]. It should be noted that the only patient who received co-trimoxazole monotherapy did not experience treatment failure.

In the co-trimoxazole group, seven patients had microbiological failure (14%) with new positive samples: three revealed the same microorganism as initially (no co-trimoxazole resistance) and four other microorganisms including two with resistance to co-trimoxazole. In the control group, 12 patients had microbiological failure (12%) with new positive samples: five revealed the same microorganism as initially, including 4 with resistance to the first-line antibiotic regimen, and 7 other microorganisms, including 1 with resistance to the first-line antibiotic regimen.

In the subgroup of patients treated by debridement and retention of the device (Table 3), there was no difference in terms
<table><caption>**Table 3.** Comparison of the primary outcome (death or failure) according to antibiotic regimen (co-trimoxazole or control group) and surgical management of the device-associated infection</caption><thead><tr><th></th><th>Co-trimoxazole group (N=50)</th><th>Control group (N=100)<sup>a</sup></th><th>P value</th></tr></thead><tbody><tr><td>Removal, n/N (%)</td><td>0/14 (0)</td><td>6/33 (18)</td><td>0.09</td></tr><tr><td>Exchange, n/N (%)</td><td>6/19 (32)</td><td>10/36 (28)</td><td>0.42</td></tr><tr><td>Debridement with retention, n/N (%)</td><td>3/17 (18)</td><td>5/29 (17)</td><td>0.97</td></tr></tbody></table>

of the primary endpoint [18% (3/17) in the co-trimoxazole group versus 17% (5/29) in the control group (P=0.97)]. In the subgroup of monomicrobial staphylococcal infections (Table 4), there was also no difference in mortality and/or failure between the co-trimoxazole and control groups [18.2% (4/22) versus 18.2% (8/44), P=0.99]. All patients received combination therapy; nine patients received rifampicin as a second agent in the co-trimoxazole group, with a failure rate of 22% (2/9).

The co-trimoxazole group was not associated with an unfavourable outcome in the univariate analysis. This result was confirmed after controlling for potential factors (Table 5).

## Safety

Treatment-related adverse events were reported in 34% (17/50) of patients in the co-trimoxazole group versus 18% (18/100) in the control group (P=0.03) (Table 6). However, no significant difference was observed in premature discontinuation of treatment due to an adverse event between the groups (14% versus 12%, P=0.73). Adverse events were classified as grade I in 45.7% of cases (CTCAE4 classification), and grade II in 48.5% of cases, with no difference between the two groups. One patient in each group had a serious adverse event requiring hospitalization.

In the co-trimoxazole group, the most frequently reported adverse events were haematotoxicity (18%, 9/50), followed by skin rash (8%, 4/100) and renal failure (8%, 4/50). Renal failure and haematotoxicity were more frequent in the co-trimoxazole group than in the control group (P=0.01).

Adverse events were significantly more frequent in patients receiving 640/3200 mg/day (66.6%, 4/6 patients) of co-trimoxazole than in patients receiving 480/2400 mg/day (0%, 0/11 patients, P<0.01) or 320/1600 mg/day (17.3%, 4/23 patients, P<0.05).

Adverse events were reported with a median delay of 28 days (IQR 17.5-50) after initiation of treatment in the co-trimoxazole group and 29 days (IQR 24-51) in the control group.

## Discussion

The major findings of this retrospective case-control study of device-related BJI are the following: (i) the failure rate was similar in patients treated by co-trimoxazole and in controls; (ii) treatment-related adverse events were more frequent in the co-trimoxazole group; but (iii) with no difference in terms of premature discontinuation of treatment due to an adverse event.

<table><caption>**Table 4.** General characteristics, type of treatment and outcome of patients with staphylococcal device-related bone infection</caption><thead><tr><th></th><th>Co-trimoxazole group (N=22)</th><th>Control group (N=44)</th><th>P value</th></tr></thead><tbody><tr><td>Age, years, median (IQR)</td><td>78 (46-83)</td><td>73 (43-81)</td><td>0.71</td></tr><tr><td>Male sex, n (%)</td><td>9 (40.9)</td><td>30 (68.2)</td><td><strong>0.03</strong></td></tr><tr><td>Comorbidity</td><td></td><td></td><td></td></tr><tr><td>Charlson CI, median (IQR)</td><td>3.5 (1-5)</td><td>3 (0.75-5)</td><td>0.69</td></tr><tr><td>Diabetes, n (%)</td><td>3 (13.6)</td><td>3 (6.8)</td><td>0.36</td></tr><tr><td>Malignancy, n (%)</td><td>2 (9.1)</td><td>7 (15.9)</td><td>0.45</td></tr><tr><td>Obesity, n (%)</td><td>1 (4.5)</td><td>4 (9.1)</td><td>0.51</td></tr><tr><td>Chronic renal failure, n (%)</td><td>2 (9.1)</td><td>3 (6.8)</td><td>0.74</td></tr><tr><td>Cardiopathy, n (%)</td><td>5 (22.7)</td><td>7 (15.9)</td><td>0.50</td></tr><tr><td>Surgical treatment, n (%)</td><td></td><td></td><td></td></tr><tr><td>Debridement with retention</td><td>8 (36.4)</td><td>13 (29.5)</td><td>0.58</td></tr><tr><td>Exchange</td><td>11 (50)</td><td>14 (31.8)</td><td>0.15</td></tr><tr><td>Permanent removal</td><td>3 (13.6)</td><td>17 (38.6)</td><td><strong>0.03</strong></td></tr><tr><td>Treatment, n (%)</td><td></td><td></td><td></td></tr><tr><td>Bitherapy</td><td>22 (100)</td><td>44 (100)</td><td>0.99</td></tr><tr><td>Fluoroquinolone</td><td>6 (27.3)</td><td>38 (86.4)</td><td>&lt;0.01</td></tr><tr><td>Rifampicin</td><td>9 (40.9)</td><td>31 (70.5)</td><td>0.02</td></tr><tr><td>Primary outcome (death or failure), n (%)</td><td>4 (18.2)</td><td>8 (18.2)</td><td>0.99</td></tr></tbody></table>

Bold values correspond to significant values (P < 0.05). CI, comorbidity index.

The failure rate in our study is comparable with rates published in the few studies that have examined the efficacy of co-trimoxazole in BJI. This rate was 21.6% at 90 days in the study by Deconinck et al.,¹³ which included 51 patients with BJI, 11% in the study of Euba et al.,¹⁴ which included 28 patients with osteomyelitis, and 21.4% in the study by Nguyen et al.,¹² which compared 28 patients treated with co-trimoxazole plus rifampicin with 28 patients treated with linezolid plus rifampicin. Conversely, a recently published study found a particularly high failure rate in patients treated with co-trimoxazole and rifampicin (38%),¹⁶ but the number of patients in this subgroup was small (24 patients), and only patients with staphylococcal acute peri-prosthetic infection were included. These failure rates remain difficult to compare. Indeed, the populations involved and the judging criteria differ from one study to another. In our study, the failure rate should also be considered in the light of the population studied, which was a comorbid referral centre population with device-associated BJI. Moreover, if we focus on the cases treated by DAIR, where the failure rate is normally higher, there was no difference in efficacy between the two groups, and the failure rate was only 18% in the co-trimoxazole group.

The rate of adverse events associated with co-trimoxazole therapy varies widely in the literature. While 46.4% of patients receiving co-trimoxazole treatment experienced at least one adverse event in the Nguyen et al.¹² study, this was the case for only 8% of patients in the Deconinck et al.¹³ study and 17.9% in the study of Euba et al.¹⁴ Duration of use (respectively 17.8, 6.7 and 13.6 weeks), dosage and type of infection could explain some of these differences. Indeed, in our study, we report a

<footnote>aTwo missing data.</footnote>
<table><caption>**Table 5.** Crude and adjusted ORs (aORs) to determine factors associated with unfavourable outcome</caption><thead><tr><th></th><th>Favourable<sup>a</sup><br>(N=120)</th><th>Unfavourable<br>(N=30)</th><th>Univariate<br>OR (95% CI)</th><th>P value</th><th>Multivariate<br>aOR (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Co-trimoxazole group, n (%)</td><td>41 (34.2)</td><td>9 (30.0)</td><td>0.81 (0.33-2.01)</td><td>0.65</td><td>0.8 (0.31-2.06)</td><td>0.64</td></tr><tr><td>Female gender, n (%)</td><td>45 (37.5)</td><td>13 (43.3)</td><td>1.13 (0.34-3.8)</td><td>0.84</td><td>0.98 (0.28-3.5)</td><td>0.98</td></tr><tr><td>Charlson CI, median (IQR)</td><td>2 (1-4)</td><td>4 (1.25-5)</td><td>1.37 (0.82-2.31)</td><td>0.23</td><td>1.25 (0.72-2.15)</td><td>0.43</td></tr><tr><td>Removal of material, n (%)</td><td>41 (34.2)</td><td>6 (20.0)</td><td>0.43 (0.12-1.48)</td><td>0.18</td><td>0.5 (0.13-1.93)</td><td>0.31</td></tr></tbody></table>

<table><caption>**Table 6.** Adverse events reported in patients of the co-trimoxazole group and control group</caption><thead><tr><th></th><th>Co-trimoxazole<br>group<br>(N=50)</th><th>Control<br>group<br>(N=100)</th><th>P<br>value</th></tr></thead><tbody><tr><td>Adverse events, n (%)</td><td>17 (34)<sup>a</sup></td><td>18 (18)<sup>b</sup></td><td><strong>0.03</strong></td></tr><tr><td>Grade I<sup>c</sup></td><td>7 (14)</td><td>9 (9)</td><td>0.35</td></tr><tr><td>Grade II<sup>c</sup></td><td>9 (18)</td><td>8 (8)</td><td>0.07</td></tr><tr><td>Grade III or more<sup>c</sup></td><td>1 (2)<sup>d</sup></td><td>1 (2)<sup>e</sup></td><td>0.61</td></tr><tr><td>PAD, n (%)</td><td>7 (14)</td><td>12 (12)</td><td>0.73</td></tr><tr><td>Type of adverse events, n (%)</td><td></td><td></td><td></td></tr><tr><td>Gastrointestinal disturbance</td><td>2 (6)</td><td>3 (2)</td><td>0.75</td></tr><tr><td>Renal impairment</td><td>4 (6)</td><td>0</td><td><strong>0.01</strong></td></tr><tr><td>Skin rash</td><td>4 (8)</td><td>6 (6)</td><td>0.64</td></tr><tr><td>Elevated hepatic enzymes</td><td>1 (2)</td><td>3 (3)</td><td>0.72</td></tr><tr><td>Haematotoxicity</td><td>9 (18)</td><td>4 (4)</td><td><strong>0.01</strong></td></tr><tr><td>Musculoskeletal disorders</td><td>0</td><td>3 (3)</td><td>0.55</td></tr><tr><td>Delay of adverse events, days,<br>median (IQR)</td><td>28 (17.5-50)</td><td>29 (24-51)</td><td>0.42</td></tr></tbody></table>

Bold values correspond to significant values (P < 0.05).

PAD, premature antibiotic discontinuation due to adverse events.

<sup>a</sup>Three patients had two adverse events.

<sup>b</sup>Two patients had two adverse events.

<sup>c</sup>According to the Common Terminology Criteria for Adverse Events (CTCAE).

<sup>d</sup>Hospitalization for skin rash.

<sup>e</sup>Hospitalization for neutropenia.

significant association between co-trimoxazole dosage and the rate of adverse events. By carrying out a case-control study, detailing the severity of adverse events and analysing treatment discontinuations linked to an adverse event (which are less subject to data collection bias), we provide precise, comparative data that demonstrate the acceptable safety of co-trimoxazole compared with controls. Interestingly, the literature is in agreement on the late onset of adverse effects (median between 3 and 4 weeks;<sup>12,13</sup> 4 weeks in our study).

When we examine how co-trimoxazole was used in our four reference centres, we observe that: (i) co-trimoxazole was often used to treat polymicrobial infections; (ii) co-trimoxazole was used at lower doses than those recommended in French and US guidelines since the majority of patients received a co-trimoxazole dose of 320/1600 mg/day;<sup>17</sup> (iii) co-trimoxazole

was combined with rifampicin in some cases. In our study, nine patients received a combination of these two antibiotics without any impact on prognosis. Although the combination with rifampicin theoretically reduces co-trimoxazole plasma concentrations,<sup>18</sup> this combination has already been tested with discordant results: in the studies of Beldman et al.<sup>16</sup> and Tornero et al.,<sup>19</sup> co-trimoxazole combined with rifampicin showed a higher rate of treatment failure compared with other associations. Conversely, Nguyen et al.<sup>12</sup> found no difference whether rifampicin was combined with co-trimoxazole or linezolid in BJI. Finally, Harbarth et al.<sup>11</sup> demonstrated the non-inferiority of co-trimoxazole plus rifampicin versus linezolid for the treatment of MRSA infections. The reduction of serum levels of antibiotics induced by rifampicin depends on the dosage of the co-antibiotic administered and seems not to be always clinically relevant (i.e. association of clindamycin and rifampicin).<sup>20,21</sup>

Our study has several limitations. Firstly, this was a retrospective study with a limited number of patients, and the absence of a statistically significant difference could be linked to a lack of power. Nevertheless, as device-related BJIs treated with co-trimoxazole are quite rare, to our knowledge this is the largest study of co-trimoxazole in osteoarticular infections published to date. Although a randomized controlled trial is the design that minimizes biases, observational studies have the advantage of portraying a real-life assessment of treatment effects. Moreover, the study question was prospectively defined, before the start of data collection. Secondly, our study included a heterogeneous population, particularly regarding microbiology features (Gram-positive, Gram-negative and polymicrobial infections). However, all patients had a device-associated BJI, and we matched patients on microorganism to increase comparability between the co-trimoxazole group and the control group. Thirdly, we have no information about the type of infection (acute or chronic) that could impact the outcomes: nevertheless, this was a homogeneous population, and consecutive patients were recruited to limit the risk of recruitment bias. Fourthly, some late failures may have been missed despite our mean follow-up of 22 months, which is longer than most other studies published on this topic. Fifthly, like all observational studies, we cannot exclude that patients are selected to receive one treatment or another by clinicians, but multivariate analysis was performed to limit this selection bias. In addition, all but one of the patients in the co-trimoxazole group received dual therapy, which in 48% of cases was with a fluoroquinolone (Table 1), which limits the interpretation of the efficacy of the antibiotic regimen. Finally, the control patients came from a single centre, whereas patients

<footnote><sup>a</sup>Favourable outcome is a composite criterion defined by death or treatment failure during follow-up.</footnote>
treated with co-trimoxazole came from four different centres. This choice constitutes a bias, but which is controlled by several factors: (i) the patients included were all treated in a reference centre for osteoarticular infection and discussed in a multidisciplinary consultation meeting, which guarantees a high level of expertise; (ii) the four centres are part of the CRIOGO network, where numerous common studies and the development of common management guidelines have been carried out; and (iv) in the co-trimoxazole group, most patients were included from the main centre [Nantes hospital, 68% (n=34/50)], which is the centre from where the controls were included.

In summary, co-trimoxazole could be an effective alternative for the treatment of BJI, even when it occurs on a device. Its broad spectrum including Gram-positive and Gram-negative bacteria could provide an interesting alternative, particularly for polymicrobial infections. Nevertheless, the safety profile requires close monitoring of adverse effects throughout the course of treatment. Further studies are needed to confirm these results, especially in patients treated with co-trimoxazole monotherapy.

## Acknowledgements

Members of the CRIOGO study group: Pierre Abgueguen, Marin Caubrière, Carole Lemarie, Rachel Chenouard, Hélène Pailhories, Amandine Vildy, Séverine Ansart, Luc Quaesaet, Eric Stindel, Didier Tandé, Claudie Lamoureux, Anais Greves, David Boutoille, Raphaël Lecomte, Colin Deschanvres, Antoine Asquier-Khati, Marie Chauveau, Benjamin Gaborit, Christophe Nich, Vincent Crenn, Pascale Bémer, Stéphane Corvec, Louise Ruffier d'Epenoux, Axelle Paquin, Matthieu Grégoire, Céline Bourigault, Barbara Plantard, France Cazenave-Roblot, Gwenaël Le Moal, Pierre Pries, Chloé Plouzeau-Jayle, Céline Thomas, Cédric Arvieux, Marion Baldeyrou, Harold Common, Vincent Cattoir, Sophie Reissier, Anne Méheut, Louis Bernard, Adrien Lemaignen, Marion Lacasse, Philippe Rosset, Louis-Romée Le Nail, Marie-Frédérique Lartigue, Isabelle Laplaige and Laura Chaufour.

## Funding

This study was carried out as part of our routine work.

## Transparency declarations

All authors: none to declare.

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